Bladder Cancer Second Edition 2012 PDF

BLADDER CANCER
EDITORS
MARK SOLOWAY - SAAD KHOURY
2nd International Consultation on Bladder Cancer - Vienna
Second Edition
2012
1
ICUD
Acknowledgement :
We wish to express our sincere appreciation to Adrienne Carmack for her amazing editorial
assistance in reading each chapter and modifying syntax where appropriate. Despite her dual
role as a mother and urologist she was able to find the time to help us once again with the
Bladder Cancer Recommendations.
For information
Distributor : EDITIONS 21
5 Boulevard Flandrin - 75016 Paris - FRANCE

E-mail : consulturo@aol.com
ICUD-EAU 2012
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in
any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior permission of the publisher.
Accurate indications, adverse reactions, and dosage schedules for drugs are provided in this book, but it is possible
that they may change. The reader is urged to review the package information data of the manufacturers
of the medications mentioned.
The Publishers have made every effort to trace the copyright holders for borrowed material. If they have inadvertently overlooked any, they will be pleased to make the necessary arrangements at the first opportunity.
The great tragedy of science :

The slaying of a beautiful hypothesis by an ugly fact
Thomas Huxley (1825-1895)
ISBN: 978-9953-493-20-6
Contents
- Contents
3
- ICUD Evidence Based Medicine Overview
4
- TNM
6
- Faculty
7
- Editorial
13
Committee 1: Screening, Diagnosis, and Evaluation
23
Dr. Paul K. Hegarty, Dr. Ashish M. Kamat, Mohan Arianayagam,
Peter Black, Sam S. Chang, Peter E. Clark, Judson D. Davies, Jinhai Fan,
Jason R. Gee, Nicholas J. Hegarty, Murugesan Manoharan, Tim S. OBrien,
Amit Patel, SudhirRawal, Rafael Sanchez-Salas, Robert S. Svatek, William Turner
Committee 2: Pathology Consensus Guidelines by the Pathology
63
of Bladder Cancer Work Group
Mahul B. Amin, Victor E. Reuter, Jonathan I. Epstein, David J. Grignon,
Donna E. Hansel, Oscar Lin, Jesse K. McKenney, Rodolfo Montironi,
Gladell P. Paner, Mark Soloway, and Members of the Pathology of Bladder Cancer
Work Group
Committee 3 A: Molecular Markers for Bladder Cancer Screening,
169
Early Diagnosis, and Surveillance
Shahrokh F. Shariat, Pierre I. Karakiewicz, Bernd J. Schmitz-Drger,
Michael Droller, Yair Lotan, Vinata B. Lokeshwar, Bas W. van Rhijn,
George P. Hemstreet, PerUno Malmstrom, Yves Fradet, MLiss Hudson,
Osamu Ogawa, Michael J. Marberger
Committee 3 B: Molecular Markers for Bladder Cancer Staging and Prognosis
207
Shahrokh F. Shariat, Pierre I. Karakiewicz, Michael J. Droller, Yves Fradet,
George P. Hemstreet, MLiss Hudson, Yair Lotan, Peruno Malmstrom,
Michael J. Marberger, Osamu Ogawa, Bernd J. Schmitz-Drger, Christian Seitz,
Maxine Sun, Bas W. Van Rhijn, Vinata B. Lokeshwar
Committee 4: Low Grade Ta Urothelial Carcinoma of the Bladder
231
Badrinath Konety, Willem Oosterlinck, Sam Chang, Sigurdur Gudjonsson,
Raj Pruthi, Mark Soloway, Eduardo Solsona, Paul Sved
Committee 5: High grade Ta, CIS, and T1 Urothelial Carcinoma
247
Maximilian Burger, Fred Witjes, Marko Babjuk, Maurizio Brausi,
Chris Cheng, Eva Comperat, Colin Dinney, Wolfgang Jager, Wolfgang Otto,
Jay Shah, Joachim Throf
Committee 6: Muscle-invasive, Presumably Regional, Tumor
269
Jason Efstathiou, David I. Quinn, Arnulf Stenzl, Joaquim Bellmunt,
Michael S. Cookson, Georgios Gakis, Khurshid A. Guru, Axel Heidenreich,
Patrick Keegan, Seth P. Lerner, Edward M. Messing, Arthur I. Sagalowsky,
Mark P. Schoenberg, William U. Shipley, Arlene O. Siefker-Radtke, Cora Sternberg
Committee 7: Urinary Diversion
343
Richard E. Hautmann, Bjoern G. Volkmer, Hassan Abol-Enein,
Thomas Davidsson, Sigurdur Gudjonsson, Stefan H. Hautmann, Henriette V. Holm,
Cheryl T. Lee, Fredrik Liedberg, Stephan Madersbacher, Murugesan Manoharan,
Wiking Mansson, Robert D. Mills, David F. Penson, Eila C. Skinner, Raimund Stein,
Urs E. Studer, Joachim W. Thueroff, William H. Turner
Committee 8: Urothelial Carcinoma of the Prostate
379
Joan Palou, David Wood, H. Al-Ahmadie, B. Bochner, Henk van der Poel,
Ofer Yossepowitch
Committee 9: Chemotherapy for Metastatic Urothelial Carcinoma
393
CN. Sternberg, D. Bajorin, R. Dreicer, M. Galsky, D. George, M. Milowsky,
D. Quinn, G. Sonpavde, WM. Stadler, D. Theodorescu, D. Vaughn
Committee 10: Non-urothelial Cancer of the Urinary Bladder
409
Bruce R Kava, Hassan Abol-Enein, Jack Baniel, Adrienne Carmack,
Alexandra Coquhoun, William Turner
3
EVIDENCE BASED MEDICINE OVERVIEW OF THE MAIN STEPS FOR

DEVELOPING AND GRADING GUIDELINE RECOMMENDATIONS.
INTRODUCTION
2.2 How papers are analysed?
The International Consultation on Urological Diseases (ICUD)

is a non-governmental organization registered with the World
Health Organisation (WHO). In the last ten years Consultations
have been organised on BPH, Prostate Cancer, Urinary Stone
Disease, Nosocomial Infections, Erectile Dysfunction and
Urinary Incontinence. These consultations have looked at
published evidence and produced recommendations at four
levels; highly recommended, recommended, optional and not
recommended. This method has been useful but the ICUD
believes that there should be more explicit statements of the
levels of evidence that generate the subsequent grades of
recommendations.
Papers published in peer reviewed journals have differing

quality and level of evidence.
Each committee will rate the included papers according to
levels of evidence (see below).
The level (strength) of evidence provided by an individual
study depends on the ability of the study design to minimise
the possibility of bias and to maximise attribution.
is influenced by:
the type of study
The hierarchy of study types are:
The Agency for Health Care Policy and Research

(AHCPR) have used specified evidence levels to justify
recommendations for the investigation and treatment of a
variety of conditions. The Oxford Centre for Evidence Based
Medicine have produced a widely accepted adaptation of the
work of AHCPR. (June 5th 2001 http://minerva.minervation.
com/cebm/docs/levels.html). The ICUD has examined the
Oxford guidelines and discussed with the Oxford group
their applicability to the Consultations organised by ICUD. It
is highly desirable that the recommendations made by the
Consultations follow an accepted grading system supported
by explicit levels of evidence.
- Systematic reviews and meta-analysis of randomised

controlled trials
- Randomised controlled trials
- Non-randomised cohort studies
- Case control studies
- Case series
- Expert opinion
how well the study was designed and carried out
Failure to give due attention to key aspects of study
methodology increase the risk of bias or confounding factors,
and thus reduces the studys reliability.
The ICUD proposes that future consultations should use a

modified version of the Oxford system which can be directly
mapped onto the Oxford system.
The use of standard check lists is recommended to insure

that all relevant aspects are considered and that a consistent
approach is used in the methodological assessment of the
evidence.
1. 1st Step: Define the specific questions or statements

that the recommendations are supposed to address.
2. 2nd Step: Analyse and rate (level of evidence) the
relevant papers published in the literature.
The objective of the check list is to give a quality rating for

individual studies.
The analysis of the literature is an important step in preparing

recommendations and their guarantee of quality.
how well the study was reported
2.1 What papers should be included in the analysis?
The ICUD has adopted the CONSORT statement and its

widely accepted check list. The CONSORT statement and
the checklist are available at
Papers published, or accepted for publication in the peer

reviewed issues of journals.
T
he committee should do its best to search for papers
accepted for publication by the peer reviewed journals in
the relevant field but not yet published.
http: //www.consort-statement.org
2.3 How papers are rated?
Papers are rated following a Level of Evidence scale.
A
bstracts published in peer review journals should be
identified. If of sufficient interest the author(s) should
be asked for full details of methodology and results. The
relevant committee members can then peer review the
data, and if the data confirms the details in the abstract,
then that abstract may be included, with an explanatory
footnote. This is a complex issue it may actually increase
publication bias as uninteresting abstracts commonly do
not progress to full publication.
ICUD has modified the Oxford Center for Evidence-Based

Medicine levels of evidence.
The levels of evidence scales vary between types of studies
(ie therapy, diagnosis, differential diagnosis/symptom
prevalence study).
the Oxford Center for Evidence-Based Medicine Website:
http://minerva.minervation.com/cebm/docs/ levels.html
3. 3rd Step: Synthesis of the evidence
Papers published in non peer reviewed supplements will

not be included.
After the selection of the papers and the rating of the level
of evidence of each study, the next step is to compile a
summary of the individual studies and the overall direction of
the evidence in an Evidence Table.
An exhaustive list should be obtained through:

I. the major databases covering the last ten years (e.g.
Medline, Embase, Cochrane Library, Biosis, Science
Citation Index)
4. 4
th Step: Considered judgment
individual clinical expertise)
II. the table of contents of the major journals of urology and

other relevant journals, for the last three months, to take
into account the possible delay in the indexation of the
published papers in the databases.
(integration
of
Having completed a rigorous and objective synthesis of the

evidence base, the committee must then make a judgement
as to the grade of the recommendation on the basis of this
evidence. This requires the exercise of judgement based on
clinical experience as well as knowledge of the evidence and
the methods used to generate it. Evidence based medicine
requires the integration of individual clinical expertise with best
It is expected that the highly experienced and expert

committee members provide additional assurance that no
important study would be missed using this review process.
available external clinical evidence from systematic research.

Without the former, practice quickly becomes tyrannised
by evidence, for even excellent external evidence may be
inapplicable to, or inappropriate for, an individual patient:
without current bestevidence, practice quickly becomes
out of date. Although it is not practical to lay our rules for
exercising judgement, guideline development groups are
asked to consider theevidence in terms of quantity, quality,
and consistency; applicability; generalisability; and clinical
impact.
6.2 Grades of Recommendation

The ICUD will use the four grades from the Oxford system.
As with levels of evidence the grades of evidence may apply
either positively (do the procedure) or negatively (dont do the
procedure). Where there is disparity of evidence, for example
if there were three well conducted RCTs indicating that Drug
A was superior to placebo, but one RCT whose results show
no difference, then there has to be an individual judgement
as to the grade of recommendation given and the rationale
explained.
5. 5th Step: Final Grading
Grade A recommendation usually depends on consistent

level 1 evidence and often means that the recommendation is effectively mandatory and placed within a clinical care
pathway. However, there will be occasions where excellent
evidence (level 1) does not lead to a Grade A recommendation, for example, if the therapy is prohibitively expensive,
dangerous or unethical. Grade A recommendation can
follow from Level 2 evidence. However, a Grade A recommendation needs a greater body of evidence if based on
anything except Level 1 evidence
The grading of the recommendation is intended to strike an

appropriate balance between incorporating the complexity of
type and quality of the evidence and maintaining clarity for
guideline users.
The recommendations for grading follow the Oxford Centre
for Evidence-Based Medicine.
The levels of evidence shown below have again been
modified in the light of previous consultations. There are now
4 levels of evidence instead of 5.
Grade B recommendation usually depends on consistent

level 2 and or 3 studies, or majority evidence from RCTs.
The grades of recommendation have not been reduced and a

no recommendation possible grade has been added.
6. Levels of Evidence and Grades of Recommendation
Therapeutic Interventions
Grade C recommendation usually depends on level 4 studies or majority evidence from level 2/3 studies or Dephi
processed expert opinion.
All interventions should be judged by the body of evidence

for their efficacy, tolerability, safety, clinical effectiveness and
cost effectiveness. It is accepted that at present little data
exists on cost effectiveness for most interventions.
Grade D No recommendation possible would be used

where the evidence is inadequate or conflicting and when
expert opinion is delivered without a formal analytical process, such as by Dephi.
6.1 Levels of Evidence
7. Levels of Evidence and Grades of Recommendation

for Methods of Assessment and Investigation
Firstly, it should be stated that any level of evidence may be

positive (the therapy works) or negative (the therapy doesnt
work). A level of evidence is given to each individual study.
From initial discussions with the Oxford group it is clear that

application of levels of evidence/grades of recommendation
for diagnostic techniques is much more complex than for
interventions.
L
evel 1 evidence (incorporates Oxford 1a, 1b) usually
involves meta-anaylsis of trials (RCTs) or a good quality
randomised controlled trial, or all or none studies in which
no treatment is not an option, for example in vesicovaginal
fistula.
The ICUD recommend, that, as a minimum, any test should

be subjected to three questions:
1. d
oes the test have good technical performance, for
example, do three aliquots of the same urine sample give
the same result when subjected to stix testing?
Level 2 evidence (incorporates Oxford 2a, 2b and 2c)

includes low quality RCT (e.g. < 80% follow up) or
metaanalysis (with homogeneity) of good quality prospective
cohort studies. These may include a single group when
individuals who develop the condition are compared with
others from within the original cohort group. There can be
parallel cohorts, where those with the condition in the first
group are compared with those in the second group.
2. D
oes the test have good diagnostic performance, ideally
against a gold standard measure?
3. D
oes the test have good therapeutic performance, that is,
does the use of the test alter clinical management, does
the use of the test improve outcome?
For the third component (therapeutic performance) the same
approach can be used as for section 6.
L
evel 3 evidence (incorporates Oxford 3a, 3b and 4)
includes:
8. L
evels of Evidence and Grades of Recommendation
for Basic Science and Epidemiology Studies
good quality retrospective case-control studies where

a group of patients who have a condition are matched
appropriately (e.g. for age, sex etc) with control individuals
who do not have the condition.
The proposed ICUD system does not easily fit into these
areas of science. Further research needs to be carried out,
in order to develop explicit levels of evidence that can lead
to recommendations as to the soundness of data in these
important aspects of medicine.
good quality case series where a complete group of patients

all, with the same condition/disease/therapeutic intervention,
are described, without a comparison control group.
CONCLUSION
The ICUD believes that its consultations should follow
the ICUD system of levels of evidence and grades of
recommendation, where possible. This system can be
mapped to the Oxford system.
L
evel 4 evidence (incorporates Oxford 4) includes expert
opinion were the pinion is based not on evidence but on
first principles (e.g. physiological or anatomical) or bench
research. The Delphi process can be used to give expert
opinion greater authority. In the Delphi process a series of
questions are posed to a panel; the answers are collected
into a series of options; the options are serially ranked;
if a 75% agreement is reached then a Delphi consensus
statement can be made.
There are aspects to the ICUD system that require further

research and development, particularly diagnostic
performance and cost effectiveness, and also factors
such as patient preference.
P. Abrams, S Khoury, A. Grant 19/1/04
TNM staging
T (Primary tumour)
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Ta Non-invasive papillary carcinoma
Tis Carcinoma in situ (flat tumour)
T1 Tumour invades subepithelial connective tissue
T2 Tumour invades muscle
T2a Tumour invades superficial muscle (inner half)
T2b Tumour invades deep muscle (outer half)
T3 Tumour invades perivesical tissue:
T3a Microscopically
T3b Macroscopically (extravesical mass)
T4 Tumour invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal
wall
T4a Tumour invades prostate, uterus or vagina
T4b Tumour invades pelvic wall or abdominal wall
N (Lymph nodes)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node 2 cm or less in greatest dimension
N2 Metastasis in a single lymph node more than 2 cm but not more than 5 cm in greatest
dimension, or multiple lymph nodes, none more than 5 cm in greatest dimension
N3 Metastasis in a lymph node more than 5 cm in greatest dimension
M (Distant metastasis)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Faculty
(Chairs are underligned)
Editors
Mark S. Soloway,
Department of Urology
University of Miami,
Miami, USA
Saad Khoury,
Departement of Urology
Hopital de la Piti
Paris, France
Committe 1
Screening, Diagnosis, and
Evaluation
Mohan Arianayagam,
Urology department
University of Miami
Miami, FL 33136
USA
Jinhai Fan,
First Affiliated Hospital of Xian,

Jiaotong University College of
Medicine Xian 710061,
China
Jason R Gee,
Lahey Clinic Medical Center

Associate Professor of Urology
Tufts University School of Medicine
Burlington, Massachusetts
USA
Nicholas Hegarty,
Consultant Urologist,
Mater Private Hospital,
Dublin (Ireland).
Paul K. Hegarty,
Consultant Urologic Surgeon

Guys and St Thomas Hospital,
London, UK
Ashish M. Kamat,
William Bill Turner,

Addenbrookes Hospital
Cambridge University
Hospital NHS
Foundation Trust
Cambridge
UK
Committee 2
Pathology Consensus
Guidelines by the Pathology
of Bladder Cancer Work
Group
Mahul B. Amin,
Department of Pathology &

Laboratory Medicine,CedarsSinaiMedicalCenter,Los
Angeles,CA,USA
Director of Urologic Oncology

Followship
Dept. of Urology / Unit 1373 UT
MD Anderson Cancer Center
Houston, USA
Jonathan I. Epstein,
University of British Columbia,

Dept. of Urologic Sciences
Vancouver Campus
Vancouver, B.C.,
Canada
Murugesan Manoharan,
David J. Grignon,
University of Miami
Department of urology
Miami, FL 33136
USA
Department of Pathology &

Laboratory Medicine, Indiana
University Purdue University
Indianapolis, Indianapolis, IN, USA
Sam S. Chang,
Tim O Brien,
Donna E. Hansel,
Peter Black,
Vanderbilt University Medical

Center
Dept. of Urologic Surgery &
Vanderbilt-Ingram Comprehensive
Cancer Center
Nashville,
USA
Peter Clark,

Center
Dept. of Urologic Surgery &
Vanderbilt-Ingram Comprehensive
Cancer Center
Nashville,
USA
Judson D Davies,

Center, Dept. of Urologic
Surgery & Vanderbilt-Ingram
Comprehensive Cancer Center
Nashville
USA

London, UK
Amit Patel

London, UK
Rafael Sanchez-Salas,
Institut Montsouris
Paris, France
Robert Svatek,
UT Health Science Center San

Antonio
Dept. of Urology, Division of
Urologic Oncology
San Antonio, USA
Sudhir Rawal,
Director of Surgical Oncology

Chief Urogenital oncology
Rajiv Gandhi Cancer Institute &
research centre
Sector 5 Rohini, New Delhi ,
India
Department of Pathology,
JohnsHopkinsMedical
Institutions,Baltimore,MD,USA
Department of Anatomic
Pathology, Cleveland Clinic,
Cleveland, OH, USA
Oscar Lin,
Department of Pathology, Memorial Sloan-Kettering Cancer Center,

New York, NY, USA
Jesse K. McKenney,
Department of Pathology, Stanford University School of Medicine,

Stanford, CA, USA
Rodolfo Montironi,
Section of Pathological Anatomy,

Polytechnic University of the Marche
Region, School of Medicine, United
Hospitals, Ancona, Italy
Gladell P. Paner,
Department of Pathology, University of Chicago, Chicago, IL, USA
Victor E. Reuter,
Pierre I. Karakiewicz,
Mark Soloway,
Bernd J. Schmitz-Drger,
Department of Pathology, Memorial Sloan-Kettering Cancer Center,

New York
Department of Urology, University
of Miami, Miami, FL, USA
committee 3A
Molecular Markers for
Bladder Cancer Screening,
Early Diagnosis, and
Surveillance
Michael J. Droller,
Department of Urology, Mount Sinai

School of Medicine, New York,
NY, USA
Yves Fradet,
Department of Urology,
Laval University, Laval,
Quebec, Canada
George P. Hemstreet,

of Nebraska Medical Center and
Omaha Veterans Affairs Hospital,
Omaha, Nebraska,
USA
MLiss Hudson,
Division of Urologic Surgery,

Washington University,
St. Louis, Missouri, USA
Vinata B. Lokeshwar,
University of Miami, Miami,
USA
Yair Lotan,
UT Southwestern Medical Center,
Dallas, TX, USA
PerUno Malmstrom,
University Hospital, Uppsala,
Sweden
Michael J. Marberger,
Department of Urology, Medical

University of Vienna, Vienna,
Austria
Osamu Ogawa,
Graduate School of Medicine,
Kyoto University, Kyoto,
Japan

of Montreal, Montreal,
Quebec, Canada
Urologie, EuromedClinic,
Europa-Allee 1, 90763 Frth,
Germany
Shahrokh F. Shariat,
Department of Urology and Division

of Medical Oncology, Weill Cornell
Medical College,
New York-Presbyterian Hospital,
New York, NY, USA
Bas W. van Rhijn,
Department of Urology, Antoni van

Leeuwenhoek Hospital/Netherlands
Cancer Institute, Amsterdam, The
Netherlands
Commette 3 B
Molecular markers for
bladder cancer staging and
prognosis
Michael Droller,
Department of Urology, Mount Sinai

School of Medicine, New York, NY,
USA
Yves Fradet,
Department of Urology, Laval

University, Laval, Quebec, Canada
George P. Hemstreet,

of Nebraska Medical Center and
Omaha Veterans Affairs Hospital,
Omaha, Nebraska
MLiss Hudson,
Division of Urologic Surgery,

Washington University, St. Louis,
Missouri, USA
Pierre I. Karakiewicz,

of Montreal, Montreal, Quebec,
Canada
Vinata B. Lokeshwar,
Departments of Urology and Cell

Biology and Anatomy, University of
Miami Miller School of Medicine,
Miami, Florida, USA
Yair Lotan,
Department
of
Urology,
UT
Southwestern Medical Center,
Dallas, TX, USA
Peruno Malmstrom,

Hospital, Uppsala, Sweden
Michael J. Marberger,
Department of Urology, Medical

University of Vienna, Vienna,
Austria
Osamu Ogawa,
Department of Urology, Graduate

School of Medicine, Kyoto
University, Kyoto, Japan
Bernd J. Schmitz-Drger,
Urologie, EuromedClinic, EuropaAllee 1, Frth, Germany
Christian Seitz,
Department of Urology, St John of

God Hospital, Vienna, Austria
Department of Urology and Division

of Medical Oncology, Weill Cornell
Medical College, New YorkPresbyterian Hospital, New York,
NY, USA
Maxine Sun,

of Montreal, Montreal, Quebec,
Canada
Bas W. van Rhijn,
Netherlands Cancer Institute,
Antoni van Leeuwenhoek Hospital,
Amsterdam, the Netherlands.
Committee 4
Low Grade Ta Urothelial
Carcinoma of the Bladder
Sam S. Chang,
Department of Urologic Surgery

Vanderbilt University School of
Medicine
Nashville, Tennessee, USA
Sigurdur Gudjonsson,
Department of Clinical Sciences

Urology, Skne University Hospital
Malm, Sweden
Badrinath Konety,
University of Minnesota
Minneapolis, MN USA
Willem Oosterlinck,
Ghent University Hospital

Ghent, Belgium
Raj Pruthi,
Division of Urologic Surgery

UNC Department of Surgery
Chapel Hill, NC 27599-7235
USA
Mark S. Soloway,
University of Miami,
USA
Eduaro Solsona,
Service of Urology
Valenciano Oncology Institute
Valencia, Spain.
Paul Sved,
University of Sydney
Sydney, Australia
Committee 5
High grade Ta, CIS and T1
Urothelial carcinoma
Marko Babjuk,
Hospital Motol
2nd Faculty of Medicine
Charles University in Praha
Czech Republic
Wolfgang Jager,
University Medical Center
Johannes Gutenberg University
Gebude 604
Langenbeckstrae 1
55131 Mainz, Germany
Wolfgang Otto,
Dept. of Urology
Caritas St. Josef Medical Centre,
University of Regensburg
Landshuterstr. Regensburg,
Germany
Jay Shah,
UT MD Anderson Cancer Center
Houston, TX
USA
Joachim W. Throff,
University Medical Center
Johannes Gutenberg University
Gebude 604
Langenbeckstrae 1
55131 Mainz, Germany
J. Alfred Witjes,
Dept of Urology
Radboud University Nijmegen
Medical Centre
The Netherlands
Maurizio A Brausi,
Ausl Modena
Dept of Urology
B Ramazzini Hospital Modena
Italy
Max Burger,
Dept. of Urology
Caritas St. Josef Medical Centre,
University of Regensburg
Landshuterstr. Regensburg,
Germany
Christopher Cheng,
Singapore General Hospital
Singapore
Eva Comprat,
Service dAnatomie Pathologique

Hpital La Piti Salptrire,
UPMC Paris VI
Paris, France
Colin Dinney,
UT MD Anderson Cancer Center
1515 Holcombe Blvd., Unit 1373
Houston,
USA
Khurshid A. Guru,
Department of Urology, Roswell

Park Cancer Institute, Buffalo, NY,
USA
Axel Heidenreich,

Hospital, RWTH Aachen
University, Aachen, Germany
Patrick Keegan,
Department of Urology, Vanderbilt

Medical Center, Nashville, TN,
USA
Seth P. Lerner,
Scott Department of Urology,

Bayor College of Medicine,
Houston, TX, USA
Edward M. Messing,

of Rochester, Medical Center,
Rochester, NY, USA
David I. Quinn,
Keck School of Medicine,

University of Southern California,
Los Angeles, CA, USA
Arthur I. Sagalowsky,
Department of Urology, UT
Southwestern Medical Center,
Dallas, TX, USA
Mark P. Schoenberg,
Committee 6
Muscle-invasive,
Presumably Regional,
Tumor
Joaquim Bellmunt,
Medical Oncology, University

Hospital del Mar, Barcelona, Spain
Department of Urology, James

Buchanan Brady Urological
Institute, Johns Hopkins Medical
Institutions, Baltimore, MD, USA
William U. Shipley,
Department of Radiation Oncology,

Harvard Medical School and
Massachusetts General Hospital,
Boston, MA, USA,
Arlene O. Siefker-Radtke,
Department of Urology, Vanderbilt

Medical Center, Nashville, TN,
USA
Department of Genitourinary
Medical Oncology, Division of
Cancer Medicine, The University
of Texas MD Anderson Cancer
Center, Houston, TX, USA
Jason Efstathiou,
Arnulf Stenzl,
Michael S. Cookson,
Department of Radiation Oncology,

Harvard Medical School and
Massachusetts General Hospital,
Boston, MA, USA,
Georgios Gakis,

Hospital, Eberhard-Karls
University, Tbingen, Germany

Hospital Tbingen, Eberhard-Karls
University Tbingen, Germany
Cora Sternberg,
Department of Medical Oncology,

San Camillo and Forlanini
Hospital,
Rome, Italy
Committee 7
Urinary Diversion
David F. Penson,
David Wood,
Eila C. Skinner,
Offer Yossepowitch,

Center, Nashville, TN,
USA
Mansoura University, Mansoura,
Egypt
Keck USC School of Medicine,

University of Southern
California, Los Angeles, CA,
USA
Thomas Davidsson,
Raimund Stein,
Hassan Abol-Enein,
Kristianstad County Hospital,
Kristianstad,
Sweden
Skane University Hospital, Malm,
Sweden
Johannes Gutenberg University,
Mainz, Germany
Urs E. Studer,
Inselspital Bern,
Switzerland
Joachim W. Thueroff,
University of Ulm,
Germany
Johannes Gutenberg University,
Mainz, Germany
Stefan H. Hautmann,
William H. Turner,
Richard E. Hautmann,
Mrkische Kliniken Ldenscheid,
Germany
Henriette V. Holm,
Oslo University Hospital, Oslo,
Norway
Cheryl T. Lee,
Addenbrookes Hospital,
Cambridge University,
UK
Bjoern G. Volkmer,
Klinikum Kassel,
Kassel, Germany
Committe 8
Comprehensive Cancer Center,

University of Michigan,
Ann Arbor, MI,
USA
Urothelial Carcinoma of the

Prostate
Fredrik Liedberg,
Hikmat Al-Ahmadie,
Sweden
Stephan Madersbacher,
Donauspital, Vienna,
Austria
University of Miami, Miami, FL,
USA
Wiking Mansson,
InstituteofUrology
RabinMedicalCenter
TelAvivUniversity
Tel Aviv
Israel
Committee 9
Chemotherapy for
Metastatic Urothelial
Carcinoma
DF Bajorin,
Memorial Sloan-Kettering Cancer

Center
Weil Medical College of Cornell
University
New York, USA
Robert Dreicer,
Department of Solid Tumor

Oncology,
Taussig Cancer Institute,
Cleveland Clinic, Cleveland, OH,
USA
Matthew D. Galsky,
Genitourinary Medical Oncology

Tisch Cancer Institute
Mount Sinai School of Medicine
New York, USA
Daniel George,
Department of Pathology
Center
New York, NY 10044, USA
Divisions of Medical Oncology and

Urology
Duke University Medical Center
Durham, NC 27705
USA
Bernard H. Bochner,
MI Milowsky,
Memorial Sloan Kettering Cancer

Center
Weill Medical College of Cornell
University
USA
Joan Palou,
Sweden
Urological Oncology Dept.

Fundaci Puigvert
Barcelona
Spain
Robert D. Mills,
Henk g van der Poel,
The Norfolk and Norwich

University Hospital,
Norwich,
UK
University of Michigan
USA
Dept urology
Netherlands cancer institute
Amsterdam
The Netherlands
10

Center
New york, USA
DI Quinn,
Kenneth J. Norris Jr.

Comprehensive Cancer Center
University of Southern California,
Los Angeles, CA 90033
USA
Guru Sonpavde,
Texas Oncology and the Veterans

Affairs Medical Center
Baylor College of Medicine
Webster, Texas,
USA
Walter M. Stadler,
Sections Hematology/Oncology &

Urology
University of Chicago
Chicago, IL
USA
Cora N. Sternberg,
William H Turner,
Addenbrookes Hospital
Cambridge University Hospitals
NHS Foundation Trust
Cambridge
United Kingdom
Department of Medical Oncology

San Camillo and Forlanini
Hospital
Rome - Italy
Dan Theodorescu,
University of Colorado Cancer

Center
University of Colorado
Denver, CO,
USA
David J. Vaughn,
Abramson Cancer Center

University of Pennsylvania
Philadelphia, PA
USA
Committee 10
Non-urothelial Cancer of
the Urinary Bladder
Hassan Abol-Enein,
Urology and Nephrology Center

Mansoura University
Mansoura, Egypt
Jack Baniel,
Urology Department
Rabin Medical Center, Beilinson
Campus
Petach Tikva,
Israel
Adrienne J. K. Carmack,
Brenham Urology
Brenham, Texas,
USA
Alexandra J Colquhoun,
Cambridge University Hospitals

NHS Foundation Trust
Cambridge,
United Kingdom
Bruce R Kava,
University of Miami Miller School of
Medicine
Department of Veterans Affairs
Medical Center, Miami
Miami, Florida,
USA
11
12
Editorial
Mark S. Soloway
It has been my privilege to chair the recently completed International Consultation on Urologic
Diseases (ICUD) Recommendations on Bladder Cancer (BC). After over one year of intense
interactive and enthusiastic collaboration with over 100 experts in various aspects of BC the
recommendations from the 10 committees were presented at the 2011 European Association
of Urology Congress in Vienna on March 18, 2011. Each committee had a chair and co chair
and they selected a broad based group of men and women with expertise in bladder cancer.
This editorial will provide only some of the highlights of the consultation. The entire proceedings will be found in this book . The comprehensive nature of this text will serve as a superb
resource for many years. Of note the first author of each chapter is not necessarily the same
as the chair or co chair of the committee.
Bladder cancer is the second most common malignancy of the genitourinary tract. Its protracted course and requirement for frequent monitoring is responsible for the huge costs involved with the care of patients with BC. It has been stated that it is one of the most expensive
cancers. It is a heterogeneous neoplasm and even within some categories there are significant differences in behavior among different histologic variants. These nuances are critical to
proper management. Unlike prostate cancer the level of awareness for this neoplasm is quite
low among not only the public but primary care physicians as well. This is one of the primary
problems that leads to a delay in diagnosis which may adversely impact survival in men and
women with high grade BC. Thus one of our challenges is to educate the public and members
of the medical profession about the association of risk factors such as cigarette smoke and
pelvic radiation with the development of bladder cancer as well as the need for prompt investigation of hematuria or persistent irritative bladder symptoms.
13
their overall medical history and their prior history

of urothelial cancer. In a discussion of some of the
new techniques to enhance endoscopy and TURBT
they highlight the fact that residual or new tumors
are found in up to 50% of patients at their first post
diagnosis follow up or at a reTUR. Many if not most of
the tumors identified at a repeat endoscopy/TURBT
performed within 4 to 6 weeks of the prior procedure
are due to missed or incompletely resected tumor.
This fact highlights the difficulty in performing this
procedure as the goal is always to remove all evident
tumor at the initial TURBT.
Committee 1: Diagnosis and

staging
Committee 1 was charged with reviewing the
diagnosis and staging of BC. The co chairs are
Ashish Kamat and Paul Hegarty. The sections are
repleat with valuable information about all aspects
of the diagnosis, endoscopic management, and
imaging of BC.
The authors stress the importance of prompt
investigation of men and women with gross or
microscopic hematuria to determine whether a
malignancy is the cause of the bleeding. Although
the liklihood of identifying cancer as the source of
microhematuria is low, upper urinary tract imaging
as well as cystoscopy are indicated particularly
if there are any risk factors or the individual is
over 50. There is no absolute recommendation on
the method of imaging the upper urinary tract. In
most centers the CTurogram is the most common
technique to provide excellent anatomy of the
kidneys and ureters as well as the urinary bladder.
The excretory urogram (IVP) is gradually going the
way of the rotary dial telephone. Nonetheless CT
requires intravenous contrast, subjects the patient
to significant radiation and is expensive. Urinary
cytology should be considered part of the hematuria
work up. Urine cytology is specific and sensitive for
the detection of high grade BC. Although cytology
is not very sensitive for the detection of low grade
tumors this is not a reason to shun its use as
there is no necessity to detect low grade tumors
early. Although cytology and other urine based
markers are recommended for the investigation of
individuals with hematuria the committee concluded
that urinary markers including cytology have not
been shown to be helpful in detecting BC in an
asymptomatic high risk group, e. g. occupational
exposure, smokers. This is largely related to the low
prevalence of bladder cancer even in a so called
high risk population. Among the various urine based
markers the committee indicated that the FISH test
is expensive and there are false positive tests. As
a result a patient may be subjected to a thorough
urologic investigation following a positive FISH test
yet no urothelial cancer is detected. Its use might be
beneficial when there is an atypical cytology reading.
Thus the routine use of urinary markers other than
cytology have yet to find a place in routine urology
practice.
Several new methods are nicely described that

might improve the urologists ability to resect all
the tumor, i.e. perform a complete TURBT. These
technical innovations include photodynamic
diagnostic cystoscopy (PDD), narrow band
imaging (NBI), Ramon spectroscopy, and optical
coherence tomography. These techniques are
designed either to aid in the detection of tumors
not seen by standard white light endoscopy or offer
the potential to provide in situ tumor staging. I have
had experience with PDD and NBI and they do
provide added benefit in some patients, particularly
in identifying papillary tumors and distinguishing
CIS. There are a number of trials demonstrating
that PDD can detect more tumors and this leads
to a lower recurrence rate presumably as a result
of a more complete TURBT. The relative reduction
in recurrent tumors was 16% in one prospective
randomized multicenter trial. This technique requires
the intravesical instillation of a solution containing
hexaminolevulinic acid 1 hour before the endoscopy/
TURBT. NBI has the advantage of not requiring
instillation of any exogenous material. It is initiated
by touching a button on the camera or light source
which places a filter in the optical system. Papillary
tumors in particular are identified by a characteristic
blue appearance.
Upon identifying a bladder tumor the urologist must
decide upon the depth of resection required to
properly stage the tumor. The TURBT provides the
tissue i.e. tumor, which is the foundation for the
decision making and treatment of bladder cancer.
If the endoscopic appearance suggests a possible
T1 or T2 tumor (lamina propria or muscularis propria
invasion) the resection must contain muscle from the
muscularis propria in order to determine the depth
of penetration. In the case of an invasive tumor the
specimen should be analyzed for lymphovascular
invasion as this is an important prognostic factor
along with grade and depth of invasion.
The committee thoroughly reviewed lower urinary

tract endoscopy and discussed in detail some of
the more recent approaches to enhance endoscopy
and endoscopic tumor resection (TURBT). A
TURBT is an under estimated surgical procedure
and requires skill and judgement. The procedure
begins with a thorough history including a review
of the patients unique background which includes
I was particularly pleased to note that the authors

reiterated that bladder perforation should be
discouraged. Many years ago urologists thought
it was acceptable to resect through the wall of the
bladder in an effort to remove a bladder tumor.
The risks clearly outweigh the potential benefit of
eradicating a T3 tumor by endoscopic resection.
14
All pathology reports will be accompanied by the

pertinent histology. Viewing histology via the internet
should be similar to what most of us currently rely
on for viewing images of the upper urinary tract.
We would not make a decision to remove a kidney,
for example, without reviewing the actual CT/MRI.
Why should we not have the same opportunity with
biopsy material?
Committee 2: Pathology
Committee 2 was devoted to the pathology of
BC. The co chairs are M. Amin and Victor Reuter.
They collaborated with a virtual whos who of GU
pathologists to write an outstanding chapter. The
text is accompanied by superb photomicrographs.
The chapter provides an overview of both urothelial
(UC) and non urothelial cancers of the bladder. The
authors carefully illustrate the differences between
dysplasia (not cancer) and carcinoma in situ (CIS).
CIS is a flat, high grade cancer confined to the
urothelium. Dysplasia may require monitoring while
CIS is treated with intravesical therapy, e. g. BCG.
This extensive review of the pathology of bladder

cancer will serve as a superb reference for anyone
interested in this subject. This is emphasized by the
number of references 761!
Committee 3: Molecular
Markers for Bladder Cancer
There are many important variants of urothelial

cancer (UC) and they have important implications
for treatment beyond grade and stage. For example
both micropapillary and the nested variant of UC
have a distinct histologic appearance and behave
in amore aggressive manner than other high grade
UCs. The implication is therefore that a diagnosis
of nested or micropapillary UC at stage T1 should
include a discussion of total cystectomy at the time
of diagnosis.
Committee 3, authored by S. Shariat et al, details

the various molecular markers which might be
useful in BC. As it is a heterogeneous neoplasm
there are numerous molecular signature patterns
which potentially may be immensely helpful for
directing treatment. Some of these markers include
p53, p21, pRB, and p27 among others. Despite a
host of studies that have analyzed the addition or
deletion of these and other genes or gene products
the information derived from these studies have yet
to impact on the decisions we make in the clinic.
The authors discuss a number of reasons for this
which include the differences in the antibodies used
to identify the marker in question and the statistical
methodology in specific studies. For those interested
in the state of the art of this subject this chapter is
a terrific resource.
Another tumor type that has important treatment

implications is small cell carcinoma (SCC) of the
bladder. Like SCC at other sites (lung, prostate) these
tumors metastasize early and the initial treatment
should be systemic chemotherapy, not cystectomy.
This chapter has a superb section detailing the use
of immunohistochemistry which may aid in the
diagnosis of different subtypes of bladder cancers.
There are some markers which may provide
prognostic information as well. Most urologists like
myself are not terribly conversant with this area but
should attempt to become conversant about the
potential role this plays in our ability to decide the
best treatment approach. There is also a section
on urinary markers including cytology and the
chromosome addition/deletion FISH test from the
pathologists perspective.
The second part of this chapter reviews the current

status of urinary markers for screening, diagnosis,
and surveillance of BC. The authors stress the
importance of urinary markers and the opportunity
they might have to play a larger role in the diagnosis
and monitoring of BC. Unfortunately the potential
of urinary cytology and other urine based markers
has yet to be realized. Although these markers
have some efficacy in detecting patients with BC
the specificity and sensitivity is such that they have
not found wide utilization by most urologists. The
discussion of cytology and its lack of sensitivity in
low grade BC must be countered with the fact that
an early diagnosis of the benign acting low grade
tumor is not critical however we have abundant
evidence that there is a substantial delay in the
diagnosis of high grade potentially lethal BC. Thus
the authors highlight the potential role of cytology
or other markers for the early detection of bladder
cancer in a high risk population, i. e. hematuria,
smokers, etc.
The authors detail the necessary information

that constitutes an adequate report from the
pathologist to the clinician. Although there are
many occasions when it would be useful for the
urologist or other oncologist to look at the slides with
the pathologist this is often not feasible so the report
is the primary communication and must contain the
critical information the urologist/oncologist requires
to make treatment decisions. This includes not only
the tumor grade and stage but more precisely the
depth of lamina propria invasion, presence of LVI,
presence or lack thereof of muscularis propria, and
whether there is CIS. In the not too distant future
I believe we will have a readily available method
to access our patients histology on the internet.
The authors comment on why most of the urine based

markers have not been integrated into a routine work
15
up for patients with hematuria. This is partly related to

the relatively high rate of false positive tests and thus
their lack of specificity. In contrast when one has a
report of malignant cells identified in a urine cytology
the clinician has the obligation to search for a tumor
as the chance of a false positive is very low.
BCG is not recommended as first line intravesical

therapy in low risk patients as the side effect profile
is higher than with chemotherapy and the efficacy is
equivalent. BCG should be considered for patients
who develop a high grade Ta or T1 tumor as well
as those who have multiple recurrences despite
intravesical chemotherapy.
Committee 4: Low Grade Ta

Bladder
Committee 5: High grade Ta,

CIS, and T1 Urothelial
Carcinoma
Committee 4 concentrated on low grade Ta bladder

tumors. The chairs are B. J. Konety and Wim
Oosterlinck. Similar to the conclusions noted above
as related to cytology and urine based markers
these authors make it clear that cytology and urine
based markers do not have a role in the monitoring
of patients with low grade tumors. The cost and
problems with false positives and/or low sensitivity
in the context of an already highly sensitive and
specific although minimally invasive test to diagnosis
and treat these tumors i. e. cystoscopy have
relegated these tests to a minor role. The authors
emphasize that the risk of a subsequent upper tract
tumor following initial diagnosis and treatment of a
low grade Ta tumor is low and therefore there is no
indication for regular monitoring of the upper tract,
e. g. IVP, CT. This recommendation, if followed, will
save money as well as lessen the risk of radiation
for patients who have LG Ta tumors. Obviously any
change in grade, unexplained hematuria or positive
cytology would prompt consideration for upper tract
imaging.
Committee 5 chaired by Fred Witjes and Max Berger

provided recommendations on high grade Ta, CIS,
and T1 UC. They indicate that the risk of developing
an upper tract tumor over the course of a patients
life is sufficiently high to warrant periodic upper tract
surveillance. Unfortunately there is a paucity of data
on how frequently to perform upper tract imaging
and importantly whether any schedule identifies a life
threatening upper tract UC in a timely fashion. Most
guidelines suggest performing an imaging study
every 1- 3 years following resection of a high grade
Ta/T1 but a high grade upper tract urothelial tumor
is likely to grow and invade or metastasize within
this time frame. If one is really concerned about
detecting a high grade upper tract tumor promptly
then frequent cytology possibly supplemented by
ultrasonography might be a practical and potentially
useful alternative.
Cystoscopy is recommended every 3-4 months for
BC surveillance following the diagnosis of a high
grade UC because there is concern about waiting
too long before detecting and treating a high grade
recurrence. In contrast to the patient with low grade
Ta tumors the risk of recurrence and progression is
substantial. Tumors of the urinary bladder which are
high grade and Ta are initially treated by complete
endoscopic resection which may be facilitated by
the use of photodynamic diagnostic techniques
using blue light technology. If the surgeon is not
confidant that he/she has performed a complete
resection then a re-resection should be performed
within 4 to 6 weeks. Once a complete resection has
been assured intravesical BCG should be initiated
2 weeks after the TURBT. The accepted instillation
is weekly for six weeks with maintenance therapy for
a minimum of one year. There is no data on what
is the optimal maintenance schedule although
most studies have used the schema initiated by the
SOG group. There is evidence that an initial single
instillation of chemotherapy provides a longer
tumor free interval. The precise role of post TURBT
intravesical chemotherapy in these patients is
controversial.
There are a variety of ways the urologist can

manage the patient with a low grade Ta tumor:
cold cup resection/fulguration in the operating
room, office fulguration, formal TURBT, and
initial observation for recurrent very small tumors
which appear to be Ta. The goal is to minimize
the risks of therapy in a tumor that rarely, if ever,
progresses in stage. Because patients with a low
grade Ta tumor infrequently develop a high grade
BC the committee recommends less vigorous
endoscopic surveillance. Thus if the initial three
month cystoscopy is negative the next cystoscopy
may be at 1 year.
Following the removal of one or more low grade
Ta tumor(s) all current guidelines recommend the
instillation of at least one dose of intravesical
chemotherapy to be instilled into the bladder
within hours of the resection. This should not be
prescribed if there has been perforation of the
bladder. Although this recommendation is consistent
among most guideline committees (EAU, AUA, SIU)
data from insurance providers in the US indicate it
is infrequently practiced. This may in part be related
to the obstacles of giving chemotherapy in the
postop recovery room. The committee indicated that
Carcinoma in situ is usually multifocal and often

seen in conjunction with other tumors in the bladder.
Its presence signifies multifocal urothelial cancer.
16
When identified as the only tumor it is treated with

intravesical BCG.
reviewing the treatment alternatives for muscle

invasive UC (MIBC). This is a wonderful and
comprehensive overview of the surgical approaches
to MIBC which include partial and total cystectomy,
and TURBT alone. The initial part of the chapter
deals with the procedure of total cystectomy
which in men traditionally includes removal of the
prostate and in women removal of the uterus and
the anterior vaginal wall. The precise extent of the
procedure may vary depending on the extent of the
tumor, patient age, etc. They discuss the variations
of this procedure and note there may be occasions
when the prostate and uterus and vagina may be
spared. The authors caution that the surgeon must
weigh any potential quality of life benefit from a
less extensive procedure with the risk of leaving
an aggressive cancer in situ. A particular example
would be the woman who is having a cystectomy for
high grade Ta/T1/CIS UC and wishes an orthotopic
neobladder. As long as the staging is accurate it may
be wise to preserve the anterior vaginal wall and
uterus if no prior hysterectomy to act as a support
for the pouch.
Patients with a high grade T1 tumor(s) are a

particular challenge as the risk of initial under staging
and progression is substantial. Some will advocate
cystectomy at initial diagnosis in patients which
have particularly adverse prognostic factors such as
multifocal T1 tumor, associated CIS, lymphovascular
invasion (LVI) or tumors that cannot be completely
resected. There is a strong recommendation that
following the resection of a high grade T1 urothelial
carcinoma with or without muscularis propria in the
specimen a reTURBT should be performed to ensure
complete removal of all tumor before commencing
BCG.
It is important to emphasize that 10 to 20% of
patients with an initial high grade T1 UC who are
treated by a TURBT followed by BCG ultimately die
of metastatic urothelial carcinoma. Thus there should
be some consideration and discussion regarding
initial cystectomy.
One of the important subjects discussed in this
chapter are the definitions of BCG failure. Patients
who are refractory to BCG never achieve a disease
free status with one or two six-week courses of BCG.
Patients who have an initial complete response to
TURBT followed by BCG and develop another tumor
after a year without therapy can be considered for
re-treatment with BCG after complete resection of
their tumor. Patients who have an initial complete
responseto TURBT followed by BCG and develop
another tumor after a year without therapy can be
considered for re-treatment with BCG after complete
resection of their tumor. Lastly there are patients
who are intolerant of BCG. For patients with high
grade urothelial carcinoma that recur promptly
despite BCG there are several alternatives but
cystectomy should be considered the initial option
with alternative intravesical therapies reserved for
those unfit for cystectomy.
The literature outlining the extent of the pelvic

lymph node dissection is detailed. There is
substantial data from a number of sources stressing
the benefit of extending the node dissection superior
to the external iliac vessels and removing lymph
nodes along the common iliac vessels and possibly
even to the aortic bifurcation. Although removing the
lymph nodes superior to the external iliac vessels
yields more negative and positive nodes it remains
unclear that the additional dissection results in a
longer disease free survival. It is clear however that
the quality of the cystectomy and node dissection
is a factor in the prognosis of patients undergoing
this procedure. The percentage of patients with
one or more positive lymph nodes is approximately
25% from large RC series and further highlights the
aggressive nature of high grade MIBC and the need
for some early detection program to improve upon
the survival rate from this disease.
Patients who receive BCG after resection of a

high grade Ta/T1 tumor and have not achieved a
complete response at three months are given the
alternatives of another 6 weeks of BCG or proceed
to cystectomy. Although the authors stress there are
insufficient data to direct the timing of abandoning
bladder preservation there is a growing consensus
that if the tumors are T1 a cystectomy in medically
fit patients is appropriate. The chance that the tumor
is understaged is substantial and delay in removing
the bladder can be lethal.
The complication rate from radical cystectomy

ranges from 30 to 50%. There is a long list of medical
and surgical problems that can occur after a RC/
urinary diversion and some can be addressed with
appropriate attention to detail and risk factors. Once
again a plea to have these procedures concentrated
in centers where there are surgeons and medical and
surgical intensivists accustomed to this operation as
well as the perioperative care of high risk patients.
Thanks to technical improvements to aid the surgeon
such as vascular staplers, bipolar cautery devices as
well as an improved understanding of pelvic anatomy
particularly related to the prostate the blood loss
from this surgery has declined. The perioperative
mortality remains relatively stable and ranges from
1 to 5% depending on a number of factors such as
patient comorbidity, age, prior surgery, etc.
Committee 6: Muscle-invasive,
Presumably Regional, Tumor
Committee 6 chaired by Jason Efstathiou, David
Quinn and Arnulf Stenzl aided by 13 urologists,
radiation or medical oncologists had the task of
17
Another alternative for the management of muscle

invasive bladder cancer is bladder preservation.
This approach is for selected patients who meet
a short list of inclusion criteria which includes a
normal upper urinary tract (no hydronephrosis), an
adequate bladder capacity, and they must have
had acomplete TURBT. It is preferable they do not
have CIS. This program requires the interest and
expertise of three disciplines: urology, radiation and
medical oncology.
and cisplatin. Randomized studies have shown

equivalence between MVAC and GC in metastatic
urothelial cancer with less toxicity with the two drug
regimen
One of the important conclusions is that patients are
more likely to receive the intended chemotherapy
if given before cystectomy, i. e. induction rather
than as an adjuvant. This is largely related to delays
or failure to receive chemotherapy as a result of
the frequent complications following this extensive
operation. This is a disease of elderly patients and
many simply refuse or cannot tolerate our optimal
chemotherapy regimen after a cystectomy and
diversion. These factors are less operative when
considering induction chemotherapy.
The treatment plan calls for an initial complete

endoscopic tumor resection followed by 40 Gy
radiation therapy with concomitant cisplatin based
chemotherapy. At this point a repeat cystoscopy
is required to determine whether there has been
a complete response. If not the patient is advised
to have their bladder removed. If there has been a
complete response the initial treatment is consolidated
with additional radiation and chemotherapy with
careful endoscopic monitoring. Over the last 20
years the protocol has been changed from a
neoadjuvant chemotherapy approach with cisplatin
based combination chemotherapy to be followed by
radiation therapy and cisplatin to the current approach
of twice a day radiation and concurrent cisplatin
and a taxane. This is then followed by four cycles
of gemcitabine and cisplatin. The results from this
bladder sparing approach in a highly selected group
of patients is similar in disease free survival to initial
radical cystectomy. A high percentage of the patients
have adequate bladder function.
This chapter has excellent sections discussing the

role of RC as initial therapy for several variants
of high grade UC. Specifically they discuss the
nested variant, micropapillary, and UC with adeno
and squamous elements. All of these tumors are
associated with a poorer prognosis and thus a
RC should be seriously considered when they are
diagnosed at stage T1.
Another section discusses the role of monitoring
the upper tract following a diagnosis of MIBC
of the bladder. Some of the key points relate to a
risk related strategy for monitoring the upper tract
since there are no optimal recommendations for
imaging the upper tract. No strategy to date has
demonstrated that frequent CT or other imaging
modality performed at one or two year intervals will
detect tumors in a timely fashion. Thus patients with
tumor at the ureteral margin or with bladder CIS
should have more frequent monitoring. Cytology
might be a reasonable adjunct to imaging as it can
be performed frequently at relatively little cost and
does not add the risk of radiation associated with CT
scanning.
The important subject of perioperative systemic

chemotherapy is addressed by a group of
outstanding medical oncologists. The disease free
survival following radical cystectomy has plateaued
over the last decade. In order to improve the
cure rate we will require either effective systemic
therapy or a better method to identify and treat
patients with high grade UC before metastases
occur. We have systemic chemotherapy that can
produce major responses in locally advanced and
metastatic UC although complete responses in the
latter category are no more than 10%. It is thus a
reasonably chemotherapy sensitive tumor with the
use of cisplatin based combination chemotherapy.
Prospective randomized trials have examined the
benefit of induction (neoadjuvant) and adjuvant
chemotherapy. These results are thoroughly
reviewed in this chapter. There have been two
prospective randomized trials that indicate at least
a 5% survival advantage in favor of patients who
received induction or neoadjuvant chemotherapy
before cystectomy or radiation. Meta analysis of
these neoadjuvant trials support the benefit of
cisplatin based combination chemotherapy as
induction treatment. The authors indicate that at
this time the four drug combination identified as
MVAC remains the regimen of choice although in
practical terms most oncologists use gemcitabine
The committee dealing with muscle invasive bladder

cancer also stressed the importance of initial
chemotherapy using cisplatin and etoposide for
small cell carcinoma. Most of these patients have
metastatic disease at diagnosis despite negative
staging studies and therefore it is a recommendation
to initiate treatment with chemotherapy. Once
a complete response is achieved consolidation is
performed with surgery or radiation.
Committee 7: Urinary Diversion

Committee 7 deals with urinary diversion. This
committee is chaired by Richard Hautmann and
Bjoern Volkmer. The 19 member committee stresses
that a radical cystectomy and urinary diversion
may be the most difficult operation in urologic
surgery. The procedures are often performed in
18
elderly patients with significant co morbidity usually

related to years of cigarette smoking. The operation,
whether by a standard open approach or with
laparoscopy, is long and requires that the surgery
be performed with attention to detail. At this time
most of the urinary diversions are being performed
with an open technique even if the RC is performed
laparoscopically.
for a neobladder. Many patients more than 70

years old wish to avoid an abdominal stoma. The
motivation of the patient is the most important factor
in the decision to perform a bladder substitute. The
urethral anastomotic stricture rate is low. With
procedures performed at centers of excellence the
stricture or stenosis at the uretero-ileal junction is
less than 5%. Orthotopic diversion in women is
becoming increasingly utilized and the motivation of
the patient is critical. One would hesitate to perform
a neobladder if the carcinoma invades the bladder
neck or vaginal wall.
The committee points out that there are few studies

which adequately address the complications
related to radical cystectomy. An ideal analysis
should include operative time, length of stay,
estimated blood loss, time to return to work, as well
as operative mortality. Few reports detail readmission
rates, reoperation rates, time in intensive care, and
additional interventional radiologic procedures both
in the short-term and long-term. Since there are no
randomized studies all recommendations are level
III or IV and mostly expert opinion.
The authors discuss the role of renal function both

in deciding the type of diversion and the need to
monitor renal function after the diversion. In order to
perform an orthotopic diversion the patient must have
a creatinine clearance of >50 cc/min. Few patients
have a decline in renal function following a diversion.
One should monitor the upper tract with periodic
creatinine levels as well as by renal ultrasound. Early
diagnosis of stricture at the ureteroileal anastomosis
is important.
This committee surveyed the members of the

working group and note that approximately 50%
of men and women who have a urinary diversion
at these centers of excellence had an orthotopic
neobladder, most of the remaining patients had an
ileal conduit. A continent diversion to the skin is
uncommon. Of interest in population based surveys
of the type of diversion only 15% of patients undergo
an orthotopic diversion however in centers devoted
to the care of these patients up to 70% have an
orthotopic neobladder. The committee suggests that
a high volume center should perform at least 25 RCs
per year. At many centers, including ours, one of us
performs the RC and another the diversion. This
limits the time in the operating room to under 2 - 3
hours for each and I believe has some benefits.
The authors have an excellent section discussing

perioperative complications of urinary diversion.
They stress some practical points such as the
preservation of the anterior vaginal wall, when
possible, and the use of an omental interposition flap
to decrease the chance of a urethral vaginal fistula.
Committee 8: Urothelial
Carcinoma of the Prostate
Committee 8, authored by Juan Palou, David
Wood, and four other urologists reviewed the
topic of urothelial carcinoma of the prostate. Many
years ago this was thought to be a rare entity. With
improvements in endoscopy and TURBT along
with intravesical therapy urothelial carcinoma of the
prostate is more frequent. With control of tumors in
the bladder we have changed the natural history of
UC of the lower urinary tract. The urologist managing
patients with high grade Ta/T1/CIS of the bladder
must always consider the status of the prostatic
urethra and guard against a non visible area of
high grade cancer in the prostate. A positive urinary
cytology in the absence of a visible source in the
bladder requires a biopsy of the prostatic urethra,
which should be a TUR resection biopsy.
The committee highlights the fact that the extent of

the cancer in the pelvis is not always a barrier to
perform an orthotopic neobladder. Positive lymph
nodes, for example, should not exclude a patient
from a neobladder. There is no consensus on the
need for preoperative biopsy of the prostate to
determine the acceptability for an orthotopic urinary
diversion as the frozen section of the urethral margin
will serve as the determining factor of whether an
anastomosis can be made to the urethra. Some
surgeons like to have information on the status of
the prostatic urethra in hand to discuss the type
of diversion. I rely on the intraoperative frozen
section.
It is important to accurately stage the extent of high

grade urothelial carcinoma of the prostatic urethra.
The stages are: carcinoma in situ (CIS), involvement
of the prostatic ducts, and invasion of the prostatic
stroma. The latter portends a particularly adverse
prognostic factor. The 5 year survival is 60% if there
is no stromal invasion and 30% if there is. Stromal
invasion can either occur by direct extension of a
muscle invasive tumor from the bladder or by growth
Nerve sparing can be utilized depending on the

extent of the tumor and will allow preservation of
erectile function in some young men who undergo
a total cystoprostatectomy. The committee indicates
that preserving the seminal vesicles and the
nerves surrounding them may be beneficial
in preserving more nerves involved in erectile
function and continence. There is no age cut off
19
from the prostate urothelium down the ducts into the

stroma. When stromal invasion occurs by extension
from the bladder the survival is particularly poor
despite cystoprostatectomy.
first line chemotherapy. Unlike other cancers in which

there are effective second and third line programs
there is a lack of effective salvage therapy in UC.
Treatment for CIS of the prostate is endoscopic

resection followed by BCG. High grade tumor
after an initial course of BCG should prompt
consideration for a RC. Tumor in the ducts can
be initially treated similarly although some advocate
cystoprostatectomy at initial diagnosis of ductal
involvement. The prognosis for patients with stromal
invasion is poor despite a cystoprostatectomy.
Induction chemotherapy should be considered in
such cases.
Chapter 10: Non-urothelial

carcinoma of the urinary
bladder
Chapter 10 authored by Bruce Kava, Alex
Colquhoun, Jack Baniel et al reviews non-urothelial
carcinoma of the urinary bladder. This category
includes squamous cell, adenocarcinoma, and
small cell carcinoma of the urinary bladder. Other
very rare histologic types are also mentioned.
There is a paucity of information based upon any
randomized trial to determine the optimal approach
for the first two of these tumor types. Since there is
no effective systemic therapy for squamous cell or
adenocarcinoma there is a consensus that the best
option for the majority of these tumors is RC.
Papillary low-grade tumors of the prostate

have a good prognosis and can be managed with
endoscopic resection with or without intravesical
chemotherapy.
Committee 9: Chemotherapy
Squamous cell carcinoma is relatively infrequent

outside of Egypt or other countries in which
schistosomiasis is endemic. Squamous cell
carcinoma of the bladder may be caused by
chronic inflammation of the bladder. Patients with
an indwelling catheter, bladder calculi, spinal cord
injured patients who have a neurogenic bladder are
at an increased risk for squamous cell carcinoma of
the bladder. The local failure rate for squamous cell
carcinoma appears to be higher than for UC of the
bladder.
Committee 9 is authored by Cora Sternberg with

the help of 9 outstanding medical oncologists and
one urologist. Their chapter discusses the role of
systemic chemotherapy for advanced BC. There are
several prospective, randomized trials which have
examined the activity of systemic chemotherapy
using the four drug combination referred to as MVAC
or the combination of cisplatin and gemcitabine.
An important 400 patient prospective, randomized
trial compared these two regimens and demonstrated
equivalent efficacy and less toxicity with the two drug
combination. Thus although some oncologists feel
that in the healthy patient MVAC might be superior
the majority of oncologists use the two drug regimen
for the majority of patients for first line chemotherapy
in locally advanced or metastatic UC. The committee
also discussed the role of high-dose MVAC with
G-CSF rescue.
Adenocarcinoma of the bladder has several

subtypes which include urachal and non urachal
tumors. The former are usually treated by extensive
partial cystectomy ensuring negative margins at
frozen section.
Despite apparent local control the incidence of local
and systemic failure is high. Unfortunately there is
no effective adjuvant chemotherapy although in
some instances radiation might be considered.
The authors discuss the common problem of

cisplatin ineligible patients. Cisplatin is the most
active single agent for UC however many patients
with advanced urothelial cancer are elderly and/or
have reduced renal or cardiac function. Fourty per
cent of patients are ineligible to receive cisplatin
due to renal impairment. Most studies which have
given chemotherapy in these patients have used
carboplatin in place of cisplatin. One of the problems
of evaluating these reports is the variability in the
definition of unfit patients. The traditional exclusion
criteria are a performance status less than 60% and
a creatinine clearance less than 30 ML per minute.
Patients also require a cardiac ejection fraction better
than 40% in order to receive cisplatin.
Small cell carcinoma has been discussed in

part in the sections on pathology and MIBC. The
key here is to make the diagnosis after the initial
diagnostic TURBT. After thorough staging the initial
treatment is cisplatin and etoposide systemic
chemotherapy. The initial response is usually
excellent. Following chemotherapy there are no data
driven recommendations on whether the optimal
approach is RC, radiation, or observation. I have
treated patients using each of these with success.
The chapter discusses the many agents that have

been used for patients who have progressed despite
20
BLADDER CANCER
Editors
Mark S. Soloway and Saad Khoury,
21
22
Committee 1
Screening, Diagnosis,
and Evaluation
Chairs:
Dr. Paul K. Hegarty,
Dr. Ashish M. Kamat
Members:
Mohan Arianayagam,
Peter Black,
Sam S. Chang,
Peter E. Clark,
Judson D. Davies,
Jinhai Fan,
Jason R. Gee,
Nicholas J. Hegarty,
Tim S. OBrien,
Amit Patel,
SudhirRawal,
Rafael Sanchez-Salas,
Robert S. Svatek,
William Turner
23
Table of Contents
A. SCREENING AND DIAGNOSIS:
EVALUATION OF PATIENTS WITH
HEMATURIA
D. Imaging and Bladder Cancer
I. SCREENING
I. Methods
II. PRESENTATION
II. Virtual Cystoscopy
III. INVESTIGATION
III. C
T in Localized Bladder Cancer Staging
IV. URINE CYTOLOGY
IV. MRI in Localized Bladder

Cancer Staging
V. URINARY BIOMARKERS
V. Detection of Nodal Disease

and Metastasis
B. Endoscopic Examination of
the Lower Urinary Tract
VI. Imaging after Bladder Cancer Treatment
I. White Light Cystoscopy

II. FLUORESCENCE CYSTOSCOPY
VII. G
eneral Comments
III. New OPTICAL IMAGING Techniques for Bladder Cancer

DIAGNOSIS
Summary of the Recommendations
C. Transurethral Resection
of Bladder Tumors
I. Preoperative assessment
II. Technique
II. Technique
III. T
URBT in
stances
Specific
Circum-
IV. S
ample Transportand Pathologic Processing: Or How
best to help your pathologist give you the most useful pathology report
24
Screening, Diagnosis, and Evaluation

Dr. Paul K. Hegarty, Dr. Ashish M. Kamat
Mohan Arianayagam, Peter Black, Sam S. Chang,
Peter E. Clark, Judson D. Davies, Jinhai Fan, Jason R. Gee,
Nicholas J. Hegarty, PaulK. Hegarty, Murugesan Manoharan,
Tim S. OBrien, Amit Patel, SudhirRawal, Rafael Sanchez-Salas
Robert S. Svatek, William Turner
cancer on subsequent investigation is 5% [level of
evidence 2; Britton et al, 1989]. It is unknown if early
detection of bladder cancer following investigation
of asymptomatic microscopic hematuria leads to an
improved outcome. Findings on physical examination
are unremarkable in patients with noninvasive
bladder cancer.
A. SCREENING AND DIAGNOSIS:

EVALUATION OF PATIENTS WITH
HEMATURIA
III. INVESTIGATION
I. SCREENING
Cystoscopy is the cornerstone investigation in

patients with suspected bladder cancer. Flexible
cystoscopy can be performed in the office with local
anesthetic lubricant. The office-based procedure can
be omitted in patients in whom bladder cancer has
already been identified on imaging and who proceed
directly to transurethral resection.
The object of screening is to identify disease at an

earlier stage when it is more amenable to treatment.
An evaluation of the quality of studies concluded that
there were no randomized controlled trials or highquality controlled observational studies comparing
screening to not screening for bladder cancer [Chou
2010]. No study was identified that randomized
screen-detected cancers to treatment versus nontreatment. Thus the recommendations on screening
remain unchanged from the 2006 ICUD guidelines.
In patients with hematuria, imaging is an important

part of the evaluation; imaging is used primarily to
visualize the upper urinary tract as cystoscopy allows
inspection of the lower urinary tract. The incidence
of upper urinary tract malignancy among patients
undergoing evaluation because of hematuria is 0.20.7% [level of evidence 2; Khadra et al, 2000, Edwards
et al, 2006]. Options for imaging are ultrasonography,
IVU, CT urography, MRI, or a combination of these.
Ultrasonography and IVU appear to be equally
sensitive in diagnosing upper tract disease [level of
evidence 2; Khadra et al, 2000]. Using CT as the gold
standard, ultrasonography has a positive predictive
value of 100% in detecting renal cancer [level of
evidence 2; Datta et al, 2002]. Improvements in the
technical quality of ultrasonography have resulted
in improved performance of this imaging modality
in detecting bladder cancer; reported sensitivities
are 63-98%, and reported specificity is 99% [level
of evidence 2; Datta et al, 2002]. Thus, diagnostic
flexible cystoscopy can be omitted in cases in
which ultrasonography reveals bladder cancer. CT
II. PRESENTATION
Hematuria, typically painless, is the cardinal
presenting symptom of noninvasive bladder cancer.
In patients with CIS, hematuria may be accompanied
by irritative voiding symptoms. The incidence of
bladder cancer is 17-18.9% in patients presenting
with macroscopic hematuria and 4.8-6% in patients
presenting with microscopic hematuria [level of
evidence 2; Edwards et al, 2006, Datta et al, 2002,
Mishriki et al, 2008]. The prevalence of asymptomatic
hematuria ranges from 0.19% to 21% depending
on the population being studied, and prevalence
appears to increase with age [Rodgers et al, 2006].
The prevalence of microscopic hematuria is 23% in
men over 60 years of age, and in men older than 60
years with microscopic hematuria, the risk of bladder
25
urography has reported sensitivities of 88-100%

and specificities of 93-100% in diagnosing urothelial
carcinoma. A meta-analysis of 5 studies of CT
urography yielded a pooled sensitivity of 96% and a
pooled specificity of 99% in diagnosing upper urinary
tract malignancy [level of evidence 2; Chlapoutakis
et al, 2010]. The disadvantages of CT urography are
relatively high radiation dose, need for intravenous
contrast medium, limited availability, and relatively
high cost.
positive only when tumor cells are identified, the

positive predictive value of this test is very high
[Bastacky et al, 1999]. The diagnostic yield of urine
cytology is increased if more than 3 samples are
analyzed [Planz et al, 2005].
Sampling error and tumor load are 2 parameters that
have to be considered in the interpretation of urine
cytology. Voided urine specimens have a lesser
diagnostic yield than bladder washings. There have
been instances in which findings on cytology are
positive but findings on cystoscopy or imaging are
negative.
Edwards et al (2010) tested a protocol in which

patients with hematuria underwent flexible
cystoscopy, ultrasonography, and plain radiography
as first-line procedures and IVU if there were
abnormal findings on first-line procedures or there
was persistent hematuria in a patient over 40 years
of age. With a medium follow-up time of 4 years, the
risk of missing a tumor with this protocol in a patient
with microscopic hematuria was less than 1%. For
macroscopic hematuria, the risk of missing a tumor
was 2% for men over 30 years of age and women
over 50 years of age, and the risk increased a further
1% for each decade over 50 years of age for both
sexes [level of evidence 2]. These so-called missed
tumors probably represent new tumors or tumors
not visible on initial cystoscopy [level of evidence 3;
Messing et al, 2005].
The role of urine cytology in the diagnosis of

bladder cancer has been universally accepted and
extensively analyzed. However, a critical review
of the literature reveals a paucity of randomized
controlled trials of urine cytology. Most of the earlier
studies concentrated on the sensitivity, specificity,
and positive predictive value. A pooled analysis
of 36 studies reported a sensitivity of 44% and a
specificity of 96% for urine cytology [Mowatt et al,
2010]. Once urinary biomarkers were introduced,
the focus of research shifted to comparison of
cytology and biomarkers and subsequently to the
utility of biomarkers as an adjunct to cytology. In
a meta-analysis comparing fluorescence in situ
hybridization (FISH) and cytology, even though the
sensitivity and specificity of FISH were superior to
those of urine cytology, the sensitivity of FISH was
lower than that of cytology for higher-stage tumors
[Yang et al, 2009].
IV. URINE CYTOLOGY

Urine cytology is not a laboratory test; rather, it is
a pathologists interpretation of the morphologic
features of urothelial cells. The combination of urine
cytology and cystoscopy has been the gold standard
for the diagnosis and surveillance of bladder
cancer.
The American Urological Association best practice

policy recommends voided urine cytology for all
patients with risk factors for urothelial carcinoma. For
patients with asymptomatic microscopic hematuria
without risk factors for urothelial carcinoma, either
urine cytology or cystoscopy can be used [Grossfeld
et al, 2001].
Cytology is a simple, noninvasive, cost-effective

procedure and the the combination of urine cytology
and cystoscopy is superior to cystoscopy alone in
the detection of high-grade flat lesionsi.e., CIS and
dysplasia; in the detection of high-grade urothelial
cancer; and in the detection of upper urinary tract
tumors. Urine cytology is especially valuable for
differentiating high-grade urothelial carcinomas from
low-grade urothelial neoplasms, a feat that urinary
biomarkers [see the next section] have not yet
achieved [Lokeshwar et al, 2005].
Because of its high specificity and sensitivity in the

detection of pTis disease, urine cytology fulfills the
requirements for an adjunct to cystoscopy in the
surveillance of patients with pTa-T1 bladder urothelial
carcinoma [Babjuk et al, 2008]. A multicenter study
performed in the United States to compare the
performance of cytology, the ImmunoCyt tumor
marker test, and the combination of cytology and
ImmunoCyt in patients monitored for recurrence
of bladder cancer showed that ImmunoCyt
enhanced the sensitivity of cytology [Messing et
al, 2005]. About 50-70% of patients with superficial
bladder cancer develop recurrence within 5 years,
and 25% eventually develop invasive disease.
Lifelong surveillance is therefore mandatory in
the management of non muscle invasive cancer
[Fritsche et al, 2010]. Urine cytology remains the
gold standard for surveillance of patients with non
muscle invasive cancer.
Urine cytology in the diagnosis of bladder cancer has

a moderate sensitivity overall that is complemented
by high specificity. Cytology has a high sensitivity
and high negative predictive value in detecting
high-grade bladder tumors; it has a low sensitivity
and low negative predictive value in detecting lowgrade bladder neoplasms. The specificity of cytology
is superior to that of most of the currently available
bladder tumor markers [see the next section].
Because findings on urine cytology are considered
26
Other recent studies regarding FISH in the diagnosis

of bladder cancer call into question the role of this
assay in clinical practice. In a study by Ferra et al
(2009), patients with suspicious findings on urine
cytology were also evaluated by FISH. When
findings on cystoscopy and biopsy were used as the
gold standard, the sensitivity of FISH was 68.3% and
the specificity was 39.7%, indicating that in patients
with suspicious findings on urine cytology and
negative findings on cystoscopy, positive findings
on FISH could not justify aggressive evaluation
[Ferra et al, 2009]. Youssef et al (2010) performed
a review of 142 patients undergoing cystoscopic
surveillance and confirmed that a cancer diagnosis
in patients with negative findings on both cystoscopy
and cytology was rare (1/111 patients). Furthermore,
cancer in patients with equivocal or positive findings
on cystoscopy was relatively common, such that
the authors concluded that FISH was not useful in
these cases either and that a cost analysis should
be done before adoption of widespread use of FISH
in patients with negative findings on urine cytology
[Youssef et al, 2010].
V. URINARY BIOMARKERS
Urinary biomarkers for the diagnosis of bladder
cancer have been evaluated extensively, but to date,
there have been relatively few completed randomized
trials. Glas et al (2003) performed a meta-analysis
of 42 case series (n=5,706) that compared urine
cytology versus urinary biomarkersincluding
NMP22, telomerase, BTA, BTA-Trak, and BTAStatin the diagnosis of primary bladder cancer.
None of the urinary biomarkers exhibited sensitivity
that would justify the use of biomarker measurement
as a substitute for cystoscopy. Furthermore, when
all studies were combined, urine cytology had
a specificity of 94%, which was higher than the
specificity of any of the biomarker tests evaluated.
Twenty-two of the 42 studies included in the metaanalysis used a case-control design, which can be
associated with bias [Glas et al, 2003]. In a more
recent, cross-sectional study involving 668 patients,
Grossman et al (2006) found that the sensitivity of the
NMP22 test as a point-of-care test for the detection
of recurrent bladder cancer was 49.5%, versus only
12.2% for urine cytology. While these results cannot
justify the use of NMP22 in lieu of cystoscopy, the
addition of the NMP22 assay did improve sensitivity
compared with cystoscopy alone (99% vs. 91%),
whereas the addition of voided urine cytology did not
significantly increase the sensitivity compared with
cystoscopy alone (94% vs. 91%) [Grossman et al,
2006].
Combinations of urinary biomarkers have also been

explored. In a study by Horstmann et al (2009), 221
patients undergoing cystoscopic surveillance for
non-muscle-invasive bladder cancer were evaluated
with urine cytology, NMP22 testing, FISH, and
ImmunoCyt. Sensitivity was increased to over 90%
and negative predictive value was increased to
over 80% with combinations of 2 or 3 biomarkers,
although specificity was reduced to an average of
44% with 2 biomarkers and 35% with 3 biomarkers
[Horstmann 2009].
Results for urinary biomarker tests vary widely. For

instance, for NMP22, the sensitivity has been found
in cohort studies to be as low as 44% [Chahal et al,
2001] and as high as 91% [Miyanaga et al, 1999]. The
specificity of NMP22 in the Chahal et al and Miyanaga
et al studies was 91% and 76%, respectively, and
in another series, the specificity was only 40%
[Tritschler et al, 2007]. Significant variability has also
been noted for other urinary biomarkers, including
BTA (sensitivity of 28% [Johnston et al, 1997] versus
80% [Leyh et al, 1997]]; telomerase (specificity of
24% [Cassel et al, 2001] versus 100% [Kinoshita et
al, 1997]]; and cytokeratin 8/18 (UBC) (sensitivity of
12.1% [Babjuk et al, 2008] versus 70.5% [Hakenberg
et al, 2004]].
Currently, there is no consensus regarding the use of

urinary biomarkers for the diagnosis of bladder cancer.
While results of many carefully conducted clinical
studies have been reported, randomized clinical
trials are needed to determine the appropriate use
of urinary biomarkers in diagnosis and surveillance
of bladder cancer.
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Oehlschlaeger S, Rathert P, Meye A, Wirth MP. Qualitative
and quantitative assessment of urinary cytokeratin 8 and
18 fragments compared with voided urine cytology in
diagnosis of bladder carcinoma. Urology 2004; 64: 1121-6.
Level of Evidence 2
19. Horstmann M, Patschan O, Hennenlotter J, Senger E, Feil
G, Stenzl A. Combinations of urine-based tumour markers
in bladder cancer surveillance. Scand J Urol Nephrol 2009;
43: 461-6. Level of Evidence 2
29. Planz B, Jochims E, Deix T, Caspers HP, Jakse G,

Boecking A. The role of urinary cytology for detection of
bladder cancer. Eur J Surg Oncol 2005; 31: 3048. Level of
Evidence 2
30. Rodgers MA, Hempel S, Aho T, Kelly JD, Kleijnen J,
Westwood M. Diagnostic tests used in the investigation
of adult haematuria: a systematic review. BJU Int 2006;
98:1154-60. Level of Evidence 2
31. Tritschler S, Scharf S, Karl A, Tilki D, Knuechel R, Hartmann
A, Stief CG, Zaak D. Validation of the diagnostic value of
NMP22 BladderChek test as a marker for bladder cancer
by photodynamic diagnosis. Eur Urol 2007; 51: 403-7.
Level of Evidence 2
32. Tritschler S, Sommer ML, Straub J, Hocaoglu Y, Tilki
D, Strittmatter F, Zaak D, et al. Urinary cytology in era
of fluorescence endoscopy: redefining the role of an
established method with a new reference standard. Urology
2010; 76: 677-80. Level of Evidence 3
33. Yang MG, Zhao XK, Xiao N. Meta analysis of fluorescence
in situ hybridization and cytology for the diagnosis of
bladder cancer. Chin J Cancer 2009; 28: 655-62. Level of
Evidence 2
34. Youssef RF, Schlomer BJ, Ho R, Sagalowsky AI, Ashfaq R,
Lotan Y. Role of fluorescence in situ hybridization in bladder
cancer surveillance of patients with negative cytology. Urol
Oncol 2010 May 5. Urol Oncol 2010 May 5 Epub ahead of
print Level of Evidence 2
28
The large bore of rigid cystoscopes typically allows

for excellent irrigation flow and visualization, even
when there is mildly to moderately bloody urine or
debris, and provides a port that can accommodate
a variety of instruments. However, because of their
large size and rigid nature, rigid cystoscopes typically
cannot be used effectively in the office; most often,
particularly in men, rigid cystoscopes are used in
an operating room with the patient under general or
some form of regional anesthesia. In addition, for a
rigid cystoscope to be used effectively, the patient
must be placed in a dorsal lithotomy position, and in
the occasional patient this may pose difficulties.
B. Endoscopic Examination of
the Lower Urinary Tract
Sam S. Chang, Peter E. Clark, Judson D. Davies,
Murugesan Manoharan, Tim S. OBrien, Amit Patel,
Jinhai Fan
One of the cornerstones of the diagnosis and
management of urothelial carcinoma is cystoscopic
examination of the lower urinary tract. In this
section, we will provide an overview of white light
cystoscopy (WLC); the techniques of lower urinary
tract endoscopy; and newer optical technologies
that can enhance endoscopy, including fluorescence
cystoscopy, narrow band imaging (NBI), Raman
spectroscopy (RS), and optical coherence
tomography (OCT). The evidence presented in
this section is level 3 unless stated otherwise, and
all recommendations presented in this section are
grade C unless stated otherwise.
2. Flexible Cystoscopy
Rigid cystoscopy was the standard of care in urology
for many years, but starting in the early 1970s, the
advent of better fiberoptic technologies permitted
the development of flexible instruments that could
be used more easily than rigid cystoscopes in the
office. The first published report of use of a flexible
fibercystoscope for examination of the bladder
neck was by Tsuchida and Sugawara in 1973.[1] This
report was followed over a decade later, in 1984,
by the development of the first commercial flexible
instrument built specifically for cystoscopy. Since
that time, the use of flexible fiberoptic cystoscopy
has grown rapidly, and flexible cystoscopy is now a
standard method for diagnosis and surveillance of
a variety of lower urinary tract disorders, including
urothelial carcinoma. The fact that flexible cystoscopy
can generally be performed without anesthesia has
led to widespread acceptance of this procedure; it
is now the most common office-based procedure
performed by urologists in developed countries such
as the United States. Over time, manufacturers have
developed improved optics that permit smaller-caliber
scopes while maintaining high image quality, and the
development of a working channel allowed for the
use of flexible instruments. This, coupled with the
advent of active deflection, has permitted a range of
office-based procedures that can potentially be done
without the need for general anesthesia. In addition
to decreased discomfort, the other advantage of
flexible cystoscopy is the use of active deflection to
improve visualization of the anterior bladder neck.
I. White Light Cystoscopy

White light endoscopic examination of both the
urethra and the bladder (white light cystoscopy;
WLC) remains the gold standard for screening and
diagnosis for multiple diseases of the lower urinary
tract, including urothelial carcinoma. Cystoscopy not
only permits visualization of the bladder urothelium
but also affords access to the ureteral orifices to
facilitate assessment and treatment of the upper
urinary tract.
Cystoscopy can be performed utilizing either rigid
or flexible endoscopes, depending on the clinical
circumstances.The standard caliber measurement
for all endoscopes is based on the French (Fr) scale,
in which 1 Fr equals 1/3 mm (for example, a 12-Fr
endoscope has a diameter of 4 mm). Endoscopes
from 8-12 Fr are typically used for pediatric patients,
and endoscopes from 16-28 Fr are typically used for
adult patients.
1. Rigid Cystoscopy
For screening and diagnostic work, most often
sheaths of 20-22 Fr are used for adult patients,
and smaller sizes are used for pediatric patients.
For suspected urethral neoplasms, a 0-degree lens
is useful. For examination of the prostatic urethra,
the bladder trigone, and the bladder wall except
the part immediately adjacent to the bladder neck,
a 30-degree lens is generally used. For more
acute or difficult angles, particularly at the anterior
bladder neck, a 70-degree or 90-degree lens may be
employed, although in such cases, use of adjunctive
implements, such as catheters or biopsy forceps, is
typically not possible without specialized deflecting
bridge adaptors.
Despite their advantages and widespread use,

flexible cystoscopes have some disadvantages
compared to rigid endoscopes, such as the small
irrigation port and lack of a separate working sheath,
which limits the ability to irrigate and use instruments
simultaneously. Typically only the smallest of tumors
can be ablated or biopsied using only flexible
endoscopy. Finally, flexible endoscopes are typically
more costly and more prone to damage than rigid
endoscopes if not handled properly, including during
cleaning and sterilization between cases.
The flexible fiberoptic cystoscopes commonly in
29
use today also have some optical disadvantages

compared to rigid endoscopes. These disadvantages
are due to the inherent imaging limitations of fiberoptic
technology. The diameter of the glass fibers carrying
the image is finite; this results in a pixelated or
screen door image appearance.[2] The shaft of a
flexible cystoscope typically has 3 fiberoptic bundles.
Two carry the light from the generating source, and
the third carries the image back to the eye piece.
As a consequence, the image obtained is actually
a composite matrix of each of the individual fibers
in the bundle. This creates an image that is in fact
the merging of the individual dots in the matrix into
1 image, analogous to what is seen in newspaper
images. This is an inherent limitation of fiberoptic
technology, but digital endoscopy, as discussed
below, overcomes these limitations.
First introduced commercially in 2005, digital

endoscopes have been studied to a limited degree
in the clinical setting. Quayle et al[6] found that
digital-sensor-based flexible scopes had better
optics than fiberoptic cystoscopes. Okhunov et al
conducted a prospective clinical trial comparing
digital cystoscopes to fiberoptic cystoscopes for
office-based flexible cystoscopy in over 1,000
patients.[7] These authors reported that operating
surgeons found the digital cystoscopes to be lighter
and easier to maneuver. There was better deflection
with instruments placed in the working channels
of digital endoscopes without apparent loss of
instrument functionality. Both types of endoscope
were found to be relatively durable; both had a 0.2%
repair rate over the course of the study. It should be
emphasized that digital endoscopes are often more
expensive, so whether they will ultimately prove to be
cost-effective remains to be seen. The development
of digital endoscopes has, however, permitted the
development of other promising technologies to be
discussed later in this chapter, such as NBI.
3. Advances in White Light

Cystoscopy (WLC)
Video cameras as an adjunct to endoscopy were
first introduced by French researchers in 1956,[2]
and this concept has led to improved ergonomics,
improved safety through avoidance of contact with
body fluids, enhanced patient and resident education,
and improved documentation of findings and sharing
of information among physicians through the use
of digital cameras and recording devices.[3] One
study showed that male patients who were able to
monitor their cystoscopy by watching the procedure
on a video monitor experienced up to 40% less
pain and discomfort during endoscopy compared
to patients who did not watch their procedure on a
video monitor.[4]
4. Conclusion
WLC, whether performed in the office utilizing flexible
instruments or performed in the operating room
using rigid instruments, is the standard approach
to diagnosis and management of lower urinary tract
disease, including urothelial carcinoma, and is the
gold standard against which other approaches must
be compared.
II. FLUORESCENCE CYSTOSCOPY
Perhaps the biggest recent advance in WLC has

been the development of digital endoscopy. With
this method, light from the generating source still
travels through the traditional fiberoptic imaging
bundle. However, the image is no longer carried
back along fiberoptic bundles to the eye piece.
Instead, there is a digital sensor at the very tip of the
endoscope that is based on a charge-coupled device
and complementary metal oxide semiconductor
chips. The image is acquired through the digital
sensor through millions of photodiodes that convert
the photons of light into an electric current that
is subsequently transformed into voltage, then
amplified and converted to a digital format.[2] The
semiconductor chips transfer the information to a
receiver that presents the image on a monitor and/
or stores it digitally.
1. P
hotodynamic Diagnosis of
Bladder Tumors
Non-muscle-invasive bladder cancer is associated
with a significant risk of recurrence; thus, lifelong
patient surveillance is required. Recurrence of nonmuscle-invasive bladder cancer has been postulated
to result either from failure to identify abnormal
mucosal areas or from incomplete resection under
conventional WLC. After WLC and resection,
reported rates of residual or recurrent disease
at follow-up WLC can be as high as 55%.[9-11]
Fluorescence cystoscopy (photodynamic diagnosis;
PDD) can improve the visualization of bladder tumors
compared to standard WLC. Improved visualization
has led in turn to reduced rates of residual tumor at
first-check cystoscopy and in some series to reduced
rates of recurrence.[9-11]
Digital endoscopy offers the promise of improved

optical resolution, contrast, and color differentiation
and may be more durable than traditional flexible
endoscopy. Ex vivo studies have suggested that
distal endoscopes are superior to more traditional
fiberoptic cystoscopes in terms of resolution, contrast
discrimination, and red color differentiation.[5]
However, many of the studies to date on PDD have

shortcomings, including inclusion in the studies of
both patients with newly presenting and patients
with recurrent tumors; failure to use the best current
30
standard of carefor example, transurethral resection

plus immediate single instillation of intravesical
mitomycin Cin the control arm of studies; use of
surrogate endpoints such as histology rather than
the more clinically relevant endpoint of recurrence;
and, in older studies, use of the photosensitizer
5-aminolevulinate (5-ALA) rather than the currently
licensed product hexylaminolevulinate (Hexvix,
Cysview; see the next section).
At the molecular level, a photon of light interacts with

the electron shell of a single PPIX molecule, causing
excitation. Fluorescence is emitted as the electron
returns to its ground state. When tissues with high
levels of PPIX are illuminated by a blue light, they
fluoresce red (Figure 1).
b) Practical Considerations
Fluorescence cystoscopy uses a normal rigid
cystoscope combined with an excitation light source
called a D-light. The D-light consists of a shortarc xenon lamp and an integrated observation
filter to filter out all but the fluorescence emission
wavelength that is of interest and enough excitation
blue light back-scattered to suppress nonspecific red
fluorescence. Urine fluoresces yellow-green under
fluorescence (blue light) cystoscopy; therefore,
the bladder should be emptied before blue light
illumination.
a) Principle of PDD
PDD relies on an endogenous or exogenous
photosensitizer that causes abnormal cells to
fluoresce under a specific wavelength of light.
Currently, the most frequently used exogenous
photosensitizers are derived from the heme
biosynthetic pathway. Nonactive molecules are
converted in a series of enzymatic reactions to
the active fluorescent molecule protoporphyrin
IX (PPIX), which under normal conditions is then
rapidly converted to heme. This metabolic reaction
takes place in all nucleated cells.
Lowering of the intensity of the bright blue light to

the tone of fluorescence results in images 10 times
darker than those produced by WLC. As a result of
the darker image, the video photography is done
at 15 rather than 50 frames per second, and the
cystoscope needs to be moved slowly to reduce
strobe effect. It is recommended that the bulk of
tumor resection be carried out under WLC with blue
light reserved for checking the resection margins.
The starting point of the heme biosynthetic pathway

is 5-ALA. Administration of exogenous 5-ALA causes
rapid rises in the levels of PPIX. Fluorescence
microscopy following administration of 5-ALA has
shown tumor selectivity of PPIX accumulation,
which is at least 5 times as great in tumors as in
normal urothelium.[1] Significant differences in heme
metabolism have been demonstrated between
tumor and normal cells, and these differences
promote the selective accumulation of PPIX.[1]
Higher concentrations of intracellular 5-ALA are
from the reduced diffusion barrier to the absorption
of exogenous 5-ALA. This is in part due to fewer
intercellular tight junctions and recruitment of
transmembrane channel proteins, which provide
active transport of 5-ALA into the cytoplasm.[2]
The intensity of PPIX fluorescence diminishes with

time, a process referred to as photobleaching.
Illumination causes the degradation of the tetrapyrole
ring of PPIX and return of the delocalized electrons
to ground state and a reduction in fluorescence. This
effect is greatest at the blue-light wavelength but
also occurs under white-light conditions, although
at a less rapid rate. Reducing the viewing distance
between the cystoscope and the urothelium also
increases the rate of photobleaching. Fluorescence
is greatly reduced when the viewing distance is
halved.[3]
Fluorescence of PPIX is achieved by the presence

of pyrole rings, which have photo-optical properties
and fluoresce when excited by light of certain
wavelengths. PPIX absorbs light at around 400 nm
(violet blue) and emits fluorescence at 635 nm (red).
Artifact fluorescence is defined as an increase

in fluorescence intensity not due to tumor. False
Figure 1. Cystoscopy of papillary bladder tumours under white (left) and blue (right) cystoscopy
31
fluorescence is usually a less-bright pink color and

less discrete than the fluorescence in tumor cells
and occurs at sites of thickened urothelium. Folds
of the urothelium will cause such artifact, and
therefore the bladder should be sufficiently full to
minimize folds. Other common sites where artifact
fluorescence is seen are along blood vessels, on the
trigone, and around the ureteric orifices. Squamous
metaplasia at the bladder neck and the trigone
produces nonspecific fluorescence, which is used
as a control to confirm the adequate absorption
of the fluorophore when there is no fluorescence
elsewhere in the bladder. The viewing angle
between the cystoscope and the bladder can also
give rise to false fluorescence due to increasing the
thickness of the urothelium with tangential viewing
angles. This problem can be overcome by using
a range of cystoscopes to distinguish pathological
from tangential fluorescence.
underwent WLC resection and 11% of those who

underwent PDD resection [20]. If validated, these
results would indicate improved visualization of the
tumor with PDD and thus more complete resection.
Improved detection and resection of bladder tumors
with PDD has been reported to improve recurrencefree survival compared to WLC. Stenzl et al
performed a multicenter randomized controlled trial
and over a 9-month follow-up period found that the
tumor recurrence rate was lower in the PDD group
(47%; 128 of 271) than in the white light group (56%;
157 of 280) (p=0.026); the relative reduction in the
recurrence rate was 16% [21]. Trials with a longer
follow-up duration but using 5-ALA have shown that
the reduction in recurrence extends up to 8 years of
follow-up.
3. E
xamination of Patients with
Positive Findings on Voided Urine
Cytology but Negative Findings on
WLC (Grade C)
Recommendations for Use of PDD

PDD is currently recommended for treatment
of patients with newly presenting non-muscleinvasive bladder tumors; examination of patients
with positive findings on voided urine cytology but
negative findings on WLC; treatment of multifocal
recurrent bladder tumors; and teaching of urological
surgeons in training. Each of these situations is
discussed below.
PDD has been shown to detect new bladder tumors

in approximately 30% of patients with positive
findings on urine cytology and negative findings
on urinary tract investigations [23]. This rate can
rise to approximately 66% in patients previously
treated for bladder cancer. Patients with negative
findings on PDD and normalized cytology usually
have a clear urinary tract for at least 2 years[14]. If
findings on cytology remain positive, an abnormality
is likely to be detected within 1 year. Improved
detection of bladder lesions can reduce the need
for bilateral ureterorenoscopy and stents and their
associated morbidity. Tritschler et al evaluated the
use of fluorescence endoscopy and found that the
sensitivity and specificity of bladder wash cytology
was greater with fluorescence cystoscopy than with
white light endoscopy. However, 3.4% of tumors
were diagnosed by bladder wash cytology only, and
most of these were high-grade tumors [Tritschler et
al, 2010].
2. Evaluation and Treatment of

Patients with Newly Presenting
Non-muscle-invasive Bladder
Tumors (Grade C)
The advantage of WLC plus PDD over WLC alone
in the visualization and staging of bladder tumors is
widely recognized.[12-17] The tumor detection rate is
73-96% with WLC alone, compared to 90-96% with
WLC plus PDD.[12-17] PDD is particularly helpful
in the detection of carcinoma in situ (CIS); rates of
detection are 23-68% with WLC alone, compared to
91-97% with WLC plus PDD. While PDD improves
sensitivity in the diagnosis of non-muscle-invasive
bladder tumors, there remain issues surrounding its
specificity. Early studies suggested a slightly higher
false-positive rate of 3-8%[13-15] due to nonspecific
inflammation that can occur after treatment of
a urinary tract infection, after TURBT, or after
intravesical therapy with bacillus Calmette-Gurin
(BCG). It is therefore recommended that PDD be
delayed for 9-12 weeks after any activity that could
result in bladder inflammation [18]. Intravesical
mitomycin C is not associated with a higher falsepositive rate [19].
4. T
reatment of Multifocal
Recurrent Bladder Tumors
(Grade C)
Patients with multifocal bladder tumors are at high
risk for the development of recurrence. Holmang
et al reported that 88% of patients with 3 or more
tumors experienced recurrence within 5 years after
diagnosis [24]. Ray et al showed that PDD detected
additional disease in 8 (57%) of 14 patients with
already confirmed recurrence [18]. Four patients in
whom additional disease was detected were found
to have CIS, and thus had treatment with BCG
initiated. Only the results from a phase II trial as
to whether PDD in patients with multifocal disease
affects recurrence rates on follow-up, the results of
phase III trials are awaited.
PDD may also be able to improve the quality of

resection compared to WLC. Geavlete et al reported
at repeat TURBT 6 weeks after initial resection that
residual tumor was found in 31% of patients who
32
5. Teaching Urological Surgeons in

Training (Grade D)
follow-up of non-muscle-invasive bladder cancer.

However, these techniques have a low sensitivity
and other limitations. First, CIS may easily be
missed by standard WLC. Second, no information
on histopathologic information is provided during
WLC, which often makes discrimination between
inflammatory lesions and CIS difficult because both
can appear as mucosal red spots. Finally, estimates
of grade or stage of bladder cancer made during
cystoscopy are often not accurate even when
they are made by an experienced urologist [26].
New optical imaging modalities for bladder cancer
diagnosis have been developed to overcome the
limitations of cystoscopy and cytology. These new
techniques include PDD, NBI, RS, and OCT. We
herein present our review of these new techniques
for detecting bladder cancer (except for PDD, which
was discussed earlier in the chapter) and speculate
regarding their potential future applications.
PDD offers endoscopists better visualization of tumors

and their resection margins, thereby facilitating
improved transurethral resection of bladder tumor
(TURBT) technique. Thus, PDD is a useful tool for
teaching urological surgeons in training.
6. Additional Considerations
Whether early repeat cystoscopy is required after
initial tumor resection with PDD is not yet known.
PDD cystoscopy could potentially help rationalize
the use of early resection, optimize case selection,
improve outpatient management modalities, and
permit more precise tumor resection. PDD is not
currently recommended in patients for whom
cystectomy is indicated or in the outpatient setting
with flexible cystoscopes. Although PDD flexible
cystoscopy has been shown to be feasible and as
effective as PDD rigid cystoscopy [25], the need for
a second cystoscopy under a general anesthetic for
biopsy has not made this approach cost-effective.
1. Narrow Band Imaging

a) Principle of NBI
For NBI, modified optical filters are used in the
light source of a video endoscope system to
narrow the bandwidth of spectral transmittance.
NBI enhances the differences in penetration depth
between wavelengths. Light penetration depth within
tissue is highly dependent on wavelength: shorter
wavelengths produce only superficial penetration
and longer wavelengths produce deeper penetration.
Blue light, therefore, penetrates supercially, while
red light penetrates deeply [27]. NBI narrows the
bandwidth of light output from the endoscope
system to between 415 nm and 540 nm. The relative
intensities of blue and green light are increased,
while the intensity of red light is decreased to a
minimum. This narrow bandwidth of green and blue
light is strongly absorbed by hemoglobin, so NBI
enhances visibility of surface capillaries and blood
vessels in the submucosa without the use of dyes
(Figure 2). Systems that have integrated NBI and
WLC are already commercially available. With the
Conclusions
Non-muscle-invasive bladder cancer is associated
with a significant risk of recurrence; thus, lifelong
patient surveillance is required. PDD can improve
detection of disease, especially CIS; improve
completeness of resection; and, most importantly,
reduce rates of recurrence of non-muscle-invasive
bladder cancer. Improved initial resection, such as
with PDD, has been suggested to improve recurrence
rates after intravesical chemotherapy, but this needs
to be further evaluated in clinical trials.
III. New OPTICAL IMAGING

Techniques for Bladder
Cancer DIAGNOSIS
Cystoscopy and cytology are considered to
be the current gold standard for detection and
Figure 2. Representation of the narrowed bandwidth of light (a), its penetration of tissue (b)
33
push of a button, the NBI mode is activated by

mechanical insertion of a narrow-band filter in front
of the white light source.
Possible limitations of the currently published studies

are their monocentric nature and the possible
observer bias since WLC and NBI were performed
sequentially and observed by the same urologist. Ye
et al conducted a study designed to compare the rate
of detection of non-muscle-invasive bladder cancer by
NBI cystoscopy versus WLC in a multicenter setting
with a randomized sequence of the 2 procedures.
One hundred three consecutive patients from 4
academic centers in China were included in this
prospective, multicenter, phase III trial presented in
abstract form in 2010 [34]. Eighty-seven patients had
confirmed bladder tumors. In 29 of these 87 patients,
tumors were detected by NBI cystoscopy only, and in
4 patients, tumors were identified by WLC only. The
mean number of detected tumors per patient was
1.45 with WLC and 1.85 with NBI cystoscopy.
b) NBI Cystoscopy for Detection of Nonmuscle-invasive Bladder Cancer

NBI cystoscopy is easy for surgeons to adopt and
has a high sensitivity for detecting small papillary and
otherwise undetectable cancers, especially CIS.
NBI was initially shown to be useful in gastrointestinal
disease, particularly for detection of adenomas
at colonoscopy and for follow-up of Barretts
esophagus [30]. The first report of NBI in bladder
cancer was published by Bryan et al in 2008 [31].
These authors performed WLC and subsequent NBI
flexible cystoscopy to detect bladder cancer in 29
patients with recurrent non-muscle-invasive bladder
cancer [31]. NBI flexible cystoscopy provided
much better visualization of bladder cancer than
did conventional flexible WLC. NBI cystoscopy
revealed 15 additional tumors (in 12 patients) not
detected by WLC. However, these additional tumors
were not confirmed histopathologically because all
tumors were treated by diathermy ablation following
cystoscopic examination. With NBI cystoscopy, the
vasculature appears dark green or black against the
almost white normal urothelium, whereas with WLC,
tumors appear red in a background of normal pink
urothelium (Figure 3).
c) NBI Cystoscopy for Detection of Residual

Cancer after Treatment
Two trials to detect residual cancer by NBI cystoscopy
were conducted in patients with high-risk nonmuscle-invasive bladder cancer. In a series of 47
patients, all patients were examined with WLC and
NBI cystoscopy and underwent a second TURBT
procedure approximately 1 month after an initial
TURBT. Overall, 16 of 47 patients were discovered to
have residual or recurrent cancer, including 6 patients
with high-grade cancers detected only by NBI [35]. In
another series, 61 patients were evaluated with both
WLC and NBI cystoscopy 3 months after beginning
induction therapy with BCG. NBI correctly identied
21 of 22 cases of residual cancer [36].
Sensitivity and specicity rates for NBI cystoscopy and

WLC in patients with non-muscle-invasive bladder
cancer and CIS are presented in Table 1. Herr et al
described a series of 427 patients who underwent
follow-up with WLC and NBI cystoscopy, 103 of
whom had tumor recurrence [32]. Ninety patients
(sensitivity 87%) had their disease diagnosed by
WLC, and the other 13 (sensitivity 100%) had their
disease detected only by NBI cystoscopy, including
8 patients with CIS, 4 patients with Ta disease, and 1
patient with T1 disease. NBI cystoscopy performed
better than WLC in demarcating margins of CIS
lesions from surrounding normal-appearing mucosa.
In another series, Tatsugami et al performed WLC
and then NBI cystoscopy in 104 consecutive patients
[27]. In 39 (26.9%) of 161 sites suspicious for tumor,
bladder tumors were identied only by NBI. These
tumors were CIS in 25 patients, Ta tumors in 12
patients, and T1 tumors in 2 patients. In this entire
series, 14 of 30 patients with CIS had their disease
detected only by NBI. However, the aforementioned
studies might be flawed owing to observer bias since
WLC and NBI cystoscopy were performed by the
same urologist. To avoid observer bias, Cauberg et al
conducted a trial in which WLC and NBI cystoscopy
were performed by different surgeons in 95 patients
[33]. Seventy-eight patients had histopathologically
conrmed non-muscle-invasive bladder cancer. NBI
identied additional tumors in 28 of those 78 patients.
In contrast, WLC identied additional tumors in only
3 of those 78 patients.
d) NBI Cystoscopy as a Follow-Up Tool

Another trial compared the usefulness of WLC and
NBI cystoscopy as follow-up tools. Patients were
followed up with WLC for 3 years and with NBI
cystoscopy for the next 3 years. The trial revealed
fewer tumor recurrences, smaller numbers of
recurrent tumors, and a longer recurrence-free
survival time with NBI cystoscopy. Small solitary
papillary tumors and clusters of papillary tumors
were more efficiently treated with NBI cystoscopy
than with WLC [37]. However, only patients with
frequently recurrent tumors were included in this
study. Hence, the authors were unable to discriminate
the natural history of disease from an influence of
NBI cystoscopy on outcomes. With longer follow-up
periods, tumors generally recur less frequently [38].
More investigation appears to be indicated to confirm
this trials conclusions.
e) WLC versus NBI Cystoscopy for TURBT

NBI technology is available for rigid cystoscopy and
bladder tumor resection. One feasibility report of
TURBT performed with NBI cystoscopy indicated
shorter operative times, shorter time to catheter
34
Figure 3. Examples of the differences between tumors visualized with WLC (left) and NBI cystoscopy (right).
(Photos were cited from Case study of NBI (Specific Wavelength Light) Vol.1 which was published by Olympus
medical systems Corporation.)
35
Table 1. Comparison of sensitivity and specicity between NBI and WLC for NMIBC
Reference
Number of patients
Tatsugami et al
Herr et al
27
32
Cauberg et al
33
Ye ZQ et al34
NBI
Sensitivity
WLC
Specicity
Sensitivity
Specicity
104
92.7
70.9
57.3
86.2
427
100.0
82.0
87.0
85.0
95
94.7
68.4
79.2
75.5
103
96.4
60.9
75.4
58.6
removal, and shorter time to hospital discharge

with NBI cystoscopy than with WLC, although the
differences were not statistically significant [39]. The
authors speculated that use of NBI cystoscopy for
TURBT would substantially reduce the recurrence
rate of bladder tumors. However, the observer in
this trial was allowed to take a second look with
the alternative form of imaging, which may have
introduced a bias.
associated with inflammatory mucosal appearances

mimicking urothelial tumors (see Figure 3). In view of
its low specificity (60-85%), use of NBI in combination
with other modalities such as urine cytology, RS, or
OCT that allow histopathologic diagnosis may well
be advised.
f) Learning Curve for NBI Cystoscopy
Raman
spectroscopy
measures
molecular
components of tissue both qualitatively and
quantitatively. Photons interact with laser light
to contribute to or derive energy from a tissues
intramolecular bonds. The result is a change in the
bonds vibrational state and emission of a different
wavelength of scattered light [43]. Each molecule has
unique vibrational energy levels and corresponding
wavelength shifts. When a tissue is exposed to laser
light, altered wavelengths from different molecules
combine to form the Raman spectrum, which
depends on the molecular composition of the tissue
being investigated. Using RS, a pseudocolor map of
examined tissue is created. Tissue areas with similar
molecular composition, and therefore with similar
spectra, are depicted in the same color. Such images
are comparable to histopathology and images of
stained tissues. Molecular composition changes
if pathologic transformations occur. Thus, RS can
provide an objective prediction of the pathologic
diagnosis [26].
2. Raman Spectroscopy
a) Principle of RS
Herr et al demonstrated that both experienced and

relatively inexperienced urologists quickly learned
NBI cystoscopy as a supplement to WLC [40]. That
is, use of NBI cystoscopy to detect and characterize
bladder tumors is not associated with a steep learning
curve. Bryan et al confirmed these findings [41].
g) NBI Cystoscopy Controversies

By permitting better visualization of the margins
of non-muscle-invasive papillary and at bladder
lesions, NBI cystoscopy facilitates more thorough
excision of tumor. Fluorescence cystoscopy (PDD)
using 5-ALA or its hexyl ester has been recognized
to improve the detection of non-muscle-invasive
papillary and at bladder lesions compared to WLC
and to reduce the recurrence rate of non-muscleinvasive bladder cancer [17]. However, whether the
better visualization and high sensitivity associated
with NBI cystoscopy compared to WLC likewise
translate into lower tumor recurrence rates cannot
be confirmed. Prospective randomized trials with
long-term follow-up are ongoing to compare the
efficacy of TURBT performed with WLC and with NBI
cystoscopy [39]. Results of these trials are eagerly
awaited.
b) RS for Detection of Non-muscle-invasive

Bladder Cancer
Several trials were performed to compare the
diagnostic accuracy of RS and histology in ex vivo
bladder samples. A study of 15 tumor and nontumor
bladder tissue samples demonstrated that RS had
a sensitivity of 92% and a specificity of 94% in the
diagnosis of bladder cancer [44]. In another series,
of 75 bladder tissue samples, Crow et al showed
that RS could differentiate normal, inflammatory, and
malignant tissue with a sensitivity of 90-95% and a
specificity of 95-98% [46]. Discrimination between
grade 1 or 2 and grade 3 malignant samples was
achieved with sensitivity and specificity of greater
than 93%. The ability to discriminate between CIS,
Because NBI cystoscopy detects ulcers of bladder

mucosa and areas of angiogenesis more readily
than does WLC, the value of NBI cystoscopy in
the diagnosis of interstitial cystitis/painful bladder
syndrome is apparent [42]. One notable deficiency
of NBI cystoscopy for bladder cancer detection is
its low specificity (high false-positive rate), which
leads to unnecessary resection of noncancerous
tissue. Intravesical agents (immunotherapy or
chemotherapy), cystitis, and hematuria may be
36
inflammation, and the changes associated with

intravesical therapy, all of which can appear as red
spots in the bladder mucosa, is an important finding.
Draga et al were the first to perform RS in vivo [47].The
microber optic probes were utilized endoscopically
through a working channel. These authors found
that RS distinguished normal bladder from cancer
with a sensitivity of 85% and a specificity of 79%.
Combining the new diagnostic modalities of RS
and 5-ALA, Grimbergen et al showed that applying
5-ALA affected the Raman spectra of bladder tissues
[48]. Whether combining fluorescence with RS could
improve its diagnostic capability is unknown.
Shapiro et al used RS to detect tumor epithelial cells
in urine samples and in a broader sense to diagnose
cancer in isolated cell samples [49]. Baseline spectral
features were obtained from bladder cancer tissue
for high-grade (T2), low-grade (Ta), CIS, and normal
bladder tissue (Figure 4). The signal obtained from
epithelial cells in urine samples correctly diagnosed
bladder cancer with a sensitivity of 96% (100% of
the high-grade tumors) and a specificity of 90%
(Figure 5). Furthermore, the authors delineated the
thresholds for normal tissue, low-grade tumors, and
high-grade tumors, which makes the use of RS for
bladder cancer diagnosis feasible.
c) Future of RS for Detection of Bladder

Cancer
To date, only a few small-scale clinical trials have
conducted of RS for detection of non-musclebeen
invasive
bladder cancer. Small, flexible fiberoptic
probes compatible with the working channel of a rigid

or flexible cystoscope have been developed [45]. In
other fields of medicine, findings have been reported
for use of RS to check intraoperative margins during
partial mastectomy and for use of RS to characterize
atherosclerotic plaques during vascular surgery.
In bladder cancer, RS must be targeted at visually
suspicious lesions or lesions identified by other
methods, such as PDD or NBI cystoscopy. The
potential advantage of RS is its ability to provide a
noninvasive, real-time, and objective prediction of
the pathologic diagnosis [46].
Application of RS to urine samples presents an
exciting approach to the diagnosis of bladder cancer,
one with sensitivity and specificity similar to that of
cystoscopy. Maybe one day RS can be used instead
of urine cytology as the preliminary screening study
for bladder cancer. Further investigations are needed
to verify the performance of RS in urine samples
and also in other cellular systems to determine the
applicability of RS to other malignancies.
3. Optical Coherence Tomography

a) Principle of OCT
OCT produces high-resolution, cross-sectional
images of tissue. OCT is similar to B-mode
ultrasound imaging except that OCT measures
reflected infrared light rather than acoustic waves.
The intensity of back-reflected light from structures
within tissue is displayed as a function of depth [52].
Because of its high resolution (approximately 10
micrometers), superior dynamic range (approximate
Figure
4. Raman spectrum obtained from high-grade urothelial carcinoma (UC; dashed) tissue, low-grade
Figure4.Ramanspectrumobtainedfromhighgradeurothelialcarcinoma(UC;dashed)
UC tissue (dotted), and normal tissue (solid). The 1584-cm-1wave is higher in high-grade tumors but is also
present in low-grade tissue (The figure was cited from Shapiro A 49).
tissue,lowgradeUCtissue(dotted),andnormaltissue(solid).The1584cm1waveishigher
inhighgradetumorsbutisalsopresentinlowgradetissue(ThefigurewascitedfromShapir
37
A49).
Page 45: TEXT: The signal obtained from epithelial cells in urine samples correctly diagnosed bladder cancer
with a sensitivity of 96% (100% of the high-grade tumors) and a specificity of 90% (Figure 4).
Raman shift (-cm-1)

Figure 5. Raman spectra of cumulative single, exemplary cells from cases of high-grade (solid bold), lowgrade (dotted), and normal cells (solid) (The figure was cited from Shapiro A 49).
140 dB), and optimal depth of penetration (up to

2-3 mm), OCT is potentially useful for noninvasive
screening for superficial lesions in bladder mucosa
[53]. The 3 anatomic layers of the normal bladder
wall (the urothelium, lamina propria, and muscularis
propria) can be clearly distinguished from one
another with OCT. This is possible because of the
different scattering properties of each distinct layer
[52].
WLC; 97.5% and 78.6%, respectively, for PDD; and

97.5% and 97.9%, respectively for PDD combined
with OCT (Figure 6 and 7). Thus, combining PDD
with targeted OCT increased specicity substantially.
To enhance the accuracy of detection of CIS, Ren
et al used 3-dimensional OCT [60]. Sensitivity and
specificity were 56.5% and 61.5%, respectively,
with 2-dimensional OCT and 95.7% and 92.3%,
respectively, with 3-dimensional OCT.
b) OCT for Detection of Bladder Cancer
c) Limitations of OCT
OCT allows noninvasive acquisition of real-time,

high-resolution images of the bladder and provides
information about the depth of tumor growth. As of
this writing, results of 5 studies on the diagnostic
accuracy of OCT have been published [54-58]. Goh
et al and Sengottayan et al found similar results:
OCT in the diagnosis of muscle-invasive bladder
cancer had a sensitivity of 100% and a specificity
of 90%. However, these studies were flawed by the
inclusion of only a few muscle-invasive tumors.
Some authors point out that most false-positive

findings on OCT are caused by inflammatory lesions
of the bladder. Whether or not previous intravesical
instillations or radiotherapy, both of which can
cause inflammation, influence the accuracy of OCT
is unknown. In addition, OCT may have limited
reliability in the measurements of muscle-invasive
tumors because of insufficient imaging depth.
Furthermore, OCT is not ideal for screening the
entire bladder because, in the absence of visually
suspect lesions, OCT must be used in combination
with other diagnostic methods (e.g., NBI or PDD) to
identify the region of interest [26].
Schmidbauer et al performed WLC followed by

fluorescence cystoscopy (PDD) and OCT scanning
[59]. These investigators found sensitivity and
specicity rates of 69.3% and 83.7%, respectively, for
In contrast to ultrasonography, OCT can be
38
Figure 6. (a) Optical coherence tomography image of normal bladder wall: urothelium (U), lamina propria
(LP), and muscularis layer (MP); (b) OCT probe placed on the bladder wall, as seen during cystoscopy (The
figure was cited from Schmidbauer J [59]).
Figure 7. Pathologic findings on optical coherence tomography imaging: (a)dysplasia; (b) carcinoma in situ;
(c)papillary Ta lesion; (d)T1 lesion; (e)muscle-invasive urothelial cell carcinoma( The figure was cited from
Schmidbauer J [59]).
39
performed at other sites within the urinary tract

through optical fibers without the need for a distal
transducer or transducing medium [52]. The
interpretation of OCT scans requires some training
and is operator dependent. To address this problem,
Lingley-Papadopoulos et al presented an automated
algorithm that uses texture analysis to discriminate
bladder cancer in OCT images [61]. In differentiating
benign from malignant tissue, this algorithm had a
sensitivity of 92% and a specificity of 62%.
performed in vivo and have shown impressive

preliminary results. RS may be utilized to detect
tumor epithelial cells in urine samples, which may
represent a new approach for preliminarily screening
of patients who present with hematuria. However,
more research must be conducted to assess the
advantages of these new techniques.
Since RS and OCT have a limited field of view,
screening the entire bladder with either of these
techniques would be excessively time-consuming.
On the other hand, while NBI cystoscopy and PDD
allow the operator to quickly assess the entire
bladder wall, these techniques suffer from low
specificity. Therefore, a strategy in which RS or OCT
measurements are targeted at visually suspicious
lesions or lesions identified by PDD and/or NBI
cystoscopy may overcome the drawbacks of the
various modalities to increase both the sensitivity
and the specificity of bladder cancer detection.
Encouragingly, the first steps with this approach
have been taken, and promising preliminary data
indicate that RS and/or OCT combined with PDD
and/or NBI likely will lead to better characterization of
non-muscle-invasive bladder cancer. We speculate
that RS for detection of tumor epithelial cells in
urine samples might be the alternative to cytology
for preliminarily screening patients with hematuria
or a history of non-muscle-invasive bladder cancer.
NBI cystoscopy or PDD combined with either RS
or OCT could produce more sensitive and specific
detection, more complete endoscopic resection,
and lower recurrence rates for non-muscle-invasive
bladder cancer. However, whether the combinations
predict a better prognosis and fewer inspections by
cystoscopy is unknown. Also, we must consider the
efficacy of inspection against the cost. More research
has to be conducted before these techniques can
be implemented in the management of non-muscleinvasive bladder cancer.
4. Summary
Compared to WLC, NBI, the newest optical diagnostic
technique, permits an improved evaluation of nonmuscle-invasive bladder cancer, particularly at
the margins of non-muscle-invasive papillary and
at bladder lesions. Furthermore, NBI cystoscopy
significantly enhances tumor detection compared
with WLC. NBI cystoscopy plus WLC appears to
be superior to WLC alone, and NBI cystoscopy is
an easy-to-handle complement to WLC. However,
whether NBI cystoscopy alone is as good as WLC
alone has yet to be established in larger series.
No trials have confirmed the superiority of TURBT
performed with NBI cystoscopy to TURBT performed
with WLC after long-term follow-up. However,
ongoing trials might generate more robust data
concerning these applications of NBI. In future
studies comparing NBI cystoscopy and WLC, we
should avoid the observation bias introduced by
permitting a second look.
PDD has been applied extensively to enhance the
rate of detection of non-muscle-invasive bladder
cancer. However, PDD is costly and time-consuming:
5-ALA is expensive, and the time between instillation
of 5-ALA and fluorescence endoscopy is at least
1 hour. To date, PDD has been shown to have
sensitivity and specificity similar to that of NBI
in the detection of non-muscle-invasive bladder
cancer. It is difficult to compare these 2 modalities
because of different protocols, and no 3-arm study
is yet available. Nevertheless, 3-arm studies for
direct comparison of NBI cystoscopy versus PDD
versus WLC in terms of tumor detection rates, falsepositivity rates, recurrence rates, mortality rates,
and cost would be helpful. However, because of the
different principles underlying NBI cystoscopy and
PDD, the additional tumors identified by them may
not be the same ones.
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1. Imaging
Prior to TURBT, imaging studies are generally
recommended. Imaging studies should also be
performed in the investigation of hematuria, and hence
they may already have been done prior to TURBT. In
general, imaging is required to evaluate the upper
tracts. Ultrasonography is primarily used to evaluate
the renal parenchyma. Intravenous urography (IVU)
can be used to evaluate the urothelium, and lesions
may be apparent as filling defects on the pyelogram
for the upper tracts. Filling defects within the bladder
are also seen. Increasingly, CT is being performed
rather than intravenous pyelography.[1] CT is faster
and more informative than IVU but is associated with
significantly more radiation exposure (Level 4).
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CT urography permits evaluation of both the renal

parenchyma and the urothelium and hence is the
imaging modality of choice in patients scheduled
to undergo TURBT. Critical components of CT
urography include the use of multidetector CT, thin
slice imaging, administration of contrast medium,
and imaging in the excretory phase.[2] CT urography
also allows evaluation of other pathologic conditions
within the genitourinary system, especially
urinary calculi, which may be a benign cause of
hematuria. Multiplanar reformatted images and
3-dimensional volume rendering are also useful
adjuncts to CT urography, yielding 3-dimensional
images that clinicians are familiar with and allowing
accurate evaluation of the upper tracts.[3] Magnetic
resonance urography provides information similar to
that provided by CT urography; however, magnetic
resonance urography is less accurate for calculi and
takes significantly longer to perform.[4] (Level 2B)
54. Hermes, B., Spoler, F., Naami, A. et al.: Visualization of

the basement membrane zone of the bladder by optical
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55. Manyak, M. J., Gladkova, N. D., Makari, J. H. et al.:
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56. Goh, A. C., Tresser, N. J., Shen, S. S. et al.: Optical
coherence tomography as an adjunct to white light
cystoscopy for intravesical real-time imaging and staging of
bladder cancer. Urology, 72: 133, 2008
57. Karl, A., Stepp, H., Willmann, E. et al.: Optical coherence
tomography for bladder cancer -- ready as a surrogate for
optical biopsy? Results of a prospective mono-centre study.
Eur J Med Res, 15: 131, 2010
58. Sengottayan, V. K., Vasudeva, P., Dalela, D.: Intravesical
real-time imaging and staging of bladder cancer: Use
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59. Schmidbauer, J., Remzi, M., Klatte, T. et al.: Fluorescence
cystoscopy with high-resolution optical coherence
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60. Ren, H., Yuan, Z., Waltzer, W. et al.: Enhancing detection
of bladder carcinoma in situ by 3-dimensional optical
coherence tomography. J Urol, 184: 1499, 2010
In imaging of the bladder, ultrasonography and CT

urography have similar specificities in the diagnosis
of bladder cancer, namely, 94.7% and 96.5%,
respectively. However, CT urography has higher
sensitivity (89.7% versus 69%).[5] In addition, CT
urography demonstrates the size of lesions within
42
the bladder, extravesical spread, and pelvic lymph

node status whereas ultrasonography may not.[4]
Magnetic resonance urography is similarly effective.
[4] (level 2B)
hypotension during regional anesthesia. Diuretics

may cause hypokalemia, which can alter the effect
of muscle relaxants. (level 4)
Diabetic patients need to have their medications
reviewed and need to be given instructions regarding
the use of oral hypoglycemics and insulin while
fasting prior to TURBT.
2. Laboratory Investigations
Only basic laboratory investigations are required prior
to TURBT. Urine should be cultured, and infections
should be treated. In patients with infections, it is
unclear if a subsequent negative culture is required
before TURBT. A complete blood cell count and
measurement of electrolytes and creatinine are
also required as anemia or elevated creatinine
or potassium levels may have implications for
anesthesia. A coagulation profile should be obtained
if indicated. (Level 4)
Finally, patients need to be evaluated to ensure

that they are able to tolerate the surgical position.
Particular care is needed in placing patients with hip
and knee replacements in the lithotomy position.
Previous spinal surgery may make it difficult to use
spinal or epidural anesthesia.
II. Technique
3. Medical Clearance and Anesthesia

Review
1. Anesthesia
Bladder cancer is usually a disease of the elderly,

and hence preoperative medical clearance or
anesthesia review is beneficial and may lead to a
lower rate of cancellation at the time of surgery.[6]
Patients should be evaluated at a preanesthesia
clinic for any issues pertaining to the airway and
respiratory and circulatory systems, for medications,
and for anemia and diabetes. Referral for further
cardiac or respiratory evaluation can then be initiated
as needed.
For TURBT, the goal of anesthesia is to enable

safe resection of the bladder tumor with appropriate
analgesia and relaxation. General or regional
anesthesia or a combination of the two can be used.
Regional anesthesia in the form of spinal or epidural
blockade is effective. It also provides the advantage
of a conscious patient, which means that any
intraperitoneal bladder perforation can be identified
by abdominal or shoulder-tip pain.
General anesthesia with or without paralysis can
also be used. The obturator reflex can be a technical
challenge during TURBT, and full relaxation is
recommended when tumors on the lateral bladder
walls are resected. Alternatively, transvesical
obturator nerve block can be performed using
lidocaine. (Level 1B)
The major components of the clinical evaluation

are the history, physical examination, and
electrocardiography, the goal of which is to identify
any coronary artery disease, previous myocardial
infarction, angina pectoris, or other serious cardiac
disorders like heart failure or disorders requiring
pacemakers.[7] It should be determined whether
the patient has chronic obstructive or restrictive
pulmonary disease, diabetes mellitus, peripheral
vascular disease, or another major comorbid
condition and whether the patient has previously
undergone major vascular, thoracic, or abdominal
surgery. Renal dysfunction is common in elderly
patients, and creatinine level, potassium level,
and estimated glomerular filtration rate are useful
in calculating the dose of antibiotics as well as
anesthetic agents, particularly muscle relaxants.
(Level 4)
2. Antibiotic Prophylaxis
The goal of antibiotic prophylaxis is to prevent
infectious complications from TURBT. As stated
earlier, a preoperative urine culture should be
performed, and any infection should be treated
preoperatively. However, antibiotic prophylaxis is still
recommended at the time of surgery. Oral agents
with good bioavailability can be given several hours
prior to TURBT, but common practice is to administer
an intravenous antibiotic at the time of anesthesia to
ensure that peak plasma concentrations have been
achieved at the time of instrumentation. (Level 4)
A thorough medication history is critical. Antiplatelet

agents may be discontinued 7-10 days prior to
surgery. Warfarin should be discontinued and the
international normalized ratio (INR) should be
checked on the day of surgery. While the INR is
subtherapeutic, low-molecular-weight heparin may
be required. Spinal or epidural anesthesia should
not be performed if the INR is greater than 1.5.[8]
(level 4) Beta-blockers should not be discontinued
before TURBT; however, alpha blockers may need
to be documented as they may result in marked
There is a paucity of data on the role of antibiotics

in TURBT[11]; however, without prophylaxis, the
risk of subsequent urinary tract infection may be
as high as 39%.[12] Two randomized trials have
been performed comparing antibiotic prophylaxis to
placebo following TURBT. MacDermott et al found
a significantly reduced rate of bacteriuria in patients
who received antibiotics compared to patients who
did not receive antimicrobials.[13] Most of the data
43
on antibiotic use in genitourinary surgery is related

to transurethral resection of the prostate (TURP), in
which the benefits of antibiotic prophylaxis are clear.
Systematic reviews by Berry and Barratt and by
Qiang et al demonstrated that prophylactic antibiotics
reduced the incidence of bacteriuria and sepsis
following TURP. Hence, it is recommended that prior
to TURBT, urine should be sterilized if possible, and
prophylactic antibiotics should be administered.
There is no evidence to support prolonged use of
antibiotics after TURBT in the absence of specific
indications like persistent bacteriuria from calculi or
anatomic abnormalities.
The cystoscope is inserted, and the entire urethra is

examined. It is possible to obtain a urine sample by
barbotage immediately after the scope is inserted into
the bladder using gentle irrigation with normal saline
through a catheter, the cystoscope sheath, or the
resectoscope sheath. However, it is recommended
that urine be collected after complete inspection of
the bladder because during barbotage the bladder
wall can be drawn against the sheath, causing
urothelial trauma that may mimic the appearance of
CIS.
The bladder should be examined with both a 30degree and a 70-degree lens. Visualization of
the anterior bladder neck may be enhanced by
using a 120-degree scope or by using retroflexion
with a flexible cystoscope. The dome and anterior
bladder are examined by applying gentle suprapubic
pressure to move the bladder mucosa down and
closer to the lens. It is critical to maintain optimal
bladder distention during cystoscopy and TURBT.
Underdistention prevents complete examination of
the mucosal surface and can result in inadvertent
bladder perforation during TURBT. Overdistention,
on the other hand, can result in thinning of the
bladder mucosa, increasing the likelihood of bladder
perforation and inducing mucosal hemorrhage.
Cystoscopic findings recommended to be reported
are listed in Table 2.
3. Indications for Hospital Admission

Following TURBT, the majority of patients can be
discharged home with a Foley catheter, which can
be removed 1-2 days after the procedure. Indications
for admission to the hospital with continuous bladder
irrigation are very large resections, significant
hematuria, and bladder perforation.
4. Surgical Technique
TURBT in conjunction with cystoscopy and
examination under anesthesia serves both a
diagnostic and a therapeutic purpose. The diagnostic
purpose of TURBT is to obtain a specimen sufficient
to permit proper estimation of the natural history of
the tumor, which is currently based largely on stage,
grade, histological subtype, and the presence of
lymphovascular invasion. The therapeutic purpose
of TURBT is to remove all tumor and provide the best
milieu for intravesical therapy to be most effective.
The smallest resectoscope necessary should be

introduced in an atraumatic fashion. Continuous
irrigation is usually recommended to improve
visualization and prevention overdistention of the
bladder. Delicate movements of the sheath should
be used, along with delicate movement of the loop
itself to adjust the depth of resection.
The surgical technique of TURBT is largely based on

surgeon experience. The description herein expands
on the review provided by Committee 1 of the First
International Consultation on Bladder Tumors [17].
There are 2 basic approaches to performing TURBT:

staged resection and en bloc resection. Both are
described below.
The appropriate anesthesia to use during TURBT is

individualized according to the patient and to surgeon
and anesthesiologist preference. General anesthesia
with endotracheal intubation or a laryngeal mask
airway, spinal anesthesia, or epidural anesthesia
may be appropriate. Resection of tumors along the
lateral wall may elicit an obturator nerve reflex[17].
For such procedures, neuromuscular blockade is
recommended; the use of an obturator nerve block
is optional and is unnecessary in the majority of
patients (Level 4).
a) Staged Resection
Staged TURBT is done in several phases (Level
3). First, the most superficial portion of the tumor
protruding into the bladder is resected, and the
surgeon starts medially and works laterally if
possible. Next, the next layer of tissue is resected in
a similar fashion. Layers of tissue are resected in this
manner until the base of the tumor is reached. Finally,
the base of the tumor is resected. For resection of
the base of the tumor, some authors recommend
starting just adjacent to the bladder tumor to include
normal adjacent mucosa to help guide the depth of
the subsequent resection, progressing towards the
tumor and towards the adjacent normal mucosa on
the other side. Other authors advocate removing
the bulk of the tumor base first and then performing
a third phase in which the tissue surrounding the
tumor base is removed. The resected tissue may be
sent together for collective analysis, or tissue from
The patient is positioned in a dorsal lithotomy

position with the buttocks at the edge of the table and
all pressure points padded. Special care should be
taken to pad the lateral proximal fibula to avoid foot
drop due to neurapraxia of the common peroneal
nerve. An examination under anesthesia prior to
tumor resection is optional. An examination under
anesthesia should always be performed, however,
after tumor resection (see the section Examination
Under Anesthesia below).
44
Table 2. Recommended documentation at the time of TURBT
Cystoscopy
Number of tumors
Description of gross tumor architecture
Size (cm)*
Tumor location(s)
Examples or comments
2
Flat papillary or sessile
3-4cm
1 Right lateral wall
Suspected depth of invasion

Adjacent mucosa (trabeculated, normal)
Presence of diverticula
Ureteral orifices
2- trigone
Appears Non-invasive
Normal adjacent mucosa
No diverticula seen
Normal location, clear efflux of urine
TURBT
Approximate Depth of resection
Superficial, into muscle, into perivesical fat depth
Completeness of resection
Ureteral orifice(s)
Complications
of resection
Complete resection of tumor
Resected or intact ureteral orifice
No complications
EUA (following resection)

Prostate
Bladder
Bladder mass (estimate 3 dimensions when present)
Smooth, symmetric, no nodules, 40grams

Freely mobile
3cm x 3cm x 4cm (mobile)
* Use loop (1cm) as reference
d) Examination under Anesthesia
each stage may be sent separately for a differential

analysis[17-19].
Examination under anesthesia should be performed

following resection of the bladder tumor. The objective
of the examination under anesthesia is to properly
stage the disease and to help guide appropriate
therapy. A properly performed examination under
anesthesia includes a bimanual examination
following drainage of the bladder and without a
catheter in place so that the bladder is completely
empty. One hand is placed in the suprapubic region,
and 1 or 2 fingers of the other hand are placed
into the anus (males) or vagina (females)[17]. The
hand on the abdomen displaces structures, and
the posterior finger or fingers are used to note the
anatomic features. The bladder, prostate, and
other pelvic structures are palpated between the
2 hands[17]. If clinical stage T3 disease (palpable
mass on examination under anesthesia) is present,
this should be recorded, along with an estimate of
the 3-dimensional size of the mass. If a mass or the
bladder is fixed, the location of the fixation should
be noted (Table 2). Involvement of adjacent organs
should be assessed. In addition, the prostate should
be examined.
b) En Bloc Resection
En bloc resection may be used for small tumors,
generally those less than 3 cm in greatest
dimension[20-22] (Level 3). Reported advantages of
en bloc resection include more accurate pathologic
assessment because of decreased cautery artifact,
avoidance of tumor fragmentation, and preservation
of the spatial orientation of the tumor relative to
the bladder wall. There have been no comparative
studies of en bloc TURBT versus staged TURBT.
c) Hemostasis
Following resection, it is important to achieve
hemostasis. Hemostasis may be achieved by
selective cautery of obviously bleeding vessels,
to avoid unnecessary bladder contracture due to
excessive cautery. An alternative approach is to
cauterize the entire base of the resection site to
prevent subsequent bleeding. Cautery near the
ureteral orifices should be avoided if possible to
avoid ureteral stricturing[23-25].
45
tomy, or radical cystectomy should be considered

(Level 4). Small, low-grade lesions can be managed
with careful resection or fulguration (Level 4). In addition, intravesical therapy should be considered,
especially if the completeness of excision is in doubt
(Level 4).
III. TURBT in Specific

Circumstances
1. Diffuse CIS
For patients with diffuse bladder lesions and/or
suspected diffuse CIS, excessive bladder biopsies
and cauterization are not recommended. TURBT
is not therapeutic for most cases of CIS, and there
is clinical evidence indicating that the appropriate
treatment of diffuse CIS is intravesical therapy[26]
(Level 1).
5. Muscle-invasive Tumors
When a muscle-invasive tumor is suspected, the
depth of resection largely depends on the clinical
context. In general, sufficient tissue should be
resected to reveal whether or not tumor is present in
the muscularis propria. Intraoperative frozen tissue
assessment may be used to ensure that sufficient
muscle is available for proper evaluation. In addition,
proper staging of muscle-invasive bladder cancer
requires an examination under anesthesia performed
following complete transurethral resection of
intravesical tumor[33]. Among patients treated with
neoadjuvant chemotherapy, patients with pathologic
T0 disease on radical cystectomy performed after
systemic chemotherapy have a significantly better
prognosis than patients with residual intravesical
disease[34]. However, it is unclear if the completeness
of TURBT influences the response to neoadjuvant
chemotherapy. In general, it is advised that as much
tumor be removed as is safe to decrease the local
tumor burden and possibly optimize the response to
chemotherapy prior to radical cystectomy (Level 5).
For patients who are deemed not candidates for or
who refuse a radical cystectomy, TURBT should be
as thorough as possible to provide the patient with
the best opportunity for cancer control. In such cases,
re-resection to include deep tissue, sometimes into
the perivesical fat, may be warranted[20] (Level 3).
2. Tumors at the Ureteral Orifice

Cautery should be used sparingly near the ureteral
orifice. When cutting current is used to remove
tumors at or near the ureteral orifice, ureteral
stenosis is uncommon (Level 3). A ureteral stent
may be used to prevent temporary obstruction due
to postoperative edema, but whether ureteral stents
prevent ureteral stenosis is unknown [17] (Level 3).
A functional study, such as IVU or a renal scan, is
generally recommended 3-6 weeks after resection
over the ureteral orifice[27] (Level 4). Resection of
the ureteral orifice may lead to vesicoureteral reflux,
which may increase the risk of upper tract recurrence
(Level 3). Therefore, more frequent surveillance may
be needed in patients with reflux (Level 3).
3. Tumors on the Anterior Surface

and Lateral Wall
The anterior surface of the bladder is one of the
most challenging locations for TURBT. Resection of
tumors on the anterior surface can be made easier
by applying counterpressure to the bladder in the
suprapubic region[17] (Level 4). Resection of tumors
on the lateral wall may stimulate the obturator
nerve and result in a sudden adduction of the leg
and subsequent bladder perforation. Maneuvers
to decrease the risk of eliciting an obturator nerve
reflex include use of neuromuscular blockade,
use of obturator block, avoiding overdistention of
the bladder, using intermittent cutting current, and
lowering the resection current (Level 4).
6. Repeat TURBT
Current management guidelines for bladder
cancer are based on the depth of invasion, and
therefore it is critical that the urologist obtain the
most accurate staging assessment. Several cohort
series indicate that the depth of tumor invasion is
often underestimated on an initial TURBT. Herr 101
reported on 150 patients with bladder cancer who
underwent a repeat TURBT; 28 (29%) of the 96
patients with non-muscle-invasive bladder tumors
were reclassified as having muscle-invasive disease
at repeat biopsy. In addition, of the 23 patients
with T1 lesions without muscle in the specimen on
primary resection, 49% had their disease reclassified
as T2 at the second TURBT. However, the patients
in that series represented a unique populationthey
were all referred to a tertiary care center, and the
completeness of the primary TURBT in that setting
may have been limited because of the expectation
of subsequent referral to the tertiary care center.
Nevertheless, others have reported similar findings.
Dutta et al reported understaging in 64% of patients
with T1 disease when muscle was not present in the
specimen versus 30% of patients with T1 disease
4. Tumors in Bladder Diverticula

Diverticula of the bladder lack the muscularis propria, and thus diagnosis and treatment of tumors
in diverticula is challenging. The lack of a muscular
component precludes proper assessment for muscle
invasion. On the other hand, deep biopsies of bladder tumors in diverticula should be avoided because
of the high risk of perforation due to a thin bladder
wall. No prospective comparative trials have been
published on different therapeutic approaches for diverticular tumors. However, general guidelines are
as follows: For large or high-grade tumors arising
from diverticula, a diverticulectomy, partial cystec-
46
when muscle was present (Level 3)102. Zurkirchen

et al reported that 37% of patients with T1 bladder
tumors at initial diagnosis had persistent tumor on
repeat resection[35]. Grimm et al reported finding
residual tumor in 22% of patients, including 53%
of those with bladder tumors initially diagnosed as
T1 (Level 3)[36]. Brauers et al reported that 24% of
patients with non-muscle-invasive bladder cancer
had their disease reclassified as T2 or CIS on repeat
TURBT (Level 3)[37]. A prospective cohort evaluation
by Schips et al revealed residual disease in at least
50% of patients at repeat TURBT, and patients with
multifocality and high-grade disease were more likely
to have persistent disease at repeat resection[38].
Kln et al [39] identified residual tumor at repeat
TURBT in 20 (43.5%) of 46 patients and noted that
patients who underwent a staged resection (see
the section Staged Resection above) had a lower
incidence of tumor at repeat TURBT. Recently, Shen
et al reported results of a large observational study
that included 125 patients with non-muscle-invasive
disease who underwent a repeat TURBT[40]. Of
the 125 patients,43 (34.4%) had residual tumor on
repeat TURBT, and the presence of muscle tissue
in the initial TURBT specimen was significantly
associated with a decreased likelihood of having
residual disease (Level 3)[40].
The percentage of patients with tumor on random

bladder biopsies ranges from 1.5-14.5%[42-45]. In a
European Organisation for Research and Treatment
of Cancer study, 393 patients with solitary Ta and
T1 tumors underwent a biopsy of normal-appearing
mucosa, and CIS was detected in 1.5%[44]. Taguchi
et al reported that CIS was detected in12 (14.5%) of
83 patients who underwent random bladder biopsies
[45]. Fujimato et al performed random bladder
biopsies in 100 consecutive patients with non muscle
invasive cancer, and in 8 of them, biopsy revealed
additional tumor[43]. May et al [46], in a large series,
reported finding urothelial tumor on random bladder
biopsies in 12.4% of patients, including 4% of those
with CIS (Level 3). Moreover, these authors reported
that random bladder biopsy findings influenced the
management in 7% of patients (Level 3)[46].
The risk of tumor implantation and subsequent
tumor recurrence due to random bladder biopsy is
controversial. Levi et al reported that bladder biopsy
using a cold-cup biopsy grasper increased the risk
of tumor recurrence in the presence of CIS[47]. Mufti
and Singh [42], on the other hand, did not find tumor
implantation to be a risk factor for subsequent tumor
development.
A consensus opinion is that routine random bladder
biopsies do not change the clinical treatment in most
cases and are generally not recommended (Level
5). Random bladder biopsies are recommended in
cases of discordance between urine cytology findings
and the gross appearance of the bladder mucosa
and in bladder mapping prior to consideration of a
partial cystectomy. Finally, although there is little
evidence to support recommendations regarding the
location and number of random bladder biopsies, it
is common practice to obtain 5 biopsy specimens,
of the lateral walls, trigone, posterior bladder, and
dome.
Recently, a prospective, randomized trial was

conducted to address the value of repeat TURBT
in patients undergoing intravesical therapy with
mitomycin C. Divrik et al randomly assigned patients
with newly diagnosed T1 bladder cancer to a second
TURBT with adjuvant intravesical mitomycin C (74
patients) or adjuvant mitomycin C following the
initial resection without repeat TURBT (68 patients).
Patients with CIS, incomplete resection, or muscleinvasive disease were excluded from the study. At
a mean follow-up time of 31.5 months, the authors
observed a significantly higher recurrence rate in the
group that did not undergo a second TURBT (63.2%)
than in the group that did undergo a second TURBT
(25.7%). In addition, the progression rates were
higher in the group that did not undergo a second
TURBT (11.8% vs. 4.05%; p=0.097). In summary,
this trial provides evidence that a second TURBT
decreases recurrence rates for patients with T1
bladder cancer (Level 2)[41].
IV. Sample Transport and

Pathologic Processing:
Or How best to help your
pathologist give you the most
useful pathology report
7. Random Bladder Biopsies During

Routine TURBT
The pathologic evaluation of bladder tumor specimens

acquired by TURBT differs markedly from the usual
pathologic evaluation of tumor specimens. This
is due in large part to the nature of the procedure,
which cuts the bladder tumor into multiple fragments
with electrocautery. The pathologist receives a
specimen without any anatomic orientation, has to
process multiple fragments of the specimen, and has
to deal with potentially extensive cautery artifacts.
The pathologists interpretation of this specimen
will guide decisions about subsequent treatment
repeat TURBT, observation, intravesical therapy, or
Random bladder biopsies are performed to identify

the presence of CIS or dysplasia, which may not
be discernible by gross inspection but could alter
management recommendations. Unlike site-selected
biopsies, random bladder biopsies are performed in
completely normal appearing urothelium. The role
of random bladder biopsies during routine TURBT
has not been resolvedthere is a lack of convincing
evidence either for or against routine random bladder
biopsies.
47
radical cystectomy or radiotherapy. The most critical

information gained from pathologic interpretation
of TURBT specimens is information about whether
there is invasion of the lamina propria or muscularis
propria. Detection of lamina propria invasion usually
leads to re-resection and intravesical therapy, if not
immediate cystectomy, and detection of muscularis
propria invasion leads to radical cystectomy,
sometimes preceded by neoadjuvant chemotherapy.
It is imperative that TURBT specimens be handled
and processed optimally to help the pathologist
make the most accurate assessment.
tumor should be sent as a separate specimen to allow

optimal assessment of depth of invasion. Separate
evaluation of each tumor should facilitate detection
of lamina propria invasion in any 1 tumor, reveal
whether the surgeon should perform repeat resection
of specific tumor beds because of inadequate depth
of resection on initial TURBT, and reveal whether the
presence of lamina propria invasion requires second
resection (level 4).
When repeat TURBT is required for more certain
staging of high-grade and/or T1 bladder tumors, the
surgeon should resect the resection bed 4-6 weeks
after initial TURBT. Specimens from repeat TURBT
are generally flat and are sent to the pathologist as
a single specimen per tumor site, without a separate
sample from the tumor base. Interpretation of
specimens from repeat TURBT can be complicated
by inflammatory changes due to the preceding
resection.
1. Tissue Acquisition
The specimen delivered to the pathologist by the
urologist depends on the type of resection. Bladder
biopsies are often performed to evaluate suspiciousappearing areas of bladder mucosa or performed
randomly to rule out CIS. Bladder biopsies are
typically performed with cold-cup biopsy forceps
and include mucosal tissue with a varying depth of
subepithelial tissue, sometimes including muscularis
propria. The specimens are small and friable. They
must be minimally handled to prevent distortion[4850]. Specimens are generally placed immediately
on nonadherent gauze (e.g., Telfa, Kendall) and
transferred directly into formalin (level 4). Orientation
of cold-cup biopsy specimens is often straightforward
because the lesions are generally small and this
facilitates the identification of early invasion[51].
Cautery artifacts are not an important issue in coldcup biopsy specimens, but denudation of mucosa
is a significant risk. Denudation is seen commonly
with CIS, and hence a denuded biopsy specimen is
concerning but nondiagnostic.
Laser TURBT is a novel procedure that has not found

widespread application. In principle, use of laser
energy for resection does not change the handling
and processing of tissue specimens[54]. The
principal limitation of laser TURBT is the potential
for tissue alteration and destruction that prevents
adequate pathologic investigation[55].
En bloc TURBT is a novel approach that is designed
to allow better pathologic evaluation of tumors. Like
laser TURBT, however, en bloc TURBT is not widely
practiced. With en bloc TURBT, the surgeon uses a
flat loop electrode, laser, or knife to resect tumors up
to 3 cm in diameter as a single specimen. This gives
the pathologist more accurate anatomic orientation
and potentially enables better assessment of depth
of invasion.
TURBT of a unifocal tumor is the most common

clinical scenario. If the tumor is small, removal with
cold cup biopsy is often preferable to resection with
a cautery loop to minimize the cautery artifact. If the
tumor is larger, the final specimen will be a collection
of tissue chips, each measuring approximately 6
mm in diameter. These will have varying length and
depth and will be derived from different portions
of the tumor (superficial, middle, and base with
interface to bladder wall). Larger tumors should be
sent as 2 separate samples: 1 from the bulk of the
tumor and 1 from the tumor base[50] (level 4). This
enables the pathologist to make the most accurate
assessment possible of whether there is invasion
into the lamina propria or muscularis propria and
decreases the likelihood that such invasion could be
missed because of sampling errors.
2. Urine Cytology
Urine samples sent for cytologic evaluation also
require special handling and processing [58].
Cytologic evaluation of a urine specimen involves
a certain degree of subjectivity. Interpretation errors
will occur if specimens are collected, handled, and
processed incorrectly[59]. Optimal diagnosis can
only be obtained by following best practices.
Urine for cytologic analysis can be voided, obtained
during catheterization, or taken at the time of
instrumentation. The quantity of cellular material and
the quality of the specimen are best for instrumented
specimens, intermediate for specimens obtained
during catheterization, and worst for voided
specimens[60-62].
TURBT of multifocal tumor requires some additional

considerations. To map the bladder adequately,
each tumor should be sent as a separate specimen.
This practice requires that the surgeon document
pictorially the location of the tumors in the bladder in
the written operative note. The base of each larger
Instrumented urine samples can be obtained by

barbotage, which involves irrigating in and out
to release more cells and thereby enhance the
diagnostic quality of the specimen. It is important
to use normal saline, and not water or glycine for
barbotage, in order to preserve cellular morphology.
48
It is equally critical to obtain specimens prior to

instillation of contrast dye or any other agents.
Ideally, the cystoscope is inserted into the bladder,
and barbotage is performed with saline through the
cystoscope (level 4). As is the case for cytology in
general, these maneuvers are best for detecting
high-grade carcinoma, and both the sensitivity
and specificity are low for low-grade lesions. The
pathologist must be wary of the risk of overdiagnosing
low-grade urothelial neoplasms, especially in the
case of instrumented urine specimens. These
samples often contain benign cellular clumps that
can resemble urothelial carcinoma but usually have
more defined borders and a more densely staining
cytoplasmic collar[63-65].
filtration (Magna MCE nitrocellulose filter, BioBlock

Scientific, Illkirch, France); and Monoprep (Monogen,
Lincolnshire, IL )[66]. These methods deliver a more
uniform, single-layer preparation with more cells,
better preserved morphology, and less background
debris[66-69] (level 3). Urine samples are placed
immediately into proprietary fixatives, which provide
immediate and superior preservation.
Recently, immunocytochemistry for vimentin (but
not high-molecular-weight cytokeratin) has been
reported to better differentiate reactive renal tubular
cells from low-grade urothelial carcinoma cells in
voided urine. Thus this technique eliminates one
specific confounding factor in the evaluation of urine
cytology.
A urine specimen for cytology should not be taken

from the first voided urine of the day. The premise
for this recommendation is that the first voided urine
of the day has likely dwelled in the bladder for a
relatively long time and will have poorly preserved
cellular architecture. A common recommendation is
to have the patient empty the bladder in the morning
and collect the next specimen after 2-3 hours of
adequate hydration (level 4).
3. Clinical Information
Adequate clinical information allows the pathologist
to initiate any specific tests required to guide
clinical management and to avoid unnecessary
investigations[72]. Clinical information may accelerate
the diagnostic process. For example, the pathologist
may request additional immunohistochemical
analyses based on clinical data. Conversely, the
written pathology report is the principal line of
communication from the pathologist back to the
treating clinician, and this report can be tailored to
the clinical need, thereby enhancing communication.
The essential clinical information is highlighted in
Table 3.
The ideal urine specimen volume is poorly defined,

but 25 mL can be considered a minimal volume. A
larger volume may come at the expense of longer
dwell time in the bladder, which can be detrimental.
It is not advisable to collect urine for a defined period
of time, such as 12 or 24 hours, because this leads
to poor specimen quality due to specimen storage
(level 4).
Table 3. Recommended essential clinical information

for pathologic specimen submission
There are no well-defined timelines for processing

urine for cytologic examination, but it is clear that the
degree of cellular deterioration increases with time.
The diagnostic accuracy therefore increases with
the expediency of specimen processing. The time
from specimen collection to processing should not
exceed 8 hours [58] (level 4). Urine is best examined
as a fresh specimen for cytology but, if expeditious
examination of a fresh specimen is not feasible, the
specimen can be preserved with various solutions,
including 70% ethyl alcohol (2:1 dilution by volume),
polyethylene glycol, or the solution in kits used for
liquid-based Papanicolaou testing (level 3).
Tumor characteristics:
Flat
Papillary
Nodular
Ulcerated
Location in the bladder
Clinical history:
P
rior bladder tumors (grade/stage/histology/
location)
P
rior intravesical chemotherapy/
Techniques for processing urine specimens for

cytologic analysis in the laboratory vary. Conventional
methods include using filters, cytocentrifugation
(cytospin), or concentrated smears. Newer techniques
include various commercial kits using liquidbased methods: ThinPrep (Hologic, Inc., Bedford,
Massachusetts); SurePath (Becton Dickenson
Company, Franklin Lakes, New Jersey); Millipore
filter preparations (Millipore Corporation, Billerica,
Massachusetts); AutoCyte PREP (BD Diagnostics
Tripath, Burlington, NC); Shandon Cytospin (Thermo
Electron, Waltham, MA); nitrocellulose membrane
immunotherapy
Prior systemic chemotherapy
Prior radiation therapy to the bladder/pelvis
Prior instrumentation
H
istory of stones, infection, other urologic
conditions
P
rior non-bladder malignancy (type and
location)
49
Documentation of the site of tissue acquisition is

essential for pathologic identification and evaluation.
In the context of TURBT, the primary information
required is whether the specimen was taken from
the bladder or the urethra. Within the bladder,
documentation of the location from which tissue was
obtained may be important for mapping of tumors
for example, should there be a need for re-resection
of 1 or more sites. Location on the dome may be
relevant for diagnosing urachal carcinoma.
may lead to understaging because of missed focal

invasion into the lamina propria or muscularis propria.
The presence of muscularis propria in the specimen
is considered a measure of quality control[79], and
it is therefore important to obtain a biopsy sample
that includes muscularis propria. If not all chips are
sampled, the pathology report should indicate what
proportion of the chips was sampled[49] (level 4).
The College of American Pathologists has developed
a Protocol for the Examination of Specimens from
Patients with Carcinoma of the Urinary Bladder
(http://www.cap.org/apps/docs/committees/cancer/
cancer_protocols/2009/UrinaryBladder_09protocol.
pdf)[80]. The panel drawing up this protocol was
made up primarily of United States contributors but
also included some members from other countries.
This document focuses mostly on standard
reporting for TURBT specimens but also includes
recommendations for tissue processing.
The pathologist should also be given information

about the patients relevant medical history. A prior
history of kidney stones or urinary tract infection may
affect the interpretation of bladder biopsies. A prior
history of BCG instillation may aid in the diagnosis
of granulomatous changes. Use of photodynamic
agents such as hexaminolevulinate at the time of
TURBT does not appear to affect the pathologic
specimen.
For cytopathology requisitions, it must be noted
whether a patient has an intact bladder or has
undergone prior urinary diversion. Inflammatory
changes associated with urinary diversion may lead
the cytopathologist to be concerned about atypia if
the prior urinary diversion is not mentioned. Previous
BCG therapy and previous stone disease are also
relevant as both can cause artifact.
The College of American Pathologists protocol calls

for examination of 1 microscopic section for every
1 cm of tumor diameter up to 10 sections. If this
evaluation reveals that tumor invades into muscle,
sampling can be considered adequate. If, however,
there is evidence of invasion into the lamina propria
but not muscle, further sampling is necessary to
exclude muscularis propria invasion. Similarly, if
there is no evidence of invasion on the initial analysis,
more tissue must be sampled. Depending on the
size of the tumor, it may be necessary to examine
the entire specimen (level 4).
4. Pathologic Processing
a) Tissue Fixation
In the operating room, all tissue must be placed
immediately in 10% neutral buffered formalin in a
10:1 ratio by volume of fixative to tissue to ensure
adequate fixation. Filling a specimen cup with
tumor chips without adequate fixative will lead to
poor fixation and increased tissue degradation.
Alternatively, 4% paraformaldehyde may be used
instead of neutral buffered formalin. In fact, 4%
paraformaldehyde may even be a superior fixative
for immunohistochemistry as it tends to yield reduced
background staining. However, it must be freshly
made just before use. The duration of fixation can be
12-24 hours for TURBT specimens since each tissue
fragment tends to be small (level 4).
The European Society of Uropathology and the

Uropathology Working Group have also described
standardized methods for handling and reporting
bladder tumor specimens. Their report stems from
a Uropathology Workshop held in Sesto Fiorentino,
Italy, in 2003 and represents a statement of expert
opinion. The standardized methods outlined in the
report incorporate recommendations made by the
College of American Pathologists and the Association
of Directors of Anatomic Pathology and are in line
with the recommendations for tissue sampling
described above. In addition, the European Society
of Uropathology and the Uropathology Working
Group emphasize that the number, size (aggregate
dimensions), and weight of each sample must be
recorded (level 4).
In the pathology laboratory, it is important to avoid

overfilling the specimen cassettes, as this is more
likely to lead to undersampling of some tissue
fragments (level 4).
Assessment of lamina propria invasion is one of the

most significant challenges in bladder pathology.
There is a high degree of interobserver variability in
the assessment of lamina propria invasion, and the
clinical relevance of such assessment is substantial,
as patients with T1 lesions are considered at high
risk for recurrence and progression when bladder
preservation is attempted. The status of the lamina
propria can determine the need for repeat resection
and intravesical BCG or, in patients who have had
prior treatments, the need for cystectomy.
b) Specimen Examination
Every sample sent from the operating room should
be processed individually and reported separately.
Expert pathologists recommend that all tissue
fragments from any TURBT sample be processed.
The degree to which these samples are sectioned
and analyzed is, however, not clearly established, and
practice in this area is not uniform. Undersampling
50
One of the most significant obstacles to accurate

assessment of invasion is poor orientation of the
specimen due to the piecemeal fashion in which it is
delivered to the pathologist and tangential sectioning.
There is a risk that papillary tumors can be sectioned
in such a way that isolated clusters of noninvasive
tumor cells are visualized with surrounded stroma,
giving the appearance of invasion. The pathologist
must deduce from smooth and regular contours
that this is an artifact of sectioning, while irregular
contours with haphazard arrangement favor true
invasion. If necessary, re-embedding and further
sectioning can be helpful[50].
criteria would demand specific immunohistochemical

staining with endothelial markers such as factor-VIIIrelated antigen, CD31, or CD34[48]. In some cases,
staining will not resolve the problem of differentiating
lymphatic from artifactual space entrapment by
tumor cells. Retraction artifact is also prominent in
the micropapillary variant of urothelial carcinoma
which has been well described by Kamat et al.
Cautery artifact can be one of the principal factors
limiting pathologic analysis of TURBT specimens.
Cautery can cause severe morphologic distortion
that prevents adequate interpretation. Lopez-Beltran
et al suggest 2 methods to help overcome cautery
artifact[51]: deeper sections can uncover regions
of tissue that are better preserved, and immunohistochemistry with anti-cytokeratin antibodies can delineate tumor tissue. If adequate interpretation is not
possible despite these methods, that fact needs to
be documented in the pathology report.
Accurate identification of the presence of muscularis

propria in the TURBT specimen is essential for
accurate staging and determination of the appropriate
subsequent clinical management [81]. As mentioned
above, the presence of muscularis propria in the
TURBT specimen is also evolving as an important
quality indicator of the TURBT itself[79].
5. Pathology Reporting
The pathologist must be careful to distinguish

muscularis mucosa from muscularis propria and
sometimes even myofibroblasts in desmoplastic
stromal reaction associated with the carcinoma.
Muscularis mucosa consists of thin muscle bundles
in the lamina propria that are classically described
as being arranged in a single interrupted, dispersed,
or continuous layer[82]. In practice, however,
the distinction may be less obvious, especially
if the muscularis mucosa is hyperplastic, and
immunohistochemical staining with anti-smoothmuscle-specific actin[53] or smoothelin can help in
selected cases (level 3). Smoothelin is a marker of
terminally differentiated smooth muscle cells and
has recently been shown to stain muscularis propria
with relative specificity. Smoothelin stains muscularis
mucosa either weakly or not at all and does not stain
myofibroblasts in desmoplastic stroma.
Careful harvesting, handling, and processing of

TURBT specimens is ultimately of little benefit if the
findings are not reported clearly[92-94]. The presence
of key findings such as focal invasion or concomitant
CIS can be missed by the treating physician if these
findings are not clearly documented in the pathology
report[92]. The goal of the pathologic investigation
and the final report is to provide the urologist or
other treating physician with the most accurate
information possible so that he or she can make
the most appropriate management decisions for the
patient from whom the specimen was obtained[95].
An important component of pathology reporting
is specific documentation of known risk factors for
disease recurrence and progression as well as
predictive factors for response to therapy.
The College of American Pathologists Protocol
for the Examination of Specimens from Patients
with Carcinoma of the Urinary Bladder includes a
component on the optimal reporting of pathologic
findings in bladder tumor specimens (http://www.
cap.org/apps/docs/committees/cancer/cancer_
protocols/2009/UrinaryBladder_09protocol.pdf).
This protocol was first published in 1996[96] and
was updated in 2003[80]. These standards were
subsequently adopted by the Commission on
Cancer of the American College of Surgeons as a
mandated checklist in its Cancer Program Standards
for Approved Cancer Programs (2004). The checklist
is reproduced with permission in Figure 8 (level 4).
After
routine
hematoxylin-eosin
staining,
immunohistochemical analysis of tissue samples
with uncertain histology may be necessary to confirm
or rule out the diagnosis of urothelial carcinoma. The
most common distinction that needs to be made
is the distinction between urothelial carcinoma
and high-grade prostate cancer [86]. Urothelial
carcinoma typically stains positive for uroplakin III,
thrombomodulin, cytokeratin 7, and cytokeratin
20. Negative immunostaining for prostate-specific
antigen and prostatic acid phosphatase is an
important indicator of urothelial carcinoma as
opposed to prostate cancer (level 3).
The Association of Directors of Anatomic Pathology

has generated a Final Anatomic Diagnosis Checklist
for Urinary Bladder Neoplasms, but these guidelines
are for cystectomy specimens only.
Lymphovascular invasion (LVI) is an established

biomarker used for risk stratification in cystectomy
specimens[88-90] as well as in TURBT samples
[91] and hence LVI is often used clinically in bladder
cancer care decision-making. It is therefore relevant
for the pathologist to inspect the sections for LVI and
comment correspondingly in the report (level 3). Strict
It is important that the pathologist state not only

what is present in, but also what is absent from, the
TURBT specimen. It is vital, for example, to state the
51
FIGURE 8 Checklist for pathologic reporng

.
Figure 8. Checklist for pathologic reporting
52
Figure 8. Checklist for pathologic reporting (ctd)
53
10
absence of LVI or the absence of muscularis propria if

the pathologist has examined the specimen carefully
and not identified these features. In patients with
urothelial malignancy, a report of denuded biopsy
(most probably related to CIS) is significantly different
from one stating that no tumor is seen [52]. Tumor
in fat should not be interpreted as perivesical fat
invasion, because the bladder wall can contain fat.
8. Cherian V. Anesthetic implications of urology surgery.

Indian journal of urology 2006;22:194-200.
Just as the pathologic requisition is an important

document for communicating the clinical scenario to
the pathologist, the pathology report is the principal
means by which the pathologist communicates back
to the urologist and to subsequent treating physicians.
In complex cases, face-to-face communication
between the pathologist and the urologist can be
essential for accurately conveying the findings. Such
communication can involve the surgeons delivering
the specimen to the pathologist with specific details
on orientation of the specimen or the pathologists
demonstrating the pathology under the microscope
to the urologist. A more intimate working relationship
is likely to enhance patient care[95]. Nuances are
conveyed better on the telephone or in person than
in the pathologic report.
11. Bootsma AM, Laguna Pes MP, Geerlings SE, Goossens A.

Antibiotic prophylaxis in urologic procedures: a systematic
review. Eur Urol 2008;54:1270-86.
9. Khorrami MH, Javid A, Saryazdi H, Javid M. Transvesical

blockade of the obturator nerve to prevent adductor
contraction in transurethral bladder surgery. J Endourol
2010;24:1651-4.
10. Tatlisen A, Sofikerim M. Obturator nerve block and
transurethral surgery for bladder cancer. Minerva Urol
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13. MacDermott JP, Ewing RE, Somerville JF, Gray BK.
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14. Delavierre D, Huiban B, Fournier G, Le Gall G, Tande
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When there is diagnostic uncertainty, the pathologist

should make this clear but still provide a likely
diagnosis. The opinion of additional pathologists or
a reference pathologist may be helpful. Finally, the
pathology report should not include management
recommendations because many possible clinical
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17. Kirkali Z, Chan T, Manoharan M, et al. Bladder Cancer:

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patients with negative lymph nodes at radical cystectomy. J
Clin Oncol 2005;23:6533-9.
72. Burton JL, Stephenson TJ. Are clinicians failing to supply

adequate information when requesting a histopathological
investigation? J Clin Pathol 2001;54:806-8.
91. Kunju LP, You L, Zhang Y, Daignault S, Montie JE,

Lee CT. Lymphovascular invasion of urothelial cancer
in matched transurethral bladder tumor resection and
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73. Anagnostopoulou I, Rammou-Kinia R, Likourinas M. Urine

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74. Wolinska WH, Melamed MR. Urinary conduit cytology.
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92. Powsner SM, Costa J, Homer RJ. Clinicians are from Mars
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2000;124:1040-6.
75. Betz SA, See WA, Cohen MB. Granulomatous inflammation

in bladder wash specimens after intravesical bacillus
Calmette-Guerin therapy for transitional cell carcinoma of
the bladder. Am J Clin Pathol 1993;99:244-8.
93. Gephardt GN, Baker PB. Interinstitutional comparison of

bladder carcinoma surgical pathology report adequacy. A
College of American Pathologists Q-Probes Study of 7234
bladder biopsies and curettings in 268 institutions. Arch
Pathol Lab Med 1995;119:681-5.
76. Bhan R, Pisharodi LR, Gudlaugsson E, Bedrossian

C. Cytological, histological, and clinical correlations in
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94. Murphy WM. ASCP survey on anatomic pathology

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1994;102:715-23.
77. Kannan V, Gupta D. Calculus artifact. A challenge in urinary

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95. Thompson JF, Scolyer RA. Cooperation between

surgical oncologists and pathologists: a key element of
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96. Hammond EH, Henson DE. Practice protocol for the
examination of specimens removed from patients with
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urethra. Arch Pathol Lab Med 1996;120:1103-10.
97. Recommendations for the reporting of urinary bladder
specimens containing bladder neoplasms. Association of
Directors of Anatomic and Surgical Pathology. Am J Clin
Pathol 1996;106:568-70.
98. Murphy WM, Crissman JD, Johansson SL, Ayala AG.
Recommendations for the reporting of urinary bladder
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1996;9:796-8.
99. Philip AT, Amin MB, Tamboli P, Lee TJ, Hill CE, Ro JY.
Intravesical adipose tissue: a quantitative study of its
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78. Highman W, Wilson E. Urine cytology in patients with

calculi. J Clin Pathol 1982;35:350-6.
79. Mariappan P, Zachou A, Grigor KM. Detrusor muscle in the
first, apparently complete transurethral resection of bladder
tumour specimen is a surrogate marker of resection quality,
predicts risk of early recurrence, and is dependent on
operator experience. Eur Urol 2010;57:843-9.
80. Amin MB, Srigley JR, Grignon DJ, et al. Updated protocol
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81. Ro JY, Ayala AG, el-Naggar A. Muscularis mucosa of
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82. Paner GP, Ro JY, Wojcik EM, Venkataraman G, Datta MW,
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56
or ultrasonography [Qu 2010]. However, the risks

associated with exposure to radiation limits the use
of repeated CT virtual cystoscopy in bladder cancer
surveillance.
100. Coblentz TR, Mills SE, Theodorescu D. Impact of second

opinion pathology in the definitive management of patients
with bladder carcinoma. Cancer 2001;91:1284-90.
101. Herr HW. The value of a second transurethral resection in
evaluating patients with bladder tumors. J Urol 1999; 162:
74-6.
Recommendation
102. Dutta SC, Smith JA Jr, Shappell SB, Coffey CS, Chang
SS, Cookson MS. Clinical under staging of high risk
nonmuscle invasive urothelial carcinoma treated with
radical cystectomy. J Urol 2001; 166: 490-3.
It is difficult to assess the role of virtual cystoscopy

in clinical practice. Certainly catheterless forms of
virtual cystoscopy may allow patients to avoid the
discomfort associated with standard cystoscopy.
Cystoscopy does, however, offer the advantages
of being able to detect tumors of all sizes, being
able to detect areas of mucosal irregularity or CIS,
and allowing biopsy or definitive treatment to be
performed. The broad availability of cystoscopy
and familiarity with its use mean that it remains the
gold standard. Grade C
D. Imaging and Bladder Cancer

I. Methods
Medline, Embase, the Cochrane Library, Biosis, and
Science Citation Index were searched using the
terms bladder cancer, IVU, US, CT, MRI, and PET.
In addition, a direct search was done of the last 3
months issues of the major urology and radiology
journals.
III. CT in Localized Bladder

Cancer Staging
Cross-sectional imaging has a very real role in
assessing the local extent of bladder cancer. The
National Comprehensive Cancer Network guidelines
for Bladder Cancer [Version 1. 2011] state that if the
cystoscopic appearance of a tumor is solid, is high
grade, or suggests invasion into muscle, a CT scan
of the abdomen and pelvis is recommended before
TURBT [Level 4]. CT can be used on its own or in
combination with positron emission tomography
scanning in the detection of both local and distant
disease. The reported sensitivity of CT for detecting
and staging bladder cancer ranges from 62-91%, and
the reported specificity ranges from 63-95% [Baltaci
2008, Blanco Diez 2003, Jaume 2003, Kim 2004,
Koplay 2010]. Studies with multidetector CT showed
sensitivity of 89-91% and specificity of 92-95% [Kim
2004, Koplay 2010]. Protocols for CT for localized
bladder cancer staging vary, as do CT machines
themselves. It has been suggested that acquisition
60 seconds after the administration of contrast yields
the best results [Kim 2004]. In staging patients who
have undergone TURBT, delaying the scan until at
least 1 week after surgery facilitates interpretation
of images and reduces the number of false-positive
results associated with postoperative inflammatory
changes [Kim 2004].
Overall, 3,586 articles were retrieved. The decision

was made to limit the review to articles published
within the last 10 years, which left 1,814 articles.
From these articles, case reports, articles that
pertained to benign disease, and articles that did not
refer to bladder cancer per se were excluded. A total
of 186 articles remained.
These 186 articles were then analyzed as to the
level and quality of evidence and recommendations
made according to the International Consultation on
Urological Diseases guideline [Abrams 2010]. All
evidence quoted is Level 3 unless otherwise stated.
II. Virtual Cystoscopy

Both the American Urological Association and
the European Association of Urology recommend
WLC as the gold standard for the assessment of
suspected bladder tumors [Babjuk 2008, Hall 2007].
However, discomfort or pain is reported by more than
one-third of people undergoing flexible cystoscopy
[Van der Aa 2007]. In an effort to reduce discomfort
while providing information equivalent to or perhaps
superior to the information provided by flexible
cystoscopy, virtual cystoscopy was developed.
Initially, CT virtual cystoscopy was described;
subsequently, MRI virtual cystoscopy was described.
The place of virtual cystoscopy in the diagnostic
pathway is discussed elsewhere in this document.
Virtual cystoscopy has reported sensitivities and
specificities of the order of 90-95%. A meta-analysis
of 26 virtual cystoscopy studies involving 3,084
patients concluded that CT virtual cystoscopy has
higher diagnostic value than MRI virtual cystoscopy
RecommendationS
CT cannot reliably differentiate non-muscleinvasive bladder cancer from T2 disease. Thus,
TURBT with inclusion of muscle layer remains the
preferred diagnostic option. Grade C
CT and in particular multidetector CT is of use in
detecting extravesical spread. Grade B
CT should be delayed for at least 7 days in patients
who have undergone TURBT. Grade B
57
technique, including sensitivity of 94% and specificity

of 95% [Deserno 2004], other studies have shown
little difference compared to contrast-enhanced MRI
[Thoeny 2009, Harisinghani 2005].
IV. MRI in Localized Bladder

Cancer Staging
MRI is performed using T1-weighted, T2-weighted
imaging, with or without gadolinium enhancement
and diffusion weighting. Studies with diffusionweighted MRI show that this method can detect 98100% of bladder tumors [El-Assmy 2009, Matsuki
2007]. Staging sensitivity ranges from 68-80%
and specificity ranges from 90-93% [Tillou 2008,
Watanabe 2009]. Overall, MRI is probably not more
sensitive in defining the T classification than is
TURBT, but in cases in which there is discordance
between findings, close follow-up with early secondlook surgery is advised because as many as 60% of
cases may be understaged on initial TURBT [Tillou
2008]. There is some evidence that MRI can predict
tumor grade [Takeuchi 2009] and other biological
processes such as angiogenesis [Tuncbilek 2009].
2. PET Scanning
A number of tracers have been explored in positron
emission tomography (PET) scanning for bladder
cancer, including 11C-methionine [Ahlstrom 1996)
and 11C-choline [Picchio 2006, de Jong 2002). The
utility of PET for local staging of bladder cancer
has been similar to that of CT; the utility of PET in
evaluation for lymph node metastases has been
superior to that of CT.
F-fluorodeoxyglucose (FDG) is the contrast agent
most widely studied in PET imaging for bladder
cancer. Excretion of FDG in the urine can lead to
misdiagnosis: focal FDG accumulation may mimic
tumor uptake of FDG, whereas diffuse FDG activity
may obscure an FDG-avid pelvic lesion. Repeated
bladder irrigation and retrograde filling and proneposition imaging are useful techniques to ascertain
the nature of any observed FDG accumulation
[Anjos 2007, Lin 2009). Diuretic protocols have been
described that can significantly lower bladder FDG
activity and potentially improve image quality [Nijjar
2010].
18
Comparative studies suggest that MRI is superior

to CT in preoperative staging of bladder cancer,
detecting 78-90% of tumors compared to 67-85%
with CT [Akmangit 2003, Fernandez Mena 2001].
MRI also has the advantage of considerably less
artifact in patients with hip prostheses [Charnley
2005].
Recommendations
Studies using FDG-PET/CT in patients with

muscle-invasive bladder carcinoma cancer show a
sensitivity of 57-81% and a specificity of 88-100%
in the detection of pelvic lymph node metastases
[Apolo 2010, Drieskens 2005, Lodde 2010, Kibel
2010]. Similar results are seen in the assessment of
recurrent disease [Jadvar 2008].
Diffusion-weighted MRI has poor sensitivity in

differentiating between Ta, T1, and T2 bladder
tumors. Grade B
Diffusion-weighted MRI is, however, very useful in
the detection of T3 and T4 disease. Grade B
While comparative studies generally indicate

superiority of PET scanning over CT and MRI in
the detection of lymph node metastases [Apolo
2010, Lodde 2010], at least 1 study has reported
equivalence of PET and CT [Swinnen 2009].
V. Detection of Nodal Disease

and Metastasis
1. CT and MRI
Recommendations
Lymph node metastases in bladder cancer are

detected by CT with a sensitivity of 31-50% and
specificity of 68-100% [Baltaci 2008, Lodde 2010,
Picchio 2006]. While MRI can detect more lymph
nodes overall than CT and is in particular better
than CT in the detection of nodes smaller than
5 mm [Saokar 2010], the ability of MRI to identify
tumor in normal-sized or slightly enlarged nodes
is poor. Efforts to image tumor in normal-sized
nodes with ultrasmall superparamagnetic iron
oxide particles have met with mixed results. These
particles are taken up by macrophages, which
allows the architecture of individual, even normalsized, nodes to be identified. Areas not taking up
ultrasmall superparamagnetic iron oxide particles
are presumed to contain metastases. After early
studies reported very encouraging results with this
CT, MRI, and PET scanning are all of use in the

detection of lymph node metastasis. Grade B
Of the 3 modalities, PET scanning appears to have
the greatest accuracy. Grade C
Experience with ultrasmall superparamagnetic iron
oxide particles is not broad enough to recommend
their routine use. Grade D
VI. Imaging after Bladder

Cancer Treatment
CT after TURBT has a sensitivity of 89% and a
specificity of 95% for the detection of extravesical
spread [Kim 2004]. PET has accuracy similar to
58
that of CT in detecting residual bladder cancer after

TURBT and outperforms CT in detecting lymph node
enlargement [Picchio 2006].
7. Baltaci, S., B. Resorlu, et al. (2008). Computerized

tomography for detecting perivesical infiltration and lymph
node metastases in invasive bladder carcinoma. Urol Int
81:399-402
MRI can differentiate between responders and

nonresponders to chemotherapy with a sensitivity
of 91% and specificity of 93% [Schrier 2006]. In
patients receiving chemotherapy and radiotherapy
prior to surgery, MRI has 57% sensitivity and 92%
specificity in predicting the final histology, and
diffusion-weighted MRI demonstrates significantly
greater accuracy than T1- and T2-weighted MRI
[Yoshida 2010].
8. Blanco Diez, A., L. Alvarez Castelo, et al. (2003). Staging of

infiltrating bladder cancer. Role of CT scan. Arch Esp Urol
56(1):23-29.
9. Charnley, N., A. Morgan, et al. (2005). The use of CTMR image registration to define target volumes in pelvic
radiotherapy in the presence of bilateral hip replacements.
Br J Radiol 78(931): 634-636.
10. de Jong, I.J., J. Pruim, et al. (2002). Visualisation of bladder
cancer using (11)C-choline PET: first clinical experience.
Eur J Nucl Med Mol Imaging. 2002; (10):1283-8.
11. Deserno, W.M, M.G. Harlsinghani, et al. (2004) Urinary
bladder cancer: Preoperative nodal staging with
ferumoxtran-10-enhanced MR imaging. Radiology 233:449456
Chemotherapy results in reduced cellular activity in

viable cancer cells. Thus, the sensitivity of PET for
the detection of metastatic disease drops from 77%
in untreated patients to 50% in patients treated with
chemotherapy [Liu 2006].
12. Drieskens, O., R. Oyen, et al. (2005). FDG-PET for

preoperative staging of bladder cancer. Eur J Nucl Med Mol
Imaging 32(12):1412-7.
VII. General Comments
13. El-Assmy, A., M. E. Abou-El-Ghar, et al. (2009). Bladder

tumour staging: comparison of diffusion- and T2-weighted
MR imaging. Eur Radiol 19(7): 1575-1581.
There is a paucity of randomized controlled trials

of imaging for bladder cancer, which is somewhat
surprising as bladder cancer would seem to lend
itself to such studies. Many of the studies that have
been published were underpowered and quote
differences in outcomes that are frequently based
on trends rather than proven differences. The only
meta-analysis identified in the search was that by
Qu et al. The ICUD has suggested that different
considerations should be applied in the assessment
of diagnostic and investigative tools. One of the tests
that they have suggested is to ask whether the tool
has an effect in clinical practice. By this test, virtual
cystoscopy is disappointingwhile virtual cystoscopy
has been the subject of numerous articles over the
last decade, few centers have adopted this technique
into routine clinical practice.
14. Fernandez Mena, F. J. and Y. C. Moreno-Torres (2001).

[Bladder cancer]. Arch Esp Urol 54(6): 493-510.
15. Hall MC, Chang SS, Dalbagni G, et al. (2007) Guideline
for the management of nonmuscle invasive bladder cancer
(stages Ta, T1, Tis): 2007 update. J Urol 178:2314-2330
16. Harisinghani, M.G., M.A. Saksena, et al. (2005).
Ferumoxtran-10-enhanced MR lymphangiography: Does
contrast-enhanced imaging alone suffice for accurate
lymph node characterization? AJR 186(1):144-148
17. Jadvar, H., V. Quan, et al. (2008). [F-18]-Fluorodeoxyglucose
PET and PET-CT in diagnostic imaging evaluation of
locally recurrent and metastatic bladder transitional cell
carcinoma. Int J Clin Oncol 13(1): 42-47.
18. Jaume, S., Ferrant, M., et al (2003). Tumor detection in the
bladder wall with a measurement of abnormal thickness in
CT scans. IEEE Trans Biomed 50(3): 383-390
19. Kibel, A.S., F. Dehdashti, et al.(2009) Prospective study of
[18F]fluorodeoxyglucose positron emission tomography/
computed tomography for staging of muscle-invasive
bladder carcinoma. J Clin Oncol. 27(26):4314-20.
20. Kilickesmez, O., T. Cimilli, et al. (2009). Diffusion-weighted
MRI of urinary bladder and prostate cancers. Diagn Interv
Radiol 15(2): 104-110.
21. Kim, J.K., P. Soo-Youn, et al. (2004). Bladder cancer:
Analysis of multi-detector row helical CT enhancement
pattern and accuracy in tumor detection and perivesical
staging. Radiology 231(3): 725-731
22. Koplay, M., M. Kantarci, et al. (2010). Diagnostic efficiency
of multidetector computed tomography with multiplanar
reformatted imaging and virtual cystoscopy in the
assessment of bladder tumors after transurethral resection.
J Comput Assist Tomogr 34:121-126.
23. Lin, W.Y., K.B. Wang, et al. (2009). Unexpected accumulation
of F-18 FDG in the urinary bladder after bladder irrigation
and retrograde filling with sterile saline: a possible pitfall in
PET examination. Clin Nucl Med. 34(9):560-3.
24. Liu, I. J., Y. H. Lai, et al. (2006). Evaluation of
fluorodeoxyglucose positron emission tomography imaging
in metastatic transitional cell carcinoma with and without
prior chemotherapy. Urol Int 77(1): 69-75.
25. Lodde, M., L. Lacombe, et al. (2010) Evaluation of
fluorodeoxyglucose positron-emission tomography with
computed tomography for staging of urothelial carcinoma.
BJU Int. epub Feb 11.
References
1. Abrams, P. and S. Khoury. (2010). International Consultation
on Urological Diseases: Evidence-based medicine overview
of the main steps for developing and grading guideline
recommendations. Neurourol Urodyn 29:116-118
2. Ahlstrom, H., P.U. Malmstrom, et al. (1996). Positron
emission tomography in the diagnosis and staging of
urinary bladder cancer. Acta Radiol 37: 1805
3. Akmangit, I., H. Lakadamyali, et al. (2003). [Staging of
urinary bladder tumors with CT and MRI]. Tani Girisim
Radyol 9(1): 63-69.
4. Anjos, D.A., E.C. Etchebehere, et al. (2007). 18F-FDG
PET/CT delayed images after diuretic for restaging invasive
bladder cancer. J Nucl Med. 48(5):764-70.
5. Apolo, A.B., J. Riches, et al. (2010). Clinical value of
fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission
tomography/computed tomography in bladder cancer. J
Clin Oncol. 28(25):3973-8.
6. Babjuk, M., W. Oosterlinck, et al. (2008) EAU guidelines
on nonmuscle invasive urothelial carcinoma of the bladder.
Eur Urol 54:303-314
59
Summary of the
Recommendations
26. Matsuki, M., Y. Inada, et al. (2007). Diffusion-weighted MR

imaging for urinary bladder carcinoma: initial results. Eur
Radiol 17(1): 201-204.
27. Nijjar, S., J. Patterson, et al. (2010). The effect of
furosemide dose timing on bladder activity in oncology
imaging with 18F-fluorodeoxyglucose PET/CT. Nucl Med
Commun.31(2):167-72.
1. Screening and Diagnosis:

a. Currently, the available evidence indicates
that bladder cancer screening is not helpful in
improving survival. Further studies to evaluate
the utility of bladder cancer screening are
warranted (Grade C).
28. Nishimura, K., C. Fujiyama, et al. (2009). The effects of

neoadjuvant chemotherapy and chemo-radiation therapy
on MRI staging in invasive bladder cancer: comparative
study based on the pathological examination of whole layer
bladder wall. Int Urol Nephrol 41(4): 869-875
b. Bladder cancer screening should probably be

confined to patients at high risk for bladder
cancer (Grade C).
29. Picchio, M., U. Treiber, et al. (2006). Value of 11C-choline

PET and contrast-enhanced CT for staging of bladder
cancer: correlation with histopathologic findings. J Nucl
Med. 47(6):938-44
c. Screening in high-risk patients should consist

of yearly cytologic examination of urine (urine
cytology) and dipstick urinalysis to evaluate
for hematuria (Grade C).
30. Qu, X., X. Huang, et al. (2010). Comparison of virtual

cystoscopy and ultrasonography for bladder cancer
detection: A meta-analysis. Eur J Radiol 2010 May 7 Epub
31. Saokar, A., T. Islam, et al. (2010). Detection of lymph
nodes in pelvic malignancies with Computed Tomography
and Magnetic Resonance Imaging. Clin Imaging 34(5):
361-366.
d. T
here is no correlation between the number of
red blood cells per high-power field seen on
urine microscopy and the diagnosis of bladder
cancer (Grade B).
32. Schrier, B. P., M. Peters, et al. (2006). Evaluation of

chemotherapy with magnetic resonance imaging in patients
with regionally metastatic or unresectable bladder cancer.
Eur Urol 49(4): 698-703
e. Nearly all patients with bladder cancer

diagnosed on cystoscopy have some form of
microscopic or macroscopic hematuria. Hence,
patients with microscopic or macroscopic
hematuria require further evaluation, such as
with flexible cystoscopy (Grade D).
33. Swinnen, G., A. Maes, et al. (2009) FDG-PET/CT for the

Preoperative Lymph Node Staging of Invasive Bladder
Cancer. Eur Urol. 2009
34. Takeuchi, M., S. Sasaki, et al. (2009). Urinary bladder
cancer: diffusion-weighted MR imaging-accuracy for
diagnosing T stage and estimating histologic grade.
Radiology 251(1): 112-121.
f. M
icroscopic hematuria in patients with bladder
cancer varies in intensity and is intermittent;
hence, lack of hematuria on a single urinalysis
does not exclude bladder cancer (Grade C).
35. Thoeny, H.C., M. Triantafyllou, et al. (2009). Combined

ultrasmall superparamagnetic particles of iron oxideenhanced and diffusion-weighted magnetic resonance
imaging reliably detect pelvic lymph node metastases
in normal-sized nodes of bladder and prostate cancer
patients. Eur Urol 55: 761-769.
g. In patients with irritative voiding symptoms

such as dysuria, frequency, and urgency,
bladder cancer, particularly carcinoma in situ
(CIS), must be ruled out (Grade C).
36. Tillou, X., E. Grardel, et al. (2008). [Can MRI be used to

distinguish between superficial and invasive transitional
cell bladder cancer?]. Prog Urol 18(7): 440-444.
37. Tuncbilek, N., M. Kaplan, et al. (2009). Value of dynamic
contrast-enhanced MRI and correlation with tumor
angiogenesis in bladder cancer. AJR Am J Roentgenol
192(4): 949-955.
h. For patients with asymptomatic microscopic

hematuria without risk factors for urothelial
carcinoma, urine cytology or cystoscopy can
be used (Grade B).
38. Van der Aa, M.N., E.W. Steyerberg, et al. (2008). Patients
perceived burden of cystoscopic and urinary surveillance
of bladder cancer: a randomized comparison. BJU
Int101(9):1106-1110
i. For initial work-up of patients with hematuria,

imaging of the upper tracts must be performed
(Grade B).
39. Watanabe, H., M. Kanematsu, et al. (2009). Preoperative T

staging of urinary bladder cancer: does diffusion-weighted
MRI have supplementary value? AJR Am J Roentgenol
192(5): 1361-1366.
2. Cystoscopy and Urinary Markers

a. Cystoscopy alone is the most cost effective
method to detect recurrence of bladder cancer.
Among urinary markers, urine cytology is the
gold standard for surveillance of patients with
non muscle invasive cancer (Grade B).
40. Yoshida, S., F. Koga, et al. (2010). Initial experience of

diffusion-weighted magnetic resonance imaging to assess
therapeutic response to induction chemoradiotherapy
against muscle-invasive bladder cancer. Urology 75(2):
387-391.
b. C
ytopathologists
should
nomenclature (Grade C).
use
uniform
c. Bladder wash cytology provides a better

diagnostic yield than voided urine cytology
(Grade B).
60
d. When cystoscopy is performed, thorough

cystoscopy with minimal manipulation should
be performed, the residual urine should be
collected, and then a formal bladder lavage
should be performed. Both the residual urine
and the bladder lavage specimen should be
sent for cytology (Grade D).
e. For patients with invasive bladder tumors,

evaluation for metastatic disease should
include chest radiography, liver function tests,
and alkaline phosphatase measurement
(Grade C).
f. B
one scan is not necessary in all cases but
should be performed in patients with bone pain
or elevated alkaline phosphatase concentration
(Grade B).
e. In the follow-up of patients with urothelial

neoplasms, urine cytology is most useful for
diagnosis of high-grade tumor recurrence
(Grade B). Urine cytology is especially
valuable
for
differentiating
high-grade
urothelial carcinomas from low-grade urothelial
neoplasms (Grade B).
5. Technique of TURBT
a. A
t present, there is insufficient information
to support the recommendation of a specific
technique for TURBT (Grade D).
f. T
here is no consensus on the application of
urinary markers in the diagnosis of bladder
cancer (Grade D).
b. Patients undergoing TURBT should be given

appropriate prophylactic antibiotics (Grade
B).
g. T
he role of urinary markers in particular FISH
(fluorescence in situ hybridization) appears
to be most useful in the setting of a negative
cystoscopy and atypical cytology. (Grade C).
c. T
he shape, size, and location of the
tumor should be documented explicitly as
these details provide important prognostic
information (Grade C).
3. Newer Modalities for Endoscopy
d. T
he appearance of the base of the tumor,
whether sessile or pedunculated, should be
documented as the appearance often predicts
the invasiveness of the tumor (Grade C).
a. White light cystoscopy (WLC) is the gold

standard for evaluation of the lower urinary
tract (Grade B).
e. Separate tumor base and margin biopsies

should be performed during TURBT (Grade
C).
b. Fluorescence cystoscopy improves the rate of

detection of carcinoma in situ (CIS) (Grade B).
Fluorescence-guided transurethral resection
of bladder tumor (TURBT) decreases the
likelihood of leaving behind residual tumor
(Grade B).
f. During TURBT, complete tumor resection

should be attempted except in patients with
diffuse CIS (Grade C).
g. CIS may manifest as velvety erythematous
patches. Endoscopists should specifically look
for such changes, and all suspicious lesions
should be biopsied (Grade C).
c. Fluorescence cystoscopy can be used in the

examination of patients with positive findings
on voided urine cytology but negative findings
on WLC (Grade C).
h. During TURBT, bladder perforation should be

avoided (Grade C).
4. Imaging
a. For initial work-up of patients with hematuria,
imaging of the upper tracts must be performed
(Grade B).
i. When the ureteral orifice is resected, cutting

current should be used; coagulation of the
ureteral orifice should be avoided. Three to 6
weeks after resection of the ureteral orifice, a
functional study should be obtained to check
for stenosis (Grade C).
b. While computed tomography (CT) urography

is becoming the de facto standard imaging
modality for patients with bladder cancer,
intravenous urography (IVU), CT of the
abdomen and pelvis, ultrasound, and magnetic
resonance imaging (MRI) are options (Grade
C).
j. A
ggressive resection of a tumor in a bladder
diverticulum can lead to perforation. Low-grade,
noninvasive tumors in a bladder diverticulum
may be treated with transurethral resection or
fulguration with or without intravesical therapy
(Grade C).
c. Imaging for staging should be obtained prior to

TURBT or delayed for 1-2 weeks after TURBT
to avoid artifacts (Grade C).
k. A
second TURBT should be performed in all
patients with a high-grade Ta lesion or any T1
lesion (Grade B). The optimal timing of repeat
TURBT is within 1-4 weeks after the first
resection (Grade C).
d. A
bdominal and pelvic imaging (MRI or CT)
is not accurate for staging of primary bladder
tumors but may be useful for confirming or
ruling out metastatic disease (Grade B).
61
l. Routine random bladder biopsies are not

recommended (Grade C). Patients with positive
findings on urine cytology and normal findings
on cystoscopy should undergo random bladder
biopsies (Grade B). Patients undergoing
partial cystectomy should undergo random
bladder biopsies (Grade C).
m. Routine prostatic urethral biopsy is not
recommended at initial evaluation. Prostatic
urethral biopsy is indicated in cases of
multifocal urothelial carcinoma of the bladder,
CIS, and visible abnormalities of the prostatic
urothelium (Grade B).
n. Prostatic urethral biopsy should be performed
using electrocautery loop resection including
the 5 oclock and 7 oclock positions of the
verumontanum (Grade B).
62
Committee 2
Pathology Consensus Guidelines

by the Pathology of Bladder
Cancer Work Group
Chairs:
Mahul B. Amin,
Victor E. Reuter
Members:
Jonathan I. Epstein, David J. Grignon, Donna E. Hansel,
Oscar Lin, Jesse K. McKenney, Rodolfo Montironi,
Gladell P. Paner, Mark Soloway,
and
Members of the Pathology of Bladder Cancer Work Group

Participants:
Hikmat A. Al-Ahmadie, MD (New York, NY, USA)
Ferran Algaba, MD (Barcelona, Spain)
Syed Ali, MD (Baltimore, MD)
Isabel Alvardo-Caberrera, MD (Mexico City, Mexico)
Lukas Bubendorf, MD, PhD (Basel, Switzerland)
Liang Cheng, MD (Indiana, IN, USA)
John C. Cheville, MD (Rochester, MN, USA)
Glenn Kristiansen, MD (Zurich, Switzerland)
Richard J. Cote, MD (Miami, FL, USA)
Brett Delahunt (Wellington, New Zealand)
John N. Eble, MD (Indianapolis, IN, USA)
Mahmoud Elbaz, MD (Cairo, Egypt)
Elizabeth Genega, MD (Boston, MA, USA)
Christian Gulmann, MD (Dublin, Ireland)
Arndt Hartmann, MD (Erlangen, Germany)
Cord Langer, MD (Graz, Austria)

Antonio Lopez-Beltran, MD (Cordoba, Spain)
Cristina Magi-Galluzzi, MD, PhD (Cleveland, OH, USA)
Jorda Merce, MD, PhD (Miami, FL, USA)
George J. Netto (Baltimore, MD, USA)
Esther Oliva, MD (Boston, MA, USA)
Priya Rao, MD (Houston, TX, USA)
Jae Y. Ro, MD, PhD (Seoul, S. Korea)
John R. Srigley, MD (Toronto, ON, Canada)
Satish K. Tickoo, MD (New York, NY, USA)
Toyonori Tsuzuk, MD, PhD (Nagoya, Japan)
Saleem A. Umar, MD (Miami, FL, USA)
Theo Van der Kwast, MD (Toronto, ON, Canada)
Robert H. Young, MD (Boston, MA, USA)
63
Table of Contents
Introduction
III. Prognostic and Predictive Biomarkers

in Urothelial Carcinoma
A. Urinary Bladder Histoanatomy and

Impact on Cancer Diagnosis and Staging
IV. The Utility of Immunohistochemistry

In The Differential Diagnosis Of Primary
Versus Metastatic Tumors To The Urinary
Bladder
I. Epithelial Changes
II. Lamina Propria (LP)
V. The Use of Immunohistochemistry in

Flat Urothelial Lesions with Atypia
III. Muscularis Mucosae

IV. Indeterminate Muscle type
V. Muscularis Propria
F. RECOMMENDED NOMENCLATURE FOR URINE

CYTOLOGY
VI. Adipose Tissue
I. Nomenclature and Reporting
VII. Regional Variations in Bladder Wall
II. Role of urine cytology in screening

and monitoring patients with bladder
cancer
B. Classification and Grading of Noninvasive Urothelial Neoplasms
III. Role of FISH in screening and

monitoring of bladder carcinoma
C. UPDATES ON GRADING OF NON-INVASIVE

AND INVASIVE UROTHELIAL CARCINOMA OF THE
URINARY BLADDER
G. UPDATED PROTOCOL FOR THE EXAMINATION

AND HANDLING OF SPECIMENS FROM PATIENTS
WITH URINARY BLADDER CARCINOMA
I. Grading Non-invasive Papillary

Urothelial Neoplasms: Tumor
Distribution and Impact to Outcome of
WHO (2004) Versus the Prior 1973 WHO
Grading System
I. Introduction
II. Relevant Clinical History
III. Urologists Handling of Specimens
IV. Pathologist Handling of Biopsy
Specimens
II. Inter- and Intra-Observer

Reproducibility Studies on Grading
V. Pathologist Handling of
Transurethral resections
III. Grading Papillary Urothelial

Neoplasms with Histologic Heterogeneity
VI. Pathologist Handling of Cystectomy

Specimens
IV. Grading of Invasive Urothelial

Carcinomas (pT1 and pT2+ tumors)
VII. Reporting of Histologic Grade
D. Histologic Types of Bladder Cancer

Including Variants of Urothelial
Carcinoma
VIII. Reporting Variant Urothelial

Histology
I. UROTHELIAL CARCINOMA VARIANTS

Carcinoma
IX. Lymphovascular Invasion (LVI)
II. SQUAMOUS CELL CARCINOMA
X. Reporting on Lymph Nodes
III. ADENOCARCINOMA VARIANTS
XI. Reporting of Prostate Involvement
IV. NEUROENDOCRINE NEOPLASMS
XII. Frozen sections
E. ROLE OF IMMUNOHISTOCHEMISTRY AND

ANCILLARY DIAGNOSTICS IN THE DIAGNOSIS,
STAGING, PROGNOSTICATION AND PREDICTION
OF BLADDER CANCER IN CONTEMPORARY
CLINICAL PRACTICE
I. Immunohistochemical Markers for
Staging of Bladder Cancer
II. Summary of molecular/genetic
alterations in urothelial carcinoma
64
Pathology Consensus Guidelines

by the Pathology of Bladder Cancer
Work Group
Mahul B. Amin, Victor E. Reuter,
Jonathan I. Epstein, David J. Grignon, Donna E. Hansel, Oscar Lin,
Jesse K. McKenney, Rodolfo Montironi, Gladell P. Paner,
Mark Soloway,
and

by the pathologist in order to provide optimal pathologic reporting of bladder cancer, 4) on nomenclature
for inverted lesions of the bladder, 5) the histologic
types of bladder cancer and the variants of urothelial cancer, some relatively recently described, with
a focus on definition for diagnosis and their implied
clinico-pathologic significance, 6) role of immunohistochemistry and molecular studies in contemporary
routine practice diagnosis, prognostication or predicition of bladder cancer, 7) the reporting of bladder
cancer in transurethral resection of bladder tumors
(TURBT) and cystectomy specimens, and 8) recommended nomenclature for urine cytology and role of
ancillary testing in urine specimens.
Introduction
There have been several forums in the last two
decades in which an international consensus
dialogue pertaining to the pathology of the bladder
cancer have been conducted and promulgated.
In this document we provide new consensus
guidelines built on past such endeavors, supported
by comprehensive literature review of the recent
literature where possible, and based on the best
practices of an expert group of 38 international
urologic pathologists from 13 countries. While strong
evidence is commonly lacking to make many of the
recommendations herein, the proposals made are in
the interest to move the field forward, acknowledging
where data is lacking, but at the same time providing
consensus guidelines to our clinician colleagues to
provide optimal patient care. It is hoped that when
the guidelines made here are based on the absence
of a high level of evidence in the literature, they will
prompt future studies using these guidelines as a
common platform of nomenclature and the state of
understanding of the pathology of bladder cancer
as it pertains to contemporary patient care in the
year 2011. Where possible, levels of evidence and
grades of recommendation (Table 1) are provided.
It must be noted, however, that the criteria for
levels and grades of recommendation are primarily
promulgated for clinical studies and have been used
by our Pathology of Bladder Cancer Work Group as
a framework to support their guidelines.
Table 1. Levels of evidence and grades of

recommendation*
Levels of Evidence
Level 1: Metanalysis of randomized trials of a good

quality randomized trial
Level 2: Low quality randomized trial or metanalysis
of good quality prospective cohort studies
Level 3: Good quality retrospective case control
studies or case series
Level 4: Expert opinion based on first principles or
bench research, not on evidence
Grades of Recommendation
Grade A: Usually consistent level 1 evidence
Grade B: Consistent level 2 or 3 evidence or
majority evidence from randomized trials
Grade C: Level 4 evidence, majority evidence from
level 2-3 studies, expert opinion
Grade D: No recommendation possible because of
inadequate or conflicting evidence
In this international consultation, we focus on a select important unique aspects and provide an update
on: 1) the knowledge of the histoanatomy of the
bladder as it pertains to the diagnosis and staging of
bladder cancer, 2) the prognostic significance of histologic grading by the WHO (2004)/ISUP system, its
contributions, shortfalls and opportunities for refinement, 3) the information needed from the clinicians
*Adapted from Evidence-based medicine: Overview

of the main steps for developing and grading
guideline recommendations, by P Abrams, A Grant,
and S Khoury, January 2004
65
2. Urothelial Hyperplasia
A. Urinary Bladder
Histoanatomy and Impact on
Cancer Diagnosis and Staging
Urothelial hyperplasia is defined as markedly

thickened urothelium in the absence of cytologic
atypia, and can be flat or papillary. Flat hyperplasia
may be seen adjacent to low-grade papillary tumors
[4]. Papillary urothelial hyperplasia is characterized
by presence of undulating hyperplastic urothelium
arranged into thin mucosal papillary folds of varying
heights in a non inflamed setting [4]. The lack of
cytological atypia and true fibrovascular cores
distinguishes this lesion from papillary neoplasia.
Papillary hyperplasia (Figure 3) is often seen in
patients with prior and subsequent diagnosis of lowgrade papillary urothelial lesions (Level 3), and for
a subset of patients is suggested to be a precursor
lesion for mainly the low-grade lesions [4,5]. This
hypothesis is further supported by the presence of
some genetic alterations found in bladder cancer that
also occur in urothelial hyperplasia [6-8]. Hyperplastic
urothelium may also harbor a varying degree of
atypia, and is suggested to be associated with CIS
and high-grade papillary urothelial carcinoma (Level
3) [9].
I. Epithelial Changes
1. Urothelial Denudation
Prior instrumentation and prior intravesical therapy
are frequent contributors to denudation at cystoscopy
or in bladder specimens. Urothelial carcinoma in situ
(CIS) is also often associated with prominent cellular
discohesion and exfoliation of neoplastic cells in
the urine. The presence of extensive denudation
in bladder biopsy samples has been shown to be
associated with CIS on prior or subsequent bladder
biopsies[1]. (Figure 1) Tissue specimens obtained
by hot wire loop may show urothelial denudation
which can be attributed mainly to thermal effects of
the proceedure, and can be seen even in low risk
patients for CIS. In contrast, substantially denuded
biopsy samples obtained by cold cup biopsy are in
most cases related to CIS. Levi et al [1] showed that
31% of patients with denudation on cold cup biopsy
developed CIS within 24 months, and that CIS was
seen in 75% and 29% of patients with and without
history of CIS, respectively. This demonstrates a
higher risk for subsequent CIS in denuded biopsy
samples in the setting of both cold cup procedure
and with prior CIS (Level 3). In cold cup biopsies with
denudation cystitis, 54% of patients had concurrent
positive urine cytology, stressing the importance of
performing concurrent bladder wash, which has
higher sensitivity for detecting urothelial carcinoma
(Level 3) [2]. Denudation may also have some
implications in papillary urothelial lesions. Papillary
urothelial lesions with extensive urothelial denudation
are more often high-grade carcinomas[3]. (Figure 2)
In denuded papillary lesions, pathologists should do
careful search for residual high-grade cells in order
to avoid under diagnosis (Grade C). Denuded flat
and/or papillary urothelial neoplasms may occur
with prominent cautery artifact or in an anatomically
confined area implicating iatrogenic or mechanical
contributing factors for the epithelial exfoliation.
Figure 1. Urothelial
denudation.
Extensive or complete urothelial denudation in

bladder biopsy samples should be reported (Grade
C). Correlation of denuded biopsy samples with
concurrent cytology results may yield a positive
diagnosis of malignancy in these patients (Grade
C). Urothelial denudation in cold cup biopsies of
cystoscopically abnormal areas in patients with prior
CIS and without any recent intravesical interventions
should be dealt with caution by urologists.
carcinoma
in
situ
with
Figure 2. High-grade papillary urothelial carcinoma

with denudation.
66
From a practical viewpoint there is difficulty and

controversy in diagnosing lesions which do not have
fully established features of papillary neoplasia and
also have accompanying cytologic atypia exceeding
reactive changes. This type of setting may occur in
the seeting of prior treatment and in surveillance
biopsies. As an approach, first, strict criteria including
the absence of true fibrovascular cores are necessary
for the diagnosis of papillary urothelial hyperplasia
versus papillary urothelial neoplasia. Second, the
degree of urothelial atypia when present in the
hyperplastic urothelium should be reported using the
2004 WHO/ISUP terminology for urothelial neoplasia
(e.g. dysplasia or CIS) (Grade C). Third, correlation
with cystoscopy would be valuable to ascertain if
clinically the lesions were deemed to be papillary.
In the absence of true papillae histologically and
in the absence of a clinical papillary presentation,
terminology such as dysplasia with early papillary
formations or CIS with early papillary formations
may be used when criteria for papillary neoplasia
are not fulfilled but there is a background of cytologic
atypia (Grade C). These terms are only descriptive
diagnoses as outcome studies using this terminology
are unavailable. Until substantial evidence for
urothelial hyperplasia as precursor lesion to papillary
urothelial neoplasia becomes available, reporting of
papillary hyperplasia in the absence of dysplasia or
CIS is optional (Grade D).
cell carcinoma, and thus, must be closely followed

(Grade C) [13]. Keratinizing squamous metaplasia
is also related to vesical carcinoma and associated
complications, such as bladder contracture and
ureteral obstruction [14]. Squamous metaplasia is
not uncommon in patients with spinal cord injury or
paraplegia with prolonged catheterization or chronically infected bladders [15,16], and higher risk for
squamous cell carcinoma is reported in these patients (Level 3) [17].
The presence of squamous metaplasia in bladder
biopsies should be reported by pathologists with
specification whether keratinizing or not and focal
or multifocal (Grade C). The word squamoid
should be avoided and unequivocal criteria for
squamous differentiation i.e. intracellular bridges
or evidence of keratinization should be present.
Current evidence does not support any form of
intervention including surveillance cystoscopy for
patients with focal changes, although multifocal and/
or extensive lesions often require intervention due
to intractable symptoms or because they precede
or may be associated concurrent with neoplasia
(Grade C). Spinal cord injury or paraplegic patients
with squamous metaplasia must be followed and
evaluated regularly because of the increased risk for
squamous cell carcinoma (Grade C).
Figure 4. Squamous metaplasia, non-keratinizing.
Figure 3. Papillary urothelial hyperplasia.
4. Glandular Metaplasia
3. Squamous Metaplasia
Glandular metaplasia (cystitis glandularis) (Figure 5)

is a benign proliferative change that may occasionally
show presence of intestinal-type goblet cells (cystitis
glandularis, intestinal type or intestinal metaplasia)
(Figure 6). Glandular metaplasia is supposed
to relate the risk of neoplastic transformation
because intestinal metaplasia often coexists with
adenocarcinoma of the urinary bladder [18,19].
Recent studies however showed that glandular
metaplasia of the urinary bladder is not a strong risk
factor for adenocarcinoma or urothelial cancer (Level
3) [20,21]. The significance of glandular metaplasia as
a pre-neoplastic lesion, particularly in the absence of
intestinal metaplsia, is still controversial, however, its
There are two type of squamous metaplasia in the

urothelial tract, non-keratinizing and keratinizing.
Non-keratinizing squamous epithelium is present in
the trigone in 7586% of women and is considered
to be a normal finding (Figure 4) (Level 2) [10-12]; its
occurrence outside this region is considered metaplastic. Keratinizing type of squamous metaplasia
usually occurs in response to chronic irritative stimuli to bladder such as cystitis, lithiasis, diverticula,
or schistosomiasis. Keratinizing type of squamous
metaplasia can be associated with subsequent
or concurrent in situ or invasive carcinomas with
squamous differentiation (Level 3) and has been
suggested to be a precursor lesion for squamous
67
presence should be reported as it is often associated

and correlates with a cystoscopic abnormality.
Multifocal disease with intestinal metaplasia or that
associated with dysplastic changes may warrant
close clinical follow-up (Grade C). Rare cases of
florid intestinal metaplasia and extensive mucin
extravasation (exuberant cystitis cystica) may result
in a pseudotumorous mass and histologically may
mimic adenocarcinoma [22].
have conditions that may explain the presence of an

environment of ischemia or injury, such as cardiac
and vascular diseases. Viral infection related cellular
changes, for example polyoma (BK) virus-type cellular changes can also mimic urothelial carcinoma [27].
Knowledge of prior therapy procedures is invaluable
for pathologists and clinicians should provide this information as some reactive changes may mimic and
complicate the diagnosis of neoplastic conditions.
Figure 5. Cystitis cystica and glandularis.

Figure 7. Urothelial atypia due to radiation.
Figure 6. Cystitis
metaplasia.
glandularis
with
intestinal
Figure 8. Urothelial atypia after BCG therapy. Note
the presence of granuloma.
5. Reactive Changes
Therapeutic procedures for bladder cancer, such
as chemotherapy, immunotherapy, radiotherapy,
photodynamic and laser treatment, previous resection and gene therapy, may produce alterations in
the urothelial mucosa, and some of these changes
may be mistaken for carcinoma [23]. (Figures 7-9)
Intravesical stones, prolonged indwelling catheter,
trauma, infection, etc. also cause epithelial changes
that can mimic epithelial malignancy. Radiation or
chemotherapy cystitis may show epithelial proliferations that may be confused with invasive urothelial
carcinomas even when the therapy was remotely
performed [24,25]. Pseudocarcinomatous epithelial
hyperplasia occurs most commonly after radiation
or chemotherapy but may also occur in relation to
localized ischemia or injury to urothelium [26]. Most
of these patients without radiation or chemotherapy
Figure 9. Urothelial atypia after mitomycin therapy.
68
basement membrane, should ideally be employed

(Grade C). Studies are needed to establish a
clinically significant definition of microinvasive
urothelial carcinoma. Future studies should also
take into account the LP regional variations such as
the trigone where LP is the thinnest (0.46-1.58 mm)
and muscularis propria boundary is not well defined
[37]. Until there is understanding of the definition, it
is recommended that only stringent criteria (similar
to those proposed above) be used or the term
microinvasive carcinoma not be used (Grade C).
II. Lamina Propria (LP)

1. Interpretation Variability of
(Early) Lamina Propria Invasion
(pT1)
The morphologic features of stromal invasion
include retraction artifact, individual tumor cells,
irregular cords, and strands, or isolated single cells,
cytoplasmic eosinophilia (paradoxical maturation)
and desmoplasia [28-30]. When many or most
of these features are appreciable, diagnosis of
invasion is more definite and reproducible. However,
there are issues with interobserver reproducibility in
the diagnosis of early lamina propria (LP) invasion
[31,32]. In one study, 35% of pT1 carcinomas were
downstaged to pTa, and the reviewers staging
allowed a better estimate of risk for subsequent
progression than the initial staging [32]. Another
study showed agreement for pTa versus pT1 in 80%
among 15 pathologists and in 88% upon re-review,
and consensus and original diagnosis agreed in 68%
of cases [33]. Re-staged pT1 by consensus manner
had better prognostic significance compared to its
original non-pT1 diagnosis [33]. In an interobserver
reproducibility study that focused on early invasion,
Shen et al. showed diagnostic agreement in at
least 15 of 19 genitourinary pathologists in 17 of 26
(65%) of cases and highlighted certain problems
when evaluating early invasive cancer (Level
3). von Brunns nest involvement by urothelial
carcinoma and in the background of inflammation
may be mistaken for invasion and has no impact for
disease progression [34]. Because of the diagnostic
difficulty, when early invasive urothelial carcinoma
is suspected, diagnosis through examination of
additional levels, or in a consensus manner with
a pathology colleague or thru quality assurance
meeting is encouraged (Grade C).
3. Substratification or Substaging of
LP Invasion (pT1)
The usefulness of subclassification or substaging
of LP invasion is still controversial. Subjective and
objective methods have been proposed in the
literature. Subjective methods rely on the presence
of muscularis mucosae (MM) and the vascular
plexus in the LP, which are both inconsistent
histoanatomic landmarks (Level 3) [37] (Figure 10).
Depth of invasion may be established either by twotiered or three-tiered systems. Two-tiered system is
by identifying LP invasion up to (pT1a) or beyond
the MM or vascular plexus (pT1b) and three-tired
system is by identifying submucosal tumor invasion
up to (pT1a), in (pT1b), or beyond (pT1c) the MM or
vascular plexus (Level 3) [38-44]. Since the anatomic
landmarks essential for substatification are not always
present, substaging is not currently recommended in
routine surgical pathology sign out. More objective
methods propose measuring the depth of invasion
with thresholds of 0.5 mm [45] or 1.5 mm [46,47].
Problems precluding use of the depth of invasion
criteria include lack of consistent orientation with
the basement membrane, specimen fragmentation,
issues with reproducibility in measurement, and
lack of established clinical significance. Further, this
method may not be practical for general pathologists,
as it may be laborious particularly when multiple
minute invasion foci are to be measured.
2. Microinvasive Urothelial
Carcinoma
Platz et al. evaluated the reproducibility of pT1

substaging and showed little concordance between
participating pathologists (kappa = 0.22; 95%
C.I. = 0.08-0.36) [48]. Non-biased specimens
obtained from various institutions were used which
is important because handling and processing of
TURBT materials varied among institutions [48].
They concluded that substaging was technically
difficult and has little merit, at least for the general
pathologists and urologists. Other than this study, no
other study has been done to evaluate the usefulness
of pT1 substaging among general pathologists.
The concept of microinvasive urothelial carcinoma

is still controversial and criteria for diagnosis had
varied. Initially, microinvasion was defined as LP
invasion by carcinoma to a depth of 5 mm or less
from the urothelial basement membrane [35]. Others
defined microinvasion as infiltration to a depth of
within 2 mm or less in the LP [30,36]. Lopez-Beltran
et al most recently proposed that the microinvasive
tumor into the LP should be composed of no more
than 20 invading cells measured from the stromaepithelial interface [29].
Substaging of pT1 (Figure 11) is currently not

recommended by the WHO/ISUP consensus
guidelines and this committee due to the lack of
widely accepted and reproducible criteria although
we acknowledge there is much need for future
studies (Grade C). It is however recommended for
Currently, there are no standardized criteria or

prospective study for microinvasive urothelial
carcinoma (Level 4). To diagnose early invasion,
stringent criteria such as: only focal invasion, less
than 1 high power field, or 0.5 mm from the nearest
69
pathologists to provide some form of estimate of

the LP invasion in pT1 tumors with respect to depth
and/or quantity of invasion (e.g. focal, multifocal,
extensive, etc.) (Grade C).
these variations from MP. Weaver et al. [52] have

shown that MM was more often seen in female than
in male bladder LP.
For staging of invasive bladder cancer, involvement
of MM is equivalent to LP invasion or pT1 and
involvement of MP is staged as pT2. Distinction is
very important in initial tumor resection or biopsy
as a vital determinant for subsequent therapeutic
decisions. MM when hyperplastic may be difficult
to differentiate from MP [37,53]. Hyperplastic MM
is composed of more than 3 layers of muscle fibers
thick appearing either as fibers parallel to the surface
mucosa or as small rounded bundles when cut in
cross sections [37,53]. Although hyperplastic MM is
present in the LP of different topographic regions of
the entire bladder specimen, it is most often seen in
the dome [37,53]. There are two described patterns:
(a) aggregates of hyperplastic MM with haphazard
(Figure 12) orientation and irregular outlines
morphologically distinct from that of MP and (b)
hyperplastic compact MM with small parallel muscle
fibers and regular outlines arranged singly or in small
groups (Figure 13). The latter may strongly resemble
MP muscle, and the most reliable distinguishing
feature from MP is on the basis of location in LP [37],
which is not always possible in limited specimens
such as in TURBT (Level 3). Attention to quantity
(usually rare and isolated), location, and comparison
(size being much smaller) with more characteristic
MP, if present, would be helpful; isolated bundles
close to urothelium with haphazard fiber orientation
and irregular outlines favor MM over MP [37]. Other
mimickers of MP are cauterized vascular wall and/or
collagen fibers (Level 3) (Figure 14).
Figure 10. Lamina propria vessels are usually seen

at the level of the muscularis mucosae muscle, but
the location may also vary as shown here.
To avoid confusion in interpretation of the pathology

report, documentation of MM-only invasion by
carcinoma is not required, and should be reported
as urothelial carcinoma with LP invasion (pathologic
stage atleast pT1) when MP is not present and
urothelial carcinoma with LP invasion ( pathologic
stage pT1) when MP is present (Grade C).
Involvement of MM may be included in a comment
to provide information on depth/extent of invasion. It
is important to document whether MP is present in a
bladder specimen with at least high-grade pTa and
all invasive urothelial neoplasia (Grade B). Based on
institutional and clinical preference, some centers do
not report the presence or absence of uninvolved MP
in TURBT specimens containing low-grade papillary
tumors and mention the presence of uninvolved MP
in TURBT specimens containing high-grade tumors,
irrespective of invasion only. Although formal studies
are lacking, information on the amount of MP included
in the specimen (isolated and rare muscle bundles
versus established groups of muscle bundles); or MP
in the area of tumor or not in the vicinity of the tumor,
may yield useful information in the management of
invasive bladder cancer. At this point, reporting this
information is optional and may be communicated in
multidisciplinary conferences (Grade D).
Figure 11. Invasive urothelial carcinoma involving

muscularis mucosae muscle (pT1).
III. Muscularis Mucosae

The muscularis mucosae (MM) is an important
histoanatomic structure to differentiate from
muscularis propria (MP) or deep muscle when
staging invasive urothelial carcinoma in the bladder.
MM muscle bundles are typically thin slender
bundles arranged in single layer of interrupted,
dispersed, or continuous muscle [37,49]. The
bladder MM was initially described by Dixon et al.
[50], and Ro et al. [49] subsequently emphasized
the importance of histologic recognition of MM and
its implications in pathologic staging. Keep et al.
[51] pointed out the importance of recognition of
MM in TURBT specimens to prevent overstaging
of invasive urothelial carcinoma. Paner et al. [37]
further described morphologic variations of MM and
as it relates to the different topographical regions
of the bladder and the challenges in distinguishing
70
IV. Indeterminate Muscle type
Figure 12. Hyperplastic

haphazard type.
muscularis
It may be difficult to distinguish between MM and

MP muscle bundles in some TURBT samples.
Hyperplastic MM, desmoplasia, prior procedures,
or fracturing of muscle bundles by invasive
carcinoma often compound the diagnostic dilemma
in reliably distinguishing MM and MP. Identification
as hyperplastic MM may become challenging
and involvement is equivalent to pT1 and not pT2
invasive carcinoma. On the other hand, MP whose
muscle fibers are splayed by invasive carcinoma
and mimic MM, when involved is staged as pT2.
When indeterminate muscle bundles are observed,
the presence of vascular network with thick walled
vessels may aid in recognition as MM (Level 3)
[37,42,49,54,55]. Also, relationship or distance
from the urothelial basement membrane, quantity
and muscle fiber bundle morphology (haphazard
or in comparison to characteristic MP if present)
may provide additional clues for MM (Level 3)
[37]. Muscle bundles indeterminate between MM
and MP should be reported with terminology such
as invasive urothelial carcinoma with invasion of
muscle, indeterminate type to prompt the urologist
for a restaging biopsy procedure (Grade C). A
second biopsy may provide more definitive staging
information or resolve this problematic situation
(Grade C) [56].
mucosae,
V. Muscularis Propria
Documentation of the presence or absence of MP
and its status of involvement by invasive carcinoma is
required in reporting of biopsy or TURBT specimens
with at least high grade pTa and all pT1+ tumors.
Pathologic staging is considered not adequate
without detailing the presence of uninvolved MP
in pTa or pT1 tumors and its because of the risk
of unsampled MP-invasive disease. Current major
guidelines including those by the American Urological
Association, European Association of Urology
and National Comprehensive Cancer Network
recommend reporting whether MP component
is sampled and involved by tumor in TURBT
specimen. If MP is not present, repeat resection is
recommended for verification of pT stage before
subsequent management decision is made (Grade
B). The recent Japanese bladder cancer guideline
under the auspices of the Japanese Urological
Association and Japanese Society of Pathology also
recommends this approach.
Figure 13. Hyperplastic muscularis mucosae,

compact type which resembles muscularis propria
muscle bundles.
Several terminologies have been used to report MP

muscle such as deep muscle, muscle proper or
detrusor muscle. MM is sometimes reported as
superficial muscle. Use of different terminologies
for bladder muscles may generate confusion in
Figure 14. Dense fibrosis associated with invasive

carcinoma.
71
staging interpretation and specimen adequacy.

These terms are not recommended and use of
standardized nomenclature of MP muscle bundles
is recommended in reporting (Grade C). Obtaining
a separate deep or post tumor resection biopsy
is also recommended to ensure sampling of the
muscularis propria.
or TURBT specimens should not be interpreted as

perivesical fat involvement or pT3 disease. Involvement of adipose tissue by carcinoma in TURBT or
biopsy without MP suggests tumor involving at least
the deeper aspects of LP (Level 3).
The MP is composed of three smooth muscle layers

inner and outer longitudinal layer and a central
circular layer. MP invasion has been divided into
two categories, superficial (pT2a) and deep (pT2b)
based on the depth of tumor invasion. Substaging
of pT2 disease (Figure 15) and recognition of
invasion beyond MP (pT3 disease) is not tenable in
TURBT specimens, where only portion of MP can be
present. In cystectomy specimens, pT2 substaging
is complicated by the lack of a reliable anatomical
landmark to aid in their distinction (Level 3). Currently,
there are no data regarding the reproducibility of
pT2a/b distinction among pathologists (Level 4).
Some outcome studies have shown the lack of
prognostic impact and are against the use of pT2
substaging [57-59]. Although some reports showed
prognostic value of pT2a/b subcategories [60,61].
These varied results may be influenced by the
difficult distinction between pT2a/b, and thus, a more
objective and reproducible anatomical or extent of
disease criterion is needed between pT2a and pT2b
subcategories in cystectomy specimens.
Figure 16. Adipose tissue when present in the lamina

propria is typically situated at the deeper aspect of
lamina propria.
Figure 17. Lamina propria adipose tissue in

transurethral resection tissue fragment.
Because of the consistent presence of adipose

tissue (Figure 19) in the MP, the boundary of
perivesical adipose tissue from the deep (outer)
MP may not be easily delineated (Level 3) [62]
(Figure 20). Distinction between pT2b and pT3a
in a cystectomy is not usually straightforward and
requires the use of low power assessment to identify
tumor extending beyond the outermost boundary of
MP muscle (Level 3). The prognostic significance
of pT3a versus pT2 has also been questioned as it
has been shown to have no significant difference in
recurrence and mortality rate and incidence of lymph
node involvement [63].
Figure 15. Urothelial carcinoma invading muscularis

propria muscle (pT2).
VI. Adipose Tissue

Adipose tissue is frequently present in the LP and
MP of the urinary bladder, usually scant in the former
and abundant in the latter [62]. When fat is present
in the LP, it is more typically in the deeper aspects
or in the vicinity of the MP [37] (Figures 16, 17).
Pathologic staging (pT1 or pT2 Figure 18) should
be performed based on the type of muscle and not
based on adipose tissue. It is necessary to stress
that involvement of adipose tissue by tumor in biopsy
Similarly, there is limited reliability of pT3a vs.

pT3b subcategorization as gross involvement of
perivesical fat (extravesical fat) may not always be
readily recognizable (Level 3). Distinction between
pT3a and pT3b relies solely on gross findings, which
can be ambiguous compared to the microscopic
72
Figure 20. The typically ill-defined boundary between

muscularis propria muscle and perivesical adipose
tissue. Low power is important in distinguishing
pT2b vs. pT3a.
Figure 18. Unequivocal invasion of A) lamina propria

with wispy fascicles of muscularis mucosae (pT1)
and B) thick bundles of muscularis propria (pT2).
Figure 21. Urothelial carcinoma with microscopic

invasion of the perivesical fat (pT3a).
Figure 19. Urothelial carcinoma invading adipose

tissue within the muscularis propria (pT2).
assessment. Perivesical tissue reactions to the

tumor or prior biopsy may be over interpreted as
extravesical fat involvement. In addition, residents
or physician assistants who are less experienced
sometimes perform the bladder gross examination
and may not document subtleties at the macroscopic
level. The prognostic significance of pT3 subcategory
is controversial; some reports did not show survival
differences [64-66] while some did show differences
between pT3a and pT3b [67,68] (Figures 21, 22)
(Level 4).
Figure 22. Urothelial carcinoma with macroscopic

invasion of the perivesical fat (pT3b).
73
B. Classification and Grading

of Non-invasive Urothelial
Neoplasms
VII. Regional Variations in

Bladder Wall
There are variations in the LP among the different
topographical regions of the bladder. The trigonal
area has a relatively flatter surface and LP is
attenuated where the depth ranges from 0.46 mm to
1.58 mm [37]. In contrast, the LP is deepest at the
dome where it ranges from 0.98 to 3.07 mm [37].
The differences of the depth of the LP in the different
bladder regions need to be taken into account for
future definitions of microinvasive carcinoma or
criteria for substaging pT1 disease (e.g. 2 mm depth
can already be pT2 at the trigone). The distribution
and morphologic features of MM also varies at the
different topographical sites of the bladder [37].
The LP MM muscle bundles are not well defined
in the trigone and the MP muscle bundles in this
region become progressively smaller in caliber
more superficially as they almost reach the surface
(Figure 23A, B). Further, smooth muscle bundles
of the bladder base and the MP of the intravesical
segment of the ureter may simulate vesical MP
muscle in samples from this region. Hyperplastic
MM is most commonly encountered in the dome.
In 22%, isolated or small groups of compact regular
hyperplastic MM muscle bundles are seen in deep LP
situated between the more typical slender MM layer
and the MP. The more superficial location of the MP
and rarity of MM in the trigone, relative abundance
of hyperplastic MM in dome, and presence of the
more superficial ureteral MP at its insertion site in
the bladder complicate the traditional pT stage
evaluation of invasive cancer in these regions (Level
3) [37]. There is no data to indicate that differences in
histoanatomy of the bladder influence the prognosis
of muscle invasive urothelial carcinoma (Grade D),
although knowledge of these variations is essential
for accurate staging.
1. Introduction
The non-invasive urothelial neoplasms may be flat,
papillary (exophytic) and inverted (endophytic) depending on their growth pattern relationship with the
surface of the surrounding urothelial mucosa [69].
All 3 growth patterns may be seen concomitantly in
a single tumor (Figure 24). Extensive clinicopathological studies have been published related to the
first two growth patterns, whereas the clinical significance of the third has been dealt with only at a
limited extent.
The World Health Organization (W.H.O.) (2004) /
International Society of Urologic Pathologists (ISUP)
classification system is the recommended system for
classification and grading of urothelial neoplasms. It
has also been endorsed by the W.H.O. 2004 Blue
Book, the 4th Series Armed Forces Institutes of
Pathology Fascicle on Bladder, the 7th edition AJCC
Cancer Staging Manual and this consensus group.
W.H.O. (2004)/ISUP grading system has prognostic
(recurrence and progression potential) significance
between different grades for papillary lesions;
although risk prediction at an individual patient level
is still not possible. There is need for incorporation
of the W.H.O. (2004)/ISUP grade along with other
clinical and pathologic parameters in nomograms
and clinical decision-making algorithms to provide
personalized risk stratification in patients with noninvasive urothelial carcinoma. The aggregate data
in the literature on the W.H.O. (2004)/ISUP system
has shown the following benefits: a) establishment
Figure 23. A) Histology of the bladder at the trigone. The muscularis propria reaches to an almost suburothelial
location. B) Muscularis propria muscle bundles at trigone become progressively smaller in caliber and are
more superficial as they almost reach the surface
74
Figure 24. Examples of the spectrum of tumors in a cystectomy (A), Whole mount section of a bladder with
a preoperative diagnosis of muscle invasive high-grade papillary carcinoma; B, Urothelial dysplasia; from
the specimen shown in A), a papillary neoplasm (C, The neoplasm grows exophytically into the lumen of the
urinary system with a papillary configuration; D, Low-grade papillary carcinoma; from the specimen shown
in C), and an inverted neoplasm (E, The neoplasm, even though a polypoid appearance, is characterized
by an epithelium that shows a non-infiltrative growth into the subepithelial connective tissue; F, Low-grade
inverted urothelial carcinoma; from the specimen shown in E).
75
b) Urothelial Dysplasia
of uniform terminology and common definitions for

papillary neoplasms; b) establishment of detailed
criteria of various preneoplastic conditions and
various grades of tumor; c) correlation with urine
cytology terminology, facilitating cyto-histologic
correlation and making it easier for urologists
to manage patients; d) creation of a category of
tumor that identifies a tumor with a negligible risk
of progression (PUNLMP), whereby patients avoid
the label of having cancer which has psychosocial
and financial implications, neither is a benign lesion
(papilloma) diagnosed in these patients, so they
may still be followed up closely; e) approximately
half the cases occurring in young patients (patients
less than 20 years of age) are now diagnosed as
papillary urothelial neoplasms of low malignant
potential instead of transitional cell carcinoma grade
1 obviating a carcinoma diagnosis in patients with
biologically indolent tumors and in keeping with their
molecular profile; f) identification of a distinct group of
patients (high-grade papillary urothelial carcinoma)
who would be ideal candidates for intravesical
therapy; g) identification of a larger group of patients
at high risk for progression for urologists to follow up
more closely; h) removal of ambiguity in diagnostic
categories in WHO 1973 system (e.g., TCC grade
I-II, TCC grade II-III); h) stratification of bladder
tumors into prognostically significant categories; and
i) emergence of molecular correlates and signatures
for high grade tumors and tumors at the low-grade
end of the spectrum which may help provide ancillary
grading tools, facilitate patient management, and
possibly guide in future refinements of the current
grading system.
Urothelial dysplasia is characterized by architectural

distortion and a variable degree of atypia. The
thickness is usually normal ( but may be attenuated
or hyperplastic) and cytological changes are often
restricted to the intermediate and basal cells.
The nuclei are irregularly enlarged with loss of
polarity. Nuclear outlies are irregular and chromatin
abnormalities, although subtle, are present.
Nucleoli are variable, absent but not conspicuously
present. Mitotic activity is scant, usually involving
only the basal and intermediate cell layers. Overall
features are those of a neoplastic atypia (clear cut
nuclear atypia) but which fall short of the criteria
for CIS; dysplasia is not further graded. Low-grade
intraurothelial lesion is a synonym. There is some
evidence, largely genetic, that dysplasia shares
some abnormalities with CIS and therefore likely
represents a precursor lesion. Few studies, most
dated, indicate a 5-19% risk of developing cancer
[72]. The diagnosis of de novo dysplasia (i.e. in a
patient without history of bladder neoplasia) should
not be made or should be made with great caution
as the vast majority of patients, in the limited studies,
do not progress to cancer (Level 3). While dysplasia
likely represents a marker of urothelial instability, the
diagnosis should not by itself invoke any therapy;
continued surveillance is recommended (Grade C).
c) Urothelial Carcinoma In Situ (CIS)

CIS is characterized by architectural disorder and
distinct high-grade nuclear atypia (definitional feature)
including marked irregularities of the nuclear outlines
and chromatin distribution, nuclear pleomorphism,
prominent nucleoli throughout (if nucleoli are present),
nucleolar pleomorphism, and atypical mitoses on the
surface. There is usually loss of nuclear polarity and
the cells show a high degree of atypia. Mitoses are
generally frequent and may be seen at any level of
the epithelium. There is a spectrum of nuclear and
architectural atypia. CIS defined by WHO (2004)
/ ISUP includes cases diagnosed previously as
severe dysplasia and even some cases previously
diagnosed as moderate dysplasia. The classification
system provides detailed criteria for pathologists, as
CIS may be both over- and under-diagnosed. The
development of invasion is seen in 20 to 30% of the
cases (Level 2) [73-78]. Urothelial carcinoma in situ
of the urethra may extend into underlying prostatic
glands (Figure 25).
2. Flat Lesions and Neoplasms

The 2004 WHO/ISUP classification of the flat lesions
includes flat hyperplasia, dysplasia and carcinoma in
situ. In addition, this classification also lists reactive
atypia, secondary to inflammation, and atypia of
uncertain significance.
a) Flat Urothelial Hyperplasia

Urothelial hyperplasia is characterized by markedly
thickened urothelium with an increase in the number
of cell layers, usually 10 or more, usually with
increased cellularity (increased cells per unit area).
The cells do not show cytological abnormalities,
although slight nuclear enlargement may be focally
present. There is cellular order and morphologic
evidence of maturation from base to surface
epithelium is evident. Mitoses are generally absent. It
has been described in association with inflammatory
disorders as well as adjacent to low-grade papillary
tumours [28]. Molecular analyses have shown that
this lesion may be clonally related to the papillary
tumors in patients with bladder cancer and suggest
a role in the pathogenesis of low-grade papillary
urothelial carcinoma (Level 3) [70,71].
3. Papillary (Exophytic) Neoplasms

The lesions and neoplasms of this group grow
exophytically into the lumen of the urinary system
with a papillary configuration. According to the 2004
WHO classification, this group includes urothelial
papilloma, papillary urothelial neoplasm of low
malignant potential (PUNLMP), low-grade papillary
carcinoma and high-grade papillary carcinoma.
76
grade 1 TCC and approximately 70% of grade 2

TCC in the old 1973 WHO system. WHO grade 1
neoplasms showing mild but distinct cytological
atypia and mitoses, are diagnosed in the 2004 WHO
system as low-grade papillary urothelial carcinomas.
At low magnification the cells are relatively uniform
but enlarged in size with frequent loss of cellular
polarity (loss of linear perpendicular orientation
to basement membrane). There is no significant
pleomorphism. The nuclei tend to be uniformly
enlarged with occasional to consitent irregularities
of nuclear contours. The chromatin is relatively fine
to mildly abnormal with small nucleoli. Mitoses may
be present but are few and remain basally located.
These tumors have a significantly higher recurrence
rate than for PUNLMP (Level 2). They also have
a significantly higher rate of stage progression
than PUNLMP but significantly lower than for highgrade papillary carcinoma (Level 2). A review of the
literature reveals a mean recurrence rate of 50% and
mean stage progression rate of 10%.
Figure 25. Extension of urethral urothelial carcinoma

as urothelial carcinoma in situ involving prostatic
glands.
a) Urothelial Papilloma
Urothelial papilloma is characterized by a few
fine papillary fronds lined by normal-appearing
urothelium. Tumors contain slender minimally
branching papillae and the superficial umbrella cells
are often prominent which may show vacuolization.
Urothelial papilloma shows a very low recurrence
rate and minimal to absence progression rate (Level
2) [79-81].
d) High-grade Papillary Carcinoma

High-grade papillary carcinoma is characterized by
cells with high-grade cytologic atypia (resembling
CIS in a flat lesion) on a fibrovascular core. Cases
exhibit a spectrum with some tumors (approximately
30%) considered grade 2 TCC and most cases
of TCC grade 3 in the old 1973 WHO system. On
low power magnification, the tumor often exhibits
complex papillary architecture and fusion. Individual
cells are haphazardly arranged within the epithelium
and have a generally discohesive nature. The tumor
may show extensive denudation. There is a range
of nuclear atypia, some have obvious pleomorphism
while some have monomorphic nuclei with rounding,
nucleomegaly and irregular clumped chromatin. The
chromatin is dense, irregularly distributed and often
clumped. Nucleoli may be single or multiple and
are often prominent. Mitoses are generally frequent
and may be seen at any level of the epithelium. It
is often associated with invasive disease at the
time of diagnosis [82-89]. These tumors not only
have a risk of invasion but also have a significant
risk of recurrence and progression; association
with multifocality and CIS is common (Level 2). The
overall progression rate (to invasive carcinoma)
ranges from 15% to 40%; more than half the cases
are prone to recurrences.
b) Papillary Urothelial Neoplasm of Low

Malignant Potential (PUNLMP)
PUNLMP is characterized by cytologically bland /
normal appearing cells with hyperplasia (increased
cells per unit area and increased cell layers) on
a fibrovascular core. PUNLMP largely, though
not completely, corresponds to grade 1 papillary
transitional cell carcinoma (TCC) of the old 1973
WHO system. The lesion consists mostly of delicate
papillae with little or no fusion. The covering
urothelium shows monotony with normal size and
preserved polarity characterized by upward streaming
of cells perpendicular to basement membrane. The
umbrella cell layer is often preserved and basal cells
may show palisading. Nuclei lack significant nuclear
hyperchromasia or pleomorphism. The chromatin
is fine and nucleoli are inconspicuous. Mitoses
are infrequent and basally located. This tumor has
a significantly lower rate of recurrence than either
low- or high-grade papillary carcinomas and a very
low rate of grade and stage progression (Level 2).
In a review of published studies, a mean tumor
recurrence rate to be 36% and stage progression
rate to be 3.7% [71].
4. Inverted (Endophytic) Neoplasms

Papillary tumors may be associated with a variable
degree of inverted growth patterns. Although
focal areas of inverted growth are not uncommon,
prominent or exclusive inverted growth is much
rarer and when encountered may pose problems
related to grading or assessment of invasion. The
neoplasms with inverted growth are basically
c) Low-grade Papillary Carcinoma

Low-grade papillary urothelial carcinoma shows
cells with low-grade cytologic atypia (resembling
urothelial dysplasia in a flat lesion) on a fibrovascular
core. Cases would span some tumors considered
77
characterized by an epithelium that shows a noninfiltrative growth into the subepithelial connective
tissue, even though, cystoscopically they might show
a polypoid or dome shaped appearance. Although a
formal grading system is not proposed specifically
for lesions with a predominant inverted growth, nor is
one universally used, we recommend that for tumors
with predominalty invereted growth patterns criteria
which essentially parallels the W.H.O. (2004) / ISUP
system for exophytic tumors and flat lesions be used
(Table 2).
Inverted urothelial papilloma consists of thin

anastomosing trabeculae of urothelial cells within
the subepithelial connective tissue and covered by
a normal or attenuated urothelium without cytologic
atypia [90-92]. Inverted papilloma is associated with a
low risk of recurrence (<5%) (Level 2). In comparison
with inverted urothelial papilloma, the architectural
features favoring a diagnosis of urothelial neoplasms
with inverted growth pattern include thick columns
with irregularity in their width and transition into more
solid areas. The characteristic orderly maturation,
spindling, and peripheral palisading seen in inverted
papilloma are generally absent or inconspicuous.
Although prospective formal studies with uniform

criteria or assessing the clinical significance of the
classification terminology are not yet performed,
standardized nomenclature proposed herein may
facilitate such much needed data (Level 4).
Inverted papillary neoplasms of low malignant

potential show thicker or irregular cords, solid or
nodular growth lacking cytologic atypia; when
cytologic atypia is present tumors are graded as lowgrade or high-grade based on the degree of atypia.
Reports of non-invasive urothelial carcinomas with
inverted growth pattern are found in the literature
using variable nomenclature [28,70,93,94] with two
patterns - inverted papilloma-like pattern), or broadfront pattern (Table 3). Minor degrees of inverted
The classification system includes urothelial

papilloma, inverted papillary urothelial neoplasm of
low malignant potential, inverted low-grade urothelial
carcinoma and inverted high-grade urothelial
carcinoma; the last category may be non-invasive or
invasive.
Table 2. Analogy in nomenclature for inverted lesions
Flat Lesions
Papillary Lesions*
Predominant or Exclusive Inverted

Lesions*
Normal
Papilloma
Inverted papilloma
Urothelial hyperplasia Papillary neoplasm of low malignant
Inverted papillary neoplasm of low
potential
malignant potential
Urothelial dysplasia
Papillary urothelial carcinoma, low grade, Inverted papillary urothelial carcinoma,
non-invasive
low grade, non-invasive
Urothelial CIS
Papillary urothelial carcinoma, high grade, Inverted papillary urothelial carcinoma,
non-invasive
high grade, non-invasive
_
Papillary urothelial carcinoma, high grade, Inverted papillary urothelial carcinoma,
invasive
high grade, invasive
From Epstein JI, Reuter VE, Amin MB. Biopsy Interpretation of Bladder, 2nd Ed.
*Lesions may be both exophytic and endophytic
Table 3. Morphologic, immunologic and molecular genetic features of inverted urothelial papilloma and
urothelial carcinoma with inverted pattern
Characteristic
Inverted urothelial papilloma
Surface
Smooth, domed shaped, usually intact

cytologically normal
Endophytic, expansive, sharply
delineated, anastomosing cords and
trabeculae
Orderly polarized cells, some with
spindling and palisading at the periphery.
No significant atypia, mitoses rare
Low p53 expression and Ki-67
proliferation index
Rare deletions at chromosome 9 or 17,
rare FGFR3 mutations, low rate of LOH**
Benign, rare recurrences*
Growth pattern
Cytologic features
Immunohistochemistry
Molecular analysis
Biological potential
*Rare recurrences related to incomplete excision

**Loss of heterozygosity
78
Urothelial carcinoma with inverted

growth
Usually exophytic papillary lesions present
Endophytic, lesional circumscription
variable
Variable, nuclear pleomorphism and atypia
present
Variable, usually high p53 and Ki-67
proliferation index
Frequent FGFR3 mutation, chromosome 9
and 17 deletions
Recurrences and progression may occur
pattern should not be acknowledged in the pathologic

diagnosis. Prominent of predominant patterns may
be diagnosed using terminology such as papillary
urothelial neoplasm of low malignant potential with
prominent inverted growth pattern, no evidence of
invasion or papillary urothelial carcinoma, lowgrade, non invasive, with prominent areas of inverted
growth pattern.
low-grade papillary carcinoma represented the

largest grade category by 2004 WHO/ISUP system
which comprised 36-74% of the papillary tumors,
and G2 (31-84%) the largest when 1973 WHO
system was applied. High-grade papillary carcinoma
(2004 system) generally had greater proportion
of tumors than G3 (1973 system). In 6 of 7 series,
high-grade papillary carcinoma constituted > 10%
of tumors, whereas, G3 was comparatively smaller
and constituted > 5% of tumors in only 1 out of the
7 studies. In most studies, PUNLMP generally had
lower number of tumors than G1 tumors. In summary,
studies have attempted to correlate the 1973 and the
2004 system with variable success as there is not
a direct correlation between the 2 systems due to
differing criteria[70,79,83-85,90,91].
High grade invereted tumors may be non invasive

or invasive. The diagnosis of invasion requires the
unquestionable presence within the lamina propria of
irregularly shaped nests or single cells that may have
evoked a desmoplastic or inflammatory response.
When a stromal response is absent, irregularity
of the contours of the invasive nests, architectural
complexity and recognition of single-cell invasion
are helpful (Table 4).
Since its introduction, several studies had compared

the impact to disease outcome of the 1998 ISUP/
WHO (2004 WHO) system to the 1973 WHO system
in same patient cohort of non-invasive papillary
urothelial neoplasm (Table 6). To eliminate the
influence of stage, studies that combined noninvasive with pT1 tumors or deep muscle-invasive
tumors were not included in this review. Some studies
have shown advantage for the 2004 WHO grading
system over the 1973 WHO grading system.
C. UPDATES ON GRADING OF
NON-INVASIVE AND INVASIVE
UROTHELIAL CARCINOMA OF THE
URINARY BLADDER
Since its introduction in 1998, the different
components of 2004 WHO (1998 ISUP/WHO)
grading system for urothelial neoplasms have been
the subject of several clinicopathological validation
studies, observer variability studies, and comparative
analysis with the older 1973 WHO grading system.
This review focuses on critical diagnostic pathologyrelated issues of the 2004 WHO/ISUP grading
system, with appropriate comparison with the 1973
WHO grading system based on published studies.
Cao et al [95] reviewed 172 pTa (out of 269 non

muscleinvasive tumors) with long follow-up (up to
10 years) and demonstrated significant differences
between low-grade papillary carcinoma and highgrade papillary carcinoma in recurrence-free survival
(p= 0.05, log-rank test) and progression free-survival
(p= 0.01, log-rank test). No PUNLMP was identified
in the study cohort. The 1973 WHO system in
contrast showed significant difference only in
progression free-survival (p=0.03, log-rank test) and
not in recurrence-free survival. Both WHO grading
systems were unable to predict the overall survival.
I. Grading Non-invasive Papillary Urothelial Neoplasms:

Tumor Distribution and Impact
to Outcome of WHO (2004) Versus the Prior 1973 WHO Grading System
Burger et al [96] reviewed 104 pTa tumors that

included 51 early onset (< 45 years old patients)
(median follow-up of 48 months) and 63 regular
onset (> 45 years old patients) (median follow-up
of 43 months) tumors. In early onset pTa tumors,
both WHO grading systems were not significantly
related to recurrence-free survival or to progression
to muscle invasive disease. In regular onset, both
2004 WHO system (p=0.021, log-rank test) and
1973 WHO system (p=0.035, log-rank test) were
predictive of recurrence-free survival, however only
Table 5 shows a comparative distribution of noninvasive papillary urothelial neoplasms according

to the 2004 WHO/ISUP and 1973 WHO grading
systems in same patient cohorts. In most studies,
Table 4. Urothelial carcinoma with inverted pattern. Criteria for invasion.
Features
Contours of neoplastic nests/
cords
Size and shape of nests
Inflammatory and desmoplastic
stroma
Non-invasive
Regular
Invasive
Irregular
Similar, rounded edges

Absent
Variable, irregular and jagged edges

Present
79
the 2004 WHO system was related to progression

(p=0.002).
Schned et al [98] reviewed 504 non-invasive tumors

(mean follow-up 7.2 years) and similarly showed a
gradient of progressive lower survival times from the
lowest to the highest grade tumors in both 2004 and
1973 WHO grading systems. Compared with survival
times for PUNLMP, the hazard ratio for low-grade
papillary carcinoma was 1.9 (95% CI 1.0-3.4) and for
high-grade papillary carcinoma was 3.0 (95% CI 1.56.0). For the 1973 WHO system, compared to G1
tumors, the hazard ratio for G2 was 1.8 (95% CI 1.13.1) and for G3 was 2.4 (95% CI 1.2-4.7). The study
however did not provide information on recurrence,
progression and disease-specific survival of these
cases.
Yin and Leong [97] reviewed 84 pTa tumors and

showed significant differences in recurrence within
36 months between PUNLMP (17% recurrence) and
low-grade papillary carcinoma (45% recurrence) and
between low-grade papillary carcinoma and highgrade papillary carcinoma (74% recurrence) (p<0.5).
In contrast, no significant difference in recurrence
was observed between the 1973 WHO grades
(urothelial papilloma, G1, G2 and G3 with recurrence
of 0%, 41%, 54% and 67%, respectively).
Some studies did not show a clear-cut advantage
in terms of impact to outcome for the 2004 WHO
system over the 1973 WHO grading system.
Samaratunga et al [99] investigated 134 patients with

pTa tumors and showed no statistical significance
in recurrence rates among the 1998 ISUP/WHO
grades. The only statistically significant difference in
the 1973 WHO system was that G3 had increased
recurrences per year compared with papilloma
(p=0.02), G1 (p=0.0001), and G2 (p=0.0001).
Separate analyses showed both 2004 WHO system
and 1973 WHO system independently predicted
progression (p=0.003 and p=0.002, respectively)
together with tumor size.
May et al [76] compared the prognostic implications

of both WHO grading systems in 200 non-invasive
tumors and with mean follow-up of 72 months
using consensus diagnosis of 4 genitourinary
pathologists. No PUNLMP was identified in the
series. By 2004 WHO system, low-grade papillary
carcinoma and high-grade papillary carcinoma had
5-year recurrence free survival of 69.1% and 46.1%,
respectively (p=0.007) and 5-year progression free
survival of 93.5% and 80.2%, respectively (p=0.084).
By 1973 WHO system, G1, G2 and G3 had 5-year
recurrence free survival of 64.5%, 68.1% and 11.1%,
respectively (p<0.001) and 5-year progression free
survival of 97.2%, 86.9% and 64.8%, respectively
(p=0.002).
Oosterhuis et al [100] reclassified 322 pTa tumors

to 1998 ISUP/WHO and log rank test for five
year progression free survival (p=0.06) and five
year recurrence free survival (p=0.13) were not
significantly different between the grade groups as
a whole. The only significant difference between
Table 5. Distribution of non-invasive papillary urothelial neoplasms according to 2004 WHO (1998 ISUP/
WHO) and 1973 WHO grading systems.*
Study
Total
Cao et al, 2010
172
May et al, 2010
200
Burger et al,
2007
Schned et al,
2007
Yin and Leong,
2004
Samaratunga et
al, 2002
Oosterhuis et
al, 2002
Range
114
504
84
134
322
2004 WHO (1998 ISUP/WHO) system

1973 WHO system
Papilloma PUNLMP
LG
HG
Papilloma
G1
G2 (%)
G3
(%)
(%)
PUC
PUC
(%)
(%)
(%)
(%)
(%)
0
65 (36)
117
44
121 (70) 7 (4)
(64)
(26)
1 (0.5)
149 50 (25)
82
109 (54) 9 (5)
(74)
(41)
6 (5)
77 (71) 26 (24)
58
46 (42)
5 (5)
(53)
179 (38)
214 73 (16)
295 154 (31)
55
(46)
(58)
(11)
3 (4)
32 (38) 46 (55) 3 (4)
0
12
53 (63)
19
(14)
(23)
3 (2)
29 (22) 73 (54) 29 (22)
7 (5)
42
79 (59)
6 (4)
(31)
18 (5)
116 (36)
141 45 (14)
2 (1)
31 (9)
286
1 (1)
(44)
(84)**
2-5%
0-38%
364-64%
0-5%
9-58% 31-84% 1-23%
74%
* Includes only studies that accounted the purely non-invasive tumors; studies combining non-invasive and invasive
tumors and/or without the use of the two grading systems were not included; ** Modified 1973 WHO 2a (214, 66%)
and 2b (72, 22%).
80
Table 6. Outcome of non-invasive papillary urothelial neoplasms by 2004 WHO (1998 WHO/ISUP) and 1973 WHO grading systems.
Study
May et al, 2010
Grade
2004 WHO
1973 WHO
Burger et al, 2007
2004 WHO
1973 WHO
2004 WHO
81
1973 WHO
Yin and Leong,

2004
1998 ISUP/WHO
1973 WHO
Samaratunga et
al, 2002
1998 ISUP/WHO
1973 WHO
PUNLMP
LG PUC
HG PUC
G1
G2
G3
PUNLMP (< 45 years)
LG PUC (< 45 years)
HG PUC (< 45 years)
G1 (< 45 years)
G2 (< 45 years)
G3 (< 45 years)
PUNLMP (> 45 years)
LG PUC (> 45 years)
HG PUC (> 45 years)
G1 (> 45 years)
G2 (> 45 years)
G3 (> 45 years)
PUNLMP
LG PUC
HG PUC
Papilloma
G1
G2
G3
Papilloma
PUNLMP
LG PUC
HG PUC
Papilloma
G1
G2
G3
Total
1
149
50
82
109
9
0
34
12
30
15
1
6
43
14
28
31
4
12
53
19
3
32
46
3
3
29
73
29
7
42
79
6
Recurrence
0 (0%)
55(37%)
29 (58%)
36 (44%)
40 (37%)
8 (89%)
2 (17)
24 (45)
14 (74)
0
13 (41)
25 (54)
2 (67)
0.0/year
0.025/year
0.045/year
0.047/year
0.02/year
0.027/year
0.059/year
0.3/year
p-value
<0.001
<0.001
<0.05
<0.05
NS
G3 vs. papilloma, 0.02

G3 vs. G1, 0.00001
G3 vs. G2, 0.00001
Progression
0
10 (67%)
8 (16%)
4 (5%)
11 (10%)
3 (30%)
2 (6%)
3 (25%)
1 (3%)
3 (20%)
1 (100%)
0 (0%)
0 (0%)
5 (36%)
2 (71%)
2 (65%)
1 (25%)
0%
8%
13%
51%
0%
11%
24%
60%
p-value
0.084
0.002
0.085
G1 vs. G2/3, 0.0105
0.002
G1 vs. G2/3, 0.310
Table 6. Outcome of non-invasive papillary urothelial neoplasms by 2004 WHO (1998 WHO/ISUP) and 1973 WHO grading systems. (continued)
PUNLMP vs. LG PUC, 0.0.36

HG PUC vs. PUNLMP, 0.04
HG PUC vs. LG PUC, 0.16
NS
NS
100% PFS
97% PFS
96% PFS
92% PFS
88 PFS
92 PFS
99 PFS
PUNLMP vs. LG PUC, 0.35
HG PUC vs. PUNLMP, 0.1
HG PUC vs. LG PUC, 0.42
86% RFS
68% RFS
66% RFS
57% RFS
80% RFS
68% RFS
55% RFS
18
116
141
45
31
214
72
1
1973 WHO
Papilloma
PUNLMP
LG PUC
HG PUC
G1
G2a
G2b
G3
1998 ISUP/WHO
Oosterhuis et al,
2002
* NS, not significant; RFS, recurrence free survival; PFS, progression free survival
82
two groups was for five-year progression free

survival between PUNLMP and high-grade papillary
carcinoma (p=0.04, log rank test). By 1973 WHO
system, log rank test for five year progression free
survival and five year recurrence free survival were
not significantly different between the grade groups.
The study by Hlmang et al [101] showed usefulness
of 1998 ISUP/WHO grading system, but also
highlighted an advantage for the 1973 WHO grading
system. 363 primary pTa tumors with follow-up of at
least 5 years were classified according to the 1998
ISUP/WHO grading system. There was recurrence
in 35% PUNLMP compared to 71% low-grade
papillary carcinoma and 73% of high-grade papillary
carcinoma (p<0.0001). Progression was 0%, 4% and
23% for PUNLMP, low-grade papillary carcinoma
and high-grade papillary carcinoma, respectively
(p<0.0001). However, when the 108 high-grade
papillary carcinoma where further subdivided by
1973 WHO system into G2 (95) and G3 (13), there
was a significant difference in progression of 20%
and 45%, respectively (p<0.0022).
In terms of tumor distribution, the grading categories
of the 2004 WHO system did not directly translate
from the 1973 WHO system categories (Level 2).
An advantage for the 2004 WHO system was it
allowed identification of a larger number of patients
with non-invasive papillary urothelial carcinoma that
were at higher risk of recurrence and progression,
as comparatively a higher proportion of tumors were
categorized as high-grade papillary carcinoma than
G3 of the 1973 WHO system (Level 2).
In terms of impact to disease outcome, grade overall
provided important prognostic information in most
of the published studies of non-invasive papillary
urothelial neoplasms, with the 2004 WHO system
demonstrating either comparable results or with
some advantages in predicting recurrence and/or
progression than the 1973 WHO system (Level 3).
However, there was evidence suggesting that highgrade papillary carcinoma is heterogeneous in terms
of outcome and subdivision into G2 and G3 by 1973
WHO system may provide additional prognostic
information (Level 3). This data may be helpful in
future refinements of the WHO grading system
to increase the predicitive power of high grade
tumors focusing on morphologic and/ or molecular
subcategorization. Accumulated evidences thus far
support for the continued application of the 2004
WHO system in grading non-invasive papillary
urothelial carcinoma (Grade B).
II. Inter- and Intra-Observer

Reproducibility Studies on
Grading
The percentages of the grading categories for both
WHO grading systems in non-invasive papillary

urothelial neoplasms had varied significantly in
previous studies (Table 5). The percentages of 2004
WHO PUNLMP, low-grade papillary carcinoma and
high-grade papillary carcinoma were 0-38%, 36-74%
and 4-64%, respectively. The percentages of 1973
WHO G1, G2 and G3 were 9-58%, 31-84% and
1-23%, respectively. Differences in patient cohort
geography may partly explain the broad differences,
but the influence of interpretation variability among
pathologists as well cannot be discounted.
Thus, the 2004 WHO system did not show better

intra or inter-observer reproducibility than the 1973
WHO system. The group suggested that the degree
of variability between pathologists could be quantified
using a mean grade, and such can be a potential tool
for quality assurance in pathology.
In the study by Gnl et al [104] of 258 papillary
urothelial carcinoma, the overall degree of
reproducibility between 2 pathologists was higher in
the 2004 WHO system ( 0.59) than the 1973 WHO
system ( 0.41), although both were still moderate
in agreement. PUNLMP showed the lowest degree
of agreement and if excluded from the analysis,
interobserver concordance of the 1998 WHO/ISUP
increased significantly ( 0.84).
Table 7 summarizes several published grading

observer variability studies in papillary urothelial
neoplasms, and includes some that compares the
2004 WHO system with the 1973 WHO grading
system.
In the study by Mamoon et al [105], the agreement

on 80 urothelial neoplasms between 2 pathologists
for the 2004 WHO system was excellent ( 0.91),
whereas agreement for 1973 WHO system was good
( 0.68). By 2004 WHO system, the kappa value for
low grade and high grade tumors showed excellent
agreement while the kappa value for papilloma and
PUNLMP showed fair to good agreement.
In the study by May et al [76], 200 papillary urothelial

carcinomas were reviewed independently by 4
genitourinary pathologists and graded according to
both 2004 WHO and 1973 WHO grading systems.
Owing to the rare PUNLMPs in the cohort, the WHO
2004 approached a two-tiered system (low and high
grades) and showed less interobserver variability
than the 1973 classification ( 0.30-0.52 vs. 0-0.37,
respectively). In comparing the power of both
classifications to separate indolent from aggressive
papillary carcinoma, striking pathologist-dependent
differences were observed. Only 2 of 4 pathologists
provided a grading under the 2004 WHO system that
was significantly prognostic regarding recurrence
and progression.
Campbell et al [106] showed moderate agreement in

grading 49 non-invasive papillary urothelial neoplasm
using WHO 2004 system whether by one ( 0.45) or
two ( 0.60) pathologists.
Yorukoglu et al [107] in a review of 30 papillary
urothelial neoplasms with 6 genitourinary pathologists
showed for both 1998 ISUP/WHO system and 1973
WHO system moderate interobserver agreement
( 0.56 and 0.48, respectively). For both grading
system the mean rate of agreement was lowest for
the lowest grades (PUNLMP and G1) and highest for
highest grades (high grade papillary carcinoma and
G3). There was substantial intraobserver agreement
for both 2004 WHO system and 1973 WHO system
( 0.67 and 0.66, respectively).
In the review by Miyamoto et al [102 ] of a single

institution cohort of 112 low-grade urothelial carcinomas, 8 of 55 cases (14.5%) originally diagnosed
as low grade by general surgical pathologists were
reclassified as high-grade urothelial carcinomas after review by 2 genitourinary pathologists. The main
reason for the upgrade was the presence of previously undetected focal high-grade areas amidst the
predominantly low-grade urothelial carcinoma.
In the study by Murphy et al [108], 247 biopsies

were reviewed by 3 pathologists and by the
1998 ISUP/WHO system, there were substantial
interobserver agreement for high grade papillary
carcinoma and CIS ( 0.75 to 0.82) compared with
slight to moderate agreement for PUNLMP and lowgrade papillary carcinoma ( 0.12 to 0.50). When
discriminating PUNLMP vs. low-grade papillary
carcinoma, discrepancies were 50% after educating
the pathologists compared to 39% before education.
In discriminating low-grade vs. high-grade papillary
carcinoma and PUNLMP vs. high-grade papillary
carcinoma, discrepancies were 15% and no
discrepancy after education.
Van Rhijn et al [103] compared the 2004 WHO system

and 1973 WHO system for observer variability and
prognosis in 173 non-muscle invasive bladder
cancers. For 2004 WHO system, the intraobserver
and interobserver agreements were 71% to 88% (
0.55-0.81) and 39% to 74% ( 0.17-0.58 in first round
and 0.14-0.41 in second review), respectively. If
PUNLMP and low-grade papillary carcinoma were
condensed, the intraobserver agreement increased
to 85-97% ( 0.68-0.91) and interobserver agreement
varied from 68% to 87% ( 0.68-0.91). For WHO
1973, intraobserver and interobserver agreements
(for 2 pathologists) were 80% to 81% ( 0.67-0.69)
and 39% to 64% ( 0.15-0.41). If G1 and G2 were
condensed to one grade, intraobserver agreement
increased to 91-95% ( 0.64-0.88) and interobserver
agreement ranged from 81% to 91% ( 0.47-0.67).
Most published observer variability studies showed

that both 2004 and 1973 WHO grading systems for
bladder urothelial neoplasms suffered from suboptimal
observer agreement among pathologists, with most
83
Table 7. Inter and intra observer variability studies in grading of papillary urothelial neoplasm.
Study
May et al, 2010
Cases
Grading system
Grades (No.)
200 papillary urothelial

neoplasm
2004 WHO
PUNLMP (1)
LG PUC (149)
HG PUC (50)
G1 (82)
G2 (109)
G3 (9)
LG PUC (13)
HG PUC (297)
G1 (0)
G2 (112)
G3 (198)
PUNLMP
LG PUC
HG PUC
1973 WHO
Otto et al, 2010
310 pT1 papillary

urothelial carcinoma
2004 WHO
1973 WHO
Van Rhijn, 2009
173 non-muscle
invasive papillary
urothelial neoplasm
2004 WHO
No. of
Interobserver agreement
pathologists
4
71.5% to 82.5% ( 0.30-52, fair
genitourinary
to moderate)
pathologists
38.0% to 73.0% ( 0-0.37 fair
to moderate)
3
90.3%
39% to 74% (first round

0.17-0.58 and second round
0.14-0.41)
Gnl et al, 2007

neoplasm
2004 WHO
1973 WHO
G1 (68)
G2 (79)
G3 (26)
PUNLMP
LG PUC
HG PUC
G1
G2
G3
Intraobserver
agreement
-
83..2%
71% to 88% ( 0.550.81)
39% to 64% ( 0.15-0.41)
4 (2
pathologists),
at least 6
months
interval
2 (2
pathologists),
at least 6
months
interval
4
75% ( 0.59, moderate)
84
1973 WHO
No. of times
reviewed
1
62% ( 0.41, moderate)
80% to 81% ( 0.670.69)
Table 7. Inter and intra observer variability studies in grading of papillary urothelial neoplasm.
Mamoon et al,
2006

neoplasm
2004 WHO
1973 WHO
Overall
Papilloma
PUNLMP
LG PUC
HG PUC
Overall
Papilloma
G1
G2
G3
PUNLMP (12)
LG PUC (28)
HG PUC (9)
6
genitourinary
pathologists
49 non-invasive
papillary urothelial
neoplasm
1998 WHO/ISUP
Yorukoglu et al,
2003
30 non-invasive
neoplasm
1998 WHO/ISUP
Overall
1973 WHO
PUNLMP (10)
LG PUC (10)
HG PUC (10)
Overall
85
Campbell et al,
2004
Murphy et al,
2002
247 biopsies
1998 WHO/ISUP
G1
G2
G3
PUNLMP
LG PUC
HG PUC
In situ
95% ( 0.91, excellent)

0.67
0.75
0.92
0.96
80% ( 0.68, good)
0.25
0.79
0.82
0.82
52% ( 0.45, moderate) with 1
pathologist
71% ( 0.60, moderate) with 2
pathologists
70.9% ( 0.56, moderate)
2, at least 4
weeks interval
78.3% ( 0.67,
substantial)
77.8% ( 0.66,
substantial)
-
48%
72.7%
92%
65.1% ( 0.48, moderate)
56%
67.3%
72%
0.12 - 0.50, slight to
moderate
0.7 - 0.82, substantial
1 (divided into
learning and
study sets)
studies showed only moderate agreement (Level 2).

When compared, the 2004 WHO system showed
relatively better reproducibility than the 1973 WHO
system (Level 3). Among the WHO 2004 grades,
PUNLMP and papilloma had the lowest interobserver
reproducibility and distinction of PUNLMP from
low-grade papillary carcinoma appeared to be the
most difficult. Condensing PUNLMP and low-grade
papillary carcinoma improved grading reproducibility
of the 2004 WHO system. Evidence showed that
education of pathologists might help improve
interobserver reproducibility of PUNLMP versus lowgrade papillary carcinoma. For high-grade papillary
carcinoma, a reason for interobserver variability was
tumor heterogeneity wherein a focus of high grade
was not accounted for amidst a predominantly lowgrade papillary tumor.
secondary (p=0.001) and combined (p=0.0001) were

all significant in predicting progression. Significant
difference in progression free survival between
patients with a combined score of 5 (low grade +
high grade) and those with a score of 6 (pure high
grade papillary carcinoma) (p=0.02) was observed.
Of note among mixed tumors with predominant lowgrade papillary carcinoma, more minor component
of high-grade papillary carcinoma (21%, score of 5)
than PUNLMP (6%, score of 3) was observed, the
former by conventional WHO 2004 grading will be
designated as high-grade papillary carcinoma.
Billis et al [109] applied a similar approach to Cheng
et al [114] in 293 bladder tumors but instead used
the 1999 WHO grading system and correlated
with stage. The study was able to stratify G2 into
subgroups (mixed [G1 + G2] and pure [G2+G2]),
which were statistically different when considering
stage. In G3, there was also a trend for statistical
difference between mixed (G2 + G3) and pure
(G3 + G3) tumors. The study however provided no
information on disease outcome.
The few studies that reviewed intraobserver

reproducibility among pathologists showed no
differences between the 2004 and 1973 grading
systems with both showed moderate to substantial
agreement (Level 3).
Bircan et al [110] applied a similar approach to

Cheng et al [111] and Billis et al [109] in 87 bladder
carcinomas and used 1998 ISUP/WHO, 1973 WHO
and 1999 WHO grading systems and correlated
with stage. Mixed histology (odd number scores)
constituted 18%, 29% and 33% of tumors by 1998
ISUP/WHO, 1973 WHO and 1999 WHO grading
systems, respectively. In the 1998 ISUP/WHO
system, there was significant difference between
low-grade and high-grade carcinomas (p=0.000) and
between mixed low-grade and high-grade (p=0.011)
when correlated to stage. The 1998 ISUP/WHO
system positively correlated with stage, but the 1998
combined scoring did not. The 1973 WHO system
positively correlated with stage, and there was a
weak association between the 1973 combined
scoring and stage. The study also did not provide
information on disease outcome.
III. Grading Papillary

Urothelial Neoplasms with
Histologic Heterogeneity
Grade represents a morphological spectrum, and
variation in the degree and distribution of atypia within
one tumor is well-recognized by pathologists (Figure
26). Admixture of at least two different grades in a
papillary urothelial neoplasms is not uncommonly
encountered, and is reported in 3% to 43% of
tumors [76,109-112]. This histologic heterogeneity
contributed to the lumping of grades (e.g. G1-G2,
G2-G3 or G2-G3) in the older grading systems, and
avoidance of these non-definitive lumped grades
was one impetus for modifications toward a more
defined grading system. The 1998 ISUP consensus,
cognizant of urothelial tumors with variable histology,
suggested that grade should be reported according
to the highest grade present in heterogenous tumors,
but stressed the need of studies to determine how
significant a minor component must be in order to
have an impact on overall prognosis [113].
Cheng et al [111] took into account the heterogeneity
in papillary urothelial neoplasms and proposed a
modified grading approach by combining the most and
second most common 1998 ISUP/WHO grades with
corresponding number designations (e.g. PUNLMP =
1, etc.) to come-up with a score, in a similar manner
to Gleason scoring. The volume of a grade should
be >5% to be considered for grading. The combined
scores resulted in a scale of grades 2 to 6, wherein
the odd numbers 3 and 5 representing mixed grades
accounted for 32% of tumors. Histologic grade based
on the worst grade (p=0.0009), primary (p=0.0004),
Figure 26. Grade heterogeneity in papillary urothelial

carcinoma. Low (right) and high grade (left) areas
86
Krger et al [112] examined the prognostic

significance of grade taking into account the presence
tumor heterogeneity in 151 muscle-invasive bladder
carcinomas. Using the 1998 ISUP/WHO grading
system, 43% of tumors had mixed low-grade and
high-grade papillary carcinoma components, which
resulted in a three-tiered grading of low-grade, mixed
and high-grade papillary urothelial carcinomas. By
Kaplan-Meier analysis, both the 1998 ISUP/WHO
grading system and the three-tiered grading failed to
reach the level of statistical significance. However,
when low-grade were combined with mixed versus
high-grade, this approach allowed stratification of
patients showing a significant difference in diseaserelated survival (p=0.0404). In multivariate analysis
however, this two-tiered grading approach did not
reach the level of significance.
(2004) / ISUP grade to manage patients and to determine intervention. Sharing such difficult cases
in a consensus manner either with other pathology
colleagues or through quality assurance meeting is
encouraged (Grade B). While currently there are no
reliable or acceptable immunohistochemical or molecular markers to assist in grading of borderline lesions, there are promising markers under investigation that may complement histological grading in the
future, especially for difficult cases.
From the few studies available, there is evidence to
suggest that pure high-grade papillary carcinoma has
a different biologic behavior or has higher disease
progression than mixed high-grade and low-grade
tumors (Level 3). Additional studies with long-term
follow-up are needed to determine the prognostic
impact and define the allowable extent or percentage
cut-off of high-grade focus in heterogeneous papillary
urothelial neoplasm. More studies are needed to
determine whether the broader scale summation
grading provides advantage in outcome information
and observer agreement than the conventional WHO
2004 grading system.
May et al [76] identified 3% in 269 non-muscle

invasive tumors that contained elements of both lowgrade papillary carcinoma and high-grade papillary
carcinoma and were able to classify these tumors
into low-grade or high-grade grades by separating
high-grade papillary carcinoma based on 5% cut-off
for high grade areas.
IV. Grading of Invasive

Urothelial Carcinomas (pT1
and pT2+ tumors)
Grade heterogeneity is not uncommonly encountered

in papillary urothelial neoplasms. The 2004 WHO
(1998 ISUP/WHO) system recommends grading of
heterogeneous tumor to be based on the highest
grade present in a tumor (Grade C). There is no
current widely acceptable definition or criteria to
provide quantitative estimate of size of smallest focus
required to upgrade a lesion. While arbitrary criteria
of ignoring less than 5% have been proposed, the
prognostic impact of this criterion in unknown (Level
4). Studies are needed to establish quantitative/
semi-quantitative criteria that need to be present
to alter assignment of grade in tumors with grade
heterogeneity.
Unlike non-invasive papillary urothelial neoplasms

(pTa), the role of histologic grade in pT1 and higher
stage tumors has been suggested to be of only
relative importance. The 1998 ISUP consensus
proposed that invasive tumors should be graded
as low or high grade similar to the scheme used
for grading non-invasive lesions [113]. Herein, we
review the impact of 2004 WHO (1998 ISUP/WHO)
system and 1973 WHO system in grading pT1
tumors. Distribution of pT1 tumors from previous
studies according to the 2004 WHO and 1973 WHO
system is shown in Table 8. In this summary, studies
combining pT1 with pTa tumors are not included, as
it is known that grading has impact on non-invasive
papillary tumors.
For high-grade papillary carcinoma, a reason for

interobserver reproducibility is tumor heterogeneity wherein a focus of high grade is not accounted
amidst a predominantly low-grade carcinoma. Some
authors use the term high-grade urothelial carcinoma arising in a background of low-grade urothelial
carcinoma when unequivocal areas of high-grade
carcinoma are seen. While the distinction between
PUNLMP and low-grade papillary carcinoma is not
that critical in an individual patient, distinction of low
grade from high-grade carcinoma is very important.
When assigning the tumor grade in tumors with
borderline grade histology, other tumor parameters
such as multifocality, previous grade of the tumor,
size of lesions, frequency of recurrence, presence
of concurrent CIS, positive cytology may be factored
in the grading; and the presence of a few or many
of these parameters may influence upgrading
to a high grade lesion (Grade C). Urologists often
use these tumor parameters in addition to W.H.O.
In the study of Cao et al [95], 41 of 42 (98%) pT1

tumors were classified as high grade based on the
2004 WHO system. By 1973 WHO system, these
high grade tumors were classified into 27 (64%) G2
and 15 (36%) G3. No significant differences were
noted in recurrence-free survival, progression-free
survival, or overall survival between G2 and G3
pT1 tumors. Analysis cannot be performed with the
2004 WHO system because of the few numbers of
invasive low-grade tumors.
In the study of Otto et al [115], 310 pT1 tumors were
mostly graded as high grade (96%) and only few
were low grade (4%) by 2004 WHO system. By 1973
WHO system, these invasive tumors were classified
87
Table 8. Distribution of pT1 urothelial carcinoma according to 2004 WHO (1998 ISUP/WHO) and 1973 WHO
grading systems.
Study
Total
2004 WHO system

LG PUC (%) HG PUC (%)
Cao et al, 2010
42
1 (2)
41 (98)
Otto et al, 2010
310
13 (4)
297 (96)
Van Rhijn et al, 2009
164
37 (23)
127 (77)
Kamel et al, 2006
105 high grade tumors
105
into G2 (36%) and G3 (64%) with no G1 tumors

identified. The 10-year recurrencefree survival and
overall survival did not differ significantly between
high grade and low-grade tumors (2004 WHO) or
between G2 and G3 tumors (1973 WHO), but the
cancer-specific survival between pT1G2 and pT1G3
by 1973 WHO system was shown to be highly
significant (p<0.001). This is in contrast to the low
grade versus high-grade tumors by 2004 WHO
system that did not significantly differ in cancerspecific survival.
G1 (%)
0
0
0
-
1973 WHO system

G2 (%)
G3 (%)
25 (64)
15 (36)
112 (36%)
198 (64)
74 (45)
90 (55)
61(58)
44 (42)
high-grade G3) (Level 3); such grade assignments

are difficult in routine practice, and criteria for grading
in invasive settings or impact on management based
on grade are not well defined.
It is recommended therefore that when tumors
are invasive, irrespective of depth, they should be
graded as high grade (Grade C). This rule is also
applicable to the general surgical and urologic
pathology community as deceptively bland variants
such as the nested or small tubular variants that
histologically appear low-grade, tend to behave like
invasive high-grade tumors of similar stage (Grade
C). If for institutional disease management teams or
clinical trials (e.g. for some institutions and protocols
in Europe), assigning grade G2 and G3 is important,
the practice should continue based on respective
protocols or institutional guidelines.
In the study by van Rhijn et al [103] of 164 pT1 tumors,

the 1973 WHO system (p=0.032) and not 2004 WHO
system was significant in univariate analyses for
tumor progression. But both WHO grading systems
were not significant in the multivariate analysis, in
contrast to the reviewed stage and presence of CIS.
Kamel et al [116] reviewed 105 pT1 high-grade
tumors by 2004 WHO system with median follow-up
of 4 years and divided these tumors into G2 (61) and
G3 (44) by 1973 WHO grading system. In terms of
actuarial disease specific survival, 20 of 44 (45%)
patients with high-grade/G2 tumors were alive versus
22 of 61 (36%) patients with high-grade/G3 tumors
(p=0.04). In terms of tumor progression, 13 of 44
(30%) of high-grade/G3 tumors progressed versus
12 of 61 (20%) high-grade/G2 tumors (p=0.02).
There was a trend for high-grade/G3 tumors to have
worse progression free survival rates than high
grade/G2 tumors after controlling treatment modality
chosen, and was not statistically significant owing
to the smaller numbers. In multivariate analysis
high grade/G3 was a significant predictor of tumor
progression (p=0.05) and marginally non-significant
predictor of poor patient survival (p=0.056).
D. Histologic Types of
Bladder Cancer Including
Variants of Urothelial
Carcinoma
Bladder carcinoma may exhibit a diverse array of
morphologies and may mimic many non-epithelial
and non-bladder tumorigenic processes. Greater
than 95% of bladder carcinoma consists of urothelial
carcinoma (formerly, transitional cell carcinoma)
and numerous variants thereof. Other major
subclassifications include squamous cell carcinoma,
adenocarcinoma and neuroendocrine carcinoma.
Although virtually all bladder carcinomas arise from
the associated urothelium, the pathogenesis of most
forms of carcinoma remains unknown with the
exception that tobacco smoking and male gender
play a signficant role.
Both W.H.O. (2004) / ISUP and the older 1973

WHO grading systems when applied to pT1 tumors
are confronted by the fact that the vast majority of
invasive tumors are high-grade (high grade by the
W.H.O. (2004) / ISUP system or G2 and G3 by 1973
WHO system), with only few tumors classified as lowgrade. Because of the predominance of high-grade
tumors, no study has shown the value of W.H.O.
(2004) / ISUP system in pure pT1 tumors (without
including pTa tumors). The older WHO (1973) system
has shown the ability in some studies to provide
grade dichotomy (or divisions) in the invasive pT1
tumors (i.e. G2 versus G3 or high-grade G2 versus
Of the less common major subdivision of bladder

carcinoma, squamous cell carcinoma occurs in
<5% of bladder cancer patients in the Western
hemisphere. Higher rates (although declining) are
seen in parts of the Middle East and Africa, where
infection with Schistosomal species plays a causative
role. Adenocarcinoma affects approximately 2% of
bladder cancer patients and may arise either from
the bladder urothelium or the urachus. Clear cell
adenocarcinoma a distinct form of adenocarcinoma
at this site may arise in a background of
88
endometriosis and resemble its counterparts in

the female genital tract. Finally, neuroendocrine
carcinoma may arise in pure form or be associated
with other forms of bladder carcinoma.
c)
Clinical: The presenting symptoms are

nonspecific and typical for urothelial neoplasms
in general with hematuria as the most common
manifestation[125-131].
Level I evidence is limited for most bladder carcinoma

variants, given their relative rarity. Especially
aggressive forms include micropapillary urothelial
carcinoma, sarcomatoid carcinoma, undifferentiated
carcinoma NOS, signet ring adenocarcinoma and
small cell carcinoma, among others. Variants that are
easily missed due to challenging histopathological
features may result in delayed diagnosis and
treatment; a sampling of such variants includes
nested urothelial carcinoma, large nested variant of
urothelial carcinoma, urothelial carcinoma with small
tubules and plasmacytoid urothelial carcinoma.
d) Gross Appearance: No information available.

e) Microscopic Features: Approximately 10%
of urothelial carcinomas contain foci of glandular

(Figure 27) and approximately 60% show variable
amounts of squamous (Figure 28) differentiation.
This may not reflect the actual frequency as this information is not consistently or accurately recorded
by pathologists. Glandular differentiation is usually in
the form of small tubular formations in conventional
urothelial carcinoma or as a histology similar to enteric adenocarcinoma (Figure 27). Rarely, a coexistent signet ring cell or mucinous component may be
present [117-124].
In general, treatment for muscle-invasive disease

involves complete surgical resection (generally radical
cystectomy) and lymph node dissection, regardless
of morphological subtype. Neoadjuvant or adjuvant
chemotherapy may have a role although treatment
regimens may vary for some of the histologic types or
between institutions. Earlier interventions have been
recently described to improve survival and outcomes
for patients with micropapillary urothelial carcinoma.
As our knowledge of these variants expands, it is
likely that more tailored, personalized therapies
may evolve depending on pathological diagnosis.
To designate squamous differentiation, one must

see clear-cut evidence of squamous production
(intracellular keratin, intercellular bridges or keratin
pearls), and the degree of squamous differentiation when present - usually parallels the grade of urothelial
carcinoma (Figure 28). Therefore, the presence of
squamous or glandular differentiation in a poorly
differentiated neoplasm, particularly at metastatic
sites and in the context of a bladder primary, should
suggest the possibility of urothelial differentiation.
To designate a bladder tumor as squamous cell or
adenocarcinoma, a pure or almost pure histology
of squamous cell carcinoma or adenocarcinoma is
required. From a practical viewpoint, we do make note
of prominent squamous or glandular differentiation
in urothelial carcinoma using diagnostic terminology
such as invasive urothelial carcinoma with prominent
squamous (40%) and glandular (25%) differentiation
[117-124]. In the case of metastatic tumors from the
bladder, knowledge of the presence and percentage
of divergent differentiation may be useful to facilitate
comparison with the bladder primary. The diagnosis
of adenocarcinoma is reserved for pure tumors
[117-124].
I. UROTHELIAL CARCINOMA
VARIANTS
1. Urothelial Carcinoma with
Divergent Differentiation
a) Definition: Urothelial carcinoma has propensity
for divergent differentiation, with the most common

being squamous differentiation followed by glandular
differentiation [117-124]. Virtually the whole spectrum
of bladder cancer variants may be seen in variable
proportions accompanying otherwise conventional
urothelial carcinomas, mostly in cases of high-grade
and high-stage disease. The clinical outcome of
some of these variants differs from typical urothelial
carcinoma, therefore recognition of these variants is
important [125-131]. When divergent differentiation
is seen together with conventional urothelial carcinoma, the pathologist should use the terminology
of urothelial carcinoma with ____ differentiation,
inserting the type of differentiation observed.
f) Differential Diagnosis: The main differential
diagnostic considerations include squamous cell

carcinoma and adenocarcinoma. In the urinary
bladder, the term squamous cell carcinoma should
be reserved for tumors with an exclusive squamous
cell component. Basaloid or clear cell-type squamous
differentiation can be observed rarely, and the
pathologist should be aware of this before making
a diagnosis of urothelial carcinoma with a mixed
squamous cell component [117-124]. The diagnosis
of adenocarcinoma of the bladder is reserved for
pure tumors.
b) Incidence:The actual frequency varies, as

this information is not consistently recorded by
pathologists. Some form of divergent differentiation
may be seen in 7% to 27% depending on the type
of specimen (cystectomy vs. transurethral resection)
[125-131].
g) Ancillary Diagnostic Tests: A recent study

found 74% of urothelial carcinomas with squamous
differentiation showed expression of urothelial and
squamous associated markers (S100P 83%, GATA3
89
35%, uroplakin III 13%, CK14 87% and desmoglein-3

70%)[132]; although reactivity for individual markers
within some tumors did not always correspond with
morphologic differentiation. Of the remaining 26%, 4
cases showed an overall squamous immunoprofile
while 2 cases showed an urothelial immunoprofile
[132]. This particular study showed that a panel of
five antibodies reliably distinguishes carcinomas
of the urothelial tract with squamous and urothelial
differentiation suggesting potential utility due to
management implications. Immunostaining in tumors
with both urothelial and squamous differentiation
showed a mixed profile. The expression of MUC5ACapomucin may be useful as immunohistochemical
marker of glandular differentiation in urothelial
tumors [133].
Figure 27. Urothelial carcinoma with glandular

differentiation.
h) Prognosis: The prognostic significance of squa-
mous or glandular differentiation is unclear, although

some studies have suggested an adverse outcome
[117-124]. This difference in prognosis may not be
apparent when corrected for stage of the disease.
Some studies have shown poor response to chemotherapy or radiation therapy, but it is unclear whether
the poor response is a reflection of histology or the
advanced stage of the disease [125-131]. Some
studies have suggested that these variants may be
more resistant to chemotherapy or radiation therapy
than pure urothelial carcinoma, but this has not been
confirmed [125-131]. A recent meta-analysis of reported data sugested that all of the variant histologies portend a worse prognosis than pure urothelial
carcinoma [126]. Classic studies suggest that squamous differentiation is associated with high-grade
disease and advanced stage and predicts a poor response to chemotherapy, radiotherapy, and surgery
[125-131]. In the context of radical cystectomy, a
recent series determined that squamous differentiation within urothelial carcinoma was an independent
predictor of local recurrence on multivariate analysis
[125]. Also, there is no indication that radiotherapy
would offer any benefit to mixed urothelial carcinoma
with squamous differentiation [125-131]. The presence of mixed histologic features at transurethral
resection could indicate locally aggressive disease.
Of 91 patients with metastatic carcinoma, cancer
progressed despite intense chemotherapy in 83%
with mixed adenocarcinoma and 46% with mixed
squamous cell carcinoma, whereas it progressed in
<30% of patients with pure urothelial carcinoma[125131].
Figure 28. Urothelial carcinoma with squamous

differentiation.
2. M
icropapillary Variant of
Urothelial Carcinoma
a) Definition: Micropapillary carcinoma (MPC) of the
urinary tract is a special type of urothelial carcinoma,

which has papillary structures reminiscent of those
seen in ovarian papillary serous neoplasms and
typically lacks central fibrovascular cores seen within
usual papillary urothelial carcinoma [134]. Most cases
of MPC have been reported in the urinary bladder,
and MPCs of the upper urinary tract including renal
pelvis, ureter and ureteropelvic junction have rarely
been reported [135,136].
The majority of tumors present with advanced
stages and are muscle invasive (> T2) at the time
of presentation. Histologically, the MP component
is encountered in the (a) non-invasive surface
component, (b) invasive component and (c) in
metastasis. The MP pattern may be pure, but is
frequently associated with a high grade conventional
urothelial carcinoma. There is no specified criterion
required to designate a case as MPC, but most
series in the literature have included cases even
with <10% to almost pure MP histology [137,138].
The percentage of MP component has been shown
The presence of squamous or glandular differentiation

in locally advanced urothelial carcinoma of the
bladder does not confer resistance to MVAC and in
fact may be an indication for the use of neoadjuvant
chemotherapy before radical cystectomy [131].
Low-grade urothelial carcinoma with focal squamous
differentiation has a higher recurrence rate [123].
90
to be a significant adverse prognostic factor with the

more MPC component, the worse prognosis[139].
However, since any amount of MPC impacts the
prognosis, no percent limitation is required for the
diagnosis of MPC, but the percentage of the MPC
component should be reported.
invasive component and in all metastatic sites, the

tumor cells are arranged in small tight nests or balls
(Figure 29). The tumor cells in the invasive and
metastatic components are aggregated in lacunae
or stromal retraction spaces, which mimic vascular
invasion. This feature is characteristic of the invasive
MPC. The spaces may be lined focally by flattened
spindled cells or may be devoid of any lining. In most
instances, there is no host response to the tumor
cells that merely seem to occupy hollow spaces
at various random intervals within the tumor. This
pattern of lacunae containing neoplastic cells is also
seen in the metastatic sites. Multiple small cell nests
in the same lacunar spaces are characteristically and
frequently seen. MPC always shows a high nuclear
grade (high grade by the WHO/ISUP classification)
with peripherally oriented nuclei and inverted pattern,
although some areas within a neoplasm may parallel
low-grade urothelial carcinoma. Lymphovascular
invasion (LVI) is present in most of invasive MPCs.
A high frequency has been confirmed by Factor
VIIIR-Ag and Ulex europaeus agglutinin I lectin[1]
as well as CD 31, CD34 and D2-40 [143]. However,
awareness that lacunae of MPC may mimic LVI is
important so as not to overdiagnose the presence of
this feature as LVI . Psammoma bodies, a feature
of ovarian papillary serous neoplasia, are either not
present or exquisitely rare.
b) Incidence: Although it is difficult to estimate
the exact number of reported cases of MPC, at

least 500 cases of this variant have been reported
since the first description of a series of cases in
the urinary bladder in 1994 by Amin et al [134].
This rare histological variant comprises 0.68.2%
of urothelial carcinomas and shows a definite male
predominance (male to female ratio, 5:110:1), which
is higher than in conventional urothelial carcinoma
(3:1) [134,137,138,140]. As mentioned above, since
the amount of MPC component necessary to make
the diagnosis has not been specified, the reported
incidence has varied depending on the amount of
MPC component deemed necessary for diagnosis.
In early studies, the reported incidence of MPC was
0.61.0% of UC. Tumors in these series had at least
10% or 20% with most cases displaying greater
than 50% of MPC. In a recent series, the incidence
was found to be 6-8.2% [140]. In the largest series
reported to date, urothelial carcinoma with any
amount of a MP component was considered as
MPC [137,138]. It is likely that the recently increased
incidence of MPC is due to reporting cases with any
MPC as well as the increased awareness of MPC
by pathologists. Another factor for the different
incidence may be the diagnostic criteria of MPC. A
recent consensus opinion diagnosis result showed
only moderate overall diagnostic reproducibility (k:
0.54). Depending on pathologists, MPC may be
overdiagnosed or underdiagnosed [140].
Cytologic features of MPC include the presence

of singly scattered tumor cells with high nuclear to
cytoplasmic ratio and pleomorphic nuclei, clustered
cells devoid of fibrovascular core (micropapillae),
3-dimensional
cell
aggregates,
cytoplasmic
vacuoles, and micropapillae exhibiting some features
of low-grade urothelial neoplasms[144]. In addition,
urothelial carcinoma in situ is demonstrable in >1/3 of
the cases and concurrent glandular or villoglandular
differentiation is known to occur; rare cases of
mixed trophoblastic differentiation, carcinosarcoma
(sarcomatoid carcinoma), pleomorphic giant cell
carcinoma, lipid cell variant or plasmacytoid UC
have also been reported [145-151].
c) Gross Appearance: There are no specific
gross features to distinguish from other variants

of urothelial carcinoma. MPC shows both surface
papillary and deep invasive component. MPC may
be grossly papillary, polypoid, nodular, ulcerative
and or solid infiltrative. MPC is usually solitary,
but may be multifocal. The size of the tumor is
variable, ranging from a few millimeters to about 10
cm in greatest dimensions. The appearance of the
underlying bladder wall significantly depends on the
extent of invasion, which is commonly extensive in
MPC [141].
The uninvolved mucosa is usually normal, but
sometimes erythematous which may represent
microscopic areas of CIS. No currently well defined
imaging techniques can reliably diagnose MPC
[142].
d) Microscopic Features: The MPC histology
has two distinct patterns; on the surface, it forms

slender, delicate filiform processes with no or rarely
with a fibrovascular core. When cut in cross-sections,
these papillae appear as glomeruloid bodies. In the
Figure 29. Micropapillary variant of urothelial

carcinoma.
91
e) Differential Diagnosis: The main differential
and 4) micropapillae with elongated and slender

nests with average width <4.5 nuclei. Whereas nonclassic MPC with retraction usually showed large
to medium sized nests with >4.5 nuclei and nest
anastomosis and confluence or branching. This
study demonstrated that the overall reproducibility
for the diagnosis of MPC in invasive UCs showing
stromal retraction was only moderate. The diagnosis
of MPC was more reproducible when very restrictive
criteria were applied, but it is not known whether
the use of this diagnostic threshold correlates best
with the clinical outcome. These findings clearly
suggest that more studies are needed to identify the
individual pathological features that might potentially
correlate with an aggressive outcome and lack of
response to intravesical therapy. Finally, caution
should be exercised when considering the use of a
reported MPC diagnosis as the sole determinant in
selecting therapeutic options for individual patients
with invasive urothelial carcinoma.
includes: 1) distinguishing MPC of the bladder from

that of the different sites; and 2) how to separate
classic MPC from conventional UC with retraction
artifact [140,152]. In women, a metastatic papillary
serous carcinoma of the ovary or peritoneal primary
is the main differential diagnosis from MPC of
the bladder, especially if the tumor is originally
discovered in the peritoneum, abdominal lymph
nodes and mesentery or as a carcinoma of unknown
origin. Clinical/radiographic correlation is usually
required, but the possibility of a bladder primary may
be suggested if there is no obvious primary tumor at
another anatomic site. Identification of an admixed
urothelial carcinoma of more typical morphology or
immunohistochemical support (CK 7, CK 20 and
uroplakin III positivity) would be helpful. In a bladder
tumor, pure MP histology may raise concern for a
primary adenocarcinoma of the bladder; however,
the MP architecture is due to neoplastic urothelial
cells in a MP configuration and not due to true
glandular differentiation as also supported by
immunohistochemistry. In primary adenocarcinoma
of the bladder, there is a greater variability of gland
shape and size and of the range of differentiation in
contrast to the typically uniform appearance of MP
component of UC. Carcinomas with MP histology
have also been reported in the lung, breast,
pancreas, colon, stomach and salivary glands. The
best markers to identify urothelial MPC are uroplakin
and CK20, whereas p63, high molecular weight
cytokeratin, and thrombomodulin are less sensitive
and specific. Lung MPC is uniformly TTF-1 positive.
Breast MPC is ER and mammaglobin positive,
while ovarian MPC is ER positive and PAX8/WT-1
positive. No reliable markers for pancreas, stomach
and salivary glands have been reported, but CK20
and CDX2 positivity may be useful to make a
diagnosis of colon primary. In the metastatic setting,
or when MPC occurs without an associated in situ
or conventional carcinoma component for the certain
organ, staining for uroplakin, CK20, TTF-1, ER and
WT-1, and/or PAX8, and mammaglobin is the best
panel for accurately classifying the likely primary site
of MPC [152].
f) Ancillary diagnostic tests: To make a MP

morphology diagnosis, MUC1 expression along
the membrane segment facing the stroma [153]
has been reported to be a feature of MPCs in other
organ systems. Similarly immunohistochemical
expression of CA125, HER2/neu and KL-6 [154,155]
has been reported as distinctive markers of MPC.
However, Sangoi et al stained immunohistochemical
expression of MUC1, CA125 and HER2/neu and
reported that these markers are not entirely specific
for MPC when compared specifically with invasive
urothelial carcinoma having prominent stromal
retraction. As such, these markers lack reliable
diagnostic utility in challenging cases, further casecontrolled studies are needed to compare specificity
versus invasive urothelial carcinoma with prominent
stromal retraction. At present, there are no specific
markers for MPC and no published molecular
comparative data to address this specific diagnostic
issue.
As mentioned in the differential diagnosis, to make

a diagnosis of bladder MPC and to differentiate
from other sites of primary tumor, the most sensitive
marker is reported to be pan-uroplakin, which shows
membranous and/or cytoplasmic staining in most
of bladder cases with negative for breast, lung and
ovary, making it a specific marker for urothelial MPC.
Other markers including EMA, CK20, high molecular
weight cytokeratin, p63, and thrombomodulin are
also positive in urothelial MPC, but less sensitive
and specific compared to pan-uroplakin. Other
markers including CA125, B72.3, Leu M1, BerEp4,
placental alkaline phosphatase have been reported
to be positive. Samaratunga and Khoo also reported
immunohistochemical findings of MPC similar
to conventional urothelial carcinoma with CK7,
CK20, EMA, CEA and high molecular cytokeratin.
However, CA125 staining was seen only in MPC.
Another diagnostic challenge is the differentiation of

classic MPC from conventional UC with retraction
(non-classic). A recent consensus study conducted
by Sangoi et al [140] found that interobserver
reproducibility for a diagnosis of classic and nonclassic MPCs in the 30 study cases was only
moderate (k: 0.54). Although classification as MPC
among the 10 classic MPC cases was relatively
uniform (93% agreement), the classification in the
subset of 20 invasive UCs with extensive retraction
and varying sized tumor nests (non-classic) was
more variable. Classic MPC features included 1)
multiple nests within the same lacunar space, 2)
intracytoplasmic vacuolization, 3) epithelial ring forms,
92
Based on the morphology and immunohistochemical

profile of the MPC, Samaratunga and Khoo [156]
suggest that MPC may be a form of glandular
differentiation in urothelial carcinoma. MPC displays
overexpression of p53 and MIB-1, Aurora-A, but
no statistically significant difference could be made
with conventional urothelial carcinoma except for
Aurora-A. Aurora-A overexpression in MPC may
play a role in aggressive clinical behavior of MPC
[157]. E-cadherin is positive in MPC as seen in usual
urothelial carcinoma, whereas plasmacytoid and
signet ring cell differentiation in UC shows loss of
E-cadherin [158]. The immunoreactivity to Her2Neu
and PTEN has been reported in MPC and might be
relevant in terms of future targeted therapy [159].
percentage of the MP component of the carcinoma.

Radical surgery is mandatory in muscle-invasive
disease, even though patients with lymph node
involvement die from the disease. However, in
non-muscle-invasive disease and in the absence
of associated carcinoma in situ, intravesical BCG
treatment may be offered when the MP component
of the carcinoma component is a small percentage.
The prognosis is uniformly unfavorable; the 5-year
and 10-year survival in the largest study was 51
and 24%, respectively. Samaratunga and Khoo
[156] reported that the prognosis is related to the
proportion and location of the MPC. Cases with
moderate or extensive (> 10%) MPC are at high risk
of being advanced at presentation. Cases with focal
(<10%) MPC and surface MPC have a high chance
of detection at an early stage.
g) Prognosis: There are several important reasons
for recognizing MP variant of urothelial carcinoma.

Most are muscle invasive at presentation and
frequent lymph node and distant metastases
with common sites being lung, liver and bone. (1)
There is an ample evidence to suggest that this
unique MP configuration of UC connotes a more
aggressive clone of neoplastic cells(a) these
tumors are invariably high grade and usually of
high stage and are frequently associated with LVI;
(b) the amount of MP component is correlated
inversely with prognosis, (c) the MP component has
a higher DNA index than did conventional urothelial
carcinoma; and (d) metastatic sites of tumors have a
predominant MP component. (2) Initial presentation
with MP histology in metastatic sites should prompt
consideration of the possibility of UC, especially if the
MP configuration is encountered in the peritoneum,
abdominal lymph nodes or mesentery of a male
patient with an unknown primary or in a female with
normal appearing ovaries. (3) The high association
of MPC with muscle-invasive disease should alert
the pathologists to recommend a clinician to get a
deep biopsy, if the initial biopsy is superficial and
lacks muscularis propria. (4) Recent data suggest
that because of limited response to intravesical
BCG, one group has advocated for early cystectomy
for pTa and pT1 tumors with MP histology, as these
tumors are unlikely to respond to chemotherapy
when used as a secondary treatment modality.
Kamat et al [138] from MD Anderson Cancer Center
reported BCG treatment in 27 of 44 non-muscle
invasive MPCs of bladder (5Ta, 4 CIS and 35T1),
and of these 27 patients, 67% had progression (T2 or
greater), including 22% in whom metastatic disease
developed. Based on their findings, they reported
that the optimal treatment strategy for nonmuscle
invasive MPC is radical cystectomy performed before
progression. However, this recommendation is not
universally accepted as there needs to be confirming
studies from other institutions and also due to the
interobserver variability in the diagnosis of MPC.
3. Nested Variant of Urothelial

Carcinoma
a) Definition: A variant of invasive urothelial
carcinoma consisting of small irregularly distributed

nests with bland cytology which may simulate benign
processes such as Von Brunn nests [143,160-164].
b) Incidence: Rare with less than 100 cases

reported in literature between 1979 and 2007 the
estimated incidences 0.3% [143].
c) Clinical: The tumor typically affects men in later
adulthood (after 50 years of age) [143,162]. The

most frequent clinical manifestations are hematuria,
urgency and signs of ureteral obstruction. At
endoscopy, the tumors may be slightly raised and
erythematous or nodular and infiltrative.
d) Gross Appearance: Tumors typically involve
urinary bladder most commonly involving a trigone or

ureteric orifice. Involvement of ureter or renal pelvis
may also be noted. The size range is from less than
1 cm to 8 cm [143].
e) Microscopic Features: The nested variant of
urothelial carcinoma typically consists of nests of
bland appearing urothelial cells irregularly distributed
within lamina propria and often showing invasion
of muscularis propria (Figures 30, 31). Overlying
papillary tumor or in-situ disease is generally not
present. This tumor has different appearances in
the superficial and deep aspects. In the superficial
zone, the nests are tightly packed but somewhat
haphazardly arranged and often confluent with
little intervening fibromuscular stroma. Sometimes
abortive tubules are noted and this pattern overlaps
with urothelial carcinoma with small tubules (see later
section). The nests generally have bland cytologic
appearance but occasional ones may demonstrate
more atypia with pleomorphic nuclei and enlarged
nucleoli (Figure 31) [165,166]. In the deeper
portions, the tumor cells have a greater degree
of cytologic atypia and the cytoplasm tends to be
Gaya et al [139] recently reported that tumor stage

and patient outcome of MPC may be related to the
93
g) Ancillary Studies: The nested variant of
more eosinophilic than the nests in the superficial

portions. Commonly the nested variant is associated
with deep infiltration of muscularis propria.
urothelial carcinoma typically displays positivity for

high molecular weight keratin (34BE12), cytokeratins
7 and 20 and p63, similar to usual urothelial carcinoma
[143,170]. In comparison to benign mimickers such
as Von Brunn nests, nested urothelial carcinoma
typically shows higher MIB-1 labelling although
examples of nested variant of urothelial carcinoma
showing low MIB-1 expression have been reported
[160,168]. The nested variant of urothelial carcinoma
has also been shown to high positivity for p53 in
comparison to Von Brunn nests. Loss of p21 and
p27 expression has also been observed [160].
h) Prognosis: The nested variant of urothelial
carcinoma usually presents with muscle invasion

and tends to be aggressive [143]. The reported
series are relatively small and it is difficult to
extrapolate specific prognostic information. Some
authors suggest that this tumor is more aggressive
than usual invasive urothelial carcinoma while
others suggest that the prognosis and clinical course
is similar to high grade urothelial carcinoma stage
for stage [143,162,171,172]. The optimum treatment
for nested urothelial carcinoma has not been
established due to the rarity of the tumor. Specifically,
no significant benefit of adjuvant chemotherapy or
radiation has been established [143,162,172].
Figure 30. Nested variant of urothelial carcinoma,

low power.
4. Large Nested Variant of

a) Definition: A variant of nested urothelial
carcinoma consisting of large, irregular to regular
nests with bland cytology [164].
b) Incidence: Rare with the only series reporting 23

consult cases over a 9 year interval.
Figure 31. Nested variant of urothelial carcinoma,

high power.
c) Clinical: Mean patient age is 63.7 years (3989) and 86% are male.
hematuria.
diagnosis is a proliferation of Von Brunn nests [167169]. The latter are generally superficial and closely
related to the overlying urothelium. Proliferating Von
Brunn nests tend to have a rounded interface with
lamina propria and exhibit both architectural and
cytological uniformity. In contrast the nested variant of
urothelial carcinoma is more architecturally complex
with irregularly distributed nests within lamina propria.
Confluence and anastomosis of nests is seen and
the lesion is often deeply invasive into a muscularis
propria. Nephrogenic adenoma may occasionally
enter the differential diagnosis although that lesion
does not often consist entirely of small nests and
cords. It usually has tubular, papillary, cystic or
signet-ring features [167,169]. Other neoplasms
including paraganglioma, carcinoid tumor, secondary
prostatic adenocarcinoma and melanoma may enter
the broad differential diagnosis [143,170]. In these
cases the selective use of immunohistochemistry
can help to resolve the diagnostic problem[170].
Typically present with

e) Microscopic Features: Cases are composed of
medium to large sized nests with either rounded or

irregularly shaped borders, composed of cytologically
bland urothelial cells (Figure 32). In a minority of
cases the invasive component has a broad, pushing
invasive front, similar to that identified in verrucous
squamous cell carcinomas. Unlike the nested
variant of urothelial carcinoma, the large nests are
often separated by broad areas of fibrous tissue
and/or smooth muscle with little to no back-to-back
nests present. Also unlike usual nested carcinoma a
surface component is present in most cases, typically
low grade papillary urothelial carcinoma. At the time
of diagnosis, the large nests are invasive into the
muscularis propria in almost all cases. In a minority
of cases, focal areas of conventional patterns of
invasive urothelial may be identified [167,169,173].
94
urothelial-type cells which may be quite attenuated.

True cuboidal or columnar cells are not seen. The
tumor shows a diffuse pattern of infiltration with
haphazard arrangement of nests and tubules. The
cytologic appearance is low grade but at least focally,
some degree of nuclear pleomorphism may be seen.
Invasion of muscularis propria is often seen.
Figure 32. Large nested variant of urothelial

carcinoma.
f) Differential Diagnosis: The major diagnostic
pitfall is in distinguishing large nested variant from

either a proliferation of von Brunn nests or from an
inverted growth pattern of non-invasive papillary
urothelial carcinoma.
Figure 33. Urothelial carcinoma with small tubules.
g) Ancillary Diagnostic Tests: None available.

h) Prognosis: Follow-up was available for 17 of
f) Differential Diagnosis: The differential diagnosis
the 23 reported cases with an average interval of

43 months (range 5 months - 9 years). In 11 of 17
patients, there was no evidence of disease, while 3
patients were alive with disease and 3 had died of
their disease. In two cases, metastases to the lung
were present. While distinguishing the presence of
invasion from either an inverted growth pattern of
non-invasive papillary urothelial carcinoma or a florid
proliferation of von Brunn nests is difficult, recognition
of large nested variant of urothelial carcinoma is
imperative, as they have the ability to metastasize
and result in death [167,169,173].
includes cystitis glandularis and nephrogenic

adenoma. The glands of cystitis glandularis are
architecturally uniform and are lined by cuboidal to
columnar lining cells in contrast to the urothelialtype cells of urothelial carcinoma with small tubules.
Nephrogenic adenoma typically displays a tubular
pattern but the tubules are often tiny and associated
with other typical patterns of nephrogenic adenoma
such as microcystic, signet-ring and cord-like areas.
a) Definition: A variant of nested urothelial
carcinoma having a major component of small to

medium sized tubules which may be confused
with benign or malignant glandular processes
[164,167,169].
Adenocarcinoma of the urinary bladder displays true

glandular structures lined by cuboidal or columnar
cells. Another important differential diagnosis is
secondary adenocarcinoma of prostate [173].
Marker studies for PSA, PAP, high molecular weight
keration, cytokeratins 7 and 20 and p63 are useful to
distinguish between secondary prostatic carcinoma
and urothelial carcinoma with tubular differentiation
[173].
b) Incidence: Extremely rare with less than a dozen
g) Ancillary Studies: Urothelial carcinoma with
5. U
rothelial Carcinoma with Small
Tubules
reported cases.
small tubules typically shows the marker profile of

urothelial carcinoma which includes positivity for
high molecular weight keratin (34BE12, CK7, CK20)
[173].
c) Clinical: Similar to a nested variant of urothelial

carcinoma.
d) Gross Appearance: Similar to a nested variant
h) Prognosis: Little is known about the prognosis
of urothelial carcinoma.
of urothelial carcinoma with small tubules. Since

urothelial carcinoma with small tubules is often
admixed with solid nests and likely represents part
of the spectrum of nested urothelial carcinoma, an
adverse outcome may occur [174].
e)
Microscopic Features: This deceptively

bland variant of nested urothelial carcinoma is
characterized by irregularly infiltrative small to
medium sized tubules usually admixed with small
solid nests (Figure 33). The tubules are lined by
95
6. Microcystic Urothelial Carcinoma
adenoma sometimes has a microcystic appearance

and enters the differential diagnosis with microcystic
urothelial
carcinoma,
however,
nephrogenic
adenoma typically displays other patterns as well.
In problematic cases, a racemase and Pax 2 or 8
stains maybe useful since it strongly decorates
nephrogenic adenoma.
a) Definition: A variant of urothelial carcinoma
characterized by dilated tubules with microcysts and

macrocyts [169,175-177]. It has been suggested
that the tumor should have at least 25% microcytic
change in order to be designated as microcystic
urothelial carcinoma [143].
Additionally, primary vesicular adenocarcinoma and

secondary adenocarcinoma is sometimes in the
differential diagnosis. Immunohistochemical studies
may be required to resolve the differential diagnosis
[170].
b) Incidence: Rare with less than 20 reported

cases [143].
c) Clinical: No specific clinical features.

d) Gross Appearance: Gross features similar
to nested and small tubular variants of urothelial
carcinoma occasional 1-2 mm macrocysts may be
identified.
g)
Ancillary Studies: Microcystic urothelial

carcinomas stain in a similar fashion to other
urothelial carcinomas [143,177-179].
e) Microscopic Features: The tumor consists of
h) Prognosis: Due to the limited number of cases,
very little is known about the prognosis of this variant,

however, in reported cases, the prognosis has been
similar to usual invasive urothelial carcinoma [143].
tubular structures which are cystically dilated forming

microcysts and occasionally macrocysts (Figure
34). Eosinophilic luminal material and necrotic debris
are often seen. Luminal secretions may display a
targetoid appearance. The luminal secretions stain
positively for periodic acid-Schiff and alcian blue
stains. Calcifications may be present within the cysts.
Urothelial cells, many of which are flattened, line
the cystic structures. Focal mucinous differentiation
may be noted but cuboidal or columnar cells are
not seen. The nuclei are typically bland although
focal atypia may be identified. The tumor has an
infiltrative appearance with involvement of lamina
propria and muscularis propria. A stromal reaction
of varying degree may be identified. The microcystic
pattern may be associated with more typical nested
and small tubular patterns of urothelial carcinoma as
described in prior sections of this publication.
7. Lymphoepithelioma-Like Carcinoma
a) Definition: Lymphoepithelioma-like carcinoma
of the urinary bladder is a variant of urothelial
carcinoma in which there is a dense inflammatory
infiltrate surrounding nests of poorly differentiated
carcinoma cells, imparting a close resemblance to
the well-known lymphoepitheliomas of the head and
neck.
b) Incidence: Although lymphoepithelioma-like
carcinoma was first recognized two decades ago

in 1991, the largest series is 28 cases and the next
three largest series encompass only 13, 11, and 9
cases so lymphoepithelioma-like carcinoma of the
bladder appears rare [180-184].
f) Differential Diagnosis: The most common
differential diagnosis is nephrogenic adenoma

and cystitis cystica glandularis. The latter lesion is
superficial and shows very regular with rounded
epithelial-stromal borders. The glands of cystitis
cystica are often lined by attenuated cuboidal
cells rather than urothelial-type cells. Nephrogenic
c) Clinical: In the 4 largest series, 70% of the
patients have been men. Ages ranged from 44 to

90 years with a median age of 70 years. The age
distribution for women appears to be the same as
for men. The age distribution for patients with pure
lymphoepithelioma-like carcinoma does not appear
to be different from that for patients with mixed
tumors. Macroscopic hematuria is the most common
presenting complaint. Urgency, burning sensation
at micturition, increased frequency of micturition,
and difficulty in micturition have also been reported,
although the last two may be symptoms of
concurrent prostatic hyperplasia. Little information
is available about the cystoscopic appearances of
these tumors.
d) Microscopic Features: As the name indicates,
the essence of the histology of these tumors is

a resemblance to the lymphoepitheliomas of the
nasopahrynx: syncytial-looking nests sheets and
cords of large poorly differentiated carcinoma
cells in a stroma heavily infiltrated by lymphocytes
Figure 34. Microcystic urothelial carcionoma.
96
f) Prognosis: For 28 patients from the major series
(Figure 35). The carcinoma cells have large vesicular

nuclei with prominent nucleoli and mitotic figures
are usually numerous. Rarely, the nuclei may be
dramatically pleomorphic [185]. The lymphoid infiltrate
may includes populations of plasma cells, histiocytes,
and granulocytes. While some lymphoepitheliomalike carcinomas are tumors composed entirely of this
element, many times the diagnosis is applied when
areas of lymphoepithelioma-like carcinoma are
found in tumors which also contain garden-variety
urothelial carcinoma, with or without other variants of
urothelial carcinoma. With no well-defined lower limit
for the amount of lymphoepithelioma-like carcinoma
needed to support the diagnosis, it is possible
that this variant is underdiagnosed. Amin et al
stratified their cases into those composed purely of
lymphoepithelioma-like carcinoma, those composed
predominantly of lymphoepithelioma-like carcinoma,
and those with only focal lymphoepithelioma-like
carcinoma [180]. Tamas et al simplified this approach
by stratifying their cases into those composed purely
of lymphoepithelioma-like carcinoma and those in
which other elements were present. This distinction
appears to have prognostic implications (vide infra)
[183].
with pure lymphoepithelioma-like carcinoma of the

urinary bladder with follow up of 4 months to 216
months (median 29 months) only one is recorded as
having died of the carcinoma and only 2 more are
recorded as having spread or recurrence but had not
died at the time of the report. The outlook for those
with mixtures of other elements may be less favorable.
For 10 patients with focal lymphoepithelioma-like
carcinoma of the urinary bladder, 9 died of the
carcinoma and 1 died shortly after diagnosis of
other causes. For 29 patients with predominant
or mixed lymphoepithelioma-like carcinoma of
the urinary bladder, 10 died of the carcinoma and
3 had major progression of the carcinoma at the
time of the report. While the numbers are small,
the differences in reported outcomes between
pure lymphoepithelioma-like carcinoma and tumors
with other components seems likely to matter. In
pathology reports, it would be appropriate to state
whether or not the tumor is pure lymphoepitheliomalike carcinoma.
8. Lipoid-Rich Variant of Urothelial

Carcinoma
a) Definition: Lipid-rich (lipoid) variant is defined by
the presence of large carcinoma cells with multiple

large, clear cytoplasmic vacuoles, morphologically
similar to lipoblasts [188].
b) Incidence: This is a rare variant of urothelial
carcinoma. Following the initial description [189],

two published series included a total of 32 patients
[148,190].
c) Clinical: Patients have typical symptoms of
urothelial cancer; all studied cases had hematuria

but other symptoms included pain, irritation and
obstruction. There is a striking (>90%) predominance
of males with most patients in the 7th decade of life.
d) Gross Appearance: Cystoscopically and grossly
Figure 35. Lymphoepithelioma-like carcinoma
these tumors show no distinctive features. Most

cases of the lipid-rich variant of urothelial carcinoma
arise in the bladder.
e) Ancillary Diagnostic Tests: In most cases,
no ancillary tests should be required to make the

diagnosis. However, if lymphoma is a consideration
on routine sections, immunohistochemistry to detect
markers of epithelial differentiation will quickly clarify
the situation because the carcinoma cells mark
strongly with antibodies to a variety of markers of
epithelial differentiation. Cytokeratin AE1/3, epithelial
membrane antigen, cytokeratin 7, and cytokeratin 8
are some of the most frequently detected epitopes.
Tumor protein p53 is also frequently detectable in
lymphoepithelioma-like carcinoma of the urinary
bladder. Epstein-Barr virus is found in nasopharyngeal
carcinomas but is not found in lympho-epitheliomalike carcinoma of the urinary bladder [186,187].
e)
Microscopic Features: The low power

appearance is that of high-grade urothelial carcinoma
admixed with large, multi-vacuolated cells that
constitute 10- 50% of the lesion [148]. At high-power,
the diagnostic cells have optically clear vacuoles
which often indent an eccentric nucleus (Figure
36). Some cases may also exhibit other subtypes of
urothelial carcinoma [148,191,192]. Histochemistry
and electron microscopy indicate that the vacuoles
contain lipid rather than mucin [117,148]. The
lipidized cells are carcinoma cells and have similar
immunoprofile to urothelial carcinoma and stain
with EMA, cytokeratins (including cytokeratin 7 in
all cases and cytokeratin 20 and 34BE12 in most
97
b) Incidence: Rare with less than 20 documented
cases) and more specific urothelial markers such as

thrombomodulin. They are negative for S100 [148].
cases in the English literature [198-203] and has so

far not detailed in any large-scale series.
c) Clinical: Patients present with typical symptoms

of urothelial carcinoma, mainly hematuria. Mean age
is 64 (41-82) years.
d) Gross Appearance: Most cases occur in bladder
but ureter/renal pelvis and urethral origin are also

described [198,200,201]. There is no information
available to suggest that gross appearance of tumors
differ from usual type.
e) Microscopic Features: Tumors are typically
high-grade and invasive with papillary and/or solid

growth pattern similar to usual type urothelial
carcinoma. In the majority of cases, more typical
urothelial carcinoma is recognized elsewhere [117]
and tumors may also display other variant types
[199]. Tumor cells are large with abundant clear
cytoplasm and well defined cell membranes and
centrally placed pleomorphic nuclei (Figure 37).
Figure 36. Lipoid-rich variant of urothelial carcinoma.

Solid sheets of high-grade urothelial carcinoma with
abundant vacuolated clear cells, many of which
have a multivacuolated, lipoblast-like appearance
(arrows).
diagnosis includes sarcomatoid carcinoma with

heterologous liposarcomatous differentiation and
signet ring cell carcinoma. As both tumors can be
either primary or secondary [193,194], this may be
of importance.
g) Ancillary Diagnostic Tests: Lipid rich cells are
negative for mucin histochemical stains and S100

immunostain. As these cells are immunopositive
for cytokeratin, a panel of mucin stains, S100
immunostain and cytokeratin immunostain may
be useful to rule out sarcomatoid and signet ring
cell carcinoma [121,148,195]. Tumors retain the
immunoprofile of usual type urothelial carcinoma
(positive for cytokeratin 7, and focally positive for
thrombomodulin, cytokeratin 20 and high-molecular
weight cytokeratins) [121,170].
Figure 37. Clear cell (glycogen-rich) variant of

urothelial carcinoma. Expansile, invasive nests
sheets of high-grade urothelial carcinoma showing
clear cytoplasm.
h) Prognosis: The outcome for this variant is poor.
In two series [148,190] that included 32 cases, 27

(84%) were muscle-invasive or beyond (and all of
those not diagnosed as muscle-invasive were staged
based on transurethral tumor resection). The vast
majority of patients (94%) had progressive (local or
metastatic) disease and death occurred in almost
two thirds of patients.
f) Differential Diagnosis: It is important to
9. Clear Cell (Glycogen Rich) Variant

of Urothelial Carcinoma
recognize that clear cell variant urothelial carcinoma

can be confused histologically with other clear cell
neoplasms. Clear cell adenocarcinoma [204-206] and
metastatic renal cell carcinoma [207-211] both enter
into the differential diagnosis as may on occasion
prostatic adenocarcinoma and paraganglioma [212].
Finally, urothelial carcinomas of usual type frequently
exhibit artifactual cytoplasmic clearing, especially in
TURBT specimens where diathermy was used.
a) Definition: Cytoplasmic clearing is focally
g) Ancillary Tests: Immunohistochemistry is similar
present in many, otherwise typical, urothelial

carcinomas [124] as well as in occasional cases of
urothelial dysplasia [196]. In rare instances, clear
cell change is the predominant pattern in which case
the term clear cell variant of urothelial carcinoma is
used [197].
to that of usual type urothelial carcinoma, i.e. positive

for high-molecular weight cytokeratins, cytokeratin 7,
p63, GATA-3, thrombomodulin and variably positive
for cytokeratin 20 [117,170,202,203,213]. Negativity
for renal, prostatic and neuroendocrine markers may
be of help in above differentials.
98
h) Prognosis: The prognostic and therapeutic
(mean 68.7 years). In the pediatric cases, all patients

have been girls; at presentation, one patient was 2
years old, two were 4 years of age and one was
six years old. Hematuria appears to be the most
common presenting sign.
implication of clear cell variant histology remains

uncertain given lack of large series. Tumors are
typically muscle invasive [198-203] and have been
associated with a high (50%) frequency of nodal
metastases [198-203]. See Table 9.
d) Gross: These tumors do not have a specific
Table 9. Clear cell variant. Small series and case

reports. Gender, age and stage
Reference
Kotliar et al, 1995
Braslis et al, 1997
No. Stage
2 N/A
T4
2 T3+
Perez-Montiel et al,
2006
T3+
T3
Yamashita et al,
2006
Rotellini et al, 2010
T4
T3+
Domanowska et al,
2001
gross appearance; some have been described as a

polypoid or submucosal mass [216,217].
Outcome
Not stated
Not stated
6 months
AWOT
Not stated
Not stated
e) Microscopic Features: Tumors with rhabdoid
differentiation have a very distinct microscopic appearance. They are characterized by large discohesive tumor cells that have distinct cell borders,
abundant cytoplasm with a perinuclear eosinophilic
inclusion, and a large nucleus, sometimes eccentrically located within the cell, with a prominent nucleolus (Figure 38). The tumor cells may be arranged
singly, in small clusters or in more diffuse sheets.
Ultrastructural studies have shown that the cytoplasmic inclusion consists of whorls of intermediate filaments.
Not stated
7 months
AWOT
T3+
12 months
AWOT
T3+ N0 Not stated
T3+ N0
T3+ N0
T3+ N1
T3+ N1
T3+ N1
Not stated
Not stated
Not stated
Not stated
Not stated
AWOT, alive without evidence of tumor.
10. Urothelial Carcinoma with

Rhabdoid Features
a) Definition: Urothelial carcinoma with rhabdoid
differentiation is a rare, aggressive tumor. Typically,

in adults, rhabdoid features are seen within an otherwise poorly differentiated conventional urothelial
carcinoma [214]. Pure rhabdoid tumors of the bladder (extra-renal malignant rhabdoid tumor) are even
rarer, and those reported have occurred in pediatric
patients [215-217].
Figure 38. Urothelial carcinoma with rhabdoid

features.
f) Differential Diagnosis: Given that most bladder
tumors with rhabdoid features, at least in adults,

are poorly differentiated urothelial carcinomas
morphologically, diagnoses should not be too
problematic. If, however, the entire tumor consists of
rhabdoid cells, the main differential diagnosis would be
an extra-renal malignant rhabdoid tumor. Much less
likely would be other tumors with dense eosinophilic
cytoplasm, including adrenal cortical carcinoma,
hepatocellular carcinoma, rhabdomyosarcoma, and
epithelioid angiomyolipoma.
b) Incidence: A specific incidence is unknown,
given the rarity of these tumors in the bladder.

Approximately 6 cases have been reported in adults,
all associated with other morphologies including
conventional urothelial carcinoma, malignant fibrous
histiocytoma, and small cell, sarcomatoid, and
myxoid histologies [218-220]. One case of urothelial
carcinoma with sarcomatoid growth and rhabdoid
differentiation in a 2 year old girl has also been
reported [221]. Pure rhabdoid tumors of the urinary
bladder are exceedingly rare with only 3 possible
cases reported to have occurred in pediatric patients
[215-217].
g) Ancillary Diagnostic Tests: Malignant rhabdoid
tumors have a deletion or mutation of the hSNF5/

INI1 gene on chromosome 22q11.2 [222,223]. For
bladder tumors that consist entirely of rhabdoid
cells, some advocate that molecular analysis should
be performed to determine if the tumor is a primary
extra-renal malignant rhabdoid tumor or a urothelial
carcinoma with rhabdoid differentiation [214]. Loss
c) Clinical: In adults, most of the tumors have
occurred in men with an age range of 53-86 years
99
of nuclear INI1 immunohistochemical expression

has been demonstrated to be useful in distinguishing
malignant rhabdoid tumors from other tumors that
may demonstrate rhabdoid features [224] and,
therefore, this test could also be performed.
degree of nuclear pleomorphism is low to moderate.

Binucleation may be present [150,233]. Nucleoli may
be present. The tumors cells are often in a stroma
that appears edematous or myxoid and can be arranged in cords, small nests, sheet-like or scattered
discohesive cells [214,233,235]. The plasmacytoid
tumor cells usually co-exist with conventional urothelial carcinoma, sarcomatoid carcinoma, nested or
micropapillary urothelial carcinoma, glandular morphology, urothelial carcinoma in situ or high grade
papillary urothelial carcinoma [150,228,233,235].
h) Prognosis: In general, bladder urothelial
carcinomas with rhabdoid differentiation are

aggressive high grade, high stage neoplasms and
the patient prognosis is poor [214,219,220]. For the
pediatric patients diagnosed with pure rhabdoid
bladder tumors, two were alive without evidence
of disease at follow-up of 2 years and 9 years
[216,217]. Given the behavior of these tumors, at
least in adults, radical resection seems prudent.
Some pediatric patients received chemotherapy
and/or partial cystectomy or transurethral resection.
11. Plasmacytoid Urothelial

Carcinoma
a) Definition: Plasmacytoid urothelial carcinoma is
a rare variant of urothelial carcinoma characterized
by tumor cells that morphologically resemble plasma
cells. This malignant tumor has been recognized
by the most recent World Health Organization
classification as a distinct variant of urothelial
carcinoma [225].
Figure 39. Plasmacytoid urothelial carcinoma.
b) Incidence: This tumor is not common; the
f) Differential Diagnosis: At cystectomy, plasma-
literature contains individual cases reports and

relatively small series [150,184,192,226-239]. To
date, less than 100 cases have been reported. In
one series of 720 high grade urothelial carcinomas
of the bladder, the incidence of the plasmacytoid
urothelial carcinoma was less than 1% [228], and in
another series of 260 invasive urothelial carcinomas,
the plasmacytoid variant accounted for 2.7% of
cases [231].
cytoid carcinoma is usually associated with conventional urothelial carcinoma. In the setting of a small
bladder biopsy or metastatic tumor containing only
plasmacytoid cells and the absence of a precursor
urothelial neoplasm (in situ carcinoma or papillary
urothelial carcinoma) in a bladder biopsy, the differential diagnosis of plasmacytoid urothelial carcinoma is broad and includes lymphoma/plasmacytoma,
malignant melanoma, rhabdomyosarcoma, lobular
breast carcinoma, gastric adenocarcinoma, neuroendocrine carcinoma, paraganglioma [214,235].
c) Clinical: The majority of patients with plasmacytoid
urothelial carcinoma are men [150,184,192,226239]. The age range at presentation is broad (46-89
years). In some of the larger series, the mean age at
presentation was 64.3 years [235], 66.2 years [227],
67 years[150] and 70 years [233]. Most patients
present with hematuria, with fewer complaints
related to irritative voiding symptoms [150,192,226,
227,230,231,233,235,238,239].
g) Ancillary Diagnostic Tests: Plasmacytoid
urothelial carcinomas are positive for pancytokeratin,

CK7, CK20 and uroplakin III [150,233,235,240].
CD138 is a marker expressed in normal and malignant
plasma cells and is also expressed in plasmacytoid
urothelial carcinoma [150,232-234,240]; therefore,
it cannot be used alone to diagnose plasmacytoid
urothelial carcinoma. In one of the largest and
most recent studies, 78% of the tumor cells were
positive for CD138 [240]. In this same study, 64.5%
of the tumors had loss of membranous E-cadherin
expression and the authors propose that loss of this
expression is a feature of plasmacytoid urothelial
carcinoma. Depending on the specific differential
diagnosis, other immunohistochemical markers can
be performed as necessary.
d) Gross Appearance: The gross findings are
non-specific and little information is provided in the

literature. Only a few reports provide a description of
the tumors appearance which includes sessile [192]
and ulcerated, firm mass or masses [227].
e) Microscopic Features: The tumor is character-
ized by discohesive round to oval tumor cells with

dense eosinophilic cytoplasm which may occasionally contain small vacuoles [150,235]. The nuclei are
round to oval and hyperchromatic and are located
eccentrically within the cell (Figure 39). Typically the
h) Prognosis: Plasmacytoid urothelial carcinoma
typically presents at an advanced stage and, in
100
f) Differential Diagnosis: The differential diagno-
general, the prognosis is poor [150,214,233,235,240].

Treatment options are variable. Some patients
receive neoadjuvant or adjuvant chemotherapy and
resection may consist of a transurethral resection or
cystectomy.
sis includes benign conditions such as pseudosarcomatous myofibroblastic proliferations (including

postoperative spindle cell nodules and inflammatory
myofibroblastic tumors) or more aggressive lesions
such as urothelial carcinoma with chondroid or osseous metaplasia, and leiomyosarcoma [252,253].
12. Sarcomatoid Carcinoma of The

Urinary Bladder
a)
g) Ancillary Diagnostic Tests: The immunohis-
Definition: A malignant urothelial-derived
tochemical profile of sarcomatoid carcinoma includes

immunoreactivity for pancytokeratin, high molecular
weight cytokeratin, CK5/6 and p63. Smooth muscle
actin is only variably positive at best and Alk-1 is
negative these markers are frequently expressed
in inflammatory myofibroblastic tumors/pseudosarcomatous myofibroblastic proliferations and leiomyosarcomas [254,255].
carcinoma that displays both spindle cell and

epithelial elements (formerly carcinosarcoma).
b) Incidence: Sarcomatoid carcinoma accounts

for approximately 0.6% of all bladder cancers
[241,242].
c) Clinical: The mean patient age is 66 years and
the male to female ratio is 3:1. Similar to other bladder

carcinomas, patients with sarcomatoid carcinoma
typically present with hematuria [243-251].
h) Prognosis: An estimated 70% of patients

die within 2 years of diagnosis. Compared with
patients with pure urothelial carcinoma, patients with
sarcomatoid carcinoma are at a greater risk for death
even after adjusting for the stage at presentation.
d) Gross Appearance: The majority of lesions

appear as a solitary, polypoid mass that may involve
any portion of the bladder.
13. Undifferentiated Urothelial

Carcinoma with Trophoblastic
Giant Cells
e) Microscopic Features: The spindle cell com-
ponent usually shows high-grade morphology with

nondescript architecture that often resembles malignant fibrous histiocytoma. (Figure 40) Heterologous
differentiation is often present that may contain - in
decreasing order of frequency - areas that resemble osteosarcoma, chondrosarcoma, rhabdomyosarcoma, liposarcoma, angiosarcoma or a mixture
of sarcomatoid histologies [245,247]. Despite the
morphologic resemblance to sarcoma, it is currently
recognized that these spindle cell areas are derived
from an underlying epithelial malignancy, hence the
revised terminology of sarcomatoid carcinoma. Often associated with areas of sarcomatoid morphology may be foci of overlying flat urothelial carcinoma
in situ or adjacent invasive high grade urothelial carcinoma, squamous cell carcinoma, adenocarcinoma,
or small cell carcinoma.
a) Definition: Trophoblastic differentiation may be
seen in several settings in urothelial carcinoma: 1)

Serologically and/or immunohistochemically in otherwise typical urothelial carcinoma; or 2) Morphological evidence of trophoblastic differentiation either
with scattered trophoblastic giant cells in urothelial
carcinoma or with a biphasic tumor indistinguishable
from choriocarcinoma [256-260]. It is considered
that this phenomenon represents either morphologic
and/or functional trophoblastic differentiation from
reactivation of embryonal cellular programs in tumor
cells.
b) Incidence: 1) Human chorionic gonadotropin
(HCG) and to a lesser extent human placental lactogen (HPL) and pregnancy-specific beta-1-glycoprotein (SP-1) immunoreactive cells have been found
in a minority of urothelial carcinomas, typically high
grade. Although different grading systems have been
used, the incidence for high grade tumors has been
19%, 21%, 40%, and 55% in various studies. Most
studies have found no immunohistochemical HCG
production in low grade tumors, although one study
found 26% [229,256,261-263]. Serum HCG levels
have also been shown to be elevated in some of the
cases with immunohistochemical evidence of HCG
expression.
c) Clinical: In patients with usual urothelial carcinoma expressing HCG immunohistochemically or

by the presence of scattered syncytiotrophoblastic
giant cells, there is no endocrinologic manifestations
related to HCG. Tumors with pure choriocarcinoma
or choriocarcinoma associated with poorly differentiated urothelial carcinoma have in some cases been
associated with gynecomastia.
Figure 40. Sarcomatoid urothelial carcinoma.
101
d) Gross Appearance: High grade tumors
g) Ancillary Diagnostic Tests: Comparative ge-
associated immunohistochemical evidence of HCG

or those with choriocarcinoma usually have been
described as large, exophytic, or fungating, often
with hemorrhage and necrosis.
nomic hybridization showed that both the urothelial

carcinoma and choriocarcinoma shared losses of
chromosomes 9 and 17, similar to the genetic findings previously reported for urothelial carcinoma
[264]. The less well-differentiated choriocarcinomatous component showed more genetic alterations
than the papillary urothelial carcinoma component.
In a case of micropapillary urothelial carcinoma and
choriocarcinoma, the trophoblastic component was
positive for high molecular weight cytokeratin, which
typically is not seen in trophoblasts yet can be seen
in urothelial carcinoma. One case of pure choriocarcinoma has been shown to have an isochromosome
12p, as seen in germ cell tumors [265]. All of the
above findings support that choriocarcinoma is of
urothelial origin and acquires varying degrees of
trophoblastic differentiation.
e) Microscopic Features: Areas of high grade
pleomorphic urothelial carcinoma, whether non-invasive papillary, CIS, or invasive are the most likely
to immunohistochemically express HCG. The HCG
positive cells morphologically look indistinguishable
to adjacent HCG negative cancer cells. Morphological evidence of trophoblastic differentiation shows
either scattered syncytiotrophoblastic giant cells or
choriocarcinoma with both syncytiotrophoblastic
giant cells admixed with cytotrophoblasts indistinguishable from choriocarcinoma. Scattered syncytiotrophoblastic giant cells can be seen in a wide
spectrum of urothelial carcinomas including noninvasive papillary low and high grade urothelial carcinoma, as well as invasive carcinoma. Many cases
reported as choriocarcinoma are not classic choriocarcinomas and when their photomicrographs are
evaluated they represent undifferentiated urothelial
carcinoma with scattered tumor giant cells. Cases
which appear histologically identical to choriocarcinoma typically are admixed with high grade urothelial carcinoma. Even rarer cases appear to be typical
choriocarcinoma from inception without associated
urothelial carcinoma (Figure 41).
h)
Prognosis: HCG immunoreactivity in

pretreatment in some studies has been a strong
predictor of treatment response (22 of 29 patients
with HCG-positive specimens did not respond to
treatment versus 29 of 71 patients with HCG-negative
specimens. Of the few patients with choriocarcinoma,
most have died of disease. Although there has
been anecdotal treatment specifically directed at
trophoblastic tissue, it has failed to influence the
course of the disease. Falling levels of HCG is
not invariably associated with tumor response to
chemotherapy.
f) Differential Diagnosis: Urothelial carcinoma
14. Undifferentiated Urothelial

Carcinoma with Osteoclastic
Giant Cells
with trophoblastic differentiation can be confused

with choriocarcinoma, whereby inappropriate
chemotherapy may be utilized or there could be
a delay in treatment while looking for a primary
elsewhere. In the setting of a primary choriocarcinoma
of the bladder, spread should be excluded from a
gynecological or testicular primary, in women and
men, respectively.
a) Definition: Tumors closely recapitulating the
morphology of osteoclastic giant-cell tumors of

bone or soft parts, with a biphasic tumor composed
of both mononuclear cells and osteoclast-like giant
cells. Tumors are considered a variant of urothelial
carcinoma based on their association with usual
urothelial carcinoma and various ancillary studies
(see below).
b) Incidence: Rare with the largest series composed
of 6 cases from a consult service [266-271]. As of

2006, there were 20 reported cases with a few case
reports reported subsequently.
c) Clinical: Approximately two-thirds of patients are
male with most in their 7th decade. The presenting

symptoms are nonspecific and typical for urothelial
neoplasms in general with gross hematuria as the
most common manifestation. Other complaints
reported in the literature are flank pain, renal colic,
and dysuria.
d) Gross Appearance: Approximately 50% are
Figure 41. Urothelial carcinoma with trophoblastic

giant cells. Pure primary choriocarcinoma of
the bladder with syncytiotrophoblasts and
cytotrophoblasts intimately admixed.
located in the renal pelvis and involve the kidney.
e) Microscopic Features: Neoplasms closely recapitulate giant-cell tumors of bone and soft tissues.
102
h) Prognosis: Renal pelvis tumors are often high
They are composed of a mixture of oval to plump

mononuclear cells and multinucleated osteoclastlike giant cells, which form sheets and nodules
(Figure 42). The stroma is richly vascularized with
frequent areas of erythrocyte extravasation, occasionally forming large blood filled lakes. Large areas
of necrosis are seen in a minority of cases. Osteoclast-like giant cells exhibit phagocytic features with
erythrocytes, hemosiderin, mononuclear cells, or debris readily found within their cytoplasm. Neoplasms
are unencapsulated and demonstrated a tongue-like
infiltrative growth pattern. Lymphovascular invasion
is present in many cases. The vast majority of cases
are associated with either CIS or non-invasive high
grade papillary urothelial carcinoma.
stage at presentation (pT3) with invasion of the renal

parenchyma, hilar adipose tissue, and thick walled
veins. Bladder tumors have been of variable stage
from T1 to T3. In many cases, the disease-free
follow-up is too short to be useful. Of cases with
more meaningful yet still short follow-up, about 50%
of patients have been without evidence of disease
for 1.5-3.5 years. The remaining approximately 50%
of patients have died of disease within a short time
with pulmonary metastases the most common site
of distant disease. Death typically occurs less than
1 year following radical surgery. Extensive surgical
excision appears to be the common consensus
for primary or recurrent lesions until the treatment
benefits of adjuvant chemotherapy or radiotherapy
can be established.
15. U
ndifferentiated Carcinoma
(Including Giant Cell Carcinoma)
a) Definition: Carcinomas of the urinary bladder
with a phenotype composed of sheets or isolated

undifferentiated cells that do not fit into urothelial,
squamous, adenocarcinoma or any other recognized
category of bladder carcinoma [117,118,120,121,14
9,188,199,272,273]. Some authorities would classify
these cases as large-cell undifferentiated carcinoma
[120,149,273]. Others may prefer to denote
these lesions as high-grade urothelial carcinoma,
given that this is the most common cancer within
the bladder and that this pattern of tumor most
likely represents the most poorly differentiated
manifestation of conventional urothelial carcinoma
(Figure 43) [120,149,273]. Giant cell carcinoma
is an undifferentiated carcinoma of the bladder
that occasionally may be composed predominantly
or purely of poorly differentiated, pleomorphic,
multinucleated, and multinucleated anaplastic cells
with abundant eosinophilic or amphophilic cytoplasm
[117,118,120,121,149,273]. The tumor cells often
contain multiple nucleoli and are similar to giant cell
carcinomas seen in the lung and in other parts of the
body (Figure 44) [274].
Figure 42. Undifferentiated urothelial carcinoma

with numerous osteoclastic giant cells.
f) Differential Diagnosis: One of the differential
diagnoses would be a sarcomatoid urothelial carcinoma, if associated with a conventional urothelial

carcinoma component. If conventional urothelial carcinoma was not identified, the tumor might not be
recognized as a variant of urothelial carcinoma. It
may be misdiagnosed as a sarcoma, either primary
in the bladder or spread to the bladder from an occult primary.
g) Ancillary Diagnostic Tests: In most but not all
cases, the mononuclear cells immunohistochemically demonstrate epithelial differentiation with focal
positivity for various keratins or epithelial membrane
antigen. Ultrastructurally, the mononuclear cells display few desmosomes, microvilli, and intracytoplasmic keratin. The multinucleated cells have identical
morphological and immunohistochemical properties
of osteoclasts; positive for CD-68, LCA, CD51 and
CD54, and primarily negative for cytokeratins and
EMA. Varying percentages of mononuclear cells
express alpha-smooth muscle actin, desmin, S-100,
and CD68. The mononuclear cells have a relatively
high proliferation index of between 20-50%. Based
on these findings the mononuclear cells are regarded as undifferentiated urothelial carcinoma with the
osteoclast-like giant cells representing reactive histiocytes.
b) Incidence: Rare with the largest series composed

of 8 cases of large cell undifferentiated carcinoma,
five of them seen in consultation, and an additional
series of 8 cases of giant cell carcinoma [149,273].
c)
Clinical: The presenting symptoms are

nonspecific and typical for urothelial neoplasms in
general with gross hematuria as the most common
manifestation. Approximately two-thirds of patients
are male with most in their 6th or 7th decade. Large
cell undifferentiated and giant cell carcinomas
present at an advanced stage [149,273].
e) Microscopic Features: Neoplasms closely
recapitulate large-cell undifferentiated or giant-
103
cell carcinoma seen in the lung and in other parts

of the body [274]. They are composed of sheets
of large polygonal or round cells with moderate
to abundant cytoplasm and distinct cell borders
[117,118,120,121,149,188,199,272-274]. The architectural pattern of the tumor varies from infiltrating tumor to solid expansile nests of undifferentiad
cells. Pleomorphic giant cells are prominent in the
giant cell variant. Typical or atypical mitotic figures
are common. Rarely, the stroma is hypocellular and
desmoplastic. The vast majority of cases are associated with invasive high grade conventional urothelial
carcinoma [149,273]. Lymphovascular invasion is
present in many cases.
patient had no evidence of disease at 74 months

[149]. Extensive surgical excision appears to be the
common consensus for primary or recurrent lesions
until the treatment benefits of ad juvant chemotherapy
or radiotherapy can be established.
f)
Differential Diagnosis: If present in a

metastatic site, the histology of undifferentiated
carcinoma would not suggest an urothelial primary
[117,118,120,121,149,188,199,272-274]. The high
degree of nuclear anaplasia helps differentiate
giant cell carcinoma from the osteoclast-type giant
cells that may be seen in urothelial carcinoma
[267]. Other giant cells that may be seen with
urothelial carcinoma include syncytiotrophoblastic
giant cells or foreign body giant cells secondary to
previous biopsy or resection. In limited samples,
undifferentiated carcinoma may be misdiagnosed
as secondary carcinoma or sarcoma, a pitfall of
paramount importance for its clinical management
[117,118,120,121,149,188,199,267,272-274].
Figure 43. Giant cell carcinoma of urinary bladder.
g) Ancillary diagnostic tests: Immunohistochemical staining demonstrated that large cell undifferentiated carcinoma cases were positive for cytokeratins AE1/AE3 and 7; CAM 5.2, CK20, thrombomodulin and Uroplakin III were positive in 6, 3, 3 and
2 cases, respectively.2 Both pleomorphic giant cell
and associated conventional urothelial carcinoma
were positive for cytokeratins 7, CAM 5.2 and AE1/
AE3, and epithelial membrane antigen; P63, thrombomodulin and Uroplakin III were positive in 6, 3 and
2 cases, respectively. 1 Other immunohistochemical
markers performed in the differential diagnosis context included -Feto-protein, HCG, PSA, Vimentin,
synaptophisin and chromogranin and all were negative [149].
Figure 44. Giant cell carcinoma of urinary bladder.
II. SQUAMOUS CELL CARCINOMA

1. Squamous Cell Carcinoma, NonSchistosomal
a) Definition: Urinary bladder squamous cell
carcinoma is a primary malignancy of urothelial

origin that consists almost entirely of keratin-forming
squamous carcinoma.
h) Prognosis: Large-cell undifferentiated bladder
carcinoma is an aggressive variant of urothelial

carcinoma [117,118,120,121,149,188,199,267, 272274]. All patients had advanced stage cancer (>
pT3); and 87.5 % had lymph node metastases. 2On
follow up 75% of patients died of disease from 5 to
26 months and 2 patients were alive with metastases
at 6 and 14 months. The prognosis of large-cell
undifferentiated bladder carcinoma was compared
with conventional urothelial carcinoma of similar
stages showing survival differences (P=0.0004).
Five (62%) of patients with giant cell carcinoma died
of disease from 6 to 17 months and 2 patients were
alive with metastases at 11 and 19 months. One
b) Incidence: Squamous cell carcinoma compris-
es approximately 5% of all bladder cancers in the

Western world [275]. Excluded from this category
are urothelial carcinomas with extensive squamous
differentiation (urothelial carcinoma with divergent
differentiation), although the distinction of these two
entities on histological review may be challenging,
especially on small tissue samples. Risk factors are
associated with long standing inflammation and include long-term indwelling catheters, chronic infection, chronic bladder neck obstruction and bladder
calculi [13,14,276,277]. Human papillomavirus (HPV)
104
g) Differential Diagnosis: The differential diag-
is generally not associated with squamous cell carcinoma except in extremely rare cases [13,278-281].
nosis of bladder squamous cell carcinoma includes

urothelial carcinoma with extensive squamous differentiation (divergent differentiation) or squamous cell
carcinoma secondarily involving the bladder from
sites such as the cervix or anus.
c) Clinical Features: Squamous cell carcinoma
occurs most frequently in the seventh decade [275].

The male to female ratio is approximately 2:1 and
African-Americans are twice as likely to be affected
[281]. Clinical presentation is similar to patients with
urothelial carcinoma and includes hematuria and
irritative voiding symptoms.
h) Prognosis: There are few studies available on
pure non-Schistosomal squamous cell carcinoma

of the bladder. Five-year disease-free survival following radical cystectomy ranges from 43 to 57%
[130,279,282]. The poor outcomes associated with
this disease may be attributed to the high stage at
initial presentation and relative frequency of regional
lymph node metastases in 24% of patients at the
time of cystectomy [279]. However, when compared
to urothelial carcinoma on a stage-by-stage basis,
outcomes appear similar, with a 5-year disease specific survival rate of 57% [130,283]. Squamous cell
carcinoma has been associated with limited responsiveness to chemotherapy and radiation treatment.
d) Gross Appearance: At cystoscopy, squamous
cell carcinoma is frequently sessile, solid and often

demonstrates a white, flaky surface secondary to
keratin formation. Ulceration may occur in up to half
of all carcinomas [279]. Lesions are predominantly
solitary, may involve any aspect of the bladder wall,
although the posterior and lateral walls are most
commonly affected, and range in size from 0.8-6.4
cm (average 3.8 cm) [279].
e) Histologic Features: Squamous cell carcinoma
shows nests of invasive squamous carcinoma cells

with glassy, pink cells and variable keratin formation, often described as keratin pearls. (Figure 45)
Other classic histologic features include intercellular
bridges and sloughed keratin debris. All squamous
cell carcinomas are considered to be high-grade.
Associated mucosal findings include keratinizing squamous metaplasia (62%), nonkeratinizing
squamous metaplasia (44%), squamous cell carcinoma in situ (36%), flat urothelial carcinoma in situ
(16%), squamous metaplasia with dysplasia (9%),
verrucous squamous hyperplasia (7%) and rarely
condyloma accuminata (2%) [279].
A key challenge is in the management of patients

who present with squamous cell carcinoma on initial
biopsy or transurethral resection. Due to sampling,
the exclusion of a high-grade urothelial carcinoma
with squamous differentiation is challenging and
this distinction can be made primarily on radical
cystectomy when the entire lesion is available
for histologic analysis. A second challenge is the
management of in situ squamous lesions found
on biopsy. The most concerning of all associated
mucosal lesions is squamous cell carcinoma in situ,
which has a high likelihood of progression to invasive
carcinoma in patients and one study that followed up
on these in situ lesions found that 5/7 patients with
squamous cell carcinoma in situ on initial sampling
developed subsequent invasive carcinoma [13].
f) Ancillary Diagnostic Tests: Immunohistochemical staining is similar to squamous cell carcinoma arising at other locations and includes positive immunoreactivity to p63, high-molecular weight
cytokeratin and pancytokeratin. Recent studies are
evaluating markers that may distinguish between
squamous cell carcinoma and urothelial carcinoma
with extensive squamous differentiation, which will
be of high utility on biopsy or transurethral resection
specimens.
2. Verrucous Carcinoma
a) Definition: Verrucous carcinoma, a tumor much
more common in the upper aerodigestive tract, anus

and genitalia than the urinary bladder, is a rare subtype of squamous cell carcinoma that is most often
related to urinary schistosomiasis infection [284287], but may also rarely occur in its absence [288294]. It is a well-differentiated invasive squamous
neoplasm with a broad deep border that pushes
into the underlying stroma rather than demonstrating frank stromal invasion typical of a conventional
squamous cell carcinoma.
b) Incidence: In areas with endemic urinary schis-
tosomiasis, verrucous carcinoma accounts for up to

3.4% of all bladder carcinomas [285-287] and 4.66.5% of squamous cell carcinomas [286,287].
c) Clinical: The tumor occurs more frequently in
men than women [285-287], and in regions with endemic urinary schistosomiasis, tends to occur at a
younger age (mean age 44-46 years) in those with
Figure 45. Squamous cell carcinoma.
105
the parasitic infection than in those without the infection (mean age 53 years) and those with bladder cancer in general, who typically present in the
sixth and seventh decades of life [284-287]. In nonendemic regions of the world, a few cases of verrucous carcinoma have been reported to be related
to condyloma acuminatum [288,293], chronic urinary
tract infection [288,289,294] and bladder diverticula
[290]. In some patients, the tumors are not associated with other genitourinary diseases [291,292].
Patients usually have irritative bladder symptoms
at presentation and urine analysis may reveal white
cellular debris, consistent with keratin [284,290,292].
Patients have also reported seeing white material in
their urine [286,287,292]. Hematuria is not common
[286,287].
section, can be very difficult to make. Superficial biopsy samples may not include the base of the lesion,
and may consist only of thickened, well-differentiated, almost benign-appearing, squamous epithelium.
Transurethral resections may not be particularly useful either, as they may be maloriented and muscularis propria, useful to evaluate for invasion, may not
be present. The main differential diagnosis includes:
verrucous squamous hyperplasia, squamous papilloma, pseudoepitheliomatous hyperplasia, condyloma
acuminatum and a conventional invasive squamous
cell carcinoma that contains foci morphologically resembling a verrucous carcinoma.
d) Gross Appearance: Most tumors are solitary
ated with urinary schistosomiasis, the patient follow-up is relatively short (3 months-3 years) [288290,292,294]. Nevertheless, while some of the patients experienced tumor recurrence in the bladder
due to lack of radical resection initially [290,292,294],
all did well after total cystectomy. In larger series
of verrucous carcinoma that occurred in areas with
endemic schistosomiasis, specific outcomes are
not provided [285,286]. However, if these tumors
are diagnosed with strict adherence to histologic
criteria, given that these neoplasms are low grade
neoplasms without a propensity for lymph node metastases, the implication from these studies is that
patients do well. If, however, an invasive component
typical of a conventional squamous cell carcinoma is
present, the possibility for more aggressive behavior
exists. Therefore, in the latter situation, the World
Health Organization [225] has recommended that
such tumors not be diagnosed as verrucous carcinoma. Due to the tendency for tumor recurrence
and potential to be associated with a conventional
squamous cell carcinoma, the treatment of choice
is complete resection, usually by total rather than
partial cystectomy. Radiation treatment is not advocated because of the possibility of development of
anaplasia within the tumor and risk of more aggressive behavior, as documented in these tumors that
occur at other sites [286,289,296-298].
g) Ancillary Diagnostic Tests: None available.

h) Prognosis: For tumors that are not associ-
[287,294]. While the tumor may occur anywhere

within the urinary bladder, one series reported that
80% occurred on the posterior wall or dome [287].
The tumor is typically exophytic, firm, white, and
wart-like.
e) Microscopic Features: Verrucous carcinoma is
a well-differentiated neoplasm, with both exophytic

and endophytic growth, characterized by hyperplastic, parakeratotic squamous epithelium that has minimal cytologic atypia and few mitoses (Figure 46).
The surface of the neoplasm projects as epithelial
papillae above the bladder mucosa. The thickened
squamous epithelium invaginates into the underlying stroma; the deep border consists of a round,
wide base of epithelium that pushes, rather than
frankly invades, into the stroma. A chronic inflammatory infiltrate may be present in the lamina propria,
adjacent to the base of the tumor. Parasite ova may
be present in the bladder tissue. Within the bladder,
verrucous carcinoma arises from areas of squamous
metaplasia; the metaplastic change develops secondary to chronic irritation most often caused by the
parasite [284,295].
f) Differential Diagnosis: A definitive diagnosis of
verrucous carcinoma, without its complete intact re-
3. Squamous Cell Carcinoma,

Schistosomal
a) Definition: Urinary bladder squamous cell carcinoma that consists almost entirely of keratin-forming
squamous carcinoma and is associated with a precedent or concurrent infection with schistosomal species.
b) Incidence: This form of squamous cell carcinoma

occurs most frequently in the Middle East and Africa
and - until recently - represented the most common
form of bladder cancer in Egypt [299-301]. Risk factors
include infection with Schistosoma hematobium [276,
277], exposure to nitrate-based fertilizers, pesticides,
and smoking. Schistosomal eggs deposited within
Figure 46. Verrucous carcinoma.
106
the bladder result in inflammation of the bladder wall

and subsequent carcinoma development.
rarity of these tumors. In larger series, adenocarcinomas constituted 0.55% to 2.6% of all urinary bladder malignancies [302-306], although these data are
hampered by the inclusion of cases of urachal carcinoma. Lack of histological review is also likely to
have a confounding effect, as in one series 58.7%
reported cases of bladder adenocarcinoma were
found, on review, to be other forms of malignancy
[307]. In particular this included urachal adenocarcinomas, urothelial carcinomas with focal glandular
differentiation and metastatic extravesical adenocarcinomas.
c) Clinical Features: The male to female ratio is

slightly higher than non-Schistosomal squamous
carcinoma at 4-5:1, which has been attributed to
the increased exposure of men to infested water
while laboring outdoors. In these endemic areas,
squamous carcinoma often develops decades earlier
than in Western countries.
d) Gross Appearance: Similar to its non-Schis-
tosomal counterpart, squamous cell carcinoma is

frequently solitary and fungating with a white, flaky
surface secondary to keratin formation. Ten to 20
percent of cases may be multifocal.
There is an association between schistosomiasis

and bladder adenocarcinoma and in cases from
Egypt, 5.2% to 11.4% of bladder tumors were found
to be adenocarcinomas [308-310]. An increased
incidence of these tumors is also seen in individuals
with bladder extrophy [310,311].
e) Histologic Features: Schistosomal-associated
squamous cell carcinoma is morphologically similar

to non-Schistosomal disease, with well- to moderately-differentiated carcinoma comprising the majority
of cases. In many instances, calcified Schistosomal
eggs may be found within the bladder wall and show
an associated granulomatous reaction. Superficial
changes include squamous metaplasia in 80% of
cases and squamous carcinoma in situ in 50% of
cases [295].
c) Clinical Features:
Adenocarcinoma of the
bladder occurs most frequently in the fifth to seventh decades, although rare pediatric cases have
been reported [312]. In registry-based studies that
focus on adults and in larger clinical series, patients
ranged in age from 15 to 93 years with mean ages
of 60 to 64 years [303-305,307]. In these series the
male:female ratio was 1.7:1 to 3.2:1. In schistosoma
endemic areas, patients present at a younger age
(mean age 46 to 50.4 years) with a male to female
ratio of 2.18:1 to 2.25:1[308-310,313].
f) Ancillary Diagnostic Tests: Ancillary diagnostic testing is identical to non-Schistosomal disease.
g) Differential Diagnosis: The differential diagnosis of bladder squamous cell carcinoma is similar to
non-Schistosomal disease and includes urothelial
carcinoma with extensive squamous differentiation
(divergent differentiation) or squamous cell carcinoma secondarily involving the bladder from sites such
as the cervix or anus.
Adenocarcinoma is the most common malignancy

associated with bladder extrophy and occurs in
approximately 10% of cases [314,315]. In these
patients tumor development is usually a late
phenomenon and may occur in individuals who
have undergone surgical repair at a young age
[311,316,317].Although adenocarcinomas have
been reported in association with neurogenic bladder
and chronic in-dwelling catheters, these conditions
do not appear to be predisposing factors for these
tumors [318]. There is evidence that non-urothelial
bladder malignancies occur more frequently in
bladder diverticula although, due to small sample
size, it remains uncertain if this is specific for primary
adenocarcinoma [319].
h) Prognosis: The five-year overall survival for
Schistosomal-associated squamous cell carcinoma

is approximately 50%, which reflects recent improvements in early diagnosis and peri-operative
outcomes. Tumor stage, grade and lymph node
involvement are most significantly associated with
survival outcomes. Treatment is primarily surgical in
nature with little benefit from chemotherapy or radiation therapy.
Hematuria is the most common presenting symptom

for bladder adenocarcinoma with other presenting
features being irritative bladder symptoms, flank
pain secondary to outflow obstruction, suprapubic
pain, urinary frequency, dysuria and mucosuria
[302,304,305,307,315,320,321].
III. ADENOCARCINOMA VARIANTS

1. Primnary Adenocarcinoma of
Bladder
d) Gross Appearance: At cystoscopy primary
a) Definition: Urinary bladder adenocarcinoma is a
bladder adenocarcinoma is more frequently solid or

sessile than papillary, and there is usually extensive
ulceration [312,315,322]. Tumors may be mucinous
and hemorrhage is frequently seen. There may be
associated inflammation with the tumor forming an
ill-defined mass [315]. Adenocarcinomas are solitary
primary malignancy that shows glandular differentiation, with features of enteric, mucinous or signet ring
cell carcinoma.
b) Incidence: Population based studies on the incidence of bladder adenocarcinoma are limited by the
107
in >50% of cases and while the trigone is the most

common primary site, all parts of the bladder may be
involved [302,305,307,312,315,322,323]. Infiltration
of the bladder wall and beyond is frequently detected
by physical examination at presentation and at cystoscopy.
intestinal metaplasia [20,325]. Although both

metaplastic conditions result from chronic urothelial
irritation/inflammation, more recent studies have
suggested that these have no associated risk for
the development of adenocarcinoma [20,21]. It has,
however, been noted that the epithelium adjacent to
foci of adenocarcinoma may show atypia or in situ
carcinoma, and in one report this was present in
17% of cases [323,325].
Signet ring cell carcinomas are almost always

invasive at diagnosis. Features of linitis plastica with
diffuse thickening of the bladder wall are commonly
present and the mucosa is frequently ulcerated
[312,320,324].
e) Histologic Features: Urinary bladder adeno-
carcinomas show a morphologic spectrum similar

to that of colonic adenocarcinoma (Figure 47) and
five specific morphotypes have been described
[307,325]. 1. Enteric tumors are acinar, cribriform,
villous or solid. Occasionally these tumors may contain cells that show neuroendocrine differentiation
[325]. 2. Mucinous or colloid carcinomas consist of
individual cells and cell nests within lakes of mucin.
These tumors may also contain mucin filled acini and
occasional signet ring cells may also be seen[320].
3. Signet ring cell carcinoma (Figure 48) is restricted
to those tumors that show a diffuse signet ring morphology with varying amounts of mucin and without
foci of glandular, urothelial or squamous differentiation [195,320,323,326]. 4. Adenocarcinoma not otherwise specified (NOS) is applied to tumors where
the architectural pattern does not conform to the preceding three morphotypes. 5. Mixed forms showing
two or more morphologic patterns. (Figure 49) It has
been suggested that to be included in this category,
a tumor should not exhibit >75% of one tumor morphotype [325] Rare hepatoid forms have also been
described [327].
Figure 47. Adenocarcinoma with enteric features.
In some series clear cell adenocarcinoma of

apparent Mllerian origin are included as variants of
bladder adenocarcinoma, while in other series they
are considered to be a separate entity [307]. The
features of these tumors are considered elsewhere
in this work.
Figure 48.
variant.
Adenocarcinoma,
signet-ring
cell
Of the five morphological variants of bladder

adenocarcinoma, enteric and colloid carcinoma
are the most commonly encountered morphotypes,
although in one series 42% of tumors were
classified as adenocarcinomas NOS, while only
25% of tumors had the features of enteric/mucinous
adenocarcinoma. Signet ring cell carcinomas are
rare and with less than 100 cases reported to date
these tumors constitute approximately 5% of cases
of bladder adenocarcinoma [307,323].
Various grading systems, including that of the World
Health Organization, have been employed for these
tumors. In general signet ring cell adenocarcinomas
are considered to be high grade [322,326].
Figure 49. Adenocarcinoma, enteric and mucinous

features.
Bladder adenocarcinoma is often found in

association with cystitis glandularis and urothelial
108
f) Ancillary Diagnostic Tests: Immunohistochem-
likely to have less of a mucinous component when

compared to tumors of gastrointestinal origin.
ical staining may assist in the diagnosis of primary

urinary bladder adenocarcinoma of non-urachal origin [170,328-331]. These tumors show variable expression of cytokeratin 20, E48, carcinoembryonic
antigen, LeuM1 and catenin. Positive staining for
cytokeratin 7, OC125 and Her-2/neu may occasionally be present [320,330,331]. Tumors are usually
negative for thrombomodulin, monoclonal prostate
specific antigen, prostate specific acid phosphatase
and vimentin, although occasional tumors show
positive staining for prostate antigen P501S [329],
prostate specific membrane antigen[329] and polyclonal prostate specific antigen. In bladder adenocarcinomas, bcl-2 expression has been shown to
decrease, while p53 expression increased, with increasing grade[332], and this may have prognostic
significance.
Signet ring cell adenocarcinoma may occasionally

mimic lobular carcinoma of the breast; however,
immunostaining for ER, PR and GCDFP-15 should
lead to the correct diagnosis.
h) Prognosis: Most studies relating to the outcome
of primary adenocarcinomas of the urinary bladder

are hampered by small sample size. Further confounding factors are that in many series urachal and
non-urachal carcinomas, are admixed [304-306]. In
further series adenocarcinomas, which contained
areas of typical urothelial carcinoma were included
[307]. Bladder adenocarcinomas are often of advanced stage at presentation. On imaging studies
75% of primary non-urachal adenocarcinoma were
found to have diffuse thickening of the bladder wall on
computerized tomography, while 88% had stranding
of perivesical fat. Lymphadenopathy was visible in
25% of cases and in 25% there was direct invasion of
the rectus muscle [334]. These results are reflected
in cystoscopic and gross pathological findings, with
most tumors showing infiltration into the bladder wall
at diagnosis[302,307,312,322,335]. Metastases are
present in approximately 25% of cases with secondary sites in descending order of frequency being liver,
bone, regional lymph nodes, adrenals, peritoneum
and skin [302,307,312,322,335]. Bladder adenocarcinoma has a poor prognosis with 5-year survivals of
11% to 55% being reported [242]. In various studies tumor stage at diagnosis has been shown to be
an important prognostic feature [307,315,322,325].
In a recent registry-based study of 306 patients with
bladder adenocarcinomas [303], the distribution of
cases according to pT staging category was pTis/a
0.3%, pT1 7.8%, pT2 30.4%, pT3 28.4% and pT4
33%, and cancer specific 5-year survival rates for organ-confined and extravesical disease were 82.5%
and 43.3% respectively. Comparison showed that
adenocarcinomas had the same natural history as
urothelial carcinoma following radical cystectomy,
but that patients with adenocarcinoma were usually
of a more advanced stage at the time of treatment.
In a separate study the median survival for patients
with localized tumors was 64 months, while median
survivals for patients with tumors showing regional
and distant spread were 29 and 8 months respectively [242].
g) Differential Diagnosis: The differential diagnosis of bladder adenocarcinoma includes other forms
of bladder neoplasia and secondary adenocarcinoma of the stomach, appendix, large bowel, breast,
endometrium and prostate gland.
Rare villous adenomas of the bladder may resemble
enteric type adenocarcinomas, although they lack
the degree of atypia seen in carcinoma and do
not infiltrate the bladder wall. Villous adenomas
show membranous expression of prostatic specific
membrane antigen and while this may also be seen
in mucinous and signet ring cell adenocarcinomas,
enteric adenocarcinomas usually show cytoplasmic
staining [329]. Urothelial carcinomas may show cystic
change with gland-like lumens, however, in these
tumors more typical areas of urothelial carcinoma
may be identified.
Infiltration of the bladder by prostatic adenocarcinoma may be differentiated from primary bladder
adenocarcinoma by immunohistochemistry as bladder tumors are negative for monoclonal prostate
specific antigen and prostate specific acid phosphatase [333]. Colonic adenocarcinoma infiltrating
or metastatic to the bladder may mimic bladder adenocarcinoma although careful examination will confirm that colonic metastases do not have any in situ
component. Immunohistochemical expression may
also be helpful as positive staining for cytokeratin 7
and negative staining for cytokeratin 20 is seen in
41% of bladder tumors but is not a feature of colonic
adenocarcinoma [170]. Additionally bladder adenocarcinomas often show positivity for thrombomodulin, while colon adenocarcinomas are negative and
unlike bladder tumors, often show nuclear staining
for -catenin [331].
Morphology has been associated with outcome,

with 5-year survival rates being 64% for tumors
showing mixed morphology, 55% for mucinous
adenocarcinomas, 51% for adenocarcinoma NOS,
and 27% for signet ring cell adenocarcinomas,
although these data did not achieve statistical
significance[326]. Signet ring cell carcinoma are
usually of an advanced stage at diagnosis, with mean
survivals of 9 to 12 months, and a 5-year survival of
<11% being reported [195,326,336].
Signet ring cell adenocarcinoma of the bladder may

resemble metastatic gastrointestinal tumors. These
tumors have an immunoexpression similar to enterictype bladder adenocarcinoma and further they are
109
Other features also shown to be of prognostic

significance are tumor size, histological grade and
method of treatment. It is, however, evident that
the prognostic significance of treatment modality
is stage dependent as this determines treatment
selection [322,325].
presenting signs and symptoms are abdominal

mass or pain, suprapubic mass, umbilical mass or
discharge, recurrent urinary tract infections, irritative
voiding symptoms, or urinary outflow obstruction,
while mucinuria is seen in 25% of urachal
adenocarcinomas [338,340,347].
It has been suggested that for localized tumor

observed poor outcomes following cystectomy relate
to occult spread of tumor [322,325]. This may explain
the significantly improved 5-year survival rates (58%
versus 44%) for patients treated with neoadjuvant
radiotherapy, four to ten weeks post-operatively
[337].
d) Gross Appearances: During fetal development,
the urachus contains the allantois and connects the

umbilicus to dome of the bladder. Following birth the
urachus undergoes involution to form the median
umbilical ligament [350]. In one third of individuals the
epithelial-lined urachal lumen persists as urothelium
or mucinous columnar epithelium, resulting in patent
urachus, cysts or tubular canals of varying size and
complexity within the median umbilical ligament
or bladder wall [339]. The embryogenesis of the
urachus accounts for the observation that urachal
carcinomas are seen as a mass at the bladder
dome or on the anterior surface of the bladder.
There is usually infiltration into the bladder wall
although occasionally this may be absent, with the
tumor having a pushing margin and being clearly
demarcated from adjacent bladder tissue. Tumors
are usually bulky at diagnosis with extension beyond
the bladder within the space of Retzius or through
to the anterior abdominal wall in the midline [323].
Less frequently urachal carcinomas infiltrate the
bladder mucosa [340] and may appear grossly as
ulcerated, mucinous or papillary masses [338].
2. Urachal Carcinoma
a) Definition: Urachal carcinomas are malignant
tumors arising in urachal remnants. While the great

majority of these tumors are adenocarcinomas
originating from vestigial urachal epithelium,
squamous cell carcinoma, urothelial carcinoma,
neuroendocrine carcinoma and sarcomas have also
been reported, albeit rarely [338].
b) Incidence: Although urachal remnants are
seen in up to one third of post mortems [339],

urachal malignancies are rare tumors with many
reports consisting of single cases and small
series[340,341]. In population based studies from
the Swedish Cancer Registry, the annual incidence
was 1 in 5 x 106 [342], while in Massachusetts
these tumors comprised 0.01% of all malignant
tumors[343]. Urachal carcinomas have been shown
to constitute 0.07% - 0.7% of bladder carcinomas
in North America and Europe and 0.55% - 1.2% of
bladder carcinomas in Japan [344]. In a separate
study these tumors were shown to comprise 0.17%
- 0.34% of bladder neoplasms and 20% - 39% of
all bladder adenocarcinomas [345]. More recently
urachal cancer was found to account for <0.1% of
all bladder cancers reported to the Ontario Cancer
Registry [346].
Imaging studies suggest a diagnosis of urachal

carcinoma when tumors are seen in the bladder
dome or extending to the anterior abdominal
wall in the midline [349,351]. Calcification is
frequently present within the tumor and is seen on
computerized tomography in approximately 70% of
cases [349,352].
e)
Histological Features: Because of the

morphologic overlap of vesical and urachal
adenocarcinoma, several diagnostic criteria for
urachal tumors have been proposed (Table 10). It
is considered that the Wheeler and Hill [353] and
Mostofi [323] criteria are too restrictive and likely to
exclude cases of true urachal adenocarcinoma. For
this reason the criteria of Gopalan et al. (2009) [340]
are preferred.
c) Clinical Features: There is a male predominance
for all types of urachal cancers with male to female

ratios of 1.8:1 to 3:1 being reported [338,341,347].
In various series, patients ranged in age from 16 to
87 years and the mean age ranged from 50 to 60.7
year[338,340,341,345,347-349]. Approximately 70%
of patients were aged between 41 and 70 years at
diagnosis [338,345].
The
majority
of
urachal
carcinoma
are
adenocarcinoma [325,341,347] and closely resemble
colonic adenocarcinoma. Many of the tumors have
a pronounced mucinous component and this has
been considered as a separate subtype consisting
of single tumor cells or cell nests within lakes of
extracellular mucin [325]. Less frequently the tumor
has a signet ring cell morphology [325,341,347].
For urachal adenocarcinomas the male to female

ratio ranged from 1.35:1 to 3:1[338,346]. Greater
than 70% of patients were aged 41 to 70 years,
while 20% of patients were less than 40 years of
age at diagnosis[338,345]. In a further series 20% of
patients who presented with urachal adenocarcinoma
were greater than 70 years of age[346].
Rare carcinomas have features other than

those of typical adenocarcinoma and cases of
squamous cell carcinoma [341,347,354,355],
urothelial carcinoma[347,355], lymphoepithelial-like
Hematuria is the most common presenting feature

in 55% to 80% of cases [340,344,345,347]. Other
110
carcinoma[341], clear cell carcinoma[341] and small

cell/neuroendocrine carcinoma[347,356,357] have
been described. On occasion more typical urachal
adenocarcinomas may contain focal areas of these
rare forms of carcinoma. Several cases of urachal
sarcoma with features resembling leiomyosarcoma,
rhabdomyosarcoma and hemangiopericytoma have
also been reported [338,358-360].
Extravesical genital tract carcinomas may be

differentiated from urachal adenocarcinomas by
prostate specific antigen, vimentin and CA125
immunohistochemistry [330,362]. Vesical urothelial
carcinomas are usually negative for carcinoembryonic
antigen.
There is often an overlap in the morphologic features
of vesical, colonic and urachal adenocarcinoma and
clinicopathologic correlation, with application of the
defining criteria for urachal carcinoma (Table 10),
usually leads to the correct diagnosis. Each of
these primary tumors may show positive staining
with carcinoembryonic antigen, however, diffuse
expression favors a urachal origin [330]. Unlike
urachal adenocarcinoma, colonic tumors are likely
to show diffuse cytokeratin 20 staining and are
cytokeratin 7 negative.
In larger series tumor grading is reported, although

no formal grading system for these tumors has been
established. In these series tumors are subjectively
graded as well differentiated/poorly differentiated
[347] or well/moderately/poorly differentiated [346].
f) Ancillary Diagnostic Tests:
Studies on
the immunohistochemical expression of urachal
carcinomas are limited [361]. These tumors are
usually positive for carcinoembryonic antigen,
7E12H12 IgM isotype, CDX2 and Leu-M1, while
focal positivity has been reported for cytokeratin 7,
cytokeratin 20, 34E12 and E48 antibody. Stains
for vimentin, Her-2/neu and prostate specific
antigen are negative. Cytoplasmic -catenin and
CA19-9 positivity is seen in the majority of urachal
adenocarcinomas, while CA125 positivity is only
rarely present [330,340,362].
h) Prognosis: In earlier series the prognosis of

urachal carcinoma was found to be poor with overall
survivals of 22.7% and 31%, and a 5 year survival
of 61% being reported [344,363]. In more recent
studies mean overall survival was 122 months[9]
and a meta-analysis of 312 patients showed 5 year
post-operative cancer free survivals to range from
43% to 70%[325,341,345-348,363-367].
A staging system for urachal carcinoma was

established by Sheldon et al [345]. This was
hampered by a relatively large number of categories
and a simplified staging classification has been
proposed [347,365] (Table 11). Advanced tumor
g)
Differential Diagnosis: The differential

diagnosis includes primary adenocarcinoma of the
bladder and metastatic colonic, ovarian and prostatic
carcinomas.
Table 10. Criteria for diagnosis of urachal adenocarcinoma

Wheeler and Hill, 1954
1.
2.
3.
Tumor in dome of bladder.

Absence of cystitis cystica or cystitis glandularis.
Predominant involvement of muscularis rather than submucosa, with
intact or ulcerative bladder epithelium.
4.
5.
Urachal remnant connected to neoplasm.

Suprapubic neoplastic mass.
1.
2.
Criteria additional to Wheeler and Hill

Location in anterior wall of bladder.
Sharp demarcation of tumor and surface epithelium.
3.
Extension to space of Retzius, to umbilicus or anterior abdominal wall.
1.
2.
Tumor in bladder dome.

Sharp demarcation between tumor and bladder epithelium.
3.
Exclusion of another primary (non-urachal) adenocarcinoma.
1.
2.
3.
Tumor in dome/anterior wall.

Epicenter of carcinoma in bladder.
Absence of widespread cystitis cystica/glandularis beyond the dome/
anterior bladder.
No known primary elsewhere.
Mostofi et al, 1955
Johnson et al, 1985
Gopalan et al, 2009
4.
111
3. Clear Cell Adenocarcinoma
stage is associated with a less favorable outcome,

with reported 5 year survivals of 93% for patients
with tumor confined to the urachus and bladder,
69% for extra-vesical and peri-urachal tumors and
0% for tumors within the peritoneal cavity [341,347].
In a further series all patients who developed local
recurrence or metastases were Sheldon stage T3 or
higher [340]. Other features associated with poor
survival are high tumor grade and positive surgical
margins [341,346,347].
a) Definition: This designation should be reserved
for tumors resembling to a significant degree clear cell

adenocarcinoma of mllerian type as encountered
in the female genital tract and should have one or
more of the typical tubulocystic, solid and papillary
patterns as well as one or more of the typical cell
types including clear cell, non-specific cuboidal and
hobnail [205,377].
b) Incidence: These are rare neoplasms and are of
Successful management of urachal carcinoma

is dependent on complete surgical excision of
tumor. This involves partial or radical cystectomy,
removal of the medial umbilical ligament/urachus
and resection of the umbilicus, and in recent
years laparoscopic surgical techniques have been
described [368-370]. Recurrence are more likely
following partial cystectomy [347,371,372] and
common metastatic sites are liver, lung, bone and
peritoneum [340,341,343-347], while metastasis to
the brain and skin are less common [347,373,374].
For patients who developed local recurrence or
metastases, time to relapse is usually short, ranging
from 10 to 22 months [340,341]. Salvage surgery
has been shown to result in a long term cure for 50%
of patients with local recurrence [347].
two fundamental types. Those that arise in females

from endometriosis and accordingly histogenetically
as well as morphologically are identical to mllerian
clear cell carcinoma. The second group includes
neoplasms without a proven association with
endometriosis but with morphologic similarity to
tumors having such an association. Even when both
subsets are combined this is amongst the rarest of
all bladder cancers accounting for no more than
0.01% of cases.
c) Clinical: The great majority (approximately 80%)
of these tumors have occurred in females. There is

a wide age distribution in adult life from the early
twenties to late years but the majority occur in a
somewhat old population (mean 57 years). There is
no unique aspect to the clinical presentation amongst
the reported cases although it is conceivable that
an association in a female of symptoms with the
menstrual cycle could indicate an endometriosis
associated carcinoma.
Adjuvant chemotherapy currently has a limited

efficacy for urachal adenocarcinoma. Although tumor
regression has been reported following chemotherapy
for a few cases [339,340,346,351,375], it has been
noted that this does not alter survival interval for
patients with metastatic disease [347]. Despite this,
it has recently been suggested that 5-fluorouracilbased chemotherapy may have some efficacy
[376].
d) Gross Appearance: Most of the reported
tumors have been polypoid to papillary. An entirely

mural neoplasm, although not reported, could be
encountered due to the origin of some cases in
endometriosis within the muscularis propria of the
Table 11. Staging systems for urachal carcinoma.

1.
2.
Sheldon staging classification

Stage I
Stage II
Stage III
IIIA
IIIB
IIIC
IIID
Stage IV
IVA
IV
Confined to urachal mucosa.

Confined to urachus.
Extension to bladder.
Peri-urachal and vesical fat invasion.
Extension to peritoneum.
Extension to viscera other than bladder
Metastases to regional lymph nodes.
Metastases to other organs.
Mayo staging classification

Stage I
Stage II
Stage III
Stage IV
Confined to urachus and bladder.

Beyond muscular layer of urachus and/or bladder.
Infiltration of regional lymph nodes.
Infiltration of non-regional lymph nodes or distant sites.
112
bladder. The reported tumors have ranged up to 7

cm in greatest dimension.
epithelium may rarely be difficult to distinguish from

dilated glands of associated endometriosis should
the specimen be from a female patient, particularly
if the patient is postmenopausal and atrophy of
the stromal component of endometriosis would be
expected.
e) Microscopic Features: The typical triad is
that of tubulocystic, papillary and diffuse (solid)

arrangements. The commonest is tubulocystic,
the lumens of these formations often containing
basophilic or eosinophilic secretion that may be
mucin positive (Figure 50). The papillae are generally
small and rounded but may be large and delicately
filiform. Rarely they are hyalinized. In tumors with a
diffuse growth the cells may have conspicuous clear
cytoplasm and appreciable clear cytoplasm may
be a feature of the cells lining tubules and cysts or
forming papillae although generally the cells of these
structures have non-specific lightly eosinophilic
cytoplasm of modest amount. A variety of other
rare patterns may be encountered including solid
tubular formations. Some of the cells lining tubules
and cysts may have the features of hobnail cells but
they are generally predominantly non-specific and
cuboidal in nature [205,377].
The differential of clear cell carcinoma also includes

a urothelial (transitional) carcinoma with glandular
differentiation in which the latter resembles to
a degree the pattern of clear cell carcinoma.
Thorough sampling can be crucial in this distinction
and in biopsy or curettage material it may not be
possible to make the distinction but it rarely has
therapeutic implications. Spread to the bladder from
a clear cell carcinoma of the genital tract in females
is excluded primarily by clinical findings. There is
little resemblance between clear cell carcinoma and
metastatic renal cell carcinoma despite the shared
population of clear cells in many cases.
g) Ancillary Diagnostic Tests: These are
rarely needed to establish the diagnosis but

some information potentially of benefit has
accrued, albeit overall knowledge on this aspect is
limited. Most of the reported tumors have stained
immunohistochemically for CA-125 and CK7. CK20
has usually been only focally and weakly positive
although it was strongly positive in one tumor.
h) Prognosis: The prognostic parameters are
similar to those of conventional carcinoma of the

bladder and standard parameters such as invasion
of the lamina propria, and its extent, and even more
so invasion of the muscularis propria are guides to
both therapy and prognosis. There is no evidence
that the behavior, stage for stage, is different from
usual bladder cancer.
Figure 50. Clear cell variant urothelial carcinoma,

tubulocystic pattern. This neoplasm, from a female,
was associated with endometriosis.
IV. NEUROENDOCRINE NEOPLASMS
f) Differential Diagnosis: The major differential
1. Neuroendocrine Carcinoma of The

Bladder
diagnosis is with nephrogenic adenoma because the

tubular and papillary patterns of clear cell carcinoma
may occasionally be reminiscent of similar patterns
of nephrogenic adenoma. It is helpful in many cases
that the gross characteristics are highly suspicious for
a neoplasm although it should be noted that a mass
lesion may be seen in some cases of nephrogenic
adenoma. The typical tiny tubules of nephrogenic
adenoma usually are of much smaller caliber than
the great majority of tubular formations in clear cell
carcinoma. Treacherously, hobnail cells may be
seen in both the benign and malignant processes.
Clear cells are only rarely a feature of nephrogenic
adenoma. There is generally much greater cytologic
atypia and in particular more conspicuous mitotic
activity in cases of clear cell carcinoma than ever
seen in nephrogenic adenoma.
a) Definition: A group of tumors comprising small

cell carcinoma and large cell neuroendocrine
carcinoma and mixed patterns [378].
b) Incidence: Large cell neuroendocrine carcinoma
of the urinary bladder is extremely rare with less than

ten cases reported in the literature [379]. Small cell
carcinoma of the urinary bladder, although relatively
much more common than both carcinoid and large
cell neuroendocrine carcinoma, is an extremely rare
primary bladder malignancy, accounting for less than
1% of urinary bladder cancers [120,380-382].
c) Clinical: Although there are no more than single
cases of primary large cell neuroendocrine carcinoma

of the urinary bladder, the age at diagnosis ranges
from 32 to 82 years, and patients may present with
Dilated cysts lined by compressed neoplastic
113
symptoms similar to those of carcinoid tumor [383385]. Small cell carcinomas mostly occur in the sixth
to seventh decade of life, the mean age being 66
years at the time of diagnosis (range 36 to 85 years),
and have a male preponderance [386]. Patients
usually present with hematuria, which may be
accompanied by dysuria, frequency, nocturia, urinary
obstructive symptoms, or localized abdominal/
pelvic pain [380,386]. Small cell carcinomas arise
most frequently in the lateral walls and dome of the
bladder, and rarely in bladder diverticula [119,120].
be mistaken for malignant lymphoma, poorly differentiated urothelial carcinoma, and even exuberant
inflammation in the background of crush or electrocautery thermal artifact, especially in a superficial or
scant specimen. Pulmonary metastasis or extension
from adjacent viscera must be ruled out by clinicoradiologic correlation, as immunohistochemistry offers
limited assistance in this setting. An additional rare
but significant consideration is alveolar rhabdomyosarcoma, a subset of which can impart a primitive
round cell appearance, imparting a histology reminiscent of small cell carcinoma [120].
d) Gross Appearance: The few reported cases of
g) Ancillary Diagnostic Tests: Tumor cells of
large cell neuroendocrine carcinomas have not been

associated with any one single modality of growth.
Small cell carcinoma may manifest as a single large,
solid, polypoid, sessile or ulcerated mass, which may
be infiltrative at presentation [119,120,387].
large cell neuroendocrine carcinoma are immunopositive for neuroendocrine markers chromogranin A,
synaptophysin, CD56, and neuron-specific enolase,
and for cytokeratins CAM 5.2 and AE1/AE3, and
epithelial membrane antigen. Small cell carcinoma
tumor cells are immunopositive for chromogranin A
and synaptophysin (greater than 60% of cases) and
frequently demonstrate a dot-like immunopositivity
for pan-cytokeratin. TTF-1 may be immunopositive in
up to 40% of cases [388]. Unlike neuroendocrine tumors, lymphomas are immunopositive for leukocyte
common antigen and negative for keratin and neuroendocrine markers. Poorly differentiated urothelial
carcinoma does not express neuroendocrine markers such as chromogranin or synaptophysin, thereby
differentiating it from small cell carcinoma. Prostatic
adenocarcinoma, unlike small cell carcinoma, would
be immunopositive for prostate-specific markers,
prostate specific antigen and prostatic acid phosphatase. Lastly, alveolar rhabdomyosarcoma with
small cell differentiation would be immunopositive
for desmin, myogenin and Myo D1 and negative for
keratin. Interestingly, this tumor is associated with
immunopositivity for the neuroendocrine marker synaptophysin, necessitating the employment of a panel
of immunohistochemical markers.
e) Microscopic Features: Large cell neuroendo-
crine carcinoma is poorly differentiated and highgrade. At low magnification, it demonstrates a noticeable histologic pattern of growth in the form of nests
and trabeculae. Tumor cells have irregular angulated nuclear outlines and prominent nucleoli. Pure
small cell carcinomas have a patternless pattern of
growth, meaning at low magnification, the tumor cells
grow in a diffuse fashion with no clear organization.
As an exception however, one may find focal nesting
pattern. Tumor cells have very little cytoplasm; as a
result, they show nuclear crowding and molding as
though being pushed in to one another (Figure 51).
Nucleoli are inconspicuous and the chromatin is
evenly dispersed. Small cell carcinomas carry a high
proliferation rate, as evidenced by frequent mitoses,
crush artifact, geographic necrosis, and the subsequent Azzopardi effect, whereby blood vessel walls
undergo encrustation by excess liberated DNA.
f) Differential Diagnosis: Large cell neuroen-
docrine carcinoma, also due to its exquisite rarity,

ought not be confused with a metastatic deposit of
its pulmonary counterpart. Small cell carcinoma may
h) Prognosis: Large cell neuroendocrine carcino-
ma appears to behave by way of small cell carcinoma, being aggressive with high metastatic potential, with most reported cases having a fatal outcome
[383,384]. As with primary pure carcinoid tumors of
the urinary bladder, large studies have not been possible due to the limited number of reported cases.
Small cell carcinoma of the urinary bladder often
presents at an advanced stage, with up to 94% of
cases having muscularis propria invasion or extravesical extension. Metastasis at time of presentation is not uncommon, to sites that include regional
lymph nodes, liver, bone, and lung. Treatment recommendations for small cell carcinoma of the urinary
bladder have been based on case reports and small
retrospective series. Cisplatin and etoposide-based
chemotherapy in conjunction with surgery has been
associated with significantly improved survival, including reports of long-term survivors. Various clini-
Figure 51. Small cell carcinoma with squamous

differentiation.
114
f) Differential Diagnosis: Carcinoid tumors can be
cal studies have addressed patient management by

way of different combinations and modalities of surgery, chemotherapy and radiation therapy, making it
exceedingly difficult to correlate outcome between
the different series. Mean survival ranges from 6 to
34.9 months and the reported 5-year survival rate
ranges from 8 to 40%. Organ-confined disease is
more amenable to therapy and is associated with
more favorable patient survival. In sum, prognosis
is influenced by disease extent at diagnosis, employment of chemotherapy, and the patients performance status [386,387,389].
histologically confused with nested variant of urothelial carcinoma, inverted urothelial papilloma, and
metastatic tumors arising in the prostate, gastrointestinal tract and lung. The rarity of carcinoid tumors
of the urinary bladder coupled with the prognostic
significance of its differentials makes it paramount
to employ ancillary studies and clinicoradiologic correlation as part of case work-up.
g) Ancillary Diagnostic Tests: Carcinoid tumor
cells are immunopositive for neuroendocrine markers chromogranin, synaptophysin, serotonin, and
neuron-specific enolase, and for cytokeratin AE1/
AE3.
2. Carcinoid Tumor
a) Definition: A well-differentiated neuroendocrine
h) Prognosis: In the largest series to date, all 6
tumor similar to that seen in other organs which is

part of a very broad spectrum neuroendocrine tumors in the bladder [378].
pure carcinoid tumors with similar morphology had

excellent prognosis [390]. However, the number of
cases reported is still relatively small and the tumors
likely had been completely removed by biopsies.
Pure primary carcinoid tumor of the bladder and
prostatic urethra, when presenting as small polypoid nodules in the bladder is associated with a very
favorable outcome. However, there are reports of
larger more invasive lesion with regional lymph node
or distant metastases [119,392]. Some of the early
reported cases with aggressive behavior were found
to be mixed tumors with associated small cell carcinoma or adenocarcinoma components.
b) Incidence: Pure carcinoid tumor of the urinary

bladder are extremely rare. By way of criteria applied
to their more common pulmonary counterparts, less
than ten cases have been reported in the literature
[390,391].
c) Clinical: Carcinoid tumors of the urinary bladder
have been reported to occur solely in adults ranging from 29 to 75 years of age, with a slight male
preponderance. These patients may present with
hematuria and irritative voiding symptoms.
d) Gross Appearance: Carcinoid tumors usually
E. ROLE OF
IMMUNOHISTOCHEMISTRY
AND ANCILLARY DIAGNOSTICS
IN HE DIAGNOSIS, STAGING,
PROGNOSTICATION AND
PREDICTION OF BLADDER CANCER
IN CONTEMPORARY CLINICAL
PRACTICE
present as small polypoid masses at the bladder

neck/trigone[390].
e) Microscopic Features: Microscopically, carcinoid tumors are submucosal and confined within
the lamina propria, often associated with adjacent
cystitis cystica et glandularis. The tumors are composed of uniform, cuboidal, or columnar cells with
finely stippled chromatin and inconspicuous nucleoli
in a prominent pseudoglandular pattern composed
of acinar and cribriform structures (Figure 52).
I. Immunohistochemical
Markers for Staging of
Bladder Cancer
1. Introduction
Pathologic staging of bladder cancer identified
in transurethral resections or biopsies is the
clinically most powerful determinant with regard
to treatment decision, in addition to grading[393].
Although grading is the strongest prognosticator
for progression of bladder cancer in the subset of
non-invasive (pTa) bladder cancers, grading tends
to lose its independent prognostic value in invasive
bladder cancers[115]. Pathologic staging depends
on the morphologic recognition of invasion beyond
the basement membrane into the lamina propria,
Figure 52. Carcinoid tumor involving the bladder.
115
while invasion of the detrusor muscle serves as a

landmark for T2 bladder cancer.[393] The diagnosis
of muscularis propria invasion generally leads to the
clinical decision to perform a major surgery, including
cystectomy or nephroureterectomy. Histopathological
assessment of invasion of the lamina propria may be
hampered by several factors, which include artefacts
related to the procurement of the tissue and the
morphologic variation of bladder cancers.[393]
Indeed, sometimes it is impossible for a pathologist
to determine whether a bladder cancer is invasive.
Artifactual confounders are the occurrence of severe
cautery and crush effects related to the urological
procedure and the lack of spatial orientation due to the
random embedding of the bladder tissue chips. If the
biopsy or transurethral resection is very superficial,
underlying stroma may be too scarce or even
absent, again precluding the staging of the tumour
sample. Biological tumor-associated factors that
may preclude a proper assessment of pathological
stage are the presence of an inverted growth
pattern, which is more commonly associated with a
trabecular or even pushing invasive growth pattern,
and the occurrence of a florid desmoplastic reaction,
which in particular could hamper the identification
of the detrusor muscle. Further, the variation in
thickness of the muscularis mucosae, which are
normally represented by thin wisps of smooth
muscle fibers may lead to an erroneous assignment
of T2 bladder cancer, particularly when this layer
becomes hypertrophic in appearance. At various
sites in the bladder (e.g. the trigone, the bladder
neck, or the renal calyces), the detrusor muscle may
be located superficial, and as a consequence, its
invasion may spuriously be deemed as invasion of
the muscularis mucosae, resulting in under-staging
of the bladder cancer. Finally, in resected cancers
of bladder diverticula (in fact pseudo-diverticula) it
is generally impossible to distinguish pT1 from pT2
or even pT3 stages as this site generally lacks the
landmark detrusor muscle.
cytokeratin antibodies can facilitate the diagnosis

of invasion in cases with prominent inflammation
obscuring the interface between epithelium and
stroma. The most commonly employed antibodies
for this purpose are pan-keratins, like AE1 / AE3 and
antibodies against cytokeratins 8 and 18[396]. (Table
13) Also, in case of cautery artefacts or as a sequel
to a previous urological procedure, cytokeratin
staining may allow the identification of carcinoma
cells infiltrating the (cauterized) stroma[393,397].
A potential pitfall, particularly in the setting of a
previous urological procedure such as a transurethral
resection, is the positive staining for cytokeratins of
myofibroblasts and smooth muscle cells[397]. Both
myofibroblasts and smooth muscle cells generally
express only low-molecular weight cytokertins,
while epithelial cells will show immunorecativity
to high molecular weight forms. Most importantly,
a correlation of the cytologic appearance of the
cytokeratin positive cells is essential in order to
obtain a correct diagnostic interpretation.
Table 12. Interobserver variation for staging of
bladder cancers.
Author
(reference)
Down staging pT1 Upstaging

-- pTa
pT1 pT2
Abel, 1988
13%
1%
Van der
Meijden, 2000
53%
10%
Bol, 2003
56%
13%
Tosoni et al,
2000
35%
3%
Experimental studies have shown that tumour

invasion is associated with dysregulation of both
adhesion molecules, involved in cell-cell interactions
and cell-basement membrane structures like
hemidesmosomes, and endopeptidases with the
capacity to de-grade extracellular matrix proteins
[398]. Cadherins are a family of cell-cell adhesion
molecules whose expression is altered during
the epithelial mesenchymal transition which is
characteristic of tumour invasion [399,400]. Whereas
carcinoma in situ of the urothelium expresses high
levels of E-cadherin, its expression is reduced, and
a switch to N-cadherin and in particular P-cadherin
expression has been reported in invasive bladder
cancers [399]. Negative markers such as E-cadherin
are obviously not suitable for diagnostic use to
detect invasion, but markers which are selectively
up-regulated in invasive cells may hold diagnostic
promise. P-cadherin expression was shown to be
elevated in particular in the invading edge, but this
molecule is also predominantly expressed in the
A few studies have demonstrated a substantial level

of inter-observer variation among pathologists for
staging of bladder cancers (Table 12)[33,394,395].
For this reason, several attempts have been made
to identify easily applicable histological markers that
would increase the accuracy of pathological staging
of cancers of the urinary tract.
2. Determination of invasiveness of
bladder cancer
The identification of invasive bladder cancer cells
can be challenging, especially when the number of
invading cells is small or in the presence of cautery
or mechanical artefacts. In addition, some tumours
may show pushing growth deep in the lamina propria
without an obvious invasive pattern. Although no
formal studies have been reported in the literature,
it is well-established that immunostaining with anti-
116
Table 13. Most commonly employed immunohistochemical markers for staging of bladder cancers
Pathological issue
Immunohistochemical marker
Caveats
Detection of micro-invasion
into cauterized or damaged
tissue
Pan-keratin, keratin 8, 18
Keratin positive myofibroblasts
Residual cancer cells postTUR
Pan-keratin
Keratin positive myofibroblasts
pT1 substaging
Desmin, pan-keratin
pT1 versus pT2 staging
Smoothelin, vimentin
basal layers of the non-invasive bladder cancers

[398], precluding its use as a diagnostic adjunct for
invasion.
heterogeneous, particularly with regard to risk of

progression and death of disease during followup. Several attempts have been made to substage
T1 bladder cancers. The most often employed
substaging system employs the muscularis mucosae
and the associated plexus venosus in the lamina
propria as reference point, distinguishing a substage
pT1a, pT1b and pT1c [44]. pT1a cancers are the
most superficial bladder cancers, with invasion above
the muscularis mucosae, while pT1c cancers would
invade beyond the plexus venosus. A condensed and
probably more robust substaging system aggregates
pT1a and pT1b cancers in the substage of minimally
invasive bladder cancers [40]. Several studies
reported a considerable inter-observer variation for
this substaging system, while it was also noted that
in a variable proportion of cases pathologists were
not able to assign a substage due to absence of
the muscularis mucosae / plexus venosus and poor
orientation. As a consequence, pT1 substaging has
not been included in the WHO 2010 classification
of bladder cancers. One attempt was made to use
immunohistochemistry for improvement in the
accuracy of pT1 substaging (18), using antibodies
against desmin and pan-keratin; in a series of 93
consecutive pT1 bladder cancers, they observed
that in a small proportion of cases immunostaining
could eliminate the disagreement with regard to pT1
substage among two pathologists when reviewing
H&E stained slides [406]. Thus, it was concluded that
the use of desmin and cytokeratin immunostaining
could be of help to improve the precision of
substaging pT1 bladder cancers; however, there is
no data to show that using immunohistochemistry
for substaging improves the prediction of recurrent
or progressive disease and therefore it is not
recommended for routine application.
Among the extracellular matrix degrading endopeptidases, collagenase-3 (matrix metalloproteinase-13)

and stromelysin-3 have been studied in relatively
small series of bladder cancers for their diagnostic
and prognostic use [401-403]. MMP-13 was expressed predominantly at the invading edge and
invasive nests of about 60% of the invasive carcinomas. Further, a weak expression was also noted
in the stromal fibroblasts of some of the invading
cancers [403]. Given the low sensitivity of MMP-13,
this marker does not seem useful in diagnostics of
bladder cancer invasiveness. Stromelysin expression was particularly noted in the stromal fibroblasts
adjacent to the invasive carcinoma nests of about
70% of carcinomas, but not in the carcinoma cells.
However, a small proportion of non-invasive bladder
cancers were also positive for this marker, diminishing its diagnostic significance [401,402]. Of interest,
stromelysin expression showed a statistically significant correlation with lymphatic vessel invasion.
Further, some studies addressed the potential of
immunostaining for basement membrane proteins as
an adjunct to the morphologic detection of invasive
cells in bladder cancer. Laminins are glycoproteins
which represent a major component of the basement
membrane and they consist of three subunits, i.e. an
, and chain. The LN-5 chain is a specific target
of MMP-2, and this cleavage is critical for tumor
invasion and tissue remodeling. It was reported
that expression of LN-5 2 is increased in the
carcinoma cells at the invasive edge of the bladder
cancers [404,405]. Although LN-5 2 was strongly
and independently associated with unfavourable
prognosis, only about one third of the invasive
carcinomas expressed this marker as compared
to 7% of the non-invasive bladder cancers, which
renders LN-5 2 unsuitable as a diagnostic marker.
4. Immunohistochemical markers for

identification of detrusor muscle
Particularly in transurethral resections of the bladder,
the distinction between T1 and T2 bladder cancer may
be challenging. For this reason immunohistochemical
markers have been employed to help discriminate
muscularis mucosae from muscularis propria.
3. Immunohistochemical markers for

substaging pT1 bladder cancers
Stage
pT1
bladder
cancers
are
Overlap in staining intensity of

muscularis mucosae and detrusor
muscle
clinically
117
Initially, the utility of desmin and/or smooth muscle

type actin in the identification of the detrusor muscle
was evaluated, but these markers do not allow a
differential staining of the muscularis mucosae and
muscularis propria. Histochemical stains such as
hematoxylin-phloxine-saffron or Mallory trichrome
have been used to identify muscle fibers in areas
of desmoplastic stroma or cautery artifact. Although
many pathologists do utilize such stains, there
are no published series reporting on use of any of
these markers in a routine pathology setting. There
is no good data on the value or the validity of this
approach; therefore, these cannot be recommended
for routine use.
and vimentin could help distinguish detrusor

muscle from muscularis mucosae. Two subsequent
studies addressed the question of whether
immunohistochemistry with smoothelin would help
resolve pathologic staging difficulty in problematic
transurethral resection specimens [412,413]. Both
studies confirmed the diagnostic utility of this marker.
In the first study, 4 cases with equivocal muscularis
propria on standard H&E stains were examined and
in the latter a series of 34 specimens submitted
for consultation because of questions relating to
pathological stage were stained for smoothelin. This
publication mentioned that the staining intensity of
blood vessel wall was similar to that of the detrusor
muscle, implying that the vessel wall musculature
could be used as an internal reference [412]. The
latter publication noted occasional overlap in
intensity of smoothelin staining for the two muscle
layers, which might lead to spurious pathological
staging results [413]. Since all studies to date have
demonstrated that immunostaining for smoothelin
with clone R4A monoclonal antibody can help
differentiate between muscularis mucosae and
detrusor muscle, this marker may be employed in
controversial cases as a diagnostic tool. Since a
minority of samples displayed a similar intensity of
staining in both muscle types, the immunostaining
should always be used in conjunction with the H&E
findings. Further, vimentin immunostaining may be of
additional help in distinguishing muscularis mucosae
from detrusor muscle [411].
Smoothelin was identified in 1996 as a marker

for smooth muscle tissue, and two isoforms,
smoothelin-A (59kDa) and smoothelin-B (110-kDa)
have been described [407]. Their function is related to
the contractility of smooth muscle and its expression
is absent in non-contractile or proliferative smooth
muscle cells. (Table 13) Smoothelins are actinbinding proteins that are expressed abundantly in
terminally differentiated visceral (smoothelin-A) and
vascular (smoothelin-B) smooth muscle and both
types can be visualized by monoclonal antibody R4A.
The latter antibody is the most commonly employed
antibody for the immunohistochemical detection of
smoothelin in a diagnostic setting. Recently, Paner
et al. reported the differential staining of detrusor
muscle and muscularis mucosae by this antismoothelin antibody to help distinguish muscularis
mucosae versus detrusor muscle invasion of bladder
cancer [408]. Similarly, in the gastro-intestinal tract
smoothelin is now being studied to distinguish
between pT1 and pT2 adenocarcinomas of Barrett
esophagus [409]. After a second confirmatory
study by Paner et al[410] on a larger series of 70
TUR samples, a subsequent study by Council et al.
compared the diagnostic value of smoothelin with
that of smooth muscle actin, desmin, caldesmon,
and vimentin on a series of 15 cystectomies [411].
In contrast to the similar intense expression levels
of muscularis mucosae and detrusor muscle for
smooth muscle actin, desmin, and the variable
expression levels of caldesmon, smoothelin and
vimentin displayed a differential expression pattern.
Smoothelin was intensely positive for all detrusor
muscle samples and negative or weakly positive for
muscularis mucosae, whereas vimentin was rarely
expressed in the detrusor muscle and positive in 9 of
11 specimens with muscularis mucosae. Council et
al. also noted that antibodies specific for caldesmon
and desmin and to a lesser extent - smoothelin
were able to selectively stain smooth muscle cells
as compared to reactive myofibroblasts [411]. These
authors recommended the use of caldesmon and
desmin immunohistochemistry to distinguish reactive
myofibroblasts, e.g. in desmoplasia from smooth
muscle cells, while a combination of smoothelin
5. Conclusions
Although these markers have been shown to have
promise, the studies are limited and from only a
few institutions. Substantially more data is needed
before these could be recommended for routine
application.
Level of evidence: 4
Recommendation: C
II. Summary of molecular/

genetic alterations in
1. Introduction
Despite the extensive new information and
knowledge on bladder cancer genetics, epigenetics
and gene expression, much is needed to satisfy
several unanswered questions.
Much of the work is following, and pointing toward,
two distinct pathways that correspond to two main
groups of tumors; superficial (papillary and flat) and
muscularis propria-invasive urothelial carcinoma.
A major question is whether the existing molecular
information can explain tumorigenesis along the
118
Table 14. Common genetic and epigenetic aberrations in urothelial carcinoma

Gene
Location
Deletion/Mutation
12q14.3-q15
Tumor
Suppressor
Oncogene
Clinicopathological Diagnostic Prognostic

Association
Role
Role
HGUC
Y/N
Y/N
Amplification
HGUC
HRAS*
11p15
Oncogene
FGFR3
4p16.3
Oncogene
E2F3
6p22
CCND1
TP53
17p13.1
MDM2
Role
Abnormality
Y/N
Oncogene
Activating Mutations All grades and

stages, up to 15%
Activating Mutations Predominantly lowgrade/stage
Amplification
Invasive HGUC
11q13
Oncogene
Amplification
CDKN2A
9p21
Tumor
Suppressor
Deletion/Mutation/
Methylation
RB1
13q14.2
Deletion/Mutation
Y/N
ERBB2
17q21-q22
Tumor
Suppressor
Oncogene
All grades and

stages, up to 20%
All stages and
grades, primarily
HGUC
Invasive HGUC
Amplification
Invasive HGUC
MYC
8q24.21
Oncogene
Amplification
Invasive HGUC
PTEN
10q23.3
Deletion/Mutation
HGUC, all stages
RASSF1A
3p21.3
Tumor
Suppressor
Tumor
Suppressor
FHIT
3p14.2
Y/N
PTCH
9q22.3
DBC1
9q32-33
TSC1
9q34
Tumor
Suppressor
Tumor
Suppressor
Tumor
Suppressor
Tumor
Suppressor
Methylation
Invasive HGUC,
associated with
progression
Deletion/Methylation HGUC, associated
with progression
Deletion/Mutation
All grades and
stages
Deletion/Methylation All grades and
stages
Deletion/Mutation
All grades and
stages
proposed two major tumor groups in regard to the

molecular events and of the biochemical signaling
pathways involved. Another equally important
question is whether currently available information,
or future knowledge, can predict which superficial
bladder tumors will later progress to become
invasive. Similarly, will there be any marker that
can have prognostic significance within any given
stage of the tumor. Despite this being a goal of many
molecular studies, to date molecular information has
failed to provide robust or reliable predictive markers.
Possibly, key markers still remain to be identified.
chromosome 9 by far the most common cytogenetic

finding (refer to tables 15 and 16 for more details).
2. Molecular alterations in
There seems to be distinct signaling pathways in

two groups of urothelial carcinoma. The association
of FGFR3 or HRAS mutations in the majority of
superficial tumors suggests that they share changes
in pathway activation, whereas, the common
inactivation of RB1 and TP53 pathways in invasive
tumors may indicate a distinct signaling status.
In invasive urothelial carcinoma, many genetic

alterations have been reported in addition to frequent
chromosome, which involve dysregulations of several
oncogenes and tumor suppressor genes. It has been
recently shown that tumors with aberrations in p53/
MDM2, RB1 and E2F3 are associated with more
genomic instability.
3. Signalling pathways in urothelial

carcinoma
Molecular, genetic and epigenetic aberrations

commonly involved in urothelial carcinoma are
listed in Tables 15 and 16. Briefly, most studies of
low-grade papillary urothelial carcinoma show few
molecular alterations apart from deletions involving
chromosome 9 and mutations of FGFR3 and HRAS.
These tumors are often near-diploid with loss of
Activation of the PI3K/Akt pathway in urothelial

carcinoma could occur via the known mutation
119
of PTEN and TSC1. A number of therapeutic

applications targeting molecules in these pathways
have been developed and are being tested for
potential roles in treating urothelial carcinoma.
provide support for the nuclear shape and also

involved in DNA replication, in RNA transcription
and in regulation of gene expression. This protein
is reported to have a concentration as high as 25
times in urothelial carcinoma as compared to normal
urothelial cells. This assay is approved for both
the detection of new cancers and the follow-up of
patients with a prior history of urothelial carcinoma.
The reported sensitivity ranges are 34.6%100%,
and 49.5%65.0%, but false positive results have
been reported.
4. Biomarkers with diagnostic/

prognostic values in urine
samples
a) BTA tests
This test is based on the detection of the human
complement factor H-related protein, which is
reported to be expressed only in bladder tumor cells.
The sensitivity of the BTA stat is reported to be 50%
for low grade urothelial carcinomas, which is higher
than cytology. Conversely, the specificity of BTA stat
is reportedly lower than cytology.
c) B
ladder Cancer Immunofluorescence Assay
This is an immunofluorescence assay designed
to improve the sensitivity of urine cytology. It
employs a cocktail of three monoclonal antibodies;
M344, LDQ10 and 19A211. The first two detect a
mucin-like antigen, while the third one recognizes
a high molecular weight glycosylated form of
carcinoembryonic antigen in exfoliated tumour
cells. This assay is approved only for use as a
b) Nuclear Matrix Protein 22 (NMP22)

This test is based on the detection of NMP22,
which is a member of a family of proteins that is
part of the structural framework of the nucleus and
Table 15. Common aberrations in urothelial carcinoma as detected by loss of heterozygosity (LOH) and
comparative genomic hybridization (CGH) analyses
LOH
CGH
Location Clinical Association
Location
9p, 9q, 10q, 11p,Y
Type of
Aberration
Loss
Clinicopathological
Association
non-invasive UC
3p
high grade/high stage
4p
1q, 17, 20q
Gain
non-invasive UC
4q
11q
Amplification
non-invasive UC
8p
Invasive UC
9q
all stages/grades
2q, 4p, 4q, 5q, 6q, 8p, 9p, 9q, 10q, Loss
11p, 11q, 13q, 15q, 17p, 18p, 18q,
Y
1q, 3p, 3q, 5p. 6p, 7p, 8q, 10p, 17q, Gain
19p, 19q, 20p, 20q, Xq
11p
Invasive UC
11q
recurrence
1q2224, 3p2425, 6p22, 8p12, Amplification

8q22, 10p1214, 10q2223, 11q13,
12q1221, 17q21, 20q13
14q
carcinoma in situ
Invasive UC
Table 16. Established clinicopathologic prognostic parameters in superficial and muscle invasive urothelial
carcinoma of bladder.
Clinicopathologic Prognostic Parameters
Superficial urothelial carcinoma
Muscle invasive urothelial carcinoma
WHO/ISUP Grade
pT stage
Presence of associated CIS/Dysplasia
Disease duration
Time to and frequency of recurrences
Multifocality
Tumor Size (>3 cm)
Failure of prior BCG Rx
Presence of LVI
Depth of Lamina propria Invasion
pTNM
LVI
Resistance to neoadjuvant chemotherapy
Divergent Histology:
Micropapillary
Osteoclast rich
Undifferentiated/Giant cell
Plasmacytoid
120
surveillance test if used in conjunction with cytology.

The overall sensitivity of the combined Bladder
Cancer Immunofluorescence Assay and cytology is
approximately 84%, which is better than either test
alone and it performs better at the detection of low
grade urothelial carcinoma.
types in regards to biologic behavior and prognosis.

Increasingly, molecular evidence supporting two
divergent pathways of pathogenesis for superficial
and invasive disease is accumulating. Superficial
BC is thought to originate from benign urothelium
through hyperplasia with only a small contribution
(10-15%) to the pool of high grade non-invasive and
subsequently invasive BC. The majority of invasive
tumors appear to originate through progression from
dysplasia to flat CIS and high grade non invasive BC
where genetic instability lead to accumulation of genetic alterations promoting progression to invasive
lesions [414-417].
d) UroVysion
This is a fluorescent in situ hybridization (FISH)
probe set with FDA approval for use in monitoring
tumor recurrence and primary detection of urothelial
carcinoma in voided urine specimens from patients
with gross or microscopic hematuria, but no previous history of urothelial carcinoma. The UroVysion
test probe set contains a mixture of four fluorescent
labeled DNA probes; a locus specific probe to the
9p21 band on chromosome 9 and to the centromere
of chromosomes 3, 7 and 17. The individual sensitivity of the centromeric probes for chromosome 3,
7, 17 is reported to be 73.7%, 76.2% and 61.9%,
respectively, while the sensitivity of homozygous
9p21 deletion for urothelial carcinoma has been reported as 28.6%. The UroVysion test is based on
combination of these probes and the sensitivity and
specificity has been reported to be 72% and 83%,
respectively. This test, however, is not free of false
positive and false negative results.
Clinically, a significant proportion of superficial tumors (pTa and pT1) are deemed to recur following
transurethral resection (TURB) with only a relative
minority of cases enduring progression to highergrade, deeply invasive aggressive tumors.
The superficial BC pathogenesis pathway appears
to be primarily based on alterations in the tyrosine
kinase receptor FGFR-3 and H-RAS[418] and PIK3CA-Akt in a subset of cases [414,419,420]. The
RAS-MAPK and PI3K-Akt pathways are potentially
the most important pathways promoting cell growth
in urothelial neoplasia. RASgenes activating mutations lead to activation of Mitogen-activated protein
kinases (MAPK) and PI3K pathways. Activating mutations in upstream tyrosine kinase receptor FGFR3
seems to be mutually exclusive withRASmutations
given that both signal through a common downstream pathway in urothelial oncogenesis. On the
other hand,PIK3CAmutations generally co-occur
withFGFR3mutations suggesting an additive oncogenic effect ofPIK3CAtoFGFR3mutations.
Recommendation: C
III. Prognostic and Predictive

Biomarkers in Urothelial
Carcinoma
The pathogenic pathway for muscle invasive BC

primarily involves alterations in tumor suppressor
genes p53, p16 and Rb [416,417,421].
1. Introduction
Molecular diagnostics applications are now an
integral part of the management algorithms of
several solid tumors such as breast, colon, and lung.
In stark contrast, the current clinical management of
urologic malignancies is lagging behind. Clinically
robust molecular tests that can identify patients
that are more likely to respond to a given targeted
agent or even those in need of a more aggressive
treatment based on well-validated molecular
prognosticators are still lacking. Table 17 and 18
outline traditional and potential molecular markers
in bladder cancer. Several promising biomarkers for
detection, prognosis, and targeted therapeutics are
now under evaluation. The following is a discussion
of some candidate biomarkers that may soon
make their transition to clinical assays in urothelial
carcinoma patients.
As illustrated in figure 53, subsequent p53 and Rb

alterations are also needed for the progression of
a subset of superficial lesions into a higher grade
muscle invasive BC.
3. P
rognostic Biomarkers in
Superficial Non-Muscle Invasive
(NMI-BC) and Muscle Invasive
Urothelial Carcinoma (MI-BC)
The currently established clinicopathologic prognostic
parameters in superficial lesions include: pTNM
stage, WHO/ISUP grade, size of tumor, disease
multifocality, presence of CIS and frequency and rate
of prior recurrences [422]. Prognostic parameters
that can accurately predict the subset of superficial
tumors that will progress are actively sought in order
to identify patients in need for vigilant surveillance
and aggressive treatment plan [423,424]. Equally
needed are markers that will improve prognostication
in muscle invasive disease given the current poor
2. Divergent Molecular Pathogenesis

in Urothelial Carcinoma
Superficial and muscle invasive bladder urothelial
carcinoma (BC) display two distinct clinical pheno-
121
Figure 53. Divergent molecular pathways of oncogenesis in superficial and muscle invasive urothelial
carcinoma of urinary bladder. Genetic alterations are depicted in key stages of disease progression.
Table 17. Potential molecular prognostic parameters in superficial and muscle invasive urothelial
carcinoma of bladder.
Emerging Molecular Prognostic Markers
Superficial Non Muscle Invasive Urothelail Carcinoma (NMIBC)
**Proliferation index (Ki67, MIB1, S phase)
**FGFR3 Mutation/Overexpression (protective)
**mG (FGFR#/MIB1)
**p53 inactivation/accumulation
**DNA Ploidy Status
Multi Traget FISH
HRAS
ERBB3, ERBB4 overexpression (protective)
Loss of E Cadherin
Cell Cycle Control:
Downregulation of Rb expression
Downregulation of p21 expression
Downregulation of p27 expression
Cyclin D3 overexpression
Cyclin D1 overexpression
Muscle Invasive Urothelial Carcinoma (MI-BC)

p53 inactivation/accumulation
Alterations of Rb expression
Loss of p21 expression
Alteration of p16 expression
Loss of E Cadherin
RTK:
EGFR overexpression
HER2 overexpression/amplification
Angiogenesis Markers:
VEGF overexpression
HIF 1A overexpression
TSP1 Overexpression
mTOR-Akt Pathway:
mTOR
Phos S6 expression (protective)
**Multimarker Immunexpression Analysis:

(p53,p27,ki67,Rb,p21)
Genomic and Gene Expression Array Panels
Angiogenesis Markers:
VEGF overexpression
HIF 1A overexpression
TSP1 Overexpression
Epigenetic Alterations:
RASSF1 promotor hypermethylation
E Cad promotor hypermethylation
EDNRB promotor hypermethylation
Genomic and Gene Expression Array Panels

Epigenetic Alterations:
RASSF1 promotor hypermethylation
DAPK promotor hypermethylation
APC promotor hypermethylation
E Cad promotor hypermethylation
EDNRB promotor hypermethylation
122
outcome (60% or less overall survival rate) in this

group of patients [425-427].
prospective study should support a additive role for

the inclusion of the new biomarker in existing management algorithm(s) [445,446]. It is the lack of the
latter crucial steps in biomarkers development that
had hindered the streamlining of clinical utilization
of several promising markers in BC patient management.
The current increasingly detailed understanding of

the molecular pathways involved in urothelial bladder cancer (BC) development and progression
has fueled the field of molecular prognostication,
theranostics and targeted therapy in this disease
[73,424,428-444]. Incorporating molecular biomarkers in clinical management can only be done after
rigorous and extensive validation process. Initial retrospective discovery studies need to be confirmed
and validated in large independent cohorts. The
crucial subsequent step in developing a prognostic
or predictive biomarker is validating the robustnest
of the proposed biomarker in well controlled multiinstitutional randomized prospective study. Such
a) Chromosomal Numerical Alteration

Chromosome 9 alterations are the earliest genetic
alterations in both of the above described divergent
pathways of BC development. They are responsible
for providing the necessary milieu of genetic instability that in turn allows for the accumulation of subsequent genetic defects. Several additional structural/
numerical somatic chromosomal alterations are also
a common occurrence in BC. Among these, gains of
chromosomes 3q, 7p, and 17q and 9p21 deletions
(p16 locus) are of special interest given their potential
diagnostic and prognostic value [447,448]. A multitarget interphase FISH based urine cytogenetic assay
was developed (39) based on the above numerical
chromosomal alterations and is now commercially
available and commonly used in clinical management. Initially FDA approved for surveillance of recurrence in previously diagnosed BC patients, the
test subsequently became approved for screening in
high risk (smoking exposure) patients with hematuria. The multicolor FISH assay appears to enhance
the sensitivity of routine urine cytology analysis and
can be used in combination with routine cytology
as a reflex testing in cases with atypical cytology. A
sensitivity range of 69-87% and a specificity range
of 89-96% have been reported with the multitarget
interphase FISH assay [449]. With the exception of
one study [450], the multitarget FISH urine assay has
been shown to be more sensitive than routine cytology. An additional advantage of urine based FISH
testing could be the anticipatory positive category of
patients identified by such assay. This refers to patients where FISH assay detects molecular alteration
of BC in urine cells several months prior to cancer
detection by cystoscopy or routine cytology. In the
study by Yoder et al [451], two thirds of the 27% of
patients categorized as anticipatory positive developed BC that was detected by cystoscopy up to 29
months later. Such encouraging results point to the
great potential of molecular testing in early detection
and allocation of vigorous/frequent follow-up cystoscopy in at risk patients [452-455].
Table 18. Recommended Nomenclature for Urine

Cytology
I. Adequacy Statement (Optional)

Satisfactory for evaluation
List any quality factors affecting specimen
Unsatisfactory for evaluation (give reason)
II. General Categorization
Negative for epithelial cell abnormality (see
Descriptive Diagnosis)
Epithelial cell abnormality present (see Descriptive
diagnosis)
III. Descriptive Diagnosis
Negative for epithelial cell abnormality
Infectious agents
Bacterial organisms
Fungal organisms
Viral changes (CMV, herpes, adenovirus,
polyomavirus)
Nonspecific inflammatory changes
Acute inflammation
Chronic inflammation
Changes consistent with xanthogranulomatous
pyelonephritis
Cellular changes associated with:
Chemotherapeutic agents
Radiation
Epithelial Cell Abnormalities
Atypical urothelial cells (*see comment)
Low-grade urothelial carcinoma
High-grade urothelial carcinoma (invasive
carcinoma vs. carcinoma in situ)
Squamous cell carcinoma
Adenocarcinoma
Other malignant neoplasms (specify type)
Finally, several recent studies have pointed to

the potential prognostic role for multitarget FISH
analysis [447,448,456-458]. Maffezini et al. were
able to demonstrate that low-risk FISH-positive
patients, defined as 9p21 loss/Ch3 abnormalities,
had a higher rate of recurrence as compared to
FISH-negative patients [456]. The recurrence rate
was even greater in patients with a high-risk positive
FISH (Ch7/Ch17 abnormality). Both Kawauchi et
al., using bladder washings and Kruger et al., using
IV. Other
A comment section should be available and used
at the discretion of the cytopathologist in which
additional findings can be listed and/or further
clarification of findings within one or more of the
above diagnostic categories made. At the discretion
of the cytopathologist, ancillary studies may be
included in the report.
123
formalin fixed paraffin embedded transurethral

biopsy samples, independently found loss of 9p21 to
predict recurrence but not progression in superficial
BC [447,448]. Furthermore, both Savic et al [457].
and Whitson et al [458]. found urine cytology and
FISH in post-BCG bladder washings to be predictive
of failure to BCG therapy in patients with non muscle
invasive disease. Such promising prognostic role
for multitarget FISH awaits prospective randomized
trial before clinical integration into practice
algorithm. Clear guidelines for interpretation and test
performance parameters in terms of interobserver
reproducibility is also needed [459].
and compared it to the European Organization for

Research and Treatment of Cancer (EORTC)NMIBCcalculator[472] (weighted score of six variables
including WHO 1973 grade , stage, presence of CIS,
multiplicity, size, and prior recurrence rate). The mG
(89%) was more reproducible than the pathologic
grade (41-74%). FGFR3 mutations significantly correlated with favorable disease parameters, whereas
increased MIB-1 was frequently seen with pT1, high
grade, and high EORTC risk scores. EORTC risk
score remained significant in multivariable analyses
for recurrence and progression. Importantly, mG also
maintained independent significance for progression
and disease-specific survival and the addition of mG
to the multivariable model for progression increased
the predictive accuracy from 74.9% to 81.7%.
b) Receptor Tyrosine Kinases

Recent studies have pointed to the potential
prognostic value of evaluating the expression of
receptor tyrosine kinases (RTK) such as FGFR-3,
EGFR and other ERB family members (HER2/neu
and ERBB3) [89,417,429,460-467] in superficial and
muscle invasive bladder cancer disease.
Several studies have suggested a negative prognostic

role for HER2/neu amplification/overexpression
in MI-BC [446,473-475]. Most recently, Bolenz et
al. found HER2/neu positive MI-BC patients to be
at twice increased risk for recurrence and cancer
specific mortality on multivariable analyses adjusted
for pathological stage, grade, LVI, lymph node
metastasis and adjuvant chemotherapy [461].
FGFR3 mutations are a common occurrence in

NMIB and can theoretically be used alone or combined with RAS and PIK3CA oncogenes as markers
of early recurrence during surveillance. Both Zuiverloon et al [468] and Miyake et al [469] independently
developed sensitive PCR assays for detectingFGFR3 mutations in voided urine. A positive urine sample by the assay developed by Zuiverloon group was
associated with concomitant or future recurrence in
81% of NMI-BC cases [468]. An even higher positive
predictive value of 90% was achieved in patients
with consecutive FGR3 positive urine samples. Similarly, Miyake et al. were able to detect FGR3 mutation in 53% of their 45 patients and found their assay
to be superior to cytology (78% vs 0) in detecting
post TURB recurrence in NMI-BC harboringFGFR3
mutations in primary tumors [469].
c) P53, Cell Cycle Regulators and Proliferation

Index Markers:
Early studies by Sarkis et al revealed p53 alterations
to be a strong independent predictor of disease
progression in BC (superficial, muscle invasive
as well as CIS) [476-478]. P53 has also been
shown to be predictive of increased sensitivity to
chemotherapeutic agents that damage DNA [479481]. Recent studies have further supported the
prognostic role of p53 in pT1-pT2 patients following
cystectomy showing an independent role for p53
alteration in predicting disease free survival ( DFS)
and disease specific survival (DSS) [482].
Among other G1-S phase cell cycle regulators,
Cyclin D3 and Cyclin D1, p16, p21 and p27 have
also been evaluated as prognosticators in NMI-BC
[480,483-488]. Lopez-Beltran et al [485], confirmed
their initial finding of the independent prognostic
role of cyclin D3 and cyclin D1 overexpression in
predicting progression in pTa and pT1 tumors [480].
Their findings however are in contrast to subsequent
findings by Shariat et al. emphasizing the need for
further validation in muti-institutional large cohorts of
patients [487].
Kompier et al. were recently able to develop multiplex PCR assay for mutational analysis detecting the
most frequent mutations hot spots of HRAS, KRAS,
NRAS, FGFR3 and PIK3CA in formalin fixed paraffin embedded (FFPE) TURB samples [419]. They
demonstrated evidence of at least one mutation in
up to 88% of low grade NMI-BC samples. Hernandez et al revealed that FGFR3 mutations were more
common among low malignant potential neoplasms
(LMPN; 77%) and TaG1/TaG2 tumors (61%/58%)
than among TaG3 tumors (34%) and T1G3 tumors
(17%) [470]. On multivariable analysis, mutations
were associated with increased risk of recurrence in
NMI-BC.
A synergistic prognostic role for combining p53

evaluation with other cell cycle control elements such
as pRb, cyclin E1, p21 and p27 is emerging both in
NMI-BC and MI-BC [424,435,479,489,490]. In a study
by Shariat et al [424], NMI-BC patients with TURB
demonstrating synchronous immunohistochemical
alterations in all four tested markers (p53, p21, pRb
and p27) were at significantly lower likelihood of
sustaining disease free survival (DFS) compared
Van Rhijn et al previously proposed a molecular

grade parameter (mG) based on a combination
of FGFR3 gene mutation status and MIB-1 index
as an alternative to pathologic grade in NMI-BC
[471]. Recently, the same group elegantly validated their previously proposed mG parameter[89]
124
to patients with only three markers. The negative

predictive effect was decreased witthe number of
altered markers (3 vs 2 vs 1). Similarly, the same
group later found that combining p53, p27 and Ki67
assessment in pT1 radical cystecomy specimens
improved the prediction of DFS and DSS [489].
using genes differentially expressed in superficial Vs

muscle invasive tumors. Accuracies of 82% (entire
cohort) and 90% (MI-BC) were also obtained for
predicting overall survival. A genetic profile consisting
of 174 probes was identified in patients with positive
lymph nodes and poor survival.
A similar synergistic prognostic role of assessment

of immunoexpression of multiple molecular markers
(p53, pRb and p21) was demonstrated by Chatterjee
et al in patients undergoing cystectomy for MI-BC
[435].
Recently, Birkhahn et al attempted to identify genes

predictive for recurrence and progression in Ta using
a quantitative pathway-specific approach in a set of
24 key genes by real-time PCR in tumor biopsies at
initial presentation 73.They found CCND3 expression to be highly sensitive and specific for recurrence
(97% and 63%, respectively). While HRAS, E2F1,
BIRC5/Survivin and VEGFR2 were predictive for
progression by univariate analysis, on multivariable
analysis the combination of HRAS, VEGFR2, and
VEGF expression status predicted progression with
an impressive 81% sensitivity and 94% specificity.
The superiority of multimarkers approach compared

to prior single marker approach certainly merits further assessment [476-478,491]. Such multimarker
approach of prognostication could soon be integrated in the standard of care in BC management
once additional multi-institutional, prospective, trials
confirm the above promising findings.
In a recent landmark study, Lindgren et al suggested

that a combined molecular and histopathologic
classification of BC may prove more powerful in
predicting outcome and stratifying treatment [497].
The authors combined gene expression analysis,
whole genome array-CGH analysis and mutational
analysis of FGFR3, PIK3CA, KRAS, HRAS, NRAS,
TP53, CDKN2A, and TSC1 to identify two intrinsic
molecular signatures (MS1 and MS2). Genomic
instability was the most distinguishing genomic feature
of MS2 signature, independent of TP53/MDM2
alterations. Their genetic signatures were validated
in two independent data sets that successfully
classified urothelial carcinomas into low-grade
and high-grade tumors as well NMI-BC and MI-BC
with high precisions and sensitivities. Furthermore,
a gene expression signature that independently
predicts metastasis and disease-specific survival
was also defined. This clearly supports the role of
molecular grading as a complement to standard
pathologic grading.
Tumor proliferation index measured immunohistochemically by either Ki-67 or MIB-1 has been
consistently shown to be a prognosticator in bladder cancer [89,471,480,484,492-495]. As mentioned
above, tumor proliferation index (MIB1) in NMI-BC
plays a prognostic role as one of the elements of the
mG paramater forwarded by Van Rihjn et al [471].
The independent prognostic role of proliferation index measured by Ki-67 has also been shown. In the
study by Quintero et al. Ki67 index in NMI-BC TURB
biopsy was predictive of PFS and DSS [494].
A similar role for proliferation index assessment as
prognosticator is established in MI-BC. Building on
initial findings of significance in an organ confined
subset of MI-BC by Margulis et al a recent report
of the bladder consortium multi-institutional trial (7
institutions and 713 patients) confirmed the role
of proliferation index, measured in cystectomy
specimens [492]. In the later study, Ki-67 improved
prediction of both PFS and DSS when added to
standard prediction models supporting a role for
proliferation index assessment in stratifying patients
for peri-operative systemic chemotherapy. This has
certainly taken Ki-67 assessment a step closer to
clinical applicability in MI-BC.
Mengual et al performed gene expression analysis

in 341 urine samples from NMI-BC and MI-BC
patients and 235 controls by TaqMan Arrays [444].
A 12+2 gene expression signature demonstarted
a staggering 98% sensitivity and 99% specificity
in discriminating between BC and control and 79%
sensitivity and 92% specificity in predicting tumor
aggressiveness (NMI-BC vs MI-BC). The signature
was then validated in voided urine samples and
maintained accuracy. In an integrated genetic/
epigenetic approach, Serizawa et al prospectively
performed mutational screen of a set of 6 genes
(FGFR3, PIK3CA, TP53, HRAS, NRAS and KRAS)
and quantitatively assessed promoter methylation
status of 11 additional genes (APC, ARF, DBC1,
INK4A, RARB, RASSF1A, SFRP1, SFRP2, SFRP4,
SFRP5 and WIF1) in NMI-BC tumor biopsies and
corresponding urine samples from 118 patients and
33 controls.501 A total of 95 oncogenic mutations
d) Gene Expression and Genomic Analysis

Several recent gene expression studies have
highlighted sets of differentially expressed genes
that may play a role in diagnosis and in predicting
recurrence and progression in BC [73,102,416,430433,443,444,496-501].
In a landmark study by Sanchez- Carbayo et al
oligonucleotide arrays were used to analyze transcript
profiles of 105 cases of NMI-BC and MI-BC.433
Hierarchical clustering and supervised algorithms
were used to stratify bladder tumors based on stage,
nodal metastases, and overall survival. Predictive
algorithms were 89% accurate for tumor staging
125
and 189 hypermethylation events were detected.

The total panel of markers provided a sensitivity
of 93% and 70% in biopsies and urine samples
respectively. FGFR3 mutations in combination with
three methylation markers (APC, RASSF1A and
SFRP2) provided a sensitivity of 90% in tumors and
62% in urine with 100% specificity.
dependent probe amplification assay (MS-MLAP), to

analyze 25 tumor suppressor genes (TSG) that have
been thought to play a role in BC oncogenes.502.
The TSG included PTEN, , CD44, WT1, GSTP1,
BRCA2, RB1, TP53, BRCA1, TP73, RARB, VHL,
ESR1, PAX5A, CDKN2A, and PAX6. The authors
found BRCA1, WT1, and RARB to be the most
frequently methylated TSGs with receiver operating
characteristic curve analyses revealing significant
diagnostic accuracies in two additional validation
sets.
With the impending cost and turn around time

advantages of next generation sequencing
technology, the power of genomic approach in
providing a non-invasive diagnostic and predictive
tool should be heavily pursued in a prospective large
cohort.
Finally, assessment of promoter methylation is giving

additional insights on BC oncogenesis. Promoter
methylation of CpG Islands and shores controlling
miRNA expression is one such example [505].
e) Epigenetic Alterations
Epigenetic analysis is also gaining momentum in
BC as a non invasive diagnostic tool for screening
and surveillance. As a prognostic tool, epigenetic
analysis has similarly shown promising potential in
BC patients [501-514].
f) Ploidy and Morphometric Analysis

Several studies have pointed to the indepedent
prognostic role of ploidy and S phase analysis in
NMI-BC [495,515-521]. Ploidy analysis can be
performed by flow cytometry or automated image
cytometry (ICM) and is applicable to urine cytology
specimens as well as biopsy supernatant[ 521] and
disaggregated TURB FFPE specimens [516].
In an early study by Catto et al hypermethylation

anlaysis at 11 CpG promoters islands was performed
by MSP PCR in 116 bladder and 164 upper-tract
tumors [503]. Promoter methylation was found in 86%
of all tumors and the incidence was relatively higher
in upper tract tumors compared to BC. Methylation
was associated with advanced tumor stage and
higher tumor progression and mortality rates. Most
importantly, on multivariate analysis methylation
at the RASSF1A and DAPK genes promoters was
associated with disease progression independent of
tumor stage and grade.
In one of the largest studies assessing DNA ploidy in

NMI-BC (377 test set; 156 validation set); Ali-Et-Dein
et al. found stage, DNA ploidy, tumor multiplicity,
history of recurrence, tumor configuration and type of
adjuvant therapy to independently predict recurrence
[515]. Recurrence at 3-month, grade and DNA ploidy
were the only predictors of progression to muscleinvasion. The constructed Predictive Index model
successfully stratified patients in a second validation
set into three risk groups. Likewise, Baak et al were
able to show ploidy status and S phase measured
by an automated image cytometry platform (ICM) to
be strong independent predictiors of recurrence and
progression in pTa and pT1 patients [516].
The same group, using quantitative methylationspecific PCR (MSP) at 17 candidate gene promoters, found five loci to be associated with progression (RASSF1a, E-cadherin, TNFSR25, EDNRB,
andAPC) [513]. Multivariate analysis revealed that
the overall degree of methylation was more significantly associated with subsequent progression and
death than tumor stage. An epigenetic predictive
models developed using artificial intelligence techniques identified likelihood and timing of progression
with 97% specificity and 75% sensitivity.
Despite all the above encouraging data, ploidy

analysis still await a prospective randomized trial to
bring ICM or flowcytometry technique into current
standard management algorithms for NMI-BC.
g) Emerging Potential Biomarkers:
Among the studies on the diagnostic role of promoter

methylation, the study by Lin et al used MSP assay
in 4 genes (E-cadherin, p16, p14, and RASSF1A)
in primary tumor DNA and urine sediment DNA
from 57 bladder cancer patients 508. MSP detected
hypermethylation in the urine of 80% of tested
patients. Hypermethylation analysis of E-cadherin,
p14 or RASSF1A in urine sediment DNA detected
85% of superficial and low grade BC and 79% of
high grade and 75% of invasive bladder cancers.
The study highlighted the great potential of such
test in detecting NMI-BC. Similar diagnostic role
was also found by Cabello et al. using a novel
technology, methylation-specific multiplex ligation-
Other biomarkers with encouraging but less robust

data on their potential prognostic role in BC include
tumor microenvironement markers such as cell
adhesion E Cadherin and N Cadherin [439,522]
and angiogensis modulators such as HIF 1a, HIF 2,
VEGF, CA IX and Thrombospondin-1 [438,523-528].
In addition, our group and others have demonstrated
a potential prognostic role for mTOR-Akt pathway
markers [439,522,529-532]. Other markers such as
Aurora-A have also been investigated in this setting
[533,534]. Finally, miRNA profile alterations will
certainly be a new area of heavy investigation as a
non invasive diagnostic and as a prognostic tool in
BC patients [505,535-537].
126
The current clinicopathologic based prognostic

approach to predicting progression in superficial BC
[102,494,538-540] will potentially be supplemented
in the not so distant future by a molecular guided
approach based on markers among those listed in
table 16 and 17, [422,427,435,503,513,524,525,
53,532,541-544].
solitary lesions, often (more than half) are located in

the neck or trigone, and the vast majority correspond
to adenocarcinomas [193]. It is important to separate
metastases from primary urinary bladder tumors
as they are associated with different managerial
approaches and ominous prognoses. However, this
distinction may represent an important challenge for
urologists and pathologists. In this section we will be
discussing specific immunohistochemical markers
used in distinguishing primary from secondary
tumors of the urinary bladder.
Finally, from a targeted therapy perspective,

RTK-HRAS-MAPK (superficial disease) and
p53-pRb (muscle-invasive disease) pathogenic
pathways as well as angiogenesis pathway of the
tumor microenvironment offer tremendous new
opportunities for future management of BC. Phase
II trials evaluating the role of tyrosine receptor kinase
inhibitors (TKI) targeting EGFR with small molecules
such as Gefitinib and Sorafinib or monoclonal
antibodies (MoAb) such as Cetuximab are underway.
Other Phase II trials are addressing the role of
Herceptin (anti HER2 MoAb) and Bevacizumab
(anti VEGF MoAb) in BC. Phase I trials testing
the safety of p53 or Rb intravesical gene therapy
are being evaluated. One strategy example is the
intravesical introduction of a wild type p53 loaded
replication deficient Adenovirus (Ad5CMV-TP53) in
an ambitious attempt to compensate for the loss of
p53 function in invasive BC [545-549].
2. Prostatic Adenocarcinoma
Direct invasion is the most frequent mechanism of
bladder involvement by prostatic adenocarcinoma.
The latter can be morphologically indistinguishable
from poorly differentiated urothelial carcinoma,
especially when glandular differentiation or clear
cell features are exhibited by urothelial carcinomas.
This distinction is critical given the staging,
therapeutic, and prognostic implications. Several
immunohistochemical markers have been reported
to reliably differentiate poorly differentiated urothelial
carcinoma from prostatic adenocarcinoma. However,
none of them is sufficiently sensitive and/or specific to
be used alone, and therefore immunohistochemical
panels are recommended. Kunju et al [556] evaluated
the joint utility of prostatic specific antigen (PSA),
prostate acid phosphatase (PAP), high-molecular
weight cytokeratin (HMWCK) (clone 34E12), CK7,
CK20, p63 and -methylacylcoenzyme (P504s) in
this differential diagnosis. They found that 95% of
documented prostatic adenocarcinoma demonstrated
a PSA+, HMWCK/p63- immunohistochemical profile
whereas 97% of urothelial carcinomas tested were
PSA-, HMWCK/ p63+. Negative PSA associated with
HMWCK and/or p63 positivity may also establish
a diagnosis of urothelial carcinoma. Even though
PSA and PAP are reliable markers of prostatic
adenocarcinoma [556-561], their expression can be
absent or only focally and weakly seen in high-grade
tumors. PSA expression is frequently heterogeneous
and consequently, immunostains may need to be
performed on multiple blocks containing tumor
[562]. Additionally, PAP is slightly less specific for
prostatic origin as a minority of urothelial carcinomas
(approximately 10%), may be focally positive for
this marker [562]. Although the majority of prostatic
adenocarcinomas are CK7-/CK20-, while urothelial
carcinomas are CK7+/CK20+ or CK7+/CK 20[556,557,559,563-565], results frequently overlap
making these markers less sensitive and specific
when used in isolation. However, the coordinate
expression patterns of CK7 and CK20 in conjunction
with PAP may be very helpful in differentiating
prostatic carcinoma (PAP+/CK7/CK20) from
urothelial carcinoma (PAP/CK7+/CK20+ or PAP/
CK7+/CK20), especially when the results of the
preliminary panel of PSA, HMWCK, and p63 are
all negative. Furthermore, in the occasion where
h) Conclusion:
At present, there are no prognostic or predictive
biomarkers for urothelial carcinoma that significantly
improve on pathologic grade and stage information;
therefore, none of these evaluations are currently
recommended for routine clinical practice.
Recommendation: C
IV. The Utility of

Immunohistochemistry In The
Differential Diagnosis Of
Primary Versus Metastatic
Tumors To The Urinary
Bladder
1. Introduction
Tumors metastatic to the urinary bladder are
relatively uncommon accounting for 2 to 14% of all
bladder malignancies [193,194,550,551]. Secondary
neoplasms may affect the urinary bladder by either
direct extension from adjacent anatomic sites or, less
frequently, by lymphovascular spread [552]. Tumors
that may extend directly to the urinary bladder include
colon (21%), prostate (19%), rectum (12%), and
uterine cervix (11%). Distant sites include stomach,
skin, lung, breast, kidney, and testis [193,550,553555]. These tumor deposits are almost always
127
the primary panel demonstrates negative results,

addition of uroplakin III and thrombomodulin may help
as both markers are negative in adenocarcinomas
of prostatic origin. Alphamethylacyl-CoA-racemase
(P504s) is not a useful marker to distinguish prostatic
from urothelial carcinomas since it is also expressed
in approximately one third of urothelial carcinomas
[556,566-568].
rectal or colonic carcinoma, which may secondarily

invade the urinary bladder, may have significant
morphologic overlap with high-grade urothelial
carcinoma with glandular differentiation (either
with mucinous, enteric, or signet ring cell features)
or pure urinary bladder adenocarcinoma. Even
though clinical history is essential and the findings
of cystitis glandularis of intestinal type, carcinoma
in situ, or tumor centered in the inner half of the
bladder wall would favor a primary urothelial origin,
in small specimens these findings may not be seen
and immunohistochemistry may be needed in
elucidating the origin of the tumor [193]. Urothelial
carcinoma with glandular differentiation may be
separated from secondary involvement by colonic
carcinoma as it is positive for CK7 and CK20, but
negative for villin. Colonic adenocarcinoma is
typically CK7 negative and CK20/villin positive
[579,580]. However, it is important to keep in mind
that colonic carcinomas, although uncommonly,
can express CK7 along with CK20 [581]. Although
bladder carcinomas generally lack of villin and CDX2
staining, primary vesical carcinomas with gland
formation may take on an enteric immunophenotype
[579,582,583]. Other markers that may be used as
part of a panel include thrombomodulin, uroplakin
III and -catenin. Thrombomodulin is expressed in
urothelial carcinomas, but it is negative in colorectal
carcinomas, and it appears to be a more sensitive
marker than CEA in this differential diagnosis [584].
Up to date, uroplakin III has only been demonstrated
in urothelial carcinomas [557,585,586]. -catenin
is highly expressed in colonic carcinoma cells
as a result of mutated adenomatous polyposis
coli gene [331], but its expression is minimal to
absent in tumors of urothelial origin including
adenocarcinomas [331,587]. CEA and P504s are not
helpful in either differential diagnosis [193,582]. The
latter is observed in approximately 30% of urothelial
carcinomas [566,588] and up to 65% of urinary
bladder adenocarcinomas [582]. In difficult cases,
colonoscopy should serve as the gold-standard in
this distinction.
Newer prostate restricted markers such as prostate

specific membrane antigen (PSMA) and prostein
(P501S) have been proposed to be a useful adjunct
in the diagnosis of prostate adenocarcinoma as they
have a high sensitivity [569-576] and can be used
in the differential diagnosis between prostatic and
A novel marker NKX3.1, an androgen regulated homeodomain gene whose expression in prostate epithelium has been extensively studied, has been established as part of the immunohistochemical panel
to distinguish metastatic prostatic adenocarcinoma
and high grade urothelial carcinoma [333,577]. The
sensitivity of NKX3.1 in prostatic adenocarcinoma
(Gleason scores 8 to 10) ranges from 92% to 94%.
Specificity for prostate versus urothelial origin has
been reported to be 100%, as all urothelial carcinomas are NKX3 negative [577]. The predominant
NKX3 nuclear staining in primary and metastatic prostatic adenocarcinomas is useful when compared to
other prostate specific markers (e.g. PSA, PAP, and
P501s) that exhibit cytoplasmic staining. This staining pattern can be of additional diagnostic benefit
when there is only weak and focal cytoplasmic staining of other prostate markers.
Glutamate decarboxylase 1 (GAD1) is also a
sensitive and specific for prostate tissue, whereas
bladder neoplasms are entirely negative [578]. When
compared to the sensitivity and specificity profile
of PSA and PSMA, GAD1 has been found to as
reliable as PSA and to show higher specificity than
PSMA. GAD1 shows consistent strong expression
in both benign and malignant prostate tissues, while
cancers from the urinary bladder, rectum, and lung
are almost entirely negative [578].
4. Cervical/Vaginal Carcinoma
Squamous cell carcinoma of the cervix or vagina can
secondarily involve the urinary bladder and mimic
a primary squamous cell or high-grade urothelial
carcinoma with or without squamous differentiation
[118]. Likewise, adenocarcinomas of the cervix with
or without intestinal differentiation and transitional cell
carcinoma of the cervix or corpus (the latter very rare)
or vagina, may simulate a primary adenocarcinoma
or urothelial carcinoma of the urinary bladder [589595].
In an attempt to find better markers for urothelial

carcinoma, Higgins et al identified S100P and GATA3
as two distinct genes showing consistently high and
uniform expression in urothelial carcinoma when
compared to prostatic adenocarcinoma[213] In an
immunohistochemical analysis on tissue microarrays,
polyclonal antiserum against S100P protein stained
86% of urothelial carcinomas but only 3% of prostatic
adenocarcinomas and monoclonal antibody against
GATA3 stained 67% urothelial carcinomas but none
of the prostate carcinomas.
In general, all squamous cell carcinomas,

independent of site of origin, are CK7, CK5/6,
cytokeratin 34E12, and p63 positive; therefore,
these markers are not helpful in establishing the site
3. Colorectal carcinoma
The morphologic appearance of poorly differentiated
128
of origin [596-598]. Even though p16, a surrogate

marker of human papilloma virus (HPV), is widely
expressed in squamous cell carcinomas of the cervix
and vagina,[599,600] it has also been reported in
one third of squamous cell carcinomas of the urinary
bladder in both males and female patients [601] and
in high-grade urothelial carcinomas [313]. The use
of in situ hybridization for HPV DNA can be helpful
as this is positive in most squamous cell carcinomas
of the cervix, but not of the bladder (Figure 54A,B)
[602].
and 35 adenocarcinomas of the endometrium [605].

Two relatively new markers proposed by some
investigators to be highly expressed in urothelial
carcinomas of the bladder, namely S100p and
GATA3, have been shown to be also positive in
transitional cell proliferations/tumors of the ovary
[213], but no experience is reported in transitional
cell proliferations of the lower female genital tract.
Cervical adenocarcinomas of the usual or intestinal
type, or even those with signet ring cells, are typically
CK7 positive. Intestinal type adenocarcinomas are
also often positive for CK20 and CDX2, in contrast
to usual cervical adenocarcinomas, which rarely
stain for these markers [590]. However, cervical
carcinomas with signet ring morphology have been
reported to be CK20 and CDX2 negative [590].
Thus, these markers are not useful in distinguishing
secondary involvement by cervical adenocarcinoma
from urinary bladder adenocarcinoma, especially
when the tumor has intestinal morphology. CEA is
not helpful in this differential diagnosis either, while
thrombomodulin expression in urinary bladder
adenocarcinomas is much lower (approximately
17%) when compared to conventional urothelial
carcinomas. Thus, if positive, thrombomodulin is
helpful in favoring a urinary bladder origin of the
adenocarcinoma [584]. Uroplakin expression has
been reported in 50 to 60% of all urothelial carcinomas
[557], but results on urothelial carcinomas with
glandular differentiation or pure adenocarcinomas
are lacking. p16, as discussed in the differential
diagnosis of squamous cell carcinomas, is typically
positive in cervical adenocarcinomas (related to
HPV infection); however, it has not been studied in
primary adenocarcinomas of the urinary bladder and
should be used with caution as it has been shown
to be expressed in endometrial and colorectal
carcinomas [606,607].
Urothelial carcinomas of the urinary bladder are

typically positive for CK7, CK20, uroplakin, and
thrombomodulin with the latter two having 100%
and 96% specificity and 57% and 69% sensitivity,
respectively [585,603]. They are also typically p63
positive [255]. Squamotransitional cell carcinomas
of the uterus have been shown to be CK7 and p63
positive and uroplakin negative, but experience is
very limited [604]. Transitional cell carcinomas of
the uterus and vagina as well as those arising from
the urinary bladder are both positive for CA19.9 and
CEA [603]. No experience has been reported with
thrombomodulin in squamotransitional carcinomas
of the uterus, although Ordoez reported negative
staining on 7 squamous cell carcinomas of the cervix
Clear cell carcinoma can arise in the uterine cervix

or vagina and may secondary involve the urinary
bladder. In such cases, the differential diagnosis
includes a clear cell carcinoma of the urinary bladder
or a urothelial carcinoma with clear cytoplasm
[205,608]. A prior clinical history of diethylstilbestrol
or finding areas of typical urothelial neoplasia would
favor a primary cervical or urinary bladder origin,
respectively. Clear cell carcinomas of the urinary
bladder express low-molecular weight keratins,
CK7 and CK20, but are negative for estrogen and
progesterone receptors [114,204,609-611], an
immunohistochemical profile that overlaps with
that seen in clear cell tumors of the female genital
tract. Primary urinary clear cell carcinomas are also
typically positive for CD10, P504s, and they can
be positive for PAX2 [608]. In contrast, clear cell
carcinoma of the cervix and vagina has been reported
to be CD10 negative, although experience with this
marker is limited [612]. Up to date, PAX2 and P504s
have not been studied in clear cell carcinomas of the
Figure 54. A) Cervical squamous cell carcinoma

involving the urinary bladder shows B) positivity by
HPV in situ hybridiization.
129
female genital tract. PAX8, another positive marker

of clear cell carcinoma of the urinary bladder [613] is
expressed in tumors arising from the ovary [614], but
no experience is reported in clear cell carcinomas of
the uterus or vagina.
setting [618]. Thyroid transcription factor-1 (TTF-1)

plays a role in the development and physiology of the
thyroid gland and lungs, and it is used as a marker of
carcinomas originating in these organs. Commercially
available clones of TTF-1 monoclonal antibodies,
8G7G3/1 and SPT24, have been reported to have
different sensitivities for the detection of neoplasms
of different origins. SPT24 clone detects a significant
number of non-pulmonary primary tumors, especially
invasive urothelial carcinoma (5%) [619]. Therefore,
if SPT24 is used, results should be interpreted with
caution.
5. Gastric carcinoma
Advanced gastric carcinoma, especially if poorly
differentiated or signet ring cell type, may secondarily
involve the urinary bladder. The morphologic
appearance may overlap with that seen in poorly
differentiated or plasmacytoid urothelial carcinoma.
These tumors typically show a CK7+/CK20+
immunohistochemical profile that overlaps with
that observed in urothelial carcinoma. Uroplakin
may be helpful in separating a poorly differentiated
urothelial carcinoma from a poorly differentiated
gastric carcinoma, but is not helpful in the differential
diagnosis with plasmacytoid carcinoma, as the latter
is frequently negative or shows minimal positivity
[233]. Thrombomodulin, another useful marker in
the diagnosis of urothelial carcinoma, has not been
reported in gastric carcinoma, but in some pancreatic
carcinomas [170].
Even though small cell carcinoma of the urinary

bladder accounts for less than 1% of all bladder tumors, the urinary bladder is the most frequent location of extrapulmonary small cell carcinoma [620].
Morphologically, this tumor is identical to its lung
counterpart. The finding of associated conventional
urothelial neoplasia or its variants would favor a primary origin from the urinary bladder, as one third of
small cell carcinomas are admixed with conventional
urothelial carcinoma. Both pulmonary and urinary
bladder small cell carcinomas share a dot-like positive staining with pan-keratin and have variable expression of neuroendocrine markers (chromogranin,
synaptophysin and CD56). Although TTF-1 was initially proposed as a useful marker to confirm the lung
as the origin of a metastatic adenocarcinoma, its expression has been increasingly reported in tumors
from other origins including small cell carcinomas of
the urinary bladder [621].
6. Malignant Melanoma
Melanoma can be primary [615,616] or involve
secondarily (more commonly) the urinary bladder
[194]. In most cases a prior history of melanoma, the
finding of typical histologic patterns and the presence
of melanin pigment are helpful in the diagnosis of
melanoma. Specifically, the finding of an in situ
component may be helpful in establishing a primary
origin in the urinary bladder. However, it is well
known that malignant melanoma in the urinary tract
may closely mimic the appearance of a urothelial
carcinoma, as it can have a papillary, nested,
sarcomatoid, plasmacytoid and even pagetoid
growths as described in urothelial carcinomas
[617]. When separating melanoma from urothelial
carcinoma, it is important to remember that the latter
is frequently positive for S-100[213] and melanomas
may rarely be positive for pankeratins [150], and thus
a panel of antibodies including HMB45, melan-A and
cytokeratins should be used to establish the nature
of the tumor.
When squamous differentiation is the predominant

pattern in a urinary bladder neoplasm in a patient
with a known lung squamous cell carcinoma,
the differential diagnosis between a primary and
a secondary neoplasm may be difficult. A panel
including TTF-1, napsin A and p16 may be helpful,
with TTF-1 and/or napsin A positivity favoring a lung
primary, while p16 positivity typically would favor an
extrapulmonary site [597].
8. Breast Carcinoma
Breast carcinoma metastatic to the urinary bladder
is a rare event [622]. For the most part, the
morphologic appearance of typical ductal carcinoma
(which metastasizes to the urinary bladder less
commonly than lobular carcinoma) does not create
problems in differential diagnosis; however, when
tumors have a micropapillary architecture or are
composed of signet ring cells (either ductal or
lobular), the histologic appearance overlaps with
primary urothelial neoplasms [233,623,624]. When
using immunohistochemistry, it is important to keep
in mind that CK7 expression is seen in both breast
and urothelial carcinomas,[563] although primary
and metastatic ductal carcinoma show important
differences in CK7 expression [625]. Cytokeratin 5/6
positivity can be detected in about half of urothelial
7. Lung Carcinoma
Lung adenocarcinoma is the most frequent type
of pulmonary neoplasm and therefore is the most
frequent type found in a metastatic setting, followed
by small cell and squamous cell carcinoma. When
glandular morphology is the predominant pattern in
a bladder neoplasm in a patient with a known lung
carcinoma or lung mass, the differential diagnosis
between a primary and a secondary neoplasm
should be entertained. The use of a limited
immunohistochemical panel including napsin A,
GATA3, and S100P may be extremely helpful in this
130
carcinomas, but can also be seen in one third of

breast ductal but not lobular carcinomas [626].
Estrogen receptor (ER) expression is typically
seen in breast carcinomas [627], but urothelial
carcinomas can also express ER, especially when
invasive, higher grade and high stage [628-630]. It
is primarily form that is expressed with expression
of the form being much less frequent (95). CK20
is rarely expressed in ductal and lobular carcinoma
in contrast to 30% of transitional carcinomas [563].
Thus, a CK7+/CK20- profile would favor a breast
carcinoma while a CK7+/CK20+ profile would
support the diagnosis of urothelial carcinoma [564].
However, unusual subtypes of breast carcinomas
including mucinous and papillary can be CK20
positive [627,631]. Gross cystic disease protein
15 (GCDP-15), a fairly specific marker for breast
carcinoma, is only expressed in approximately 60%
of these tumors. Thus, a positive stain supports
a diagnosis of metastatic breast carcinoma, but
a negative stain does not exclude it [632]. Other
markers including EMA, CEA are not helpful in this
differential diagnosis as both tumors may stain for
these markers [558,633]. Thrombomodulin and
CK34BE12, reported to be positive in up to 70% and
100% of urothelial carcinomas, can be expressed
also in breast carcinoma [170].
CD10 membranous immunoreactivity is frequently

used in the diagnosis of renal cell carcinoma,
clear cell type [638]. However, there is a growing
list of neoplasms that can be CD10 positive,
including urothelial carcinomas. Bahadir et al [639]
demonstrated that this marker is positive in more
than 40% of urothelial carcinomas and its expression
is strongly correlated with high tumor grade and
stage. Therefore, in a setting where metastatic
renal cell carcinoma is in the differential diagnosis,
CD10 should be interpreted with caution. CK7 and
P504s are sensitive markers for papillary renal
cell carcinoma [613]; however, they also can be
expressed in carcinomas of urothelial origin [556].
Although PAX2 and PAX8 are sensitive and relatively
specific markers for renal neoplasms, regardless
of subtype [638], these two markers have recently
been also found in clear cell adenocarcinoma of the
lower urinary tract limiting its value in this setting
as discussed earlier [613]. C-kit is expressed in
most chromophobe renal cell carcinomas and
oncocytomas, however, clear and papillary renal
cell carcinomas are negative for this marker as are
urothelial carcinomas, except small cell carcinomas
of the urinary bladder (approximately one third are
immunoreactive) [640]; therefore, this marker may
have limited utility in the differential diagnosis of
renal versus urothelial carcinoma. In conclusion,
it is suggested that a panel which includes PAX2
or PAX8 and CD10, supplemented by a urothelial
marker would reliably differentiate the majority of
metastatic renal cell carcinomas from urothelial
carcinoma [638].
9) Renal Cell Carcinoma

Renal cell carcinoma is an uncommon source of
bladder metastasis with fewer than forty reported
cases [208,554,634-637]. When metastatic renal cell
carcinoma is encountered, immunohistochemistry
may be very helpful as: a) either metastatic renal
cell carcinoma may precede the primary tumor or in
patients with a known prior history of renal carcinoma,
metastatic foci may develop after a prolonged period
of time and slides from the primary neoplasm may
not be available for review; and b) metastatic renal
cell carcinoma may look morphologically different
from the primary tumor. Furthermore, in patients
with a prior history of renal carcinoma and a new
bladder tumor, it is extremely important to know if the
tumor is a new primary versus metastases. Typically,
patients with renal cell carcinoma metastatic to the
bladder present with gross hematuria demonstrating
sessile bladder lesions [554]. Histological evaluation
is usually straightforward, however, on occasions,
the differential diagnosis between a metastatic renal
cell carcinoma and urothelial carcinoma is difficult
as both may show overlapping morphologies,
particularly if urothelial carcinoma has clear [202] or
lipid-type cells [148]. A large variety of markers have
been proposed for the diagnosis of primary renal cell
carcinoma, however, studies on the immunoprofile
of metastatic tumors are scarce. Metastatic renal
cell carcinoma usually retains an immunoprofile that
is similar to the one seen in primary neoplasms;
however, intensity and proportion of staining tends
to decrease.
When renal carcinoma originates from the collecting

ducts (collecting duct carcinoma) and metastasizes
to urinary bladder, the differential diagnosis with
urothelial carcinoma with glandular differentiation
can be extremely challenging. Highmolecularweight cytokeratin is expressed in most collecting
duct and urothelial carcinomas [638,641]. Adding
urothelial markers like p63 can be useful in this
differential diagnosis [638,641]. Finally, renal pelvis
urothelial carcinomas are generally morphologically
and immunophenotypically indistinguishable for
their bladder counterpart; however, strong PAX8
expression is seen in a subset of renal pelvic
urothelial carcinomas (unpublished data).
10. Testicular Neoplasms

Metastatic testicular germ cell tumor to the urinary
bladder is extremely rare with few reported cases
in the literature [553,642]. Still, distinguishing
metastatic germ cell from a non germ cell tumor has
important clinical managerial implications. Markers
used in the diagnosis of testicular germ cell tumors
have included placental-like alkaline phosphatase
(PLAP), CD30, CD117(C-KIT), and a-fetoprotein
(AFP). Although these markers are useful, they
131
show only moderate sensitivity/specificity and

significant immunophenotypic overlap with somatic
malignancies that may show PLAP and CD30
expression [643]. Furthermore, as their expression
can be lost in metastatic foci, other markers have
been recently investigated. Glypican 3 has been
proposed as a new marker for yolk sac tumor, but
its staining is typically focal and is not highly specific
[644]; it has been shown to be positive in urothelial
carcinomas with myxoid stroma [645]. Also, novel
embryonic stem cell markers have been identified
as being sensitive and specific for testicular germ
cell tumors. Cheng et al established the sensitivity
and specificity of OCT4 in detecting metastatic germ
cell tumors in retroperitoneal lymph nodes and found
that all embryonal carcinomas and seminomas
showed diffuse and strong OCT4 nuclear staining. In
contrast, yolk sac tumors, choriocarcinoma, mature
teratomas, primitive neuroectodermal tumors,
malignant lymphomas, melanomas and carcinomas
from other sites including prostate, urinary bladder,
pancreas, lung, colon, and kidney, were negative for
this marker [646]. SALL4 has also been reported as
a marker of seminoma and embryonal carcinoma,
but unlike OCT4, SALL4 is also strongly expressed
in yolk sac tumors [647,648].
urothelial dysplasia, which would require clinical outcome studies to be of any value to clinical management. Studies of adjunctive methods of classification in the urothelial atypia of uncertain significance/
urothelial dysplasia histologic spectrum have underscored the problems with immunohistochemistry in
that specific diagnostic setting [649]. We discuss the
use of adjunctive immunohistochemistry to distinguish between urothelial carcinoma in situ and benign reactive lesions in routine diagnostic practice.
2. p53
Urothelial carcinoma in situ may show strong,
diffuse nuclear immunoreactivity for p53 [650-654];
however, the sensitivity has been reported to be as
low as 57%. It is important to acknowledge that the
evaluation of p53 by immunohistochemistry can be
difficult [655]. The intensity of the antibody staining
may fluctuate significantly with small variations in
titer and inter-laboratory variation is not uncommon.
Normal or reactive urothelium, therefore, may show
numerous cells with weak to moderate nuclear
staining. It is critical that one use a high threshold for
a positive result when evaluating p53 in flat urothelial
lesions. Only diffuse 3+ nuclear immunoreactivity in
the neoplastic cell population should be regarded as
positive.
11. Conclusions
3. Cytokeratin 20
Immunohistochemistry is commonly employed, and

sometimes essential, in routine diagnostic practice
for the distinction between a primary bladder
carcinoma and secondary involvement form another
anatomic site. The exact immunohistochemical
panel required, if any, depends on the histologic
features of a given case.
CK20 expression has been studied by numerous

groups that have all verified the typically strong and
diffuse cytoplasmic immunoreactivity in urothelial
carcinoma in situ cells (Figure 55 A,B) [649651,656-658]. The reported sensitivity of CK20 for
carcinoma in situ has ranged from 72-89%, while
the specificity is over 90%. The extent of staining
depends on the pattern of the urothelial carcinoma
in situ being evaluated. Carcinoma in situ shows
full thickness staining when the neoplastic cells
comprise the full thickness of the urothelium;
however, in cases of pagetoid carcinoma in situ, this
staining is restricted to the individual neoplastic cells
without reactivity in the surrounding benign urothelial
cells. In normal urothelium and in reactive urothelial
atypia, cytokeratin 20 expression is restricted to the
superficial umbrella cell layer. In our experience, the
CK20 expression in carcinoma in situ is preserved
after both intravesical and radiation therapy
(unpublished data).
Recommendation: C
V. The Use of
Immunohistochemistry in Flat
Urothelial Lesions with Atypia
1. Introduction
The histologic classification of flat urothelial lesions
with atypia (i.e. reactive urothelial atypia, urothelial
atypia of uncertain significance, urothelial dysplasia,
and urothelial carcinoma in situ) can be one of the
most difficult diagnostic challenges in genitourinary
pathology. Numerous studies have investigated the
potential utility of adjunctive immunohistochemistry
in the diagnosis of these flat urothelial lesions.
4. CD44s
The CD44s antibody has been suggested as a useful
comparative immunostain to use in conjunction with
CK20 because it has the reverse staining pattern
[651]. In normal urothelium, the basal cell layer shows
membranous reactivity for CD44s, occasionally with
some extension to the intermediate cell levels. In
reactive urothelial atypia, the full thickness of the
urothelium often shows this basal-like membranous
The ability of a given immunophenotype to predict

disease progression, independent of histology, has
not been adequately studied. We, therefore, do
not endorse using immunohistochemistry to distinguish urothelial atypia of uncertain significance from
132
7. Conclusions
staining pattern. In contrast, the neoplastic cells of

urothelial carcinoma in situ do not express CD44s,
and the normal basal cell population is frequently
absent.
Despite the reported prototypical immunostaining

profiles of flat urothelial lesions with atypia, the
authors of this document have anecdotally seen
cases of both morphologically obvious carcinoma
in situ and benign reactive urothelium with
unexpected immunophenotypes. Any adjunctive
immunohistochemistry must be carefully correlated
with the morphologic features of the urothelial
lesion being evaluated. Currently, routine
morphologic evaluation should remain as the goldstandard for the diagnosis of flat urothelial lesions
with atypia. As stated, we do not endorse the
use of immunohistochemistry in the distinction of
dysplasia and atypia of uncertain significance. Of the
immunostains that might be used as confirmatory
adjuncts for carcinoma in situ or reactive atypia
in select difficult cases, CK20, CD44s, and p53
currently offer the most potential utility.
5. p16ink4
A few groups have evaluated the staining pattern
of p16 in urothelial carcinoma in situ [488,649].
Strong and diffuse cytoplasmic expression of p16
is reported in urothelial carcinoma in-situ, while
normal and reactive urothelium both show uniform
weak expression. As with the use of p16 in cervical
dysplasia, the interpretation of varying levels of
intensity may present problems, and one must
maintain a high threshold for a positive result. There
are very few studies with this antibody, and we have
not had similar success with its use.
6. Ki-67
Proliferation markers have also been evaluated
as adjuncts to the diagnosis of carcinoma in situ.
[650,652,657,658] The proliferation rate of carcinoma
in situ, as defined by Ki-67 immunohistochemistry,
has significant overlap with florid reactive atypia,
particularly when inflammatory infiltrates are present.
[657] Therefore, proliferation markers have little role
as diagnostic markers in this setting.
Recommendation: C
F. RECOMMENDED NOMENCLATURE FOR URINE CYTOLOGY
55A
I. Nomenclature and
Reporting
The Papanicolaou Society of Cytopathology
Practice and Guidelines Task Force recommends
a diagnostic format that mimics the Bethesda 2001
System for reporting cervical cytology format. (Table
18), The diagnostic section for urinary cytology
should include a statement as to the site of origin of
the urinary tract specimen (urethra, urinary bladder,
or ureter/renal pelvis).and also state the technique
used forobtaining the specimen when known (voided
urine, washing, brushing, etc.) [659].
This classification nomenclature raises few issues in
urine cytology diagnosis, particularly in the atypical
and low grade urothelial carcinoma categories. The
diagnosis of low grade urothelial carcinoma is rarely
used due to the lack of specific criteria; therefore,
most low grade urothelial carcinomas are included
in the atypical category. Regarding the atypical
urothelial cells terminology, there is little consensus
in the literature on the criteria for inclusion in this
category Nonetheless, it has been suggested
that this atypical category can be subdivided
into 2 subcategories, atypical urothelial cells of
undetermined significance (AUC-US) and atypical
urothelial cell, cannot rule out high grade urothelial
carcinoma or favor neoplasm. The rationale for this
subclassification is that specimens diagnosed in the
latter category should be referred to cystoscopy while
Figure 55. Urothelial carcinoma in situ on A) H&E

showing B) diffuse cytoplasmic immunoreactivity
for cytokeratin 20.
133
the ones diagnosed as AUC-US could be followed

with repeat urines [660-662].
72 and 83%[679], UroVysion FISH has a sensitivity of 90100% for the detection of invasive bladder
cancer (pT14) and a carcinoma specificity of 95%
while for low-grade non-invasive the sensitivity increases from 25 to 6075% when compared to cytology [680]. Use of Urovysion has been advocated
in equivocal urine specimens, either suspicious or
atypical [455,457,681-684] due to its Increased sensitivity. Skacel et al [685] retrospectively evaluated
the UroVysion FISH assay in 120 urine specimens
and found a sensitivity of 100 and 89% in patients
with suspicious and atypical urine cytology specimens, respectively, while the overall specificity was
97%. A negative FISH result in case of a negative or
atypical cytology does not exclude low-grade urothelial neoplasia, since up to 30% of these tumors are
negative with the FISH assay.
A positive Urovysion test (Figure 57) has been
associated with higher rate of recurrence in patients
treated with intravesical bacillus Calmette-Guerin
(BCG) for high-grade non-muscle invasive urothelial
carcinoma [453,457,458,686,687]. A higher rate
of recurrence has also been noted in patients with
positive Urovysion test and negative cystoscopy and
cytology [455,678,688,689] although this was not
confirmed in all studies [454,690]. Pitfalls of Urovysion
have been associated with overinterpretation of
benign tetraploid cells [691], or chromosomal
aberrations following pelvic irradiation [692], except
deletion of 9p21.
Recommendation: C
II. Role of urine cytology in

screening and monitoring
patients with bladder cancer
Urinary cytology is a simple, noninvasive, and
relatively inexpensive method for detecting UC [663].
It has consistently shown to have high specificity,
especially in detecting carcinoma in situ and highgrade, flat lesions (Fig 56) [664,665]. However, it is
also accepted that urine cytology has low sensitivity
that varies particularly for low grade urothelial
carcinoma [449,450,666-674]. Factors leading to
the low sensitivity of urine cytology include minimal
atypia seen in low grade UC, paucity of tumor cells in
an inflammatory background, instrumentation effect,
lithiasis, reactive changes, post BCG treatment,
degenerative changes and viral cytopathic effect
[675,676]. Diagnostic accuracy is also dependent on
diagnostic expertise [677].
Level of evidence: 3C
Recommendation: B
The wide application of UroVysion in routine practice

is still controversial due to its high cost [693-695].
Although there is higher accuracy in the detection of
high-grade lesions, the benefit achieved from better
diagnosis of clinically harmless low-grade lesions by
Urovyion is minor and it is achieved at a much higher
cost [661]. The low cost efficiency is also cited as
a problem when Urovysion is used in a population
of patients with hematuria but no increased risk for
urothelial carcinoma [680,693,694].
Level of evidence: 3C
Recommendation: B
Figure 56. High grade urothelial carcinoma in urine
cytology
III. Role of FISH in screening

and monitoring of bladder
carcinoma
Urovysion has been approved by the US Food
and Drug Administration for screening of urothelial
carcinoma in patients with hematuria and monitoring
for tumor recurrence in patients with a prior history of
urothelial carcinoma [449,678].
The overall sensitivity and specificity of Urovysion is
Figure 57. Positive UroVysion in a urine specimen
134
With some updates in select topics, this proposed

guideline aim at standardizing descriptions of
diagnosis and reporting of urothelial carcinoma of
the bladder and to help optimize uniformity between
individual pathology practices and institutions (Grade
C). This protocol may assist pathologists in providing
clinically useful and relevant reporting information in
a multidisciplinary care setting.
G. UPDATED PROTOCOL FOR THE

EXAMINATION AND HANDLING OF
SPECIMENS FROM PATIENTS WITH
URINARY BLADDER CARCINOMA
I. Introduction
II. Relevant Clinical History
Providing the best management for patients with

bladder neoplasia relies on close cooperation and
teamwork among urologists, oncologists, radiologists
and pathologists. The pathologist is involved in
the diagnosis and assessment of prognostic and
therapeutic variables in surgical specimens such
as bladder biopsies, transurethral resection (TUR)
and cystectomy specimens. Pathologists must
report accurately and with minimal variability the key
pathologic parameters using terminologies that are
well understood by clinicians [696].
The ability to have an open communication is

essential for pathologists, urologists and oncologists
in the decision-making process for diagnosis
and management. Adequate clinical information
is important to pathologists in deciding the best
approach in handling and processing the surgical
specimens and directing the most essential
information which to be reported. The pathology
specimen requisition form must be filled with
relevant and sufficient information the clinicians
can provide. With the high degree of accuracy
of cystoscopy, the pathologists should also take
extrameasures of reviewing cystoscopic impressions
before diagnosing a tumor in biopsy or TUR samples
[700,701]. With differing implications for non-invasive
papillary versus flat (carcinoma in situ) tumors and
advent of enhanced cystoscopic (e.g. fluoroscopic)
visualization, urologists impression provides helpful
information to the pathologist in difficult situations,
such as when the entire lesion architecture is not
obvious on the slides (e.g. fragmented or superficial
sections). Indications of the surgical procedure,
such as for surveillance or post intravesical therapy
biopsies, initial or second TUR (e.g. for deep muscle
assessment or completion of resection), early or
salvage cystectomy, among others, are important
for pathologists in specimen handling and reporting.
Other relevant information includes history of
bladder cancer and prior intravesical or neoadjuvant
chemotherapy. Presence of calculi, catheterization
or infection may explain reactive changes (versus
dysplasia) when under consideration.
The most common tissue specimens encountered are

biopsy and TUR, which provide the main information
essential in tailoring the patient subsequent therapy
that includes more aggressive treatment options.
Additional information on curative-intent resections
(e.g. cystectomy) determines the adequacy of
therapy and appropriate surveillance or further
need for surgery or adjuvant chemotherapy and/
or radiotherapy [697]. The recent literature is not
short of satisfactory checklists and commentaries
for handling and reporting of genitourinary pathology
specimens [174,393,698,699]. Organizations such
as the College of American Pathologists (CAP)
recommend reporting in a checklist/synoptic format
and have outlined essential elements for reporting
specimens resected for invasive bladder cancer
[698]. However changes remain in flux as recent
advancements, shift to multidisciplinary care, and
regular introductions of updated clinical guidelines
in bladder cancer diagnosis and management
diversify the nature of specimens and impact the
manner of handling and assessment. For example,
other than the usual cystectomy for muscle invasive
cancer, contemporary cystectomies include early
(non-muscle invasive tumors), post neo-adjuvant
chemotherapy, salvage, or palliative resections.
Eventual pT0 or pTis cystectomies that contain no
invasive cancer are becoming much more common.
Segmental cystectomy for solitary lesions without
pTis lesions amenable to resection with adequate
margin is now considered a feasible surgical option.
Second TUR procedures can be received for prior
inadequate initial TUR staging or deep muscle
sampling, prior incomplete tumor resection, or
bladder-preservation treatment. The differences in
indications and characteristics of tumor content in
these specimens evoke re-appraisal instead of being
uniformly processed in the traditional manner.
III. Urologists Handling of

Specimens
Tissue preservation is required and samples should
be handled the minimum way possible. Ideally, tissue
container with fixatives for biopsy or TUR specimens
should be readily available in the operating rooms. In
situations where patients are part of study protocols
or clinical trials requiring fresh tissue preservation,
the specimen should be sent without any delay to
pathology gross room for immediate processing.
In TUR, a deeper bite for assessment of MP
involvement is preferably submitted separately in
another container especially in situations of larger
135
VI. Pathologist Handling of

Cystectomy Specimens
tumors. This will facilitate search for muscle invasive

component of the tumor. Biopsy or TUR of multifocal
tumors should also be submitted separately according
to site. Cold cup mapping biopsies of visually normal
mucosa and prostatic urethra are needed to exclude
flat lesions and should also be submitted separately
per site. This provides a better picture of the extent
of the lesions in the bladder. Any erythematous or
velvety area should be sampled. In cystectomy,
ureter margins submitted separately should have
proper labelling of the distal end (true margin). In
partial or segmental cystectomy, the bladder wall
resection margins should be marked with identifiers
such as suture to facilitate identification.
The bladder must be opened and after adequate

fixation samples must be taken from representative
areas of the tumor, normal-appearing bladder, the
prostate, seminal vesicles, or other organs included
in the surgical specimen. Minimum sections of the
bladder should include at least the tumor/s including
its deepest penetration, and representative sections
of the dome, trigone, anterior, posterior and lateral
walls. In potential cystectomy with no residual tumor
(pT0), prior surgical sites or mucosal ulcerations
should be submitted entirely for any possible residual
tumor. Adequate mapping of different regions of
the bladder should be performed, as well as in
early cystectomy or in setting of post-neoadjuvant
chemotherapy with less visible or no gross residual
tumors. Any suspicious-looking areas of reddening
and mucosal induration (for CIS) need to be
sampled. Grossly visible tumour in perivesical fat
(pT3b) or at resection margins (R2) must be stated
in the gross examination. For tumor grossly invading
the bladder wall, multiple full thickness sections
including the area grossly suspicious for deepest
penetration should be included in the sections to
assess pT2a/b vs. pT3a. The underlying soft tissue
margin should be examined, inked and sampled.
Unless submitted separately for frozen section,
ureter and urethral margins should be sampled,
preferably taken as shave cross sections so that
the entire mucosal circumference can be visualized.
In case of segmental cystectomy, bladder wall
margins of resection should be identified for tumor
involvement. In cystoprostatectomy specimens,
right and left prostate should be inked differently
and representative sections from both sides are to
be taken including perpendicular sections of the
apical margins, to secure assessment of important
variables in case of concomitant prostate cancer,
which is not uncommon to occur. Sections of the
prostate should include the prostatic urethra to
identify possible tumor invasion originating from
a separate urethral carcinoma (pT2). Sections of
possible deep penetration to prostate from bladder
by the tumor should also be taken to document
higher stage (pT4) bladder cancer. Likewise, tumor
mass along the distal ureter/ureteral orifice should
be closely examined whether or not tumor is arising
from the distal ureter, for appropriate staging. Lymph
nodes must be dissected from the lymphadenectomy
specimens and all grossly and tentatively identified
lymph nodes in the specimen should be submitted.
(Table 20)
IV. Pathologist Handling of

Biopsy Specimens
All biopsy-sampled tissues should be submitted
for processing. Effort should be made to identify
the mucosal aspect of tissue fragments to allow
embedding on edge and better visualization of the
surface urothelium, although this may not always be
possible. For histologic evaluation, at least 3 levels of
tissue sections for each biopsy should be prepared.
Deeper levels into the block are recommended if the
surface urothelium is deemed not entirely visible or
in situations of denuded samples, particularly with
known risk for CIS, to exclude the possibility of
denuded CIS (clinging type) (Grade C).
V. Pathologist Handling of
Transurethral resections
The conventional way of processing TUR specimens
is to submit the tissue entirely. In large tumors
exceeding 10 cm, one approach is to submit 1 section
per cm of tumor diameter (up to 10 cassettes), and
additional selective sampling until MP invasion is
identified, or submitting the rest of the sample if no
MP invasion is recognized after the first selective
sampling. The second TURs for deep muscle
staging are typically low volume samples, which
can be processed entirely. Large bulk completion
TUR for incompletely resected tumors may have an
option to submit less if the initial TUR has already
established the diagnosis and attributed risk (e.g
pT2 stage). Follow-up TUR for bladder-preservation
treatment after chemotherapy and/or radiotherapy
however should be processed the conventional way.
(Table 19)
136
system represents the gold standard for prediction

of recurrence after radical cystectomy in patients
with invasive bladder cancer. Thus, accurate staging
provides broadly applicable prognostic information
and is the basis of all authoritative patient
management decisions [706].
VII. Reporting of Histologic

Grade
Use of the WHO (2004) / ISUP classification system
is recommended (Grade B) [113,275]. Based on
institutional / clinician preference, other systems may
be used along side. Grading should also take cancer
heterogeneity into consideration; approximately onethird of patients with pTa tumor had cancer containing
a different histologic grade. Currently, grading of
papillary urothelial tumors is typically based on the
worst grade present (Grade C).
In addition to advanced tumour stage, however, other

pathological factors have been evaluated as possible
risk factors for recurrence and poor survival. Among
them, lymphovascular invasion (LVI) marks the initial
step of the metastatic process. Its significance in
predicting outcome of affected patients, however,
remains controversial.
VIII. Reporting Variant

Urothelial Histology
According to literature data, LVI can be observed in

about 30-50% of cystectomy specimens (Table 21)
[60,707-717]. Prevalence of LVI correlates significantly with increasing T classification [708,710,712714, 717-721], high tumour grade [712-714,717,718],
and presence of lymph node metastasis [710,712714,717,721,722]. However, in a considerable
number of patients with histologically proven nodal
disease LVI is not detected within the bladder wall.
In the comprehensive study by Lotan et al. LVI was
observed in 9.0% of T1, 23.0% of T2, 50% of T3, and
78% of T4 tumours, respectively [712]. Likewise, the
authors detected LVI in 151 out of 581 (26%) nodenegative and 122 out of 169 (72%) node-positive
cancers. In a recent international validation study
collecting 4,257 patients from 12 centres, Shariat et
al. rendered similar data: LVI was present in 11.0%
of T1, 31.3% of T2, 52.3% of T3, and 60.9% of T4
tumours, respectively, and its presence was significantly associated with high tumour grade (5.1% G1,
38.2% G2, 33.5% G3) and presence of lymph node
metastasis (22.5% N0, 64.7% N1-2) [717].
Urothelial cancer is known to show variant histologic

features otherwise known as divergent differentiation,
with estimates ranging from 7% to 81% in series
specifically reporting differentiation patterns of
urothelial carcinomas [117,702]. Current evidence
suggests that urothelial cancer with divergent
differentiation has a worse prognosis when compared
with pure urothelial cancer, although stage matched
cohorts show limited differences (Level 3). Billis and
colleagues [703] in a study of 165 TURBT noted that
7% of tumors showed squamous and/or glandular
differentiation. Those patients with divergent
differentiation had higher clinical stage at presentation
compared to conventional urothelial carcinoma [703].
Wasco et al [704] in a study of 448 consecutive
TURBTs and 295 subsequent cystectomy, noted
that urothelial cancers with divergent differentiation
were more likely to be muscularis propria invasive at
TURBT and extravesical fat invasive at cystectomy
compared to pure urothelial cancers. Jozwicki et
al [705] performed mapping in 38 cystectomies
specimens, and then correlated the mapping studies
with survival time, the presence of greater than 80%
pure urothelial cancer within a specimen was a
favorable prognostic factor, and increasing numbers
of histologic subtypes (increasingly divergent
differentiation) led to a less favorable prognosis.
LVI has repeatedly been associated with poor

outcome of patients undergoing radical cystectomy
for invasive bladder cancer. This effect is primarily
observed in patients with node-negative cases
disease [708,712-714,717,718,723]. In detail, LVI
proved to be a predictor of local, distant, and overall
tumour recurrence as well as a predictor of adverse
overall and disease-specific survival, independent of
tumour stage and grade [711,712,715-718,724,725].
In some studies, however, discordant results were
obtained. Thus, in the study by Canter et al., LVI
independently predicted overall and disease-specific
survival, whereas no independent influence on
recurrence-free survival was noted [708]. In other
studies, some of them involving rather low numbers
of patients, LVI was identified as an adverse
prognostic variable only in univariate analysis, yet
lost prognostic significance in multivariate analysis
[709,710,713,726-728]. Finally, in two studies, both
involving less than 100 patients, the presence of LVI
was not found to be significantly related to outcome
[729,730].
Divergent morphology must be documented because

of its prognostic implications (Grade B). Further,
reporting facilitate correlation with subsequent
metastasis, were it to occur at remote sites. When
multiple divergent (aberrant) morphologies are
present, one should provide relative percentages for
each of the pattens e.g. invasive urothelial carcinoma
(75%) with squamous (20%) and glandular (5%)
differentiation.
IX. Lymphovascular Invasion

(LVI)
Tumour stage reflected by the AJCC/UICC TNM
137
____ Dysplasia
___ Carcinoma in situ
___ Cannot be determined
Histologic Grade
__ Not applicable
__ Cannot be determined
Urothelial Carcinoma (WHO 2004/ISUP)
___ Papilloma
___ PUNLMP
___ Low-grade
___ High-grade
___ Primary Grade
___ Secondary grade
___ Other (specify): _________________________
Urothelial Carcinoma ( WHO 1973)
__Papilloma
__ Grade 1
__Grade 2
__ Grade 3
__ Primary Grade
__ Secondary Grade
Table 19. URINARY BLADDER: Biopsy and

Transurethral Resection of Bladder Tumor (TURBT)
Note: Use of checklist for biopsy specimens is

optional
Select a single response unless otherwise
indicated.
Table 19. URINARY BLADDER: Biopsy and

Transurethral Resection of Bladder Tumor (TURBT)
Note: Use of checklist for biopsy specimens is

optional
indicated.
Relevant Clinical History
___ Cystoscopic impression of the mucosa
___ Indication of procedure
___ Previous history of cancer in bladder or
elsewhere in the genitourinary tract
___ Prior therapy
Procedure
__ Biopsy
__ TURBT
__ Other (specify): _________________________
__ Not specified
Histologic Type
__ Urothelial (transitional cell) carcinoma
__ Urothelial (transitional cell) carcinoma with % of
squamous differentiation
glandular differentiation
micropapillary component
__Urothelial (transitional cell) carcinoma with
variant histology (specify): ___________________
__ Squamous cell carcinoma, typical
__ Squamous cell carcinoma, variant histology
(specify): _______________________
__ Adenocarcinoma, typical
__ Adenocarcinoma, variant histology (specify):
___________________________
__ Small cell carcinoma
__Undifferentiated carcinoma (specify):
___________________________
__ Mixed cell type (specify):
___________________________
__ Other (specify):
___________________________
__ Carcinoma, type cannot be determined
Associated Epithelial Lesions (select all that
apply)
__ None identified
__ Urothelial (transitional cell) papilloma (World
Health Organization [WHO] 2004/ International
Society of Urologic Pathology [ISUP])
__ Urothelial (transitional cell) papilloma, inverted
type
__ Papillary urothelial (transitional cell) neoplasm,
low malignant potential
(WHO 2004/ISUP)
____ Hyperplasia
Adenocarcinoma and Squamous Cell Carcinoma
__ GX: Cannot be assessed

__ G1: Well differentiated
__ G2: Moderately differentiated
__ G3: Poorly differentiated
__ Other (specify): __________________________
Tumor Configuration (select all that apply)
__ Papillary
__ Solid/nodule
__ Flat
__ Ulcerated
__ Indeterminate
__ Other (specify): __________________________
pT1 Tumors
___ Muscularis Mucosae Present
___ Thin-Walled blood vessels present
___ Depth of Lamina propria invasion (micrometer)
Type of tumor invasion
___ Single cells
___ Nodular
___ Trabeculae
___ Infiltrative
Stromal Reaction
___ Stromal retraction
___ Stromal edema
___ Inflammation
___ Fibroblastic proliferation
___ Fibrosis
Adequacy of Material for Determining Muscularis
Propria Invasion
___ Muscularis propria (detrusor muscle) not
identified
___ Muscularis propria (detrusor muscle) present
___ Presence of muscularis propria indeterminate
Lymph-Vascular Invasion
___ Not identified
___ Present
___ Indeterminate
138
Microscopic Extent of Tumor (select all that

apply)
___ Cannot be assessed
___ Noninvasive papillary carcinoma
___ Flat carcinoma in situ
___ Tumor invades subepithelial connective tissue
(lamina propria)
___ Tumor invades muscularis propria (detrusor
muscle)
___ Urothelial carcinoma in situ involving prostatic
urethra in prostatic chips sampled by TURBT
___ Urothelial carcinoma in situ involving prostatic
ducts and acini in prostatic chips sampled by
TURBT
___ Urothelial carcinoma invasive into prostatic
stroma in prostatic chips sampled by TURBT
Additional Pathologic Findings (select all that apply)
___ Urothelial dysplasia (low-grade intraurothelial
neoplasia)
was independently associated with cancer-specific

survival, yet not with recurrence-free survival [731].
In all, six studies have so far evaluated the
significance of LVI in TURB material [721,732-735].
The reported prevalence of LVI is 6-28%, which not
unexpectedly is lower than in radical cystectomy
specimens [721,732-735]. According to a recent
investigation involving matched TURB and radical
cystectomy material from 75 patients, concordance
between LVI diagnoses of TURB and cystectomy
material is good in muscle-invasive cancers, while
it is only low in superficial tumours [721]. Overall
sensitivity and specificity of LVI detection in TURB
samples were 37% and 87%, and positive predictive
values were 65% and 67%, respectively. Similar to
the situation in cystectomy specimens, presence of
LVI in TURB material proved to be an independent
predictor of tumour recurrence [733] and progression
[732,733] as well as patients overall [734] and
disease-specific [732] survival, particularly in clinical
stage I or II [723].
Non-neoplastic changes
___ Inflammation/regenerative changes
___ Therapy-related changes
___ Cautery artifact
___ Cystitis cystica glandularis
___ Keratinizing squamous metaplasia
___ Intestinal metaplasia
___ Denuded urothelium
___ Other (specify): _________________________
Comment(s)
Whether or not lymphatic invasion and venous

invasion should be considered separately has
not been adequately addressed because most
studies have not attempted to differentiate between
venous and lymphatic invasion [60,709,712715,717,718,724,730,731,734,735]. Lotan et al
refer to difficulty and lack of reproducibility when
using routine light microscopic examination of
haematoxylin and eosin stained slides [712].
Some studies have, however, differentiated between
lymphatic and venous invasion and defined venous
invasion as tumour present in vessels with a thick
vascular wall and blood cells within the lumen
[720,726,728,736,737]. Using this definition, the
prevalence of venous invasion was generally lower
than that of lymphatic invasion [710,719,726728,736,737]. With respect to prediction of outcome,
venous invasion proved to be superior to lymphatic
invasion in two of these studies [720,737], whereas
a stronger prognostic effect for lymphatic invasion
was noted in one study [736].
Adding LVI, together with other morphological

(presence of carcinoma in situ in the cystectomy
specimen) and clinical (neoadjuvant chemotherapy,
adjuvant chemotherapy, adjuvant radiotherapy)
parameters to multivariate nomograms assessing
risk for disease recurrence or survival significantly
improved accuracy of prediction compared with the
AJCC/UICC staging system [711,716]. Likewise,
adding LVI alone to a base model including tumour
stage and grade, surgical margin status, number of
lymph nodes removed, and adjuvant chemotherapy
significantly improved predictive accuracy for
disease recurrence and cancer-specific survival in
node-negative cases, yet only marginally in nodepositive cases [717].
Despite unanimity regarding the relationship between

presence of LVI and bladder cancer aggressiveness,
there are major issues of concern that have hindered
its integration in treatment guidelines for bladder
cancer and clinical decision making. In fact, the major
factor is poor diagnostic reproducibility: reported
prevalence and levels of prognostic significance vary
considerably, differing from one study to another.
The lack of reproducibility when using routine light
microscopic examination of haematoxylin and eosin
stained slides is well-known [712,738].
The significance of LVI has additionally been

addressed in patients undergoing partial cystectomy
or transurethral tumour resection for bladder cancer
(TURB). Thus, Zhang et al. recently presented 100
patients with muscle-invasive bladder cancer who
underwent bladder-conserving therapy, i.e. partial
cystectomy. LVI was present in 16% of cases and
These differences have mainly been attributed

to lack of standardized assessment of LVI, as
demonstrated by divergent, often poorly described
histological criteria used by pathologists to identify
139
Associated Epithelial Lesions (select all that

apply)
___ None identified
___ Urothelial (transitional cell) papilloma (World
Health Organization [WHO] 2004/ International
Society of Urologic Pathology [ISUP])
___ Urothelial (transitional cell) papilloma, inverted
type
___ Papillary urothelial (transitional cell) neoplasm,
low malignant potential
(WHO 2004/ISUP)
___ Hyperplasia
___ Dysplasia
___ Carcinoma in situ
Table 20. URINARY BLADDER: Cystectomy, Partial,

Total, or Radical; Anterior Exenteration
indicated.
Relevant Clinical History

___ Diagnosis of previous material
___ Chemotherapy
___ Radiotherapy
___ Preoperative Examination
Specimen
___ Bladder
___ Other (specify): _________________________
___ Not specified
Procedure
___ Partial cystectomy
___ Total cystectomy
___ Radical cystectomy
___ Radical cystoprostatectomy
___ Anterior exenteration
___ Other (specify): _________________________
___ Not specified
Histologic Grade
___ Not applicable
Urothelial Carcinoma (WHO 2004/ISUP)
___ PUNLMP
___ Low-grade
___ High-grade
___ Primary Grade
___ Secondary Grade
___ Other (specify): _________________________
Tumor Site (select all that apply)

___ Trigone
___ Right lateral wall
___ Left lateral wall
___ Anterior wall
___ Posterior wall
___ Dome
___ Other (specify): _________________________
___ Not specified
Urothelial Carcinoma (WHO 1973)

Papilloma ___
Grade 1 ____
Grade 2 ____
Grade 3 ____
___ Primary pattern
___ Secondary pattern
Tumor Size
Greatest dimension: ____ cm
Additional dimensions: ___x____ cm
___ Cannot be determined (see Comment)
Adenocarcinoma and Squamous Cell Carcinoma

___ GX: Cannot be assessed
___ G1: Well differentiated
___ G2: Moderately differentiated
___ G3: Poorly differentiated
___ Other (specify): _________________________
Histologic Type
___ Urothelial (transitional cell) carcinoma
___ Urothelial (transitional cell) carcinoma with % of
squamous differentiation
___ Urothelial (transitional cell) carcinoma with % of
glandular differentiation
___ Urothelial carcinoma with % of Micropapillary
component
___ Urothelial (transitional cell) carcinoma with
variant histology (specify): ____________________
___ Squamous cell carcinoma, typical
___ Squamous cell carcinoma, variant histology
(specify): ________________________
___ Adenocarcinoma, typical
___ Adenocarcinoma, variant histology (specify):
____________________________
___ Small cell carcinoma
___ Undifferentiated carcinoma (specify):
____________________________
___ Mixed cell type (specify):
____________________________
___ Other (specify): _________________________
___ Carcinoma, type cannot be determined
Tumor Configuration (select all that apply)

___ Papillary
___ Solid/nodule
___ Flat
___ Ulcerated
___ Indeterminate
___ Other (specify): _________________________
140
vagina, pelvic wall, abdominalwall

Tumor invades prostatic stroma or
uterus or vagina
___ pT4b:
Tumor invades pelvic wall or
abdominal wall
Regional Lymph Nodes (pN)
___ pNX:
Lymph nodes cannot be assessed
___ pN0:
No lymph node metastasis
___ pN1:
Single regional lymph node metastasis in the true pelvis (hypogastric,
obturator, external iliac or presacral
lymph node)
___ pN2:
Multiple
regional
lymph
node
metastases in the true pelvis
(hypogastric, obrutrator, external iliac
or presacral lymph node metastasis)
___ pN3:
Lymph node metastasis to the
common iliac lymph nodes
____ Number of nodes examined
____ Number with metastases
____ Size of largest metastases
____ Number of nodes with micrometastasis or
isolated tumor cells
____ Extracapsular extension of metastasis
Microscopic Tumor Extension (select all that

apply)
___ None identified
___ Perivesical fat
___ Rectum
Prostate
___ Prostatic stroma
___ Prostatic urethra
___ Focal involvement
___ Extensive involvement
___ Seminal vesicle (specify laterality):
_______________________
___ Vagina
___ Uterus and adnexae
___ Pelvic sidewall (specify laterality):
_______________________
___ Ureter (specify laterality):
_______________________
___ Other (specify): _________________________
___ pT4a:
Margins (select all that apply)

___ Cannot be assessed
___ Margins uninvolved by invasive carcinoma
Distance of invasive carcinoma from closest
margin: ___mm
Specify margin: ____________________________
___ Margin(s) involved by invasive carcinoma
Specify margin(s): __________________________
___ Margin(s) uninvolved by carcinoma in situ
___ Margin(s) involved by carcinoma in situ
Specify margin(s): __________________________
Distant Metastasis (pM)

___ Not applicable
___ pM1:
Distant metastasis
Specify site(s), if known: _____________________
Additional Pathologic Findings (select all that
apply)
___ Adenocarcinoma of prostate (use protocol for
carcinoma of prostate)
___ Urothelial (transitional cell) carcinoma involving
urethra, prostatic ducts and acini
with or without stromal invasion (use protocol for
carcinoma of urethra)
___ Urothelial dysplasia (low-grade intraurothelial
neoplasia)
___ Inflammation/regenerative changes
___ Therapy-related changes
___ Cystitis cystica glandularis
___ Keratinizing squamous metaplasia
___ Intestinal metaplasia
___ Other (specify): _________________________
___ Tumor Bank
Lymph-Vascular Invasion
___ Not identified
___ Present
___ Indeterminate
Pathologic Staging (pTNM)
TNM Descriptors (required only if applicable) (select
all that apply)
___ m (multiple primary tumors)
___ r (recurrent)
___ y (post-treatment)
Primary Tumor (pT)
___ pTX:
___ pT0:
___ pTa:
___ pTis:
___ pT1:
Primary tumor cannot be assessed

No evidence of primary tumor
Noninvasive papillary carcinoma
Carcinoma in situ: flat tumor
Tumor invades subepithelial connective tissue (lamina propria)
pT2: Tumor invades muscularis propria (detrusor
muscle)
___ pT2a:
Tumor invades superficial muscularis
propria (inner half)
___ pT2b:
Tumor invades deep muscularis
propria (outer half)
pT3: Tumor invades perivesical tissue
___ pT3a:
Microscopically
___ pT3b:
Macroscopically
(extravesicular
mass)
pT4: Tumor invades any of the following: prostatic
stroma, seminal vesicles, uterus,
Comment(s)
141
TABLE 21. Literature review of significance of LVI in bladder cancer (studies with >100 patients)
Author
Surgery
Year
Type of
Surgery
No. Pts
pT
stage
+LN
(%)
+ LVI BI LI
(%) (%) (%)
Followup
(months)
Evolution
(survival
/progression)
Statistical
Significance
(MVA)
Abdel-Latif
et al, 2004
97-99
RC, LA
418
T1-T4
26
32
n/a
n/a
36.6
(mean)
+LVI: 27*
-LVI:56*
(3-ys survival
+LN)
Independent
(+LN)
Bassi et al,
1999
82-94
RC, LA
369
T1-T4
21
n/a
30
48.5
(median)
+BI: 29%
-BI: 56%
+LI: 39%
-LI: 61%
(5-ys survival)
Not
independent
Bolenz et
al, 2010
85-08
RC, LA
1099
T1-T4
None
27
n/a
n/a
n/a
+LVI: 69%
-LVI:74%
Independent
(RFS, CSS,
OS)
Carter et
al,
2008
88-06
RC, LA
356
T1-T4
28
32
n/a
n/a
45.4
(mean)
+LVI: 52 mo
OS
-LVI: 97 mo OS
Independent
(CSS, OS)
Cho et al,
2009
01-07
TURBT
118
T1
n/a
28
n/a
n/a
35
(median)
+LVI: 30%
-LVI:11%
Independent
(progression,
metastasis)
Hara et al,
2001
85-00
RC, LA
154
T1-T4
20
50
n/a
n/a
23
(mean)
+LVI: 42%
-LVI:83%
Not
independent
Harada et
al, 2005
89-03
RC, LA
114
T1-T4
18
n/a
33
48
n/a
+BI: 49%
-BI: 67%
+LI: 53%
-LI: 68%
Not
independent
Harada et
al, 2006
89-04
RC, LA
124
T1-T4
18
n/a
28
47
n/a
+BI: 37%R
-BI: 12%R
+LI: 34%R
-LI: 6%R
Not
independent
Herrmann
et al, 2008
86-05
RC, LA
614
T1-T4
28
n/a
n/a
n/a
44
(mean)
+LVI vs LVI:
1.7 RR
Independent
(CSS, OS)
Hong et al,
2005
91-02
RC, LA
125
T1-T4
None
n/a
21
41
(median)
+BI: HR 4.88
-BI: HR 1
+LI: HR 1.2
-LI: HR 1
Independent,
BI only
(CSS)
Leissner et
al, 2003
87-97
RC, LA
283
T1-T4
31
n/a
13
54
32.8
(mean)
+BI vs BI: RR
1.82
Independent,
BI only
(RFS)
Lotan et al,
2005
84-03
RC, LA
750
T1-T4
22
36
n/a
n/a
15
(mean)
-LN, +LVI:
86.9%
-LN, -LVI:
72.1%
Independent
in -LN,
(RFS, CSS,
OS)
Manoharan
et al, 2010
92-08
RC, LA
357
T1-T4
20
29
n/a
n/a
n/a
+LVI: 42%
-LVI:67%
(10-ys CSS)
Not
independent
Palmieri et
al, 2010
95-07
RC, LA
265
T1-T4
23
29
n/a
n/a
108
(median)
+LVI: 29%
-LVI:53%
(10-ys CSS)
Independent
(CSS)
Quek et al,
2005
71-04
RC, LA
702
T1-T4
22
35
n/a
n/a
132
(median)
-LVI: 74%
+LVI: 42%
(10-ys RFS)
Independent
(RFS, OS)
Shariat et
al, 2010
79-08
RC, LA
4257
T0-T4
25
33
n/a
n/a
43
(median)
+LVI: 39%
-LVI:72%
(10-ys CSS)
Independent
(RFS, CSS)
142
TABLE 21. Literature review of significance of LVI in bladder cancer (studies with >100 patients)
(continued)
Author
Surgery
Year
Type of
Surgery
No. Pts
pT
stage
+LN
(%)
+ LVI BI LI
(%) (%) (%)
Sonpavde
et al, 2010
71-08
RC, LA
707
T2
None
15
n/a
Zhang et
al, 2010
02-07
PC
100
T2-T4
n/a
16
n/a
Followup
(months)
Evolution
(survival
/progression)
Statistical
Significance
(MVA)
n/a
60.9
(median)
+LVI vs LVI:
HR 2.2
Independent
(RFS)
n/a
31.5
(median)
+LVI: 32%
-LVI:72%
(5-ys CSS)
Independent
(CSS)
pTN stage = pathological tumor stage

LVI = lymphovascular invasion; BI = blood vessel invasion; LI = lymphatic invasion
+LN = lymph node metastasis; +LM = loco-regional metastasis
RC = radical cystaectomy, LA = bilateral pelvic lymphadenectomy, PC = partial cystectomy; TURBT = transurethral
resection of bladder tumor
RFS = recurrence free survival, CSS = cancer-specific survival; OS = overall survival;
HR = hazard ratio, RR = relative risk
LVI [707,738]. If histological criteria are mentioned,

most studies refer to presence of tumour cells
within endothelium-lined spaces without underlying
muscular wall [60,712-714,717,721,725]. In fact,
identification of a clear-cut endothelial lining is
considered crucial in differentiating LVI from stromal
retraction, which a frequent finding around tumour
cell nests, particularly at the leading edge of invasion
(Fig 58) [739]. Stromal retraction is commonly overdiagnosed as vascular invasion; however, at least in
the breast cancer literature, there is strong evidence
that stromal retraction is not a processing artifact, has
independent prognostic significance in node negative
disease on its own merit, and may possibly be early
phase of vascular invasion [740]. Finally, varying
levels of experience of pathologists evaluating LVI,
and knowledge of the potential problems and mimics,
may influence accuracy of diagnosis, illustrating the
need for strict morphological criteria to diminish
the problem of interobserver variability [707,738].
Another related problem that is not commonly
discussed is that the general approach to assessing
LVI in diagnostic surgical pathology does not
recognize the varied biologic mechanisms involved
tumor vascularization, some of which are not readily
visible at the light microscopic level [741].
network inherent to an abnormal stroma. Moreover,

in pseudoinvasion due to tissue retraction, the
pseudothrombus usually displays a surface with
a blurred outline and shreds of cytoplasm may be
present between the pseudothrombus and the
supposed vessel wall.
In 2006, Algaba
suggested the following
morphological criteria for the diagnosis of LVI on
haematoxylin and eosin stained slides: morphological
features in favour of LVI are tumour cell thrombi within
isolated spaces with an unequivocal endothelial
lining, preferably located next to arterioles and with
a normal surrounding stromal tissue (Figure 58
A,B) [707]. The tumour thrombus is usually floating,
completely free, within the vessel lumen and may
show some fibrin precipitate and/or blood cells around
it. The tumour cells are usually tightly cohesive and
display a smooth border, the cells in the periphery
of the thrombus having a shell-like morphology. In
contrast, morphological features arguing against LVI
are tumour cell clusters, particularly with invasion of
multiple spaces, surrounded by an ectatic capillary
Figure 58. A) Unequivocal presence of urothelial

carcinoma cells within endothelial-lined vessels.
B) Invasive urothelial carcinoma with retraction
artifact.
143
The role of ancillary techniques, such as

immunohistochemistry, in the differentiation of LVI
from pseudoinvasion still remains to be defined.
Almost all published reports on bladder cancer
rely solely on haematoxylin and eosin stained
slides, and immunohistochemistry; if used at all,
immunohistochemistry seems to be reserved for
equivocal cases. However, data obtained from other
types of cancer clearly demonstrate that additional
histochemical and/or immunohistochemical staining
may be help to identify LVI and increase the accuracy
of identification with LVI by proving true vascular
invasion and/or avoiding false-positive reporting due
to overinterpretation of stromal retraction artefacts.
Thus, immunostaining using monoclonal antibodies
directed against endothelial markers, such as
CD31 and podoplanin (D2-40), the latter specific
for lymphatic endothelial cells, have been shown
to increase the detection rate of LVI compared to
conventional haematoxylin and eosin staining and
to render clinically significant information in breast
[742,743], colorectal [744], endometrial [745],
gastric [746], and oral squamous cell carcinoma
[747,748].
survival. On multivariate analysis, blood vessel

invasion detected by CD31 immunostaining proved
to be the only independent prognostic factor. Finally,
another recent study demonstrated a significant
association between lymphatic invasion, assessed
by D2-40 immunohistochemistry, and presence of
lymph node metastasis [752].
LVI is an important prognostic marker in the
assessment of bladder cancer, including both
cystectomy and TURB specimens, and should
routinely be reported upon in the pathological report
(Grade B). LVI can predict tumor behavior and
guide treatment decisions when detected in TURBT
specimens (Level 2) [721,723,733,734]. LVI was
shown as predictor of poorer outcome including
progression and metastasis in patients with T1
bladder cancer in TUR specimens [723,733,734].
When LVI is identified in TURBT it will be present in
65% of matched cystectomies and associated with
nodal metastases in 41% of cases [721]. LVI was
also shown to be an independent prognostic variable
in bladder cancer patients treated with radical
cystectomy (Level 2) [712,714,715]. In a retrospective
study of 750 patients with bladder cancer, LVI was
shown to be an independent predictor of recurrence
and decreased cause-specific and overall survival
in node-negative invasive bladder cancer treated
with cystectomy [712]. Recent multicenter studies
clearly proved LVI to be an independent prognostic
variable, significantly improving predictive accuracy
of standard prognostic models. This effect was,
however, mainly observed in node-negative cases.
Standardization of assessment is urgently needed,
and we would recommend that the evaluation of LVI
on haematoxylin and eosin stained slides should be
performed following the criteria presented by Algaba
to ensure reproducibility and reliability of pathological
diagnoses [707]. The use of endothelial cell markers,
such as CD31 or D2-40, is an interesting tool
which may facilitate detection of LVI and improve
diagnostic accuracy in equivocal cases. The general
use of immunohistochemistry in the routine setting,
however, cannot be recommended, since performing
two immunostains on even selected paraffin blocks
with bladder cancer would be extremely time
consuming and cost intensive. In addition, the
clinical consequences of an LVI diagnosis, either
in transurethral or cystectomy specimens, currently
remains controversial due to inconsistency of studies
on adjuvant chemotherapy after radical cystectomy.
The over-diagnosis of stromal retraction as LVI,
however, does remains to be a major diagnostic
problem. Adherence to strict morphological criteria
embedded in a setting of continuous medical
education and quality control is essential.
In bladder cancer, two studies, published already in

the early nineties, indicated the potential value of
these ancillary techniques: Angioinvasion diagnosed
on haematoxylin and eosin stained slides was
confirmed by immunohistochemistry in only 5 out
of 36 [749] or 2 out of 5 [750] cases, respectively.
Both studies are fairly old and did use antibodies
directed against Ulex euopaeus agglutinin I (UEA
I), von Willebrand factor, and QBEND/10, which are
antibodies that have generally been replaced with
more specific markers in current practice. Therefore,
we cannot exclude that some technical aspects
inherent to the immunohistochemical staining
evaluation may have caused the high rate of putative
false-positive reporting of LVI on haematoxylin and
eosin stained slides. In 2009, Afonso et al. published
the first systematic study investigating the potential
value of CD31 and D2-40 immunostaining in bladder
cancer including 83 patients with radical cystectomy.
[751] Using haematoxylin and eosin stained slides,
blood and lymphatic vessel invasion were diagnosed
in 19 (23%) and 18 (22%) cases, respectively.
Immunohistochemistry significantly improved the
recognition of vascular invasion for both lymphatic
and blood vessels, regarding particularly for
identifying single intravascular single tumour cells
(40% for CD31, 37% for D2-40), yet not compared
regarding malignant to tumor emboli (13% for CD31,
19% for D2-40). Overall agreement between the
three different methods used to identify LVI was
42.2%. Univariate analysis rendered vascular
invasion diagnosed on haematoxylin and eosin
stained slides as well as blood and lymphatic vessel
invasion diagnosed by immunohistochemistry as
significant prognostic variables regarding for overall
Recommendation: C
144
with prostatic urothelial carcinoma involving

prostatic stroma have a significantly poorer 5 year
disease specific survival than patients with urothelial
carcinoma of the prostatic urethra. Shen et al [759]
showed that patients with prostatic CIS or urethral
lamina propria invasion had a similar, but higher
incidence of lymph node metastasis and lower longterm and 5-year survival than those patients without
prostatic involvement. Similarly, prostatic stromal
invasion and periprostatic/seminal vesical invasion
had a similar, but much higher nodal metastasis
and worse survival than patients with only prostatic
CIS or urethral lamina propria invasion [759]. It is
apparent that an important etiology of the wide range
of detection of prostatic stromal invasion in various
series is likely the manner of examination of the
prostate [760].
X. Reporting on Lymph Nodes

The minimum number of lymph nodes required in
cystectomy specimen is not established. Recent
studies have emphasized the importance of lymph
node density (LND) for nodal staging, LND is defined by the ratio of positive lymph nodes to the total number of lymph nodes sampled, but again, the
minimum number of lymph node in the specimen for
optimal LND estimation yet to be established [753].
Prior studies suggested that the number of lymph
node, size of tumor metastasis and presence of
extranodal extension have prognostic significance
(Level 3) [707,712,754]. Single-institutions cystectomy series have shown for both node-negative and
node-positive patients with invasive bladder cancer
that overall survival improves with an increasing
number of lymph nodes examined [754]. In a study
by Fang et al [755], minimum number of lymph
nodes submission for radical cystectomy and pelvic
lymphadenectomy was required, having to submit
more tissue, including fat, if minimum number of 16
lymph nodes was not reached. In a span of 4 years,
the median number of lymph node increased from to
20 from 15, and this policy was found to decrease
mortality risk by 48% and significant in multivariate analysis [712]. Stephenson et al [756], showed
the prognostic importance in measuring aggregate
lymph node metastasis diameter. Fleischmann et al
[757] have recently shown that extracapsular extension of lymph node metastases defines a subgroup
with a very poor prognosis.
XII. Frozen sections

Frozen section is not an optimal method for a primary
diagnosis of invasive urothelial carcinoma or to
perform pathologic staging prior to a cystectomy [761].
The criteria for indicating open partial cystectomy
are quite strict. In these cases the urologist may
send the pathologist samples of the margins in order
to determine their status. The cystectomy specimen
should be oriented or marked in such a way that the
pathologist is able to recognize the margins. These
should be suitably inked and the selection of the
margins to be frozen should be made by means of a
perpendicular section of the full thickness of the wall.
In radical cystectomy, the ureteral margins are very
rarely affected by the tumor. If the urologist suspects
this may be the case, frozen section is indicated.
Segment of ureter submitted separately should have
proper labelling of the true margin. The situation is
completely different if the macroscopic appearance is
normal, as the intraepithelial lesions are uncommon
and only the unequivocal cases of CIS should be
diagnosed. Assessment for CIS at the margin in
frozen section may be difficult. In most cases the
status of the urethral mucosa is known through
preoperative biopsies. Some institutions determine
the status of the urethral margin intraoperatively.
Lymph node frozen section evaluation is indicated
when the possibility of not performing cystectomy is
considered.
XI. Reporting of Prostate

Involvement
In surveillance biopsies of prostate/ prostatic urethra
it is important to report the status of urethral mucosa
(CIS or not), if prostatic glands are represented in
the biopsy specimen and if so, are they involved
by urothelial neoplasia or not. Involvement of the
prostatic ducts and acini without stromal invasion
is staged as pTis using the staging system for
Urothelial carcinoma of the Prostate. Involvement
of prostate may be through direct invasion from a
bladder primary (pT4, staging system for Urothelial
carcinoma of the Bladder) or urothelial carcinoma
arising from the prostatic urethra with secondary
prostatic stromal involvement or prostatic stromal
invasion secondary to urothelial carcinoma involving
prostatic ducts and acini. In the two latter situations,
the staging system for Urothelial carcinoma of the
Prostate is used. Patients with urothelial carcinoma
involving prostatic stroma have a significantly worse
5 year disease specific survival than patients with
urothelial carcinoma of the prostatic urethra (Level
3). Cheville et al [758] demonstrated that patients
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168
Committee 3 A
Molecular Markers for Bladder

Cancer Screening, Early
Diagnosis, and Surveillance
Chairs:
Pierre I. Karakiewicz
Members:
Bernd J. Schmitz-Drger, Michael Droller, Yair Lotan,
Vinata B. Lokeshwar, Bas W. van Rhijn, George P. Hemstreet,
PerUno Malmstrom, Yves Fradet, MLiss Hudson, Osamu Ogawa,
Michael J. Marberger
*Address all correspondence to:

S.F. SHARIAT
Weill Medical College of Cornell University
New York Presbyterian Hospital,
525 East 68th Street
New York, NY 10021
Email: sfshariat@gmail.com
Telephone: 469 363 8500
169
Table of Contents
I. Introduction
III. Marker performance

1. Diagnosis and surveillance
1. Why did we fail in the past?
2. Screening
2. Potential indications for marker

use
3. Problems in marker comparison

4. Recommendations
5. Marker performance
II. Materials and Methods
6. Problems in the assessment of

marker trials
7. Key questions
1. Data collection
2. Criteria for assessment of
reporting, marker status and LoE
IV. Appendix
Abstract:
Due to the lack of disease-specific symptoms diagnosis and follow-up of bladder cancer has remained a
challenge to the urologic community. Cystoscopy, commonly accepted as a gold standard for the detection of
bladder cancer, is invasive and relatively expensive while urine cytology is of limited value specifically in low
grade disease. Through the last decades numerous molecular assays for the diagnosis of urothelial cancer
have been developed and were investigated with regard to their clinical use. However, although all of these
assays have been shown to have superior sensitivity as compared to urine cytology, none of them has been
included in clinical guidelines. The key reason for this situation is that none of the assays has been included
into clinical decision making so far. We reviewed the current status and performance of modern molecular
urine tests following systematic analysis of the value and limitations of commercially available assays. Despite
considerable advances through recent years the authors feel that at this stage the added value of molecular
markers for the diagnosis of urothelial tumors has not yet been identified. Current data suggest that some
of these markers may have the potential to play a role in screening and surveillance of bladder cancer. Well
designed protocols and prospective, controlled trials will be needed to provide the basis to determine whether
integration of molecular markers into clinical decision-making will be of value in the future.
170

Cancer Screening, Early Diagnosis,
and Surveillance
Bernd J. Schmitz-Drger, Michael Droller, Yair Lotan,
Vinata B. Lokeshwar, Bas W. van Rhijn, George P. Hemstreet,
PerUno Malmstrom, Yves Fradet, MLiss Hudson, Osamu Ogawa,
Michael J. Marberger, Pierre I. Karakiewicz, Shahrokh F. Shariat
such as fluorescence or narrow-band imaging are
emerging, the invasiveness and added costs of these
procedures underscores the need for better, simpler
and cheaper diagnostic tests in the management of
bladder cancer patients.[5-7]
I. Introduction
Bladder cancer represents an important cause of
cancer morbidity and mortality. In 2010, once again,
it was the second most common genitourinary
cancer in the United States, with a projected 70,530
new cases and 14,680 deaths.[1] Currently, it is
estimated that there are more than 1,000,000 men
and women alive in the United States and Europe
who have a history of bladder cancer. At the time of
initial diagnosis, approximately 70% of patients have
cancers confined to the epithelium or the subepithelial
connective tissue. These cancers usually are
managed with endoscopic resection and the selective
use of intravesical therapy. The recurrence rate for
these tumors ranges from 50% to 70%, and between
10% and 15% progress to muscle-invasive disease
over 5 years.[2,3] Disease recurrence may occur in
the bladder or in the upper urinary tract even after
several years, necessitating life-long surveillance.
Management of this population is costly because of
the extended surveillance and need for repeated use
of endoscopic and intravesical therapies. Patients
with muscle-invasive and metastatic disease have
a much more precarious survival outcome and also
contribute greatly to the cost of bladder cancer care
because of the expense of radical cystectomy and
systemic chemotherapy. As a result, bladder cancer
is the most expensive cancer to treat on a per patient
basis in the United States.[4]
Voided urine cytology is a highly specific,

noninvasive adjunct to cystoscopy. It has good
sensitivity for detecting high-grade urothelial cancer,
but sensitivity for detection of low-grade tumors
ranges from only 4% to 31%.[8] Furthermore the
accuracy of cytology is dependent upon the level of
expertise of the pathologist and, in consequence,
not readily available in all places. Thus, specifically
in the surveillance of papillary low grade tumors a
noninvasive, highly sensitive and specific bladder
cancer marker could decrease the frequency of
cystoscopies, thereby improving patient quality of
life, and potentially decrease costs by substituting
a less expensive, noninvasive test for the more
expensive endoscopic procedure. In high grade
disease increased sensitivity of markers might lead
to earlier detection of tumor recurrence and, in
consequence improve patient survival.
The potential to decrease costs associated with
cystoscopy would depend upon the cost of the noninvasive biomarker and its specificity such that a false
positive result and the unnecessary need for further
evaluation and associated patient anxiety would not
be a frequent occurrence. Correspondingly, the use
of urinary cytology in monitoring for persistence or
recurrence of high grade disease would also allow
for a decrease in the frequency of cystoscopies if
its specificity were sufficiently high and pathologists
were adequately trained so that they could deliver
a reliable negative reading. Use of other urinary
markers would depend upon their having a similarly
high specificity for high risk disease in this context.
Due to the lack of disease-specific symptoms

diagnosis and follow-up of bladder cancer has
remained a challenge to the urologic community.
Cystoscopy, commonly accepted as a gold standard
for the detection of bladder cancer, is invasive and
relatively expensive thus limiting the frequency of
its use. Although new cystoscopic technologies
The requirements for an ideal marker have been
171
defined using the terms easier, better, faster,

cheaper.[9] Easier in this definition refers to the
assays analytical performance and robustness. For
an assay to be clinically applicable, it should be able
to be performed easily and promptly in a clinical
environment. Better is by the far the most important
challenge that has to be addressed. Demonstrating
information equal to current clinically available
variables is not enough. Any newly discovered
marker should provide additional information that
is helpful to the clinician for the management of the
disease thus providing an added value to the current
situation. Faster means that a new marker should
be able to make the information available in an
efficient and timely manner. Even if the marker has
been proven to offer valuable information regarding
the disease, an unreasonable period of time for its
delivery could considerably decrease its practical
utility. Cheaper is essential for a marker to be costeffective. With health care expenditures reaching
record levels, medical decision making is increasingly
affected by economic concerns. Nevertheless, many
parameters must be considered when assessing
economic impact of a marker: in addition to the
mere costs of the assay, potential clinical benefits
(avoidance of further diagnostic interventions or
ineffective therapy, or benefit from targeted therapy)
need to be considered.
prostate cancer screening where the diagnosis is

usually being sought in asymptomatic individuals
who may themselves request a screening test.
It seems obvious that new tests for the initial
diagnosis of bladder cancer should be investigated in
patients with symptoms and/or signs associated with
this disease. This will pertain largely to patients who
have gross hematuria, those who may have irritative
voiding symptoms without urinary tract infection, and
those found on routine urinalysis to have microscopic
hematuria. However, an investigation of the literature
shows that this approach is often neglected. In
contrast, the vast majority of studies are case-control
trials comparing artificially composed study cohorts,
in which the prevalence of the disease frequently
exceeds 50%. High disease prevalence is usually not
seen in urological practice and such an evaluation
is likely to result in an optimistic assessment of the
positive predictive value. Therefore, this study design
may be misleading when the findings are translated
into routine clinical use.
In conclusion, an insufficient evaluation process is
one of the reasons for the lack of incorporation of
modern bladder cancer tests into clinical decision
making. We still lack good clinical practice
guidelines for the evaluation of diagnostic markers.
The different phases for development and validation
of diagnostic markers in clinical practise have been
defined.[12] However, these four phases, defined
in analogy to the classification used for therapeutic
trials, still provide only a framework for the detailed
assessment of a new diagnostic marker.[7,13]
A significant amount of laboratory and clinical

investigations have developed numerous new urine
markers for the diagnosis of bladder cancer. Many
of them exhibit sensitivity considerably superior to
that of standard urine cytology, particularly in low to
moderate grade diatheses, and are frequently used.
However, despite FDA approval of some of these
assays, none of them has achieved acceptance as a
standard diagnostic procedure in clinical guidelines.
[10,11]
2. Potential indications for marker

use
The following putative indications for the use
of diagnostic bladder cancer markers can be
delineated:
In this report we try to delineate the reasons for

this situation. Furthermore, we will focus in this
manuscript on characterizing any added value and
corresponding clinical utility of modern diagnostic
markers. To this end, we define added value as
either improvement of diagnostic accuracy, reduction
(not necessarily replacement) of other diagnostic
(occasionally invasive) measures, improvement
in quality of life, and/or reduction of costs. Each of
these will be assessed in the context of requirement
for an ideal marker as described above.
Screening
Voiding symptoms, hematuria, risk populations
(occupational exposure/life style)
Reflex testing
Follow-up of patients with bladder cancer
a) Screening
Bladder cancer screening could be an indication for
the use of a non-invasive diagnostic test. Although
the mortality/incidence ratio is higher for bladder
than prostate cancer, the low prevalence of bladder
cancer in the general population along with the low
mortality from bladder cancer due to a large number
of cases with non-fatal tumors has been an obstacle
to develop effective screening strategies for bladder
cancer. Nevertheless, data from a few screening
trials and theoretical considerations on costeffectiveness issues recently have revitalized this
1. Why did we fail in the past?

Although non-invasive tests are labelled to diagnose
bladder cancer, it remains unclear how they can
effectively be integrated into clinical decision
making, particularly when making an initial diagnosis
because the presenting signs and symptoms may
be caused by a number of different diseases and
conditions. This situation is different from that in
172
discussion.[14] Screening of well-defined high risk

populations with a disease prevalence comparable
to other tumor entities that have been accepted for
screening (e.g. breast cancer or colorectal cancer)
may offer a solution to this problem.[15]
Since hematuria assessment is not a screening

approach in its original sense the respective studies
were grouped below among the diagnostic studies.
1. Voiding symptoms
Exposure to specific chemical carcinogens is a wellestablished risk factor for urothelial cancer. Exposure
to aromatic amines, in chemical industry workplaces
involving use of these chemical substances and in
the rubber industry, is associated with bladder cancer.
An excess risk was also reported for dyers in textile
industries, painters, varnishers and hairdressers.
Other agents having been associated with UBC are
polycyclic aromatic hydrocarbons (PAHs), used in
aluminum production, coal gasification, coal tars,
roofing and carbon black manufacture [25]
3. Risk populations
Irritative voiding symptoms may occur in patients

with bladder cancer. This may occur in association
with gross hematuria in which the bleeding itself may
produce irritation, or the involvement of the trigone,
bladder neck, or prostatic urethra by carcinoma in
situ. However, the prevalence of bladder cancer
in patients with irritative voiding symptoms barely
exceeds that of age-matched controls because of so
many other conditions that cause these symptoms.
For example the close association of voiding
symptoms due to prostate enlargement common
in the male population with bladder cancer is a
significant confounding factor and might prevent
adequate patient selection. An effective selection of
patients at risk of having bladder cancer based upon
any degree of voiding symptoms appears impossible.
In consequence, despite a good correlation between
irritative voiding symptoms and bladder cancer,
this condition alone is currently not suited for the
identification of a patient cohort that should undergo
further assessment for bladder cancer.
While these professions are rarer today and safety

measures reducing exposure were introduced at
least in Western plants an excess risk of bladder
cancer still exists among workers exposed to diesel
engine exhaust, such as drivers. In a meta-analysis,
the relative risk among truck-drivers was 1.17
(95%CI 1.06-1.29) and among bus drivers, it was
1.33 (95%CI 1.22-1.45) [26]
Today, cigarette smoking is the most important
risk factor for UBC, accounting for 50% of cases in
men and 35% in women. A meta-analysis reported
that current cigarette smokers have a risk of 2.57
(95%CI 2.20-3.00) compared with non-smokers.[27]
A positive dose-response relationship is found with
both number of cigarettes smoked daily and number
of years of smoking.
2. Hematuria
We do have increased bladder cancer prevalence
rates in gross hematuria justifying a complete
clinical work-up of these patients.[15-19] This is in
contrast to microhematuria, a frequent condition in
the general population. Although the prevalence
of bladder cancer [20,21] is lower in patients with
microscopic hematuria, complete urological workup remains a matter of discussion.[22] This dilemma
has resulted in the discrimination between high risk
and low risk populations with a focus of diagnostic
efforts on those patients at higher risk. However,
apart from bladder cancer, there may be other
conditions correlated with hematuria that may
require urological intervention. However, information
on these additional conditions is rare. Finally, there is
concern that primary care physicians do not always
refer patients with hematuria for evaluation thus
introducing a further selection bias.[23,24]
Screening for bladder cancer requires definition

of cohorts with adequate disease prevalence.
The prevalence data provided above suggest
that professional exposure alone may not justify
screening; however, professional exposure in
combination with other risk factors may yield
populations with disease prevalence suitable for a
screening approach. However, this will be further
modulated by performance characteristics of the
marker used and cost/benefit considerations.
b) Reflex testing
Use of molecular markers for so-called Reflex
testing has gained some interest. The idea behind
this strategy is to improve the accuracy of a previous
test (mostly cytology) but also to minimize expenses
for molecular assays. In most cases bladder cancer
patients with a negative cytology test subsequently
undergo reflex testing with a more sensitive assay.
This procedure makes use of the high specificity of
urine cytology on the one hand and aims at improving
sensitivity of non-invasive diagnosis. Several studies
on reflex testing have been published using the
UroVysion assay.[28,29] As with most findings, it is
important to validate the clinical utility of markers. One
study prospectively validated the role of Urovysion in
The current pathways for the assessment of

patients with hematuria have disadvantages. While
endoscopy remains invasive and costly, it is still
required because of the low sensitivity of urine
cytology. In addition, the sensitivity of imaging for the
detection of upper urinary tract tumors is insufficient;
further confounding the problem of reaching an
accurate diagnosis of urothelial cancer. As a result,
assessment of patients with hematuria could be an
area where new diagnostic markers could be clinical
helpful.
173
patients with atypical cytology and noted cystoscopic

findings had an important effect on the performance
of the marker.[30] Nevertheless, any added value
of this approach in the context of what we have
described above requires validation.
2. C
riteria for assessment of
reporting, marker status and LoE
c) Follow-up
T
he Level of Evidence (LoE) for diagnostic
procedures (Oxford classification) [36].
It was a specific challenge of this assessment to

classify the different markers and trials according to
Surveillance of patients with a history of bladder

cancer is a key area for the use of new diagnostic
markers, because the prevalence of the disease is
high in this group and new urinary tests will therefore
have a better positive predictive value than urine
cytology. These tests can detect bladder cancer
before they are visually evident. [28,31] However,
this causes a significant problem in defining negative
tests. Currently, there is no easy way of separating
false positive tests from true positive tests when
patients do not have clinically evident tumor.
T
he accuracy of data reporting according to the
STARD criteria [37,38] .
T
he status of the marker with regard to clinical
implementation (IBCN classification) [12].
By this procedure we intended that readers should
be informed on the quality of marker studies and
the status of a given marker with regard to clinical
implementation in a structured and reproducible
way. Furthermore, use of the respective tools were
to be made in order to
In general, two different directions for a use of urine

tests are conceivable:
encourage readers, reviewers and publishers

to use a structured and transparent process for
manuscript assessment, but also
Surveillance of patients with low risk tumors aimed

at a reduction of the frequency of diagnostic
cystoscopies.
to identify deficiencies of the tools available and

produce proposals for their improvement.
Follow-up of patients with high risk tumors with

the intention to recognize tumor recurrence and
progression as early as possible.
All statements and recommendations were

discussed within the group. Recommendations were
provided and categorized according to the criteria
of the Agency for Health Care Policy and Research
(AHCPR) [39] and required consensus of the group.
Some studies suggest that a use of non-invasive

diagnostic markers in follow-up of bladder cancer
may be helpful; [8,32-34] however, prospective
analyses to define the consequences from a negative
or positive test result are still lacking.
III. Marker performance

In this part of the assessment, information on the
performance of commercially available molecular
diagnostic markers is provided. This information
is based upon a critical evaluation of the currently
available literature.
II. Materials and methods

1. Data collection
As of March 2010, six urinary tumor marker tests

have been cleared by the U.S. Food and Drug
Administration (FDA) and are in clinical use. These
tests are:
This review was restricted to commercially available

assays (Tab. 1). The assessment was based upon
a systematic literature search in medical databases
(PubMed). All studies on the diagnostic use of the
respective markers were screened and reviews
as well as repeated publications of the same data
were identified and excluded. Studies investigating
prognosis were not considered for this analysis but
are part of a second paper. [35] For some markers,
well-executed meta-analyses were used as a basis
for assessment [33,34] while for other markers
detailed analysis of studies that had been published
in English through January 2011 was performed.
Sensitivity was assessed based upon histopathologic
results only. Studies on non-urothelial tumors or
trials not comprising information required for a basic
assessment (e.g. stage, grade) were excluded. If
deemed necessary additional publications in other
languages were considered.
T
he quantitative BTA TRAK and the qualitative
point-of-care BTA (bladder tumor antigen) stat
test (both by Polymedco Inc., Cortlandt Manor, NY,
USA).
T
he quantitative immunoassay NMP22 and
the qualitative, point-of-care test NMP22
BladderChek (Matritech Inc.,Newton, MA, USA).
T
he UroVysion Bladder Cancer Kit (Vysis Inc.,
Downers Grove, IL, USA), a multiple marker
fluorescence in situ hybridization (FISH) test.
T
he uCytTM test, an immunocytochemical assay
(Scimedx Inc., Denville, NJ, USA).
With the exception of the uCyt test, which is only
174
Table 1. Commercially available bladder tumor markers (basic information)

Test/
marker
Cytology
Marker
detected/ Specimen
Marker type
Tumor cells
Hematuria A: Hemoglobin
detection
B: Red blood cells
Assay type
F
D
A Manufacturer
approval
Voided urine Microscopy

Barbotage
specimen
Exfoliated cells
A:
Voided A: Dipstick
urine
n.a.
B:
urine
Voided B: Interference-contrast
microscopy or
Red blood cell analyzer
BTA-Stat
Complement
factor Voided urine
Dipstick immunoassay Diagnosis,
H-related protein (and
follow-up
also
Complement
factor H)
BTA-TRAK Complement
factor Voided urine
Sandwich ELISA
Diagnosis,
H-related protein (and
follow-up
also
Complement
factor H)
NMP-22
Nuclear
mitotic Voided urine
Sandwich ELISA
follow-up
apparatus protein
A: Bayer Corp.
B: -
B a r d / B i o n
Diagnostics
B a r d / B i o n
Diagnostics
Matritech, Inc.
NMP-22
Nuclear
mitotic Voided urine
apparatus protein
Point-of-care device
BLCA-4
Nuclear matrix protein
Voided urine
ELISA (using a rabbit polyclonal antibody)
E i c h r o m
Technologies
Survivin
A member of inhibitors Voided urine

of apoptosis gene
family
F u j i r e b i o
Diagnostics, Inc.
UBC
Cytokeratin 8 and 18 Voided urine

(cytoskeletal proteins)
Bio-dot test
(dot blot assay using
a
rabbit
polyclonal
antibody
Sandwich ELISA or a point of care test
C Y F R A Cytokeratin
19
(a Voided urine
21-1
cytoskeletal protein)
Bio
International;
Roche Diagnostics
DD23
Immunoradiometric assay
or
electrochemiluminescent immuno assay
185-kDa
tumor Exfoliated cells Immunocytochemistry
associated Antigen
UroCor
Labs,
Oklahoma City, OK,
USA
Carcinoembryonic
antigen, 2 bladder
tumor cell-associated
mucins
Alterations
in
chromosomes 3, 7, 17
and 9p21
Scimedx, Inc.
uCyt+
UroVysion
Voided urine, Immunocytochemistry

Exfoliated cells
Voided urine, Multi-colored,

Exfoliated cells probe FISH
175
Diagnosis Matritech, Inc.

high risk,
follow-up
Follow-up
IDL Biotech.
multi- Diagnosis, Abbott, Vysis

follow-up
cleared for monitoring bladder cancer recurrence,

all tests are FDA-approved as adjunctive tests for
use in the initial diagnosis of bladder cancer and
surveillance of bladder cancer patients, in conjunction
with standard procedures.
tests. A negative predictive value represents the

percent of negative tests in patients without disease
versus all negative tests. Tests with high positive
predictive value will accurately identify patients with
disease by a positive test result. Tests with high
negative predictive value will accurately identify
patients without disease by negative test results.
Both depend on the prevalence of disease in the
test population because a greater proportion of test
results will then more accurately reflect the true
status of disease in that population. Thus, according
to the contingency table the resultant numerator will
be greater and the denominator less, each leading to
a higher predictive value.
The performance of biomarkers depends upon their

sensitivity (positivity of a marker in the presence
of disease), specificity (negativity of a marker in
the absence of disease), positive predictive value
(probability of disease if a marker is positive), and
negative predictive value (probability of no disease
if a marker is negative). A threshold can be set for
interpreting a test result as positive or negative, this
in turn influencing a markers sensitivity or specificity
(Fig. 1). A markers predictive value will be influenced
by the prevalence of a condition in a test population,
thereby affecting calculations of the probability
of the presence or absence of the disease in that
population on the basis of a positive or negative test
result (Fig. 2).
Of relevance to each of the biomarkers discussed

in this survey is the concern that decisions may be
based on an arbitrary threshold. This will dichotomize
a test that biologically is actually a continuous
variable. Thus, although thresholds may be set to
determine the likelihood of detecting true versus
false positives and true versus false negatives, this
may be misleading in interpreting test results and
their use. This can be important in both low risk and
high risk disease in influencing how a marker may
be applied in screening, surveillance, or determining
efficacy of treatment.
In applying these contingency tables, sensitivity

represents the performance of a test in patients
withd isease (true positives versus all patients
with disease) (Fig. 1). Specificity represents the
performance of a test in patients without disease
(true negatives versus all patients without disease).
Tests with high sensitivity will not overlook patients
with disease. This may allow earlier diagnosis and/
or prevent a delay in diagnosis. Tests with high
specificity may not subject patients who do not have
disease to unnecessary procedures.
1. Diagnosis and surveillance

Performance characteristics may be obtained
by assessment of trials claiming to investigate a
diagnostic use of non-invasive molecular markers.
These trials are inhomogeneous since they are
composed from case control studies with a high
prevalence of cases and from trials targeting
frequently poorly characterized cohorts (usually
designed as cases suspicious for bladder cancer,
hematuria in some cases) with a lower prevalence
of bladder cancer. Therefore, the reported range of
sensitivity is usually wider as compared to that in
follow up studies.
In bladder cancer, the value of biomarkers according

to their sensitivity and/or specificity will depend
upon the particular objectives in screening versus
monitoring in the context of low risk versus high risk
disease and the definition of risk as the disposition to
recurrence versus progression.
Thresholds can be set to determine the likelihood of
detecting true versus false positive and true versus
false negative test results. The resultant increased
or decreased sensitivities or specificities can
determine the usefulness of a biomarker meeting
particular objectives in screening versus monitoring
for disease recurrence. Accordingly, high thresholds
will increase specificity while decreasing sensitivity
because of fewer false positives and more false
negatives (Fig. 1). Correspondingly, low thresholds
will increase sensitivity while decreasing specificity
because of fewer false negatives and more false
positives.
Few trials may be classified as true screening trials

investigating predefined cohorts of asymptomatic
individuals (e.g. smokers, professionally exposed
individuals, cohorts randomly invited for screening)
rendering marker positive individuals for urological
evaluation. These studies are addressed separately.
a) Urine-based Markers
1. NMP22
Nuclear matrix proteins (NMPs) are part of the
structural framework of the nucleus and provide
support for the nuclear shape. These proteins have
also been attributed roles in DNA replication, in
ribonucleic acid transcription and in the regulation
of gene expression. One member of this family,
nuclear mitotic apparatus protein (NMP22), is much
more prevalent in malignant urothelial cells than in
their normal counterparts. Apoptosis is accompanied
Predictive values in bladder cancer can also be

placed in the context of low risk versus high risk
disease and the role that biomarkers play depending
upon the threshold that is set for positivity or
negativity of a particular test value (Fig. 2). A positive
predictive value represents the percent of positive
tests in patients with disease versus all positive
176
Contingency Analysis of
Sensitivity and Specificity
Disease Status
Absent (-)
Present (+)
Pos (+)
Test Result
Neg (-)
Sensitivity = true positives a / (true positives a + false negatives)

Sensitivity = true negatives d / (true negatives d + false positives)
Figure 1. Contingency analysis of sensitivity and specificity
Contingency Analysis
of Predictive Values
Disease Status
Absent (-)
Present (+)
Pos (+)
Test Result
Neg (-)
Positive Predictive Value = true positives a / (true pos a + false positive)

Negative Predictive Value = true negatives d / (true neg d + false negative)
Figure 2. Contingency analysis of predictive values
177
with a release of NMP22 into the urine, and patients

with bladder cancer have a significantly elevated
concentration of NMP22. Both a laboratory-based
quantitative microplate enzyme immunoassay and
a qualitative point-of-care test (BladderChek Test;
Matritech Inc., Massachusetts, USA) are available
and are FDA-approved for use in bladder cancer
surveillance. The latter is also approved for detection
of bladder cancer in high-risk patients.
significant overlap in studies comparing markers and

cytology for high grade cancer, high stage cancers
and patients with CIS (Tab. 2 and 3). Nevertheless,
in general urinary bladder markers also perform
better in patients with higher stage disease (Tab. 4)
and higher biologic aggressiveness (Tab. 5).
Boman and colleagues evaluated NMP22 (cut-off
> 4 U/ml) sensitivities in 250 patients and found
sensitivities of 46% (41/90), 58% (21/36), 76%
(22/29) in detecting tumors < 10 mm, 1120 mm
and > 21 mm, respectively.[40] Sanchez-Carbayo
and colleagues evaluated 187 patients with NMP22
(cut-off >14.6 U/ml) and reported sensitivities of 83%
(19/23), 81% (34/42) and 93% (38/41) in detecting
tumors < 5 mm, 530 mm and > 30 mm, respectively.
[41]
Sensitivity
There have been several meta-analyses that have
evaluated the sensitivity of commonly used markers
(Tab. 2). When compared with cytology, NMP22 as
well as other markers generally have a significantly
higher sensitivity for detecting bladder cancer. This
improvement in sensitivity is primarily in detection
of low grade and low stage bladder cancers with
The data on the impact of tumor number on sensitivity
Table 2. Marker Sensitivity and Specificity of Cytology and Commercially Available Markers (data from Metaanalyses)
Marker
Median Sensitivity (range) Median Specificity (range) Total Number of Patients
Cytology
Glas (51)
55 (48-62)*
94 (90-96)*
3,444
Lotan (8)
34 (20-53)
99 (83-99)
2,767
Van Rhijn (32)
35 (13-75)
94 (85-100)
5,545
Mowatt (52)
44 (38-51)*
96 (94-98)*
14,260
BTA stat
Glas (51)
70 (66-74)*
75 (64-84)*
1,160
Lotan (8)
71 (57-82)
73 (61-82)
2,534
Van Rhijn (32)
58 (29-74)
73 (56-86)
3,461
67 (60-73)*
78 (72-83)*
2,290
Lotan (8)
73 (47-87)
80 (58-91)
2,413
Van Rhijn (32)
71 (47-100)
73 (55-98)
2,041
Mowatt (52) pooled
68 (62-74)*
79 (74-84)*
10,119
Mowatt (52) BladderChek
65 (50-85)
81 (40-87)
2,426
Van Rhijn (32)
67 (52-100)
75 (62-82)
959
Mowatt (52)
84 (77-91)*
75 (68-83)*
3,041
This assessment
81 (42-100)
75 (62-95)
4,899
NMP22 (assay/bladder check)

Glas (51)
uCyt+/Immunocyt
FISH (Urovysion)
Hajdinjak (31)
72 (69-75)*
83 (82-85)*
2,477
Mowatt (52)
76 (65-84)*
85 (78-92)*
3,101
This assessment
72 (23-100)
80 (40-100)
2,852
*95% CI
178
Table 3. Sensitivity of Cytology and Commercially Available Markers (data from Meta-analyses) Based on
Tumor Grade
Marker
# studies
Grade 1
Grade 2
Grade 3
Lotan (8)
.12 (.04-.31)
.26 (.17-.37)
.64 (.38-.84)
Van Rhijn (32)
0.17
0.34
0.58
Lotan (8)
.47 (.38-.56)
.73 (.59-.83)
.94 (.55-.99)
Van Rhijn (32)
0.45
0.6
0.75
Van Rhijn (32)
0.41
0.53
0.8
Lotan (8)
.61(.35-.81)
.71 (.41-.90)
.79 (.63-.89)
Van Rhijn (32)
0.78
0.9
This assessment
19
0.75
084
0.84
Van Rhijn (32)
0.56
0.78
0.95
This assessment
21
0.53
0.81
0.79
Cytology
BTA stat
NMP22
Immunocyt
FISH (Urovysion)
Table 4. Association of Cytology and Commercially Available Markers (data from Meta-analyses) with Tumor
Stage [Lotan (8)]
Marker
# studies
Ta
T1
>T2
TIS
Cytology
.15 (.09-.25)
.46 (.34-.59)
.55 (.35-.73)
.63 (.29-.87)
BTA stat
.57 (.47-.67)
.82 (.63-.92)
.91 (.74-.97)
.66 (.42-.83)
NMP 22
.60 (.42-.76)
.85 (.27-.97)
.89 (.50-.98)
.73 (.54-.86)
Table 5. Sensitivity of Cytology and Commercially Available Markers (data from Meta-analyses) and
Association with Tumor Aggressiveness [Mowatt (52)]
Less aggressive/lower
risk (pTa, G1, G2)
median% (range)
More aggressive
(pT1, G3, CIS)
median% (range)
CIS median% (range)
Number of Patients
(total)
Cytology
27 (0-93)
69 (0-100)
78 (0-100)
12,566
NMP22
50 (0-86)
83 (0-100)
83 (0-100)
7556
FISH (Urovysion)
65 (32-100)
95 (50-100)
100 (50-100)
2164
Immunocyt
81 (55-90)
90 (67-100)
100 (67-100)
2502
is still controversial. Poulakis et al. evaluated 739

patients using NMP22 (cut-off 8.25 U/ml) and
found sensitivities of 79% (165/208), 90% (83/92)
and 97% (96/99) in patients with one, two to three,
and more than three tumors, respectively.[42] On
the other hand, Sanchez-Carbayo and colleagues
evaluated 187 patients using NMP22 (cut-off 14.6
U/ml) and found sensitivities of 72% (18/25) and 75%
(61/81) in patients with single and multiple tumors,
respectively.[41] This discrepancy may relate to
the level of NMP22 reaching threshold based upon
the amount of apoptotic cell debris (the basis of a

positive test) shed into the urine. Tumor volume may
reflect either size or number of lesions in contributing
to a positive test result.
There is also a possible impact of marker sensitivity
based on whether the marker is used for detection or
surveillance. However, this may be related to the fact
that tumors are larger at diagnosis or have a more
advanced stage than during surveillance. Boman
found that NMP22 has higher sensitivity for new as
compared to recurrent tumors; this appeared due to
179
higher stage and grade at presentation and larger

tumor size.[40]
quality of reporting according to the STARD criteria

is moderate to poor, in part due to the fact that the
majority of trials were conducted earlier.[37,38]
We conclude that the level of evidence of studies
on NMP22 is LoE III and in some studies LoE IIb
according to the Oxford classification.[36] Phase
III IBCN trials are lacking.[12,51] This translates
into a maximal LoE Grade IIa for meta-analyses.
[8,33,34,52,53]
In two large prospective multicenter studies using

the NMP22 BladderChek test, the NMP22 assay was
positive in 44 of 79 patients with cancer (sensitivity
55.7%; 95% confidence interval [CI], 44.1%-66.7%)
in the detection setting and sensitivity was 49.5%
(51/103; 95% CI, 39.5%-59.5%) in the surveillance
setting.[32,43] While the sensitivity for surveillance
was lower, the overlapping confidence intervals
suggest no significant difference in performance of
NMP22 in detection and surveillance setting.
2. BTA stat, BTA trak

Among the non-invasive tests developed to detect
urothelial carcinoma, those derived from basement
membrane fragments found in urine from bladder
cancer patients included a series called BTA assays.
The original BTA test was a colorimetric three-step,
latex-agglutination process that qualitatively detected
bladder tumor-associated analytes (BTA) using
human immunoglobulin G.[54-56] The BTA analytes
were polypeptides ranging from 16 to 65 kDa thought
to be released into the urine by proteases released
from tumor cells during stromal invasion.[54-56]
This test was supplanted by 2 newer versions, the
BTA stat and the BTA TRAK which detect different
protein(s) than the original.[54-57] Extrapolation
of sensitivity or specificity results from studies of
the original BTA test to BTA stat or BTA TRAK are,
therefore, not valid. The original BTA test is no longer
commercially available.
Specificity
The main disadvantage of current markers is their
lower specificity compared with cytology (Table 1).
NMP22 is a protein that localizes with the spindle
poles during mitosis and thus regulates chromatid and
daughter cell separation.[44] There is a substantially
higher level of NMP22 in the urine of patients with
bladder cancer. However, because this protein
is released from dead and dying urothelial cells,
many benign conditions of the urinary tract, such as
stones, infection, inflammation, and hematuria may
carry these proteins as well and cystoscopy can
cause a false-positive reading. In a study of NMP22
and BTA stat in 278 symptomatic patients who
presented to a urology clinic, Sharma et al found that
greater than 80% of the false-positive results were
clinically categorized as benign inflammatory or
infectious conditions, renal or bladder calculi, recent
history of a foreign body in the urinary tract, bowel
interposition segment, another genitourinary cancer
or an instrumented urinary sample.[45] History of
ureteral stents or any bowel interposition segment
had a 100% false-positive rate. Exclusion of all
6 clinical categories improved the specificity and
positive predictive value of NMP22 (95.6%, 87.5%)
and BTA stat (91.5%, 69.7%), and was similar to
urinary cytology.
Both BTA stat and TRAK detect human complement

factor H related protein (hCFHrp) and complement
factor H.[57] hCFHrp is thought to interrupt the
complement cascade and confer a selective growth
advantage to cancer cells by allowing them to evade
the host immune system. The dissociation of C3
activating convertase and degradation of C3b are
thought to be enhanced by complement factor H.[5558] Both tests are non-invasive and approved by the
Food and Drug Administration (FDA) as adjuncts
to cystoscopy in the detection of urothelial cancer,
not as primary diagnostic tools.[59,60] BTA stat is a
qualitative test, while BTA TRAK is quantitative.[1,6]
Both have been performed on fresh, refrigerated,
or frozen urine obtained as voided or catheterized
specimens.[40,42,45,49,55,59,61-74]
One consideration that is often raised is the

possibility that a urine based marker may become
positive prior to visualization of a tumor. This has
been termed an anticipatory positive result. There
are several studies that found a greater likelihood
of recurrence in patients with a positive FISH assay
compared to those with negative assays in the
absence of a visualized tumor.[46-48] This has also
been reported for NMP22 and Immunocyt/uCyt,
albeit in a small number of patients.[16,49,50] Thus
the lack of specificity is the major limitation of these
urine markers. Strategies to manage patients with
a positive marker,[12,51] without cystoscopically
visible tumor is crucial to the future applicability of
markers.
Data quality
The BTA stat is an inexpensive, office-based, singlestep, immunochromatographic assay usually performed on voided fresh or refrigerated urine samples
producing results in 5 minutes with minimal training
of personnel.[57] Five drops of urine are placed into
a well containing a colloidal gold conjugate antibody
and allowed to react. Only if tumor antigen is present does a visible colored line form when the antigen
conjugate complexes are captured by a second antibody. BTA stat has been used in the detection of initial, recurrent, and upper tract urothelial carcinoma
(Tab. 6).[40,42,45,49,62-74]
As for other markers discussed in this assessment,
The BTA TRAK is a sandwich immunoassay method
180
requiring trained laboratory technologists several

hours to complete.[75] In this assay, antihuman
complement factor H related protein monoclonal
antibody coated onto 96-well microtiter plate captures
its target in urine. A second alkaline phosphatase
labeled reporter antibody and a substrate solution
are used to detect hCFHrp. Human complement
factor H is also detected. Comparison to a calibration
curve created from kit standards is used to determine
the amount of hCFHrp present. The cut-off limit
recommended by the manufacturer is 14 units/ml,
where 1 unit is 4.7 ng of hCFHrp (Tab. 6).[58,59,61]
Level 2a evidence as identified by a meta-analysis

of data on BTA Stat and TRAK testing was provided
in these review articles, with the highest number of
subjects reported in the Glas and van Rhijn articles.
[34,52] Each included many of the same source
documents, and thus each was dependent on the
quality of these sources. As described by Glas[52],
the quality of the literature is weak and we concur,
based on our evaluation using the STARD checklist.
[38] No study met all 25 STARD items.
There are several clinical scenarios in which either
of the BTA tests could prove useful. The first is as a
diagnostic tool for the detection of primary urothelial
carcinoma in subjects with signs and symptoms of
bladder cancer or at screening of risk populations.
The FDA has not approved either BTA stat or TRAK
for this indication.[6] Tumor markers in the diagnosis
of primary bladder cancer. A systematic review by
Glas would appear to address this situation.[52] In
this meta-analysis, of 1160 subjects providing urine
samples for BTA stat testing, the sensitivity was 70%
(95% CI: 66-74I) and specificity 75% (95% CI: 64-
Using a PubMed search for BTA, we identified 7

review articles in English on bladder tumor markers
in use that included BTA stat or TRAK testing.
[34,52,54,56,58-60] Sample source documents
from these were selected based on frequency of
citation and to include global urologic participants.
With the exception of those studies performed on
archived urine specimens from prior studies,[55,61]
the majority of studies discussed are International
Bladder Cancer Network (IBCN) Phase II studies.
Table 6. BARD stat and TRAK assay: Patient demographics

Author
Gender
Sarosdy 1997 54
M
443
M
141
Partial record
Partial record
F
332
F
77
M
151
M
145
M
485
NS
M
199
NS
M
127
M
172
M
207
M
152
NS
M
208
M
80
F
28
F
23
F
254
Babjuk 2002 70
Ellis 1997 60
Tsui 2007 72
Serretta 2000 68
Giannopoulos 2000 47
Poukalis 2001 40
Nasuti 1998 66
Wiener 1998 61
Sharma 1999 43
Sozen 1999 64
Leyh 1999 62
Pode 1999 63
Ramakumar 1999 65
Raitanen 2001 69
Boman 2002 38
Schroeder 2004 71
F
92
F
13
F
68
F
43
F
44
F
96
F
35
NS = Not stated
181
Race
# of Sites
Urine sample
type
Voided Archived
frozen
Voided, NS
Age
NS
14+
NS,
NS
NS
14
NS
NS
NS
1
1
Voided, frozen
Voided
fresh
Voided Fresh &
frozen
Voided
fresh
Voided
fresh
NS
Voided Fresh &
frozen
Voided NS
Voided or cath
NS
NS
NS
NS
NS
1
1
NS
NS
98% white
Voided or cath
Yes
NS
Voided fresh
NS
NS
Voided fresh
Yes
NS
NS
18
1
Voided fresh
NS
NS
Yes
NS
Unknown Collection Yes

frozen
Yes
Yes
Yes
Yes
Yes
NS
Yes
NS
Yes
84). The sensitivity and specificity of the BTA TRAK

test was 66% (95% CI: 62-71), and 65% (95% CI:
45-81) on data collected from 829 subjects who
provided urine samples for this same meta-analysis.
Thus, level 2a evidence does not support the use of
either BTA test alone for the detection of urothelial
carcinoma (Tab 7 and 8).
than stat (71% vs. 58%, respectively). The median

specificity was higher (73%) for 2084 BTA stat-tested
subjects than for 195 BTA TRAK-tested subjects
(66%). Subset analysis of recurrent tumor stratified
by grade showed lower sensitivities for grade 1
and 2 tumors for both BTA stat and TRAK (grade 1
= 45% and 55%, respectively; grade 2 = 60% and
59%, respectively) as compared to grade 3 tumors
(75% and 74%, respectively). A trend of increasing
sensitivity and specificity for overall tumor detection
has also been noted with increasing tumor stages.
[58] Furthermore, the BTA stat test has been shown
to have a lower sensitivity for detecting recurrent as
opposed to primary tumors, possibly related to the
smaller size of recurrent tumors BTA TRAK showed
increasing sensitivity and specificity with higher
tumor grades and stages (Tab. 7 and 8).[56]
Glas[52] further contributes to our understanding of

the literature by noting how study design influenced
results. With regard to the BTA stat test, sensitivity
was estimated to be significantly lower in case control
studies (66%, 95% CI: 60-71) when compared to
cohort studies (77%; 95%CI: 71-82). Specificity of the
BTA stat test was overestimated when interpretation
of results occurred in a manner which was not
blinded. Glas[52] described the studies available
for this meta-analysis as weak as most were not a
consecutive series of subjects suspected of having a
bladder tumor with independent assessment of the
marker test and reference standard.
Unfortunately, both current forms of the BTA test

are limited by conditions producing false positive
results. Because complement factor H is present
at high concentrations in blood, a positive BTA
stat or TRAK test will occur when hematuria is
present, regardless of the presence or absence of
urothelial tumor.[59,60] Greater than 80% of false
positives to either form of BTA test occur in subjects
with hematuria, dysuria, incontinence, a history of
intravesical therapy, ureteral stents or nephrostomy
tubes, renal or bladder calculi, benign inflammatory
disease (urinary tract infections or prostatitis), bowel
interpositions or other genitourinary cancers (renal or
prostate).[45,59,60,63,67] While use of exclusionary
The second clinical situation, monitoring of subjects

with a prior history of bladder cancer for recurrence,
is the indication for which the FDA has approved the
BTA tests as an adjunct to cystoscopy.[60] Urine
markers for bladder cancer surveillance: A systematic
review by van Rhijn[34] appears to address this
scenario. These authors reported a total of 1377
subjects on whom the BTA stat was performed and
360 subjects on whom the BTA TRAK was performed
in the setting of surveillance for recurrent disease.
The median sensitivity was higher for BTA TRAK
Table 7. BARD stat assay: Individual Analyses for Overall Sensitivity and Specificity
Author
Sarosdy 54
Wiener 61
Pode* 63
Irani 114
Babjuk 2002 70
Sozen 1999 64
Leyh 1997 62
Sharma 43
Ramakumar 654
Giannopouloulos 47
Nasuti 66
Heicappell 67
Raitanen 69
Boman 38
Schroeder 71
Halling 45
Serretta 68
Poulakis 40
%
Sensitivity
327^220 58
291
57
250
83
81
65
88
87
140
69
231^107 73
278
68
196
74
168
72
100
100
354
63
445
53
250+
64
115
53
2806
78
179
57
739
70
%
Specificity
72
68
69
72
74
68
52
82
73
57
84
93
86
64
77
74
62
67
N True
Positives
147
62
106
32
N True
Negatives
75
NS
NS
23
28
40
23
48*
50
3
105
63
96
31
16
279
NS = Not stated
+ = 289 samples from 250 patients
6 = 280 samples from 250 patients
182
N False
Negatives
73
NS
22
17
%
PPV
82
56
%
NPV
51
70
68
26
201
101
28
81
174
246
91
59
N False
Positives
32
64
NS
9
18
32
45
43
38
28
16
13
81
17
18
12
15
11
15
18
0
62
55
55
28
70
67
35
54
70
16
83
87
58
*
44
85
63
82
62
68
24
223
40
110
12
120
72
65
Table 8. BARD stat and TRAK assay: Tumor Characteristics
Author
Grade 1 Grade 2 Grade 3 pTa
Sarosdy 1997 54
57
56
95
111
Babjuk 2002 70
27
27
24
29
Ellis 1997 60
53
56
96
108
Tsui 2007 72
16
14
15
NS
Serretta 2000 68
7
19
29
13
Giannopoulos 2000 47 26
39
34
49
Poulakis 2001 40
130
167
70
209
Raitanen 2001 69
48
35
3
54
Nasuti 1998 66
0
2
1
NS*
Wiener 1998 61
23
38
30
47
Sharma 1999 43
NS
NS
NS
NS
Sozen 1999 64
14
16
10
16
Leyh 1999 62
26
45
36
58
Pode 1999 63
25
58
45
72
Ramakumar 1999 65
9
26
13
25
Boman 2002 38
54
70
35
117
Schroeder 2004 71
8
26
23
28
NA = Not applicable
NS = Not stated
*included more than one group together
^grade and stage unknown in 32, 33 subjects, respectively
criteria improve the performance of both BTA tests,

the signs and symptoms of benign inflammatory
conditions overlap those seen in subjects with
urothelial carcinoma. This limits the usefulness of
these tests for discriminating between malignant
and non-malignant states.[45,67] In particular, false
positives for up to 2 years after intravesical bacillus
Calmette-Guerin (BCG) therapy limits the BTA
tests usefulness in monitoring for recurrent tumor.
[64] False positives are more commonly seen with
the BTA stat as opposed to the BTA TRAK test.[60]
False positives are seen in < 5% of subjects with no
known urinary pathology.[45]
pT1
38
26
38
NS
27
26
47
20
NS*
25
NS
10
27
29
NS*
24
13
pTIS
18
3
18
NS
3
5
29
2
0
NS
NS
NS
5
NS
11
NS
5
>pT2
50
20
50
NS
12
16
112
3
1
19
NS
14
17
27
NS*
14
11
%Sensitivities recorded
BTA stat
BTA TRAK
Yes
NA
Yes
Yes
NA
Yes
NA
Yes
Yes
NA
Yes
NA
Yes
NA
Yes
NA
Yes
NA
Yes
NA
Yes
NA
Yes
NA
Yes
NA
Yes
NA
Yes
NA
Yes
NA
Yes
NA
controls for office-based laboratory procedures such

as the BTA stat test and declining re-imbursement
for such point-of-contact testing by Medicare and
private healthcare insurance companies have likely
reduced use of these tests by many urologists. The
cost to perform BTA TRAK testing and its limited
use in only bladder cancer subjects may also have
discouraged clinical laboratories from performing this
test, particularly in comparison to cytology, which is
routinely performed on multiple fluids from multiple
organ sites.
Suggested future trials for use of the BTA stat and
TRAK tests.
Although the value of this and other biomarkers in

detecting high risk (high grade) disease has been
suggested in numerous studies, their high rate of
false positive results and consequent low specificity
(through the influence of inflammatory conditions and
prior intravesical therapies either with chemotherapy
of BCG) somewhat limits their practical usefulness
in monitoring for disease persistence or recurrence.
In this regard, urinary cytology may be of value
because of its high specificity in the setting of high
grade disease.
At this time, we have not found evidence to endorse

use of either BTA test in screening for bladder
cancer. Use of BTA stat in subjects with a history of
urothelial cancer and a normal urinalysis could be
prospectively studied to determine if this combination
of tests (which might fail to detect small, low grade
recurrences) could safely reduce the frequency of
surveillance cystoscopies without compromising
cancer control. The suggestion by Blumenstein[76]
that serial measurements of BTA TRAK tests could
be useful in predicting recurrence in the individual
patient requires confirmation in a large, prospective,
multi-center trial. As multiple candidate antibodies
were obtained during the development of the BTA
tests, it is possible that an additional antibody that
does not cross-react with substances in the urine
of those with benign inflammatory conditions and/
Relatively few recent studies have been published

on the BTA tests, and most date from 1999 to 2001.
This may in part be explained by the decreasing
levels of specificity reported for the BTA stat test
between 1997 and 2001, and thus, lower enthusiasm
for their use. Additionally, the increase in regulatory
183
or hematuria could be isolated and used to further

refine BTA testing.
two other studies, the overall sensitivity was less than

50%.[71,72] For UBC-ELISA, different studies have
used different cut-off limits with a range between
0.16 g/L and 15 g/L. In one study, the cut-off limit
was called an Index value, which was calculated
by dividing the value during follow-up divided by the
value before the first transurethral resection.[74] In
some studies, the UBC values were normalized to
creatinine, whereas in other studies they were not
normalized; the manufacturer does not recommend
such normalization. For these reasons, a metaanalysis of UBC-ELISA results from different studies
cannot be and should not be performed.
3. UBC tests
UBC-Rapid and UBC-ELISA tests are immunological
assays available from IDL, IDL Biotech, (Borlange,
Sweden). Both assays detect cytokeratin 8 and 18
fragments in urine. Cytokeratins are intermediate
filament type cytoskeletal proteins specific for
epithelial cell origin. In human cells, a total of 20
cytokeratins have been identified and the expression
of cytokeratins 8, 18, 19, and 20 at the protein or
mRNA level has been evaluated as bladder cancer
markers.[77] Since cytokeratins are intracellular
proteins, the detection of these proteins in urine
is possible only when they are released in urine
following cell death. The UBC-Rapid assay is a
qualitative point-of-care assay wherein cytokeratin 8
and 18 fragments present in urine react with goldlabeled antibodies forming a complex. This complex
migrates to the reaction zone where it reacts with
a specific antibody to produce a dark line (positive
result). Any excess of gold-labeled antibodies
continues to migrate into the second capture zone to
form a second dark line (test control).[78]
4. Survivin
Survivin is an anti-apoptotic protein that is a
member of the inhibition of apoptosis protein (IAP)
gene family. Survivin levels are elevated in bladder
cancer, and therefore, survivin has been suggested
as a promising biomarker for bladder cancer.[80-82]
The commercially available bio-dot assay (Fujirebio
Diagnostics, Inc.) for Survivin is a technique that
is routinely performed in any research laboratory
to detect a variety of proteins. In Survivin bio-dot
assay (a dot-blot assay) urine samples are blotted
onto a nitrocellulose or ImmobilonP membrane,
along with recombinant survivin protein blotted
at various concentrations. Following sequential
incubations with a rabbit polyclonal anti-survivin
antibody and a horseradish peroxidise-conjugated
secondary antibody, the dots are visualized by
chemiluminenscence. The intensity of the specimens
and the standard-dots is measured by densitometry
and the amount of survivin in specimens is determined
from a standard curve. This assay however has not
been used recently and the current assays reported
in various articles are either quantitative reverse
transcription polymerase chain reaction (Q-PCR)
or qualitative reverse transcription PCR (RT-PCR)
assays. In the latter survivin mRNA expression is
detected by agarose gel electrophoresis, followed
by ethidium bromide staining.
UBC-ELISA is a solid-phase 2-step sandwich assay.

Specimens, standards, and controls are incubated
with microtiter wells coated with a mouse monoclonal
anti-UBC antibody. Following incubation, unbound
samples are washed off and the wells are incubated
with a horseradish peroxidase second antibody.
Following washing, the wells are developed using
tetramethylbenzidine substrate and the color
intensity is measured at 450 nm. Levels of UBC in
the urine specimens are calculated from a standard
curve. The manufacturer-suggested cutoff limit for
UBC-ELISA is 12 g/L. UBC-ELISA requires sending
samples to specialized laboratories, where trained
personnel can conduct the ELISA.
Pubmed search of the term UBC and bladder
cancer resulted in 73 hits. After examining the title
and the abstract of each article, nineteen articles
were found to be on UBC tests. In these nineteen
studies, 623 subjects have been assayed by the
UBC-Rapid test and 3,102 individuals have been
assayed by UBC-ELISA.
Pubmed search of the term Survivin and bladder

cancer resulted in 126 hits, which included 12
reviews. After examining the title and the abstract
of each article, ten articles were found to have
evaluated the efficacy of survivin as a urine marker
using the bio-dot, Q-PCR or RT-PCR assays. One
of these studies was a prospective cohort screening
study but it did not include any bladder cancer cases.
[83]
According to the STARD criteria the quality of many

articles was moderate to good with a few articles
displaying excellent quality of reporting. The majority
of studies provided LoE Grade III and IV evidence.
Three cohort studies were classified as LoE IIb
and one study by Hedelin et al was a prospective
screening study.[79]
According to the STARD criteria the quality of many

articles was moderate to good, with a few articles
displaying excellent quality of reporting. The majority
of studies provided LoE Grade III and IV evidence.
Three cohort studies were classified as LoE IIb and
one study by Davies et al had both a retrospective
blinded cohort and an prospective cohort.[83]
Meta-analysis of UBC-Rapid in three studies

reporting 623 patients (but UBC-Rapid assay was
performed on 515 patients) showed an overall
sensitivity of 59.3% with 86.1% specificity. However,
it is noteworthy that barring the initial study[78], in
184
Since the dot-blot assay detects survivin protein

and the PCR assays detect mRNA expression, the
results reported in studies using the dot blot assays
and PCR assays cannot be and should not be used
to perform a meta-analysis of the Survivin marker.
Furthermore, in each study the PCR primers used
for Q-PCR or RT-PCR were different, and therefore,
no two PCR studies are alike. In addition, Q-PCR is
quantitative and RT-PCR is qualitative, and therefore,
the results of these PCR studies also should not
be used to perform a meta-analysis. Davies et al
reported that urinary survivin levels decrease after
radical prostatectomy; this study also reported an
unusually high false positive rate, at 50%. Given
that each study has used different techniques to
assay survivin expression, this marker is not ready
for diagnosis and/or surveillance of bladder cancer
patients.
three articles which evaluated the efficacy of BLCA-4

by ELISA was good. Since these were case-control
studies, the evidence provided was classified as
Grade IV. Since these three studies either used
the same or similar patient populations [86,87] or
different assays, a meta-analysis cannot be and
should not be performed.
6. Cyfra 21-1
CYFRA21-1 is a Cytokeratin (CK) based assay.
CKs are intermediate filament proteins specific
for epithelial cells. A given epithelium can be
characterized by a chain-specific CK expression
pattern. In general, overexpression of a particular
chain-specific CK is associated with bladder.
CYFRA21-1 is an ELISA that detects fragments of
CK19 with the help of two monoclonal antibodies
(BM19.21 and KS19.1) in urine. Urinary stones,
infection and previous intravesical treatment with
BCG caused false positive results.[91] In 3 studies
from 2 institutes analyzing CYFRA21.1 in patients
under surveillance, sensitivity was 85% in 156 cancer
positive patients. Specificity was 82% in 323 patients
with no tumor at cystoscopy. Sanchez et al. [41,92]
reported similar results for NMP22 and CYFRA21-1
which is not what one would expect from a urine
marker with such a high potential. Moreover, the
number of studies with CYFRA21.1 is relatively low,
cutoff values have not yet been defined properly and
the additional value over NMP22 is not obvious.
5. BLCA-4
BLCA-4 assay is a sandwich ELISA commercially
available from Eichrom Technologies. BLCA-4 is a
nuclear matrix protein and has homology to ELK3
gene, a member of the ETS family of transcription
factors.[84] BLCA-4 is differentially up-regulated in
bladder cancer cells and tissues and was identified
by two dimensional gel electrophoresis of the nuclear
matrix components from normal and tumor tissues.
[85] The initial assay for BLCA-4 measurement in
urine was an indirect ELISA.[86,87] In those studies,
the cut-off limit to detect bladder cancer was set
at 13 g/mg protein. Later a sandwich ELISA that
utilizes 2 monoclonal antibodies was developed
and a cut of limit of absorbance set at 0.04 units at
630 nm was used for calculating the sensitivity and
specificity.[88] Therefore unlike the previous indirect
ELISA, neither urine precipitation nor normalization
of the BLCA-4 levels to urinary protein concentration
is carried out when using the sandwich ELISA for
BLCA-4 measurement.
The body of evidence for CYFRA21-1 is limited.

Only few reports on marker performance have
been published. Reporting quality is moderate to
poor, the level of evidence provided ranges from 4
to 3B, marker status according to the IBCN criteria
is considered to be level I. In summary, CK based
assays, particularly CYFRA21-1, are promising;
however, current information at this stage is
insufficient for any definite statements on the clinical
use in bladder cancer detection and follow-up.
Pubmed search for the term BLCA-4 and bladder

cancer resulted in 14 hits, which included six
reviews on bladder tumor markers. After examining
the title and the abstract of each article, three articles
were found to evaluate the efficacy of the BLCA-4
marker for the detection of bladder cancer. All of
these studies were case-control and from a single
institution [86-88]. Another study also found that
BLCA-4 levels were significantly elevated among
patients who have suffered from schistosomiasis
and have developed bladder abnormalities as
evaluated by ultrasound when compared to those
without detectable bladder abnormalities [89].
Recently, in suppressive subtractive hybridization
(SSH) and cDNA microarray, conducted on voided
urine specimens showed that BLCA-4 expression
has 90% sensitivity and 85% specificity to detect
bladder cancer.[90]
b) Cell-based assays
1. DD23
DD23 is a murine monoclonal antibody that was
evaluated in 1996 with quantitative fluorescence
image analysis in exfoliated urothelial cells.[93]
When used as a quantitative marker to detect
bladder cancer, sensitivity was 85% (41 cases) and
specificity in asymptomatic age-matched controls
was 95% (41 subjects).[93] The DD23 assay test
was subsequently developed using an avidinbiotin alkaline phosphatase immunocytochemical
procedure.[94,95] A single positive cell was
considered a positive urine test. In 308 cases
under surveillance for non-muscle invasive bladder
cancer, sensitivity was 81% and specificity 60%.
[94] In another study from the same authors in 81
patients analysing 151 samples sensitivity was 70%
and specificity 60%.[95] The authors concluded
According to the STARD criteria, the quality of the
185
that DD23 was able to enhance the sensitivity of

cytology, in particular for low grade tumors.[94,95]
The first results in patients under surveillance are
characterized by a low specificity which implies that
DD23 is not an ideal marker to lower the cystoscopy
frequency in these patients.
studies was classified as LoE 2b.

One remarkable feature of the uCytTM assay is
a reproducibly high sensitivity specifically in low
grade lesions. On average, detection rate for low
grade tumors was 75%, sensitivity for G2 and high
grade tumors was approximately 85% (Tab. 9).
Overall specificity was 75%. Discriminating between
diagnostic and follow-up trials, sensitivity appears to
be lower specifically in low and intermediate grade
lesions in diagnostic studies as compared to followup trials. However, this conclusion is based upon a
small number of cases.
The body of evidence for DD23 is limited. Only few

reports on marker performance have been published.
Reporting quality is moderate to poor, the level of
evidence provided ranges from 4 to 2B, marker
status according to the IBCN criteria is considered
to be level I. In summary, current data do not permit
definite conclusions on a clinical use of DD23.
The uCytTM assay has been reported to be confounded

by a variety of different urological conditions (BPE,
hematuria, urolithiasis or inflammatory conditions).
However, studies in hematuria populations suggest
that the impact of these conditions on test specificity
is limited.[17,97]
2. uCyt+TM /ImmunocytTM
The uCyt+TM assay, formerly ImmunocytTM, is a
commercially available immunocytological assay
based upon microscopical detection of tumorassociated cellular antigens in urine-derived
urothelial cells by immunofluorescence (Scimedx
Inc., Denville, NJ, USA). For tumor cell detection
an antibody cocktail containing fluorescein-labeled
monoclonal antibodies M344 and LDQ10 directed
against sulfated mucin glycoproteins and Texasred linked antibody 19A211 against glycosylated
forms of high molecular carcinoembryonic antigens
(hmCEA) is used. After staining the samples are
studied for immunofluorescence examining more
than 500 nuclei. In most studies specimens with
>1 green or red urothelial cell are considered
immunocytologically positive.
In general, the uCytTM assay appears more sensitive

but less specific as compared with urine cytology.
Side-by-side comparisons with other assays have
been reported. However, interpretation is difficult
since adequate experience of the investigators is a
prerequisite to obtain meaningful results for the uCytTM
assay but is not disclosed in these publications.
There was one prospective trial on marker-guided
follow-up providing information that may be
classified as LoE grade 1b [130,131] according to
the Oxford classification for diagnostic procedures.
[36] The very same trial was classified as a phase
III trial concerning the IBCN classification on marker
development,[12] while all remaining studies were
considered phase II.
The uCytTM test is a cell based assay. Assay costs

and requirements concerning lab equipment, time
for specimen processing and reading as well as
experience necessary for adequate interpretation
of the staining must be considered high. These
properties restrict the use of this test to more
specialized laboratories. Reproducibility, i.e. interobserver variability, is reasonable provided that
reading is performed by trained staff with high
experience.[96]
Mian and coworkers [130] reported on a prospective

marker-based follow-up trial in 942 patients: after
an initial 3 month follow-up including cystoscopy,
cytology and uCytTM test patients were divided into
3 categories according to their risk profile. Low risk
patients were followed using uCytTM and cytology;
cystoscopy was performed if one of the tests was
positive or after 1 year. Intermediate risk tumors
were followed by cytology, uCytTM and UrovysionTM.
Negative patients or patients with a positive p16/
CEP3 FISH test were further followed as low risk
patients, while patients with positive cytology, uCytTM
and CEP7/17 positive UrovysionTM test underwent
cystoscopy. High risk patients were followed by
cystoscopy every 3 months. The authors reported
that in low risk patients the number of cystoscopies
could be safely reduced and significant costs were
saved. [131] However, precise data required for
understanding of the authors conclusions are
lacking. In addition, analysis of the benefit or added
value in comparing fewer cystoscopies in low
risk disease patients, reliability of cytology in high
risk patients, and costs of uCyt and Urovysion are
required in considering the results in the context of
the type of cancer diathesis being monitored.
A literature search on the terms immunocytology,

immunocyt, uCyt, and bladder cancer yielded
49 hits. After removal of reviews, meta-analyses and
redundant trials, 20 studies assessable for criteria
concerning assay performance and comprising
more than 5,000 individuals were identified forming
the basis for this assessment of assay performance.
[17,97-129]
Accuracy of reporting according to the STARD
criteria [37,38] was mostly moderate or poor, only few
papers displaying good reporting quality. Specifically,
information on the training and experience of
investigators a parameter highly affecting uCytTM
results was not provided and information on the
blinding of investigators towards clinical observations
was rare. The majority of trials provided LoE Grade 3
and 4 evidence; however, information from 8 cohort
186
Table 9. Performance characteristics for uCyt+TM

low grade tumors acc. to the 2004 classification were included in the G1 category acc. to the 1973/1998 classification, high grade tumors acc. to the 2004 classification and
CIS were included in the G3 category;
inf. = informative; UUT = upper urinary tract tumors; # = no. of test (not of patients; therefore not considered for specificity calculation)
cohort study: consecutive patients, no healthy controls included; marker guided prospective trial: clinical decision making based upon marker result;
LoE: case control studies were considered LoE grade IV, studies including diagnostic and follow up patients were considered LoE grade IIIb, studies including clearly defined
patient cohorts, consecutive cases were considered LoE grade IIb, results from a marker guided prospective trial were considered LoE grade Ib;
* Marker status according to IBCN classification 2008; ** no. of requirements met acc. to STARD recommendations
Note: Li data for specificity but not considered for sensitivity analysis
Study type
%
Sensitivity
% Specificity
187
Author (year) Reference
S t u d y D i a g n o s i s / No. of Grade I/
design
Follow-up
patients LG
Grade II
Grade III/ HG/

CIS
Remarks
LoE
IBCN*/ STARD**
Status
Fradet (1997) 115
C a s e mixed
300
23/27
41/43
24/25
79/102
272/300 inf.
Mian (1999) 116
control
Cohort
mixed
264
85.2
21/25
93
22/25
96
28/29
77.3
135/170
249/264 inf.
3b
16/25
II
Olsson (2001) 117
Cohort
mixed
121
84
8/8
88
14/14
97
8/8
79.4
57/83
114/121 inf.
3b
18/25
II
Lodde (2001) 118
Cohort
diagnostic
37
100
1/3
100
6/6
100
4/5
68.7
20/21
2b
15/25
II
Mian (2003) 119
(UUT!)
Cohort
mixed
181
33
25/31
100
21/24
80
23/25
95
71/101
173/181 inf.
3b
15/25
II
Feil G (2003) 120
Cohort
mixed
92
80.6
1/7
87.5
4/9
92
6/10
71
73/87
113/121 inf.
3b
16/25
II
Piaton (2003) 121
Cohort
diagnostic
236
14.3
4/10
42.9
15/17
60
23/30
83.9
130/151
231/236 inf.
2b
14/25
II
Pfister (2003) 122

Piaton (2003) 121
Cohort
Follow up
458
40
13/21
88.2
16/24
76.7
30/39
83.3
286/342
451/458 inf.
2b
19/25
II
Pfister (2003) 122

Hautmann (2004) 123
C a s e diagnostic
94
61.9
3/4
66.7
7/15
76.9
9/11
81.9
48/64
PPV 54.5
19/25
II
75
46.7
81.8
75
NPV 81.3
control
14/25
Table 9. Performance characteristics for uCyt+TM (continued)

Toma (2004) 124
Cohort
mixed
126
6/7
17/23
10/12
60/82
Cohort
Follow-up
904
85.7
48/64
73.9
Tetu (2005) 125
83.3
34/40
72.5
453/734
870/904 inf.
85
62
PPV 26
75 (LMP+LG)
Messing (2005) 126
Cohort
Follow up
Mian (2005) 127
Cohort
mixed
Mian (2006) 96
(CIS!)
M a r k e r - Follow up
341
188
prospec.
Cohort
4/6
206/274
79
90
67
75
35/35
12/17
942
96/121
74/88
100
82/89
70.6
1152/1588#
79.3
84.1
92.1
72.5
41
8/13
11/11
10/16
Schmitz-Drger (2007/2008) Cohort

diagnostic
129,49
(microhematuria)
Soyuer (2009) 130
C a s e mixed
control
Horstmann (2009) 131
Cohort
Follow up
222
62
4/6
66
91
4/4
100
63
170/201
85
Schmitz-Drger (2008/2010) Cohort
103
24/31
77.4
20/32
62
7/8
21/23
91.3
20/28
72
11/13
85
132,49
Li (2010) 133
Follow-up
9/10
35
guided
Sullivan (2007) 128
22/28
diagnostic
90
221
( g r o s s
hematuria)
C a s e mixed
87
1881/1991 inf.
II
2b
13/25
II
17/25
2b
II
19/25
3b
II
1b
15/25
III
17/25
PPV 43
NPV 88
2b
II
2b
17/25
II
18/25
31/36
86.1
78/108
72
64/78
211/222 inf.
PPV 25.8
NPV 99
PPV 90
NPV 79.5
PPV 72
NPV 74
100/103 inf.
82
PPV 57.6
4
2b
2b
II
15/25
II
17/25
II
19/25
NPV 94.4
191
control
Total
44/53
82
NPV 93
327/341 inf.
PPV 72
NPV 74
3b
4899
334/446
74.9
76/93
85/98
81.6
86.7
290/344
84.3
387/462
83.8
2.068/2.745
75.3
II
15/25
4.992/5.242
95.2
3. Urovysion
and low grade lesions. [33] This is paralleled by a

high specificity of appr. 80%, however, again with a
broad range from 43 100% (Tab. 10).
The UroVysion multicolor fluorescence in situ

hybridization (FISH) test (Vysis, Abbott Laboratories,
Des Plaines, IL, USA) is a cell based assay containing
probes to the centromeres of chromosomes 3, 7, and
17 and to the 9p21 locus. The assay was approved
by the U.S. Food and Drug Administration (FDA) for
surveillance of patients with previous bladder cancer
but also for diagnosis in hematuria. A minimum
of 25 morphologically abnormal cells is viewed.
Detection of 4 or more cells that have gains in 2 or
more of chromosomes 3, 7, and 17 in the same cell
or at least 12 cells without a signal for P16 tumor
suppressor gene locus 9p21 are mostly classified as
a pathologic result. However, a variety of different
definitions and cut-off levels are being used.[33]
In general, the UroVysion assay appears more

sensitive (even in high grade disease) but less specific
as compared with urine cytology. A recent metaanalysis of FISH showed that overall performance of
FISH was better than that of cytology (area under the
curve: 87% vs 63%).[33] This difference, however,
was almost entirely attributable to the difference in
overall performance in diagnosing pTa patients; the
higher performance disappeared when pTa patients
were excluded from the analysis (area under the
curve: 94% vs 91%). Side-by-side comparisons
with other assays have been reported; however,
interpretation is difficult since adequate experience of
the investigators is prerequisite to obtain meaningful
results for the UroVysion assay but not disclosed in
these publications.
Assay costs and requirements concerning lab

equipment, time for specimen processing and
reading as well as experience necessary for adequate
interpretation of the staining must be considered
high. These properties restrict the use of this test to
more specialized laboratories but may also explain
the great ranges in sensitivity and specificity reported
for this assay. Reproducibility has been reported to
be good provided that the reading is performed by
experienced laboratory staff. The UroVysion assay
has been reported to be confounded by a variety
of different urological conditions (other tumors,
urolithiasis or inflammatory conditions). Another
limitation is that the rate of non-informative cases of
appr. 10% must be anticipated (Tab. 10).
Mian and coworkers [130] reported on a prospective

marker-based follow-up trial in 942 patients: after
an initial 3 month follow-up including cystoscopy,
cytology and uCytTM test patients were divided into 3
categories according to their risk profile. Intermediate
risk tumors were followed by cytology, uCytTM and
UrovysionTM. Negative patients or patients with a
positive p16/CEP3 FISH test were further followed
as low risk patients, while patients with positive
cytology, uCytTM and CEP7/17 positive UrovysionTM
test underwent cystoscopy. Information on the
results of the UroVysion data, however, has not been
published yet.
A literature search on the terms FISH, UroVysion,

and bladder cancer yielded 331 hits. After removal
of reviews, metaanalyses and redundant trials, 21
studies assessable for criteria concerning assay
performance and comprising 2852 individuals were
identified forming the basis for this assessment of
assay performance.[28,46-48,99,101-106,110,132141]
Although there is a relatively high rate of falsepositive results translating into a relatively low PPV
of the test, findings from several studies suggest that
the low specificity in follow-up trials may be explained
in part as an anticipatory positive result, in which a
premalignant change precedes the discovery of a
recurrent malignancy.[28,132,142] One study [132]
found that 89% of the patients that had a falsepositive test had a positive bladder biopsy within 12
months of the test, while another found that FISH
preceded tumor recurrence in 85% of patients.
[142] Nonetheless, the real role of an anticipatory
positive result is still unclear as many patients with
non-muscleinvasive bladder cancer eventually
experience disease recurrence.
Accuracy of reporting according to the STARD criteria

[37,38] was mostly moderate or poor, few mostly
more recent - papers displaying good reporting
quality. Specifically, information on the training and
experience of investigators a parameter highly
affecting UroVysion results is not provided and
information on the blinding of investigators towards
clinical observations is rare. Ten trials provided LoE
Grade 3 and 4 evidence; however, information from
11 cohort studies was classified as LoE 2b.
In considering the observations and conclusions

reported in these studies, it also becomes important
to consider the cost of these tests, especially if
sufficient information is otherwise available through
less costly standard examinations (cystoscopy,
cytology) or other approved biomarkers. Because
of the importance of determining any added
value in the use of a particular test, costs, difficulty
in performance, confusion of interpretation in a
particular clinical setting, and the emotional stress
encountered by both patient and physician in
The broad range for sensitivity and specificity of

UroVysion FISH reported in different papers is
notable and may not only reflect patient selection,
study design or tumor prevalence but also technical
aspects such as cut-off definitions and experience of
laboratory staff. However, in systematic reviews and
meta-analyses sensitivity has been found to exceed
70% and even approach 80% when omitting small
189
Table 10. Performance characteristics for UroVysionTM

low grade tumors acc. to the 2004 classification were included in the G1 category acc. to the 1973/1998 classification, high grade tumors acc. to the 2004 classification and
CIS were included in the G3 category;
inf. = informative; UUT = upper urinary tract tumors; # = no. of test (not of patients; therefore not considered for specificity calculation)
cohort study: consecutive patients, no healthy controls included;
LoE: case control studies were considered LoE grade IV, studies including diagnostic and follow up patients were considered LoE grade IIIb, studies including clearly defined
patient cohorts, consecutive cases were considered LoE grade IIb, results from marker guided prospective trials were considered LoE grade Ib;
* Marker status according to IBCN classification 2008; ** no. of requirements met acc. to STARD recommendations
Study type
%
Sensitivity
Author (year) Reference
Study design D i a g n o s i s / No. of Grade I/

Follow-up
patients LG
Bubendorf (2001) 46
Case control
Placer (2002)
15/21 (71) 25/29 (86)
190
8/15
438
(53.3)
(83.3)
12/22 (55) 7/9 (78)
Mian (2003) 119
C o h o r t / Follow-up
Case control
(separate)
Cohort
Mixed
57
7/8 (87)
Skacel (2003) 99
Cohort
111
19/23 (83) 28/35 (80)
Sarosdy (2002) 44
mixed
91
Grade II
86
134
Case control
mixed
% Specificity
diagnostic
10/12
19/19 (100)
Grade III/
HG/CIS
16/17 (94)
Remarks
26/27 (96.3)
19/19
29/34
(100)
17/18 (94)
(85.3)
75/114 (65.8)
260/275 (94.5)
controls
1/1 (100)
11/24 (46.4)
23/24 (96)
28/29 (97)
LoE
Concordance 4
voided/ barbotage 85%
4
2b
IBCN*/ STARD**
Status
II
15/25
II
18/25
II
19/25
5/57 n. inf.
3b
II
2b
16/25
II
Reflex
19/25
Veeramachaneni (2003) 135
(neg. Cytol)
n.r.
mixed
121
Krause (2004) 136
Case control
mixed
84
Varella-Garcia (2004) 137
Cohort
Follow-up
19
Pycha (2004) 138
Cohort
Follow-up
49
1/3
12/14
0/1
n.r.
36/121
(33)
10/14
(71)
2/2
(100)
(84)
10/11
(91)
3/3
(100)
(0)
44/44
(100)
1/2
(50)
1 2 / 3 5
(34.3)
25/35
(71)
12/12
(100)
12/14 (85.7)
4/106
4
2b
2b
II
15/25
II
17/25
II
17/25
II
17/25
Table 10. Performance characteristics for UroVysionTM (continued)

Kipp (2005) 139
Follow-up
37
Laudadio (2005) 140
Cohort
Prospec-tive
Cohort
mixed
300
14/25 (56)
12/25
(48)
18/19 (95)
Junker (2006) 141
Cohort
diagnostic
121
n.r.
(37)
n.r.
(91.7)
Bergmann (2007) 142
41
Moonen (2007) 143
C o h o r t Follow-up
retrospec-tive
Cohort
Follow-up
Yoder (2007) 27
C o h o r t Follow-up
249
n.r.
(65.4)
30/39#
(77)
6/27
7/19
(21.4)
(36.8)
6 / 1 9 15/20 (75)
(31.6)
(90.5)
105
Reflex
12/12
(100)
167/256 (65)
23/28
(82.6)
80/86#
(93)
12/18
37/41
(66.7)
(89.7)
3 8 / 4 2 1 4 7 / 1 6 8
(87.5)
(neg. Cytol)
191
Riesz (2007) 144
Case control
Frigerio (2007) 145
Case control mixed

retrospec-tive
Cohort
n.r.
Ferra (2009) 113
diagnostic
50
4/9 (44.4)
56
10/18 (55)
140
9/19
(100)
21/24
(87.5)
45/60
(47.4)
(75)
Reflex
16/16 (100)
1 4 / 1 4 11/11 (100)
After intravesi- 2b
cal prophylaxis
16/141 n. inf.
3b
20/141 n. inf.
2b
16/162 n. inf.
2b
10/113 n. inf.
2b
35/56
pat. 2b
(62.5%)
UC
neg.,
FISH
pos. develop
tumor
5/55 n. inf.
4
n.r.
27/68
4
10/161 n. inf.
3b
(39.7)
II
17/25
II
16/25
II
16/25
II
17/25
II
18/25
II
20/25
I
14/25
I
(14/25)
II
17/25
Susp./pos.
Caraway (2010) 146
Cytol.
C o h o r t mixed
Youssef (2010) 147
retrospec-tive
Cohort
F o l l o w - u p 142
600
n e g a t i v e
Mian (2010) 148
Cohort
170/263
(64.6)
540/632#
65/1006 n. inf.
3b
II
19/142 n. inf.
2b
16/25
II
1/7
3/10
(85.4)
100/106
(14.3)
(30)
(94.3)
cytology!
D i a g n o s t i c 55
24/24 (100)
34/38 (89.5)
18/25
1/68 n. inf.
(UUT)
Total
2b
II
17/25
2852
124/232
152/187
2 9 6 / 3 7 3 1 0 3 6 / 1 2 9 3 206/2263 (9.1)
(53.4)
(81.3)
(79.3)
(80.1)
assessing the reliability of a test result should all

be considered in the application of any marker for
routine clinical use.
smokers with >25 RBC/l on dipstick testing might

be a scenario to be considered.
A key problem of this concept is the high prevalence
of hematuria in the general population, along with
its low specificity, raising unnecessary anxiety in
screened subjects and requiring urologic workup in a high number of individuals without bladder
cancer. Hedelin and coworkers tried to correct for
this parameter by increasing the cut-off level for
hematuria but the efficacy of this measure need
to be confirmed. On the other hand, detection of
additional diseases requiring intervention is frequent
in hematuria patients and needs also to be taken into
account when considering this approach.[19,147]
2. Screening
Screening for bladder cancer, i.e. investigation of
an asymptomatic population, represents a specific
diagnostic challenge. While screening for breast
cancer and colorectal cancer has gained social
acceptance, bladder cancer screening has not been
considered a reasonable approach mainly due to
the low prevalence of the disease in an unselected
population. Nevertheless, few studies have been
published reporting on screening for bladder cancer
in populations with an increased risk of developing
bladder cancer.
b) Smoking:
Steiner et al. invited 183 subjects identified as
smoking 40+ pack-years to join a bladder cancer
screening program including urinary dipstick test,
urine cytology, NMP 22 BladderChek and UroVysion.
[14] 75 subjects with at least one positive test result
were offered urologic work-up. 5 urothelial cancers
(3 bladder tumors 1x pTa LG, 2x carcinoma in situ
and two upper urinary tract tumors (pTaG1 and
pTxN2G3)) were detected. While this study found a
higher incidence of cancer, another study of 1502
subjects with greater than 10 years of smoking
screened for bladder cancer using BladderChek
found only 2 cancers and one patient with atypia.
[15]
a) Hematuria:
Messing et al. invited 1575 men aged 50 years
and older to test their urine repetitively with a
chemical reagent strip for hemoglobin.[21,143-145]
Participants with positive test results underwent
standard urologic evaluation. Bladder cancer stages
and grades as well as the outcomes of men with
screen-detected tumors were compared with the
grades, stages, and outcomes of an age-matched
cohort of men with newly diagnosed BC who
were reported to the Wisconsin Tumor Registry in
1988 (n=509). Two hundred fifty-eight screening
participants (16.4%) were evaluated for hematuria,
and 21 participants (8.1%) were diagnosed with
bladder cancer. Proportions of low-grade (Grade 1
and 2) superficial (Stage Ta and T1) versus highgrade (Grade 3) superficial or invasive (Stage < T2)
cancers in screened men (52.4% vs. 47.7%) and
in men from the tumor registry (60.3% vs. 39.7%)
were similar (p=0.50). The proportion of high-grade
superficial or invasive bladder tumors were lower in
screened men (10%) than in unscreened men (60%;
p=0.002). At 14 years of follow-up, cancer specific
survival in screen-detected patients was 100%,
whereas 20.4% of unscreened men had died of
bladder cancer (p=0.02).
c) Professional exposure:
In a prospective study, Hemstreet et al. assessed
the risk for the development of bladder cancer in a
group of 1788 Chinese workers who were exposed
to benzidine using a biomarker profile over a period
of 6 years.[100] This biomarker profile included
the analysis of DNA ploidy, G-actin, and tumorassociated antigen P-300. Although the biomarker
profile placed only 21% of the exposed workers in a
high or moderate risk group, 87% of the 28 bladder
cancer cases in the entire cohort were found in this
group, and all of the tumors were clinically organconfined. Interestingly, a positive biomarker profile
occurred 15 to 33 months before the clinical detection
of bladder cancer.
Hedelin et al. investigated 2000 randomly selected

men, age 60-70 years, invited to participate in
a screening program based upon dipstick for
hematuria and the UBC assay.[146] Men with 5-10
red blood cells (RBC)/l and an International Prostate
Symptom Score (IPSS) of >10 and all men with >25
RBC/l and/or elevated UBC levels underwent both
white-light and fluorescence cystoscopy. In 14% of
the responding 1096 men microhematuria with 5-10
RBC/l was observed. One tumor was detected in
the 62 men with 5-10 RBC/l and an IPSS of >10.
Among the 10% of men (n=112) with >25 RBC/l,
four bladder tumors were detected. Another two
tumors were detected in men without hematuria but
with a positive UBC test. The authors concluded
that hematuria-based screening among older male
Giberti et al. investigated 171 workers at an Italian

Coke plant with long-term exposure to PAHs using
dip stick testing for hematuria, cytology and the uCyt+
assay.[148] Although uCyt+ was positive in 12% of
the screened subjects subsequent urological work-up
yielded no urothelial cancers in this cohort. While the
relatively young age of the screened subjects (mean
53 years) may have affected disease prevalence,
a low cut-off value for the uCyt+ assay could be
responsible for the low specificity observed.
Several other studies investigating professionally
exposed risk populations (Fire fighters, chemical
192
workers, workers in alloy smelters [147,149,150]

using NMP22, uCyt+ or a mix of different molecular
markers, demonstrated good sensitivity and
specificity for the markers. However, due to the low
prevalence of disease (< 1%) in the cohorts studied,
the positive predictive value of the assays remains
unsatisfactory.
Several investigators have demonstrated a

correlation between sensitivity and specificity for a
variety of biomarkers. As for PSA in prostate cancer
for example, an increased cut-off level will both,
increase specificity and decrease sensitivity (and
vice versa for a decreased cut-off). Since different
threshold definitions are in use for several assays
(e.g. UBC, NMP22, UroVysion), the choice of a cutoff level will automatically have significant impact on
the performance of a given assay (see above).
Davies et al. targeted another risk group screening

457 patients with spinal cord injury for 5 years using
urine cytology, the BTA stat test and the survivin
assay.[83] A total of 1075 urine specimens from
457 patients were analyzed. Of the 1073 BTA stat
tests, 119 showed positive reactions (specificity
88.9%) and 954 were negative. In the survivin
assays, 47 samples had a score of one, 38 a score
of two, and 9 a score of three (specificity 91.2%). No
cytology specimens were noted to have malignant
cells (specificity 100%). None of the three patients
diagnosed with bladder cancer had a positive test
result.
While investigator bias may not play a role in pointof-care assays, this is of particular relevance for cellbased tests (e.g. UroVysion or uCyt+). The precision
of these tests is clearly correlated with training status
and experience of the laboratory staff.[96] Since the
experience of investigators is not reported in the
literature despite specific recommendations to do
this (STARD), it is impossible to estimate the impact
of investigator bias in the comparison of different
assays.
In summary, despite a limited number of studies

there is evidence that screening for bladder cancer
in general is feasible and screened subjects may
benefit from early cancer detection. However, cost
calculations based upon the results from published
trials suggest costs between $ 25.000 50.000/
cancer detected.[6] This finding clearly points at
a careful selection of high risk populations and
demonstrates the necessity of an effective design of
future protocols.
Furthermore, it is the scientific norm to report

innovations, promising results, and initially positive
observations, all of which contribute to an enthusiasm
for an early clinical application. However, such initial
reports may be limited in their study design, length of
follow-up, and numbers needed to provide statistical
power in order to validate results. These together
with misapplication of observations to different
clinical scenarios may account for the commonly
observed failure to validate initially promising albeit
preliminary reports.
3. Problems of marker comparison
With decreasing financial resources of health care

systems worldwide cost-benefit considerations
have gained considerable importance. This aspect,
however, has rarely been addressed and included in
a side-by-side comparison of different assays.
There is a variety of reasons for why a comparison

of markers, aiming at the identification of the best
marker, is of limited value:
Different performance profile
Although these problems and limitations discussed

above currently prevent a sufficient comparison
between different markers and urine cytology, it
is evident that there is an urgent need to identify
the optimal diagnostic armamentarium for the
different clinical scenarios. Therefore, well designed
prospective studies are needed to confirm the
significance of urine cytology and identify an potential
added value of the markers.
Threshold definitions
Technical aspects
Cost-benefit considerations
This assessment has demonstrated that markers
have different performance profiles. While some
of these markers may have a similar sensitivity
through all tumor grades, others may have a higher
sensitivity in high grade tumors. Similarly, specificity
particularly in urine-based markers and, to a lesser
extent of cell-based assays, is highly dependent upon
the composition of the tumor-negative cohort. While
these markers in general may have good specificity
in a healthy control population, they uniformly have
a lower specificity in cohorts comprising patients
suffering from non cancer-related urological diseases
(e.g. inflammatory conditions, stone disease,
hematuria, or BPE). As a consequence, a different
composition of a study population will directly affect
the results of a given study.
4. Recommendations
As with other previous reviews and meta-analyses,
this assessment confirms the overall superiority
of molecular markers over conventional urine
cytology concerning test sensitivity. This improved
sensitivity is more pronounced in low grade tumors
but is also seen in high grade bladder cancer. In
contrast, urine cytology is clearly superior to that
of the molecular markers with regard to specificity,
and its role in bladder cancer diagnosis needs to
be considered in this context.
193
With the exception of NMP22, only limited additional

information has been gained for other urine-based
markers (e.g. BARD stat and TRAK, Cyfra21-1,
UBC) through the last decade. In contrast, many
reports concerning cell-based markers (UroVysion,
uCyt+) were published only after 2001. Despite
numerous publications, progress with regard
to an introduction of these markers into clinical
decision-making is limited. The first prospective
trials on a marker-guided follow-up in bladder
cancer patients are currently underway. In addition,
several screening studies could demonstrate the
feasibility of a use of molecular markers for this
indication. Results of these and other such studies
will determine their usefulness and role in clinical
practice.
Furthermore, reimbursement policy in different

countries will have additional influence on the use of
molecular markers.
In order to obtain a better idea on the performance
of a given assay, marker assessment needs to
follow a standardized and transparent evaluation
process. It remains one of the great challenges in
marker development to define a standard procedure
and, finally, introduce this standard into the scientific
community.
6. Problems in the assessment of

marker trials
The question of marker performance has been
addressed within a number of meta-analyses.
[6,33,53,151]. However, the problems of these
analyses are significant for several reasons and,
in consequence, conclusions derived from these
analyses are heavily biased. One of the key problems
is the highly differing quality of the trials, which hardly
permits common analysis. Furthermore, different
study design, patient selection, tumor prevalence,
distribution of tumor grade and stage, study
endpoints and several other parameters will further
confound the results of any combined analysis.
5. Marker performance
There is no marker that meets all of the postulates
of a so called ideal marker,[9] but markers have
been described with a high overall sensitivity, a
high sensitivity for low or high grade disease, high
specificity, reasonable expense and point-of-care
capabilities. However, it is obvious that urologists
will have to select markers that meet specific clinical
needs. In a screening scenario high specificity of a
marker is mandatory since otherwise the number of
patients undergoing a marker-initiated evaluation
will be inappropriately high. This contrasts to the
requirements in a follow-up setting, when sensitivity
of an assay is of key importance in order not to
miss bladder cancer persistence or recurrence. In
addition, the diagnostic strategy might also affect
selection of a marker: several investigators may
favor markers with good performance in low grade
disease since appr. 70% of all bladder tumors are
low grade. Other urologists may prefer markers with
a high sensitivity in high grade disease, arguing that it
may be appropriate to delay detection of a low grade
tumor that does not pose life-threatening risk but that
high grade tumors should be reliably detected.
In order to standardize the evaluation of molecular

markers several tools for assessment of diagnostic
markers were used in this analysis. These tools
included for the analysis a questionnaire for the
quality of reporting (STARD), the definition of the
level of evidence according to the Oxford criteria,
and the classification of the marker status.[12,3638]
Concerning the reporting quality, no single study
included all 25 STARD items.[37,38] Certain items,
such as use of Mesh headings to identify sensitivity,
specificity or diagnostic accuracy, or reporting
of adverse events associated with testing were
uniformly missing, although these items may have
less importance to data quality than others. While
the majority of studies included some population
demographics, race, for example, was recorded in
only one of the sampled sources. All authors provided
information on test performance techniques, and
most described collection and handling of specimens;
however, information on the reproducibility of test
results, the training and qualifications of those
performing the assays, whether testers were blinded
from other results, and handling of indeterminate,
out-lying, or missing results were often lacking or
ambiguous.[70] Many studies stratified subjects
according to grade [WHO 1998 and 2004] and
stage of tumors [TMN 1997] and provided subset
analyses of sensitivity and specificity of the tests
for these subsets. Due to mostly low numbers of
subjects in some groups, the validity of drawing
conclusions from this data is uncertain. Authors
are generally to be commended for a reasonable
Importantly, there are additional obstacles that make

it difficult to identify the most accurate test system in
any clinical situation. This finding impedes a simple
comparison of tests based upon performance data
reported in case-control studies. Several parameters
have been shown to affect the performance of a
given test.
Patient selection
Prevalence of the disease
Study design
Study endpoints
Sample size
Technique/standardization/Cut-off
Experience
194
description of statistical methods used, including

confidence intervals on reported data. Clearly,
implementation of standardized reporting of studies
that adhere to consistent guidelines such as STARD
recommendations would improve our understanding
of tumor markers.
Data obtained in high-risk groups undergoing urinary

dipstick screening for bladder cancer suggest that
the bladder tumors discovered when evaluating all
patients with asymptomatic microscopic hematuria
may be more amenable to curative treatment than
those normally encountered, thereby reducing
morbidity and mortality associated with bladder
cancer in these patients. [20,21,143-145] Since
improved survival of screened patients was not
demonstrated in a randomized fashion but only
in comparison with a cancer register, this study
presents interesting information; however, it cannot
serve to provide a final decision on the benefit of
hematuria screening.
It can be argued, that STARD guidelines are

yet imperfect. According to experiences made
throughout this assessment, some items are
differently interpreted by observers and opinions on
the necessity of including all items, and the relative
importance of certain items, was not universally
agreed upon. However, currently STARD provides
us with a starting point for collecting comparable
data among studies.
Meanwhile, further studies targeting risk populations

such as smokers and professionally exposed
individuals could demonstrate that screening for
bladder cancer using molecular markers is feasible.
However, despite selecting risk populations in most
of these trials tumor prevalence was still too low
to make bladder cancer screening a cost-effective
procedure.
Recently, a new definition for diagnostic trials was

developed for the Oxford Classification on the Levels
of Evidence.[36] This classification has been used in
this assessment but appears more difficult to apply
if compared to the recommendations for therapeutic
trials. This was partly due to deficits in reporting.
But for some studies, application of certain criteria
was not possible. Nevertheless, the new Oxford
classification on diagnostic trials is promising but
may need minor modification.
Since identification of high risk populations suited

for a screening scenario remains the key problem
for bladder cancer screening the development and
validation of respective risk calculators (risk-adapted
screening) might be an option for the future.
For definition of the stage of implementing new

markers into clinical decision making the IBCN
classification has been developed and was used
in this assessment.[12] However, using this
classification it became evident that more precise
definitions on the requirements for allocating a given
study to a certain stage are mandatory and that this
classification requires revision.
Question: (How) can molecular markers support

screening of patients at risk of having or developing
bladder cancer?
Statement:
Feasibility of bladder cancer screening has been
demonstrated in several prospective trials. The results
from one study using dip-stick testing for hematuria
suggests a survival benefit of individuals undergoing
hematuria screening. Because of weak controls in this
report validation of the results and improved definition
of risk populations suited for screening is required.
7. Key questions:
a) (How) can molecular markers support
screening of patients at risk of having or
developing bladder cancer?
Considering bladder cancer screening the key
question to be answered is if early detection of
bladder cancer may have any impact on cure rates
and, subsequently, on patient survival. Through the
last decades a growing body of evidence has been
accumulated suggesting that early detection and
treatment of bladder cancer may indeed reduce
cancer specific mortality [127-129] thus providing
arguments for this procedure.
References: [14,21,143,144]
Recommendation:
Bladder cancer screening using urine for testing is
promising but cannot be recommended at present.
LoE: 1b
Grade: B
Agreement: 92%
However, due to the low prevalence of bladder

cancer in the general population (0.001%) and in
people above the age of 50 (0.67% - 1.13%), mass
screening for bladder cancer, with the possibility
of detecting a significant number of false positives
requiring an unnecessary work-up, would certainly
not be cost-effective. [6] As a consequence of these
considerations those few trials addressing screening
for bladder cancer targeted high risk populations.
b) (How) can molecular markers be used in

reflex testing for bladder cancer?
Reflex testing e.g. in the follow-up of patients with
bladder cancer with atypical cytology finding is a
logical approach. However, experience with this
procedure at present is very limited and does not
permit a definite statement. In consequence, this
strategy should be exploited in more detail within
prospective controlled studies.
195
urine cytology with regard to test sensitivity even

in high grade bladder cancer. It remains unclear if
these results are based upon a systematic deficiency
of urine cytology or if performance quality has
decreased in the last decades due to changes in the
training of pathologists.
Question: (How) can molecular markers be used in

Statement:
At present experience with reflex testing is very limited
(mostly restricted to FISH technique) and therefore
does not permit a definite statement. Reflex testing
should be explored in more detail within prospective
controlled studies
The lower specificity of molecular markers as

compared to urine cytology appears not worrisome
in this population since in the surveillance of patients
with high grade tumors sensitivity appears to be
of the utmost importance. In addition, it may be
questioned if at least a part of false positive results
may be explained as an anticipatory positive finding,
predicting tumor recurrence.[28,132]
References: [28,132,142,152]
Recommendation:
Reflex testing is considered experimental at present
and should not be used within a clinical setting.
LoE: 2b
Grade: B
Agreement: 92%
However, prospective studies demonstrating an

added value of molecular markers in the follow-up of
patients with high grade bladder cancer are missing,
thus not supporting their use in clinical practice.
c) (How) can molecular markers support

follow-up of patients with superficial low risk
bladder cancer?

follow-up of patients with superficial high risk bladder
cancer?
Statement:
Molecular markers detect high grade bladder cancer
with high sensitivity. At this stage it remains unclear
how molecular markers can support surveillance of
patients with high grade bladder cancer.
Recommendation:
A use of molecular markers in surveillance of
patients with high grade bladder cancer cannot be
recommended.
LoE: 2b
Grade: B
Agreement: 92%
There is clear evidence that modern molecular

markers outperform urine cytology concerning
sensitivity in the diagnosis of patients with noninvasive low grade tumors. In addition, due to the
low risk of tumor progression a marker-guided
surveillance could significantly reduce the number
of control cystoscopies without placing patients
at significant risk. However, until today only one
prospective trial using a marker-guided surveillance
protocol has been performed. [130] Information from
this study, however, is still preliminary and does not
yet permit recommendation of this procedure for
clinical routine use.
follow-up of patients with superficial low risk bladder
cancer?
Statement:
Marker-guided follow-up of patients with non-muscleinvasive low risk tumors appears feasible. However,
studies proving the efficacy of this concept and
demonstrating an added value for patients or the
health system are lacking.
Recommendation:
Marker-guided follow-up of patients with superficial
low grade bladder cancer appears attractive; however,
based upon current levels of evidence this procedure
cannot be recommended at present
LoE: 1b
Grade: B
Agreement: 92%
8. Outlook
Although molecular bladder cancer assays have
been shown to have superior sensitivity as compared
to urine cytology, none of them has been included in
clinical guidelines. The key reason for this situation is
that none of the assays have been incorporated into
clinical decision making so far. In consequence, an
added value of molecular markers for the diagnosis
of urothelial tumors has not yet been identified.
However, the current data suggest that some of
these markers do have the potential to play a role
in screening and surveillance of bladder cancer in
the future. Current screening protocols however are
hampered by a low disease prevalence thus inhibiting
an acceptable cost/benefit ratio. The introduction of
risk calculators into screening protocols could make
up for the deficits of a mass screening approach.
d) (How) can molecular markers support

follow-up of patients with superficial high risk
bladder cancer?
Furthermore, the introduction of molecular markers

in the follow-up of patients with low risk bladder
cancer might also represent a scenario that should
The assessment of marker performance suggests

that several molecular markers may outperform
196
be further investigated. Preliminary reports suggest

that this procedure is feasible. However, detailed
information for a definite judgment is lacking.

follow-up of patients with superficial low risk bladder
cancer?
Statement:
Marker-guided follow-up of patients with non-muscleinvasive low risk tumors appears feasible. However,
studies proving the efficacy of this concept and
demonstrating an added value for patients or the
health system are lacking.
Recommendation:
Marker-guided follow-up of patients with superficial
low grade bladder cancer appears attractive; however,
based upon current levels of evidence this procedure
The scientific community is urged to develop

protocols and conduct prospective trials to provide
the basis for an integration of molecular markers into
clinical decision making in the future.[7,84,153]
IV. Appendix
Questions
cannot be recommended at present

LoE: 1b
Grade: B
Agreement: 92%
screening of patients at risk of having or developing

bladder cancer?
Statement:
Feasibility of bladder cancer screening has been
demonstrated in several prospective trials. The results
from one study using dip-stick testing for hematuria
suggests a survival benefit of individuals undergoing
hematuria screening. Because of weak controls in this
report validation of the results and improved definition
of risk populations suited for screening is required.

follow-up of patients with superficial high risk bladder
cancer?
Statement:
Molecular markers detect high grade bladder cancer
with high sensitivity. At this stage it remains unclear
how molecular markers can support surveillance of
patients with high grade bladder cancer.
Recommendation:
A use of molecular markers in surveillance of
patients with high grade bladder cancer cannot be
recommended.
LoE: 2b
Grade: B
Agreement: 92%
References: [14,15,21,143,144]
Recommendation:
Bladder cancer screening using urine for testing is
promising but cannot be recommended at present.
LoE: 1b
Grade: B
Agreement: 92%
Question: (How) can molecular markers be used in

Statement:
At present experience with reflex testing is very limited
(mostly restricted to FISH technique) and therefore
does not permit a definite statement. Reflex testing
should be explored in more detail within prospective
controlled studies
References: [28,132,142,152]
Recommendation:
Reflex testing is considered experimental at present
and should not be used within a clinical setting.
LoE: 2b
Grade: B
Agreement: 92%
197
Levels of Evidence[34]
Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001)
Level Prognosis
1a
1b
Systematic review (SR) (with

homogeneity*) of inception cohort
studies; CDR validated in
different populations
Individual inception cohort study
with > 80% follow-up; CDR
validated in a single population
1c
All or none case-series
2a
2c
3a
SR (with homogeneity*) of either

retrospective cohort studies or
untreated control groups in RCTs
Retrospective cohort study or
follow-up of untreated control
patients in an RCT; Derivation
of CDR or validated on splitsample only
Outcomes Research
-
3b
Case-series (and poor quality

prognostic cohort studies***)
Expert opinion without explicit
critical appraisal, or based on
physiology, bench research or
first principles
2b
Diagnosis
Economic and decision

analyses
SR (with homogeneity*) of Level SR (with homogeneity*) of Level 1
1 diagnostic studies; CDR with economic studies
1b studies from different clinical
centres
Validating** cohort study with Analysis based on clinically
good reference standards; sensible costs or alternatives;
or CDR tested within one clinical systematic review(s) of the
centre
evidence; and including multi-way
sensitivity analyses
Absolute SpPins and SnNouts Absolute better-value or worsevalue analyses
SR (with homogeneity*) of Level SR (with homogeneity*) of Level
>2 diagnostic studies
>2 economic studies
Exploratory** cohort study with
good reference standards;
CDR after derivation, or
validated only on split-sample
or databases
SR (with homogeneity*) of 3b and
better studies
Non-consecutive study; or without
consistently applied reference
standards
Case-control study, poor or nonindependent reference standard

critical appraisal, or based on
physiology, bench research or
first principles
Analysis based on clinically

sensible costs or alternatives;
limited review(s) of the evidence,
or single studies; and including
multi-way sensitivity analyses
Audit or outcomes research
SR (with homogeneity*) of 3b and
better studies
Analysis
based
on
limited
alternatives or costs, poor quality
estimates of data, but including
sensitivity analyses incorporating
clinically sensible variations.
Analysis with no sensitivity
analysis
critical appraisal, or based
on economic theory or first
principles
Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin
Dawes since November 1998. Updated by Jeremy Howick March 2009.
Notes
worrisome, and not all worrisome heterogeneity

need be statistically significant. As noted above,
studies displaying worrisome heterogeneity should
be tagged with a - at the end of their designated
level.
Users can add a minus-sign - to denote the level of

that fails to provide a conclusive answer because:
EITHER a single result with a wide Confidence
Interval
Clinical Decision Rule. (These are algorithms

or scoring systems that lead to a prognostic
estimation or a diagnostic category.)
OR a Systematic Review with troublesome

heterogeneity.
See note above for advice on how to understand,

rate and use trials or other studies with wide
confidence intervals.
Such evidence is inconclusive, and therefore can

only generate Grade D recommendations.
* By homogeneity we mean a systematic review
that is free of worrisome variations (heterogeneity)
in the directions and degrees of results between
individual studies. Not all systematic reviews with
statistically significant heterogeneity need be
Met when all patients died before the Rx became

available, but some now survive on it; or when some
patients died before the Rx became available, but
none now die on it.
198
By poor quality cohort study we mean one that

failed to clearly define comparison groups and/
or failed to measure exposures and outcomes in
the same (preferably blinded), objective way in
both exposed and non-exposed individuals and/
or failed to identify or appropriately control known
confounders and/or failed to carry out a sufficiently
long and complete follow-up of patients. By poor
quality case-control study we mean one that
failed to clearly define comparison groups and/
or failed to measure exposures and outcomes in
the same (preferably blinded), objective way in
both cases and controls and/or failed to identify
or appropriately control known confounders.
applied to all patients. Poor reference standards

are haphazardly applied, but still independent
of the test. Use of a non-independent reference
standard (where the test is included in the
reference, or where the testing affects the
reference) implies a level 4 study.
B
etter-value treatments are clearly as good
but cheaper, or better at the same or reduced
cost. Worse-value treatments are as good and
more expensive, or worse and the equally or
more expensive.
** V
alidating studies test the quality of a specific
diagnostic test, based on prior evidence. An
exploratory study collects information and trawls
the data (e.g. using a regression analysis) to find
which factors are significant.
Split-sample validation is achieved by collecting

all the information in a single tranche, then
artificially dividing this into derivation and
validation samples.
*** B
y poor quality prognostic cohort study we mean
one in which sampling was biased in favour of
patients who already had the target outcome, or
the measurement of outcomes was accomplished
in <80% of study patients, or outcomes were
determined in an unblinded, non-objective way, or
there was no correction for confounding factors.
A
n Absolute SpPin is a diagnostic finding
whose Specificity is so high that a Positive result
rules-in the diagnosis. An Absolute SnNout is
a diagnostic finding whose Sensitivity is so high
that a Negative result rules-out the diagnosis.
Good, better, bad and worse refer to the
comparisons between treatments in terms of
their clinical risks and benefits.
**** G
ood follow-up in a differential diagnosis study
is >80%, with adequate time for alternative
diagnoses to emerge (for example 1-6 months
acute, 1 - 5 years chronic)
G
ood reference standards are independent of
the test, and applied blindly or objectively to
199
STARD checklist for reporting of studies of diagnostic accuracy

(version January 2003)
Section and Topic
Item
On
#
page #
TITLE/ABSTRACT/
1 Identify the article as a study of diagnostic accuracy (recommend MeSH
KEYWORDS
heading <sensitivity and specificity>).
INTRODUCTION
2 State the research questions or study aims, such as estimating diagnostic
accuracy or comparing accuracy between tests or across participant groups.
METHODS
Participants
3 The study population: The inclusion and exclusion criteria, setting and
locations where data were collected.
4 Participant recruitment: Was recruitment based on presenting symptoms,
results from previous tests, or the fact that the participants had received the
index tests or the reference standard?
5 Participant sampling: Was the study population a consecutive series of
participants defined by the selection criteria in item 3 and 4? If not, specify
how participants were further selected.
6 Data collection: Was data collection planned before the index test and reference
standard were performed (prospective study) or after (retrospective study)?
Test methods
7 The reference standard and its rationale.
8 Technical specifications of material and methods involved including how and
when measurements were taken, and/or cite references for index tests and
reference standard.
9 Definition of and rationale for the units, cut-offs and/or categories of the
results of the index tests and the reference standard.
10 The number, training and expertise of the persons executing and reading the
index tests and the reference standard.
11 Whether or not the readers of the index tests and reference standard were
blind (masked) to the results of the other test and describe any other clinical
information available to the readers.
Statistical methods 12 Methods for calculating or comparing measures of diagnostic accuracy, and
the statistical methods used to quantify uncertainty (e.g. 95% confidence
intervals).
13 Methods for calculating test reproducibility, if done.
RESULTS
Participants
14 When study was performed, including beginning and end dates of recruitment.
15 Clinical and demographic characteristics of the study population (at least
information on age, gender, spectrum of presenting symptoms).
16 The number of participants satisfying the criteria for inclusion who did or
did not undergo the index tests and/or the reference standard; describe
why participants failed to undergo either test (a flow diagram is strongly
recommended).
Test results
17 Time-interval between the index tests and the reference standard, and any
treatment administered in between.
18 Distribution of severity of disease (define criteria) in those with the target
condition; other diagnoses in participants without the target condition.
19 A cross tabulation of the results of the index tests (including indeterminate
and missing results) by the results of the reference standard; for continuous
results, the distribution of the test results by the results of the reference
standard.
20 Any adverse events from performing the index tests or the reference standard.
Estimates
21 Estimates of diagnostic accuracy and measures of statistical uncertainty
(e.g. 95% confidence intervals).
22 How indeterminate results, missing data and outliers of the index tests were
handled.
23 Estimates of variability of diagnostic accuracy between subgroups of
participants, readers or centers, if done.
24 Estimates of test reproducibility, if done.
DISCUSSION
25 Discuss the clinical applicability of the study findings.
200
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205
206
Committee 3 B

Cancer Staging and Prognosis
Chairs:
Pierre I. Karakiewicz
Members:
Michael J. Droller, Yves Fradet, George P. Hemstreet,
MLiss Hudson, Yair Lotan, Peruno Malmstrom,
Michael J. Marberger, Osamu Ogawa, Bernd J. Schmitz-Drger,
Christian Seitz, Maxine Sun, Bas W. Van Rhijn, Vinata B. Lokeshwar
Address all correspondence to:

S. F. SHARIAT
Weill Medical College of Cornell University
New York Presbyterian Hospital,
525 East 68th Street
New York, NY 10021
Email: sfshariat@gmail.com
Telephone: 469 363 8500
207
Table of Contents
I. Introduction
IV. Promising Blood-based

Prognostic Molecular
Markers
II. Evidence Acquisition
1. P
lasma-insulin Growth Factor
Binding Protein (IGFBP)-3
III. Evidence Synthesis
2. T
ransforming Growth Factor
(TGF)-1
1. Challenges and Statistical

Considerations for Bladder
Cancer Prognostic Molecular
Marker Research
3. Matrix Metalloproteinase (MMP)

4. Urokinase Plasminogen Activation
(uPA)
2. Promising Tissue-based Prognostic

Molecular Markers
5. Interleukin-6 (IL-6) and IL-6 Soluble

Receptor (IL-6sR)
3. Apoptosis
6. Soluble E-cadherin (sE-Cadherin)
4. Angiogenesis
V. High-throughput Tumor
Profiling
5. Signaling Proteins
6. Hormone Receptors
7. Combination of Tissue-Based
Molecular Markers
208

Cancer Staging and Prognosis
Shahrokh F. Shariat
Michael J. Droller, Yves Fradet, George P. Hemstreet,
MLiss Hudson, Pierre I. Karakiewicz, Yair Lotan,
Peruno Malmstrom, Michael J. Marberger, Osamu Ogawa,
Bernd J. Schmitz-Drger, Christian Seitz, Maxine Sun,
Bas W. Van Rhijn, Vinata B. Lokeshwar
gov). A MEDLINE search was performed with
emphasis on urothelial malignancies and prognostic
markers using combinations of the following terms:
urinary tract cancer, bladder carcinomas, urothelial
carcinomas,
detection,
bladder,
recurrence,
and prognostic markers. Basically, articles were
considered between 2000 and 2011. No evidence
level 1 information from prospective randomized
trials was available. Articles were selected for
this review with regards to the following criteria:
evolution of concepts, development and refinement
of techniques, quality of the study, and relevance.
Older studies were included selectively if historically
relevant or in case of scanty data in more recent
publications.
I. Introduction
Intensive molecular research over the last decade
has provided great insight to the biology of bladder
cancer and is beginning to shape clinical practice.
Technologies such as high-throughput transcript
profiling, microarrays, and proteomics have facilitated
the identification and understanding of molecular
pathways and molecules that are active in bladder
cancer. Molecular profiling of bladder cancer is
beginning to offer additional means to predict tumor
behavior and thereby potentially improve treatment
outcomes. In addition, new markers can conceivably
serve as targets for novel therapeutic approaches
and allow improved selection of therapeutic options.
III. Evidence Synthesis
It is now clear that different forms of bladder cancer

develop along independent but possibly interrelated
molecular pathways. Each of the steps associated
with the development of malignancy, including
tumor initiation, progression, and metastasis involve
multiple genetic and epigenetic events indicating
that few tumors are genetically and/or phenotypically
identical. This is reflected by the heterogeneity in
clinical and histologic presentation, intrinsic biologic
potential of the various diatheses, and treatment
outcomes. Current methods of risk stratification do not
fully predict these distinctions. In this review, we will
discuss the challenges and statistical considerations
of molecular marker research and than explore
recent advances regarding the biology and potential
clinical utility and consequent integration of molecular
markers for bladder cancer staging, prognostication,
and therapeutic development.
1. C
hallenges and Statistical
Considerations for Bladder
Cancer Prognostic Molecular
Marker Research
Despite a plethora of molecular markers reported to
be clinically promising, there is currently no single
prognostic molecular marker in routine clinical use.
Challenges for the application of molecular markers
in cancer care include analytical and regulatory
barriers.[3-8] In addition, the absent use of bladder
cancer molecular markers in clinical practice is a
result of poor application of statistics and study
design by which such markers might have been
validated. Molecular marker research is usually
done in the context of standard clinical care, rather
than clinical trials. This has been largely guided by
intuition and anecdotal experience rather that wellstructured analyses. As a result, most molecular
marker findings are not reproducible. Furthermore,
most molecular markers that appear biomedically
II. Evidence Acquisition

The literature was reviewed using the National
Library of Medicine database (http://www.pubmed.
209
prominent journals (Figure 2).[19-21] The goal

of these guidelines is to encourage transparent
and complete reporting and to help readers judge
the data and understand the context in which the
conclusions apply. Indeed, it provides a detailed
description as to the minimum amount of information
that should be given in the reporting of results from
molecular marker studies. The REMARK lists 20
items that investigators should attempt to report in
any molecular marker study. Another tool aimed
at standardizing the quality of molecular marker
research is the Tumor Marker Utility Grading System
(Figure 3).[22] This is a scale of levels of evidence,
designed to help place molecular marker studies into
a context of validity.
and statistically significant at one center are not

confirmed by studies at other centers.[9-14] This
prompted the development of guidelines intended
to ensure that molecular marker studies conform to
some basic standards in design and reporting.[4-8]
In 2002, the National Cancer Institutes Early

Detection Research Network developed a 5 phase
approach to systematic discovery and evaluation
of molecular markers.[15-17] These phases of
research are generally ordered in a sequence from
discovery to validation and ultimately to assessment
of benefit according to the strength of evidence
that each provides. This approach is not only an
intellectual process but also provides a clear scale
by which researchers, patients, reviewers, and
investors can evaluate the status of a molecular
An issue that has received less attention is the degree
marker in its development process. The phases of
to which research on molecular markers has made
research are generally ordered according to the
sufficient use of clinically relevant statistics, such
strength of evidence that each provides in favor of
as the assessment of predictive accuracy, decision
the biomarker. The results from earlier phases are
analysis, and/or experimental methodology. The
generally necessary to design later phases. This
fundamental idea behind the concept of personalized
classification of studies into a sequence of phases,
medicine is that it is possible to identify patterns of
from discovery to validation and assessment of
demographic, clinical, genomic/proteomic, and other
benefit has been adapted by several bladder cancer
types of biological data that can be used together
groups (Figure 1).
to benefit individual patients. Most molecular
markers do not provide sufficient information to be
In an effort to address the pervasive problem of
used independent of other information. However,
inadequacies
in the design, analysis, and reporting
1
the optimaltouse
molecular
markers would be in
2
Figure
Modificationstudies,
of the structured
the of
systematic
discovery,
of molecular
marker1.prognostic
a set ofphase-approach
3 recommendations such as
evaluation,
and validation
biomarkers in a model that includes standard
the of
incorporation
reporting
the REMARK
4
clinical data together with relevant additional data
has been
developed and adopted by many
5
Phase
Goals/aims
Experimentation
Sample details
Preclinical
Exploratory; nominate
Preclinical study
Possible bias: small size and
Testing
and rank candidate
for hypothesis generation
convenience sampling
biomarker profiles
0
Develop an assay with
Reproducibility and
clinically reproducible results
robustness of assay; No
assessment of benefit
II
Test on small sample to
Marker optimization, establish
Sample population assay
determine benefit
prediction rules, determine
developed from candidate
cut-offs
biomarker profile
Determine operating
Retrospective design
Sample population should be
characteristics & internal
the target population
validation
III
External validation
Retrospective or prospective,
Multi-institutional, large study
Generaliziability, Impact on
clinical decision-making
IV
Assess whether biomarker

reduces the burden of disease
Post-approval reporting and

testing for other disease
processes or disease stages
Figure 1. Modification of the structured phase-approach to the systematic discovery, evaluation, and
validation of biomarkers
210
Item
INTRODUCTION
1 State the marker examined, the study objectives, and any pre-specified hypotheses.
MATERIALS AND METHODS Patients
Describe the characteristics (e.g., disease stage or co-morbidities) of the study patients, including their
source and inclusion and exclusion criteria.
3 Describe treatments received and how chosen (e.g., randomized or rule-based).
Specimen characteristics
Describe type of biological material used (including control samples) and methods of preservation and
4
storage.
Assay methods
Specify the assay method used and provide (or reference) a detailed protocol, including specific
reagents or kits used, quality control procedures, reproducibility assessments, quantitation methods,
5
and scoring and reporting protocols. Specify whether and how assays were performed blinded to the
study endpoint.
Study design
State the method of case selection, including whether prospective or retrospective and whether
6a
stratification or matching (e.g., by stage of disease or age) was used.
Specify the time period from which cases were taken, the end of the follow-up period, and the median
6b
follow-up time.
7 Precisely define all clinical endpoints examined.
8 List all candidate variables initially examined or considered for inclusion in models.
Give rationale for sample size; if the study was designed to detect a specified effect size, give the
9
target power and effect size.
Statistical analysis methods
Specify all statistical methods, including details of any variable selection procedures and other model10
building issues, how model assumptions were verified, and how missing data were handled.
Clarify how marker values were handled in the analyses; if relevant, describe methods used for
11
cutpoint determination.
2
RESULTS
Data
Describe the flow of patients through the study, including the number of patients included in each stage
12 of the analysis (a diagram may be helpful) and reasons for dropout. Specifically, both overall and for
each subgroup extensively examined report the numbers of patients and the number of events.
Report distributions of basic demographic characteristics (at least age and sex), standard (disease13
specific) prognostic variables, and tumor marker, including numbers of missing values.
Analysis and presentation
14 Show the relation of the marker to standard prognostic variables.
Present univariate analyses showing the relation between the marker and outcome, with the estimated
effect (e.g., hazard ratio and survival probability). Preferably provide similar analyses for all other
15
variables being analyzed. For the effect of a tumor marker on a time-to-event outcome, a Kaplan-Meier
plot is recommended.
For key multivariable analyses, report estimated effects (e.g., hazard ratio) with confidence intervals
16
for the marker and, at least for the final model, all other variables in the model.
Among reported results, provide estimated effects with confidence intervals from an analysis in which
17
the marker and standard prognostic variables are included, regardless of their statistical significance.
If done, report results of further investigations, such as checking assumptions, sensitivity analyses, and
18
internal validation.
DISCUSSION
Interpret the results in the context of the pre-specified hypotheses and other relevant studies; include a
19
discussion of limitations of the study.
20 Discuss implications for future research and clinical value.
Figure 2. Reporting recommendations for tumor marker prognostic studies (REMARK) NCI-EORTC (with
permission from McShane et al.[21])
211
Figure 3. Levels of evidence for grading clinical utility of biomarkers: Tumor Marker Utility Grading System
(TMUGS) (reproduced with permission of Hayes et al. [22])
with regards to assay performance (i.e., medications

or nutrition that may interfere with an assay), so that
the model could then be used to provide individual
patient care.
impractical for most molecular markers. However,

decision analytic techniques can often be used
instead of trials. The key point of decision analysis is
that the consequences of clinical decisions would be
incorporated in these analyses. This decision analytic
evaluation should be performed during later stages
of research and before clinical implementation of a
tool. Furthermore, external validation needs to be
performed prior to utilization of the model. Wider
adoption of decision analytic methods will provide
better insights as to whether any of the plethora
of new molecular markers improves assessment,
treatment outcomes, and ultimate health.
To determine the value of a new molecular marker, it

is not sufficient to show that it is significantly related
to prognosis or outcome, statistically significant in
a multivariable model that includes the standard
clinical and pathologic factors, or more significant
than standard clinical and pathologic factors. Rather,
for a molecular marker to be clinically useful, it is
necessary to show that adding the molecular marker
to an existing model based on the most important
clinical and pathologic factors substantively
improves the predictive accuracy (discrimination
and calibration) of the model. The next step is to
assess whether the increase in accuracy and risk
assessment translates into improved individualized,
evidence-based treatment recommendations with
eventual superior patient outcomes. Indeed, an
improvement only in predictive accuracy, although
necessary, is not in itself sufficient to assess whether
using the marker in practice would actually benefit
patients.
2. P
romising Tissue-based Prognostic
Molecular Markers
a) Cell Cycle Markers
The cell cycle is a series of carefully coordinated
and regulated steps that govern cellular proliferation.
Progression through the cell cycle is mediated in part
by the buildup of cyclins, proteins that activate cyclindependent kinases (cdks). Cdks then phosphorylate
the retinoblastoma (Rb) protein, a classic tumor
suppressor and key component of the G1/S
checkpoint. This allows DNA replication to proceed.
Cdk inhibitors of both the inosin phosphokinase
(INK) family, such as p16INK4A and the KIP family,
such as p21 and p27, act as brakes on cell cycle
progression (Figure 4). The p53 protein serves as
the guardian of the genome by inducing multiple
mechanisms of cell cycle arrest after cell stress.[29]
Establishing clinical relevance of a molecular

marker test to guide therapeutic decisions requires
demonstrating that it can classify patients into
distinct subgroups with different recommended
managements. While this would be ideally assessed
in a randomized clinical trial, the substantial
human and financial resources necessary for such
randomized trials would make such an evaluation
Mutations of cell cycle regulatory genes are the
212
42
6
7
8
9
the bottom arrow. Abbreviations: FGFR3, fibroblast growth factor receptor 3 gene; mt, mutation;
, elevated expression (Ki-67, p53); CIS, carcinoma in situ.
MOLECULAR AND CLINICAL PATHWAYS OF BLADDER CANCER
FGFR3 mutation
pTa/1 G1/2
pT2 G2/3
Normal
Urothelium
Metastasis
p53
Ki-67
pTa/1 G2/3
CIS
pT2 G3
INCREASING NUMBER OF GENETIC EVENTS

10
11
Figure
12 4. Two-pathway model of the disease pathogenesis of Bladder cancer (BC). This figure shows the
combination
of molecular and pathological data. Arrow thickness is indicative for the percentage of tumors.
13
The
14 FGFR3 mutation is largely responsible for the favorable molecular pathway. Among many others, P53
and
15 Ki-67 over-expression are examples of unfavorable NMI-BC. Molecular alterations, not included in the
figure in the interest of clarity, are represented by the bottom arrow. Abbreviations: FGFR3, fibroblast growth
factor receptor 3 gene; mt, mutation; , elevated expression (Ki-67, p53); CIS, carcinoma in situ.
most common genetic alterations found in human

cancer, including bladder cancer. Alterations in
the p53 and retinoblastoma (Rb) tumor suppressor
genes are predominant components in the
development of bladder cancer, but the downstream
effectors and other pathways that contribute to
urothelial transformation remain to be more fully
defined. p21WAF1/CIP1 and p27Kip1 are cyclindependent kinase inhibitors that can arrest the cell
cycle by blocking G1/S progression. p21 is a wellcharacterized p53-inducible gene. As we will discuss,
alterations of p53, pRB, p21, and p27 expression are
markers that have prognostic significance in bladder
cancer patients.
1. p53
The tumor suppressor p53 is the most commonly
found mutated gene in human cancer. Activated
by various types of cellular stress, including DNA
damage and oncogene activation, p53 acts as a
sequence specific transcription factor and appears
to initiate a cascade of molecular events that result
in cell cycle arrest, DNA repair, and apoptosis,
thereby preventing the generation of genetically
altered cells. Mutation or loss of chromosome 17p
and consequent functional inactivation of p53 leads
to the loss of ability to affect the important cell
process and consequent uncontrolled proliferation
and growth of a malignancy.
Many studies have demonstrated that the majority of
invasive bladder cancers display allelic loss of the p53
gene. While most of these support that p53 nuclear
accumulation is predictive of outcome, particularly
for patients treated with radical cystectomy, there
is evidence for and against almost every aspect
of the role of p53 in cancer biology and clinical
outcomes or application.[9] These discrepancies

may be related to the choice of antibody used in p53
assays, variability in interpretation and stratification
criteria, and inconsistencies in specimen handling
and other technical procedures. A meta-analysis
of the role of p53 in bladder cancer, found 117
studies including 10,026 patients, with sample sizes
ranging from 12 to 270 patients (mean 86, SD 53).[9]
Immunohistochemistry was the most commonly (96%
of the 117 studies) used approach for assessment of
p53 status, with molecular analysis being used in the
other 5 studies.
In a tissue microarray study containing specimens
from over 400 bladder cancer patients, the proportion
of altered p53 progressively increased in specimens
from normal urothelium to non-muscle-invasive
bladder cancer to carcinoma in situ and then to muscleinvasive bladder cancer, being highest in metastatic
lymph node specimens. In accordance with all large
previous studies, the degree of p53 expression
(reflecting chromosome 17p abnormalities) was
significantly associated with pathologic tumor stage,
43lymphovascular invasion, lymph node metastases,
pathologic tumor grade, disease recurrence, and
bladder cancer-specific death. Interestingly, the
p53 phenotype was a stronger predictor of bladder
cancer outcomes (disease recurrence and survival)
in patients treated with radical cystectomy than
chromosomal alterations and degree of expression
of p21, pRB, p27, p16, cyclin E1, and cyclin D1. In a
multi-institutional tissue microarray study comprising
over 1200 patients treated with radical cystectomy
for bladder cancer, p53 improved the accuracy of
predictive models that included standard clinical
and pathologic features for prediction of disease
recurrence and bladder cancer-specific survival.
Interestingly, in patients with advanced bladder
213
cancer (pT3-4 N0 or pT, any N+), adding p53 to a

base model of clinical and pathologic characteristics
did not improve overall predictive accuracy.[56]
However, p53 improved prediction of recurrencefree and cancer-specific survival in patients with
pT1-2N0 disease by a statistically and prognostically
significant margin.[47], Taken together, these studies
suggest that p53 can improve bladder cancer
prognostication in high risk disease; however, the
prognostic value of p53 decreases significantly in
advanced disease.
trial found no clinical utility for p53 expression in

predicting survival in high-risk patients with T1
tumors, but this may have been affected by the low
event rate related to treatment efficacy.
Finally, in a recent study of 80 consecutive patients
with pT1N0 bladder cancer, expression of p53
was altered in 25% of patients and p53 was
independently associated with bladder cancer
recurrence (HR 3.66; p=0.033) and cancer-specific
mortality (HR 5.25; p=0.016).[57] The concordance
index of a base model that included tumor grade,
lymph node status, lymphovascular invasion, and
concomitant carcinoma in situ for bladder cancer
recurrence and bladder cancer-specific mortality
was 54.7% and 64.3%, respectively. Addition of
p53 increased the concordance indices of the base
model for bladder cancer recurrence and cancerspecific mortality to 60% and 67.9%, respectively.
The authors concluded that p53 can help stratify the
heterogeneous population of pT1 patients into risk
groups that can be used to guide clinical decisionmaking regarding observation versus adjuvant
therapy. These findings are in line with data from the
ISBC analysis combining immunohistochemical p53
staining results from 23 different studies.[50] This
combined analysis of 929 patients with T1 bladder
cancer demonstrated an independent prognostic
value of p53 immunohistochemistry in multivariable
analysis regarding tumor progression but not overall
survival. However, these observations need to be
reproduced by other groups.
Although p53 nuclear accumulation is associated

with mutations in the p53 gene of chromosome 17,
significant discordance exists. Lamy et al showed
inactive p53 variants in up to 44% of bladder
cancers, with the highest proportion in high grade
tumors.[58] Stern et al investigated the frequency of
p53 mutations in bladder cancer, taking into account
DNA repair genotypes.[59] They found that tumor
progression pathways may differ among subjects
with different DNA repair polymorphisms, possibly
explaining the inter-individual variation observed for
the type and frequency of p53 gene mutations.
In addition to genetic factors, environmental
exposures are likely to play an important role in
bladder carcinogenesis. Based on this concept, Ryk
et al suggested that the occurrence of p53 mutations
may be due to genetic polymorphisms resulting in
altered metabolism and repair.[60] This may result
from individual modulation of mutagenic DNA
adduct levels, and may then be of importance for an
individuals risk of developing bladder cancer.
At this time, the use of p53 is still not established despite more than 100 studies evaluating utility in bladder cancer patients. In the meta-analysis mentioned
above, p53 independently predicted recurrence,
progression, and mortality in only 27% (9 of 34),
50% (12 of 24), and 29% (10 of 35), respectively.9 In
the studies that used Cox regression modeling, the
overall risk of recurrence was 1.6 (95% CI 1.2-2.1),
progression was 3.1 (1.9-4.9), and mortality was 1.4
(1.2-1.7). Nevertheless, given that most larger, welldone studies have shown a prognostic value to p53
in patients with advanced urothelial carcinoma of the
bladder, a large multicenter adjuvant chemotherapy
study was initiated with the goal of randomizing patients with a nuclear p53 accumulation (p53+) to adjuvant chemotherapy or observation within 10 weeks
following radical cystectomy (for details see: https://
www.uscnorris.com/p53/). This clinical trial might
shed more light on the role of p53 in identifying patients at high risk for disease recurrence as well as
response to adjuvant chemotherapy using MVAC.
Accurately sub-stratifying patients with high grade

urothelial carcinoma involving the lamina propria
(stage T1) regarding risk and potential treatment
outcomes represents a particular challenge for
urologists. There is conflicting data on whether
p53 immunohistochemistry can reliably categorize
patients with T1 tumors into different risk strata
with regards to clinical outcomes.[33,48] A
preliminary report from the EPICURO showed that
p53 overexpression correlated with higher grade
and stage of the disease in 995 patients with nonmuscle-invasive bladder cancer.[61] However,
the prognostic significance of p53 dropped out in
multivariate analyses. In a follow-up study, using
both immunohistochemistry and gene sequencing
of 119 tumors, these authors found that the p53
pathway is inactivated in most T1 grade 3 tumors,
but failed to identify any prognostic value for p53
in these patients.[61] Moonen et al also reported
no additional value for p53 mutation analysis over
known prognostic factors using specimens from 105
patients with high-risk non-muscle-invasive bladder
cancer.[62] Another group reported that p53 nuclear
accumulation was not predictive of response to
intravesical BCG, cancer recurrence, progression,
or cancer-specific survival.[63] A recent prospective
2. pRB
The retinoblastoma protein (pRb) is a pivotal
cell cycle regulator that plays a role in stem cell
maintenance, tissue regeneration, differentiation,
and developmental programs. Interference with
214
the function of pRb or components of its pathway is

a major mechanism by which cancer cells escape
normal growth control mechanisms. Specifically,
pRb plays a key role in coordinating cell-cycle
control and G1/S phase progression. Rb regulated
protein-to-protein activation of E2Fs and other
transcriptional regulators leads to phosphorylation
of cyclin-dependent kinases (cdk4/cdk6 and cdk2)
and release of E2F factors, which initiate the DNA
duplication machinery and G1/S transition. Over
the past decade, it has become clear that the
genomic or epigenetic loss of pRb function leads to
uncontrolled cell growth. This is not only an initiating
event in tumorigenesis, but also a step associated
with malignant progression and aggressive outcome.
However, recent studies suggest that the predictive
power of pRB may be inferior to that of other cell
cycle regulators both in non-muscle-invasive and
muscle-invasive bladder cancer. This may be the
result of the complex redundant pathway that pRb
coordinates.
an independent role in predicting outcome but this

varies by disease stage. In patients with muscleinvasive bladder cancer, p21 was an independent
predictor of both disease recurrence and cancerspecific mortality. In patients with organ-confined
disease, p21 remained independently associated
with disease recurrence and bladder cancer-specific
death. In addition, the authors found that p21 has
cooperative/synergistic action with p53, p27, and
pRB.49 Conversely, in a study of 80 patients with
pT1N0 bladder cancer who underwent cystectomy,
p21 was not an independent predictor of disease
recurrence or cancer-specific mortality.[57] Similarly,
p21 was not an independent predictor in patients
with advanced disease (T4, N positive).[45,55] p21
may be most useful in patients with T2, T3, nodenegative disease especially in combination with
other markers.[49]
4. p27
p27Kip1 is a member of the Cip/Kip family of Cdk
inhibitors, which binds to Cdk2 (and to other Cdks)
and potently inhibits Cdk2 kinase activity,[66]
potentiating cell-cycle arrest in the G1 phase. In
quiescent cells (G0 phase), p27 levels are high
concomitant with low Cdk activity. As cells progress
through the cell cycle and enter S phase, p27 levels
decrease, allowing the kinase activity of Cdks to
increase.
3. p21
The product of the p21 gene binds to and inhibits
the activity of cyclin-dependent kinase 2 or cyclindependent kinase 4 complexes, and thus functions
as a regulator of cell cycle progression at G1.[65] In
a large immunohistochemical study of p21 and p53
expression in 242 patients, a multivariate analysis
showed that p21 status was an independent
predictor of tumor recurrence and survival after
radical cystectomy.[36] Moreover, patients with p53altered/p21-altered tumors demonstrated a higher
rate of disease relapse and worse cancer-specific
survival, compared with those with p53-altered/p21normal tumors.[36]
Two studies have found limited predictive value

for p27 in patients with non-muscle-invasive
bladder cancer. However, in patients with muscleinvasive disease treated with radical cystectomy,
p27 significantly improved prediction of bladder
cancer recurrence and survival. In patients treated
with radical cystectomy, p27 is a key component
of a panel of immunohistochemical markers
which improved predictive value of a nomogram
based on standard clinical and pathological
characteristics both in patients with broad stage
characteristics (pT1-3N0M0) and in a more select
population of pT1 patients. Furthermore, p27 was
independently associated with disease recurrence
and progression.
The value of p21 expression depends on the stage

and management of bladder cancer patients. In
a study of 49 patients with carcinoma in situ only,
altered p21 expression was independently associated
with bladder cancer recurrence and progression.
[46] Patients with carcinoma in situ and altered
expression for both p53 and p21 are at the greatest
risk of bladder cancer recurrence, progression, and,
most importantly, mortality, suggesting a potential
rationale for early definitive therapy in these patients.
On the other hand, an intact pathway at the level
of p21 seems to abrogate the detrimental effects
of altered p53 immunoreactivity on the outcome of
bladder carcinoma in situ. In another study of 74
patients with non-muscle-invasive papillary bladder
cancer, p21 was independently associated with tumor
progression. Combination of p21 with p53, pRB, and
p27 stratified patients into statistically significantly
different risk groups for disease recurrence and
progression in patients with non-invasive disease.
[43]
5. Cyclins
The deregulation of the G1/S transition is a hallmark
of cancer, allowing uncontrolled cell proliferation.
Cyclins D and E are responsible for the initial and
terminal phases of G1, respectively. Cyclin E1
is the predominant regulatory protein active at
the G1/S transition and its alteration significantly
affects carcinogenesis. Normal bladder urothelium
expresses cyclin E1 only in the umbrella cells, while
cancer cells already expressed cyclin E1 in the
earliest stages of the disease process.[53] Cyclin E1
expression was significantly decreased in patients
with features of biologically and clinically aggressive
bladder cancer; decreased expression of cyclin E1
In patients who undergo cystectomy, p21 may play
215
was significantly associated with advanced pathologic

stage, lymphovascular invasion, metastases to
regional lymph nodes, and bladder cancer-specific
mortality after controlling for the effects of standard
pathologic features in both transurethral resection
and radical cystectomy specimens.
effector by cleaving multiple cellular components.

[74] Giannopolou et al studied caspase-3 expression
in 53 patients with bladder cancer and did not find
a correlation between caspase-3 expression and
tumor grade or stage.[75] Burton et al[76] evaluated
caspase-3 expression in 34 patients with carcinoma
in situ, of whom 41% developed invasive bladder
cancer. They reported that activated caspase-3
overexpression was associated with higher rates of
disease invasiveness. Conversely, a more recent
study by Karam et al[54] involving 226 consecutive
patients treated with radical cystectomy reported
that 49% of the patients had loss of caspase-3
expression, which was associated with higher
pathologic grade and stage, and presence of lymph
node metastasis. Moreover, loss of caspase-3 was
an independent predictor of bladder cancer-specific
survival after radical cystectomy.[54]
Although the same authors reported that cyclin D1

immunoreactivity was elevated in bladder cancer
patients compared to controls, it was not associated
with clinical or pathologic characteristics among
bladder cancer patients.[53] While loss of cyclin
D1 expression was associated with an increased
probability of disease recurrence and bladder
cancer-specific mortality in univariate analyses,
this association was not significant in a multivariate
analysis that adjusted for the effects of standard
pathologic features. These findings are consistent
with previous reports showing that alteration in cyclin
D1 is an early event in bladder tumorigenesis, but it
does not add prognostic significance.
c) Bcl-2
Bcl-2 is an anti-apoptotic protein present in
intracellular membranes, and controls cytochrome c
location, caspase status, and ion channels involved
in apoptosis.[77] Overexpression of bcl-2 was
found in 32% of radical cystectomy specimens,
and correlated with higher pathologic stage,
disease recurrence, and cancer-specific mortality.
[54] In agreement with these findings, two other
groups reported that over-expression of bcl-2 was
associated with worse all-cause survival and lower
response rates to chemotherapy.[79]
3. Apoptosis
Apoptosis, or programmed cell death, is a complex
and highly regulated process comprised of a series of
coordinated steps resulting in cell death. Alterations
in apoptosis pathways are important in tumorigenesis
and cancer progression, as they allow cancerous
cells to survive, resist a variety of stresses, and
express more invasiveness.[70] Bladder cancer has
been shown to resist programmed cell death with
alteration of both pro- and anti-apoptotic signaling.
a) Fas (CD95)
d) Survivin
Fas is a death receptor; when activated by Fas

ligand (FasL), Fas activates downstream signals
that induce apoptosis.[71] Fas can cause apoptosis
in immune cells and prevent inflammatory killing
of tumor cells. Svatek et al reported that the
soluble form of Fas was present in the cell lysate
and supernatant of high-grade bladder cancer cell
lines, suggesting that Fas is likely to be produced
and released by bladder cancer cells.[72] Urine
soluble Fas was an independent predictor of the
presence of bladder cancer and invasiveness in
patients with a past history of non-muscle-invasive
disease. Immunohistochemical analysis in 123
bladder cancer specimens and the mucosa of 30
benign bladders revealed that Fas was expressed
in 90% of benign specimens compared to 58% of
cancer specimens.[73] In addition, decreased Fas
expression was associated with higher tumor stage,
grade, and disease-specific mortality in univariate
analysis.[73] These observations suggest that Fas
may play a role in the local immunosuppression in
bladder cancer associated with tumor development,
biologic aggressiveness, and progression.
Survivin is a member of the Inhibitor of Apoptosis

(IAP) family, and inhibits apoptosis, at least partly, by
blocking downstream caspase activity. Survivin also
controls mitotic progression and induces changes
in gene expression that are associated with tumor
cell invasion.Survivin mRNA is selectively expressed
during embryonic and fetal development,[84]
becomes undetectable or expressed at low levels
in most differentiated normal adult tissues, and is
overexpressed in human cancers.[83] In bladder
cancer, survivin expression, both at the protein
and the mRNA level, is associated with cancer
presence, higher tumor grade, and advanced
pathologic stage.[85-87] Survivin overexpression
was present in 63% of bladder cancer specimens,
and was associated with higher pathologic stage,
presence of lymphovascular invasion, lymph node
metastasis, bladder cancer recurrence, and bladder
cancer-specific survival in 219 patients treated with
radical cystectomy.[54] In addition, the proportion of
specimens with survivin overexpression increased
gradually from non-muscle-invasive bladder cancer
to advanced bladder cancer and to metastatic lymph
node tissue.[88] In a large multicenter validation
study, addition of survivin improved the accuracy of
standard clinicopathologic features for prediction of
b) Caspase-3
Caspase-3 is a protease that acts as an apoptosis
216
disease recurrence and cancer-specific survival in a

subgroup of patients with pT1-3N0M0 disease.[89]
Survivin is a highly promising marker that deserves
further investigation as a prognostic/predictive
marker as well as a target for therapy.[90]
these 2 molecular markers were strongly correlated.

These findings were independently confirmed in a
study of 204 patients with muscle-invasive disease
treated with radical cystectomy.[99] Decreased
thrombospondin-1 was independently associated
with disease recurrence and cancer-specific survival.
Moreover, loss of thrombospondin-1 expression
was associated with alterations in other cell cycle
regulators such as p21 and p27.
4. Angiogenesis
Angiogenesis, the process of new blood vessel
formation, is a critical event in the initiation and
progression of solid malignancies. Angiogenesis
has been traditionally quantified by measuring
microvessel density. However, a variety of molecular
markers are also associated with angiogenesisrelated events.
c) Vascular Endothelial Growth Factor

Of the various angiogenic factors, VEGF has been
identified as a crucial regulator of normal and pathologic angiogenesis. VEGF produces a number of
important biological effects such as endothelial mitogenesis and migration, extracellular matrix remodeling via induction of proteases, increased vascular
permeability, and maintenance of newly formed vasculature. Several members of the VEGF family have
been characterized. In a small study of 45 patients,
VEGF-C expression was localized to the cytoplasm
of bladder cancer cells, with minimal expression in
normal bladder epithelium.[100] VEGF-C expression
was significantly associated with tumor size, pathologic stage and grade, lymphovascular invasion,
and pelvic lymph node metastasis. In multivariable
analysis, VEGF-C expression was an independent
predictor of pelvic lymph node metastasis.[100] In
addition, patients with high VEGF-C expression
had a worse prognosis compared to those with low
VEGF-C expression. In a separate study of 126 patients treated with transurethral resection of bladder
cancer, higher expression of VEGF-A, VEGF-C, and
VEGF-D were all associated with increasing tumor
stage and grade.[101] VEGF-C expression was
also associated with higher microvessel density. In
a study of 204 patients treated with radical cystectomy and bilateral pelvic lymphadenectomy, VEGF
was over-expressed in 86% of patients, supporting
its role in bladder tumorigenesis and identifying it as
a potential target for therapy.[94]
a) Microvessel density
Bochner et al[91] evaluated 164 bladder cancer
specimens and reported that patients with high
microvessel density (>100 microvessels per hpf)
were at highest risk of disease recurrence (68%
at 5 years) and cancer-specific mortality (66% at 5
years) compared to patients with lower microvessel
density (MVD). In addition, MVD was an independent
prognostic factor when adjusted for the effect of
tumor stage, grade, and lymph node status. However,
other investigators could not confirm the prognostic
value of MVD.[92-94] In 204 patients treated with
radical cystectomy, Shariat et al failed to detect an
association between MVD and prognosis, but they
found that MVD was higher in patients with lymph
node metastasis.[94] Jaeger et al examined 41
muscle-invasive tumors following radical cystectomy,
demonstrating higher MVD in the primary tumor if
LN metastases were present.[95] Explanations for
these discrepancies in prognostic value of MVD
include differences in the choice of antibody used
for immunohistochemistry, as well as staining and
scoring protocols. For example, the endothelium of
tumor and normal tissues is heterogeneous. Thus,
pan-endothelial antibodies such as CD31 may not
stain tumor vessels to the same degree and may
generally react better with larger vessels.[96]
In addition, VEGF overexpression was associated

with pathologic features, and altered expression
of p21, p27, pRB, cyclin E1 and Ki-67, suggesting
complex interactions between different bladder
cancer-associated
molecules.
While
these
associations are important, VEGF expression had
no independent prognostic value. Increased VEGF
levels can result in increased vascular permeability
and interstitial fluid pressure, impairing chemotherapy
delivery. Thus, adding anti-VEGF to chemotherapy
regimens for bladder cancer might lead to improved
responses.
b) Thrombospondin-1
Thrombospondin-1, an important component of
the extracellular matrix, has been implicated in
the regulation of cell growth and proliferation, cell
motility, cytoskeletal organization, inflammation
and wound healing, and the development and
differentiation of cell types. Recently, it has been
shown to be a potent inhibitor of angiogenesis in vitro
and in vivo, and its expression is inversely related to
microvessel density.[97] Grossfeld et al previously
reported that altered thrombospondin-1 expression
was independently associated with an increased
risk of disease recurrence and all cause mortality
in 163 patients treated with radical cystectomy.[98]
However, the prognostic value of thrombospondin-1
was not independent of p53 expression status since
d) Basic Fibroblast Growth Factor

Similar to VEGF, bFGF is a potent pro-angiogenic
growth factor. It has been hypothesized that during
wound healing and tumor development bFGF is
activated, thereby mediating the formation of new
217
blood vessels. bFGF may behave as a transforming/

oncogenic factor inducing cell proliferation and
motility. The interaction with specific receptors may
lead to unchecked proliferation via the Ras-MAPK
pathway. The most common oncogenes and some
of the tumor suppressor genes relevant to bladder
cancer are components of this pathway.
not found in bladder cancer [108].

The effect of inhibition of EGFR signaling in urothelial cells is cystostatic.[109] Therefore, although
combination therapies with conventional cytotoxic
agents are underway, the requirement for cell division to allow some agents to exert their effects may
be problematic and timing of delivery may be critical.
Inhibitors of EGFR are available and have potential
clinical efficacy. Overexpression of EGFR was associated with disease progression of pT1 high grade
urothelial carcinoma of the bladder and decreased
survival.[110] Consequently, gefitinib, which targets
EGFR, was studied in preclinical in vitro and subcutaneous in vivo models of urothelial carcinoma of the
bladder with promising results.[111] Unfortunately,
a clinical phase II trial (CALGB 90102) investigating
the treatment of measurable metastatic urothelial
carcinoma of the bladder found a high toxicity and
no survival benefit when gefitinib was added to gemcitabine and cisplatin chemotherapy.[112]
bFGF has been evaluated as a potential urinary

molecular marker in bladder cancer. Higher levels of
bFGF were found in urine samples from patients with
bladder cancer compared with those with benign
disease or a history of urothelial carcinoma but no
current tumor.[104] Others have measured urinary
bFGF in patients with various grades and stages
of urothelial carcinoma, and noted a correlation of
increased bFGF with advanced disease.[105] In a
tissue microarray study of 204 radical cystectomy
patients, bFGF was associated with established
features of biologically aggressive bladder cancer
such as pathologic stage, lymphovascular invasion,
lymph node metastasis, molecular markers
commonly altered in bladder cancer (i.e., p27, pRb,
and Ki-67) and disease recurrence. In addition,
altered bFGF expression has been associated with
resistance to cisplatin in human bladder cancer
cell lines.[106] Since bFGF may also contribute
to bladder cancer progression via its extracellular
matrix involvement, bFGF could be a candidate for
therapeutic targeting.
Patient response is clearly correlated to the presence

of activating mutations in the kinase domain or a
variant of EGFR (known as EGFRvIII). Importantly,
several studies have demonstrated that mutations
within the tyrosine kinase domain of EGFR and
expression of EGFRvIII are rare events in bladder
cancer, these likely limiting the utility of EGFR as a
prognostic marker or therapeutic target.
5. Signaling Proteins
b) RAS
Many receptor tyrosine kinases and their downstream

effectors and regulators have genetic alteration and/
or altered expression in bladder cancer. Several of
these are oncogenes that have a dominant effect on
cell phenotype and these may represent particularly
good therapeutic targets.
Approximately 13% of bladder cancers of all grades

and stages contain a mutation in one of the RAS
genes (HRAS, NRAS, KRAS2).[114] This implicates
the RAS-MAP kinase (RAS-MAPK) pathway and
potentially the PI3K pathway in these tumors.
Although the RAS proteins themselves have proven
difficult to target, there is currently much interest in
developing small molecule inhibitors of other key
proteins in these pathways that may be applicable to
RAS-mutant bladder cancers. Further confirmation
of the activation status and examination of the
relationship to RAS and other mutations, including
FGFR3 and PIK3CA mutations (see below), will be
required to allow rational selection of patients for
these types of therapy.
a) ERBB Family Receptors

Receptor tyrosine kinases are attractive therapeutic
targets and currently there is much effort to target
these either with antibodies or small molecules.
Epidermal growth factor receptor (EGFR) is a receptor
tyrosine kinase implicated in the pathogenesis of
a variety of human cancers. Overexpression of
EGFR in bladder cancer was identified more than
20 years ago [107]. The mechanism for upregulation
is unknown but is not related to gene amplification.
There are several approved drugs (antibodies and
small molecules) that interfere with signaling via this
receptor and there are now several ongoing clinical
studies in bladder cancer. However, large trials in
non-small cell carcinoma of the lung have not shown
significant benefit. And although there is some
success in specific organs, it is difficult to predict
response as this is not related directly to expression
levels. In non-small cell carcinoma of the lung,
activating mutation of the receptor has been shown
to be predictive of response. But such mutations are
c) PI3K Pathway Genes

Several genes in the PI3K pathway are implicated
in bladder cancer. PTEN, a lipid phosphatase that
removes phosphate from phosphatidylinositol 3,4,5trisphosphate produced by PI3K, is commonly deleted in muscle-invasive tumors. In some cases, biallelic inactivation by mutation in the retained allele
or homozygous deletion has been found.[115-117]
Recent studies have identified activating point mutations in the alpha catalytic subunit of PI3 kinase
p110alpha (PIK3CA) in bladder cancer, with highest
frequency in non-invasive papillary tumors.[118] This
218
mutational activation of PI3K results in phosphorylation of AKT, which in turn regulates many cellular
activities including cell proliferation, stimulation of
protein synthesis via the mTOR pathway, effects on
metabolism and evasion of apoptosis [119].
situ. This molecular evidence for the clinical twopathway model in bladder cancer (Figure 5) is
further substantiated by the absence of FGFR3
mutations in 20 cases of CIS[123] and the mutually
exclusive occurrence of FGFR3 mutations and
altered expression of Ki-67, p53, and p27.
TSC1 acts in the mTOR pathway downstream of

AKT and this pathway is activated in bladder cancer
via mutational inactivation of TSC1. Inhibitors of
mTOR (rapamycin and analogues) are approved for
clinical use in kidney cancer and other malignancies
but not yet tested in bladder cancer. Inhibitors of
other pathway molecules are in development and
some show promising activity. For example, there
are reports of successful inhibition of tumor growth
in preclinical mouse models by a dual inhibitor of
p110alpha and mTOR. For rational selection of
appropriate inhibitors in the future, it will be important
to determine the relationship of different molecular
lesions in the pathway to tumor phenotype and
clinical outcome and to test the relative sensitivity of
cells with specific pathway alterations in preclinical
models.
FGFR3 mutations were found to protect against

progression of non-muscle-invasive bladder cancer.
However, a combination of FGFR3 with another
molecular marker associated with worse prognosis
if positive, like Ki-67, seemed to confer a more
accurate prediction of progression and diseasespecific survival than FGFR3 or Ki-67 alone.
Molecular grade (mG) based on FGFR3 mutation
status and Ki-67 expression was proposed as an
alternative to pathologic grade.[127] Using these
2 molecular markers, a 3-tier grading system was
developed covering all cases: mG1 (mutation; normal
expression), favorable prognosis; mG2 (no mutation;
normal expression or mutation; high expression),
intermediate prognosis; mG3 (no mutation; high
expression), poor prognosis.[124] A recent study
compared the reproducibility of pathological grading
and mG on the same series of patients.[127] The
reproducibility of mG was almost perfect (kappa;
0.76), whereas reproducibility for pathologic grade
was only fair to substantial (kappa: 0.17-0.58). In
addition, combining the EORTC risk scores and mG
led to a more accurate prediction of progression
in patients with intermediate and high-risk EORTC
scores.[127] In this recent study with long-term followup, EORTC high-risk combined with mG3 showed
50% (15/30) progression as opposed to 20% (6/29)
progression in EORTC high-risk combined with
mG1-2. Taken together, mG (composed of 3 mGs)
proved more reproducible than pathological grade
assessment, making it a reliable and robust tool to
assess progression in non-muscle-invasive bladder
cancer. An independent prospective analysis of mG
has to be done to confirm the promising retrospective
data described in this paragraph.
d) Fibroblast Growth Factor Receptor 3

Fibroblast growth factor receptor 3 (FGFR3)
belongs to a tyrosine kinase receptor family and
regulates diverse cellular processes including
growth, differentiation, and angiogenesis. It is
activated by a point mutation in bladder cancer.
[122] Activating FGFR3 mutations are present in
up to 60% of bladder tumors, and are characteristic
of papillary, non-muscle-invasive bladder cancer.
[122] Surprisingly, FGFR3 mutations were found to
be related to favorable disease with 84% of pTaG1
tumors having a mutation as compared to 7% of
pT2G3 or higher stage tumors.[123] In general, the
FGFR3 mutation represents a subset of low grade,
low stage tumors that rarely progress and hence
have a good prognosis.[122-124]
Lindgren et al used expression profiling, mutation
analysis, and loss of heterozygosity to molecularly
characterize a cohort of 75 Ta and T1 bladder
cancers.[125] They confirmed that low grade, low
stage bladder cancer is characterized by FGFR3
receptor activity, high protein synthesis, and low
cell-cycle activity. Using screening for FGFR3
mutations by direct bidirectional sequencing and for
genome-wide molecular changes with microarray
technology of 35 low grade Ta and 50 T1 or grade
3 tumors, Zieger et al found that FGFR3-mutated
non-muscle-invasive tumors can progress and retain
their mutation and chromosomal instability patterns
during progression.[126] Their results suggest that
the decreasing frequency of FGFR3 mutations in
later stages of tumor development is caused by the
emergence of tumors following a different molecular
pathway with no FGFR3 mutations. Tumors of this
latter pathway were associated with carcinoma in
It is clear that the FGFR3 gene plays a major role in

the development of low-grade non-muscle-invasive
bladder tumors; however, there is little evidence
that it plays any role in the development of invasive
cancer or in the progression of non-muscle--invasive
to invasive disease. One of the most important
clinical questions remains whether FGFR3 can help
risk stratify the heterogeneous group of T1 grade 3
bladder cancers. As illustrated above, a combination
of FGFR3 with another molecular marker associated
with worse clinical features may be the answer.
6. Hormone Receptors
a) Human Epidermal Growth Factor Receptor 2
Human epidermal growth factor receptor 2
(HER-2) is a tyrosine kinase in the EGFR family
that can promote oncogenesis. HER-2 has been
219
best characterized in breast cancer, in which

overexpression of HER-2 is a poor prognostic factor
and inhibition of HER-2 function has proven to be an
effective approach for the treatment of breast cancer
cells that overexpress HER-2. Conflicting data exists
regarding the expression and significance of HER-2
in bladder cancer.
used tissue microarrays and different antibodies,

correlated in a blinded fashion with results observed
in two centers and included automated and manual
scoring systems. Results were further validated
and confirmed on a small representative sample
population analyzed in a previous positive study[139]
to show similar findings, despite antibody epitope,
reagents, and laboratories.
A number of studies have shown limited or no

prognostic value of examining HER-2 expression.
[128-133] For instance, Kassouf etal reported no
significant correlation between HER-2 expression
status and clinical outcome in 184 patients with
primary bladder cancer, and another study found that
HER-2/neu overexpression in primary or metastatic
tumors did not predict survival in a cohort of 80
consecutive patients with muscle-invasive bladder
cancers. However, other studies have reported that
higher HER-2 expression levels are associated with
poor prognosis[134-136]. Recently, a study of 198
patients observed on multivariable analyses that
HER-2 positive patients were at increased risk for
both bladder cancer recurrence and cancer-specific
mortality compared with patients with negative
HER-2 expression.[137]
c) E
strogen
Receptor
Receptor
and
Progesterone
Like AR, the estrogen receptor (ER) is a member

of the nuclear receptor superfamily, and acts a
transcription factor after binding to estrogens and
translocation to the nucleus. Two subtypes of ER
exist, with varying expression and functional profiles:
estrogen receptor alpha (ERalpha) and estrogen
receptor beta (ERbeta). ER is expressed in a subset
of bladder tumors; however, the prognostic and
functional significance remains unclear. ERalpha
is rarely expressed by bladder cancer specimens.
[141] It has been reported that expression of ERbeta
is associated with pathologic characteristics of
bladder cancer (stage and grade).[142] However,
several studies have shown limited or no impact of
ER expression on prognosis of patients with bladder
cancer.
These conflicting data may be partially explained by

differences in patient populations and techniques
of HER-2 analysis and immunostaining among the
various studies. Clearly, additional data is necessary
from prospective studies using standardized
analytical techniques for HER-2 expression. Clinical
trials have been initiated to investigate the efficacy
of anti-HER-2 therapy in patients with advanced
bladder cancer, and these will provide further insight
to the role of HER-2 in disease progression.
The progesterone receptor (PR) is another

intracellular steroid receptor that acts by a
mechanism similar to that of AR and ER; however, a
recent report indicates it is not expressed in bladder
cancer.[141]
7. C
ombination of Tissue-Based
Molecular Markers
b) Androgen Receptor
Given the complexity of the molecular abnormalities

associated with bladder cancer, it is improbable that
a single marker can accurately segregate tumors
of similar clinicopathologic phenotypes into distinct
prognostic categories. A marker may reflect disruption of a biochemical pathway by a particular mechanism but not by another. Therefore, as previously
shown, combinations of independent, complementary markers may provide a more accurate prediction
of outcome compared to a single marker.
The androgen receptor (AR) is a nuclear receptor

and ligand-dependent transcription factor that
mediates the biologic effects of androgens. Boorjian
et al reported that expression of androgen receptor
was inversely correlated with pathological stage in
a series of 49 patients with bladder cancer; 75%
of non-muscle-invasive tumors expressed the AR
compared with 21.4% of muscle-invasive tumors.
[138] Similarly, another study confirmed that loss
of AR expression was associated with higher grade
and invasive tumors; however, no association was
found with patient outcomes.[139]
Karam and coworkers found that p53, Bcl-2,

caspase-3, and survivin display distinct association
patterns with tumor stage and grade, lymphovascular
invasion, and carcinoma in situ.[54] The number of
simultaneously altered apoptosis markers was an
important prognostic indicator for disease recurrence
and bladder cancer-specific survival in patients
treated by radical cystectomy. Changes in expression
of markers were frequent in individuals with bladder
cancer, with only 22 patients (10%) showing normal
expression of all 4 markers. Alteration of fewer than
4 apoptosis markers did not provide independent
prognostic information after controlling for the
Although several groups have argued for a role for AR

in pathogenesis of bladder cancer, evidence for using
androgen receptor as either a prognostic marker or
therapeutic target in bladder cancer remains limited.
In a study comprising 472 patients with urothelial
bladder carcinoma from two centers, the authors
did not observe any association between AR protein
expression and bladder cancer stage, grade, or
outcomes.[140] Further data did not suggest that
loss of AR expression is gender-related. The authors
220
effects of standard pathologic features; only when

all 4 markers were altered was significance reached.
This is explained by the fact that Bcl-2, caspase-3,
p53, and survivin have not only interrelated but also
independent roles in the apoptotic pathway.
and proven in large multi-institutional prospective

controlled trials.
Analysis of any combination of cell cycle regulators

(i.e., p53, pRB, p21, p27, cyclin D1, and/or cyclin
E1) provides additional prognostic information
beyond that obtained from any single molecular
marker or combination of 2 or 3 molecular markers.
This makes sense because it investigates multiple
pathways including downstream effectors rather than
a single crossroad in a pathway. Higher total number
of altered molecular markers was associated with
a progressive, proportional increase in the risk of
advanced pathologic tumor stage, lymphovascular
invasion, lymph node metastases, disease recurrence,
and death from bladder cancer. These molecular
markers had a cooperative or synergistic role in the
biologic behavior of bladder cancer. Furthermore,
examining how many markers are altered and adding
this information to a nomogram of clinicopathologic
criteria significantly improved predictive accuracy for
disease recurrence and cancer-specific mortality.
[45] Other studies have confirmed this principle in
selected patient populations; addition of a number
of altered molecular markers to a base predictive
model significantly improved predictive accuracy
for 80 patients with T1 disease,[57] 324 patients
with organ-confined bladder cancer,[145] and 692
patients with advanced bladder cancer.[55]
Insulin growth factor (IGFs) and IGFBPs have a

central role in the regulation of growth, cellular proliferation and transformation, and apoptosis. IGFBP-3
belongs to a family of high affinity IGFBPs, which
directly mediate IGF-independent actions, such as
regulation of cell growth and induction of apoptosis,
through binding to its own putative receptor. However, evidence also suggests that IGFBP-3 has its
own pro-apoptotic effects, independent of its ability
to modulate IGF bioavailability.[148] The activities of
IGFBP-3 are regulated in a complex manner, such
as IGFBP-3 proteases like kallikreins, cathepsin,
and matrix metalloproteinases, which release IGFs
from IGFBP-3. [149] Equally noteworthy is that several studies have found that IGFBP-3 is capable of
mediating the antiproliferative effects of tumor suppressor protein p53, transforming growth factor-beta
(TGF-1), retinoic acid, vitamin D, antiestrogens,
and tumor necrosis factor-alpha. Previous investigators collected preoperative plasma levels of IGFBP-3
measured using DSL-enzyme-linked immunosorbent assays in a group of 51 patients who underwent
radical cystectomy and compared it to the levels in
blood from 44 healthy controls.[150] The association
between IGFBP-3 and IGF-I was also tested, and
authors found that both levels were strongly correlated with one and another among patients with bladder cancer (r=0.568, p<0.001). Preoperative plasma
IGFBP-3 concentration level was lower in patients
with regional lymph node metastases (p=0.047) and
was a significant predictor of lymph node involvement, independent of clinical stage and grade (HR:
0.9, p=0.047). This confirms the speculations that
a relationship between circulatory IGFBP-3 levels
and metastasis may exist. Moreover, authors of that
study revealed that low levels of IGFBP-3 portended
an increased risk of disease recurrence (HR: 0.9,
p=0.049) and cancer-specific mortality (HR: 0.9,
p=0.04) in the preoperative setting after adjusting
for the effects of clinical stage and grade. A better
understanding of the biologic mechanisms and the
role of IGFBP-3 in bladder cancer is worthy of investigation.
1. P
lasma-insulin Growth Factor
Binding Protein (IGFBP)-3
Because tumorigenesis and progression is a

process involving multiple genetic defects, it is likely
that alterations in other pathways will also affect
bladder cancer progression and metastasis. These
data, together with the current paradigm that bladder
cancer develops along multiple molecular pathways,
suggest that including multiple molecular markers in
models designed to predict outcomes could enhance
their predictive power. Therefore, use of multiple
molecular markers likely represents the future of risk
stratification and should be used to guide patient
counseling and management decisions such as
neoadjuvant and adjuvant therapy.
IV. Promising Blood-based

Prognostic Molecular
Markers
2. T
ransforming Growth Factor
(TGF)-1
The use of biomarkers in the blood offers several

advantages over tissue samples, such as that
of higher sample homogeneity and its minimally
invasive nature. Furthermore, blood samples
provide information that can be known at any
disease stage, offering an alternative to surgical and
clinical decision-making. However, whether further
value exists in regards to the clinical applicability of
these blood-based biomarkers remains to be tested
TGF-1 inhibits cell growth in cellular proliferation,

chemotaxis,
cellular
differentiation,
immune
response, and angiogenesis. Loss of response to
the antiproliferative effects of TGF-1 is associated
with the progressive stages of carcinogenesis.[151]
The effects of TGF-1 are mediated by membranebound serine-threonine kinase receptors, otherwise
known as TGF-1 receptor types I and II (TGF-
221
1-R1 and TGF-1-RII). Alteration of TGF-1 is

common in bladder cancer and overexpression of
TGF-1 is associated with the loss of expression of
its receptors.[151] An increased expression of TGF1 has also been linked with features of advanced
bladder cancer such as tumor grade, stage, and
lymphovascular invasion.[151-153] Elevated plasma
TGF-1 levels (n=51) have been associated with an
increased probability of regional and distant lymph
node metastasis even after adjusting for clinical
stage and grade (odds ratio [OR]: 12.8, p=0.03).
[153] However, others could not confirm this finding.
[152] Elevated levels of TGF-1 were associated
with an increased risk of disease recurrence and
cancer-specific mortality both in the preoperative
(HR: 1.6, p=0.009 and HR: 2.9, p=0.02, respectively)
and postoperative settings (HR: 3.1, p=0.01 and HR:
3.0, p=0.02, respectively).[153]
originate at least partly from the primary bladder

cancer cells. Nonetheless, further studies with larger
sample sizes are needed to better understand the
biologic and prognostic role of MMP-7 in bladder
cancer.
Limited data exist on other circulating MMPs
in patients with bladder cancer. Some reported
elevated concentrations of MMP-2 and MMP-3 in
patients with advanced bladder cancer (pathological
T24, N+, M+) compared to those in patients with
non-muscle-invasive bladder cancer (Ta-T1, N0,
M0). Lower levels of plasma MMP-2 (p=0.03)
have been associated with more advanced tumor
stage and grade.[163] Moreover, it appears that
the tissue inhibitor of metalloproteinases-(TIMP) 2,
which inhibits protease activity of MMP-2, could also
suppress invasion, metastasis, neovascularization,
and growth in some human tumors, and that the ratio
of MMP-2 and TIMP-2 is considered an independent
predictor of cancer recurrence.[167] Increased
MMP-9 serum levels have also been found in patients
with advanced clinical stage and grade.[168]
3. Matrix Metalloproteinase (MMP)

MMP is a family of zinc-dependent proteases involved
in the breakdown and remodeling of extracellular
matrix. A degradation of extracellular matrix is vital
in normal physiological processes, as well as in
pathological processes such as tumor progression
and metastasis. [154] In addition, MMPs can induce
several molecular processes implicated in tumor
progression through their cleaving abilities. MMPs
can mobilize pro-angiogenic factors, but are also
capable of generating angiogenic inhibitors, such
as endostatin and angiostatin. [155-157] In bladder
cancer, MMP expression has been associated with
more advanced stage and grade.[158-162] Plasma
MMP concentrations (-2, -3, -7, -8, and -9) collected
from 135 patients with high grade T1 or higher stage
bladder cancer[163] revealed that MMP-7 was
elevated in patients with advanced clinical stage
(p=0.02). Moreover, patients with MMP-7 levels
above the median (300 pg/mL) were at increased
risk of cancer-specific mortality compared to patients
with MMP-7 below the median (5-year survival
estimates: 48% vs. 74%, p=0.01). After adjusting
for the effects of clinical grade, MMP-7 remained an
independent predictor of cancer-specific mortality
(HR: 2.2, p=0.02).
4. Urokinase Plasminogen Activation

(uPA)
uPA is a serine protease involved in the formation and
regulation of blood vessels and clots, bone modeling,
and activation of metalloproteinases and growth
factors. It holds an important role in tumor invasion
and metastasis by accelerating the conversion of
plasminogen to plasmin. Subsequently, the plasmin
cleaves to components of the basement membrane
and extracellular matrix to allow tumor cells to
access lymph vessels and vasculature. The inactive
precursor of uPA is activated by binding to a specific
membrane-bound or soluble cell surface receptor
(uPAR). This hastens the conversion of plasminogen
into plasmin.
In bladder cancer cells, the presence of both uPA
and uPAR were necessary for in vitro invasion,
and invasive potential was reduced when their
interaction was interrupted. [171] Plasma levels of
uPA and uPAR were significantly higher in bladder
cancer patients (n=51) compared to healthy subjects
(n=44, p<0.001). [172] Higher uPA concentration was
associated with lymphovascular invasion (p=0.02)
and regional lymph node metastases (p=0.02),
while higher uPAR concentration was associated
with distant lymph node metastasis (p=0.04). In the
preoperative multivariable model, only uPA emerged
as an independent predictor of disease recurrence
(HR: 3.7, p=0.03) and cancer-specific mortality
(HR: 3.7, p=0.04). After validation, these markers
may be useful in selecting patients most likely to
benefit from intensified follow-up and therapy. These
markers should also be considered for integration in
prediction tools.
Szarvas et al confirmed these results in 79 serum

samples from bladder cancer patients and 19 healthy
individuals.[164] Higher levels of serum MMP-7 were
associated with bladder cancer presence (p<0.001),
lymph node metastasis (p=0.002), overall (p=0.008),
and cancer-specific mortality (p=0.006). However,
MMP-7 was not associated with tumor stage
(p=0.1) or grade (p=0.2). In multivariable analyses,
higher serum MMP-7 remained associated with
metastatic cancer (HR: 2.5, p=0.048) and cancerspecific mortality (HR: 2.0, p=0.04). Interestingly,
serum levels of MMP-7 decreased significantly after
surgery in 75% of cases suggesting that the higher
circulating MMP-7 in bladder cancer patients might
222
5. Interleukin-6 (IL-6) and IL-6 Soluble

Receptor (IL-6sR)
appropriate database and bioinformatic support, will

be effective tools to screen for novel markers and
to fingerprint each cancer. Indeed, the advent of
high-throughput methods of molecular analysis has
allowed the comprehensive survey of the genetic
profiles characteristic of distinct tumor types and
identification of targets and pathways that may
underlie particular clinical behavior. Several groups
also have used gene expression profiling of bladder
cancer tissues to identify signature genes that
distinguish bladder cancer subclasses and genetic
pathways underlying bladder cancer progression.
Such signature genes ideally would provide a
molecular basis for classification and also yield
insight into the molecular events underlying different
bladder cancer clinical phenotypes.
IL-6 is a cytokine that plays a role in the regulation of

the immune system via the proliferation and activation
of cytotoxic T cells, proliferation and differentiation of
B cells, and production of acute phase proteins. IL-6
signaling is initiated when IL-6 binds to the ligand
specific non-signaling receptor IL-6R, which also
exists in soluble form as IL-6sR. The latter arises
from 1 or 2 independent cellular processes, namely
differential mRNA splicing or proteolytic cleavage
of membrane bound IL-6 receptors. Previous data
support the hypothesis that bladder cancer cell lines
produce more IL-6 than normal urothelial cells.[173]
It seems that IL-6 confers a selective advantage for
certain disseminated cells to develop into metastatic
tumors. In a prospective study of 51 bladder
cancer patients, elevated IL-6 and IL-6sR levels
were associated with more advanced pathological
stage, lymphovascular invasion, and regional and
distant lymph node metastases.[174] Only IL-6
was correlated with clinical stage and tumor grade.
Both IL-6 and IL-6sR were independent predictors
of lymph node metastasis, disease recurrence,
and cancer-specific mortality after adjusting for the
effects of clinical stage and grade.
Microarray-based approaches have been used

extensively to look for expression profiles that could
sub-classify bladder cancers. Dyrskjot et al used
high-density oligonucleotide microarrays to identify
a 45-gene signature of disease progression in a
training set of 29 bladder cancer patients.[126] This
signature was then examined using an independent
test set (74 superficial tumor samples) revealing a
significant correlation between gene expression
classifications and clinical outcome.
Blaveri et al used cDNA microarrays (10,368 genes)
to identify differentially expressed genes along
the course of disease progression in 80 bladder
tumors, 9 bladder cancer cell lines, and 3 normal
bladder samples.[187] Unsupervised hierarchical
clustering successfully separated the samples into
2 subgroups containing non-muscle-invasive versus
muscle-invasive tumors, supported by a 90.5%
success rate. Tumors could also be classified
into transitional versus squamous subtypes (89%
success rate) and good versus bad prognosis
(78% success rate). Sanchez-Carbayo et al used
oligonucleotide arrays to identify genetic signatures
characteristic of aggressive clinical behavior in
advanced bladder tumors by transcript profiling of 52
normal urothelium, 33 superficial, and 72 invasive
tumors.[188] Unsupervised clustering classified them
with 82.2% accuracy, while predictive algorithms
rendered an 89% correct rate for tumor staging using
genes differentially expressed between superficial
and invasive tumors. Accuracies of 82% and 90%
were obtained for predicting overall survival when
considering all patients with bladder cancer or only
patients with invasive disease, respectively.
6. Soluble E-cadherin (sE-Cadherin)

E-cadherin is a member of the family of transmembrane
glycoproteins involved in calcium dependent
intercellular adhesion. [175] Normal E-cadherin
expression suppresses tumor progression. When
altered, it allows cancer cells to detach, invade,
and access the lymphatic and vascular system. In
bladder cancer, as in other malignancies, a decrease
in E-cadherin expression has been linked with an
increased risk of metastases, tumor progression,
and cancer-specific mortality. [177-182] sE-cadherin
is the degradation product of cellular E-cadherin,
generated by Ca2+ ion dependent proteolytic activity.
Several authors have found increased serum levels
of sE-cadherin in bladder cancer patients compared
to non-cancer subjects. Moreover, sE-cadherin was
significantly associated with regional lymph node
metastasis as well as disease recurrence. However,
sE-cadherin failed to achieve statistical significance
when cancer-specific mortality was the endpoint of
interest.
V. High-throughput Tumor
Profiling
Target validation of synuclein by immunohistochemistry on tissue arrays (N=294) sustained its association with tumor staging and outcome. Lindgren
et al successfully used this approach to distinguish
specific molecular subtypes of bladder cancer and
define gene signatures that can classify bladder
cancer by grade as well as muscle-invasion status.
Furthermore, they reported a gene expression sig-
As our understanding of the individuality of cancers

evolves, we will rely on molecular fingerprints to
tailor management and therapeutic approaches
to the clinical, morphological, and molecular
features of each patient. High-throughput genomic,
transcriptomic, and proteomic assays, with
223
nature that is associated with both metastasis and

survival.[189] Takata et al examined expression profiles of 27,648 genes in 27 cases of bladder cancer
to predict response to a neoadjuvant methotrexate,
vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy regimen.[190] They identified 14 genes
with a correct prediction in 8 out of 9 patients. These
studies suggest that defining gene expression signatures may be a relevant complement to standard
clinical and pathological risk stratification. However,
current costs associated with examination of such a
large number of genes make transition to the clinical
realm difficult.
9. Malats N, Bustos A, Nascimento CM, et al: P53 as a

prognostic marker for bladder cancer: a meta-analysis and
review. Lancet Oncol 6:678-86, 2005
Conclusions
14. Diamandis EP: Proteomic patterns to identify ovarian

cancer: 3 years on. Expert Rev Mol Diagn 4:575-7, 2004
10. Dalbagni G, Parekh DJ, Ben-Porat L, et al: Prospective

evaluation of p53 as a prognostic marker in T1 transitional
cell carcinoma of the bladder. BJU Int 99:281-5, 2007
11. Svatek RS, Jeldres C, Karakiewicz PI, et al: Pretreatment biomarker levels improve the accuracy of postprostatectomy nomogram for prediction of biochemical
recurrence. Prostate 69:886-94, 2009
12. Bensalah K, Lotan Y, Karam JA, et al: New circulating
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Dis, 2007
13. Check E: Proteomics and cancer: running before we can
walk? Nature 429:496-7, 2004
Bladder cancer is an especially complex and

heterogeneous disease with a broad spectrum of
histologic findings. Molecular medicine holds the
promise that clinical outcomes will be improved by
directing therapy toward the mechanisms and targets
associated with the growth of an individual patients
tumor. The advent of high-throughput technologies
is allowing comprehensive identification of molecular
targets and molecular markers specific for bladder
cancer. Such identification processes may provide a
better understanding of the biology associated with
tumorigenesis and tumor progression. However,
further research is warranted in the field to translate
the identification of these molecular targets into
potential predictive molecular markers. The challenge
remains to optimize measurement of these targets,
evaluate the impact of such targets for therapeutic
drug development, and translate molecular markers
into improved clinical management of bladder cancer
patients.
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229
230
Committee 4
Low Grade Ta Urothelial

Chairs:
Badrinath Konety,
Willem Oosterlinck
Members:
Sam Chang,
Raj Pruthi,
Mark Soloway,
Eduardo Solsona,
Paul Sved
231
Table of Contents
I. Urinary cytology, urinary
markers and the follow-up
of low grade non muscle
invasive bladder tumors
III. Expectant Management of

LG Ta Urothelial Carcinoma
IV. Intravesical Treatment for
LG Ta Tumors
II. Upper Tract Studies in

Patients with LG Ta Urothelial
Carcinoma
1. Intravesical Chemotherapy
V. Immunotherapy (BCG) in LG Ta
Patients
1. Upper Tract Studies at the Time

of Diagnosis of LG Ta Urothelial
2. Upper Tract Surveillance of
Patients with Low Grade Ta
Urothelial Cancer
VI. Other Immunomodulating

Therapies
232
Low Grade Ta Urothelial Carcinoma

of the Bladder
Badrinath Konety, Willem Oosterlinck,
Sam Chang, Sigurdur Gudjonsson,
Raj Pruthi, Mark Soloway,
Eduardo Solsona, Paul Sved
In this section we have attempted to review all the

literature pertaining to non-muscle-invasive bladder
cancer and cull out the facts specifically pertaining
to low grade Ta (LG Ta) urothelial carcinoma. The
evidence available is often buried in broad studies of
all non-muscle-invasive bladder cancer and hence
the patients with LGTa urothelial carcinoma constitute
a smaller subgroup. Such subgroup analyses may
be inadequately powered, given the original primary
endpoints of many of the studies which would have
taken into account sample sizes for all non-muscleinvasive bladder cancer together. The evidence
available was analyzed using the Oxford method
of assigning the levels of evidence and summary
recommendations based on these levels of evidence
were graded as advised by the Oxford Centre
for Evidence-based Medicine, which are similar
to the GRADE working group recommendations
[1]. At the end of each section, a summary of the
recommendations and a ready reference table with
the recommendations and the levels of evidence
as well as the grade of the recommendation are
provided.
I. Urinary cytology, urinary

markers and the follow-up
of low grade non muscle
invasive bladder tumors
Extensive laboratory research has led to the
development of numerous urinary markers for
diagnosis of bladder cancer. The number of
publications identified through a PubMed search are
enormous when bladder cancer and biomarkers
or molecular markers are searched [2]. Many of
them exhibit sensitivity superior to urine cytology,
often with lower specificity. A few of them have been
applied clinically, but none has been accepted as a
standard diagnostic test in routine urology or included
in published guidelines to date. Insufficient and
inconsistent evidence for the use of such markers in
surveillance of non-muscle-invasive bladder cancer
is the reason for this [2,3].
The aim of surveillance in LG Ta tumors is mainly
for the timely detection of recurrences. LG Ta tumors
progress to more aggressive tumors in less than
1% of the cases. Recurrences are frequent, and the
main prognostic factors are multiplicity of the tumors
and rapid recurrence. Most guidelines advocate
cystoscopy at 3 months after initial resection in order
to detect rapid recurrence but subsequent cystoscopy
at yearly intervals thereafter if no tumor is detected
on first post-resection cystoscopy [4]. Besides that,
office fulguration of small, isolated recurrences is an
acceptable and widely used method for the treatment
of recurrent LG Ta tumors.
The initial diagnosis of LG Ta urothelial carcinoma

requires the performance of a transurethral resection
or biopsy. It is recommended that the presence
of muscle on the initial resection specimen be
documented to ensure accurate stage designation
as Ta. It is not required that biopsies for recurrent
LG Ta urothelial carcinoma have muscle present in
the specimen. This may be particularly the case with
office biopsies under local anesthesia where a deep
specimen will be difficult to obtain. Forcep biopsies
can only be pursued in patients with a documented
history of recurrent LG Ta urothelial carcinoma and
not for the initial presentation of bladder tumor.
What is the role of urinary cytology and markers in

this context?
233
Requirements for a good marker in this context

follow:
Ta tumors could be better identified by urinary

markers. Hence, urinary markers may have a role
in a low intensity surveillance program where the
cystoscopy interval is longer, such as 1 year, to
monitor for larger, recurrent LG Ta tumors during the
intervals. Large prospective randomized studies
of alternative surveillance regimens incorporating
urinary markers for low grade tumors are required
to definitely establish the utility of such markers in
the surveillance of LG Ta tumors.
1. It must detect all high grade tumors while they

are still amenable to curative treatment. Urinary
cytology is highly sensitive in this regard and
most commercially available urinary markers are
even slightly more sensitive. The problem with
cytology is interobserver variability [5,6] due to the
subjectivity of the test. Urinary markers are more
objective. The problem with the urinary markers
is the frequent occurrence of false positive tests
and thus the lack of specificity. As the likelihood
of LG Ta to high grade tumors is low, cytology and
markers are of limited value in this regard.
3. T
he test should also be well accepted by the
patient, regarding the risk of overlooking a tumor
versus the discomfort and slight risks of the
cystoscopy.
2. In order to be able to replace cystoscopy, a urinary

marker should be able to detect recurrent tumors
before they are large and numerous. Cytology
performs poorly in this context. Several urinary
markers do better but still do not detect a large
proportion of the low grade tumors detectable by
cystoscopy. Among the commercially available
urinary markers, some of the best results for
detecting recurrent LG Ta tumors have been
obtained using immunocytology (uCyt). But
even this test has not demonstrated adequate
consistency and reliability to be able to replace
cystoscopy. One potential role for urinary markers
in the setting of LG Ta tumors is for reducing the
frequency of cystoscopy wherein these markers
can be utilized alternatively or interspersed with
cystoscopy for surveillance. Most protein-based
urinary markers such as NMP22 are affected
by the volume of the tumor, but recurrent low
grade tumors often are small. Larger, multiple LG
4. Preferentially tests should be point-of-care test,

with results available readily, easy to perform, with
a short learning curve, widely available, and not
too expensive. Table 1 [7] gives an overview of
how far the available urinary markers correspond
to these criteria.
Numerous reviews on urinary markers have
appeared in the last several years supporting the
statements made above [8-14]. They have all
come to the conclusion that urinary markers are
insufficiently tested in surveillance of non-muscleinvasive bladder cancer and that cystoscopy cannot
yet be omitted but at best can perhaps be delayed.
About the existing markers we can conclude the
following: The BTA test has a very limited role
because of its high false positive rate and low
sensitivity in low grade tumors [15,16]. NMP22
similarly suffers from high false positive rate but
may have higher sensitivity than cytology, and
Table 1. Summary of main urinary markers that could be used in Lg Ta UC
Markers
Overall
Overall
Interference by
BCG
Comments
UroVysion
Microsatellite
analysis
Gene microarray
sensitivity
(%)
30-72
specificity
(%)
63-95
and other bladder

conditions
No
Expensive and laborious
58
80-90
73
62-65
No
No
Immunocyt/ uCyt+
Nuclear matrix
protein 22
76-85
63-75
Yes
49-68
85.8-87.5
Yes
BTA stat
57-83
68-85.7
Yes
Low sensititivy
BTA TRAK
53.8-91
28.3-83.9
Yes
Low sensitivity
Cytokeratins
12.1-85
75-97.4
Yes
Survivin
53-90.4
88-100
No
Low sensitivity
Low sensitivity, expensive and
laborious
234

Good sensitivity in low-grade
tumors
Low sensitivity,
with selection of patients the specificity can be

improved [17-19]. Because of its high negative
predictive value, it can be used to prolong the
interval between cystoscopies. ImmunoCyt has the
highest sensitivity in detection of low grade tumors
and is less minimally affected by other urological
diseases [20], but with a 60% detection rate of low
grade tumors, the test remains largely insufficient to
replace cystoscopy. The combination of ImmunoCyt
with cytology appears to improve sensitivity and
negative predictive value, which can allow for more
accurate identification of those individuals who will
have a negative cystoscopy [21].
fluorescent cystoscopy has been shown to be able

to detect additional lesions compared to white light
cystoscopy. In at least one study, photodynamic
diagnosis using Hexvix was able to detect 25
additional LG Ta lesions in a cohort of 108 patients
with Ta bladder tumors [27]. Several randomized
studies have demonstrated the ability of fluorescent
cystoscopy-aided TUR to reduce recurrences as
well as improve recurrence-free survival. However,
these data do not specifically pertain to those with
LG Ta tumors but pertain to all non-muscle-invasive
bladder cancer [27]. At this time, the precise role of
photodynamic diagnosis in the diagnosis and followup of LG Ta tumors is evolving.
Urovysion/FISH adds little in the surveillance of low

grade tumors but can perhaps be used to adjudicate
inconclusive results of urinary cytology (e.g., atypical)
in order to prevent excessive work-up of such
patients [22]. FISH may have a larger role in high
grade and higher stage tumors as it can detect occult
disease and identify those patients who are likely to
recur and may be useful for predicting response to
intravesical therapy [23,24]. Microsatellite analysis
holds promise for predicting recurrences of low
grade tumors, as it appears to be able to identify
such recurrences in up to 80% of the cases but is
lacking in sensitivity [25,26].
More
recently,
photodynamic
diagnosis
Summary
Protein based urinary markers such as BTA and
NMP22 may have better sensitivity than cytology
for LG Ta tumors, but their specificity is too low to
allow them to replace cystoscopy. ImmunoCyt has
the best sensitivity for LG Ta tumors and can be
used to prolong intervals between cystoscopy but
cannot replace cystoscopy. FISH analysis does
not have a clear role in diagnosis of LG Ta tumors.
Photodynamic diagnosis may have benefit in
enhanced detection of LG Ta tumors but is limited by
low specificity and need for rigid cystoscopy.
or
Recommendation
Recommendation
Level of
Grade of
recommendation
B
A
BTA has little role in diagnosis of LG Ta tumors.

NMP22 has better sensitivity than cytology but cannot replace
evidence
2b
1b
cystoscopy.
ImmunoCyt has good sensitivity for LG Ta tumors and can be
2a
used to prolong intervals between cystoscopy.

UroVysion/FISH has no role in diagnosis of LG Ta tumors.
2b
II. Upper Tract Studies in

Patients with LG Ta Urothelial
Carcinoma
Information regarding the incidence of synchronous

upper tract urothelial carcinoma in patients with
noninvasive urothelial carcinoma is difficult to interpret
because most reports include patients with high risk
disease such as carcinoma in situ in addition to those
patients with low grade disease. Bajaj et al reported
that 4 of 120 (3.3%) patients with Ta bladder tumors
were diagnosed with a synchronous upper tract
tumor[28]. Palou et al, in a retrospective analysis of
1529 patients with noninvasive urothelial carcinoma,
found 6 synchronous upper tract tumors in 547
(1.1%) patients with LG Ta disease[29]. Goessl et al
reported no synchronous upper tract tumors in 207
patients with noninvasive bladder cancer [30].
1. Upper Tract Studies at the Time

of Diagnosis of LG Ta Urothelial
Urothelial carcinomas of the urinary tract exhibit a
well-known tendency for multifocal growth. Despite
this, the use of imaging to detect synchronous renal
or ureteric urothelial tumors at the time of diagnosis
of LG Ta urothelial carcinoma of the bladder is
controversial. Some authors advocate routine
imaging of the upper tracts while others suggest
restricting such imaging to high risk patients,
including those with multiple bladder lesions[28-31].
In addition, the optimal imaging technique remains
undetermined.
Little information is available regarding the

clinicopathological features of low grade bladder
cancers most likely to be associated with a
synchronous upper tract urothelial carcinoma. It has
235
been suggested that multifocal non-invasive bladder

cancer is associated with a higher risk of concomitant
upper tract disease but there is no evidence that this
is the case if the bladder cancer is low grade [32].
Palou et al reported that only trigonal involvement
was associated with upper tract urothelial carcinoma
at diagnosis [29]. However, in this study low grade
tumors were not analyzed in isolation and it is
therefore possible that trigonal tumors were in fact
high grade.
additional staging information, including imaging of

pelvic lymph nodes and the detection of other intraabdominal abnormalities. The positive predictive
value of CT urography is over 80% for lesions greater
than 5 mm [33].
Summary
Synchronous upper tract urothelial carcinoma is rare
in patients with LG Ta urothelial carcinoma. Routine
IVU or CT urography is not recommended for these
patients at the time of diagnosis. However, thorough
upper tract evaluation is required for patients
presenting with gross hematuria and/or unexplained
positive urine cytology in the presence or absence of
a low grade noninvasive bladder tumor.
Intravenous urography (IVU) has traditionally been

the gold standard in the detection of upper tract
urothelial carcinoma. More recently, CT urography
has emerged as a technique to evaluate the upper
tract[33-35]. CT urography has a higher sensitivity
and specificity compared with IVU and provides
Recommendation
Recommendation

Routine upper tract studies are not recommended for patients

with LG Ta tumors at diagnosis of index tumor.
Upper tract evaluation in patients with LG Ta urothelial
carcinoma is recommended in the presence of:
Level of
evidence
2b
Grade of
recommendation
B
2b
o gross hematuria
o unexplained positive urine cytology
2. Upper Tract Surveillance of

Patients with Low Grade Ta
Urothelial Cancer
bladder cancer, Wright et al studied almost 100,000

patients in the Surveillance, Epidemiology and End
Results (SEER) registry [42]. Of 56,271 patients
with a Ta bladder tumor at diagnosis, 472 (0.3%)
were subsequently diagnosed with an upper tract
urothelial carcinoma. This report is especially
significant as it reflects the risk of recurrence in
patients in community practice rather than from
tertiary centers alone. The SEER analysis found that
patients with Ta bladder cancer were more likely to
be diagnosed with an upper tract recurrence than
those with muscle-invasive bladder cancer, although
this may reflect poorer overall survival in the latter
group. The mean time to upper tract recurrence in
the entire cohort was 33 months. Other reports place
the risk of upper tract urothelial carcinoma in patients
with Ta bladder cancer at 0.6- 2.5% [40,42-45], with
a wide range of upper tract recurrence intervals from
5 months to 6.2 years [38,39,46].
The presence of UC in the bladder is a wellrecognized risk factor for the subsequent diagnosis
of upper tract urothelial cancer [36]. Nevertheless,
there remains considerable uncertainty regarding
the value of routine upper tract imaging in the followup of patients with non-invasive urothelial carcinoma.
Some investigators have recommended annual or
biennial IVU, while others have concluded that there
is no need for regular monitoring of the upper tracts
[37-40]. This uncertainty is reflected in the wide
variance in practice of community urologists [41].
a) Incidence and Risk factors

In a retrospective review of 375 patients with Ta
urothelial carcinoma followed for a median of 6
years, Canales et al reported a subsequent upper
tract tumor in 13 (3.4%) patients [36]. The risk of
upper tract recurrence was the same regardless of
the grade or number of initial Ta bladder tumor(s).
Upper tract tumors were diagnosed at an average
of 22 months after initial bladder tumor diagnosis. In
the largest ever review investigating metachronous
upper tract urothelial carcinoma in patients with
Canales et al used multivariate analysis to determine

predictors of upper tract urothelial carcinoma in their
cohort of patients with Ta bladder cancer [36]. They
found that only patients with 2 or more recurrences
within 12 months of diagnosis were at higher risk of
upper tract tumor. Other studies group patients with
Ta and high grade T1 disease together, making the
data very difficult to interpret. These studies suggest
236
a weak link between tumor multiplicity, vesicoureteric

reflux, and upper tract recurrence in non-muscleinvasive bladder cancer [38,42,47,48].
surveillance for LG Ta urothelial carcinoma cannot

be recommended.
Summary
There is no evidence that the prognosis of patients

with upper tract urothelial carcinoma after Ta bladder
cancer is improved by early detection using routine
surveillance IVU, compared to patients presenting
with symptoms such as flank pain or gross hematuria
[36,48,49]. This is also the case for high grade noninvasive bladder cancer requiring BCG [49,50].
Hence routine upper tract surveillance does not
appear to have a clear benefit in patients with high
grade lesions, and therefore can be expected to have
even less relevance for those with low grade lesions.
Such routine surveillance would only add cost and
inconvenience to patients and not yield demonstrable
benefit. Hence the strategy of routine upper tract
The incidence of metachronous upper tract urothelial

carcinoma in patients treated for low grade,
noninvasive bladder cancer is low, particularly in
population-based analyses. There is no consistent
risk factor for upper tract recurrence, which may
occur years after initial diagnosis. There is no
evidence that upper tract lesions detected on routine
imaging are associated with a more favorable
prognosis. Therefore, routine upper tract surveillance
in patients with low grade Ta bladder cancer is not
recommended.
Recommendation
Recommendation
Routine upper tract studies are not recommended for

surveillance of patients with LG Ta tumors during follow-up.
Level of
evidence
Grade of
recommendation
2b
grade or stage progression [55-57]. These frequent

recurrences often result in repeat TURBTs, because
urologists are taught to remove tumors when they
are identified in accordance to past teachings and
guideline recommendations. In other words, past
and present practice has suggested that many
patients will undergo multiple TURBTs to manage
these small, recurrent, low-risk tumors.
III. Expectant Management of

LG Ta Urothelial Carcinoma
Complete transurethral resection is still considered
to be the gold standard in managing noninvasive
bladder tumors. Indeed, EAU guidelines note that the
goal of TURBT in Ta tumors is to make the correct
diagnosis and remove all visible lesions, and NCCN
guidelines explicitly state that TURBT is the standard
treatment for cTa, low grade tumors.[51,52] Current
AUA guidelines also suggest that TURBT is the
treatment of choice for most non-invasive bladder
tumors, but go on to acknowledge the potential role
of conservative management for certain patients with
recurrent low risk noninvasive disease.[53]
In deciding treatment options, other important aspects

are not only tumor recurrence rates but also grade
and stage progression, as this denotes a decidedly
poorer prognosis in bladder cancer. The natural
history of low risk bladder tumors is well-established,
and the rates of progression and mortality from
bladder cancer in patients with this type of tumor are
extremely low [55-58]. This is regardless of age at
presentation. The low likelihood of progression and
the indolent nature of certain types of bladder tumors
may therefore have a negligible effect on survival in
select patients who will die with their disease and not
from it. [55]
In this section, we will address the potential role of

observation of low risk bladder tumors by evaluating
the rationale for such an approach as well as the
clinical experience and reported evidence to date.
The terms observation, expectant management,
and active surveillance will be used interchangeably
for these discussions and recommendations.
Furthermore, though tumor resection is usually welltolerated, it is not without risks, especially in the elderly
or those with significant medical comorbidities. These
patients face greater risks with regional or general
anesthesia and often require postoperative hospital
stays, both of which increase cost and the burden to
our health care systems. [59] Complications directly
associated with TURBT must also be acknowledged,
Rationale
Approximately 50% of newly diagnosed cases of
bladder cancer are low risk papillary tumors (LG
Ta) [54]. Although the majority of these patients
will recur after initial TURBT, few will demonstrate
237
including bleeding and perforation in the short-term,

and bladder contracture and urethral stricture in the
long-term. [60]
stage progression as well. Both men had evidence of

moderate tumor growth and suspicious or malignant
cytology heralding such progression and resulting
in repeat TURBT. However, similar to the results of
Soloway et al, neither of these tumors progressed to
muscle-invasive disease. [64,66] Interestingly, these
2 men had prolonged histories of recurrent LG Ta
disease before progression, thus demonstrating the
ability of low risk tumors to progress even at distant
follow-up. Accordingly, the recommendations for
lifelong surveillance of all bladder tumor patients
seem justified. In what appears to be the largest
case series, Hernandez et al recently published their
experience with observation in 66 patients with low
risk bladder tumors. [67] In this series, the authors
selected patients with smaller tumors (less than 1
cm), but also included patients with T1a disease,
which are generally accepted as being higher risk
than LG Ta tumors. Despite this, at a median followup of over 10 months, the majority of patients had
neither stage (94%) nor grade (84%) progression,
and, like the prior studies, no patient progressed to
muscle-invasive disease.
Consequently, some have recently questioned as to

whether such an aggressive follow-up and treatment
regimen is warranted for these low risk patients.
Surveillance for bladder tumors, as compared
to prostate cancer or renal masses, is relatively
easy to perform, as the clinician has direct ways
to monitor the bladder urothelium through cytology
and cystoscopy. Indeed, it has been shown in a
study by Herr et al that low grade papillary tumors
were accurately identified at cystoscopy 93% of
the time, and when information from urine cytology
was added, the accuracy increased to 99%. [61]
Furthermore, the cystoscopic findings of bladder
cancer are accurate in predicting muscle-invasive
disease as well. [62] If staging and grading can be
accurately performed by cystoscopy, many patients
may be spared unnecessary trips to the operating
room.
Therefore, the rationale for observation of low risk
bladder tumors is to spare patients the morbidity and
inherent risks of repeat TURBT. Short- or long-term
surveillance of tumors has the potential to reduce the
number of resections that patients would undergo in
their lifetime. For the bladder cancer patient and the
treating urologist, the proper balance must be found
between the risk of progression and the patients
current state of health and medical comorbidities.
The decision to observe versus intervene is a balance
between the morbidity of treatment and follow-up
versus the risks of progression in each individual
patient. As has been suggested by Soloway, the
emphasis should be to do no harm and to avoid over
treatment. [63]
From these series, there does not appear to be any

clear patient selection criteria aside from the low
risk features that were observed in the majority of
patients. [64-67] Common findings in these studies
included patients with Ta tumors, low grade disease,
and low tumor burden (smaller tumors, fewer
lesions). The studies often recommend careful
and individualized patient selection. In fact, in the
studies of Soloway et al and Pruthi et al, only a
small percentage of their patient population were
included into an observation protocol (8% and 13%,
respectively). [44,66] Furthermore, most recommend
detailed discussion with patients as to the rationale
and strategy of observation. Indeed, in the study by
Hernandez, the authors note that once the treatment
alternatives were explained, a high percentage of
patients preferred to undergo close monitoring by
cystoscopy and to delay the surgery for as long as
possible. [67]
Published Data
Soloway et al were the first to expectantly observe
patients with low risk disease. They observed that in
32 patients with stage Ta or T1 tumors, only 3 (9%)
progressed in either stage or grade, and none had
progression to stage T2 disease.[64] Similarly, Gofrit
et al also demonstrated that expectant management
may be an acceptable course in patients with low
risk disease.[65] They followed 28 patients for 38
observation periods. Although 30 of these periods
were terminated because of recurrence or additional
growth, all resected tumors were found to be Ta
and grade 1 or 2 (i.e., none had grade or stage
progression). They also observed that initial tumor
diameter was predictive of tumor growth during the
observation period.
There also exists a growing body of evidence as

to the potential use of office fulguration for low risk
tumors, i.e. partial or total tumor ablation during
local cystoscopy, often at the time of surveillance.
Although the present discussion is focused on the
potential role of observation, office fulguration may
serve as an appropriate alternative to formal TURBT
in select patients. [68-70]
As urologists, we must weigh the risks and benefits
of aggressive versus conservative treatment in
dealing with non-invasive bladder tumors. The goal
of TURBT is to eliminate any visible tumor, and
this is the most assured way to prevent disease
progression. However, it does so with an increased
surgical and perioperative risk and cost. A balance
must be found between the risk of progression and
Pruthi et al showed that the majority of patients

with low-risk disease had no evidence of stage
or grade progression on a surveillance program.
[66] Two men (9%) were observed to have grade
progression of their disease, with 1 (4.5%) having
238
the patients current state of health and medical

comorbidities. Although expectant management
appears to be a safe treatment option, it is likely not
the best choice for everyone.
Future investigation should involve better quality

studies with higher levels of evidence to evaluate 1)
oncologic appropriateness of expectant management,
2) the impact of surveillance programs on the overall
health status and survival of the patients (including
potential benefits of avoiding repeated operating
room procedures), 3) effects on quality of life in
patients undergoing tumor observation versus repeat
TURBTs, and 4) potential impact of surveillance
programs on the economic costs and utilization of
our health care systems.
Of note, observation (or office fulguration), should

not replace formal TURBT with the patient under
anesthesia as primary treatment for the initial tumor
or for recurrence suspected on gross inspection to
represent a change in tumor stage or grade. TURBT
not only establishes the clinical stage of the tumor,
but it also serves as the basis for adjuvant treatment
decisions and surveillance intervals. Whenever there
is clinical doubt whether a patient is a candidate for
observation or fulguration, the patient should always
undergo a formal TURBT.
Summary
Observation can be considered for patients with
recurrent LGTa urothelial carcinoma (or PUNLMP) as
proven by prior TURBT. Optimal tumor characteristics
include those with low tumor burden. Optimal patient
characteristics include those with advanced age and
comorbidities, those with frequent recurrences, and
those without symptoms. Younger patients can also
be offered observation as long as they are aware
of the risks and benefits of immediate TUR vs.
observation. Observation includes cystoscopy and
urinary cytology at routine surveillance intervals.
Patients should be appropriately counseled as to the
treatment strategy and rationale, as well as to the
potential risks inherent with observation of a malignant
tumor. If the cytology is suspicious or positive, the
patient should be taken to the operating room for
a formal TURBT and other appropriate evaluation
under anesthesia. If there is increase in the size and
number of lesions, or other concerning changes on
gross appearance of the urothelium, then the patient
should be taken to the operating room for a formal
TURBT under anesthesia. For small lesions (less
than 1 cm) associated with negative cytology, office
fulguration is also an option. This can be followed by
immediate instillation of intravesical chemotherapy
to prevent recurrence (see below).
We
must
acknowledge
several
possible
shortcomings of the data available in regard to
the expectant management of LG Ta urothelial
carcinoma. Most of the current evidence is from
retrospective observational case series that do not
have the strength of a randomized control trial, the
gold standard of evaluating treatment efficacy and
superiority. Accordingly, there have been no clear and
uniform selection criteria for expectant management.
In addition, certain assessments in the reported case
series were of a subjective nature, including tumor
growth assessments, decisions to intervene, and
subsequent management. Nevertheless, qualitative
assessments of tumor change combined with more
quantitative evaluations of urine cytopathology seem
to best reflect the tools used in everyday clinical
practice. Such tools combined with the ability for
urologists to appropriately determine, cystoscopically,
when a recurrent tumor has progressed (without the
need for TURBT or biopsy) as demonstrated by
Herr et al, appear to be adequate in identifying early
disease progression before muscle-invasive disease
occurs. [61]
Recommendation
Recommendation

Expectant management should be pursued only in patients

with an established history of LG Ta urothelial carcinoma.
Optimal tumor characteristics include low tumor burden.
Observation is particularly applicable to those with advanced
age or comorbidity, but can be offered to younger patients
after careful and thorough discussion.
Surveillance includes periodic cystoscopy and cytology.
Patients who demonstrate increase in size, number or
appearance of tumor(s), or develop positive urine cytology
should cease expectant management and undergo formal
TUR and further evaluation.
Office fulguration is a good option for patients with small LG
Ta urothelial carcinoma. This can be followed by immediate
instillation of intravesical chemotherapy.
239
Level of
evidence
3
Grade of
recommendation
B
3
4
B
C
3
3
B
B
IV. Intravesical Treatment for

LG Ta Tumors
ultrasound bladder scanner), and a higher mitomycin

C concentration (40 mg in 20 mL of sterile water).
Other methods exist but have been examined in
higher risk individuals.
1. Intravesical Chemotherapy
c)
Intercalating
Agents
Epirubicin, and Valrubicin)
In most cases of non-muscle-invasive bladder

cancers, TURBT plays an essential diagnostic
and therapeutic role, and this is certainly the case
for LG Ta tumors. A careful cystoscopic evaluation
and eradication of tumor is an important initial
therapeutic intervention. While in some cases tumor
ablation may suffice as initial therapy, intravesical
chemotherapy plays an important role in decreasing
the recurrence rates of these tumors.[71-73]
(Doxorubicin,
The rationale for perioperative instillation includes the

destruction of residual microscopic tumor at the site
of TURBT and of floating cells, thereby preventing
reimplantation at the time of TURBT. Intravesical
therapy can also be employed in a maintenance
fashion as opposed to an induction course alone to
prolong the beneficial effects of the chemotherapy.
Because of its high molecular weight of 580 kD,

absorption and systemic toxicity of the anthracycline
derivative doxorubicin are extremely rare. Doses
vary widely, from 10 mg to 100 mg, in instillation
schedules that range from 3 times a week to
once a month. Epirubicin is related chemically to
doxorubicin and has been used in multiple studies
for initial post-TUR instillation as well as for multidose intravesical chemotherapy. It appears to have
a favorable toxicity profile and good efficacy. It offers
an attractive alternative to mitomycin C. Valrubicin, a
semi-synthetic analog of doxorubicin, was approved
by the US FDA in 1998 for the treatment of BCGrefractory carcinoma in situ of the bladder in patients
who are medically unfit or refuse a cystectomy.
Chemotherapeutic Agents
d) Gemcitabine
Chemotherapeutic agents include thiotepa, an

alkylating agent that cross-links with nucleic acids;
mitomycin, an antibiotic that inhibits DNA synthesis;
epirubicin, doxorubicin, and valrubicin, intercalating
agents that inhibit DNA synthesis; gemcitabine, a
deoxcytidine analog that inhibits DNA synthesis.
Gemcitabine has a broad spectrum of antitumor

activity and intravesical gemcitabine has been shown
to have activity in non-muscle-invasive bladder
cancer in intermediate risk and high risk patients.
Typical intravesical doses employed include 2 g in
50 to 100 mL of saline given weekly for 6 weeks with
2 hour dwell times. Gemcitabine is currently being
tested for post-TUR instillation in all tumors as part
of a study sponsored by the Southwest Oncology
Group in the US. In a randomized placebo controlled
study, Bohle et al [76] compared post-TUR instillation
of gemcitabine to bladder irrigation with saline and
found no difference in recurrence rates for tumors
of all stages/grades. Hence immediate post-TUR
instillation of gemcitabine does not appear to yield
any benefit over bladder irrigation in preventing
recurrences in patients with LG Ta urothelial
carcinoma.
a) Thiotepa
Introduced in 1961, thiotepa is the oldest and one
of the least expensive of the intravesical drugs.
Doses range from 30 mg in 30 mL of sterile water
or saline to 60 mg in 60 mL of water or saline. The
usual regimen consists of 6 to 8 weekly instillations
followed by monthly instillations for 1 year, but there
is no standard regimen. A low molecular weight of
189 KD increases possible systemic toxicity, and
myelosuppression is a risk. Importantly, the 2007
AUA Guidelines do not recommend thiotepa as an
effective chemotherapy agent. [74]
e) Therapeutic Schedules
b) Mitomycin C
The ideal intravesical chemotherapy regimen would

maximize effectiveness while decreasing the number
of therapies and maintaining a favorable side effect
profile. Data, although sometimes conflicting, is
available regarding the likelihood of treatment
efficacy for these agents. Recent meta-analyses
have attempted to clarify a sometimes murky picture.
Further clouding the situation is the fact that most
studies do not focus solely on LG Ta tumors but
instead on higher risk tumors.
This agent has a molecular weight of 329 KD,

and the side effect of myelosuppression is less
likely. Although the optimal method of mitomycin
C administration is uncertain, Au et al [75] have
demonstrated improved recurrence-free survival
and a prolonged median time to recurrence using
methods to enhance the effectiveness of this
medication. The strategy consisted of a period of
dehydration (no fluids for 8 hours prior to treatment),
urinary alkalinization (1.3 g NaHC03 by mouth, the
night prior, the morning of, and 30 minutes prior
to the intravesical therapy), confirmed complete
bladder drainage prior to intravesical instillation of
mitomycin C (post void residual less than 10 mL by
f) Perioperative Chemotherapy
A European Organisation for Research and Treatment
of Cancer (EORTC) study comparing epirubicin to
water immediately following TURBT demonstrated
240
that patients with primary and solitary recurrent

Ta tumors had a 50% decrease in recurrence with
epirubicin. [77]
further exploration.
The most common side effect of intravesical
chemotherapy is some form of lower urinary tract
symptoms (dysuria, frequency, and urgency) and
hematuria. Perioperative mitomycin C should
not be administered to patients with a known or
suspected bladder perforation following TURBT
as a small number of serious complications
related to mitomycin C extravasation have been
reported [82].
In a meta-analysis performed by the AUA Guidelines

Panel in 2007, a statistically significant 17%
decrease (95% CI 8-28%) in median recurrence
rate was found. No effect on progression was noted
[4]. Two trials were identified by the AUA Panel as
suitable for meta-analysis and included a combined
427 patients. In the larger trial by Tolley et al [78],
60% of the subjects treated with TURBT alone had
recurrences at 5 years compared to 45% of those
receiving a single, postoperative instillation of 40 mg
of mitomycin in 40 mL of water. Solsona et al [79]
reported a statistically significant decrease in early
recurrence of up to 2 years in patients who received
the single dose of mitomycin C. This study did focus
on lower risk patients; all patients had a 3 cm or less
single, papillary, primary, or recurrent tumor and
were disease-free for more than 1 year. Patients with
muscular invasion, G3 tumor, or bladder carcinoma
in situ on pathologic examination were excluded
from this study.
g) Induction Chemotherapy
At this point, it is unclear if any chemotherapeutic
agent holds superiority over another. A recent trial
advocated the superiority of gemcitabine over
mitomycin C, but the dosing schedule used was
different from those employed in prior studies [83].
Importantly, although maintenance regimens are
essential in higher risk disease such as CIS, there
is no evidence that multiple adjuvant instillations of
either BCG or chemotherapy have additional benefit
in patients at initial diagnosis of LG Ta urothelial
carcinoma [74]. Thus, for initial LG Ta tumors, it is
difficult to justify long-term and/or maintenance
doses of therapy. Therapy should be individualized
based on the prognostic factors of the patients
tumor.
Another large meta-analysis confirms the

effectiveness of single perioperative chemotherapy
versus TURBT alone for decreasing recurrence. This
meta-analysis was performed including 7 randomized
trials, each evaluating the clinical value of a single
immediate instillation of various chemotherapeutic
agents, and reported a 39% decrease in the odds
of recurrence compared to placebo, i.e., TUR alone
[80]. In recurrent and multiple tumors, the benefit of
the early instillation is insufficiently proven by a lack
of statistical power and therefore challenged [81].
To be effective, the instillation should be performed
on the same day as the TUR, as delayed instillation
does not appear to yield similar benefits.
Summary
A well-performed, complete transurethral resection
of the bladder tumor is a critical initial step in the
management of LG Ta tumors and prevention
of recurrences. Immediate post-TUR instillation
of intravesical mitomycin C or epirubicin is
recommended, as it has been shown to prevent
recurrences. Induction with or without maintenance
intravesical chemotherapy for LG Ta tumors may
have benefit, but this has not been established
unequivocally. Given that these patients have a very
low risk of progression and metastases, the risks
of repeated courses of intravesical chemotherapy
have to be weighed against the benefit. Hence we
recommend an extremely judicious and limited use
of repeated courses of intravesical chemotherapy in
this population.
In a recent randomized placebo-controlled trial,

the efficacy of a single postoperative instillation of
gemcitabine (2 g/100 mL of saline) was examined. In
this study of 355 patients with primary or recurrent Ta
or T1, grade1-3 tumors, gemcitabine was not superior
to saline bladder irrigation in terms of recurrencefree survival [76]. The recurrence rate was very low,
suggesting that the bladder irrigation plays a role in
prevention of recurrence, an observation that needs
Recommendation
Recommendation

The initial step in management is complete TUR.

Immediate post-TUR instillation of intravesical chemotherapy
in the form of mitomycin C or epirubicin is recommended as it
can prevent recurrences.
Induction chemotherapy with or without maintenance has
unclear but potential benefit.
The risks of repeated courses of intravesical chemotherapy
have to be weighed against the benefit.
241
Level of
evidence
2b
1a
Grade of
recommendation
A
A
2b
V. Immunotherapy (BCG) in LG Ta
Patients
chemotherapy compared to BCG therapy as rescue

therapy after initial intravesical chemotherapy failure
[95].
Low risk non-muscle-invasive bladder tumors are

characterized by a moderate recurrence rate from 2437% but with very low progression rates from 0-1.7%
[4]. Taking these figures into account the primary
therapeutic objective for low risk patients is to reduce
recurrence rate and the secondary objective is early
detection of progression. To decrease progression
rates in these patients would mean an overtreatment
including unnecessary side effects, as the vast
majority of patients will never develop progression,
so this is not a realistic objective for these patients.
To reach an appropriate balance between efficacy
of the different therapeutic approaches and their
potential toxicity is the main goal for patients with
LG Ta disease.
The role of intravesical BCG as rescue therapy after

chemotherapy failure in low risk groups has been
analyzed in a meta-analysis carried out by Shelley
et al [87]. They examined 1901 patients and found
no significant difference in the efficacy between
intravesical BCG and mitomycin C. However, BCG
was significantly superior to mitomycin C in a
subgroup analysis involving patients at high risk of
recurrence (p=0.0008). Corroborating these data,
in a randomized trial including 174 patients with
recurrent papillary Ta or T1 tumors and comparing
mitomycin C versus BCG, with a median follow-up
of 64 months, BCG achieved a 43% disease-free
survival superior to 34% with mitomycin C but the
difference was not statistically significant (p=0.22)
[96]. In another randomized trial [97] including 89
patients with frequent recurrent Ta or T1 tumors
without bladder Tis, at 20 years of follow-up, 80%
of patients who received mitomycin C developed
recurrence compared to 59.1% of those who
received BCG (p=0.005). These data also show the
efficacy of BCG as rescue therapy in patients with
recurrent tumors and BCG appears to be superior to
intravesical chemotherapy in the rescue setting.
In several comprehensive studies comparing the

efficacy of intravesical chemotherapy [84,85] or
BCG [86] versus observation, there was a significant
reduction of recurrence rate in the intervention
arm compared to the observation arm and BCG
was significantly superior to chemotherapy [87].
However, according to risk groups, BCG was clearly
superior to intravesical chemotherapy in terms of
decreasing recurrence and preventing or delaying
progression, but only when BCG maintenance
is applied [88-90]. However, in intermediate risk
groups there is a great controversy regarding the
efficacy between intravesical chemotherapy or BCG
[86,91-93], but the toxicity is significantly superior
for BCG. In summary, intravesical chemotherapy
or BCG represent alternative approaches for
these patients [4]. In low risk patients, immediate
instillation of a chemotherapy agent is considered
the standard of care as a meta-analysis clearly
demonstrates a significant reduction in recurrence
rate compared to observation [91]. However, in
cases of multiple tumors, this approach is insufficient
and a complete course of chemotherapy is required
[80,94]. Although there is no evidence that BCG is
superior to intravesical chemotherapy in this setting,
intravesical BCG constitutes a clear overtreatment
with unacceptable toxicity [4] following the results in
the intermediate risk group as mentioned above.
In a randomized trial comparing intravesical BCG

and mitomycin C with planned cross-over following
failure of initial therapy, of 39 patients who failed
mitomycin C and received rescue BCG, 19 (32%)
remained disease-free. On the other hand, 21
received mitomycin C after BCG failure and 4 (19%)
also remained free of disease [96]. In a metaanalysis including 9 randomized trials on 2261
patients comparing intravesical chemotherapy and
BCG, Huncharek [92] observed that in patients with
prior intravesical chemotherapy (1480 patients),
BCG significantly reduced recurrence rate compared
to intravesical chemotherapy with a reduction in
tumor recurrence rates of 46%, 49%, and 57% at 1,
2, and 3 years respectively [92]. In another recent
meta-analysis comparing intravesical mitomycin
C and BCG, analyzing patients who received prior
chemotherapy, BCG was superior to mitomycin C
(p=0.0264), reducing recurrence rate. These data
support the superiority of BCG as rescue therapy
in cases of recurrent tumor receiving intravesical
chemotherapy [89]. Whether BCG should be used
as rescue therapy after intravesical chemotherapy
failure or after a second line of intravesical
chemotherapy is unknown. Despite the fact that
many of these studies included patients of different
stages and grades and were not restricted to LG
Ta, it appears that BCG is effective in salvaging
a response in some low risk patients who do not
respond to intravesical chemotherapy.
Despite the significant decrease in recurrence

rate with an immediate post-TUR instillation of
chemotherapy and/or following a complete course
of chemotherapy in patients with multiple tumors,
around 30% of patients will have recurrence [4]. In
these cases, a different chemotherapeutic agent can
be effective in controlling recurrence. In a recent
randomized trial of 96 recurrent Ta or T1 tumors,
intravesical mitomycin C showed a 50% diseasefree survival with a mean follow-up of 65.7 months,
outlining the equivalent efficacy of intravesical
242
Summary
Based on a review of the available data, BCG is not
an appropriate initial therapy in low risk patients with
non-muscle-invasive bladder cancer but appears to
be effective in those patients who develop recurrence
after initial intravesical chemotherapy.
Recommendation
Recommendation
Level of
evidence
Grade of
recommendation
Intravesical BCG is not appropriate as initial intravesical

therapy for patients with LG Ta urothelial carcinoma.
Intravesical BCG could potentially be used in patients with

recurrent LG Ta urothelial carcinoma who have not responded
to courses of intravesical chemotherapy.
comparable efficacy to BCG for the treatment of

urothelial carcinoma. Of the several agents showing
promise, few have been evaluated in clinical trials.
Further, none of these agents have been specifically
tested in LG Ta tumors, and, while such tumors may
have been part of the cohorts tested, the value of
these agents in treating patients with recurrent LG
Ta tumors is unclear at this time.
VI. Other Immunomodulating

Therapies
As BCG is generally considered to be the most
effective intravesical agent for non-muscle-invasive
bladder cancer (91), there has been interest in
developing and testing other immunomodulating
agents against this disease entity. The aim of
researchers has been to search for an alternative
immunological agent with one of the following
properties:
Interferon-alpha and Keyhole limpet haemocyanin

(KLH) have been compared to BCG in randomized
clinical trials to test their utility in preventing recurrence
and progression in non-muscle-invasive bladder
cancer, but both were found to be significantly less
effective [98, 99].
- is more efficient than BCG in lowering recurrences

or progression rates.
Research
on
alternative
immunomodulating
agents has primarily focused on patients with high
risk of progression, that is those in whom BCG
currently is recommended as a first-line treatment,
which is covered in another chapter.
Future
immunotherapeutic efforts will undoubtedly benefit
from the gradually increasing understanding of the
immunobiology of bladder cancer. This will hopefully
lead to new immunologic treatment alternatives for
this group of patients.
- is as effective as BCG, but has lower rates of

adverse events.
- has acceptable efficacy and adverse events,
but can be used as a secondary agent in patients
intolerant or unresponsive to BCG.
Regarding patients with low grade Ta tumors, an
agent with less adverse events but with efficacy
similar to BCG would be of clinical value. Today,
BCG is not recommended as a first-line therapy
in this group of patients [4] given the higher risk of
adverse events in comparison to recommended firstline chemotherapeutic agents, such as mitomycin C
and epirubicin.
Summary
Secondary immunomodulating therapies do not
appear to have a role in management of LG Ta
urothelial carcinoma. Most of these agents have
been tested in high risk non-muscle-invasive bladder
cancer and hence their role and efficacy against LG
Ta tumors is unclear.
So far, despite considerable efforts, no alternative

immunologic treatment has been shown to have
Recommendation
Recommendation

Secondary immunomodulating therapies do not have a role in

management of LG Ta urothelial carcinoma at this time.
243
Level of
evidence
3
Grade of
recommendation
C
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246
Committee 5
High grade Ta, CIS, and T1

Chairs:
Maximilian Burger,
Fred Witjes
Members:
Marko Babjuk,
Maurizio Brausi,
Chris Cheng,
Eva Comperat,
Colin Dinney,
Wolfgang Jager,
Wolfgang Otto,
Jay Shah,
Joachim Throff
247
Table of Contents
I. TaHigh Grade Ta Urothelial
Carcinoma
III. T1 Urothelial Carcinoma

1. Diagnosis and Risk Assessment
1. Introduction
2. Treatment
Recommendations
3. Treatment
IV. Treatment Options for BCG

Failure
Recommendations
III. Carcinoma in Situ of the

Urinary Bladder
1. Introduction
2. Defining BCG Failure
3. Treatment Options
1. Introduction
2. Diagnosis
Recommendations
3. Pathology and Risk Assessment

4. Treatment
Recommendations
248
High grade Ta, CIS, and T1 Urothelial

Carcinoma
Maximilian Burger, Fred Witjes
Marko Babjuk, Maurizio Brausi, Chris Cheng,
Eva Comperat, Colin Dinney, Wolfgang Jager,
Wolfgang Otto, Jay Shah, Joachim Throff
3. Treatment
I. High Grade Ta Urothelial

Carcinoma
a) Turbt
Studies on the quality of transurethral resection of
bladder tumors (TURBT) showed that the residual
tumor rate of Ta urothelial carcinoma was 70%
4 weeks after first resection in a high-volume
department [10]. Fluorescence-guided resection
has been proven to improve the detection rates of
bladder tumors not only in CIS but even in papillary
carcinomas of the bladder, resulting in lower residual
tumor levels and a lower subsequent recurrence
rate [11,12,13,14]. Improving TURBT has become
a major focus of attention for two reasons. Firstly,
subsequent bacillus Calmette-Gurin (BCG) and
mitomycin C (MMC) instillation therapy is more
effective in patients after a complete TURBT
[15,16]. Secondly, an adequate TURBT, i.e., one
which provides sufficient tissue for histopathological
analysis, is crucial for proper staging. The presence
of detrusor muscle in the TURBT specimen is
regarded as a surrogate parameter of resection
quality [17]. A restaging TURBT provides more tissue
for pathological examination and thus allows better
staging. Accordingly, repeat TURBT is advised in
high risk non-muscle-invasive cases.
1. Introduction
Stage pTa urothelial carcinoma represents the
majority (60-75%) of bladder cancer cases [1]. In
general, these tumors show high recurrence but low
progression rates [2].
2. Diagnosis
Pathologists diagnose pTa urothelial carcinoma when
they find a mucosal layer of more than 8 cell lines in a
resected specimen with features of anaplasia [3]. In
contrast to stage T1 urothelial cancer, the basement
membrane is always intact. Only about 20% of pTa
cancer is high grade (grade 3) [3].
In contrast to low grade disease, the diagnosis of
high grade Ta urothelial carcinoma is facilitated
by urinary cytology with sensitivity and specificity
rates of over 90% [4,5]. Urinary tumor markers are
of limited importance for Ta tumors. Markers of the
hyaluronic acid family seem to be the most promising
urinary markers for this entity, exhibiting prognostic
significance for recurrence [6]. Nuclear matrix
protein 22 (NMP22) and other commercialized tests
have not been shown to be of any advantage when
compared to cystoscopy [7].
Equally, an adequate TURBT is crucially important in

determining the optimal treatment modality for any
given patient. The presence of detrusor muscle in
the TURBT specimen is of particular importance for
pT1 tumors. Several studies dealing with the quality
of TURBT or a second TURBT also indicated that
a better resection also lowers the recurrence and
progression rates and improves the reaction to BCG
as well as the prognosis of the patient [16-19].
Without taking into account associated factors,

patients with multifocal stage Ta high grade
urothelial carcinoma have the third highest risk
of both recurrence (around 40% after 1 year) and
progression (5% after 1 year) [2]. While external
evaluation of recurrence rates showed a good
correlation with the EORTC risk tables, prediction of
progression seems less concordant [8,9].
b) Instillation Therapy
While one immediate instillation is sufficient in
249
prophylaxis of recurrence and progression for

low grade Ta urothelial carcinoma, the prognosis
of patients with high grade Ta disease can only
be improved with maintenance BCG therapy [1].
Decreased recurrence rates subsequent to BCG
maintenance have also been reported in intermediate
risk tumors, although the more severe toxicity of BCG
when compared with intravesical chemotherapy has
to be taken into consideration [20]. The impact of
maintenance BCG on progression of high grade pTa
urothelial carcinoma remains unclear [21,22].
9. Seo KW, Kim BH, Park CH, Kim CI, Chang HS. The efficacy
of the EORTC scoring system and risk tables for the
prediction of recurrence and progression of non-muscleinvasive bladder cancer after intravesical bacillus calmetteguerin instillation. Korean J Urol. 2010 Mar;51(3):165-70.
Epub 2010 Mar 19.
10. Adiyat KT, Katkoori D, Soloway CT, De los Santos R,
Manoharan M, Soloway MS. Complete transurethral
resection of bladder tumour: are the guidelines being
followed? Urology. 2010 Feb;75(2):365-7.
prospective studies. Eur Urol. 2010 Apr;57(4):595-606.
High Grade Ta Urothelial Carcinoma:

Recommendations
12. Denzinger S, Wieland WF, Otto W, Filbeck T, Knuechel R,

Burger M. Does photodynamic transurethral resection of
bladder tumour improve the outcome of initial T1 high-grade
bladder cancer? A long-term follow-up of a randomized
study. BJU Int. 2008 Mar;101(5):566-9.
1. Suspicious urinary cytology and papillary tumor

on cystoscopy are highly suggestive of high grade
Ta urothelial carcinoma. (LOE 3, Grade B)
13. Otto W, Burger M, Fritsche HM, Blana A, Roessler W,

Knuechel R, Wieland WF, Denzinger S. Photodynamic
diagnosis for superficial bladder cancer: do all risk-groups
profit equally from oncological and economic long-term
results? Clin Med Oncol. 2009 Apr 30;3:53-8.
2. A complete resection has to be pursued. If there

is any question regarding the completeness of the
initial TURBT, repeat TURBT is advised. (LOE 2,
Grade A)
14. Mowatt G, Zhu S, Kilonzo M, Boachie C, Fraser C, Griffiths

TR, NDow J, Nabi G, Cook J, Vale L. Systematic review
follow-up of bladder cancer. Health Technol Assess. 2010
Jan;14(4):1-331, iii-iv.
15. Divrik RT, ahin Af, Yildirim , Altok M, Zorlu F. Impact of
Routine Second Transurethral Resection on the Long-Term
Outcome of Patients with Newly Diagnosed pT1 Urothelial
Carcinoma with Respect to Recurrence, Progression Rate,
and Disease-Specific Survival: A Prospective Randomised
Clinical Trial. Eur. Urol. 2010 Apr; 58(2): 185-190.
16. Guevara A, Salomon L, Allory Y, Ploussard G, de la Taille
A, Paul A, Yiou R, Hoznek A, Dahan M, Abbou CC, Vordos
D. The role of tumour-free status in repeat resection before
intravesical bacillus Calmette-Guerin for high grade Ta, T1
and CIS bladder cancer. J Urol. 2010 Jun;183(6):2161-4.
17. Mariappan P, Zachou A, . Grigor KM, for the Edinburgh UroOncology Group . Detrusor Muscle in the First, Apparently
Complete Transurethral Resection of Bladder Tumour
Specimen Is a Surrogate Marker of Resection Quality,
Predicts Risk of Early Recurrence, and Is Dependent on
Operator Experience. Eur. Urol. 2010 May; 57(5): 843849.
18. Herr HW. Restaging transurethral resection of high risk
superficial bladder cancer improves the initial response
to bacillus Calmette-Guerin therapy. J Urol. 2005
Dec;174(6):2134-7.
19. Divrik RT, Sahin AF, Yildirim U, Altok M, Zorlu F. Impact of
routine second transurethral resection on the long-term
outcome of patients with newly diagnosed pT1 urothelial
carcinoma with respect to recurrence, progression rate,
and disease-specific survival: a prospective randomised
clinical trial. Eur Urol. 2010 Aug;58(2):185-90.
20. Sylvester RJ, Brausi MA, Kirkels WJ, Hoeltl W, Calais
Da Silva F, Powell PH, Prescott S, Kirkali Z, van de Beek
C, Gorlia T, de Reijke TM; EORTC Genito-Urinary Tract
Cancer Group. Long-term efficacy results of EORTC
genito-urinary group randomized phase 3 study 30911
comparing intravesical instillations of epirubicin, bacillus
Calmette-Gurin, and bacillus Calmette-Gurin plus
isoniazid in patients with intermediate- and high-risk stage
Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010
May;57(5):766-73.
3. BCG instillation therapy should be initiated in

patients with high grade pTa urothelial carcinoma.
(LOE 1a, Grade A)
References
1. Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Bhle
A, Palou J, Rouprt M. Guidelines on TaT1 (non-muscle
invasive) Bladder Cancer. EAU, 2010.
JA, Bouffioux C, Denis L, Newling DW, Kurth K. Predicting
recurrence and progression in individual patients with stage
Ta T1 bladder cancer using EORTC risk tables: a combined
analysis of 2596 patients from seven EORTC trials. Eur
Urol. 2006 Mar;49(3):466-5; discussion 475-7.
3. Amling CL. Diagnosis and management of superficial
bladder cancer. Curr Probl Cancer. 2001 Jul-Aug;25(4):21978.
4. Brown FM. Urine cytology. It is still the gold standard for
screening? Urol Clin North Am. 2000 Feb;27(1):25-37.
5. Vom Dorp F, Pal P, Tschirdewahn S, Rossi R, Brgermann
C, Schenck M, Becker M, Szarvas T, Hakenberg OW,
Rbben H. Correlation of Pathological and CytologicalCytometric Grading of Transitional Cell Carcinoma of the
Urinary Tract. Urol Int. 2010 Dec 16. [Epub ahead of print
6. Kramer MW, Escudero DO, Lokeshwar SD, Golshani
R, Ekwenna OO, Acosta K, Merseburger AS, Soloway
M, Lokeshwar VB. Association of hyaluronic acid family
members (HAS1, HAS2, and HYAL-1) with bladder cancer
diagnosis and prognosis. Cancer. 2010 Oct 19. [Epub
ahead of print]
7. Smrkolj T, Miheli M, Sedlar A, Sterle I, Osredkar J,
Sedmak B. Performance of nuclear matrix protein 22 urine
marker and voided urine cytology in the detection of urinary
bladder tumours. Clin Chem Lab Med. 2010 Dec 1. [Epub
ahead of print]
8. Ather MH, Zaidi M. Predicting recurrence and progression
in non-muscle-invasive bladder cancer using European
organization of research and treatment of cancer risk
tables. Urol J. 2009 Summer;6(3):189-93.
250
prognosis, the initial reports also described its

diffuse appearance [4,5]. Indeed, CIS is more
typically related to multiple as opposed to single
tumor locations. Urothelial cancer within the urinary
bladder is accompanied by tumors of the prostatic
urethra generally 7 times more often and by tumors
of the upper urinary tract nearly 5 times more often if
CIS is also present [15,16].
21. Sylvester RJ, van der MEIJDEN AP, Lamm DL. Intravesical
bacillus Calmette-Guerin reduces the risk of progression in
patients with superficial bladder cancer: a meta-analysis of
the published results of randomized clinical trials. J Urol.
2002 Nov;168(5):1964-70.
22. Malmstrm PU, Sylvester RJ, Crawford DE, Friedrich
M, Krege S, Rintala E, Solsona E, Di Stasi SM, Witjes
JA. An individual patient data meta-analysis of the
long-term outcome of randomised studies comparing
intravesical mitomycin C versus bacillus Calmette-Gurin
for non-muscle-invasive bladder cancer. Eur Urol. 2009
Aug;56(2):247-56.
2. Diagnosis
For most stages of bladder cancer and indeed in
most cases, macroscopic hematuria is symptomatic
of CIS. CIS causes irritative LUTS more often than
papillary lesions. Three characteristics determine the
diagnostic workup: (a) CIS lacks profound cellular
cohesion within the lamina mucosa; (b) its growth
pattern is flat and lacks protrusion into the bladder;
and (c) it may be found throughout the urinary tract.
II. Carcinoma in Situ of the

Urinary Bladder
1. Introduction
Carcinoma in situ (CIS) is malignant neoplasia
of the urothelium, which is flat and not protruding
into the bladder and which does not invade the
lamina propria. That being said, it is nonetheless
considered to be an aggressive tumor entity due
to its level of dedifferentiation. The current WHO
classification defines CIS as a non-papillary, i.e.,
flat, lesion in which the surface epithelium contains
cells that are cytologically malignant. CIS shows
nuclear anaplasia identical to high grade urothelial
carcinoma [1]. This morphological appearance is
reflected in the molecular signature of CIS. While low
grade non-invasive lesions are thought to derive from
chromosome 9 abnormalities and mutations in the
fibroblast growth factor receptor gene, CIS is marked
by deletions of 19p13 resulting in TP53 mutations
with consecutive prevention of cell cycle arrest and
generalized genetic instability [2]. DNA aneuploidy is
found in more than 90% of CIS lesions [3].
The lack of profound cellular cohesion prompts the

use of urinary cytology to aid in the diagnosis of CIS
[17]. CIS can be reliably detected and followed up
by urinary cytology, and sensitivity and specificity
have been reported to exceed 90% [18]. However,
cytology may be hampered by inflammation (e.g.,
following instillation therapy) and distinguishing
malignant from reactive non-neoplastic cells may
become challenging [19]. Accordingly, novel tests
have been described. One of the more promising is
a multicolor fluorescence in situ hybridization (FISH)
assay assessing chromosomal abnormalities in DNA
in urine samples. While this FISH test has a low
sensitivity for low grade tumors lacking chromosomal
abnormalities, it detects high grade carcinomas
and CIS with reliable sensitivity [20]. In contrast, its
specificity does not seem to exceed that of urinary
cytology significantly, and FISH has not been broadly
used in the diagnosis of CIS, although a combination
with cytology has been suggested as advantageous
in the initial detection and follow-up of patients with
CIS [21,22]. To date, no further molecular tests have
been established in the diagnosis of CIS.
CIS was first reported as a distinct phenomenon

by Melicow in 1952. [4] Despite the non-invasive
character of CIS, it was suspected to possess
aggressive tumor biology and tendencies towards
early progression were described [5]. This notion
has been supported by the incidence of CIS. CIS is
found in approximately 3% of all patients with bladder
cancer, concomitantly with invasive bladder cancer
in 50%, and with muscle-invasive disease in 60%
[6,7,8]. As a consequence, CIS has been suggested
as a precursor lesion of invasive disease [9,10] and
concomitant CIS as a significant risk factor for poor
outcome. The tendency towards progression to
muscle-invasive stages is in part determined by the
presence of CIS; the EORTC risk score by Sylvester
et al attaches significant weight to its presence [11].
While CIS is also potentially related to an adverse
outcome in muscle-invasive stages, this has not
been implied in current nomograms [12,13,14].
The second trait, i.e., its flat growth pattern, may defy
cystoscopic detection. Classic white light cystoscopy
has been shown to miss up to 50% of cases.
Photodynamic diagnosis employs a fluorescent
substance, (hexyl-)aminolevulinic acid, which
accumulates fairly selectively in neoplastic cells.
Blue violet light causes the photosensitizing agent
to emit a reddish fluorescence [23]. Randomized
trials and a recent meta-analysis show a significantly
improved diagnostic accuracy of 39% for CIS
[24,25,26] and its use has been suggested to be
especially valuable in the detection of flat lesions
when malignant cells are present in urinary cytology
and there is an absence of suspicious lesions in white
light cystoscopy [23,27,17]. Definitive diagnosis is
based on the histopathological evaluation of tissue
samples by resection or cold-cup biopsy, although
In addition to the notion that CIS conveys a poor
251
the restrictions of inter- and intraobserver reliability

also have to be taken into account [28,29].
latter location shows a significantly higher rate of

lymph node metastasis and a lower 5-year survival
rate[42]. No difference was observed in recurrence
or disease-free survival for either uni- or multifocal
CIS or CIS location (urethral vs. vesical) [43].
The third trait, i.e., the presence of CIS throughout the

urinary tract, warrants a workup of the entire urinary
tract. Although little specific data exist, sampling the
prostatic urethra and each upper urinary tract for
urinary cytology needs to be considered should no
lesions be found on cystoscopy or IVU, CT, or renal
ultrasound[17].
3. Chronology of CIS
Because of the high likelihood that CIS will progress,

subsequent follow-up to specific therapy is generally
recommended, as with patients with non-muscleinvasive bladder cancer at high risk of progression:
cystoscopy and urinary cytology every 3 months
for a period of 2 years, every 4 months in the third
year, every 6 months in the fourth and fifth years,
and annually thereafter. In addition, ultrasound,
conventional IVU, or CT imaging of the upper urinary
tract should be performed periodically [17,30].
In the group of patients with primary CIS, progression

and death from disease seems to be rather unusual,
although more common in the group with concomitant
CIS [44]. Secondary CIS associated with pTa and/
or high grade infiltrating tumors historically has had
the worst prognosis. Recent data presented results
to the contrary, with a higher rate of progression in
primary CIS rather than in secondary CIS after BCG
therapies [45]. In this series, the authors observed a
better response to treatment in the group of primary
vs. secondary CIS and the 5-year cumulative
incidence of progression was also higher in the
primary vs. secondary group of CIS [45].
3. Pathology and risk assessment
4. Intravesical Therapy and CIS
As there is a frequent association with invasive

disease, CIS is clinically classified into different
types: (a) primary CISisolated with no previous
or concurrent papillary tumors; (b) secondary CIS
detected during the follow-up of patients with a
previous papillary tumor; and (c) concomitant CIS
in the presence of papillary tumors [31,32]. Genetic
and molecular approaches have underlined the
relationship between CIS and invasive carcinoma.
CIS has a variable histological appearance with
different morphologic subtypes, described by
McKenney in 2001 [33]. All these elements are part
of the prognosis and will be discussed below.
Numerous publications have shown that response to

intravesical treatment impacts prognosis. However,
few data are available concerning patients who have
CIS without any association with a pTa or pT1 tumor.
Several small studies could not confirm a correlation
between response to treatment, type of CIS, and
prognosis [34,46,47,48]. One reason for this might
be the frequent association of CIS with high grade
tumors, which could be responsible for the difficulties
in discerning an independent prognostic effect for
CIS [34]. A lack of response to BCG should therefore
be regarded as a poor prognosticator.
5. Molecular and Immunohistologic Parameters
a) Clinical prognostic factors
Molecular signatures can be used as diagnostic or

prognostic tools [49,50,51], such as p53 mutations,
amongst others [52].
1. Gender
Men are more likely to present with CIS (p=0.001),
although gender does not seem to affect prognosis
[34]. On the other hand, age does play a role, with
younger patients having a better outcome [35,36].
Aurora-A is a serine/threonine kinase that

activates the centrosome, which plays a role in cell
division. Aurora-A overexpression results in the
misaggregation of chromosomes and chromosomal
instability that eventually explains aneuploidy [53,54].
Aurora-A overexpression in CIS has been correlated
to the risk of relapse and progression [55].
2. Location
CIS of the bladder is also a known risk factor for
developing upper urinary tract tumors after a radical
cystectomy to treat urothelial carcinoma of the bladder
[37]. Volkmer et al reported in a series of 1420 patients
that the presence of CIS after a radical cystectomy
was a risk factor for recurrence in the upper urinary
tract (RiskRatio 2,3) [38]. Similarly, Youssef et al.
demonstrated that bladder CIS is an independent
predictor of disease recurrence and cancer-specific
mortality after a radical nephroureterectomy for upper
tract urothelial carcinoma (p=0.006 and p=0.045
respectively) [39]. Prostatic urethra involvement
of CIS has been observed in less than one third
of cystoprostatectomy specimens [40,41] and in
the prostatic urethra or prostatic ducts in 15%. The
In accordance with the histological appearance

of CIS and the discohesive pattern of cell growth,
adhesion molecule expressions were evaluated.
E-cadherin negative tumor cells were able to infiltrate
the normal urothelium as individual cells, whereas
tumor cells with a homogeneous expression of
E-cadherin exhibited sharp differences with normal
tissue [56,57]. Shariat showed that E-cadherin
expression was independently associated with
disease progression and cancer-specific survival
[57].
Cyclin D3 has a pivotal role in progression from G1
252
to S phase in the cell cycle. Cyclin D3 expression is

amplified in secondary concomitant CIS as opposed
to primary isolated CIS and is related to recurrence
and progression-free survival (p=0.002) [46]. In
clinical use, however, no marker is used routinely,
and the value of other single markers, genomic
profiling, and epigenetic markers for progression in
CIS remains to be determined.
urologist should be aware of their danger, rebiopsy,

especially if the biopsy lacks detrusor muscle, and
closely follow the patient.
CIS is an aggressive high grade disease. Pathologists
should be able to recognize the different features of
CIS. Bladder biopsies and cytology are a precondition
for accurate diagnosis and targeted treatment.
An association with urothelial carcinoma of the
upper urinary tract, prostatic urethra involvement,
secondary CIS associated with other urothelial
tumors, multifocality, age, and non-response to BCG
are all negative clinical prognostic factors. Loss of
E-cadherin, MUC-1, and overexpression of Aurora-A
and CyclinD3 are considered bad molecular markers
for patient outcome.
6. Pathology
In 2001, Mc Kenney et al described four different
morphological subtypes of CIS (large cell
pleomorphic, large cell nonpleomorphic, small cell,
and clinging/denuded). The most frequent pattern is
the large cell pleomorphic type, with cells showing
considerable nuclear variations and architecture
characterized by a loss of polarity. The most difficult
form to recognize is the clinging/denuded form, when
the urothelium may be extensively denuded (Figure
2). In the latter case, cytology is very important,
as detached malignant clusters or isolated cells
in voided urine permit differential diagnosis from
artifacts of biopsy or cystitis.
4. Treatment
a) Cystectomy
In patients with CIS and concomitant muscle-invasive
bladder tumors, cystectomy is the treatment of choice.
A partial cystectomy or radiotherapy is insufficient.
In patients with CIS with and without concomitant
non-muscle-invasive (Ta or T1) papillary tumors,
there is no consensus regarding the optimal course
of treatment: cystectomy or a more conservative
treatment strategy. There are no randomized trials
that have addressed this question.
Mc Kenney et al suggested that denudation reflects

rapid cell turnover and therefore potentially more
aggressive tumors. Nevertheless, they underlined
that individual patterns do not carry any known clinical
significance and that subclassification might confuse
urologists [33]. Molecular arguments and histological
observations strongly support the hypothesis that
a natural history in the development of CIS might
exist. Molecular alterations precede phenotypic
changes and end in morphologic changes seen on
routine staining. Early alterations during mitosis,
chromosomal instability and aneuploidy are reflected
by nuclear atypia and chromatin densification,
leading to the development of malignant urothelial
cells. In a further step, polarity and cell-to-cell
adherence are altered, resulting in denuded forms
of CIS with detached cell clusters in cytology and
few cells remaining on the surface. Eventually, via
mechanisms not yet understood, CIS develops into
invasive urothelial carcinoma.
Several recent papers have discussed the cystectomy

results in patients thought to have only CIS prior to
cystectomy [60,61,62]. A common theme in these
studies was the clinical understaging in a third or
more of the patients. Although the disease-specific
survival rates in these studies ranged from 85-90%,
early cystectomy represented overtreatment in
approximately 50% of patients.
When a conservative treatment strategy is chosen,
the transurethral resection (TUR) of all concomitant
papillary tumors is mandatory for correct staging and
grade determination. A TUR alone is insufficient,
as CIS can be missed at cystoscopy and, without
further treatment, 50% or more of patients with CIS
will progress to muscle-invasive disease [63,64].
Three rare subtypes of CIS must be considered

separately for their potential prognostic significance.
The first is non-invasive micropapillary CIS. It
was recently demonstrated that CIS associated
with micropapillary invasive cancer increased
recurrence upon univariate and multivariate
analysis. Furthermore, all superficial micropapillary
CIS displayed an invasive component [58]. Another
rare variant is the in situ squamous cell carcinoma
(SCC). SCC is frequently associated with an invasive
component. The last of these rare subtypes is in situ
adenocarcinoma, which is associated with classical
CIS and frequently with invasive carcinomas with
a poor prognosis such as micropapillary and small
cell CIS [59]. If these subtypes are reported, the
b) Intravesical Chemotherapy
As previously summarized, various intravesical
chemotherapeutic regimens have been compared in
patients with CIS [65,66,67]. The number of patients
included in these studies has often been small.
Consequently, definitive conclusions cannot be drawn
from the individual studies. Complete response rates
approaching 50% have been observed; nonetheless,
there may be important differences between these
studies with respect to patient characteristics
and assessment of response to treatment (level
1). Since 50% of the complete responders on
chemotherapy recurred during follow-up, complete
response alone is not a suitable endpoint because
253
of the risk of invasion and extravesical recurrence.

Indirect comparisons in a meta-analysis of 355
CIS patients treated with intravesical mitomycin C
(MMC), Adriamycin, epirubicin, or sequential MMC/
Adriamycin suggest that long-term disease-free
rates might be better with MMC [67]. However, direct
randomized comparisons do not exist (level 2).
chemotherapy (p=0.0002. After a median follow-up

of 3.6 years, 161 (46.7%) of 345 patients on BCG
exhibited no evidence of disease compared to 93
(26.2%) of 355 patients on chemotherapy (p<0.0001).
The long-term benefit of BCG was superior to MMC
in trials with maintenance BCG (p=0.04). A reduction
of 26% in the risk of progression for patients on BCG
when compared to those receiving chemotherapy
was observed (p=0.20), consistent with the results
of the meta-analysis (level 1).
c) Intravesical BCG
Intravesical bacillus Calmette-Gurin (BCG) has
been widely used in the treatment of patients
with CIS. The standard induction schedule of 6
weekly instillations yields a complete response
rate of approximately 70%, although complete
response rates over 80% have been reported in
individual studies (level 1) [65,67,68]. About 4060% of patients who do not respond to the initial
6 instillations will respond to a second series of 6
weekly instillations (level 2) [69,66]. Based on the
results of several studies and meta-analyses, 1 to 3
years of maintenance BCG therapy is recommended
in complete responders (level 1) [70, 67, 71, 72, 73].
Only half of all CIS patients will remain disease-free;
approximately one-third of all complete responders
will eventually recur. If recurrence occurs more than
1 year after BCG treatment, a re-induction with BCG
can be considered (level 3) [74].
More recently, in patients with high grade (grade 2

or 3) T1 tumors, BCG was found to be superior to
the combination of epirubicin and interferon alpha
2b for the endpoint of disease-free survival, but only
in the subgroup of 76 patients with concomitant CIS
[76]. In a recent meta-analysis comparing BCG to
MMC, only 12% of patients had CIS and a separate
analysis of treatment efficacy was not carried out in
this patient subgroup [77].
e) Comparison of Alternating or Sequential

MMC/BCG to BCG alone or to MMC alone
There is only a limited amount of evidence assessing
alternating MMC/BCG in patients with CIS. Alternating
MMC/BCG was compared to MMC alone in 133 CIS
patients in 2 studies, with higher complete response
and disease-free rates on MMC/BCG [78,79]. In the
largest trial comparing alternating MMC/BCG to BCG
alone in patients with CIS, there was a significantly
longer disease-free interval in the BCG monotherapy
arm: 80 (55%) of 145 patients were disease-free on
BCG alone compared to 72 (45%) of 159 patients on
the alternating arm [80]. Thus, it can be concluded
that an alternating schedule of MMC and BCG is not
superior to BCG alone (level 1).
These studies have all been carried out with full

dose BCG. However, a study in 155 patients with
high risk T1G3 and CIS disease concluded that a
one-third dose was as effective as a full dose BCG
course, and was associated with significantly less
toxicity (level 1) [75].
d) Comparison of Intravesical
Intravesical Chemotherapy
BCG
to
However, in a trial comparing sequential BCG and

electromotive MMC to BCG alone in 212 patients
with high grade (grade 2 or 3) T1 tumors, subgroup
analyses based on a median follow-up of 88 months
in the 57 patients with concomitant CIS showed
a statistically significant benefit of the sequential
treatment with regard to time to recurrence,
progression, and both disease-specific and overall
survival (level 1) [81]. It was suggested that BCGinduced inflammation might increase the permeability
of the bladder mucosa such that electromotive MMC
could reach the target tissue more easily and exert
greater anticancer effect.
Various randomized studies in high risk patients

have compared intravesical BCG to either no further
treatment, intravesical chemotherapy, or other
immunotherapies post TUR. Unfortunately, separate
results in CIS patients are often unavailable in many
of these studies that also included patients with
papillary tumors. A meta-analysis of 403 patients
with CIS showed that BCG reduced the risk of
progression by 35% compared to either intravesical
chemotherapy or a different immunotherapy (level
1). Twelve percent of patients with CIS on BCG
progressed as compared to 16% of patients receiving
other treatment strategies [70].
f) Treatment of Extravesical CIS
Previous reviews in 2005 identified 12 randomized

trials that compared intravesical BCG to intravesical
chemotherapy (MMC, Adriamycin, epirubicin,
Thiotepa, sequential MMC/Adriamycin) in 845
patients with CIS [66,69]. Data for 700 patients with
CIS included in 9 trials were available for inclusion in
a meta-analysis [67]. Among 298 patients receiving
BCG, 203 (68.1%) had a complete response as
compared to 158 (51.5%) of 307 patients receiving
No randomized trials have been carried out in patients

with extravesical CIS and, as such, no definitive
treatment recommendations can be provided.
Intravesical BCG does not reach either the upper
urinary tract or the prostatic urethra. Therefore, the
treatment of CIS in the upper urinary tract involves
rinsing the renal unit with BCG or chemotherapy.
CIS may be found in the prostatic urethra at various
254
levels: in the epithelial lining of the prostatic urethra

only, in the prostatic tissue following the prostatic
ducts, or in the prostatic tissue stroma (T4),
carrying the worst prognosis. In the latter case, a
cystoprostatectomy is advised. In the other two
cases, a TUR of the prostate can be followed by
intravesical BCG. Further details concerning results
obtained in a small series of non-randomized studies
have been summarized by van der Meijden (level 3)
[69].
hexaminolevulinic acid should be considered.

(LOE 1a, Grade A)
2. Diagnosis of CIS is based on histopathological
assessment of biopsy or resection specimen.
Pathology need not report subtypes but should
note the presence of micropapillary and small
cell CIS (LOE NA, Grade A).
3. Radical cystectomy at the time of CIS diagnosis
provides for excellent disease-free survival, but
is overtreatment in up to 50% of the patients.
(LOE 2, Grade A)
g) Treatment of BCG-refractory CIS

Up to 40-50% of patients with CIS may eventually
fail intravesical BCG. These patients have a very
poor prognosis, with a high risk of progression to
muscle-invasive disease and death as a result of
bladder cancer. The 3-year bladder cancer specific
survival is 67% in patients initially presenting with
muscle-invasive disease but falls to 37% in patients
who progress after intravesical treatment [82]. There
is no universally agreed definition of BCG failure
and there are no randomized trials comparing BCG
to cystectomy. However, treatment with BCG is
generally considered to have failed in the following
cases [83,84,85]: (1) detection of muscle-invasive
disease; (2) presence of high grade papillary tumors
and/or carcinoma in situ at both 3 months and 6
months; or (3) disease worsening (stage, grade, CIS)
under BCG treatment. Herr et al concluded that a
minimum treatment and follow-up period of 6 months
is required to identify high risk, non-muscle-invasive
bladder tumors as being truly BCG-refractory [85].
4. Intravesical BCG is recommended, as it provides

the highest complete response rate as well as
the highest long-term disease-free rate among
intravesical treatments. (LOE 1a, Grade A)
5. Concomitant papillary tumors should be
completely resected prior to the start of
intravesical treatment (LOE 1b, Grade A).
Following the resection, one immediate
instillation of chemotherapy may be considered
(LOE 3, Grade C).
6. Maintenance BCG treatment is required but the
optimal maintenance schedule is unknown. In
the absence of treatment failure, at least 1 year
of maintenance BCG is recommended. (LOE 2,
Grade A)
7. T
he response to intravesical BCG should be
assessed 3 months after starting treatment. If
no response is seen, one might offer the patient
either cystectomy, another 6-week course of
BCG or 3 weekly boosters. The optimal time to
abandon conservative treatment and proceed to
cystectomy is unknown. (LOE 2, Grade B)
In BCG failures, cystectomy is the recommended

treatment option (level 3). For patients who are
unable or unwilling to have a cystectomy after BCG
failure, various alternative treatment possibilities exist
(level 3). Intravesical chemotherapy, device-assisted
chemotherapy, photodynamic therapy, and BCG
plus interferon alpha are the options most frequently
employed [86]. After a literature review in 2005 [69],
additional publications of intravesical treatment for
patients with BCG-refractory CIS became available
concerning BCG plus interferon alpha 2b [87],
hyperthermia and MMC [88], mycobacterial cell
wall-DNA complex [89], and gemcitabine [90,91]. In
general, the results for conservative treatment after
BCG failure are disappointing (level 3) and research
to discover new treatment options in these patients
is a top priority.
8. Cystoscopy and urinary cytology should be

performed every 3 months for a period of 2
years, every 4 months in the third year, every 6
months in the fourth and fifth year, and once per
year thereafter. If no recurrence, imaging of the
upper urinary tract by ultrasound, conventional
IVU, or CT should be performed periodically.
(LOE NA, Grade C)
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patients with bladder cancer who fail BCG therapy. Expert
Rev Anticancer Ther. 2009 Jun;9(6):815-20.
72. Jrvinen R, Kaasinen E, Sankila A, Rintala E; FinnBladder

Group. Long-term efficacy of maintenance bacillus CalmetteGurin versus maintenance mitomycin C instillation therapy
in frequently recurrent TaT1 tumours without carcinoma in
FinnBladder I study with a 20-year follow-up. Eur Urol.
2009 Aug;56(2):260-5.
84. Zlotta AR, Fleshner NE, Jewett MA. The management of

BCG failure in non-muscle-invasive bladder cancer: an
update. Can Urol Assoc J. 2009 Dec;3(6 Suppl 4):S199205.
85. Huguet J, Crego M, Sabat S, Salvador J, Palou J,
Villavicencio H. Cystectomy in patients with high risk
superficial bladder tumours who fail intravesical BCG
therapy: pre-cystectomy prostate involvement as a
prognostic factor. Eur Urol. 2005 Jul;48(1):53-9; discussion
59.
73. Jrvinen R, Kaasinen E, Sankila A, Rintala E; FinnBladder

Group. Long-term efficacy of maintenance bacillus CalmetteGurin versus maintenance mitomycin C instillation therapy
in frequently recurrent TaT1 tumours without carcinoma in
FinnBladder I study with a 20-year follow-up. Eur Urol.
2009 Aug;56(2):260-5.
86. Sylvester RJ.Bacillus Calmette-Gurin treatment of

non-muscle invasive bladder cancer. Int J Urol. 2011
Feb;18(2):113-20.
74. Gallagher BL, Joudi FN, Maym JL, ODonnell MA. Impact
of previous bacille Calmette-Gurin failure pattern on
87. Joudi FN, Smith BJ, ODonnell MA; National BCGInterferon Phase 2 Investigator Group. Final results from
258
in patients with stage T1 urothelial carcinoma was

unclear; of 111 patients with stage T1 disease who
underwent radical cystectomy, only 10 (9%) had
lymphovascular invasion.
a national multicenter phase II trial of combination bacillus

Calmette-Gurin plus interferon alpha-2B for reducing
recurrence of superficial bladder cancer. Urol Oncol. 2006
Jul-Aug;24(4):344-8.
88. Topic issue on new treatments in bladder cancer. Witjes JA.
World J Urol. 2009 Jun;27(3):285-7. Witjes JA, Hendricksen
K, Gofrit O, Risi O, Nativ O. Intravesical hyperthermia and
mitomycin-C for carcinoma in situ of the urinary bladder:
experience of the European Synergo working party. World
J Urol. 2009;27:319-24
A number of molecular prognostic markers have been

reported for T1 urothelial carcinoma. It has been
suggested that alterations of cell cycle regulatory
proteins involved in the progression from G1 to S
phase are among the most promising markers. The
p53 tumor suppressor gene is commonly altered
in human malignancies. Pretreatment p53 nuclear
overexpression in non-muscle-invasive bladder
tumors is associated with a high risk of disease
recurrence, progression, and cancer death after
BCG therapy [3]. Alterations of p53 were associated
with BCG failure. Others have not found that p53
expression before BCG treatment correlated with
BCG failure [2]. Controversial results have also
been reported with regard to p53 expression as an
independent predictor of progression [4]. While a
trend towards poorer clinical outcomes in high risk
patients with a p53 mutation has been observed, no
significant differences were seen in clinical outcome
parameters. A number of cell cycle regulators that
appear to be independent predictors of the survival
of patients with high grade T1 urothelial carcinoma
include p27kip1 and the cyclins D1 and D3 [5]. Many
other prognostic factors, including genetic alterations,
cell adhesion molecules, a family of proteases,
growth factors, and other molecular markers, have
been studied. To date, they do not have enough
specificity for clinical use in the management of T1
urothelial carcinoma. For patients with pT1 disease
at cystectomy, assessment of p53, p27, and Ki-67
in bladder specimens has been shown to improve
prediction of recurrence-free and disease-specific
survival. [6]
89. Morales A, Phadke K, Steinhoff G. Intravesical mycobacterial

cell wall-DNA complex in the treatment of carcinoma in situ
of the bladder after standard intravesical therapy has failed.
J Urol. 2009 Mar;181(3):1040-5.
90. Dalbagni G, Russo P, Bochner B, Ben-Porat L, Sheinfeld
J, Sogani P, Donat MS, Herr HW, Bajorin D. Phase II trial
of intravesical gemcitabine in bacille Calmette-Gurinrefractory transitional cell carcinoma of the bladder. J Clin
Oncol. 2006 Jun 20;24(18):2729-34.
91. Bassi P, De Marco V, Tavolini IM, Longo F, Pinto F, Zucchetti
M, Crucitta E, Marini L, Dal Moro F. Pharmacokinetic study
of intravesical gemcitabine in carcinoma in situ of the
bladder refractory to bacillus Calmette-Gurin therapy. Urol
Int. 2005;75(4):309-13.
III. T1 Urothelial Carcinoma

The initial assessment of T1 urothelial carcinoma does
not differ decisively from Ta urothelial carcinoma. If
pT1 cancer has been confirmed pathologically, there
are additional considerations.
Clinical predictors, including histopathologic markers,
are most useful in forecasting progression in patients
with stage T1 urothelial carcinoma. Traditional
factors used to predict the clinical outcome of T1
urothelial bladder carcinoma after an initial TURBT
include time to recurrence, tumor grade, multiplicity,
tumor extent and size, concomitant CIS, urothelial
carcinoma involving the prostatic mucosa or ducts,
and depth of lamina propria invasion [1]. The
response to intravesical therapy is a reliable predictor
of progression within 3-6 months. Eighty percent of
patients found to have evidence of tumor recurrence
at the time of their 3-month cystoscopy after BCG
induction ultimately progressed to invasive disease
[2]. The relative importance of clinical and pathologic
factors varies according to adjuvant therapy. For
example, T1 substaging has not been found to be
useful in BCG-treated patients, and recurrence or
persistence of downstaged or downgraded disease
may be evidence of response in an individual patient
[2]. Nevertheless, these prognostic factors are not
accurate enough to predict the individual clinical
behavior of T1 urothelial tumors. Therefore, more
reliable indicators of biologic aggressiveness are
needed.
In summary, useful clinical prognostic factors for

T1 urothelial carcinoma include tumor grade, early
recurrence, multiplicity, tumor size, concomitant CIS,
urothelial carcinoma involving the prostatic mucosa
or ducts, and depth of lamina propria invasion. The
response to intravesical therapy is a very useful
clinical marker. A great number of molecular and
genetic prognostic markers, including alterations of
p53, have been studied for T1 urothelial carcinoma.
However, most of these markers have not been
validated and are not yet available for clinical use.
2. Treatment
a) Turbt
A restaging TURBT is warranted in patients with pT1
urothelial carcinoma. In addition to the previously
stated aspects, some special considerations also
apply. The rate of residual tumors is high after initial
TURBT for pT1 urothelial carcinoma. Schwaibold
et al [7] showed that 52% of patients had residual
tumors at restaging TURBT for initial T1 urothelial
Lotan et al examined the association of lymphovascular

invasion with prognosis at radical cystectomy.
Unfortunately, the role of lymphovascular invasion
259
carcinoma, of which 86% were located in the base or

margins of the previous resection and 14% in other
locations. The risk of residual tumor correlates with
the initial tumor grading. Divrik et al [8] reported a
rate of 6% for initial G1, 38% for G2, and 63% for G3
tumors. Even after fluorescence diagnosis at the first
TURBT for initial high grade T1 tumors, a restaging
TURBT revealed residual tumors in 12% of cases
[9].
Hendricksen [49] studied the additive effect of early

instillation or maintenance instillations of adjuvant
intravesical epirubicin compared to the standard
schedule of epirubicin in patients with intermediate
and high risk urothelial carcinoma of the bladder.
In a randomized study (n=753), 4 weekly and 5
monthly instillations of epirubicin 50 mg in 50 mL
saline for 1 hour (group 1) were compared to the
same schedule with an additional instillation 1) < 48
hours after TUR (group 2) and 2) following the same
schedule of group 1 with additional instillations at
9 and 12 mo (maintenance schedule). The results
showed that with this quasi intention-to-treat strategy
there was no difference in the 5-year recurrence-free
period between the treatment groups. T1 disease
was present in 156 (21%) of 731 patients. Grade 2
and grade 3 disease was present in 343 (47%) and
78 (11%), respectively. The immediate instillation
was given to 68% of the patients in group 2 within
24 hours. They concluded that one immediate
postoperative instillation of epirubicin preceding a
standard schedule also was not effective in reducing
recurrences in patients with intermediate and high
risk urothelial carcinoma of the bladder.
Dutta et al [10] reported a 64% risk of tumor

understaging in the absence of muscle in the first
TURBT specimen. As 30% of tumors were upstaged
when muscle was present in the first obtained
specimen, a restaging TURBT should be performed
for all high grade T1 tumors. Dalbagni et al [11] also
reported a rate of 20% upstaging after restaging
TURBT for initial high grade T1 tumors and thus
modified patient treatment strategies. A restaging
TURBT also provides prognostic markers for disease
outcome. In a retrospective study, Herr [12] found a
significantly higher risk of tumor progression over
5 years when residual pT1 disease was found at
restaging TURBT (82% vs. 19%). Thus, a restaging
TURBT helps to identify patients who should be
immediately referred for radical cystectomy.
In a multicenter study in Sweden [15], 305 patients

with primary or recurrent Ta or T1, G1 or G2 urothelial
carcinoma of the bladder (low or intermediate risk)
were randomized to receive epirubicin 80 mg in
50 mL saline within 24 hours of TURBT or TURBT
alone. The results showed that after a median
follow-up time of 3.9 years, the recurrence rate
in the epirubicin group was 62% vs. 72% in the
control group (p= 0.016). However, in a subgroup
analysis, the treatment with epirubicin only had
profound recurrence-reducing effect in patients with
primary, single tumors, while providing no benefit in
patients with recurrent or multiple Ta or T1, G1 or G2
intermediate risk tumors.
b) Immediate Instillation of Chemotherapy

The European Association of Urology (EAU)
guidelines recommend that all patients with nonmuscle-invasive bladder cancer should receive 1
immediate instillation of chemotherapy after a TUR
(Grade B recommendation) [13]
Patients with T1 urothelial carcinoma of the bladder
are at at least intermediate or high risk for progression,
depending on the grade. After TUR, these patients
should receive further adjuvant chemotherapy or
immunotherapy (BCG) once a week for 6 weeks
with or without maintenance. The role of one single
instillation of chemotherapy immediately after TUR
in these patients (T1, any grade) has been recently
questioned due to the publication of new data.
Similar findings were reported by Berrum-Svennung

et al [16]. They reported on 307 evaluable patients
randomized between receiving 50 mg epirubicin
within 6 hours after TURBT or TURBT alone.
The recurrence rate in the epirubicin group was
significantly lower (51% vs. 62.5%, p=0.04), but
recurrences were prevented only if initial tumors were
smaller than 5 mm. The authors also concluded that
an immediate single postoperative instillation was
only effective in small (i.e., very low risk) tumors.
In a randomized placebo-controlled phase III

multicenter study, Bohle [14] compared a single
postoperative instillation of gemcitabine to placebo
in patients with low or intermediate risk urothelial
carcinoma of the bladder. In this series, 25% and
29% of patients receiving gemcitabine and placebo,
respectively, had T1 disease; 10.5% and 11.3% were
high grade. In these patients, additional BCG with
maintenance was also used. The results showed that
after a follow-up period of 24 months, the recurrencefree survival was high in both groups (77.7% vs.
76.3%). There was no significant difference between
the 2 groups. Both groups had continuous bladder
irrigation for 20 hours. The authors hypothesized
that improved TUR (cystoscopy) techniques may
have contributed to the high recurrence-free survival
in both groups.
Finally, the value of a single instillation after a TURBT

in high risk patients has been recently challenged by
Brausi [17]. In Sylvesters meta-analysis, the number
of high risk patients who received 1 perioperative
instillation and further therapy was small. The
consistency of the conclusions regarding these
patients was unclear.
In the literature, there are few randomized studies
addressing this issue. The first was published by
260
Zincke in 1983 [18]. He compared 1 single instillation

of Thiotepa or doxorubicin after TURBT followed
by BCG therapy vs. TURBT without postoperative
instillation followed by BCG in patients with CIS.
The results indicated no benefit in those patients
receiving a single instillation. A second prospective
randomized study by Cai [19] compared 1 single
instillation of epirubicin after a TURBT followed by
BCG vs. TURBT without instillation and BCG in
high risk tumors. No difference in the recurrence
or progression rate was demonstrated between
the 2 groups. The authors concluded that 1 single
instillation of chemotherapy after a TURBT in high
grade, high risk tumors is not effective in reducing
recurrence or progression.
c) Initial Bladder-sparing
Cystectomy
Approach
reports of increased mortality in patients who develop

muscle-invasive disease while receiving conservative
treatment who then require cystectomy. Obviously,
this raises concern about delaying cystectomy.
d) Intravesical Therapy
Before the advent of BCG immunotherapy, the
incidence of progression in high grade, stage T1
urothelial carcinoma ranged from 27-65% with
follow-up ranging from 36-84 months. Important and
valid information about the prognosis of patients with
non-muscle-invasive bladder cancer can be obtained
from the scoring system developed by the EORTC)
According to these risk tables, the risk of progression
in high grade T1 tumors ranges between 17% and
45% at 5 years, depending on further variables [22].
These results, however, were before the era of a
second TURBT or fluorescence-guided resection,
maintenance BCG, and the use of an immediate
postoperative instillation of chemotherapy.
vs.
The goal for the treatment of bladder cancer is to

minimize the morbidity and mortality of the disease
while maximizing patient quality of life. This is
particularly true for cases of new or recurrent T1
disease. The substantial majority of stage T1 bladder
cancer is high grade and therefore at particular risk
of progression to incurable metastases. Treatment
with TURBT alone without adjuvant intravesical
therapy carries an unacceptable risk of recurrence
and progression. Even with optimal intravesical
chemotherapy or immunotherapy, however, a
substantial proportion of patients progress to
incurable disease stages [20].
With the advent of (maintenance) BCG, reported

results of intravesical therapy in T1 disease have
improved. With follow-up times ranging from 22-78
months, overall progression is in the range of 12%,
varying from 0-35%. It is quite remarkable that the
overall incidence of progression in patients with T1
disease is less than the incidence of occult muscleinvasive disease (up to 62%) in patients who undergo
an immediate cystectomy [23,24,25].
The role of BCG in the treatment of high grade nonmuscle-invasive bladder cancer is becoming clearer.
Intravesical BCG is more effective than intravesical
chemotherapy or TURBT alone in decreasing
recurrences. This was addressed by many
prospective randomized trials and meta-analyses.
Unfortunately, these trials enrolled patients both with
intermediate and high risk tumors. For this reason,
there is no separate analysis available based on
prospective randomized data that deals with the
efficacy of different treatment modalities in high
grade T1 tumors.
The 2 treatment options available today for patients

with high grade Ta or T1 bladder cancer are
immediate cystectomy or intravesical therapy with
a delayed cystectomy for persistent or recurrent
tumors. The selection of one of these options over
the other is among the most difficult in bladder
cancer management. Quality of life data in this area
is interesting. If faced with this choice, patients are
willing to accept disabilities incurred by cystectomy
to avoid compromising survival.
Selection of the treatment strategy for stage T1
urothelial carcinoma requires consideration of the
risks and benefits of cystectomy versus a repeat
TURBT with immediate instillation of chemotherapy
and BCG immunotherapy. Understaging is frequent.
When a cystectomy is performed for clinical stage
T1 disease, 30% of patients will be found to have
unsuspected disease that is stage T2 or greater. It
was recently shown that this risk increases to 49.7%
in patients with clinical high grade T1 disease [21].
Cystectomy is therefore an option to be considered.
However, cystectomy survival is far from optimal
and around one-third of patients with pT1 urothelial
carcinoma die of the disease [21]. Because of the
lack of evidence from randomized trials, there is no
recommendation for early cystectomy in patients
with high grade T1 disease. Nevertheless there are
It has been confirmed in 5 meta-analyses that

BCG therapy after TURBT is better than TURBT
only or TURBT plus chemotherapy in preventing
recurrences of non-muscle-invasive bladder tumors
[26,27,28,29,40]. A recently published metaanalysis, which was based on individual data from
2820 patients from 9 randomized trials, compared
the efficacy of BCG and MMC. In those trials where
BCG was used with maintenance, a 32% reduction
in the risk of recurrence was found (p<0.0001) [30].
Secondly, BCG lowers tumor progression in high
grade non-muscle-invasive bladder cancer but has
not been shown to improve survival. Patients with
high grade T1 tumors are at high risk for tumor
progression, which is more important and dangerous
than the risk of tumor recurrence. The question
261
as to whether BCG can reduce the risk of tumor

progression was addressed by a meta-analysis
carried out by the EORTC that evaluated data from
4863 patients enrolled in 24 randomized trials. The
results demonstrated a 27% reduction in the odds of
progression with BCG treatment (p=0.0001). In the
20 trials in which BCG maintenance was provided,
a reduction of 37% in progression was observed
(p=0.00004) [31] (Level 1). Unfortunately, 1) the
median follow-up was only 2.5 years; and 2) for
papillary tumors, only 7.6% had high grade disease.
This individual data meta-analysis, with a median
follow up of 4.4 years, compared BCG with MMC
and has not confirmed any significant difference in
progression and mortality rates [30].
BCG instillations are given according to the empirical

6-weekly induction schedule introduced by Morales
30 years ago. However, many different maintenance
schedules have been used, ranging from a total of
10 instillations given in 18 weeks, to 30 instillations
given over 3 years according to the Southwest
Oncology Group (SWOG) schedule [37]. The quality
of the initial TURBT in adequate staging and optimal
resection has a crucial role in providing optimal
results in a bladder sparing approach to high grade
T1 cases.
Conservative therapy is an attractive option for
many patients with high grade non-muscle-invasive
bladder cancer. There is a subgroup of patients with
the highest risk of progression who benefit from
early cystectomy. These may include patients with
adverse factors, for example, patients with tumor
multifocality, tumor size of over 3 cm, and associated
CIS. It has been shown that patients with at least
two of these factors could benefit from immediate
cystectomy [38].
Indeed, there are some data indicating that the longterm risk of tumor progression remains significant
in spite of BCG treatment. It has been reported that
after 15 years of follow-up, 53% of patients with initial
high-risk non-invasive bladder cancer progressed to
muscle-invasive disease, 36% eventually underwent
cystectomy, and 34% died of bladder cancer [32].
Only 27% were living with an intact bladder. Similar
results have been reported by Shahin et al [33] from
a study with 153 patients treated with either TURBT
and BCG or TURBT alone. With a median followup of 5.3 years, disease recurred in 70% and 75%
of patients treated with BCG and TURBT alone,
respectively. Progression was seen in 33% and 36%
of cases, respectively. A deferred cystectomy was
performed in 29% and 31% of cases, respectively.
Overall and disease-specific survival for those
receiving BCG compared with TURBT alone was
42% and 77% versus 48% and 79%, respectively.
The investigators stated that BCG therapy is unlikely
to substantially alter the final outcome for patients
with high grade T1 urothelial carcinoma.
The most important prognostic factor has been

shown to be the clinical response to intravesical
therapy. A study of patients treated with intravesical
doxorubicin found that 50% of those with stage T1 or
high grade recurrent tumors progressed. [39] The
pathologic tumor stage at recurrence was the only
factor shown to be predictive of recurrence in this
study. In 80 patients given intravesical therapy for T1
disease, Solsona et al [40] demonstrated that 78%
had a complete clinical response. However, as is
the case of many studies of high risk non-muscleinvasive bladder cancer, in this study, T1 tumors
were not separated from CIS in the analysis of risk
factors for progression. In conclusion, the absence of
a 3-month clinical response seems highly predictive
of progression [41]. It is not known exactly whether
a cystectomy should be performed immediately
at 3 months in non-responders or whether we can
repeat BCG instillations and wait for a response at
6 months. There is no doubt, however, that an early
cystectomy is strongly recommended in patients with
persistent high grade tumors despite 3 and 6 month
BCG treatments, since the prognosis for progression
increases significantly [42].
BCG instillation is associated with side effects. Up

to 90% of patients have irritative lower urinary tract
symptoms, and a small number of patients have
serious, debilitating complications, such as sepsis
and contracted bladders. Lamm [34] reported that
only 16% of patients were able to tolerate a full
maintenance course of BCG secondary to adverse
effects, albeit in an earlier era. With increased
experience in the use of BCG, the side effects now
appear to be less severe. Serious side effects are
encountered in less than 5% of patients and can be
effectively treated in virtually all cases. [35] (Level
3).
e) Early Cystectomy
Disease-specific survival after cystectomy for nonmuscle-invasive urothelial carcinoma is higher than
for patients with muscle-invasive disease. However,
the benefits must be balanced against the morbidity
and mortality rates of surgery. Amling et al [43]
reported on a large series of 531 patients undergoing
cystectomy and found a perioperative mortality rate
of 2.3% and a complication rate of 20.5% (level 3).
Similar complication rates have been reported in
other large cystectomy series by Stein et al [44] and
Ghoneim et al [45] (level 3).
For optimal efficacy, BCG must be given according

to a maintenance schedule [29,30,31,36]. It is
not possible, however, to determine which BCG
maintenance schedule is the most effective [31]. In
their meta-analyses, Bhle et al concluded that at
least 1 year of maintenance BCG was required to
show the superiority of BCG over MMC in preventing
recurrence or progression [29,30,31,35,36]. Today,
262
There is significant support for early cystectomy in

T1 disease in view of the high rate of late failure
after initially successful intravesical therapy and
the good quality of life possible post-cystectomy.
[46] Fritsche [21] reported on a multicenter series
of 1136 patients with high grade T1 disease
who underwent cystectomy without undertaking
neoadjuvant chemotherapy. Upstaging to muscleinvasive disease occurred in 49.7% and 35.5%
died of metastatic disease within 8 years of their
cystectomies (level 3).
were 85% and 82% at 5 and 10 years, respectively.

A total of 246 patients (24%) had lymph node tumor
involvement. The 5- and 10-year recurrence-free
survival rates for these patients were 35% and 34%,
respectively (Level 3).
Based on the current literature, patients with high
risk disease should be offered an early cystectomy.
Likewise, those with recurrent or persistent disease
after BCG immunotherapy should also be offered
cystectomy.
T1 Urothelial Carcinoma:
Recommendations
However, the proponents of an aggressive initial

approach acknowledge that a significant number of
patients will be rendered disease free with bladdersparing strategies. Current proposed indications
for immediate surgery include younger patients
with T1 tumors with at least one additional bad
prognostic factor including multifocality, associated
CIS, prostatic involvement, and tumor at a site that
is difficult to resect. Bianco et al [47] performed
a multivariate analysis to identify risk factors in
patients undergoing a cystectomy that influenced
cancer-specific survival. They found that patients
with concomitant CIS and those who had persistent
disease after an initial course of BCG therapy were
at significant risk (level 3). Herr and Sogani [48]
retrospectively evaluated 90 patients with highrisk non-invasive bladder cancer who ultimately
underwent cystectomy. These investigators reported
improved 15-year disease-specific survival for those
who underwent cystectomy within 2 years after an
initial BCG treatment (Level 3). Moreover, those who
underwent a cystectomy for recurrent non-invasive
disease had an improved outcome compared
to those who underwent surgery for progressive
disease. The investigators thus concluded that
deferring cystectomy until progression to muscleinvasive disease may decrease a patients overall
disease-specific survival. Nevertheless, 217 patients
from their original cohort of 307 with high-risk noninvasive disease never required cystectomy and
were thus spared the morbidity associated with
cystectomy.
1. T
he assessment of T1 urothelial carcinoma
should be based on tumor grade, early
recurrence, multiplicity, tumor size, concomitant
CIS, urothelial carcinoma involving the prostatic
mucosa or ducts, and depth of lamina propria
invasion. (LOE1a, grade A).
2. T
he use of 1 immediate postoperative instillation
of chemotherapy is not supported by consistent
data and therefore it should not be recommended
for standard practice. (LOE1a, grade A)
3. H
igh risk patients and those with recurrent or
persisting disease after BCG should be offered
a cystectomy. (LOE2a, grade A)
4. If a bladder-sparing approach is desired, a
secondary TURBT should be performed and
followed with intravesical BCG therapy. (LOE3,
grade B)
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24. Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN,

Danuser H, Markwalder R, Studer UE. Radical cystectomy
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neoadjuvant therapy. J Clin Oncol 2003;21:690-6.
10. Dutta SC, Smith Jr. JA, Shappell SB, Coffey DS, Chang
SS, Cookson MS: Clinical under staging of high risk
nonmuscle invasive urothelial carcinoma treated with
radical cystectomy. J Urol 2001, 166 (2): 490-493
25. Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC,

Boyd S, Skinner E, Bochner B, Thangathurai D, Mikhail
M, Raghavan D, Skinner DG. Radical cystectomy in the
treatment of invasive bladder cancer: long-term results in
1,054 patients. J Clin Oncol 2001;19:666-75.
11. Dalbagni G, Vora K, Kaag M, Cronin A , Bochner B, Donat

SM, Herr HW. Clinical outcome in a contemporary series of
restaged patients with clinical T1 bladder cancer: Eur Urol
2009; 56(6): 903-910
26. Shelley MD, Kynaston H, Court J, Wilt TJ, Coles B,

Burgon K, Mason MD. A systematic review of intravesical
bacillus Calmette-Gurin plus transurethral resection vs
transurethral resection alone in Ta and T1 bladder cancer.
BJU Int 2001;88(3):209-16.
12. Herr HW, Donat SM, Dalbagni G: Can Restaging

Transurethral Resection of T1 Bladder Cancer Select
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75-79
27. Han RF, Pan JG. Can intravesical bacillus Calmette-Gurin

reduce recurrence in patients with superficial bladder
cancer? A meta-analysis of randomized trials. Urology
2006;67(6):1216-23.
14. Bohle A, Leyh H, Frei C et al. Single postoperative

instillation of Gemcitabine in Patients with Non-Muscleinvasive Transitional Cell Carcinoma of the bladder: A
Randomised, Double-blind, Placebo-controlled Phase III
Multicentre Study
28. Shelley MD, Wilt TJ, Court J, Coles B, Kynaston H, Mason

MD. Intravesical bacillus Calmette-Gurin is superior to
mitomycin C in reducing tumour recurrence in high-risk
superficial bladder cancer: a metaanalysis of randomized
trials. BJU Int 2004;93(4):485-90
15. Gudjonsson S, Adell L, Mersada F et al: Should all patients

with non muscle invasive bladder cancer receive early
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Eur Urol 2009: 55: 773
29. Bhle A, Jocham D, Bock PR. Intravesical bacillus CalmetteGuerin versus mitomycin C for superficial bladder cancer: a
formal meta-analysis of comparative studies on recurrence
and toxicity. J Urol 2003;169(1):90-5.
16. Berrum-Svennung I, Granfors T, Jahnson S, Boman

H, Holmng S. A single instillation of epirubicin after
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30. Malmstrm P-U, Sylvester R, Crawford DE et al. An

Individual Patient Data Meta-Analysis of the Long-Term
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invasive bladder cancer (NMIBC): single immediate
instillation of chemotherapy after transurethral resection
of NMIBC and chemotherapy versus BCG in treatment of
intermediate-risk tumours. Eur Urol. Suppl., 2010; 9:406
31. Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical
the published results of randomized clinical trials. J Urol
2002;168(5):1964-70.
18. Zincke H, Utz DC, Taylor WF, Myers RP et al: Influence of

thiotepa and doxorubicin instillation at time of transurethral
surgical treatment of bladder cancer on tumour recurrence:
a prospective, randomised, double-blind, controlled trial . J
Urol; 129:505
32. Herr HW and Sogani PC. Does early cystectomy improve

the survival of patients with high risk superficial bladder
tumours? J Urol, 2001;166:1296-9.
33. Shahin O, Thalmann GN, Rentsch C, Mazzucchelli L,
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with or without intravesical bacillus Calmette-Guerin for
primary stage T1 grade 3 bladder cancer: recurrence,
progression and survival. J Urol, 2003;169:96-100.
19. Cai T, Nesi G, Tinacci G et al: Can early single dose

instillation of epirubicin improve bacillus Calmette-Guerin
efficacy in patients with non muscle invasive high risk
bladder cancer ? Results from a prospective, randomised,
double-blind controlled study. J Urol 2008; 180:110
34. Lamm DL, Blumenstein BA, Crissman JD, Montie JE,

Gottesman JE, Lowe BA, Sarosdy MF, Bohl RD, Grossman
HB, Beck TM, Leimert JT, Crawford ED. Maintenance
bacillus Calmette-Guerin immunotherapy for recurrent TA,
T1 and carcinoma in situ transitional cell carcinoma of the
bladder: a randomized Southwest Oncology Group Study.
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20. Babjuk M. New insights in intravesical treatment for

intermediate- and high-risk non-muscle-invasive urothelial
bladder carcinoma. Eur Urol. 2010 May;57(5):774-6;
21. Fritsche HM, Burger M, Svatek RS, Jeldres C, Karakiewicz
PI, Novara G, Skinner E, Denzinger S, Fradet Y, Isbarn
H, Bastian PJ, Volkmer BG, Montorsi F, Kassouf W, Tilki
D, Otto W, Capitanio U, Izawa JI, Ficarra V, Lerner S,
Sagalowsky AI, Schoenberg M, Kamat A, Dinney CP, Lotan
Y, Shariat SF. Characteristics and outcomes of patients
35. van der Meijden AP, Sylvester RJ, Oosterlinck W, Hoeltl

W, Bono AV; EORTC Genito-Urinary Tract Cancer Group.
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Maintenance bacillus Calmette-Guerin for Ta, T1 bladder

tumours is not associated with increased toxicity: results
from a European Organisation for Research and Treatment
of Cancer Genito-Urinary Group Phase III Trial. Eur Urol
2003;44(4):429-34.
IV. Treatment Options for BCG

Failure
36. Bhle A, Bock PR. Intravesical bacillus CalmetteGuerin versus mitomycin C in superficial bladder cancer:
formal meta-analysis of comparative studies on tumour
progression. Urology 2004;63(4):682-7
1. Introduction
Although BCG is an effective therapy for urothelial
carcinoma, BCG failure remains a significant
problem. Greater patient age, previous intravesical
therapy, and failure to achieve a complete response
after induction BCG are associated with an increased
risk of progression or death for patients with nonmuscle-invasive bladder cancer [1]. Studies using
more intensive BCG treatment and extended BCG
maintenance schedules tend to show better results.
The median time to progression generally exceeds
12 months, with an estimated progression rate
of 5% by 6 months. For these patients, radical
cystectomy continues to be the gold standard.
However, patients are sometimes reluctant to
undergo major surgery for a condition that does not
pose an immediate threat to their lives. Furthermore,
radical cystectomy is not a suitable treatment option
for a subset of patients with severe comorbidities. A
number of alternatives have thus been developed.
37. Lamm DL: Efficacy and safety of bacille Calmette-Guerin

immunotherapy in superficial bladder cancer. Clin Infect
Dis.31 Suppl 3:S86-90, 2000.
38. Denzinger S, Fritsche H-M, Otto W, Blana A,Wieland W-F,
Burger M: Early Versus Deferred Cystectomy for Initial
High-Risk pT1G3 Urothelial Carcinoma of the Bladder:
Do Risk Factors Define Feasibility of Bladder-Sparing
Approach? Eur Urol 2008;53:146-52
39. Bouffioux C, Kurth KH, Bono A, et al. Intravesical adjuvant
chemotherapy for superficial transitional cell bladder
carcinoma: results of 2 European Organization for Research
and Treatment of Cancer randomized trials with mitomycin
C and doxorubicin comparing early versus delayed
instillations and short-term versus long-term treatment.
European Organization for Research and Treatment of
Cancer Genitourinary Group. J Urol. Mar 1995;153(3 Pt
2):934-941.
40. Solsona E, Iborra I, Dumont R, Rubio-Briones J, Casanova
J and Almenar S. The 3-month clinical response to
intravesical therapy as a predictive factor for progression
in patients with high risk superficial bladder cancer. J. Urol.
164 (2000), 685689.
2. Defining BCG Failure
41. Herr HW, Dalbagni G. Defining bacillus CalmetteGuerin refractory superficial bladder tumours. J Urol
2003;169(5):1706-8
In evaluating salvage therapies for use after BCG

failure, Herr and Dalbagni noted that comparisons
between therapies have been hampered by the lack
of standard definitions for BCG failure and BCGrefractory urothelial carcinoma [2]. Some series have
defined BCG failure after a single induction course
of BCG, others after 2 courses [3,4,5]. In addition,
result reporting methods have been inconsistent [6].
Most studies have included all patients who received
1 or more courses of BCG [7,8,9]. Investigators have
often combined patients with persistent disease
(nonresponders) and patients with recurrent disease
after an initial response. Some studies combined
patients who were BCG nonresponders and patients
who could not complete BCG therapy due to the
associated toxicity (BCG intolerant). Furthermore,
many studies have combined all patients with
papillary tumors both with and without CIS. Finally,
most studies did not indicate the disease-free interval
after the last BCG course. These inconsistencies
have made it more difficult to compare outcomes in
this very heterogeneous population.
42. Schrier BPH, Hollander MP, van Rhijn BWG, Ijzer

S, Kiemeney LALM, Witjes JA. Prognosis of muscle
invasive bladder cancer: difference between primary and
progressive tumours: possible implications for therapy. Eur
Urol 2004;45:292-6
43. Amling CL, Thrasher JB, Frazier HA, Dodge RK, Robertson
JE and Paulson DF: Radical cystectomy for stages Ta, Tis
and T1 transitional cell carcinoma of the bladder. J Urol,
1994;151:31-5.
44. Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd
S, Skinner E, Bochner B, Thangathurai D, Mikhail M et al.:
Radical cystectomy in the treatment of invasive bladder
cancer: longterm results in 1,054 patients. J Clin Oncol,
2001;19: 666-75.
45. Ghoneim MA, el-Mekresh MM, el-Baz MA, el-Attar IA and
Ashamallah A: Radical cystectomy for carcinoma of the
bladder: critical evaluation of the results in 1,026 cases. J
Urol, 1997;158:393-9.
46. Malavaud B. T1G3 bladder tumours: the case for radical
cystectomy. Eur Urol 2004;45:406-10.
47. Bianco FJ Jr, Justa D, Grignon DJ, Sakr WA, Pontes
JE and Wood DP Jr. Management of clinical T1 bladder
transitional cell carcinoma by radical cystectomy. Urol
Oncol 2004;22:290-4.
In the most general sense, any recurrent disease

after initiation of BCG therapy can be referred to as
BCG failure. However, to provide more uniformity
in reporting, the following alternative descriptive
terms for specific types of BCG failure should be
used whenever possible:
48. Cookson MS, Herr HW, Zhang ZF, Soloway S, Sogani PC,
Fair WR. The treated natural history of high risk superficial
bladder cancer: 15-year outcome. J Urol, 1997;158:62-7.
49. Hendricksen K, Witjes W, Idema J, Kums J, van Vierssen
Trip O,de Bruin M, Vergunst H, Caris C, Janzing-Pastors
M, Witjes J. Comparison of Three Schedules of Intravesical
Epirubicin in Patients with NonMuscle-Invasive Bladder
Cancer . Eur Urol 2008;53:984-91
BCG-refractory disease is the term used when a

disease-free state is not achieved within 6 months
of the initial BCG therapy with either maintenance
265
or retreatment at 3 months due to either persistent

or rapidly recurrent disease. The definition also
includes any progression in stage, grade, or disease
extent within 3 months of the first BCG cycle (i.e.,
non-improving or worsening disease, despite BCG).
BCG-resistant disease is the term used when there
is recurrence or persistence of disease 3 months
after the induction cycle. If it is of lesser degree,
stage, or grade, and is no longer present at 6
months following BCG retreatment with or without
TURBT, the disease has improved and is resolved
with further BCG. BCG-relapsing disease is the
term used when there is a recurrence of disease
after disease-free status has been achieved within
6 months (i.e., disease resolved after BCG but
subsequently returns). Relapse is further defined
according to the time of recurrence as either early
(within 12 months), intermediate (12 to 24 months),
or late (> 24 months). There is some overlap with
BCG-refractory disease, as disease relapse while
on active maintenance, i.e., within 3 months, may
qualify as BCG-refractory disease. BCG-intolerant
disease is the term used when disease recurs after
a less-than-adequate course of therapy is applied
because of a serious adverse event or symptomatic
intolerance that mandates discontinuation of further
BCG therapy (i.e., recurrent disease in the setting
of inadequate BCG treatment because of drug
toxicity).
patients with any grade T1 disease; another 70%

(19 of 27) responded to further TURBT and BCG,
including 64% (7 of 11) with recurrent T1 disease.
Similar results were reported by Brake et al [12] who
found a 70% (89 of 128) enduring response after 1
BCG cycle and 51% (19 of 37) after a second BCG
cycle for the remaining 37 patients (13 of whom
had already progressed). Pansadoro and De Paula
[13] reported that the response rate of 47 patients
to TUR plus 1 cycle of 6 weekly BCG instillations
was 53% (25 of 47). Of the 22 failures treated with
a repeat TUR and a second cycle of BCG, 27% (6
of 22) responded, and, of the remaining 16 patients
who received a third cycle of BCG, only 6% (1 of
16) responded. These results are similar to those
reported in BCG studies in nonT1-restricted tumors
and illustrate that a second (but not greater) course
of BCG may be appropriate in select patients with
original stage T1 disease who have a recurrence of
non-BCG-refractory disease. Unfortunately, there
are insufficient data to assess the effectiveness of
repeated BCG treatments in refractory patients or
those with recurrent T1 disease [14].
c) Intravesical salvage chemotherapy

Of the various standard intravesical chemotherapeutic
agents (Thiotepa, doxorubicin, MMC) there is
only minimal reported experience with their use
in patients failing prior BCG therapy. Malmstrom
et al [15] reported a 19% 3-year disease-free rate
among intermediate and high risk patients treated
with MMC who had failed a prior first induction
cycle of BCG. The results for T1 recurrences are
unknown. Similarly, there are few data on the newer
anthracycline derivative valrubicin. Of 90 valrubicintreated patients with CIS with and without papillary
urothelial carcinoma who had failed 2 or more cycles
of prior intravesical therapy (most commonly BCG),
only 21% had a complete response at 6 months and
8% by 24 months [16]. Notably, all 5 patients with
stage T1 disease (previously resected) plus CIS
failed to achieve a complete response. Gemcitabine
has been suggested as a potential alternative for
patients intolerant to or otherwise unable to receive
BCG due to its favorable toxicity profile. However,
gemcitabine has been shown to have an almost
two-fold recurrence rate at 44 months (53% versus
28%) when compared to BCG in a randomized
prospective study [17]. Two other studies, however,
suggest that gemcitabine could be used in BCG
failures. Addeo et al treated 120 patients, of which
109 were assessable for response [18]. Ninetyone of these 109 patients failed previous BCG, but
details on these failures were not provided. Patients
were randomized between gemcitabine and MMC,
with a 3-year recurrence-free survival of 72% and
61%, respectively. Progression was noted in 6 of
54 patients and 10 of 55 patients, respectively. Di
Lorenzo et al [19] compared 1 year of gemcitabine
to BCG Connaught. The only difference in the
Prophylactic use of ofloxacin has been reported to

decrease incidence of moderate to severe adverse
events associated with BCG intravesical therapy, but
this strategy has not been widely adopted. [10]
3. Treatment Options
a) Cystectomy
Great variation exists in actual practice with regard
to the timing of cystectomy in patients who fail
induction BCG therapy. These vary from immediate
surgery after the first follow-up cystoscopy if residual
disease is present to delaying surgery for 6 months if
a complete response is not achieved. The evidence
for this interval is not well-established at the present
time. There is general consensus that the prognosis
for some patients with aggressive disease can be
adversely affected by delaying surgery, but the
prediction of this risk in individual cases is difficult.
As such, alternative bladder-sparing strategies are
frequently used (see below).
b) Repeat BCG Treatments

This treatment may be appropriate for both BCGresistant and BCG-relapsing disease. However,
the success of a second course of BCG for stage
T1 disease has not been extensively reported,
and only a few published studies have addressed
this issue. Cookson and Sarosdy [11] reported an
initial 69% (59 of 86) complete response to BCG in
266
treatment schedule was that the 6 week induction

course was biweekly for gemcitabine in comparison
to weekly for BCG. All patients had high risk nonmuscle-invasive bladder cancer, having failed
1 course of BCG. The 2-year recurrence-free
survival was 19% for gemcitabine versus 3% for
BCG (p<0.008). Progression rates were 33% and
37.5%, respectively. In all, gemcitabine seems to
have some effect in patients who have failed BCG;
nevertheless, many patients experience recurrence
and progression, especially in the high risk group.
for BCG failures has not yet been established [29].

Furthermore, for T1 disease alone, local recurrence
or progression occurs in approximately 50% of
cases [30]. Thermo-chemotherapy has recently
been reported on in patients with recurrent disease
following BCG [31]. One hundred and eleven patients
(29 pT1) were treated with 6 weekly induction
treatments, and thereafter 4 to 6 sessions with a 6
week interval. The disease-free survival estimates
were 85% and 56% after 1 and 2 years, respectively.
Only 3 patients experienced progression. There
was no difference between the different BCG failing
groups (definitions used as outlined above), nor,
for example, for Ta versus T1. Only maintenance
hyperthermia treatment was associated with
increased efficacy. In all, hyperthermia treatment
would appear to be a possibility for these patients,
although more studies are needed.
Similarly, prospective evaluation has found

epirubicin with interferon alpha to be inferior to BCG
for prophylaxis of recurrence and therefore has
a limited role in patients experiencing BCG failure
[20]. Given these poor results, it appears that current
intravesical salvage chemotherapy has little to offer
patients who have failed BCG, especially those with
stage T1 disease.
Recommendations for BCG Failure
d) Interferon alpha Immunotherapy
1. T
he threat of progression remains real but
comfortably low enough within the first 6 months
of initiating BCG to consider alternatives to
cystectomy for those patients unfit or not willing
to undergo this standard management option
(LOE 2, Grade B).
In 2 studies, findings suggest that interferon alpha

is unlikely to be of benefit in stage T1 BCG failures.
The long-term (>2 years) success rate of interferon
alpha monotherapy of patients who fail BCG (CIS
and/or papillary urothelial carcinoma) is generally
15% [21]. Furthermore, in a study of interferon
alpha monotherapy for primary stage T1 disease,
interferon alfa was found to be no better than placebo
at 43 month follow-up [22].
2. In the case of any BCG non-response or failure,

cystectomy is recommended (LOE 2a, Grade
A).
3. T
he current best option for alternative treatment
includes repeat resection and repeat BCG (LOE
1a, Grade A), possibly with interferon alpha as a
costimulant (LOE 2, grade C). Gemcitabine and
thermo-chemotherapy have shown efficacy,
but more studies are needed. There is no
reported evidence of significant efficacy using
current intravesical chemotherapy, interferon
alpha monotherapy, photodynamic therapy, or
radiation therapy.
e) Combination BCG plus Interferon alpha

Several
single
institutional
studies
have
demonstrated that the combination of low-dose BCG
plus interferon alpha may be useful as a salvage
regimen for BCG failures [23,24,25,26]. With followup times ranging from 12-30 months, disease-free
rates were 50-60%, even in patients with recurrent T1
disease. Furthermore, no patient with an expedient
cystectomy after BCG plus interferon alpha failure
had unresectable or metastatic disease. Interim
results of an even larger group of 231 patients with
BCG failure in a multi-institutional study showed a
disease-free rate of 42% at a median follow-up time
of 24 months [27]. The efficacy results for stage T1
patients have not yet been published, but preliminary
analysis reveals a similar degree of durable response
among an approximate 10% progression rate (M.
ODonnell, personal communication).
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19. Di Lorenzo G, Perdon S, Damiano R, Faiella A, Cantiello
F, Pignata S, Ascierto P, Simeone E, De Sio M, Autorino
R. Gemcitabine versus bacille Calmette-Gurin after initial
bacille Calmette-Gurin failure in non-muscle-invasive
bladder cancer: a multicenter prospective randomized trial.
Cancer 2010 Apr 15;116(8):1893-900
20. Duchek M, Johansson R, Jahnson S, Mestad O, Hellstrm
P, Hellsten S, and Malmstrm P: Bacillus Calmette-Guerin
is superior to a combination of epirubicin and interferon-
268
Committee 6
Muscle-invasive,
Chairs:
Jason Efstathiou,
David I. Quinn,
Arnulf Stenzl
Members:
Joaquim Bellmunt,
Michael S. Cookson,
Georgios Gakis,
Khurshid A. Guru,
Axel Heidenreich,
Patrick Keegan,
Seth P. Lerner,
Edward M. Messing,
Arthur I. Sagalowsky,
Mark P. Schoenberg,
William U. Shipley,
Arlene O. Siefker-Radtke,
Cora Sternberg
269
Table of Contents
I. Overview
V. Perioperative Radiotherapy
II. Indications and Algorithm

of Treatment
VI. Bladder-sparing
Treatments for Localized
Disease
III. Radical Surgery
1. Transurethral Monotherapy
2. Partial Cystectomy
1. Removal of the Tumor-bearing

Bladder
3. Radiation-based Bladderpreserving Strategies
2. Surgical Outcome: Morbidity and

Mortality
VII. Treatment of Mixed

Histology Urothelial
Carcinoma
3.Oncological Outcome of Radical

Surgery According to TNM Staging
IV. Perioperative
Chemotherapy
VIII. Follow-up
1. Neoadjuvant Chemotherapy
1. Site of Recurrence
2. Adjuvant Chemotherapy
270
Muscle-invasive,
Jason Efstathiou, David I. Quinn, Arnulf Stenzl
Joaquim Bellmunt, Michael S. Cookson, Georgios Gakis,
Khurshid A. Guru, Axel Heidenreich, Patrick Keegan,
Seth P. Lerner, Edward M. Messing, Arthur I. Sagalowsky,
Mark P. Schoenberg, William U. Shipley,
Arlene O. Siefker-Radtke, Cora Sternberg
Summary of International Consultation on
Urological Diseases (ICUD) Modified Oxford Center
for Evidence-Based
I. Overview
A panel of an international multidisciplinary group
consisting of urologists, oncologists and radio-oncologists provide data on evidence-based management
of patients with muscle-invasive, clinically presumably node-negative, bladder cancer. The guidelines
focus on treatment options and outcome, including
radical surgery, neoadjuvant and adjuvant treatment
modalities, bladder-sparing approaches, and treatment of mixed and secondary urothelial recurrences.
In addition, specific recommendations are given for
the surgical treatment and extent as well as for follow-up strategies after curative intent. The level of
evidence and grade of recommendation given are
as outlined by the Oxford Centre for Evidence-based
Medicine [1].
Medicine
grading
recommendations
system
for
guideline
Levels of evidence
Level 1 Meta-analysis of RCTs or a good-quality
RCT
Level 2 Low-quality RCT or meta-analysis of goodquality prospective cohort studies
Level 3 Good-quality retrospective case-control
studies or case series
Level 4 Expert opinion based on first principles
or bench research, not on evidence
Grades of recommendation
References
Grade A Usually consistent level 1 evidence

Grade B Consistent level 2 or 3 evidence or
majority evidence from RCTs
1. Modified from Oxford Centre for Evidence-based Medicine

Levels of Evidence (May 2001). Produced by Bob Phillips,
Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus,
Brian Haynes, Martin Dawes since November 1998.http://
www.cebm.net/index.aspx?o=1025 [access date February
2009].
Grade C Level 4 evidence, majority evidence

from level 2 or 3 studies, expert opinion
Grade D No recommendation possible because of
inadequate or conflicting evidence
II. Indications and Algorithms

of Treatment
RCT _ randomized controlled trial.

Adapted with permission from Incontinence.[1]
Radical
cystectomy
and
bilateral
pelvic
lymphadenectomy provide excellent loco-regional
control for patients with clinical stage T2-T4a, N0NX, M0 disease. Local pelvic recurrence rates are
as low as 4% in patients with node negative disease
and 15-20% for patients with node metastases.
[1,2] Cystectomy may also be appropriate initial
treatment for some patients with first occurrence of

high risk non-muscle-invasive cancer or recurrence.
Patients with high grade papillary disease (Ta, T1)
or carcinoma in situ that recurs following treatment
with intravesical BCG or patients with intermediate
271
risk papillary disease that cannot be controlled with

transurethral resection and intravesical therapy alone
should be offered cystectomy. Surgery should not be
withheld or delayed in these patients as the longterm survival probability is decreased when there is
evidence of progression to muscle-invasive cancer.[3]
Morris et al studied how physician behavior affected
outcomes in bladder cancer management and
determined that the persistent use of conservative
therapy delays necessary, aggressive treatment.[4]
In this setting, changing physician decision-making
and/or practice patterns may decrease mortality.
Salvage cystectomy is indicated for non-responders
to conservative therapy, recurrences after bladdersparing treatments, non-urothelial carcinomas (these
tumors may respond poorly to chemotherapy and
radiotherapy), and as a purely palliative intervention
in the setting of fistula formation, pain, or recurrent
gross hematuria.
been overcome. Several randomized clinical trials

are underway comparing open versus robotic but to
date there is a paucity of long-term data to provide
guidance regarding long-term oncologic outcomes.
Surgical modifications that spare a portion of the
prostate have been developed in order to improve
continence and potency following cystectomy. It is
not clear that this technique offers an incremental
improvement in quality of life outcomes over
meticulous nerve-sparing and careful dissection
of the apical prostate and membranous urethra.
The oncologic risk for prostatic involvement with
urothelial cancer is up to 40%.[13] The incidence
of prostate adenocarcinoma is similar, and at least
one-half of these cancers are considered clinically
significant.[14]
In sexually active women, vaginal preservation and/
or reconstruction must be discussed and planned
preoperatively. Recent reports challenge the dogma
of removal of the internal female organs as the rate
of involvement of the uterus, cervix, and ovaries
is low.[15] Preservation of the vagina and uterus
provides better support for a neobladder and the
pelvic floor when the extent of the cancer or the age
and general health status of the patient does not
warrant anterior pelvic exenteration.[16] One also
needs to balance the benefits of retaining the uterus,
Fallopian tubes, and ovaries versus the increased
surgical risks of potentially requiring hysterectomy
later after a neobladder. Involvement of the urethra
or bladder neck is an absolute contraindication to
urethra-sparing in women and a posterior-based
invasive cancer is a relative contraindication.[17,18]
Much has been written about the timing of cystectomy

and long-term survival, which is inconclusive due in
part to the retrospective nature of the research and
the biology and demographics of the unique patient
populations studied. A recent population based study
from the United States SEER Medicare database
looked at patients operated on between 1992 and
2001.[5] The authors findings suggest that 12 weeks
is the outside limit beyond which there is a negative
impact on outcome (level 3b).
The goals of therapy are complete eradication of the
loco-regional disease including the primary tumor
and regional lymph nodes. The primary landing
zone for node metastases includes the obturator
and internal and external iliac lymph nodes. The
incidence of node metastases increases with tumor
stage. The majority of patients with node metastases
have multiple positive nodes and at least one-third
have node metastases in secondary landing zones
including the pre-sacral and common iliac nodes.
[6-8] Neoadjuvant or adjuvant chemotherapy
targeting occult regional node and/or visceral
metastases should be integrated with loco-regional
therapy when the risk of this occurring is high
enough.[9-12] Patients should have volitional control
of urination via the retained urethra or by a continent
catheterizable stoma (in properly selected patients)
and treatment-related morbidity should be minimized
wherever possible.
The morbidity of cystectomy can be significant

though the mortality has been reduced to 2-3% in
most contemporary series.[19] A recent report from
Memorial Sloan Kettering Cancer Center described
1145 patients operated on between 1995 and
2005 using a modified Clavien system.[20,21] The
majority of patients (64%) experienced one or more
complications and the majority of these were grade
2-5. The hospital re-admission rate was 26%. The
authors suggest that this degree of peri-operative
morbidity may limit use of adjuvant chemotherapy in
as many as 30%[20].
Recommendations
Radical cystectomy is indicated for definitive locoregional control of non-muscle-invasive urothelial
cancer that is refractory to intravesical therapy or
cannot be controlled with transurethral resection
(LE 2b GR B).
Radical cystectomy provides excellent local

control of the primary tumor. In men, this should
include the bladder and surrounding perivesical
soft tissue, prostate, and seminal vesicles, and, in
women, the ovaries, uterus with cervix, and anterior
vagina. With the pervasive use of robotic-assisted
laparoscopic radical prostatectomy, many surgeons
are applying these skill sets to radical cystectomy
(discussed in Section 2.1.6). Proof of concept has
been demonstrated as the technical hurdles have
T
he most common indication is primary treatment
for patients with initial occurrence of muscleinvasive cancer or progression to muscle-invasive
cancer that has failed intravesical therapy (LE 2a
GR B). The evidence supporting this is based on
272
an open surgical technique incorporating bilateral

pelvic lymphadenectomy.
11. Adjuvant chemotherapy in invasive bladder cancer: a

systematic review and meta-analysis of individual patient
data Advanced Bladder Cancer (ABC) Meta-analysis
Collaboration. Eur Urol. Aug 2005;48(2):189-199;
discussion 199-201.
M
inimally-invasive techniques including roboticassisted laparoscopic radical cystectomy have
been reported in increasing numbers. Shortterm
outcomes, pathologic findings, and assessments
of morbidity compared to the open technique have
been reported. Continued research with these
techniques is required and specifically results of
several randomized trials underway should be
reported prior to accepting this as an equivalent
option to open radical cystectomy (LE 2a GR C).

alone for locally advanced bladder cancer. N Engl J Med.
Aug 28 2003;349(9):859-866.
13. Shen SS, Lerner SP, Muezzinoglu B, Truong LD, Amiel
G, Wheeler TM. Prostatic involvement by transitional cell
carcinoma in patients with bladder cancer and its prognostic
significance. Hum Pathol. Jun 2006;37(6):726-734.
14. Revelo MP, Cookson MS, Chang SS, Shook MF, Smith JA,
Jr., Shappell SB. Incidence and location of prostate and
urothelial carcinoma in prostates from cystoprostatectomies:
implications for possible apical sparing surgery. J Urol. May
2008;179(5 Suppl):S27-32.
C
ystectomy is also indicated as palliation for
intractable pelvic pain and bleeding from locally
advanced or metastatic bladder cancer (LE 4 GR
C).
15. Chang SS, Cole E, Smith JA, Jr., Cookson MS. Pathological
findings of gynecologic organs obtained at female radical
cystectomy. J Urol. Jul 2002;168(1):147-149.
(Level of Evidence = LE,

Grade of Recommendation = GR)
16. Ali-El-Dein B, Gomha M, Ghoneim MA. Critical evaluation

of the problem of chronic urinary retention after orthotopic
bladder substitution in women. J Urol. Aug 2002;168(2):587592.
References
17. Schilling D, Horstmann M, Nagele U, Sievert KD, Stenzl

A. Cystectomy in women. BJU Int. Nov 2008;102(9 Pt
B):1289-1295.

neobladder era. J Urol. Aug 2006;176(2):486-492;
discussion 491-482.
18. Stein JP, Penson DF, Lee C, Cai J, Miranda G, Skinner DG.
Long-term oncological outcomes in women undergoing
radical cystectomy and orthotopic diversion for bladder
cancer. J Urol. May 2009;181(5):2052-2058; discussion
2058-2059.
2. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in

the treatment of invasive bladder cancer: long-term results
in 1,054 patients. J Clin Oncol. Feb 1 2001;19(3):666-675.
19. Lowrance WT, Rumohr JA, Chang SS, Clark PE, Smith
JA, Jr., Cookson MS. Contemporary open radical
cystectomy: analysis of perioperative outcomes. J Urol. Apr
2008;179(4):1313-1318; discussion 1318.
3. Dalbagni G, Vora K, Kaag M, et al. Clinical outcome in a

contemporary series of restaged patients with clinical T1
bladder cancer. Eur Urol. Dec 2009;56(6):903-910.
20. Donat SM, Shabsigh A, Savage C, et al. Potential impact of

postoperative early complications on the timing of adjuvant
chemotherapy in patients undergoing radical cystectomy:
a high-volume tertiary cancer center experience. Eur Urol.
Jan 2009;55(1):177-185.
4. Morris DS, Weizer AZ, Ye Z, Dunn RL, Montie JE,

Hollenbeck BK. Understanding bladder cancer death:
tumor biology versus physician practice. Cancer. Mar 1
2009;115(5):1011-1020.
21. Shabsigh A, Korets R, Vora KC, et al. Defining early

morbidity of radical cystectomy for patients with bladder
cancer using a standardized reporting methodology. Eur
Urol. Jan 2009;55(1):164-174.
5. Gore JL, Lai J, Setodji CM, Litwin MS, Saigal CS. Mortality
increases when radical cystectomy is delayed more than 12
weeks: results from a Surveillance, Epidemiology, and End
Results-Medicare analysis. Cancer. Mar 1 2009;115(5):988996.
III. Radical Surgery
6. Dangle PP, Gong MC, Bahnson RR, Pohar KS. How do

commonly performed lymphadenectomy templates influence
bladder cancer nodal stage? J Urol. Feb;183(2):499-503.
1. R
emoval of the Tumor-bearing
Bladder
7. Roth B, Wissmeyer MP, Zehnder P, et al. A new multimodality

technique accurately maps the primary lymphatic landing
sites of the bladder. Eur Urol. Feb;57(2):205-211.
a) Background
8. Leissner J, Ghoneim MA, Abol-Enein H, et al. Extended

radical lymphadenectomy in patients with urothelial bladder
cancer: results of a prospective multicenter study. J Urol.
Jan 2004;171(1):139-144.
Radical cystectomy is the standard treatment for

muscle-invasive bladder cancer in most countries
worldwide [1]. In the pre-cystectomy era, 5-year
survival rates for patients with muscle-invasive
disease rarely exceeded 3% and performing radical
surgery was associated with a considerably increased
perioperative morbidity and mortality [2]. In the last
decades, advances in the surgical technique as well
as perioperative anesthesia care have significantly
9. Neoadjuvant cisplatin, methotrexate, and vinblastine

chemotherapy for muscle-invasive bladder cancer: a
randomised controlled trial. International collaboration of
trialists. Lancet. Aug 14 1999;354(9178):533-540.
10. Neoadjuvant chemotherapy in invasive bladder cancer:
update of a systematic review and meta-analysis of
individual patient data advanced bladder cancer (ABC)
meta-analysis collaboration. Eur Urol. Aug 2005;48(2):202205; discussion 205-206.
273
decreased the complication rates associated with

this procedure and have led to radical cystectomy
now being considered the mainstay of treatment for
this muscle-invasive disease.
morbidity of radical cystectomy in select elderly patients

with bladder cancer. J Urol 2002; 167(3): 1325-8
8. Lughezzani G, Sun M, Shariat SF, Budus L, Thuret R,
Seldres C, Liberman D, Montorsi F, Perrotte P, Karakiewicz
PI. A population based competing-risks analysis of the
survival of patients treated with radical cystectomy for
bladder cancer. Cancer 2011; 117(1):103-9
In the last decade, increased interest in quality of

life issues has increased the trend toward bladder
preservation with transurethral resection followed by
chemotherapy and radiation therapy [3, 4, 5]. Also,
performance status and age were formerly reported
to influence the choice of therapy, with cystectomy
being reserved for younger patients without
concomitant disease and better performance status
[6]. Nonetheless, recent studies have demonstrated
the feasibility and safety of radical surgery in
octogenarians [7]. The value of assessing overall
health before recommending and proceeding with
surgery was emphasized in a prior report, which
demonstrated an association between comorbid
illness and adverse pathological and survival
outcome following radical cystectomy [5]. Similar
to these results, a recent analysis from the SEER
registries evaluated the impact of comorbidities
on cancer-specific and other-cause mortality in a
population-based competing risk analysis of more
than 11,260 patients. Age was found to confer the
highest risk for other-cause mortality but not for
increased cancer-specific death, whereas locally
advanced tumor stage was the strongest predictor
for decreased cancer-specific survival [8]. Stratifying
elderly patients according to their individual riskbenefit profile within a multidisciplinary team might
help to select those who may benefit most from
radical surgery and optimize their outcomes.
b) Timing and Delay of Cystectomy

It has been suggested that delaying radical
cystectomy in organ-confined disease is associated
with decreased survival [1]. These concerns regard
primary surgery as monotherapy; the time spent for
neoadjuvant chemotherapy is another matter. Even
though it is well accepted that treatment should
be instituted once a diagnosis of cancer has been
made, several factors play a role in delaying such
treatment. Some of these factors are linked to
the health care system, while others are patientrelated. The question of whether there is a window
of opportunity for the treatment of invasive bladder
cancer remains unanswered.
Reviewing all studies on this issue, it becomes evident
that there is no linear relationship between delay of
radical cystectomy and prognosis. However, delays
are associated with worse outcome. The majority
of studies suggest that a treatment delay of more
then 12 weeks from diagnosis of invasive disease
to cystectomy is associated with a significantly
impaired prognosis.
Lee et al [2] analyzed the outcome of 214 patients who
underwent radical cystectomy for muscle-invasive
bladder cancer and they observed a significant
disease-specific (p=0.05) and overall survival
(p=0.02) advantage in patients who underwent radical
cystectomy within 3 months or less as compared to
those undergoing radical cystectomy greater than
3 months after diagnosis. Interestingly, the most
common factor contributing to cystectomy delay was
a scheduling delay. In a similar study, Fahmy et al [3]
characterized various periods of delay sustained by
bladder cancer patients before radical cystectomy
across Quebec. The authors analyzed the 1633
patients being treated with radical cystectomy
between 1990 and 2002 and they identified a delay
of more than 84 days to be associated with a 1.4
times increased risk of death from bladder cancer.
Gore et al [4] examined the survival impact of a delay
in radical cystectomy using nationally representative
SEER data. The authors identified 441 patients
with stage II bladder cancer who underwent radical
cystectomy between 1992 and 2001. Delay in
radical cystectomy beyond 12 weeks and 24 weeks
resulted in a 2-fold increased risk for both diseasespecific and overall mortality when compared to
immediate radical cystectomy performed within 4 to
8 weeks after diagnosis of muscle-invasive bladder
cancer. Kulkarni et al [5] identified 2535 patients who
underwent radical cystectomy between 1992 and
References
1,054 patients. J Clin Oncol 2001; 19(3):666-75.
2. Bostrm PJ, Mirtti T, Kssi J, Laato M, Nurmi M. Twenty
year experience of radical cystectomy in a medium volume
center. Scand J Urol Nephrol. 2009;43(5):357-64.
3. Herr HW, Bajorin DF, Scher HI. Neoadjuvant chemotherapy
and bladder- sparing surgery for invasive bladder cancer:
ten-year outcome. J Clin Oncol. 1998; 16(4):1298-301.
4. International collaboration of trialists. Neoadjuvant cisplatin,
methotrexate, and vinblastine chemotherapy for muscleinvasive bladder cancer: a randomised controlled trial.
Lancet. 1999; 354(9178):533-40
5. Zietman AL, Shipley WU, Kaufman DS. Organ-conserving
approaches to muscle-invasive bladder cancer: future
alternatives to radical cystectomy. Ann Med. 2000; 32(1):3442.
6. Miller DC, Taub DA, Dunn RL, Montie JE, Wei JT. The impact
of co-morbid disease on cancer control and survival following
radical cystectomy. J Urol. 2003Jan;169(1):105-9.
7. Soulie M, Straub M, Game X, Seguin P, De Petriconi
R, Plante P, Hautmann RE. A multicenter study on the
274
2004 in Ontario. The median waiting time between

transurethral resection and radical cystectomy was
50 days. Prolonged waiting times were significantly
associated with a lower overall survival rate. A cubic
splines regression analysis revealed that the risk
of death began to increase after a waiting time of
40 days. Similar data were reported by Jger et al
[6] who identified a waiting time of longer than 4
months to be associated with a significantly reduced
5-year cancer specific survival of 77% versus 86%
(p=0.04). Ayres et al [7] recently analyzed whether
a delay to radical cystectomy affects the survival
of patients with bladder cancer in England. The
analysis of organ-confined bladder cancer revealed
that a delay of greater than 90 days was associated
with a 1.4 times increased risk of death from bladder
cancer whereas there was significant correlation
between delay and prognosis for patients with locally
advanced disease.
5. Kulkarni GS, Urbach DR, Austin PC, Fleshner NE, Laupacis

A. Longer wait times increase overall mortality in patients
with bladder cancer. J Urol. 2009 Oct;182(4):1318-24.
Epub 2009 Aug 14.
There is one recent publication in the literature which

does not demonstrate any correlation between the
delay from the last TUR to radical cystectomy and
decreased survival times [8]. The authors analyzed
the outcomes of 592 patients who underwent radical
cystectomy within a median time from TUR to radical
cystectomy of 1.8 months. However, it has to be
taken into consideration that 35% of all patients who
underwent radical cystectomy demonstrated nonmuscle-invasive disease on final pathology.
In male patients, the literature over the last two

decades has set the standard of surgical limits for
curative radical cystectomy as complete removal
of the bladder with all macroscopically visible and
resectable bladder perforating tumor extensions,
removal of the adjacent distal ureters, and the lymph
nodes corresponding to the tumor-bearing bladder.
6. Jger W, Thomas C, Haag S, Hampel C, Salzer A, Throff

JW, Wiesner C. Early vs delayed radical cystectomy for
high-risk carcinoma not invading bladder muscle: delay of
cystectomy reduces cancer-specific survival. BJU Int. 2011
Jan 18. doi: 10.1111/j.1464-410X.2010.09980.x. [Epub
ahead of print]
7. Ayres BE, Gillatt D, McPhail S, Cottrell A, McGrath J,
Cottier B, Verne J, Persad RA. A DELAY IN RADICAL
CYSTECTOMY OF > 3 MONTHS IS NOT ASSOCIATED
WITH A WORSE CLINICAL OUTCOME. BJU Int 2008;
102: 1045
8. Nielsen ME, Palapattu GS, Karakiewicz PI, Lotan Y,
Bastian PJ, Lerner SP, Sagalowsky AI, Schoenberg MP,
Shariat SF. A delay in radical cystectomy of >3 months is
not associated with a worse clinical outcome. BJU Int. 2007
Nov;100(5):1015-20. Epub 2007 Sep 3.
c) Technique
Preservation of the anterior and membranous urethra

including the rhabdosphincter in order to enable an
orthotopic neobladder; parts of the prostate and
seminal vesicles for reasons of fertility, potency, and
continence; and intrapelvic autonomic and sensory
nerves to enhance potency and continence are all
technical variations to this standard that may improve
patients quality of life but must be attentively judged
against possible oncological risks [1] (Level of
evidence: 3, grade of recommendation: C).
Recommendations
D
elay in cystectomy for muscle-invasive disease
is associated with significantly reduced overall
and cancer-specific survival (LE: 3, GR: B).
R
adical cystectomy in patients with muscleinvasive bladder cancer should be performed
within 3 months after initial diagnosis of stage T2
T4 disease (LE: 3, GR: B)
In case of leaving parts of the prostatic gland

during the resection, the hazard of an unsuspected
adenocarcinoma may be as high as 23-54% of which
up to 29% may be clinically significant, lead to local
recurrence, or even metastasis [2-4]. Furthermore,
urothelial carcinoma may be present in the prostate
and in some series up to 27% of patients undergoing
cystoprostatectomy had prostate cancer [5]. A rather
new technical variation is deliberately leaving the
seminal vesicles and prostatic capsule in order to
better preserve the surrounding autonomic nerves.
The results regarding potency versus oncological risk
in small series of selected patients are encouraging
but need long-term confirmation in larger series [6, 7].
To date these technical modifications have not been
documented to improve continence and they remain
highly controversial regarding oncologic safety.
References
1. Fahmy NM, Mahmud S, Aprikian AG. Delay in the surgical
treatment of bladder cancer and survival: systematic review
of the literature. Eur Urol. 2006 Dec;50(6):1176-82
2. Lee CT, Madii R, Daignault S, Dunn RL, Zhang Y, Montie
JE, Wood DP Jr. Cystectomy delay more than 3 months
from initial bladder cancer diagnosis results in decreased
disease specific and overall survival. J Urol. 2006
Apr;175(4):1262-7
3. Fahmy N, Kassouf W, Jeyaganth S, Amin M, Mahmud
S, Steinberg J, Tanguay S, Aprikian A. An analysis of
preoperative delays prior to radical cystectomy for bladder
cancer in Quebec. Can Urol Assoc J. 2008 Apr;2(2):102-8.
In female patients, standard anterior pelvic

exenteration includes the entire urethra, adjacent
vagina, uterus, distal ureters, and respective lymph
nodes (level of evidence: 3, grade of recommendation:
C). Unless the primary tumor is located at the
4. Gore JL, Lai J, Setodji CM, Litwin MS, Saigal CS; Urologic
Diseases in America Project. Mortality increases when
radical cystectomy is delayed more than 12 weeks: results
from a Surveillance, Epidemiology, and End ResultsMedicare analysis. Cancer. 2009 Mar 1;115(5):988-96.
275
bladder neck or in the urethra, a major part of the

functioning female urethra and, provided a complete
tumor resection is possible, its autonomous nerves
can be preserved in case of a planned orthotopic
neobladder [8, 9, 10, 11] (level of evidence: 3, grade
of recommendation: C). New data also question the
necessity to remove the uterus or any portion of the
vagina, arguing for a better anatomical support of the
neobladder and better preservation of surrounding
autonomous nerves.
cystoprostatectomy: defining risk with prostate capsule

sparing cystectomy. Urol Oncol, 2007. 25(6): p. 460-4.
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2010. 105(4): p. 468-71.
6. Ong, C.H., M. Schmitt, G.N. Thalmann and U.E. Studer,
Individualized seminal vesicle sparing cystoprostatectomy
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good functional results. J Urol, 2010. 183(4): p. 1337-41.
7. Colombo, R. and R.E. Hautmann, Open to debate. The
motion: seminal-nerve sparing radical cystectomy is an
efficacious and safe treatment for selected bladder cancer
patients. Eur Urol, 2008. 53(1): p. 203-7.
In both sexes, the length of the distal ureteral

segment to be removed with the bladder has not
been specified and depends on oncological issues
such as tumor extension or presence of carcinoma
in situ and type of subsequent urinary diversion. In
one recent study, frozen section of the distal ureteral
margins had a sensitivity of 74% and a specificity
of 99.8%, resulting in an overall accuracy of 98.3%
[12]. With a serial sectioning strategy, most initially
positive ureteral margins can be converted into
negative final margins. Those patients were also at
decreased risk of developing recurrent disease in
the upper urinary tract [13, 14].
8. Sternberg, C.N., P.H. de Mulder, J.H. Schornagel, C.

Theodore, S.D. Fossa, A.T. van Oosterom, F. Witjes,
M. Spina, C.J. van Groeningen, C. de Balincourt, and
L. Collette, Randomized phase III trial of high-doseintensity methotrexate, vinblastine, doxorubicin, and
cisplatin (MVAC) chemotherapy and recombinant human
granulocyte colony-stimulating factor versus classic MVAC
in advanced urothelial tract tumors: European Organization
for Research and Treatment of Cancer Protocol no. 30924.
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9. Herr, H.W., D.F. Bajorin and H.I. Scher, Neoadjuvant
chemotherapy and bladder-sparing surgery for invasive
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16(4): p. 1298-301.
Recommendations
10. Hautmann, R.E., H. Abol-Enein, K. Hafez, I. Haro, W.

Mansson, R.D. Mills, J.D. Montie, A.I. Sagalowsky, J.P.
Stein, A. Stenzl, U.E. Studer, and B.G. Volkmer, Urinary
diversion. Urology, 2007. 69(1 Suppl): p. 17-49.
Preservation of the anterior and membranous

urethra, including parts of the prostate and seminal
vesicles for reasons of fertility, potency, and
continence, are technical variations to the nervesparing approach that may improve patients
quality of life but must be attentively judged against
possible oncological risks. (LE 3, GR C)
11. Stenzl A, Jarolim L, Coloby P, Golia S, Bartsch G, Babjuk

M, Kakizoe T, Robertson C. Urethra-sparing cystectomy
and orthotopic urinary diversion in women with malignant
pelvic tumors. Cancer. 2001 Oct 1;92(7):1864-71.
12. Gakis, G., D. Schilling, S. Perner, C. Schwentner, K.D.
Sievert and A. Stenzl, Sequential resection of malignant
ureteral margins at radical cystectomy: a critical assessment
of the value of frozen section analysis. World J Urol, 2010.
In female patients, standard anterior pelvic exenteration includes the entire urethra, adjacent vagina,
uterus, distal ureters, and respective lymph nodes
(LE: 3, GR: C). Sparing the urethra-supplying autonomous nerves can be performed in case of a
planned orthotopic neobladder (LE: 3, GR: C).
13. Tollefson, M.K., M.L. Blute, S.A. Farmer and I. Frank,

Significance of distal ureteral margin at radical cystectomy
for urothelial carcinoma. J Urol, 2010. 183(1): p. 81-6.
14. Schumacher, M.C., M. Scholz, E.S. Weise, A. Fleischmann,
G.N. Thalmann and U.E. Studer, Is there an indication for
frozen section examination of the ureteral margins during
cystectomy for transitional cell carcinoma of the bladder? J
Urol, 2006. 176(6 Pt 1): p. 2409-13; discussion 2413.
References
d) Lymphadenectomy
1. Pelvic Lymphadenectomy in Bladder Cancer
1. Stenzl, A., U. Nagele, M. Kuczyk, K.D. Sievert, A.

Anastasiadis, J. Seibold and S. Corvin, Cystectomy Technical Considerations in Male and Female Patients.
EAU Update Series, 2005. 3: p. 138-46.
Radical cystectomy with pelvic lymphadenectomy

represents the treatment of choice for muscleinvasive bladder cancer. Pelvic lymphadenectomy is
included as part of the surgical procedure to control
loco-regional disease and to potentially improve
cancer-specific survival. Survival after radical
cystectomy is usually predicted by the pathologic
tumor stage, status of surgical margins, and the
involvement of lymph nodes.
2. Abdelhady, M., A. Abusamra, S.E. Pautler, J.L. Chin and

J.I. Izawa, Clinically significant prostate cancer found
incidentally in radical cystoprostatectomy specimens. BJU
Int, 2007. 99(2): p. 326-9.
3. Pettus, J.A., H. Al-Ahmadie, D.A. Barocas, T.M. Koppie, H.
Herr, S.M. Donat, G. Dalbagni, V.E. Reuter, S. Olgac and
B.H. Bochner, Risk assessment of prostatic pathology in
patients undergoing radical cystoprostatectomy. Eur Urol,
2008. 53(2): p. 370-5.
Although
earlier
studies
have
already
demonstrated a prognostic benefit of extended
pelvic lymphadenectomy as compared to a limited
lymphadenectomy, the anatomically adequate extent
4. Weizer, A.Z., R.B. Shah, C.T. Lee, S.M. Gilbert, S. Daignault,

J.E. Montie and D.P. Wood, Jr., Evaluation of the prostate
peripheral zone/capsule in patients undergoing radical
276
of lymph node dissection to obtain reliable staging

results is still controversial.
most important prognostic factor in these patients,

predicting significantly decreased recurrence-free
survival and overall survival compared to patients
without node metastasis [23, 33, 34]. In patients
with negative nodes, the total number of lymph
nodes removed and the anatomic extent of the node
dissection are both useful measures in evaluating
the proper extent of surgery and predicting outcome.
In patients with nodal metastasis, the number of
nodes removed and the number and percent of
positive nodes may both be independent predictors
of recurrence and survival [35-38].
In a recent prospective randomized phase III trial on

the clinical efficacy of neoadjuvant chemotherapy
plus cystectomy [1], it was shown that surgical
factors, including the extent of lymph node dissection
and the individual surgeons experience, have a
major impact on the therapeutic outcome and overall
survival [2] (Level of Evidence: 1b). The data of
this trial also indicate that chemotherapy was more
likely to be of beneficial value if patients received
a high-quality surgery by an experienced surgeon.
It was concluded that it is extremely important to
develop universally accepted standards for radical
cystectomy and pelvic lymph node dissection in
patients with invasive bladder cancer in order to
improve outcome [3].
4. Extent of Pelvic Lymphadenectomy and

Therapeutic Outcome
Despite the aforementioned data which demonstrate
that long-term survival is possible in patients with
lymph node-positive bladder cancer, the anatomical
extent of pelvic lymphadenectomy and the minimum
of lymph nodes to be retrieved for an accurate
staging have not been defined. Some others take the
crossing of the ureters with the common iliac vessels
as the most cranial limit for lymph node dissection,
[9] whereas others extend lymphadenectomy up to
the aortic bifurcation. It is generally agreed that the
more lymph nodes are removed, the higher is the
number of patients with positive lymph nodes [10]
LE 3; furthermore, it has been demonstrated that
survival after radical cystectomy is predicted by the
pathologic stage of the primary bladder tumor and
pelvic nodes. Leissner et al [11] suggested that a
significant survival benefit was maintained if more
than 16 lymph nodes were removed. Stein et al [12]
reported that survival in patients with positive lymph
node disease was better if more than 15 pelvic
lymph nodes had been retrieved. On the other hand,
Abdel-Latif and coworkers [13] and Herr [14] could
not reproduce the relationship between survival
and number of dissected lymph nodes by using
multivariate statistical analysis. In this context, it has
to be underlined that the number of retrieved lymph
nodes can be influenced by many factors such as the
surgeon[47], the extent of lymphadenectomy [9-11],
presentation of the pathological specimen [16],
and pathologic work-up and techniques of analysis
[17]. The clinical reality, however, is significantly
different: an evaluation of the SEER database in
2003 demonstrated that the majority of patients in
a population-based analysis had 4 or fewer nodes
removed with cystectomy [40, 41].
2. Threshold Number of Lymph Nodes for

Accurate Staging
Recently, Capitanio et al [17] evaluated the likelihood
of finding one or more positive lymph nodes (LNs)
according to the number of LNs removed at radical
cystectomy (Level of Evidence: 2b). Results from
731 patients who underwent radical cystectomy and
bilateral pelvic lymphadenectomy at three different
institutions were analyzed. ROC curve coordinates
were used to determine the probability of identifying
1 or more positive LNs according to the total number
of removed LNs. Lymph node metastases were
present in 174 (23.8%). The mean (median, range)
number of LNs removed was 18.7 [17, 1-80]. The
ROC coordinate-based plots of the number of
removed LNs and the probability of finding 1 or
more LN metastases indicated that removing 45
LNs yielded a 90% probability. Conversely, removing
either 15 or 25 LNs indicated, respectively, 50%
and 75% probability of detecting 1 or more LNs
metastases. These data indicate that removing 25
LNs might represent the lowest threshold for the
extent of lymphadenectomy at radical cystectomy.
In a similar approach, Koppie et al reported a study
designed to determine if there was a minimum
number of lymph nodes analyzed above which there
was no improvement in survival [53] (LE: 2b). The
cohort included 1121 patients from MSKCC accrued
over a 14-year period. The investigators determined
that there was no plateau in the dose-response curve
with an increasing number of nodes up to 23 nodes,
as very few had 24 or more nodes removed. The
authors did not indicate the percent of patients who
underwent an extended node dissection, and, in fact,
13% had no nodes identified in the pathology report.
The median number of nodes removed was 9.
Despite these suboptimal clinical factors, there are a

few studies having demonstrated a significant impact
of the technique of pelvic lymph node dissection
with regard to therapeutic outcome. Poulsen et al
[8] were among the first to compare the prognostic
significance of limited versus extended pelvic
lymphadenectomy in a retrospective analysis of
194 patients undergoing radical cystectomy [LE
3]. Limited pelvic lymphadenectomy began at
3. Anatomic Extent of Pelvic Lymphadenectomy

Lymph node metastases are found in 20-25% of
patients who undergo radical cystectomy and pelvic
lymphadenectomy for bladder cancer, and it is the
277
the iliac bifurcation including the lymph nodes

along the external and internal iliac artery and the
obturator fossa. Extended pelvic lymphadenectomy
began at the aortic bifurcation and included the
common, external, and internal iliac artery and the
obturator fossa. The authors observed a substantial
improvement of 5-year recurrence-free survival in
patients with tumors confined to the bladder wall (85%
vs. 64%, p<0.02) and without lymph node involvement
(90% vs. 71%, p<0.02). Five-year probability for
loco-regional (7% vs. 2%) and systemic recurrences
(21% vs. 10%) was reduced substantially in patients
with bladder cancer confined to the bladder wall in
the extended pelvic lymphadenectomy group, but
did not reach statistical significance.
the nodal regions of standard dissection. Although

the median number of positive lymph nodes differed
significantly between both groups (22.5 vs. 8), there
was no difference with regard to the percentage
of positive nodes, which was 21% in both groups.
Interestingly, all patients with positive nodes above
the aortic bifurcation also had positive nodes
detected in the lower packages indicating that only
extensive locoregional metastatic disease might
involve the retroperitoneal areas associated with a
dismal prognosis. Including the lymph nodes along
the common iliac artery above the iliac bifurcation,
however, appears to be of prognostic value and of
clinical significance. In the study of Bochner et al
[21], 4 patients had unexpected micrometastatic
lymph node disease at the common iliac region only.
Reflecting the survival data of patients exhibiting
micrometastatic lymph node disease at time of radical
cystectomy, most of these patients are expected to
have a relatively favorable outcome. Morbidity of
pelvic lymphadenectomy is not increased by including
the common iliac region in routine pelvic lymph node
dissection, so this area should be removed as a
standard part of staging lymphadenectomy.
In another retrospective analysis of 484 patients

undergoing radical cystectomy and pelvic
lymphadenectomy, Leissner et al [17] demonstrated
that the total number of lymph nodes retrieved had
a significant impact on recurrence-free survival
(p<0.01) (LE 2b). The 5-year recurrence-free survival
rates were 25% and 53% in patients with 14 or fewer
and 15 or more lymph nodes removed, respectively.
Furthermore, the surgeon had a significant impact
on the prognosis as it was shown the number
of lymph nodes dissected ranged between 10.6
and 25.7 and differed significantly between the
11 different surgeons in the study. These data
are further corroborated by a recent paper on the
standardization of radical cystectomy and pelvic
lymphadenectomy [3]. However, the authors did
not demonstrate a significant overall and cancerspecific survival advantage for patients undergoing
extended pelvic lymphadenectomy as compared to
those undergoing limited dissection. The authors
further evaluated the concept of extended pelvic
lymphadenectomy in a prospective clinical trial of
290 patients [20]. The cranial limit of dissection was
the inferior mesenteric artery, the lateral border was
the genitofemoral nerve, and the caudal limit was the
pelvic floor. A mean number of 43.1 16.1 lymph
nodes were removed with 27.9% of the patients
having positive lymph nodes. Although the group
identified a preferred pattern of metastatic spread,
they were not able to identify a well-defined sentinel
lymph node or lymph node area.
Further evidence to include the common iliac region

derives from the prospective multi- institutional study
published recently by Leissner et al [20], (LE 2b).
Eighty-one (27.9%) patients demonstrated lymph
node involvement and 35% of all positive lymph
nodes derived from above the iliac bifurcation.
Furthermore, 20 (6.9%) patients were shown to
harbor positive lymph nodes above the bifurcation
of the common iliac artery only. Although no data
with regard to the prognostic significance in terms
of cancer-specific or progression-free survival are
available, these data strongly support the idea to
include the lymph nodes of the common iliac region
up to the aortic bifurcation in routine lymph node
dissection for muscle-invasive bladder cancer.
In another study, Abol-Enein et al [22] evaluated the
loco-regional distribution of positive pelvic lymph
nodes in 200 consecutive patients undergoing
radical cystectomy (LE 3). The authors also
attempted to identify the probability of lymph node
clearance with increasingly wide fields of node
dissection. In their investigation, extended pelvic
lymphadenectomy included the lymphatic tissue up
to the inferior mesenteric artery and the common,
external, and internal iliac region. A mean number of
50.6 lymph nodes were retrieved per patient with 48
(24%) patients exhibiting positive nodes. More than
one-third of these patients (39.6%) demonstrated
bilateral involvement. A single positive lymph node
was identified in 22 (45.8%) patients. The authors
demonstrated that close to 80% of all positive nodes
could be cleared completely if the field of pelvic
lymph node dissection included all lymphatic tissues
along the common, external, and internal iliac
region. Metastases outside the true pelvis were only
These data are in contrast to the recently published

prospective trial of Borchner et al [21] on the
evaluation of lymph node count and lymph node
mapping (LE 3). One hundred forty-four consecutive
patients were included in this monocentric evaluation
with 56 and 88 patients undergoing standard and
extended pelvic lymphadenectomy, respectively.
Standard dissection included the nodal regions of
the external iliac, hypogastric, and obturator fossa
with the iliac bifurcation representing the cranial
limit of lymph node dissection. Extended dissection
included the lymph nodes at the aortic bifurcation to
no more than 2 cm cranially to the bifurcation and
278
detected in multinodal disease and these metastatic

deposits were always associated with metastases at
the obturator fossa and/or the internal iliac region.
Therefore, the authors conclude that standard
lymphadenectomy in bladder cancer should always
include all lymphatic tissues in the true pelvis; lymph
node dissection might be extended up to the inferior
mesenteric artery if frozen section examination
exhibits positive lymph nodes in the sentinel region
of the true pelvis.
similar in patients with lymph node involvement

above the bifurcation of the common iliac vessels
(37%) compared to the entire population with lymph
node metastasis (41%) and to those with lymphatic
metastases in the true pelvis below the bifurcation
of the common iliac vessels (42%). The survival rate
was significantly higher in patients with 5 or fewer
involved lymph nodes (50% vs. 13%, p<0.002)
and in those with a lymph node density (number of
lymph nodes involved/total number of lymph nodes
removed) less than 20% (25% vs. 47%, p<0.05),
but it did not relate to the total number of retrieved
lymph nodes. These data underscore the contention
that extended dissection not only provides the most
accurate staging but also offers the patient the best
chance of survival. Following radical cystectomy,
patients can be stratified into risk groups according
to tumor stage, lymph node involvement, number
of metastatic nodes, and lymph node density.
The results of Steven et al [24] support the idea
that the benchmark for radical cystectomy should
include extensive pelvic lymph node dissection with
anatomic boundaries including the common iliac and
presacral nodes.
Dhar and coworkers [23] evaluated the impact

of limited and extended pelvic lymphadenectomy
in a cohort of 336 and 322 patients, respectively,
who were treated at 2 different institutions (LE 3).
The overall lymph node positive rate was 13% for
patients with limited and 26% for those who had
extended pelvic lymph node dissection. The authors
identified a significantly better recurrence-free
survival for patients who underwent extended pelvic
lymphadenectomy. These figures held true for both
organ-confined and locally advanced disease. The
5-year recurrence-free survival of patients with lymph
node positive disease was 7% for limited and 35% for
extended pelvic lymph node dissection. The 5-year
recurrence-free survival for pT2pN0 cases was
67% for limited and 77% for extended pelvic lymph
node dissection, and the respective percentages for
pT3pN0 cases were 23% and 57% (p<0.0001). The
5-year recurrence-free survival for pT2pN0-2 cases
was 63% for limited and 71% for extended pelvic
lymph node dissection, and for pT3pN0-2 cases the
respective figures were 19% and 49% (p<0.0001).
These data confirm that extended pelvic lymph
node dissection allows for more accurate staging
and improved survival of patients with non-organ
confined and lymph node-positive disease.
5. Extent of an Anatomically Accurate Pelvicstaging Lymphadenectomy in Bladder Cancer

As has been shown by the previous studies, the
anatomic extent of pelvic lymph node dissection in
patients undergoing radical cystectomy for muscleinvasive bladder cancer can be well-defined. Standard
lymphadenectomy should include all lymphatic
tissues around the common iliac, intercommon iliac,
internal iliac, d the obturator groups bilaterally since
up to one-third of all positive nodes are located
around the common iliac artery. This technical variant
will allow one to clear 80% of all positive nodes; if
frozen section does not demonstrate positive lymph
nodes in the true pelvis, lymph node dissection is not
needed to be carried out further cranially. If, however,
frozen section examination is not performed or if
it identifies positive nodes, the inferior mesenteric
artery represents the cranial border of lymph node
dissection.
In another single institution analysis, the clinical

importance of dissecting all lymphatic tissue up to
the aortic bifurcation became evident when analyzing
the outcome of 336 patients who underwent radical
cystectomy and extended pelvic lymphadenectomy
including the common and external iliac lymph
nodes and the periaortic, presacral, and obturator
fossa nodes [24], (LE 3). The lymphatic tissue
removed above and below the bifurcation of the
common iliac vessels was submitted separately for
histopathological analysis. Overall, 64 (19%) patients
had lymph node metastases of whom 22 (34.4%)
had lymph node involvement above the bifurcation of
the common iliac vessels outside the template of the
standard lymph node dissection. The median number
of retrieved lymph nodes was 27 (range 7 to 78) and
in those with lymph node metastases 27 (range 11 to
49) included 8 (range 0 to 17) above the bifurcation
and 18 (range 8 to 41) below the bifurcation of the
common iliac vessels in the true pelvis. Lymph node
involvement proved a significant adverse prognostic
factor with a 5-year probability of survival of 39%
versus 76%. The overall 5-year survival rates were
6. Critical Issues in Anatomic Pelvic

Lymphadenectomy for Bladder Cancer
Although the above-cited studies have apparently
demonstrated the clinical importance of extended
pelvic lymph node dissection with regard to the most
efficient retrieval of micrometastatic lymph nodes,
there are still some unresolved critical issues.
Pathologic examination of dissected lymph node
specimens in these studies has been done more
thoroughly and extensively than in other studies
concentrating on issues such as overall survival,
cancer-specific survival, and regional versus
distant failure. Therefore, some critical facts have
to be considered for the general community if
279
extended pelvic lymphadenectomy becomes

common practice in all patients undergoing radical
cystectomy. Lymphatic tissues dissected from
different areas should be sent separately instead
of en bloc submissions for pathologic evaluation
since it has been demonstrated recently that
the yield of lymph nodes increases significantly
thereby increasing the frequency of micrometastatic
deposits [16]. Intrainstitutional standardization of
pelvic lymphadenectomy appears to be of utmost
importance to generate reliable and reproducible
results since staging lymphadenectomy is extremely
surgeon-dependent, as has been demonstrated by
Leissner et al. [17].
There is some evidence from retrospective and

prospective analysis that an extended pelvic
lymphadenectomy might be associated with an
improvement in 5-year progression-free survival
(p<0.01) (LE 2b-3, GR: B)
Standard lymphadenectomy should include all
lymphatic tissues around the normal common iliac,
external iliac, internal iliac, and the obturator groups
bilaterally since up to one-third of all positive nodes
are located around the common iliac artery (LE: 3,
GR: B).
References
Last, but not least, although the various types of

extended pelvic lymphadenectomies have been
associated with an improved progression-free
survival, none of the trials has demonstrated an
advantage with regard to cancer-specific survival.
Benefit in terms of progression-free survival might
be just due to a stage migration associated with
extensive lymph node dissection. The majority of
patients with positive lymph nodes will die due to
distant metastatic spread in the long run and only
the few patients with a single or two metastatic
lymph nodes might benefit from the extended
variant of lymphadenectomy. In order to solve this
question, the Association of Urological Oncology
of the German Cancer Society has initiated a
prospective randomized clinical phase III trial to
evaluate the true clinical efficacy of extended pelvic
lymphadenectomy.
1. Grossmann HB, Natale RB, Tangen CM, et al. Neoadjuvant

2003; 349: 859 866
2. Herr HW, Faulkner JR, Grossman HB, et al. Surgical factors
influence bladder cancer outcomes: a cooperative group
report. J Clin Oncol 2004; 22: 2781 2789
3. Herr H, Lee C, Chang S, Lerner S for the Bladder Cancer
Collaborative Group. Standardization of radical cystectomy
and pelvic lymph node dissection for bladder cancer: a
collaborative group report. J Urol 2004; 171: 1823 1828
4. Capitanio U, Suardi N, Shariat SF, Lotan Y, Palapattu GS,
Bastian PJ, Gupta A, Vazina A, Schoenberg M, Lerner SP,
Sagalowsky AI, Karakiewicz PI. Assessing
the minimum n
umber of lymph nodes needed at radical
cystectomy in p
atients with bladder cancer. BJU Int. 2009
May;103(10):1359-62
5. Koppie, T.M., A.J. Vickers, K. Vora, G. Dalbagni, and B.H.
Bochner, Standardization of pelvic lymphadenectomy
performed at radical cystectomy: can we establish a
minimum number of lymph nodes that should be removed?
Cancer, 2006. 107(10): p. 2368-74
In bladder cancer, the biological aggressiveness of a

particular cancer may have already been expressed
at time of diagnosis and the impact of less or more
extensive surgery in terms of recurrence and survival
might be completely overestimated. For the future,
it will be necessary to shed light on the important
clinical questions of the biologic role of lymph
node metastases for the likelihood of synchronous
or metachronous distant metastases. It will be
necessary to evaluate the expression of various
growth factors and mediators of systemic spread on
patients with lymph node metastases and to correlate
these findings with clinically important end points
such as cancer-specific survival, overall survival,
and locoregional versus systemic recurrence.
6. Stein, J.P., G. Lieskovsky, R. Cote, S. Groshen, A.C. Feng,

S. Boyd, et al., Radical cystectomy in the treatment of
invasive bladder cancer: long-term results in 1,054 patients.
J Clin Oncol, 2001. 19(3): p. 666-75.
7. Lerner, S.P., D.G. Skinner, G. Lieskovsky, S.D. Boyd, S.L.
Groshen, A. Ziogas, et al., The rationale for en bloc pelvic
lymph node dissection for bladder cancer patients with
nodal metastases: long-term results. J Urol, 1993. 149(4):
p. 758-64; discussion 764-5.
8. Poulsen AL, Horn T, Steven K. Radical cystectomy:
extending limits of pelvic lymph node dissection improves
survival for patients with bladder cancer confined to the
bladder wall. J Urol 1998; 160: 2015 2019
9. Mills RD, Turner WH, Fleischmann A, Markwalder R,
Thalmann GN, Studer UE. Pelvic lymph node metastases
from bladder cancer: outcome in 83 patients after radical
cystectomy and pelvic lymphadenectomy. J Urol 2001; 166:
19 23
Recommendations
The extent of lymph node dissection and the
individual surgeons experience has a major impact
on the therapeutic outcome and overall survival [2]
(LE: 1b, GR: A.)
10. Herr WH, Bochner BH, Dalbagni G, et al. Impact of the

number of lymph nodes retrieved on outcome in patients
with muscle invasive bladder cancer. J Urol 2003; 167:
1295 1297
The more lymph nodes removed, the higher is

the probability to detect at least 1 positive lymph
node. However, there is no defined threshold of the
numbers of lymph nodes that need to be removed
[4, 5] (LE: 2b, GR: B)
11. Leissner J, Hohenfellner R, Throff JW, Wolf HK.

Lymphadenectomy in patients with transitional cell
carcinoma of the urinary bladder: significance for staging
and prognosis. BJU Int 2000; 85: 817 821
280
2. Patient Selection
12. Stein JP, Cai J, Groshen S, Skinner DG. Risk factors for
patients with pelvic lymph node metastases following
radical cystectomy with en-bloc pelvic lymphadenectomy: the concept of lymph node density. J Urol 2003; 170:
35
13. Abdel-Latif M, Abol-Eneim H, El-Baz M, Ghoneim MA.
Nodal involvement in bladder cancer cases treated with
radical cystectomy: incidence and prognosis. J Urol 2004;
172: 85 89
14. Herr WH. Superiority of ratio based lymph node staging for
bladder cancer. J Urol 2003; 169: 943
16. Borchner BH, Herr HW, Reuter VE. Impact of separate
versus en bloc lymph node dissection in the number of
lymph nodes retrieved in cystectomy specimens. J Urol
2001; 166: 2295 17. Leissner J, Allhoff EP, Hohenfellner R, Wolf HK. Ranking
of pelvic lymphadenectomy in therapy and prognosis of
carcinoma of the bladder. Akt Urol 2003; 34: 392 397
Decreased blood loss and need for transfusion, less

opioid requirement, and shortened length of stay, with
comparable complications to open radical cystectomy
has led to radical cystectomy being performed in a
minimally invasive fashion. Meanwhile, immediate
oncologic results are acceptable, while mature data
on long-term oncologic results are still awaited.
Patients with clinical T3 and T4 disease should
be carefully selected for such approach following
consideration for neoadjuvant chemotherapy.[2]
Due to concerns for oncologic control and technical
difficulty, surgeons should selectively choose their
patients for this approach early in their experience.
As minimally invasive approach has evolved
since 1993, key progress has been achieved
with adoption of the robot-assisted approach.
Despite recent advances, approximately 50% of all
patients undergoing radical cystectomy experience
recurrence and subsequent mortality.[3]
18. Hollenbeck, B.K., Z. Ye, S.L. Wong, J.E. Montie, J.D.

Birkmeyer. Hospital lymph node counts and survival after
radical cystectomy. Cancer, 2008. 112(4): p. 806-12.
19. Konety, B.R., S.A. Joslyn, M.A. ODonnell. Extent of Pelvic
Lymphadenectomy and its Impact On Outcome in Patients
Diagnosed With Bladder Cancer: Analysis of Data From the
Surveillance, Epidemiology and End Results Program Data
Base. J Urol, 2003. 169(3): p. 946-950.
3. Surgical Margins
Despite advantages with magnified 3-dimensional
vision and precision achieved by robotic instruments,
in robotic interface the lack of tactile feedback has
created concerns about adequacy of wider excision
in advanced disease and avoiding soft tissue surgical
margins. Positive soft tissue surgical margins are
associated with high local recurrence, resulting
in poor overall survival. Open expert consensus
in 2005 recommended less than 10% of all cases
and less than 15% for bulky tumors as acceptable
positive soft tissue surgical margins rates in radical
cystectomy.[6]
20. Leissner J, Ghoneim MA, Abol-Eneim H, et al. Extended

cancer: results of a prospective multicenter study. J Urol
2004; 171: 139 144
21. Bochner BH, Cho D, Herr HW, et al. Prospectively packaged
lymph node dissections with radical cystectomy: evaluation
of node count variability and node mapping. J Urol 2004;
172: 1286 1290
22. Abol-Enein H, El-Baz M, Abd El-Hameed MA, Abdel-Latif
M, Ghoneim MA. Lymph node involvement in patients with
bladder cancer treated by radical cystectomy: a pathoanatomical study a single center experience. J Urol
2004; 172: 1818 1821
23. Dhar NB, Klein EA, Reuther AM, Thalmann GN,
Madersbacher S, Studer UE. Outcome
after
radical
cystectomy with limited or extended pelvic lymph node
dissection. J Urol. 2008 Mar;179(3):873-8
Data from the International Laparoscopic Cystectomy

Registry in 2008 revealed a soft tissue surgical margin
rate of 2%.[7] The International Robotic Cystectomy
Consortium, which is a consortium of over 20 robotic
surgeons from 15 institutions, demonstrated in 513
patients an overall positive soft tissue surgical margin
rate of 6.8%. Advanced stage was independently
associated with increased likelihood of a positive
margin while case number and institution volume
were not.[8] These rates are similar to larger open
series. These findings suggest that positive margins
are associated with infiltration of the soft tissue
boundaries of the bladder rather than learning curve
and surgical error. In patients with large volume
tumors and/or suspected extravesical disease, wide
dissection of the perivesical tissue is recommended
to reduce positive soft tissue surgical margin rates.
[9] Collection of data based on surgical pathology
rather than clinical stage and absence of centralized
pathology review might skew the results from the
International Robotic Cystectomy Consortium.
24. Steven K, Poulsen AL. Radical cystectomy and extended

pelvic lymphadenectomy: survival of patients with lymph
node metastasis above the bifurcation of the common iliac
vessels treated with surgery only. J Urol. 2007 Oct;178(4 Pt
1):1218-23
e) Laparoscopic
and
Robotic-assisted
Laparoscopic Cystectomy
1. Introduction
Literature on a minimally invasive approach to
radical cystectomy has evolved since 1993.[1] Over
the past decade, laparoscopic and robot-assisted
approaches have been seen as alternatives to open
radical cystectomy with the possible advantages of
decreased postoperative pain and quicker return
to normal day-to-day activity. The robotic approach
is similar to laparoscopic with the added benefits
of improved range of motion of instruments and
3-dimensional vision, affording a less steep learning
curve.
4. Lymph Node Yield

Bilateral extended pelvic lymphadenectomy is a
281
crucial part of radical cystectomy. The incidence

of positive nodes at the time of radical cystectomy
is in excess of 20%.[5] Based on the observed
therapeutic and prognostic advantages, experts
suggest removal of a minimum of 10-15 lymph
nodes and its adequacy has been criticized in
the minimally invasive approach. (see discussion
chapter 3.1.4) Guru et al reported the feasibility and
safety of performing adequate robot-assisted lymph
node dissection and demonstrated higher yield with
increasing case volume.[11] In direct comparison,
Wang and colleagues found no difference in the
number of lymph nodes retrieved via open or robotic
approach (20 vs. 17).[12] A recent prospective,
randomized, non-inferiority study by Nix et al.
demonstrated a mean lymph node yield of 19 in
the robotic-assisted group vs. 18 in the open group.
[13] Second look [open] lymphadenectomy by a
different experienced open surgeon showed minimal
additional lymph node yield (range 0 8) to the
previous median 43 lymph nodes removed by a robotassisted approach.[14] Collaborative evaluation by
the International Robotic Cystectomy Consortium,
has demonstrated a mean lymph node yield of 19
with high volume centers (>100 cases per year)
having the highest yields and high surgeon volume
(>50 cases) independently predicting extended
(rather than standard) lymphadenectomy.[15]
experienced significantly fewer total complications

and major complications at 30 and 90 days.[26]
Moreover, being operated with robot-assistance was
an independent predictor of fewer overall and major
complications.
Regardless, published series are limited in patient
number and long-term follow-up. Although the only
randomized controlled trial of radical cystectomy
was designed as a non-inferiority study regarding
lymphadenectomy and node retrieval, it also
reported no difference in complications between the
2 small groups (n=20),[13] although in this study this
endpoint was underpowered to clearly define this
relationship. Reporting of complications following
cystectomy is also limited by patient selection bias,
possible under-reporting, and non-standardized
documentation.[28] In an attempt to overcome these
biases, a group from MSKCC reported complications
on 156 consecutive (non-selected) patients who
underwent robot-assisted radical cystectomy using
standardized methodology and fulfilling the Martin
criteria for adequate reporting of adverse events
following surgery. The 90-day complication rate of
52% and overall complication rate of 65% at median
follow-up of 9 months are similar to open series.[27]
The 90-day complication-related mortality rate was
2.6% and the majority of complications were low
grade (63%). Careful reporting of complications
following the robot-assisted approach revealed rates
similar to high volume open cystectomy centers.
The number of lymph nodes retrieved depends

on node viability, method of submission (en bloc
or separately), and the processing technique. In
conclusion, a thorough anatomical dissection around
the pelvic vessels and complete clearance of all
nodal tissue within the anatomical boundaries using
a minimally invasive approach is advocated.
6. Quality of Life
Health-related quality of life (HRQoL) outcomes after
surgery remain critical for measuring the impact of
any surgical modality. Studies investigating HRQoL
in patients undergoing radical cystectomy and
urinary diversion are lacking proper credence and
power.[30] Many of the studies are retrospective or
cross-sectional by design and do not use validated
questionnaires, while lacking baseline or preoperative
assessment.
5. Complications
Despite preoperative optimization, advances
in surgical techniques, and postoperative care,
radical cystectomy remains a morbid operation
with complication rates of up to 2664% and
mortality rates of 1-7%.[16-19] Radical cystectomy
readmission rates are high with bowel-related
and urinary infectious complications being most
common.[20] One of the major attractions towards a
minimally invasive approach to radical cystectomy is
that the morbidity of this procedure could possibly be
reduced. Estimated blood loss reported in minimally
invasive series ranges from 1001100 mL, with most
series reporting a mean of less than 500 mL and
transfusion rates below 2%. Reported complication
rates following a robot-assisted approach are
similar to an open approach at 6-65%. Two small
prospective comparisons of open and robot-assisted
cases showed similar complication rates between
the two approaches. In a prospective comparison
of complications in 187 consecutive patients who
underwent radical cystectomy with either open or
robot-assisted approach, the robot-assisted group
Gilbert et al evaluated HRQoL outcomes for patients

with bladder cancer using Bladder Cancer Index (BCI)
in 315 patients. Domains of the BCI included urinary,
sexual, and bowel function and bother domain.[31]
Patients undergoing radical cystectomy had lower
sexual function scores than patients who kept their
native bladder. The difference in urinary and bowel
domains between cystectomy and non-cystectomy
patients differed by type of urinary diversion, ileal
conduit or neobladder.
As robot-assisted radical cystectomy is a relatively
new technique, there is a paucity of literature
evaluating HRLQoL in patients undergoing this
treatment modality. Yuh et al prospectively evaluated
short-term HRQoL outcomes after robot-assisted
radical cystectomy and ileal conduit diversion
using the FACT-BL questionnaire.[32] The FACT-
282
BL questionnaire includes 5 domains: well-being,

physical, social/family, emotional, and functional
as well as 12 additional bladder cancer specific
questions. Thirty-four patients were included in the
study with follow-up questionnaires at 1, 3, and
6-month postoperative time periods. As expected,
scores decreased significantly at the initial period
with improvement to baseline at the 6-month period.
Emotional domains improved almost immediately
after surgery and exceeded baseline scores at 6
months.
extravesical disease and 26% (195) had positive

lymph nodes.[38]
8. Intracorporeal Urinary Diversion

Haber et al compared outcomes of patients
undergoing complete laparoscopic intracorporeal
conduit and their modified open assisted
laparoscopic approach.[39] Specific technical
difficulties with the completely intracorporeal group
included a high anastomotic leak rate and long
operative times (mean 9.3 hours). This approach
was eventually abandoned for an open-assisted
laparoscopic approach.
It is important to keep in mind that much of the longterm morbidity of radical cystectomy is associated
with urinary diversion, not extirpation. There is
currently no evidence regarding quality of life after
intracorporeal urinary diversion.
Robot-assisted surgery has helped overcome

some of the difficulties in performing intracorporeal
urinary diversion. Two small series have described
robot-assisted radical cystectomy with the creation
of an intracorporeal ileal conduit. The construction
of an intracorporeal conduit was performed with
combination of both robotic and laparoscopic
techniques. The robot was undocked after completion
of the radical cystectomy and construction of the
ileal conduit was performed in a pure laparoscopic
fashion. The robot was repositioned and used to
perform the ureterointestinal anastomosis. When the
series are combined, ileus was the only postoperative
complication in 1 of 5 patients. Operative times
ranged from 10-13 hours and stay ranged from 5-10
days (mean 6.8).
7. Oncologic Outcomes
The long-term oncologic efficacy of robot-assisted
radical cystectomy has yet to be determined,
however, surrogate markers of oncologic outcomes
which include margin status and lymph node yield
have been described earlier in this text. Similar to
laparoscopic radical cystectomy, early studies of the
robot-assisted approach suffer from selection bias
including younger patients, lower stage, and minimal
comorbidities compared to most contemporary
open series.[33-35] That selection bias makes
interpretation of oncologic outcomes difficult.
Hayn et al recently presented a series of 96 patients

who underwent robot-assisted radical cystectomy with
creation of either an extracorporeal or intracorporeal
ileal conduit.[42] There were no differences in age,
body mass index, ASA score, estimated blood loss,
or pathologic stage between the two groups. Mean
diversion time was similar between the intracorporeal
and extracorporeal group (123 vs. 136 min) although
mean overall operative time was shorter in the
intracorporeal group (390 vs. 356 min). Thirty and
ninety-day complication rates were similar between
the two groups and there was no difference in the
grade of complications. There were no statistically
significant differences in bowel-related complications
between the extracorporeal and intracorporeal
groups (25% and 12%, respectively). Patients in the
intracorporeal group, however, had better short-term
body image scores compared to the extracorporeal
group.
Previous open series have reported that patients

who experience recurrence after cystectomy do so
at a median of 12 months.[3] Martin described shortterm survival of patients undergoing robot-assisted
radical cystectomy. Fifty-nine patients with at least
6-month follow-up were included in that study with
mean follow-up of 25 months. Clinical characteristics
of these patients appear to be similar to that of open
series with 27% of patients having extravesical
disease and 34% of patients having lymph node
positive disease.[29] Overall survival at 12, 24, and
36 months was 82, 72%, and 72%, respectively.
Recurrence-free survival was 82%, 72%, and 72%,
respectively. This is comparable to early results of
modern open series studies. The retrospective nature
of this study with potential selection bias hampers
direct comparisons at this time and further studies
will need to be performed to evaluate the oncologic
outcomes of minimally invasive approaches.
Even smaller series have reported the creation of

urinary diversions performed in an intracorporeal
fashion.
Intracorporeal
continent
cutaneous
diversions and pouches have been reported but
are rare. Gaboardi, in 2002, described the first
intracorporeal neobladder.[43]
Kaufmann et al described early oncologic outcomes

of 85 patients who underwent robot-assisted radical
cystectomy.[37] Two-year recurrence-free survival,
cancer-specific, and overall survival rates were
74%, 85%, and 79%, respectively. These outcomes
are similar to those described by Martin.[29] Recent
reports from the International Robotic Cystectomy
Consortium of 820 patients revealed overall survival
rates of 82% and 68% at 1 and 2 years, respectively.
Thirty-seven percent (288) of those patients had
Pruthi et al described a series of 8 ileal conduits and

3 orthotopic neobladders performed intracorporeally.
Estimated blood loss, recovery of bowel function,
and time to discharge were all comparable to their
series of extracorporeal urinary diversions [44].
283
A recent study of intracorporeal urinary diversions

from the International Robotic Cystectomy
Consortium included 73 patients who underwent ileal
conduit formation and 61 patients who underwent
neobladder creation.[45] ]The mean age of those
patients undergoing intracorporeal neobladder was
60. Mean diversion time was longer in the neobladder
group compared to the conduit group (224 min vs.
138 min). The 90-day complication rate was 42% for
both groups with the majority of the complications
being low grade. The neobladder group had a lower
risk of both overall complications and high grade
complications. Improvements in technology and
intracorporeal techniques may allow urologists to
become more facile with completely intracorporeal
urinary diversion, thus improving outcomes in the
future.
8. Hellenthal NJ, Hussain A, Andrews PE, et al. Surgical margin

status after robot assisted radical cystectomy: results from
the International Robotic Cystectomy Consortium. J Urol.
Jul 2010;184(1):87-91.
9. Yuh B, Padalino J, Butt ZM, et al. Impact of tumour volume
on surgical and pathological outcomes after robot-assisted
radical cystectomy. BJU Int. Sep 2008;102(7):840-843.
10. Stein JP, Cai J, Groshen S, Skinner DG. Risk factors for
patients with pelvic lymph node metastases following
radical cystectomy with en bloc pelvic lymphadenectomy:
concept of lymph node density. J Urol. Jul 2003;170(1):3541.
11. Guru KA, Sternberg K, Wilding GE, et al. The lymph node
yield during robot-assisted radical cystectomy. BJU Int. Jul
2008;102(2):231-234; discussion 234.
12. Wang GJ, Barocas DA, Raman JD, Scherr DS. Robotic
vs open radical cystectomy: prospective comparison of
perioperative outcomes and pathological measures of early
oncological efficacy. BJU Int. Sep 20 2007.
13. Nix J, Smith A, Kurpad R, Nielsen ME, Wallen EM, Pruthi
RS. Prospective randomized controlled trial of robotic versus
open radical cystectomy for bladder cancer: perioperative
and pathologic results. Eur Urol. Feb 2010;57(2):196-201.
Recommendations:
14. Davis JW, Gaston K, Anderson R, et al. Robot assisted

extended pelvic lymphadenectomy at radical cystectomy:
lymph node yield compared with second look open
dissection. J Urol. Jan 2011;185(1):79-83.
R
obot-assisted radical cystectomy is a surgical
option for locally advanced bladder cancer.
Larger series and long-term oncologic data are
still awaited and will define its permanent role in
urologic oncology. (LE 2a, GR: B)
15. Marshall SJ, Hayn MH, Stegemann AP, Argawal PK,

Badani KK, Balbay MD. Lymph node yield and predictors
of extended lymphadenectomy at the time of robotassisted radical cystectomy: Results from the International
Cystectomy Consortium. American Urologic Association
Annual Meeting. Chicago, IL2011.
H
igh volume centers with dedicated minimally
invasive surgical teams have shown better results
than smaller centers. (LE: 2c, GR: C)
16. Chang SS, Cookson MS, Baumgartner RG, Wells N,

Smith JA, Jr. Analysis of early complications after radical
cystectomy: results of a collaborative care pathway. J Urol.
May 2002;167(5):2012-2016.
17. Quek ML, Stein JP, Daneshmand S, et al. A critical analysis
of perioperative mortality from radical cystectomy. J Urol.
Mar 2006;175(3 Pt 1):886-889; discussion 889-890.
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20. Stimson CJ, Chang SS, Barocas DA, et al. Early and late
perioperative outcomes following radical cystectomy: 90day readmissions, morbidity and mortality in a contemporary
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21. Menon M, Hemal AK, Tewari A, et al. Nerve-sparing robotassisted radical cystoprostatectomy and urinary diversion.
BJU Int. Aug 2003;92(3):232-236.
4. Dotan ZA, Kavanagh K, Yossepowitch O, et al. Positive

surgical margins in soft tissue following radical cystectomy
for bladder cancer and cancer specific survival. J Urol. Dec
2007;178(6):2308-2312; discussion 2313.
22. Hemal AK, Abol-Enein H, Tewari A, et al. Robotic radical

cystectomy and urinary diversion in the management of
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5. Herr HW, Faulkner JR, Grossman HB, et al. Surgical

factors influence bladder cancer outcomes: a cooperative
group report. J Clin Oncol. Jul 15 2004;22(14):2781-2789.
23. Abraham JB, Young JL, Box GN, Lee HJ, Deane LA,
Ornstein DK. Comparative analysis of laparoscopic and
robot-assisted radical cystectomy with ileal conduit urinary
diversion. J Endourol. Dec 2007;21(12):1473-1480.
6. Herr H, Lee C, Chang S, Lerner S. Standardization of

radical cystectomy and pelvic lymph node dissection for
bladder cancer: a collaborative group report. J Urol. May
2004;171(5):1823-1828; discussion 1827-1828.
24. Murphy DG, Challacombe BJ, Elhage O, et al. Roboticassisted laparoscopic radical cystectomy with extracorporeal urinary diversion: initial experience. Eur Urol. Sep
2008;54(3):570-580.
7. Haber GP, Crouzet S, Gill IS. Laparoscopic and robotic

assisted radical cystectomy for bladder cancer: a critical
analysis. Eur Urol. Jul 2008;54(1):54-62.
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25. Pruthi RS, Wallen EM. Is robotic radical cystectomy an

appropriate treatment for bladder cancer? Short-term
oncologic and clinical follow-up in 50 consecutive patients.
Urology. Sep 2008;72(3):617-620; discussion 620-612.
outcomes between intra-corporeal and extra-corporeal

ileal conduit after robot-assisted radical cystectomy. 2011
Annual AUA Meeting. Vol Abstract. Washington, DC2011.
43. Gaboardi F, Simonato A, Galli S, Lissiani A, Gregori A,
Bozzola A. Minimally invasive laparoscopic neobladder. J
Urol. Sep 2002;168(3):1080-1083.
26. Ng CK, Kauffman EC, Lee MM, et al. A comparison

of postoperative complications in open versus robotic
cystectomy. Eur Urol. Feb 2010;57(2):274-281.
44. Pruthi RS, Nix J, McRackan D, et al. Robotic-assisted

laparoscopic intracorporeal urinary diversion. Eur Urol. Jun
2010;57(6):1013-1021.
27. Hayn MH, Hellenthal NJ, Hussain A, Stegemann AP, Guru

K. Defining morbidity of robot-assisted radical cystectomy
using a standardized reporting methodology. Eur Urol.
2011;59(2):213-218.
28. Donat SM. Standards for surgical complication reporting
in urologic oncology: time for a change. Urology. Feb
2007;69(2):221-225.
45. Guru K, Hayn MH, Stegemann AP, et al. Total intra-corporeal

urinary diversion after robot-assisted radical cystectomy:
The International Robotic Cystectomy Consortium results
after 134 cases. 2011 Annual AUA meeting. Washington,
DC 2011.
29. Martin RC, 2nd, Brennan MF, Jaques DP. Quality of

complication reporting in the surgical literature. Ann Surg.
Jun 2002;235(6):803-813.
2. Surgical Outcome: Morbidity and

Mortality
30. Porter MP, Penson DF. Health related quality of life after
radical cystectomy and urinary diversion for bladder cancer:
a systematic review and critical analysis of the literature. J
Urol. Apr 2005;173(4):1318-1322.
a) Introduction
Complications related to radical cystectomy may be
directly related to pre-existing patient comorbidities,
the surgical procedure, the bowel anastomosis, or the
urinary diversion. Variables such as hospital volume,
case mix, and surgeon skill and experience influence
the rate, type, and severity of surgical complications.
Other factors, including the availability and breadth
of consultative, diagnostic, and ancillary services,
may explain the association between cystectomy
volume and short-term surgical outcomes.[1]
31. Gilbert SM, Wood DP, Dunn RL, et al. Measuring healthrelated quality of life outcomes in bladder cancer patients
using the Bladder Cancer Index (BCI). Cancer. May 1
2007;109(9):1756-1762.
32. Yuh B, Butt Z, Fazili A, et al. Short-term quality-of-life
assessed after robot-assisted radical cystectomy: a
prospective analysis. BJU Int. Mar 2009;103(6):800-804.
33. Pruthi RS, Nielsen ME, Nix J, Smith A, Schultz H, Wallen
EM. Robotic radical cystectomy for bladder cancer: surgical
and pathological outcomes in 100 consecutive cases. J
Urol. Feb 2010;183(2):510-514.
When reporting surgical complications during

cystectomy, regardless of the technique, a
standardized and reproducible classification of
surgical complications is applied. The modified
Clavien system is one such paradigm and has been
used to evaluate complications in more than 6300
surgical procedures.[2] Recently, complications of
both open [3] and laparoscopic radical cystectomy[4]
have been reported using the modified Clavien
system. When possible, overall mortality in the
perioperative period should be captured and
reported for both the 30- and 90-day postoperative
period.[5] Morbidity occurring within 90 days should
be considered an early complication, while those
complications after 90 days are considered late.
[6,7] Despite improvements in surgical technique,
anesthetic delivery, and peri-operative care, radical
cystectomy remains a challenging procedure.
Adverse events of any grade may occur in up to 58%
of patients and mortality rates up to 3.9% occur at 30
days after cystectomy. [8, 9, 10, 11]
34. Cha EK, Wiklund NP, Scherr DS. Recent advances in

robot-assisted radical cystectomy. Curr Opin Urol. Jan
2011;21(1):65-70.
35. Hautmann RE. The oncologic results of laparoscopic radical
cystectomy are not (yet) equivalent to open cystectomy.
Curr Opin Urol. Sep 2009;19(5):522-526.
36. Stein JP, Skinner DG. Results with radical cystectomy for
treating bladder cancer: a reference standard for highgrade, invasive bladder cancer. BJU Int. Jul 2003;92(1):1217.
37. Kauffman EC, Ng CK, Lee MM, Otto BJ, Wang GJ, Scherr
DS. Early oncological outcomes for bladder urothelial
carcinoma patients treated with robotic-assisted radical
cystectomy. BJU Int. Feb 2011;107(4):628-635.
38. Hayn MH, Stegemann AP, Agarwal PK, et al. Pathologic
and early oncologic outcomes after robot-assisted radical
cystectomy: Results from the International Robotic
Cystectomy Consortium. 2011 AUA Annual Meeting.
Washington, DC2011.
39. Haber GP, Campbell SC, Colombo JR, Jr., et al.
Perioperative outcomes with laparoscopic radical
cystectomy: pure laparoscopic and open-assisted
laparoscopic approaches. Urology. Nov 2007;70(5):910915.
The following will detail rates of morbidity and mortality

associated with cystectomy and urinary diversion,
as well as candidate quality of care indicators for
treatment of bladder cancer and recommendations
from the literature to minimize complications.
40. Yohannes P, Chiou RK, Pelinkovic D. Rapid communication:

pure robot-assisted laparoscopic ureteral reimplantation for
ureteral stricture disease: case report. J Endourol. Dec
2003;17(10):891-893.
41. Balaji KC, Yohannes P, McBride CL, Oleynikov D, Hemstreet
GP, 3rd. Feasibility of robot-assisted totally intracorporeal
laparoscopic ileal conduit urinary diversion: initial results of
a single institutional pilot study. Urology. Jan 2004;63(1):5155.
b) Morbidities
1. Comorbidities
42. Hayn MH, Stegemann AP, Consiglio J, Wilding G, Guru K.

Comparison of complications and validated quality of life
There is a significant body of literature evaluating
285
patient age as a prognostic indicator for radical

cystectomy. [12,13] In general, advanced age is a
risk factor for the development of complications due
to radical cystectomy. However, chronologic age is
less the determinant than physiologic age. Other
risk factors for morbidity include female gender, prior
abdominal surgery, extravesical disease, and prior
radiotherapy.[11] Furthermore, elevated body mass
index is associated with an increased rate of wound
dehiscence and hernia.[14] Unfortunately, most
series evaluating radical cystectomy do not include
indices of morbidity in the patient evaluation. Suffice it
to say, patients with pre-existing neurologic disease,
cardiopulmonary compromise, renal insufficiency,
autoimmune disease, and bowel disease experience
higher rates of complication. [11]
bowel anastomosis, or the diversion. Paralytic ileus

is quite common during the postoperative course
of many cystectomy patients, plaguing patients as
much as 22.7% of the time. [22] Fortunately, true
small bowel obstructions or anastomotic leak are less
common, but do occur in up to 8.7% of patients. [17]
Lymphocele rates vary on the degree of dissection
utilized during pelvic lymph node dissection. With
that said, an appropriate lymph node dissection may
carry a risk of symptomatic lymphocele in up to 5%
of patients. [18] Rates of wound infection, incisional
hernia, pelvic hematoma, and fascial dehiscence are
widely variable, but may occur in as many as 9% of
patients. [23]
3. Laparoscopic Radical Cystectomy

Data from laparoscopic and robotic cystectomy
series are relatively immature and with small patient
populations. Nonetheless, complication rates are
similar to open series and demonstrate similar shortterm oncologic control. Adverse events are typically
of the same variety as those that occur during open
surgery. The typical rate of any form of complication
is 30-35% in the literature. [4,24] Not surprisingly,
in some series, there does appear to be a slightly
greater rate of higher grade complications earlier in
a surgeons experience. [24]
2. Perioperative Complications
Intraoperative complications may include acute
blood loss requiring transfusion and injury to adjacent
structures. Acute bleeding during radical cystectomy
is common and is typically associated with ligation of
the bladder pedicles or dorsal vein of the prostate in
men and excision of the anterior vagina in women.
The development of bipolar cautery devices,
surgical staplers, and improved understanding of the
prostatic anatomy have helped to reduce blood loss
during cystectomy. Regardless, average blood loss
during the procedure ranges from 600 mL to 1700
mL in large series. [14, 15, 16] Transfusion rates
are as high as 66% in some series. [17] Injuries
to associated structures, such as the rectum, may
occur in as many as 1.7% of procedures.[18]
4. Urinary Diversion
Complications due to the urinary diversion vary
depending on the type of diversion and may occur
in either an early or late fashion. Early complications
may occur in the form of urine leak, pouch leak,
excessive mucus, urethro-enteric stricture, and
ureteroenteric stricture. Urine leak from either a
pouch or ureteroenteric anastomosis is noted in as
many as 7.7% of patients. [25] Typically, prevention
involves the placement of suction drains or ureteral
catheters until adequate time for healing. However,
there is debate regarding the necessity of routine
use and duration of ureteral catheters. Ureteral
stricture may be an early or late complication and has
occurred in up to 14% of patients in some series. [26]
The etiology of the stricture may be benign or, more
concerning, a malignant recurrence. Methods for
treatment may include percutaneous nephrostomy
with antegrade stenting, ureteroscopic balloon
dilation, or open revision. The type of anastomosis
(Bricker vs. Wallace), does not appear to effect the
incidence of ureteroenteric stricture. [27, 28]
Medical complications comprise a large proportion

of the morbidity experienced by patients after
radical cystectomy. These complications include
thromboembolic, cardiac, pulmonary, infectious,
and renal adverse events. The rates of deep venous
thrombosis (DVT) and pulmonary embolus (PE)
are up to 5%. [19] Prophylaxis in the form of low
molecular weight heparin has been shown to reduce
the rates of both DVT and PE. [20] Cardiac events
such as congestive heart failure, arrhythmia, and
myocardial infarction occur in as many as 7% of
patients. [16] Pulmonary compromise in the form of
acute respiratory distress, reintubation, or pneumonia
complicate the postoperative course of up to 7.8%
of cystectomy patients. [21] As many as 13% of
radical cystectomy patients develop an infectious
complication such as pyelonephritis, sepsis, wound
infection, or UTI.[20] It is quite common for patients
to have a colonized urine specimen. However,
symptomatic urinary tract infections and pouchitis
require treatment with appropriate antibiotics. Lastly,
renal insufficiency requiring dialysis may occur in as
many as 7% of patients in some series. [17]
The urinary diversion may be the etiology of a variety

of late complications in the radical cystectomy patient,
which may be benign due to scar from ischemia,
technical error, or recurrent tumor. Stomal stenosis
has been described in as many as 1.7% of patients
and is likely related to ischemia to the conduit.
Stomal hernia is a more common occurrence,
occurring in up to 5.2% of cases. [21] Both entities
may require open revision; the latter may require
Surgical complications may arise from the

cystectomy, the pelvic lymph node dissection, the
286
transfer to the contralateral side or reinforcement with

mesh. Worsening renal function, hydronephrosis,
and ureteral reflux may occur in as many as 50%
of patients at 15 years. [25] This suggests the
importance of long-term follow-up, serial imaging,
and laboratory assessments. Metabolic changes
are noted in up to 3% of patients with urinary
diversions and include Vitamin B12 deficiency,
metabolic acidosis, and electrolyte derangements.
Concomitant urinary stone disease may occur due
to these metabolic changes. Furthermore, chronic
bacterial colonization, mucus production, urinary
retention, and enteric hyperoxaluria may exacerbate
stone formation in patients with urinary diversions.
Rates of stone formation may approach 30% in
some series. [25]
reported in a uniform grading system. Currently

the best adapted graded system for cystectomy is
the Clavien grading system (LE: 2, GR: B).
Surgical complications associated with radical

cystectomy and urinary diversion should include
the length of follow-up for the patient cohort and
a minimum of 30-day, but preferably 90-day,
reported outcome (LE 3, GR C).
A
SA score, age, previous treatment for bladder
cancer or other pelvic diseases, surgeon and

hospital volume of radical cystectomy, and type
of urinary diversion influence surgical outcome.
(LE: 3, GR: C)
Reduction in blood loss and blood transfusion is
afforded by meticulous technique, use of modern

surgical devices, and improved understanding of
pelvic anatomy. (LE: 3, GR C)
5. Mortality
Clearly, given the surgical complexity and high
rates of surgical morbidity, it is not surprising that
mortality from radical cystectomy ranges as high
as 3.9% in larger series. [15] Additionally, the rate
of mortality climbs for those patients with greater
morbidity or advanced age. Recently, Morgan and
colleagues performed a retrospective analysis of
220 patients over the age of 75 who underwent
radical cystectomy at a high volume center. They
noted a sobering 90-day mortality rate of 12.7%. In
the multivariate analysis, preoperative albumin was
as great a predictor of patient outcome as patient
age. [29]
Reduction of urinary extravasation and leak can

be achieved with careful closure of anastomosis or
pouch, stenting of the ureteroenteric anastomosis,
and maintenance of appropriate drainage. (LE: 3,
GR: C)
Reduction of symptomatic lymphocele formation
can be achieved with appropriate identification of

lymphatic channels, careful surgical technique,
and an open peritoneal window. Initial treatment
should begin with percutaneous drainage. (LE: 3,
GR: C)
6. Quality of Care Indicators
Reduction of anastomotic strictures requires
The treatment and management of bladder cancer is

complex and challenging. Metrics are being developed
to measure the quality of healthcare provided by
physicians and will likely play an increasing role in
healthcare delivery in the future. Cooperberg and
colleagues recently defined candidate measures
for quality of care in the treatment of bladder cancer
and their relationship to surgical outcomes.[30]
They note that time to cystectomy after diagnosis,
hospital volume, surgeon volume, nodal yield, and
utilization of orthotopic diversion are associated
with improved healthcare outcomes in patients
receiving radical cystectomy. However, despite
clear recommendations from multiple urologic
associations, compliance with treatment guidelines
range from a dismal 3% for postoperative mitomycin
C to 20% for surveillance cystoscopy and cytology.
[31] Likely, improved adherence to recommended
guidelines and recognition of important quality of
care measures can reduce the substantial morbidity
of radical cystectomy for bladder cancer.
meticulous surgical technique, minimal ureteral

dissection, well-perfused segment, copious
spatulation, and careful apical suture placement.
(LE: 3, GR: C)
Reduction of metabolic disorders after urinary
diversion requires preservation of distal ileum,

serial monitoring of electrolytes and vitamin
B12 levels, understanding of bowel segment
physiology, and appropriate emptying of urinary
diversion. (LE: 3, GR: C)
Reduction of DVT and PE can be achieved
with use of low molecular weight heparin, early

ambulation, and sequential compression devices.
(LE: 1B, GR: B)
References
1. Hollenbeck BK, Daignault S, et al. Getting under the hood
of the volume-outcome relationship for radical cystectomy.
2007 J Urol 177(6): 2095-2099
Recommendations
2. Dindo D, Demartines N, et al. Classification of surgical

complications: a new proposal with evaluation in a cohort
of 6336 patients and results of a survey. 2004 Ann Surg
240(2): 205-213.
Surgical complications associated with radical

cystectomy and urinary diversion should be
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3. Hautmann RE, de Petriconi, et al. Lessons learned from

1,000 neobladders: the 90-day complication rate. 2010 J
Urol 184(3): 990-994.
23. Arumainayagam N, McGrath J, Jefferson KP, Gillatt DA.

Introduction of an enhanced recovery protocol for radical
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4. Khan MS, Elhage O, et al. Analysis of early complications

of robotic-assisted radical cystectomy using a standardized
reporting system. . 2011 Urology 77(2): 357-362.
24. Hayn MH, Hellenthal NJ, Mansour AM, et al. BJU Int. Is
patient outcome compromised during the initial experience
with robot-assisted radical cystectomy? Results of 164
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5. Stimson CJ, Chang SS, et al. Early and late perioperative

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readmissions, morbidity and mortality in a contemporary
series. 2010 J Urol 184(4): 1296-1300.
25. Hautmann RE, de Petriconi R, Gottfried HW, Kleinschmidt

K, Mattes R, Paiss T. The ileal neobladder: complications
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followup. J Urol 1999;161:4227
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among patients 80 years old or older. 2004 Urology 64(2):
292-297.
26. Madersbacher S, Schmidt J, Eberle JM, et al. Long-term

outcome of ileal conduit diversion. J Urol 2003;169:985
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7. Donat SM Standards for surgical complication reporting in

urologic oncology: time for a change. 2007 Urology 69(2):
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27. Kouba E, Sands M, Lentz A, Wallen E, Pruthi RS. A

comparison of the Bricker versus Wallace ureteroileal
anastomosis in patients undergoing urinary diversion for
bladder cancer. J Urol 2007;178: 9458.
8. Novara G, De Marco V, et al. Complications and mortality

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2009 J Urol 182(3): 914-921
28. Pagano S, Ruggeri P, Rovellini P, Bottanelli A. The anterior

ileal conduit: results of 100 consecutive cases. J Urol
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from 1,000 neobladders: the 90-day complication rate.
2010 J Urol 184(3): 990-994
29. Morgan TM, Keegan KA, Barocas DA, et al. Predicting the
Probability of 90-day Survival in Elderly Bladder Cancer
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10. Svatek RS, Fisher MB, et al. Risk factor analysis in a

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30. Cooperberg MR, Porter MP, Konety BR. Candidate quality

of care indicators for localized bladder cancer. Urol Oncol
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11. Lawrentschuk N, Colombo R, et al. Prevention and

management of complications following radical cystectomy
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21. Nieuwenhuijzen JA, de Vries RR, Bex A, et al. Urinary
diversions after cystectomy: the association of clinical
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2003;169:1014
3. Oncological Outcome of Radical

Surgery According to TNM Staging
a) Survival According to AJCC/TNM Staging
Long-term oncological outcome of radical cystectomy
has been investigated in a multitude of studies which
derive mainly from high volume centers across
Europe, North Africa, and North America [1-3]. The
oncological outcomes reported in these series are
based on the TNM staging system, which consists
of three important parameters for survival. These
parameters are local tumor invasiveness (T-tumor
stage), presence of positive lymph nodes (N-nodal
stage), and distant metastatic disease (M-metastasis).
Based on this concept, patients can be categorized
according to six prognostic groups (0a, 0is, I, II, III,
IV) as proposed by the American Joint Committee on
Cancer (AJCC) [4, 5]. The TNM staging system can
be used for determining the clinical and pathological
stage of patients with invasive bladder cancer.
Tables 1 and 2 list the current 2009 TNM staging
system with the corresponding AJCC prognostic
groups [6].
One of the largest retrospective single-center series
reported oncological long-term outcomes in a total
of 1054 patients treated with radical cystectomy and
pelvic lymphadenectomy[1]. In the entire cohort,
after a median follow-up of 10.2 years, recurrencefree and overall survival rates at 5 years were 68%
288
and 66%, respectively, and at 10 years 60% and

43%, respectively. In organ-confined disease (pTaT2b N0; AJCC stages 0a, 0is, I, and II) recurrencefree and overall survival rates at 5 years were 80%
and 74%, respectively, and 77% and 54% at 10
years, respectively. By contrast, in extravesical,
node-negative disease (pT3a-4a, pN0; AJCC stage
III), recurrence-free and overall survival at 5 years
dropped to 58% and 47%, respectively, and to 55%
and 27% after 10 years, respectively. Among 236
patients with histologically confirmed lymph-nodepositive bladder cancer (stage IV according to AJCC)
the 5-/10-year recurrence-free and overall survival
were only 35%/34% and 31%/23%, respectively
[1]. In the meantime, similar single- and multicenter
series have confirmed these first cutting-edge
results and led to conclude that radical cystectomy
is the mainstay of treatment in patients with muscleinvasive bladder cancer [2, 3, 7].
Table 1. 2009 TNM Staging (6)
T Category
TX: No primary tumor assessment
T0: No primary tumor detectable
Ta: Noninvasive papillary carcinoma
Tis: Carcinoma in situ (CIS)
T1: Invasion of the subepithelial connective tissue
T2: Invasion of the muscle layer
T2a: Invasion into the inner half of the muscle layer
T2b: Invasion into the outer half of the muscle layer
T3: Invasion of the perivesical fatty tissue
T3a: Microscopic perivesical invasion
T3b: Macroscopic perivesical invasion
b) C
ontroversial Issues of the Current TNM
Staging System
T4: Invasion of organs or structures such as prostatic

stroma, the seminal vesicles, uterus, vagina, pelvic
wall, or abdominal wall
1. pT2 Substaging
T4a: Invasion of prostatic stroma, uterus, and/or

vagina
In 1997, the AJCC updated the TNM staging system

and introduced new substagings for the tumor stages
T2 and T3 [5]. The latest version was published in
2009 but without any changes to the former version
of 2002 [6]. Both substratifications were thought
to provide a better risk assessment for follow-up
strategies and improve counseling of patients for
adjuvant treatment options [4]. However, in patients
with node-negative, pT2a-T2b bladder cancer,
classified as AJCC stage II (4), recent retrospective
studies have challenged the prognostic importance
of substratifying pT2 tumors into those involving
the inner (T2a) or outer half of the detrusor muscle
(T2b) and suggested consolidating both substages
into one [8-10]. The largest of these series included
311 patients with pT2 bladder cancer but found that
pT2b classified patients still had a higher risk for
lymph node tumor involvement than pT2a classified
patients [10]. Furthermore, limitations of these
studies were that the extent of lymphadenectomy
and number of retrieved lymph nodes were not
exactly reported, which might have biased the final
survival analysis [10]. Additionally, patients with nonurothelial cell carcinoma or those who underwent
neoadjuvant chemotherapy were not excluded from
analysis [8, 9].
T4b: Invasion of the pelvic or abdominal wall

N Category
NX: Regional lymph nodes cannot be assessed due
to lack of information
N0: No regional lymph node spread
N1: Single lymph node metastasis in the true pelvic
region
N2: Multiple lymph nodes in the true pelvic region
N3: Single or multiple lymph nodes in the common
iliac region
M Category
MX: Distant metastases cannot be assessed
M0: No signs of distant metastasis
M1: Distant metastasis present
Table 2. AJCC Stages of Bladder Cancer (6)
Stage 0a:
Ta, N0, M0
Stage 0is:
Tis, N0, M0
Stage I:
T1, N0, M0
Stage II:
T2a- T2b, N0, M0
Stage III:
T3a-T4a, N0, M0
Therefore, a recent multicenter series on 565 patients

with pT2 urothelial carcinoma of the bladder has
attempted to overcome these limitations and reported
significant differences in survival between both
substages in node-negative pT2 disease [11]. These
findings were also confirmed in a mixed cohort of
1737 patients with pT2 bladder cancer of whom 54%
had squamous cell carcinoma [7]. In this study, the
Stage IV: T4b, N0, M0 or any T, N1 to N3,

M0 or any T, any N, M1
289
5-year disease-free survival was significantly higher

for patients with pT2aN0 (meanSE: 76.62.2%)
compared to those with pT2bN0 bladder cancer
(58.31.6%). In a recent series, this significant
difference in recurrence-free and cancer-specific
survival was also confirmed for patients with pT2
urothelial carcinoma of the bladder who were treated
with an extended pelvic lymphadenectomy approach
[12]. Moreover, another recent multicenter study
proposed a weighted prognostic model for patients
with node-negative pT2 bladder cancer. Among
different independent risk factors (presence of high
grade disease or lymphovascular invasion), pT2
substaging was the strongest one for recurrence-free
survival [13]. In conclusion, these data support the
prognostic importance of the current substratification
in node-negative pT2 bladder cancer.
5-year recurrence-free survival and cause-specific

survival for patients with pT3apN0 versus pT3bpN0
classified disease were not significantly different with
68% versus 72% and 54% versus 42%, respectively.
However, a larger multicenter study on 808 patients
with pT3N0 bladder cancer (median follow-up 43
months) treated with radical cystectomy without
any neoadjuvant modality reported significantly
improved 5-year recurrence-free survival (61% vs.
48%) and cause-specific survival (64% vs. 55%)
rates for patients with pT3a versus pT3b disease
[17]. This assumption is further supported by another
multicenter study in which a weighted prognostic
model was constructed for 578 patients with nodenegative pT3 bladder cancer. pT3 substaging was
found to independently contribute to a 2.05-fold
increase in the relative risk of decreased recurrencefree survival [20]. In conclusion, the present data
do support the current concept of substaging in
node-negative pT3 bladder cancer whereas in
node-positive pT3 disease a prognostic significance
cannot be attributed to this substratification [15, 18].
2. Definition of Organ-confined Bladder Cancer

The definition of organ-confined bladder cancer has
been controversially discussed in recent literature.
A prior series assumed that microscopic extension
of the tumor into the perivesical fat (pT3a) does
not significantly confer a higher risk for lymph node
involvement and decreased survival compared to
muscle-invasive bladder cancer [14]. This study
included 381 patients (pT2: 172 patients, pT3a: 88
patients, pT3b: 121 patients) and found no significant
difference for recurrence-free survival between the
stages pT2 versus pT3a, but for the stages pT2
versus pT3b. However, a trend towards significance
was reported for cancer-specific survival between
patients with pT2 versus pT3a disease (p=0.06)
[14]. By contrast, in another series with 134 pT2b
patients and 236 patients with pT3a or T3b bladder
cancer, recurrence-free and cancer-specific survival
was significantly improved for pT2b compared to
pT3a patients [15]. Moreover, a current study of the
SEER database analyzed the outcomes of 2238
patients with pT2b-T3b bladder cancer and found a
significantly higher rate of node-positive disease and
all-cause mortality in patients with node-negative
pT3a versus pT2b bladder cancer [16]. Regarding
these data, it seems anatomically intuitive to define
organ-confined muscle-invasive bladder cancer as
stages pT2bpN0cM0 or less.
4. P
rognostication in Lymph Node Positive
Bladder Cancer
Oncological outcome in patients with node-positive
bladder cancer at radical cystectomy is reported
to be generally poor with a 5-year recurrence-free
survival ranging from 34-43% [1,3, 21]. Nonetheless,
long-term survival has been described especially in
patients with low-volume lymph node metastasis [2123]. The following pathological and clinical parameters
have been investigated as critical determinants
for survival in node-positive disease: number and
size of positive lymph nodes [22], extracapsular
extension of lymph node metastasis [24], number
of retrieved lymph nodes [25], aggregate lymph
node metastasis diameter [26], and the anatomic
extent of lymphadenectomy reflecting the surgical
meticulousness of the lymph node removal [27]. The
current pTNM staging system differentiates lymph
node tumor involvement according to the number
and size of positive lymph nodes (see table 1) but
does not reflect sufficiently the surgeons capability
of removing all the affected nodal tissue.
With growing evidence of the prognostic role of the
extent of lymphadenectomy for improving outcomes
in invasive bladder cancer [22, 27], the concept of
lymph node density (LND) has been proposed [28,
29]. It is defined as the number of positive lymph
nodes divided by the overall number of retrieved
lymph nodes. In most series, a cut-off value of
20% has been reported to statistically optimally
distinguish between different outcomes [25, 30, 31].
Various studies also found that LND outperformed
the pTNM based predictions (pN1-N3) in terms of
recurrence-free and disease-specific survival [28, 29,
31]. Even more, LND was a superior prognosticator
in node-positive patients after adjusting for the
3. pT3 Substaging
The prognostic significance of substaging patients
with pT3 bladder cancer into those with microscopic
(pT3a) and macroscopic (pT3b) perivesical fat
invasion as implemented by the 2002 TNM staging
system is also controversially discussed. Most larger
series found that the risk of lymph node metastases
was significantly higher for patients with pT3b
versus pT3a classified disease [15-17] while some
smaller series did not [18]. A recent single-center
analysis focussed on outcomes in 75 patients with
node-negative pT3 bladder cancer [19]. Actuarial
290
d) Stage pT4 Bladder Cancer
use of adjuvant chemotherapy [31, 32]. On the

contrary, Fleischmann et al. reported that LND lost
its independent prognostic value after accounting for
the presence of extracapsular extension of lymph
node metastasis [24]. Although the concept of LND
seems to be a promising alternative for improving the
prognostication of patients with lymph-node positive
bladder cancer, there are several unresolved issues
which hinder its unquestionable adoption into clinical
practice. Besides the retrospective design of the
studies in favor of the concept of LND, the proposed
cut-off values are based on statistical calculations
and are highly dependent on the surgical extent
and meticulousness of lymphadenectomy. Even
when considering a defined anatomical template of
extended pelvic lymphadenectomy, the number of
retrieved lymph nodes can vary between individuals
significantly [27] and this might have implications on
the proposed cut-off values. Furthermore, different
techniques in the pathological processing and
evaluation of lymph nodes have to be taken into
account [33]. Moreover, in the neoadjuvant setting,
LND was not found to be of prognostic value [34]. In
this respect, prospective trials are certainly needed to
address more specifically the role of LND in patients
with lymph-node positive bladder cancer.
Radical cystectomy in patients with T4 bladder

cancer has been shown to be a feasible option in
terms of therapy-related morbidity [38]. Nevertheless,
the oncological outcome of these patients treated
without neoadjuvant therapy is generally poor,
although some patients may achieve long-term
survival. Risk factors that determine independently
an adverse oncological outcome are the presence
of positive soft tissue surgical margins, lymph
node metastasis, lymphovascular invasion, tumors
infiltrating the abdominal or pelvic wall (staged as
pT4b), and female patients [39]. In this respect,
several series have demonstrated that a positive soft
tissue surgical margin per se is a strong independent
risk factor for decreased recurrence-free and cancerspecific survival [40, 41]. Especially female patients
are at increased risk for positive soft tissue surgical
margins at radical cystectomy [42]. However, since
complete tumor removal cannot be achieved by
surgery alone in case of abdominal or pelvic wall
infiltration, cystectomy should be preserved in this
stage for symptom relief, such as recurrent gross
hematuria, pain, fistula formation, and therapyrefractory urgency [43].
e) Impact of Lymphovascular Invasion on

Oncological Outcomes
c) Outcomes of Patients with Stage pT0 or

Carcinoma-in-situ-only Disease
Lymphovascular invasion in pathologically nodenegative bladder cancer was found to independently

predict worse cancer-specific and overall survival
after radical cystectomy, whereas in node-positive
disease its independent prognostic significance was
not confirmed [44, 45]. Therefore, in node-negative
disease, its presence might indicate micrometastasis
and, thus, help to improve risk assessment and
guide clinicians for counseling patients for adjuvant
treatment options or clinical trials [46]. However, when
assessing lymphovascular invasion on conventional
histological sections, its accurate detection can be
hampered due to retraction artifacts and difficulties
in identifying small lymphatic or blood vessels [47]
which, in turn, limits its prognostic value and stresses
the importance of additional immunohistochemical
studies.
The percentage of patients without evidence of

the primary tumor (classified as pT0) at radical
cystectomy has been shown to range from 5-7%
with a risk of concomitant lymph node metastasis
of approximately 3-7.5% [35, 36]. In one study,
the following clinical stages were reported at
preoperative transurethral resection in 56 patients
with final pT0 disease: Tis in 5 (9%), Ta in 2 (4%), T1
in 18 (32%), T2 in 29 (52%), and T3 in 2 (4%) (36).
The probability of remaining disease-free at 5 years
in patients with invasive bladder cancer (pT1-T2)
staged pT0 at radical cystectomy is approximately
89-90% and is significantly higher than in cases with
residual pT1-T2 bladder cancer [35, 36]. In a large
international study of 228 patients with pT0 bladder
cancer at final pathologic analysis, risk factors which
independently correlated with decreased survival
were the presence of lymph node metastasis and
female gender [35].
f) Molecular Markers and Outcome

The predictive value of molecular markers for risk
assessment in invasive bladder cancer has been
evaluated in a subset of series. These markers
play an important role in cell-cycle regulatory or
angiogenic mechanisms. The following markers
have been recently investigated: E-cadherin, pRB,
survivin, p53, p16, p21, p27, cyclin E, and Ki-67 [4850]. Expression levels of these markers are assessed
in cystectomy specimens by immunohistochemical
methods and the combination of different markers
have been shown to improve the predictive accuracy
of standard clinical and pathological risk factors [49].
For patients with carcinoma in situ only, who had

undergone radical cystectomy due to refractory
conservative treatment, the overall disease-free
and cancer-specific survivals were 74% and 85%,
respectively. However, 36% of these patients
experienced disease upstaging (pT1) at radical
cystectomy. Similar to patients with pT0 disease, risk
factors for decreased cancer-specific survival were
found to be the presence of lymph node metastases,
lymphovascular invasion, and female gender [37].
291
A recent analysis incorporated serum preoperative

C-reactive protein concentration as a serological
marker in a new predictive model, termed TNR-C
score, and showed that increased levels were not
only associated with decreased cancer-specific
survival but also with an increase in the predictive
ability of standard pathologic risk factors including
tumor stage, lymph node density, and resection
margin status [51]. Nonetheless, up to now, there
are no established molecular markers that can be
unequivocally recommended for risk assessment in
invasive bladder cancer on a routine basis.
nomogram, the standard predictors of the AJCC

based prediction model, the pT and pN stage, were
complemented by the following parameters: age,
gender, tumor grade at cystectomy, presence of
lymphovascular invasion, presence of carcinoma
in situ, neoadjuvant chemotherapy, and adjuvant
chemo- and radiotherapy. The addition of these
parameters increased significantly the predictive
accuracy of the BCRC nomogram by 3.2% as
compared to the AJCC-based predictions [56].
By contrast, the IBCNC nomogram relies on more
than 9000 cystectomy patients who were treated in
12 international centers worldwide. In this nomogram,
the following parameters have been added to the pT
and pN stage: age, gender, tumor grade, number
of days from diagnosis to cystectomy, and final
histology. This nomogram has shown to improve the
AJCC based predictions by approximately 7% [55].
The original data sets of both nomograms used 200bootstrap resamples for reducing overfit bias and
for interval validation. Currently, only a few smaller
series have externally validated these data but have
confirmed an approximately 4% improvement in the
predictive accuracy for both nomograms [58].
g) Impact of Clinical Parameters on Outcome:

Follow-up Duration, Surgical Expertise, and
Age
An ongoing discussion in invasive bladder cancer
is the validity of the reported survival analyses of
retrospective studies with short or intermediate
follow-up time interval. Considering the fact that
the median time to local or distant recurrence after
radical cystectomy in studies with a median followup of more than 10 years ranges from 7-18 months
[1], a recent study was set up to investigate the
validity of disease-free survival rates reported at 2
or 3 years after radical cystectomy. This study found
that disease-free survival rates reported at 2 or 3
years correlated well with the 5-year overall survival
regardless of the use of adjuvant chemotherapy
[52].
Nevertheless, some limitations must be taken

into account when addressing the patients
individual risk of recurrence and death by the use
of these nomograms. In the IBCNC nomogram, a
considerable number of patients with squamous cell
carcinomas were included but their primary clinical
and pathological parameters were not published,
which makes its general applicability difficult [55]. In
this respect, the BCRC nomogram provides detailed
patient data but the number of included patients is
relatively low. In addition, the independent prognostic
relevance of some of the included parameters
(i.e., adjuvant treatment modalities) currently is
controversial (see subsection 4.2). Nonetheless,
both nomograms can be regarded as an important
tool for estimation of outcomes in patients treated
with radical surgery.
Another important parameter that might influence

the outcomes of bladder cancer patients is surgical
expertise. A recent meta-analysis addressed the
ongoing debate on the relationship between highvolume centers and oncologic outcome. A positive
significant association on improved survival was not
found for hospital (HR 0.89; p=0.06) or for surgeon
volume (HR 0.83; p=0.26) [53].
Nonetheless, older patients might derive the highest
benefit when treated in a high-volume center [54]. In
this respect, the largest series on cystectomy to date
from the SEER database analyzed the outcomes of
13,796 bladder cancer patients and demonstrated
that patients above 80 years had an increased risk
for postoperative morbidity but not mortality. The
ability of patients older than 80 years to undergo
cystectomy had the highest impact on risk reduction
of cancer-related and non-cancer-related mortality
[43].
Recommendations
The AJCC substratifications in node-negative pT2
and pT3 bladder cancer are of prognostic value
(LE: 3, GR: C).
According to the TNM staging system, organconfined bladder cancer has to be defined as
pT2bN0M0 or less (LE: 3, GR: B).
h) Nomograms
In 2006, bladder cancer nomograms were published
from the Bladder Cancer Research Consortium
(BCRC) and the International Bladder Cancer
Nomogram Consortium (IBCNC), and are freely
available on the Internet [55-57]. The BCRC
nomogram is based on a total of 731 patients
treated in 3 North American institutions. In this
Nomograms
provide
improved
prognostic
information for oncological outcomes after
radical surgery as compared to the pTNM stage
predictions. However, its general applicability
has not been established sufficiently by external
validation (LE: 3, GR: B).
292
In patients older than 80 years, radical cystectomy

is associated with the highest risk reduction on
cancer-related and non-cancer-related mortality
(LE: 3, GR: C).
14. Bastian PJ, Hutterer GE, Shariat SF, Rogers CG, Palapattu
GS, Lotan Y, Vazina A, Amiel GE, Gupta A, Sagalowsky
AI, Lerner SP, Schoenberg MP, Karakiewicz PI; Bladder
Cancer Research Consortium ( 2008) Macroscopic, but not
microscopic, perivesical fat invasion at radical cystectomy
is an adverse predictor of recurrence and survival. BJU Int
101., 450-454
Based on the scarce data available, the routine

use of molecular markers for risk assessment after
radical cystectomy in invasive bladder cannot be
recommended (LE: 3, GR: B).
15. Quek ML, Stein SP, Clark PE, Daneshmand S, Miranda

G, Cai J, Groshen S, Cote RJ, Lieskovsky G, Quinn DI,
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Neoadjuvant or adjuvant chemotherapy has the

potential of eradicating micrometastases and
improving survival in patients with muscle-invasive
urothelial carcinoma. This seems to be particularly
true for patients with pathologic extravesical and
lymph node-positive disease. [7]
Administration of chemotherapy prior to surgery
versus after (adjuvant) offers several potential
advantages. Patients may be able to tolerate
treatment better and the response of the primary
tumor to chemotherapy can be assessed [8-12],
providing prognostic significance. In a study of
patients treated with neoadjuvant cisplatin-based
therapy followed by definitive surgery, 91% of
patients who responded to chemotherapy (defined
as pathologic stage T1) were alive at a median
follow-up of 25 months in contrast to 37% of nonresponders [10].
Downstaging of the tumor may provide an indication of
the activity of neoadjuvant chemotherapy, especially
in patients who have a pathologic complete response
and in patients who are pT1 stage after therapy.
Those patients with residual disease at radical
cystectomy should probably be offered clinical trials
evaluating non-cross-resistant alternative agents. A
complete response after neoadjuvant therapy may
also permit consideration of organ preservation
in selected cases. The standard of care is that the
majority of patients require and undergo cystectomy
or radical radiotherapy.
IV. Perioperative
Chemotherapy
An important potential disadvantage of neoadjuvant

chemotherapy is the discordance between clinical
and pathologic staging. In a study reported by
Scher et al, [13] while 57% of patients achieved a
clinical and cystoscopic complete response following
neoadjuvant M-VAC, only 30% had a pathologic
complete response at subsequent cystectomy.
1. Application of Chemotherapeutic
Agents in Bladder Cancer:
Neoadjuvant Chemotherapy
a) Introduction
Radical cystectomy is considered to be the gold
standard of treatment for patients with clinically
localized muscle-invasive bladder cancer. However,
despite potentially curative surgery, approximately
one-half of patients with deep, muscle-invasive
urothelial carcinoma (stages T2b-4,) develop
metastatic disease within 2 years.[1] At 5 years,
the survival rate after cystectomy is at best 65%,
ranging from 36-48% (level 3) [2-4] depending on
the presence of extravesical extension (pT3) and
lymph node metastases (N1-N3). Both factors are
associated with an increased risk for recurrence
following cystectomy. In contemporary series, 5-year
overall survival rates up to 57% have been reported
in patients with clinically unsuspected N1 disease,
as compared to 0-27% for those with larger volume
N2 or N3 disease [3, 5, 6].
A potential disadvantage of neoadjuvant chemotherapy is that patients achieving a complete clinical

response at the transurethral resection of bladder
tumor after chemotherapy may refuse cystectomy.
Another theoretical disadvantage of the neoadjuvant
approach is the possibility that some low-stage, lowrisk patients may unnecessarily receive neoadjuvant
chemotherapy. Conversely, delay of definitive local
treatment could potentially be associated with disease progression [14].
The primary disadvantage of the adjuvant
chemotherapy paradigm may be that it does not
appear feasible in a third of patients within 90
days after radical cystectomy due to postoperative
complications or slow recovery of functional status
295
[15, 16]. Also, approximately 40% of patients who

would be candidates for neoadjuvant chemotherapy
may not be candidates for postoperative cisplatin
because of a perioperative decline in renal function
[17].
provide benefit to patients, whether it is given before

cystectomy or before radiotherapy. In the United
States, radical cystectomy is preferred for patients
who have a good performance status. In most of
Europe, radical cystectomy is also the preferred
option, although some institutions consider local
radical radiotherapy as an alternative.
Besides all these pros and cons, both approaches

are targeting microscopic disease and the question
is to know what the best option for an individual
patient is. No published trials have directly
compared pure populations of neoadjuvant versus
adjuvant chemotherapy. In the absence of a
specific randomized trial that has compared optimal
neoadjuvant and adjuvant chemotherapy regimens
in association with cystectomy, it is not possible to
make a definitive recommendation about the utility of
adjuvant chemotherapy as compared to neoadjuvant
treatment. This will be further discussed in the
subsequent section of adjuvant chemotherapy.
Several randomized trials have explored whether

neoadjuvant chemotherapy improves survival in
bladder cancer. The results of these randomized
trials are presented in Table 3 [18, 19]. Some
studies suffered from small sample size, suboptimal
chemotherapy, premature closure, or inadequate
follow-up [20]. Among these trials, single agent
regimens failed to show a survival benefit from
neoadjuvant therapy [21]. However, well-designed
multi-agent chemotherapy trials utilizing effective
chemotherapeutic regimens have demonstrated an
improvement in survival. These trials have shifted
the treatment paradigm in muscle-invasive disease
favoring more the use of neoadjuvant chemotherapy
[18, 22].
Before reviewing the accumulating data from

controlled, prospective trials on neoadjuvant
chemotherapy for bladder cancer, it is beneficial
to acknowledge a growing consensus among
many investigators for at least selective use of
neoadjuvant chemotherapy in subgroups of patients
who are known to be at high risk for micrometastatic
disease including those with bulky primary tumors,
hydronephrosis due to the primary tumor, mixed
histology, and possibly lymphovascular invasion
within the primary tumor.
The SWOG Intergroup Trial 0080 randomized

patients with T2-T4a urothelial carcinoma of
the bladder to radical cystectomy alone (154
patients) versus 3 cycles of M-VAC followed by
radical cystectomy (153 patients) [22]. The use of
neoadjuvant chemotherapy was associated with a
higher rate of complete pathologic response (38%
versus 15%, p<0.001). At a median follow-up of 8.7
years, improvements in median survival (77 versus
46 months, p=0.06) and 5-year survival (57% versus
43%, p=0.06) favored the neoadjuvant M-VAC arm.
Because of its size, this trial had limited potential to
discern a clinically meaningful difference. This trend
c) Data Supporting a Survival Benefit for

Neoadjuvant Chemotherapy: Randomized
Trials of Neoadjuvant Chemotherapy
Neoadjuvant chemotherapy theoretically should
Table 3.
296
toward improved survival favoring M-VACtreated

patients with an estimated reduction in the risk of
death by 25% (hazard ratio [HR], 1.33) provides
some evidence of the benefit (level 1) [22]. There
were no treatment-related deaths and neoadjuvant
chemotherapy did not adversely impact the ability to
proceed with radical cystectomy or increase adverse
events related to surgery.
with follow-up of 7.4 years, a statistically significant

improvement in survival was observed for patients
who received neoadjuvant chemotherapy (p=0.048;
HR=0.85; 95% CI 0.72-1.0). This trial, well-powered
and with adequate follow-up, demonstrated both a
survival benefit and improved loco-regional control
with neoadjuvant CMV chemotherapy, however, the
predefined endpoint with an improvement in survival
of 10% was in fact not reached. Survival at 5 years
was 50% with CMV compared with 44% with radiotherapy; at 8 years, it was 43% with CMV and 37%
with radiotherapy. (level 1).
Several studies have been published based on

retrospective analysis of this trial database. As an
example, surgical factors were evaluated in 268
underwent radical cystectomy in this Intergroup
trial [23]. Cystectomies were performed by 106
surgeons at 109 institutions. Half of the patients
received neoadjuvant M-VAC. The 5-year postcystectomy survival and local recurrence rates in all
patients who underwent cystectomy were 54% and
15%, respectively. Surgical variables associated
with longer post-cystectomy survival were negative
margins (hazard ratio 0.37; p=0.0007) and removal
of 10 or more nodes (hazard ratio 0.51; p=0.0001).
These associations did not differ by treatment
arm (p=0.21 for all tests of interactions between
treatment and surgical variables). Predictors of local
recurrence were positive margins (odds ratio 11.2;
p=0.0001) and removal of fewer than 10 nodes
(odds ratio 5.1; P = 0.002). The quality of surgery
was an independent prognostic factor for outcome
after adjustments were made for pathologic factors
and neoadjuvant chemotherapy usage (LE 2).
A trial that was almost identical to the SWOG study

was performed by the Gruppo Uro-Oncologico Nord
Est (GUONE) cooperative group in Italy [25]. Over
a 6.5-year period, 206 patients were randomly
assigned to neoadjuvant M-VAC before cystectomy
or to cystectomy alone. No clear differences in
survival were demonstrated; as 3-year survival was
62% for the M-VACtreated patients and 68% for
patients in the cystectomy alone arm (LE 2).
The Nordic cystectomy I trial evaluated neoadjuvant
doxorubicin, cisplatin, and preoperative radiotherapy
before cystectomy versus preoperative radiotherapy
and cystectomy alone. A 15% survival difference in
favor of patients treated with chemoradiotherapy
was seen in only a subset analysis of patients with
T3 or T4 disease. Investigators were unable to
confirm this survival advantage in the subsequent
Nordic cystectomy II trial, in which 317 patients
were randomly assigned cystectomy or cystectomy
preceded by methotrexate and cisplatin (without
radiotherapy) [26]. However, combining the 2 trials
provided positive results in favor of neoadjuvant
chemotherapy (LE 2) [27].
Another recent analysis evaluated the impact of

histology when neoadjuvant M-VAC was given in this
trial. There was evidence of a survival benefit from
chemotherapy in patients with mixed tumors [24].
Presence of squamous or glandular differentiation in
locally advanced urothelial carcinoma of the bladder
does not seem to confer resistance to M-VAC and in
fact may be an indication for the use of neoadjuvant
chemotherapy before radical cystectomy.
d) Meta-Analysis
Because of the uncertainties of the definitive value
of neoadjuvant chemotherapy in terms of survival,
a meta-analysis of neoadjuvant chemotherapy trials
was performed [28]. Data from 2688 patients treated
in 10 randomized trials evaluating neoadjuvant
chemotherapy for invasive urothelial carcinoma
was reviewed. Of note, this analysis did not include
data from the SWOG Intergroup trial. Compared to
local treatment alone, neoadjuvant platinum-based
combination chemotherapy was associated with a
significant benefit in overall survival [HR=0.87 (95%
CI 0.78-0.98, p=0.016)], a 13% decrease in the risk of
death, and a 5% absolute survival benefit at 5 years
(overall survival increased from 45-50%). When
trials utilizing single-agent cisplatin were included,
the survival benefit did not achieve statistical
significance [HR=0.91 (95% CI 0.83-1.01, p=0.084)].
(LE 2). However, single-agent cisplatin did not show
an improvement in survival (P=0.26) compared
with no neoadjuvant therapy. As all platinum-based
combination trials were analyzed as a group, it is not
The MRC/EORTC performed a large trial in which

976 patients were enrolled and randomized to neoadjuvant CMV (cisplatin - methotrexate - vinblastin)
(491 patients) or no neoadjuvant chemotherapy
(485 patients) over a 5.5-year period from 106 institutions. This trial was performed more or less during the same time as the SWOG trial. The results
of this trial were updated at a median follow-up of
approximately 7 years [18]. Management of the primary tumor involved cystectomy, radiation therapy,
or both and was left to the choice of investigators.
An initial 8% improvement in time to progression
and a 5.5% difference in absolute 3-year survival
(HR=0.85; 95% CI 0.71-1.02) favoring the neoadjuvant chemotherapy arm was reported. When results
were published in 1999, a non-significant trend toward improvement in survival was observed in patients in the CMV arm. In a 2002 update from the
American Society of Clinical Oncology (ASCO),
297
possible to discern the best combination for use in

neoadjuvant therapy.
without paclitaxel in patients with metastatic disease

have led to their investigation in the neoadjuvant and
adjuvant setting. Although these newer regimens are
promising, there are no data from randomized trials
supporting their use in the neoadjuvant setting [35]
and limited data form phase II trials.
A subsequently reported meta-analysis that included

individual patient data from 3005 individuals enrolled
in 11 randomized trials, including the SWOG data
extrapolated from the published report [22], confirmed
the survival benefit for neoadjuvant cisplatin-based
compared to local therapy alone [28, 29]
In a phase II trial of 68 patients with adequate renal

function and clinical T3 or T2 with hydronephrosis, N0
M0 bladder cancer received 3 cycles of neoadjuvant
paclitaxel, carboplatin, gemcitabine (PCaG) with a
primary endpoint of pCR. Patients with T4 or nodepositive disease received 6 cycles of PCaG with
an endpoint of resectability [36]. The caveat is that
this regimen was fairly toxic in a population with
adequate baseline renal function and may often
warrant prophylactic granulocyte growth factors in
accordance with guidelines. ***
A very similar meta-analysis of neoadjuvant

randomized controlled trials was conducted in
Canada.[30] A total of 16 eligible trials that included
3315 patients were identified, and 2605 patients
provided data suitable for a meta-analysis of overall
survival. The pooled HR was 0.90 (95% CI 82%
to 99%; P=0.02). Eight trials used cisplatin-based
combination chemotherapy and the pooled HR was
0.87 (95% CI 78% to 96%; P=0.006), consistent
with an absolute overall survival benefit of 6.5%
from 50% to 56.5% (95% CI 2% to 11%). A major
pathologic response was associated with improved
overall survival in 4 trials. Neoadjuvant cisplatinbased chemotherapy improved overall survival in
muscle-invasive urothelial carcinoma, but the size of
the effect was modest (LE 2).
The SWOG conducted a phase II trial of 3 cycles of

neoadjuvant paclitaxel, gemcitabine, and carboplatin
followed by cystoscopic surveillance or immediate
radical cystectomy for patients with cT0 status after
chemotherapy [37]. Patients with cT0 status could
elect immediate radical cystectomy or cystoscopic
surveillance, and those who did not achieve cT0
status underwent immediate cystectomy. There was
an unacceptably high rate (60%) of persistent cancer
at radical cystectomy in patients presumed to have
pT0 status, which suggests that radical cystectomy
is a critical component of therapy.
The use of perioperative chemotherapy has been

limited until 2003-2005, when these meta-analyses
were published. Among 7161 analyzable patients
in the National Cancer Data Base with stage III
bladder cancer diagnosed between 1998 and 2003,
perioperative chemotherapy was administered to
11.6% of patients with 10.4% receiving adjuvant
chemotherapy and 1.2% receiving neoadjuvant
chemotherapy [31]. After 2003, there has been a
slight increase in its use. In a more recent report on
40,388 patients 18 to 99 years old diagnosed with
muscle invasive (stages II to IV) bladder cancer in
2003 to 2007 from the National Cancer Database,
the incidence of those who received chemotherapy
increased from 27.0% in 2003 to 34.5% in 2007 due
to an increase in neoadjuvant chemotherapy and
chemotherapy without surgery [32]. Clinical Practice
Guidelines can help to increase the implementation
of neoadjuvant chemotherapy. A Canadian study [33]
has shown that neoadjuvant referral and treatment
rates increased after publication of the Clinical
Practice Guidelines. However, overall referral and
treatment rates remained low.
While recently, some potential benefits have been

reported with the use of the triple regimen in the
adjuvant setting [38], only the M-VAC regimen
has been extensively evaluated. On that basis
M-VAC has the strongest evidence-based data for
neoadjuvant use.
While the gemcitabine/cisplatin (table 3) doublet has
not been validated in the perioperative setting, recent
retrospective data from the Memorial Sloan-Kettering
Cancer Center (MSKCC) shows that the GC regimen
produces a pCR rate of 35%, similar to M-VAC [39].
Multiple other reports on use of this doublet for
metastatic disease show very similar response rates
and survival to that obtained with M-VAC, and with
lower toxicity. In contrast to the above MSKCC study,
data from the Cleveland Clinic showed that only 7%
of patients achieved a pCR with mostly GC and other
non-MVAC-based regimens mainly administered in
community oncology practices [35].
Based on these observations and despite

level I evidence, neoadjuvant cisplatin-based
chemotherapies continue to be underutilized in the
management of bladder cancer, even at high-volume
tertiary centers [34].
e) Novel Combinations as
Therapy for Bladder Cancer
In the absence of definitive supportive data for GC

in the neoadjuvant setting, M-VAC remains the
preferred regimen.
Trials are building upon combinations of GC
or dose-dense M-VAC (DD-MVAC) with novel
biological agents administered in 3 to 4 cycles in the
neoadjuvant setting with pCR as a key intermediate
endpoint [7] (Table 2).
Neoadjuvant
The promising results from newer combinations

such as gemcitabine and cisplatin/carboplatin with or
298
f) Developing a Personalized Neoadjuvant

Therapy: A paradigm to define risk of relapse
and response to systemic therapy
to better define the subset of patients who should

have neoadjuvant chemotherapy. Such signatures
may provide a matrix into which chemosensitivity
genes can be intercalated to prediction not only of
stage variables for risk of relapse but also benefit
from specific chemotherapy agents [44,45]. These
hypotheses require testing and validation in
neoadjuvant cohorts and more definitively in trials.
The ability to predict response to a specific therapy

is still a major challenge in oncology. Advances in
molecular research have led to the identification
of genetic markers that impact upon response
to chemotherapy. Based on detailed molecular
information for each individual tumor, the clinician
will ultimately be able to more accurately select
the appropriate therapy for each patient according
to individual predicted response. This customized
treatment using chemosensitivity markers such
as intratumoral molecular pharmacology markers
(pharmacogenomics and genetics) should aid in
improving outcome [40].
There are several studies looking at candidate

markers in cohorts of patients treated with
neoadjuvant chemotherapy. These are summarized
below:
p53 aberrancy as inferred by IHC overexpression,
confers a poor prognosis in muscle-invasive bladder

carcinoma [46, 47]. In one report of 90 patients
undergoing neoadjuvant M-VAC chemotherapy,
patients with mutant p53 were 3 times more likely
to die from their disease than those with wild-type
p53 [47]. The impact of p53 overexpression on
survival was predominantly in T2 and T3a tumors.
Conversely, a retrospective analysis of data
suggested that adjuvant chemotherapy enhanced
survival in patients with p53 mutant tumors [48].
Several reports have outlined a variety of potential

predictive markers either in localized disease or
in advanced disease. Data remains limited, but it
is conceivable that in coming years a marker or a
panel of markers may be available that achieves this
predictive goal, allowing improved patient selection
for chemotherapy.
K
i67,
p53, and angiogenesis (microvessel

staining with CD34) were assessed by
immunohistochemistry in 94 patients who accrued
to the SWOG 8710 phase III neoadjuvant M-VAC
trial [22, 49]. There was a trend toward shorter
disease-free and overall survival in patients with
higher Ki67 expression. Increased p53 nuclear
expression was associated with a shorter overall
survival but this was not statistically significant. No
association or trend between microvessel density
and outcome parameters was noted. The study
was very limited in power given the small number
of specimens available.
g) Muscle-invasive urothelial carcinoma

Neoadjuvant chemotherapy followed by cystectomy
improves survival compared to surgery alone.
However, 20 patients must be treated to cure one
additional person compared to surgery alone.
To identify those patients who will derive benefit,
limited studies have provided some hints on single
markers and which specific treatments may be of
benefit. At present, many of the published results of
gene expression profiling are preliminary, based on
small sample sizes, and it is not possible to make a
definitive statement on the role of gene expression
profiling in the molecular prognostication of invasive
urothelial carcinoma. Work in this area is directed
along 2 concurrent themes: risk stratification and
chemotherapy response prediction.
BRCA1 mRNA expression was analyzed by

quantitative PCR in tumor biopsies obtained by
transurethral resection from 51 patients with locally
advanced bladder cancer receiving neoadjuvant
chemotherapy. A close correlation was found
between BRCA1 mRNA levels and pathological
response. Low levels of BRCA1 were shown to
predict response to neoadjuvant cisplatin-based
chemotherapy, and correlated with longer diseasefree survival [50].
In vitro, XAF1 expression enhances the apoptotic
response of tumor cells to chemotherapeutic
agents. In vivo, in a paired sample study from 14
bladder cancer patients treated with a combination
of neoadjuvant gemcitabine and cisplatin, patients
with high levels of XAF1 in their tumor had increased
rates of response, progression-free survival (PFS),
and overall survival (OS)[51].
To this point, defining risk of relapse has been

dependent on clinical and imaging based staging,
which often understages the patient, with resultant
upstaging at surgery [41]. A recent study developed
a gene expression model (GEM) in primary bladder
cancer tissue to predict the presence of lymph node
involvement at cystectomy in the AUO-AB-05/95 trial
[42, 43]. A 20-gene signature has an Area under the
Receiver Operator Curve of 0.67 for prediction of
lymph node metastases and was an independent
predictor of their presence in multivariate analysis
with age, sex, pathological stage, and lymphovascular
space invasion. The gene signature divided patients
into high relative risk (1.74, 95% CI 1.03-2.93) and
low relative risk (0.70, 95% CI 0.51-0.96) of nodepositive disease. Further precision in determining
risk of lymph node involvement has the potential
Baseline tumor genomics appear promising

as predictors of pCR but limited small studies
have been reported. The Takata study [52], in
a retrospective study of patients with invasive
299
bladder cancer who received neoadjuvant M-VAC

chemotherapy, found that 14 predictive genes
separated the responder group (defined as no
residual muscle-invasive disease) from the nonresponder group. This system accurately predicted
the drug responses of 8 of 9 test cases. To further
validate the clinical significance of the system, the
investigators applied it to 22 additional cases of
patients with bladder cancer and found that the
scoring system correctly predicted clinical response
for 19 of the 22 test cases [53].
treatment for localized muscle-invasive bladder

cancer (grade B).
A
discrepancy
between clinical/cystoscopic
and pathologic staging can be anticipated
after neoadjuvant chemotherapy and therefore
cystectomy is not obviated by response (grade
B).
T
oxicity and mortality associated with neoadjuvant
chemotherapy are acceptable (grade B).

However, few data on quality of life are available.
In summary, 2 large randomized trials and a metaanalysis support the concept that neoadjuvant
chemotherapy for patients with muscle-invasive
bladder cancer provides a survival benefit greater
than with surgery alone. This approach should
be considered for patients who are candidates for
cisplatin-based combination chemotherapy and
radical cystectomy. For patients who have not
received neoadjuvant chemotherapy and who have
extravesical or node-positive disease following
cystectomy, enrollment in a clinical trial should be
encouraged. If patients are not protocol-eligible,
adjuvant cisplatin-based combination chemotherapy
is a reasonable consideration.
Meta-analysis of cisplatin-containing combination
neoadjuvant chemotherapy trials revealed

a modest difference in favor of neoadjuvant
chemotherapy (GR B).
We recommend using M-VAC [methotrexate,
vinblastine, doxorubicin, and cisplatin, (table

2)] for appropriately selected cases as the
neoadjuvant chemotherapy regimen (GR 1A).
A
lthough other regimens, such as gemcitabineplus
cisplatin[GC], have similar activity in patients

with metastatic disease, there are no data from
randomized trials in the neoadjuvant setting to
support the use of regimens other than M-VAC.
(Grade 1A)
Summary
Cystectomy is considered to be the gold standard
of treatment for patients with localized muscleinvasive bladder cancer. Neoadjuvant chemotherapy
was intended for patients with operable clinical stage
T2 to T4a muscle-invasive disease. The rationale
for giving chemotherapy before cystectomy or fulldose radiotherapy is based on the intent to treat
micrometastatic disease present at diagnosis. A
discrepancy between clinical and pathologic staging
can be expected. Toxicity and mortality associated
with neoadjuvant chemotherapy are acceptable.
Available data suggest that for average-risk
patients with cT2 cancer, the benefit of adding
chemotherapy to local therapy is at best modest.
Likewise, available studies suggest a much more
substantial benefit for patients with high-risk disease,
such as cT3b cancers. Presence of squamous or
glandular differentiation in locally advanced urothelial
carcinoma of the bladder does not seem to confer
resistance to M-VAC. The quality of the surgery is a
confounding factor in these studies. Meta-analysis
of cisplatin-containing combination neoadjuvant
chemotherapy trials revealed a 5% difference in
favor of neoadjuvant chemotherapy. Unfortunately,
in this case, in which small differences in survival
can be seen, it is regrettable that the data on quality
of life are inadequate.
A
vailable data suggest that for average-risk
cancer patients with cT2, the benefit of adding

chemotherapy to local therapy is at best modest.
Likewise, all available studies suggest a much
more substantial benefit for patients with high-risk
disease, such as cT3b cancers or those thought
to have lymph node involvement (GR B).
T
he quality of the surgery is a confounding factor
in interpreting these studies (GR B).
Following cystectomy in patients who did not

receive neoadjuvant chemotherapy, we suggest
consideration of adjuvant chemotherapy (see
below) with a cisplatin-based regimen for patients
who have perivesical tumor extension (stage T3
or higher) or regional lymph node involvement
(GR 2C).
Presence of squamous or glandular differentiation
in locally advanced urothelial carcinoma of the

bladder does not seem to confer resistance to
M-VAC and in fact may be an indication for the
use of neoadjuvant chemotherapy before radical
cystectomy (GR 3C).
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2. Application of Chemotherapeutic
Agents in Bladder Cancer:
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a) Introduction
Despite the high rate of down-staging and response
in the neoadjuvant and metastatic setting, cisplatinbased chemotherapy is underutilized in the treatment
of urothelial cancer. As a consequence, more than
50% of patients with high grade bladder cancer
and muscle invasion ultimately die of disseminated
disease. High-risk patients with pT3-pT4 and node
negative disease have no more than a 5-year overall
survival of 47% after cystectomy; patients with lymph
node metastases have an overall 5-year survival rate
of up to 31% after radical cystectomy [1, 2]. Despite
a high risk of relapse, translating the high response
seen in advanced disease into long-term survival
in the locally advanced setting has proved difficult
[3, 4]. The chemotherapy agents used in urothelial
cancer have recently been reviewed and will not be
discussed in detail here [5].
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gemcitabine plus cisplatin in muscle-invasive urothelial
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neoadjuvant chemotherapy. BJU Int 107: 58-62.
42. Lehmann J, Retz M, Wiemers C et al. Adjuvant cisplatin plus
methotrexate versus methotrexate, vinblastine, epirubicin,
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Adjuvant chemotherapy for bladder cancer is controversial. This controversy is fueled by suboptimal
outcome for locally advanced patients treated with
radical cystectomy alone, a small potential benefit
of chemotherapy and a sequence of trials that have
been underpowered and/or closed early due to poor
accrual as well as the presence of more definitive
evidence for neoadjuvant chemotherapy. Neoadjuvant cisplatin-based combination chemotherapy is
the standard of care for medically fit patients with
high-grade stage T2 or greater bladder cancer based
on level 2B evidence for improved overall survival
and is discussed in detail above. An alternative is
the use of concurrent cisplatin and radiation therapy
for which there is also level 2B evidence, albeit in a
more highly selective cohort of patients. At this time,
there is no proven value to neoadjuvant or adjuvant
chemotherapy for patients undergoing definitive
chemo-radiation (see discussion in the section on
radiation therapy).
44. Bellmunt J, Paz-Ares L, Cuello M et al. Gene expression of

ERCC1 as a novel prognostic marker in advanced bladder
cancer patients receiving cisplatin-based chemotherapy.
Ann Oncol 2007; 18: 522-528.
45. Hoffmann AC, Wild P, Leicht C et al. MDR1 and ERCC1
expression predict outcome of patients with locally
advanced bladder cancer receiving adjuvant chemotherapy.
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46. Esrig D, Elmajian D, Groshen S et al. Accumulation of
Engl J Med 1994; 331: 1259-1264.
47. Sarkis AS, Bajorin DF, Reuter VE et al. Prognostic value
of p53 nuclear overexpression in patients with invasive
bladder cancer treated with neoadjuvant MVAC. J Clin
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48. Cote RJ, Esrig D, Groshen S et al. p53 and treatment of
bladder cancer. Nature 1997; 385: 123-125.
49. Grossman HB, Tangen CM, Cordon-Cardo C et al. Evaluation
of Ki67, p53 and angiogenesis in patients enrolled in a
randomized study of neoadjuvant chemotherapy with or
without cystectomy: a Southwest Oncology Group Study.
Oncol Rep 2006; 16: 807-810.
Despite definitive evidence for its use, relatively

few patients are offered and receive neoadjuvant
chemotherapy before surgery [6, 7], although this
may be increasingly driven by clinical practice
guidelines [8-11]. In tandem with commonly
observed upstaging of bladder cancer patients
at surgery [12, 13], slow adoption of neoadjuvant
treatment has resulted in clinicians being confronted
with patients who have not had the potential benefit
of chemotherapy in combination with surgery but
50. Font A, Taron M, Gago JL et al. BRCA1 mRNA expression

and outcome to neoadjuvant cisplatin-based chemotherapy
in bladder cancer. Ann Oncol 22: 139-144.
51. Pinho MB, Costas F, Sellos J et al. XAF1 mRNA expression
improves progression-free and overall survival for patients
with advanced bladder cancer treated with neoadjuvant
chemotherapy. Urol Oncol 2009; 27: 382-390.
52. Takata R, Katagiri T, Kanehira M et al. Predicting response
302
who have pathological staging that portends a risk

of relapse of up to 70%. This scenario begs the
question as to whether patients would be better
treated with immediate postoperative chemotherapy
or observed for possible relapse and treated at that
time. This question is currently the subject of some
studies where results are awaited.
[20]. Logothetis et al administered CISCA to a

group of 71 post-cystectomy patients with resected
nodal metastases, extravesicular extension,
lymphovascular invasion, or pelvic visceral invasion
[21]. These patients were compared in a nonrandomized fashion to 62 high-risk patients and
206 low-risk patients who did not receive adjuvant
chemotherapy. They concluded that adjuvant CISCA
conferred a 2-year disease-free survival advantage
to patients with unfavorable pathologic findings (70%
vs. 30%, p=0.00012). The earliest randomized control
trial of combination chemotherapy administered to
patients after radical cystectomy was conducted at
USC [22]. Ninety-one patients with p3, p4, or nodepositive urothelial carcinoma were randomized
to receive 4 cycles of CAP or to observation.
Chemotherapy resulted in a significant improvement
in the risk of disease recurrence at 3 years (30% vs.
54%, p=0.011, unstratified Wilcoxon test) but only a
trend to benefit in the overall risk of death (34% vs.
50% p=0.099, unstratified Wilcoxon). The median
survival of patients on chemotherapy was reported
to be 4.25 years versus 2.4 years for patients in the
observation group. This study has been criticized for
the fact that only 33 out of 44 patients assigned to the
chemotherapy arm received one or more cycles of
CAP, for the small sample size, and for deficiencies
in statistical analysis such as the use of the Wilcoxon
test emphasizing early differences. Nonetheless,
the study was provocative in revealing the potential
benefit of adjuvant chemotherapy and in highlighting
the difficulties involved in conducting such trials.
Unfortunately, there have been methodological

issues with many of the studies undertaken in the
postoperative chemotherapy setting and we are left
with meta-analyses for our best evidence. A pooled
analysis supported adjuvant chemotherapy, with a
more extensive meta-analysis demonstrating a benefit
to adjuvant cisplatin combination chemotherapy [14,
15]. Since these analyses were undertaken, 4 major
phase III studies were commenced and closed:
Spanish Oncology Genitourinary Group SOGUG
99/01 [16], CALGB, Italian Multicentric [17], and
EORTC 30994 [18]. These trials continue the pattern
of premature closure for poor accrual seen in earlier
studies, but may contribute in composite to the field.
Recently, a large cohort analysis assessing the effect
of adjuvant chemotherapy from several large centers
has been published [19] suggesting the greatest
impact of adjuvant chemotherapy is seen in patients
with extravesical extension or N+ disease.
b) A Short History of Early Clinical Trials of

Adjuvant Chemotherapy in Bladder Cancer
Multiple cisplatin-based combinations have been
evaluated in the adjuvant setting (see Table 4)
Table 4. Summary of key studies of adjuvant chemotherapy in bladder cancer

Center
Regimen
Outcome
University of
Mainz
MVEC/MVAC
Early
stopping Underpowered
due
to interim
analysis favoring
chemotherapy
Modest
benefit Methodological issues
for chemotherapy
University
Cisplatin-based
of Southern
California
Stanford University Cisplatin, methotrexate, vinblastine Early
stopping
due to
interim
analysis favoring
chemotherapy
1.
SOCUG Cisplatin, gemcitabine, paclitaxel Early termination
vs. observation
due
to
poor
99/01
accrual
CALGB-90104
Rapid
sequence
AG-ITP Early termination
chemotherapy with G-CSF vs. due
to
poor
cisplatin, gemcitabine
accrual
Italian Multicentric Cisplatin,
gemcitabine
vs. Early termination
study
observation
due
to
poor
accrual
and
futility
EORTC 30994
GC, M-VAC, or DD-M-VAC vs. Early termination
chemotherapy at relapse
due
to
poor
accrual
303
Comment
Ref.
(26)
(50) (1)
Underpowered,
delayed
time to progression (p=0.01)
effect on survival
(27)
Major
benefit
chemotherapy arm
(16)
to
(30)
Non-significant,
underpowered; trend to
better outcome in nonchemotherapy arm
(17)
(18)
A subsequent trial of adjuvant chemotherapy with 3

cycles of cisplatin alone did not result in any survival
benefit in a randomized study of 77 patients [23].
Potential explanations for the lack of significant
benefit include the usage of single agent cisplatin,
the small sample size, the inclusion of patients with
lower T stage and lymph node-negative disease,
and the administration of the planned 3 cycles
of chemotherapy to only 65% of patients in the
treatment arm.
patients who were treated in adjuvant chemotherapy

trials compared to observation studies that were
published before September 2004. The analysis
was limited in its ability to be definitive in most eyes,
with only 491 patients from 6 randomized controlled
trials included. The overall hazard ratio for survival
of 0.75 (95% CI 0.60-0.96, p=0.019) suggested
a 25% relative reduction in the risk of death for
chemotherapy compared to controls (see Figures
1 and 2). The authors commented on the small
number of patients and relative poor quality of data
going into the meta-analysis and highlighted the
need for accrual to ongoing phase III trials examining
adjuvant therapy.
Given the superiority of the M-VAC combination

over single agent cisplatin in the metastatic setting
[24], it became important to evaluate the M-VAC or
M-VEC (using epirubicin rather than Adriamycin or
doxorubicin) combinations in the adjuvant setting.
Stockle et al randomized patients with pT3, pT4,
and or pelvic lymph nodes to 3 cycles of M-VAC or
M-VEC versus observation[25, 26]. While planned to
accrue 100 patients, the study was closed after an
interim analysis of 49 randomized patients revealed
a significant advantage in relapse-free survival
with chemotherapy (p=0.0015). This trial has been
interpreted with caution given its early closure and
the fact that only 62% of patients randomized to
chemotherapy completed the 3 cycles of treatment.
Furthermore, patients in the observation arm were
not offered chemotherapy at relapse. Two to three
years later, the same authors reported their longer
experience with adjuvant M-VAC/M-VEC in 83
patients. Forty-nine of the patients had been enrolled
in the prospective trial before being closed while
the remaining 38 had received M-VAC/M-VEC as a
routinely recommended therapy based on the interim
results of the trial. Longer follow-up of the patients
(38 to 78 months) who were on the trial confirmed
significant improvement in progression-free survival
in the adjuvant chemotherapy group (p=0.0005).
The continued advantage in progression-free
survival with more mature data offered support to the
beneficial role of chemotherapy.
Contemporaneously, Dr. Ruggeri and colleagues

undertook a composite analysis from published data
from all phase III studies of adjuvant chemotherapy
published [14]. While less stringent than the Cochrane
review, the conclusions were similar with a benefit
to adjuvant chemotherapy for overall survival (RR
0.74; 95% CI 0.62-0.88 [P= 0.001]) and disease-free
survival (RR 0.65; CI 0.54-0.78, [P<0.001]).
Concurrently investigators have begun to compare
different adjuvant regimens. Investigators at MD
Anderson presented data comparing 2 cycles of
preoperative chemotherapy with M-VAC and 3
afterwards with the same chemotherapy given only
postoperatively [28] in a group of patients at high risk
of extravesical extension or nodal involvement at
surgery. This study demonstrated a high likelihood of
extravesical extension or nodal involvement in nearly
80% of patients treated with initial surgery, and no
difference in survival whether the chemotherapy was
given in the neoadjuvant or adjuvant setting. While
there was no difference between the two approaches
in terms of outcome, it did demonstrate the feasibility
of preoperative chemotherapy and, in particular, that
such therapy did not result in deterioration or toxicity
so that the patient had delayed surgery or missed it
altogether. The German Urologic Oncology groups
ran a phase III trial for patients with stage pT3a-4a
and/or pathologic node-positive urothelial carcinoma
of the bladder after radical cystectomy, randomizing
327 patients to either cisplatin and methotrexate
(CM) or methotrexate, vinblastine, epirubicin, and
cisplatin (M-VEC) (29). The 5-year progression-free,
tumor-specific, and overall survival rates were not
significantly different between the 2 arms although
patients given M-VEC had higher rates of grade 3
or 4 leukopenia (22%) than those given CM (7%,
p=0.0001).
The combination of cisplatin, vinblastine, and

methotrexate was utilized as adjuvant therapy in
a prospective randomized trial of 4 cycles of CMV
versus observation following cystectomy at Stanford
University [27]. Patients accrued to this trial had
pT3b and pT4 urothelial carcinoma with or without
lymph node involvement. Data was reported on 50
out of 55 enrolled patients. Twenty-two out of 25
patients randomized to adjuvant therapy received
the total number of 4 planned cycles. With a median
follow-up of 62 months, a significant difference in
freedom from progression was noted between the
chemotherapy and the observation group (median of
37 months vs. 12 months respectively, p=0.01). No
significant difference in overall survival was noted.
The meta-analysis and composite analysis represent

a watershed in perioperative chemotherapy for
bladder cancer in part because they suggested
benefit from chemotherapy but highlighted the relative
poor quality of the trials undertaken in the area.
The advent of phase III evidence for neoadjuvant
M-VAC at around this time also shaped thinking with
c) Meta-analysis and Composite Analysis

In 2006, an analysis was published of both composite
trials and a meta-analysis of individual trials of
304
Figure 1. Composite Kaplan-Meier curve of overall survival in bladder cancer patients treated with adjuvant
chemotherapy or observation that were included in the Cochrane individual patient data meta-analysis (15).
84
Figure 2. Hazard ratios for overall survival in bladder patients treated with adjuvant chemotherapy or
observation that were included in the Cochrane individual patient data meta-analysis (15).
305
neoadjuvant therapy becoming a standard of care.

Despite this, most patients were not being offered
chemotherapy before surgery. When presented with
the all too common upstaging and/or more definitive
evidence of risk of relapse in the surgical pathology
report, many clinicians and patients considered
postoperative treatment despite deficiencies in
evidence to support this approach.
42 days and no more than 3 months after surgery.

The accrual target was 800 patients, however, the
study was halted due to slow accrual less than 2 years
after opening with fewer than 100 patients enrolled.
Subsequent analysis of Memorial Sloan Kettering
Cancer Center data from studies used to develop
the rapid cycling regimen in more advanced disease,
which also incorporated ifosfamide, suggested
issues with toxicity in the accelerated therapy arm
that was also an issue in this trial [31]. In retrospect,
CALGB 90104 may have been overly ambitious in
attempting to move a dose-dense regimen forward
in the same step as the integration of newer agents.
Published results from this trial are awaited.
d) More Recent Phase III Trials

Subsequently, 4 major phase III trials have been
formulated and opened to accrual. They share
a common theme: adjuvant chemotherapy for
transitional cell-predominant urothelial cancer
coupled with the acrimony of early closure for slow
accrual.
The Spanish Urologic Oncology Group opened

the 99/01 trial comparing 4 cycles of paclitaxel,
cisplatin, and gemcitabine (PCG) to observation
[16]. This regimen was used based on the results of
a phase I/II trial in the advanced disease setting [32].
In a subsequent phase III trial in advanced urothelial
cancer, the addition of paclitaxel increased the
efficacy in terms of response rate when compared
to GC with a benefit in overall survival seen only in
patients having the bladder as primary (post-hoc
analysis). In the intention-to-treat population, only
a trend was observed (p=0.07) [33]. The adjuvant
99/01 trial accrued patients with pT3-4 and/or lymph
node positive bladder cancer with a creatinine
clearance greater than 50 mL/min and mandated
chemotherapy commencement within 8 weeks of
cystectomy, whereas prior studies had allowed up
to 12 weeks after surgery. The trial enrolled 142
patients between July 2000 and July 2007 when it
was closed prematurely due to poor accrual. Toxicity
in the triple drug chemotherapy arm was acceptable
with a single treatment-related death due to sepsis.
At a median follow up of 30 months, overall survival
was significantly prolonged in the PCG arm (median
not reached; 5-year overall survival 60%) compared
to observation (median 26 months; 5-year overall
survival 31%) (p<0.0009). Disease-free survival
(p<0.0001) and disease-specific survival (p<0.0002)
were also superior in the PGC arm. The results from
this trial raise several questions.
The Italian multicentric trial saw 194 patients

with pT2G3, pT3-4, N0-2 transitional cell bladder
carcinoma treated with radical cystectomy who
were then randomized to immediate chemotherapy
or a control arm of observation and chemotherapy
at relapse [17]. Patients were stratified by center
and lymph node metastases. Those patients given
adjuvant chemotherapy were randomized to two
slightly different schedules of gemcitabine and
cisplatin over a 4-week cycle given for 4 cycles.
The primary endpoint was overall survival. The
3-year overall survival was 67% ( 6% SE) for
chemotherapy at relapse patients and 48% ( 6%
SE) for those given immediate adjuvant therapy
with corresponding 3-year disease-free survival of
47% and 35%, respectively. These differences were
not statistically significant. The authors concluded
that there was no role for adjuvant chemotherapy
after cystectomy for locally advanced bladder. The
outcome data from this trial run counter to prior
experience where disease-free survival has been
increased on chemotherapy arms. Publication in a
peer-reviewed journal with more data on surgical
treatment given and chemotherapy delivery in each
arm is awaited.
The Cancer and Leukemia Group B 90104 trial
saw patients with urothelial carcinoma of the bladder
treated with cystectomy and with a creatinine
clearance greater than 60 mL/min randomized to
either a rapid cycling regimen of chemotherapy with
4 cycles of doxorubicin-gemcitabine given at 14 day
intervals with granulocyte colony stimulating factor
support followed by 4 cycles of paclitaxel-cisplatin
given at 21 day intervals compared to adjuvant
gemcitabine with cisplatin in a 4-week cycle [30].
Up to 4 cycles of 4 weeks each of each regimen
were administered. Accrued patients were stratified
based on pathological criteria according to primary
tumor status (<T4 vs. T4), number of positive lymph
nodes (0 or unknown vs. 1-5 vs. >5), and number of
dissected nodes (0-10 or unknown vs. more than 10).
Patients commenced chemotherapy no earlier than
Does the addition of paclitaxel increase the efficacy

of PCG in this setting compared to GC or MVAC,
when data for the addition of paclitaxel to GC in the
advanced setting are lacking [33]?
Did the stringency of time to commencement
of chemotherapy in this trial contribute to the
difference seen in overall survival?
Given data from several centers suggesting
diminished survival outcomes in patients with
later commencement of chemotherapy compared
to those starting earlier [28], should clinical trials
and clinical practice outside trials mandate
commencement within 8 weeks of surgery?
306
The EORTC-30994 trial accrued patients with pT3-4

and/or lymph node positive urothelial cancer and
with a creatinine clearance greater than 60 mL/min
to either 4 cycles of cisplatin-based combination
of chemotherapy of physician preference (GC,
MVAC, or Dose-Dense MVAC [34]) or chemotherapy
with the same regimen at first relapse [18]. Both
standard M-VAC and GC were given on a 4-week
cycle whereas DD-MVAC was given every 2 weeks.
Patients were stratified by pT stage and number of
lymph nodes dissected. Those patients randomized
to the chemotherapy arm were required to start
treatment within 90 days of surgery. The study was
unique in allowing a range of chemotherapy regimens
including a more intense deliver of cytotoxic drug
with DD-MVAC. The accrual target was 660 patients
but this trial also closed prematurely in June 2008
due to slow accrual after accruing 278 patients.
chemotherapy but may be key in planning studies

with an initial phase II accrual in the adjuvant setting
before expanding to a larger phase III cohort of
disease-free survival and toxicity endpoints are met.
f) Biomarkers and Other Indicators of Potential

Adjuvant Chemotherapy Benefit
The literature is beset with multiple analyses of
individual markers of outcome after cystectomy.
p53 aberrance, cycle cell gene dysregulation, and
presence of lymphovascular invasion identify patients
with low risk (<pT2) disease who are at heightened
risk of relapse (36-38). Recent attempts have been
made to link these markers with systemic therapy
interventions. In the p53 M-VAC trial, patients were
screened for p53 abrogation and randomized to
either 3 cycles of M-VAC or observation [39]. The
trial was closed due to futility contingent upon
slow accrual and low event rate. The final analysis
did not demonstrate an advantage for M-VAC
chemotherapy in patients whose tumors contained
abnormal p53, in fact those patients had a nonsignificant trend to a higher relapse and death rate
with chemotherapy. This result proved disappointing
and once again highlighted the difficulty of running
trials at the adjuvant interface in bladder cancer.
Current biomarker efforts led by the International
Bladder Cancer Consortium are directed at large
scale tissue microarray construction and analysis for
putative markers of chemotherapy response such
as ERCC1 (platinum drugs) [40-43], ribonucleotide
reductase (gemcitabine) [44, 45], topoisomerase II
(doxorubicin, epirubicin) [46, 47], and beta-tubulin
(taxanes) [45, 48, 49]. Hopefully, these studies
will delineate relationships between markers and
therapies as well as defining magnitude of effect to
help power those studies. Targeted monoclonal and
small molecule agents remain of interest in urothelial
cancer and a focus of studies that will attempt to
treat patients that have the target present in their
tumor and therefore are more likely to respond.
A further meta-analysis incorporating individual

patient data from the Italian multicentric, Spanish
Urologic Oncology Group and EORTC-30994 trials
was prospectively planned and will proceed once
data from each trial becomes mature.
e) Data from Larger Cohort Studies

A recent collaborative effort between 11 major
centers has yielded an international cohort analysis
of off trial adjuvant chemotherapy [19]. Patients were
grouped into quintiles based on risk characteristics
for relapse and death and chemotherapy impact
assessed across the cohort as a whole but also within
each risk segment. The cohort consisted of 3947
patients undergoing cystectomy and lymph node
dissection between 1979 and 2008, 932 (23.6%) of
whom received adjuvant chemotherapy; the largest
analysis of an adjuvant chemotherapy cohort to
date. Adjuvant chemotherapy was independently
associated with improved survival (hazard ratio,
0.83; 95% CI 0.72-0.97%, P=0.017). Significantly,
risk group predicated the survival impact of
chemotherapy on outcome. Increasing benefit from
adjuvant chemotherapy was seen across higherrisk subgroups (P<0.001), especially in those with
extravesical extension or nodal involvement. There
was a significant improvement in survival between
the treated and non-treated patients in the highestrisk quintile (hazard ratio, 0.75; 95% CI 0.62-0.90;
P=0.002). This group was characterized by an
estimated 32.8% 5-year probability of cancer-specific
survival, with 86.6% of patients having both stage
T3 or greater and nodal involvement. These data
may be useful in stratifying and selecting patients for
future studies.
Summary
The body of evidence supports the use of
perioperative chemotherapy, however, the best
evidence is for neoadjuvant rather than adjuvant
therapy. Several studies have suggested a 5-15%
absolute advantage for chemotherapy in the
postoperative setting. Given the small incremental
benefit to adjuvant chemotherapy, the demonstration
of a survival advantage may take a trial with several
thousand patients unless patients accrued can be
stratified for risk: benefit by clinical or pathological
parameters and/or biomarkers predictive of relapse
risk and/or chemotherapy benefit. The optimal
timing and intensity of chemotherapy in the adjuvant
setting remains to be determined. Accrual to trials
of adjuvant therapy in urothelial cancer represents a
major challenge.
Analysis from the same group of investigators

suggests that 2- and 3-year disease-free survival
after cystectomy is a strong surrogate for 5-year
overall survival [35]. This surrogacy needs to be
tested in prospective cohorts treated with adjuvant
307
Recommendations
9. Sternberg CN, Donat SM, Bellmunt J, et al. Chemotherapy

for bladder cancer: treatment guidelines for neoadjuvant
chemotherapy,
bladder
preservation,
adjuvant
chemotherapy, and metastatic cancer. Urology. 2007;69(1
Suppl):62-79.
Adjuvant
cisplatin-based
chemotherapy
is
supported by a recent large cohort analysis (LE:
2A), several relatively small randomized clinical
trials (LE: 1B), and the results of a meta-analysis
and composite analysis or randomized trials (LE:
1A). However, the consensus in the writing group
is that the trials used in meta-analyses were flawed
so as to make definitive conclusions difficult. On
that basis, the group provides a Grade B level
of recommendation for adjuvant cisplatin-based
chemotherapy in the patient with pT3/4 and/or
lymph node positive cancer at cystectomy, who
has not had neoadjuvant chemotherapy and is
medically fit.
10. Miles BJ, Fairey AS, Eliasziw M, et al. Referral and treatment
rates of neoadjuvant chemotherapy in muscle-invasive
bladder cancer before and after publication of a clinical
practice guideline. Can Urol Assoc J. 2010;4(4):263-7.
11. Bellmunt J, Orsola A, Maldonado X, Kataja V, Group EGW.
Bladder cancer: ESMO Practice Guidelines for diagnosis,
treatment and follow-up. Ann Oncol. 2010;21 Suppl
5:v134-6.
12. Canter D, Long C, Kutikov A, et al. Clinicopathological
outcomes after radical cystectomy for clinical T2 urothelial
carcinoma: further evidence to support the use of
neoadjuvant chemotherapy. BJU Int. 2010;107(1):58-62.
13. Svatek RS, Shariat SF, Novara G, et al. Discrepancy
between clinical and pathological stage: external validation
of the impact on prognosis in an international radical
cystectomy cohort. BJU Int. 2011.
Adjuvant regimens not containing cisplatin

(including those containing carboplatin) should
not be routinely used outside of clinical trials
because of a lack of evidence for their benefit in
that setting. We therefore offer GR against use
of non-cisplatin containing regimens. Patients
who cannot tolerate cisplatin-based combination
therapy should be observed unless a clinical trial
is available.
14. Ruggeri EM, Giannarelli D, Bria E, et al. Adjuvant

chemotherapy in muscle-invasive bladder carcinoma:
a pooled analysis from phase III studies. Cancer.
2006;106(4):783-8.
15. Advanced Bladder Cancer Meta-analysis C. Adjuvant
chemotherapy for invasive bladder cancer (individual patient
data). Cochrane Database Syst Rev. 2006(2):CD006018.
Until the current equipoise is resolved for adjuvant

chemotherapy in this setting, clinical trial remains
the best choice for patients with locally advanced
bladder cancer.
16. Paz-Ares LG, Solsona E, Esteban E, et al. Randomized

phase III trial comparing adjuvant paclitaxel/gemcitabine/
cisplatin (PGC) to observation in patients with resected
invasive bladder cancer: Results of the Spanish Oncology
Genitourinary Group (SOGUG) 99/01 study. J Clin Oncol,
ASCO Annual Meeting Proceedings. Chicago, IL; 2010:
Abstr LBA4518.
17. Cognetti F, Ruggeri EM, Felici A, et al. Adjuvant
chemotherapy (AC) with cisplatin + gemcitabine (CG)
versus chemotherapy (CT) at relapse (CR) in patients (pts)
with muscle-invasive bladder cancer (MIBC) submitted to
radical cystectomy (RC). An Italian multicenter randomised
phase III trial. J Clin Oncol, ASCO Annual Meeting
Proceedings. Chicago, IL; 2008: abstr 5023.
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in non-small-cell lung cancer associated with beta-tubulin
gene mutations. J Clin Oncol. 1999;17(6):1786-93.
50. Skinner DG, Daniels JR, Russell CA, et al. The role of
adjuvant chemotherapy following cystectomy for invasive
bladder cancer: a prospective comparative trial. J Urol.
1991;145(3):459-64; discussion 464-7.
34. Sternberg CN, de Mulder P, Schornagel JH, et al. Seven

year update of an EORTC phase III trial of high-dose
intensity M-VAC chemotherapy and G-CSF versus classic
M-VAC in advanced urothelial tract tumours. Eur J Cancer.
2006;42(1):50-4.
V. Perioperative Radiotherapy
Adjuvant and neoadjuvant radiotherapy for muscleinvasive and locally advanced bladder cancer were
performed in the 1970s and 1980s of the last century
without many convincing results [1]. However, use
of modern radiotherapy in combination with surgery
resulted in prospective randomized clinical trials
or case-control studies which improved the local
control rate, frequency of distal metastases, and
overall survival in patients with locally advanced
bladder cancer [1] (level of evidence: 2b, grade of
recommendation: B)
35. Sonpavde G, Khan MM, Lerner SP, et al. Disease-free

survival at 2 or 3 years correlates with 5-year overall
survival of patients undergoing radical cystectomy for
muscle invasive bladder cancer. J Urol. 2011;185(2):45661.
36. Esrig D, Elmajian D, Groshen S, et al. Accumulation of
Engl J Med. 1994;331(19):1259-64.
37. Shariat SF, Chade DC, Karakiewicz PI, et al. Combination
bladder cancer. J Urol. 2009;183(1):68-75.
309
1. Background
to freedom from distant metastasis (67% vs. 54%),

disease freedom (59% vs. 47%), and overall survival
(52% vs. 40%) although these differences did not
reach statistical significance. It has to be considered
that 65% of the T3b patients in the cystectomy
only group received systemic chemotherapy so
that the results might be better than expected. In
a further analysis of the patients data, Pollack et
al [8] identified pretreatment hemoglobin, blood
urea nitrogen, and preoperative radiotherapy as
the only independent predictors of local control.
Similar results were reported by Pollack et al [8]
in an additional analysis of the patient cohort who
identified pathological response (p<0.0001), clinical
stage (p<0.01), hemoglobin level (p<0.02), pathologic
complete response (p<0.05) and BUN concentration
(p<0.05) to be significantly associated with the pelvic
control rate. Restricting the analysis to pretreatment
parameters only, clinical stage, hemoglobin, BUN
level, and sex were predictive factors of pelvic
control. Pathologic response and tumor size were
independent predictive factors associated with
overall survival and pretreatment hemoglobin and
tumor size were the only factors associated with a
long-term disease-free status.
Radical cystectomy with urinary diversion represents

the treatment of choice for muscle-invasive bladder
cancer according to the most recent guidelines.
However, especially for patients with locally
advanced disease, the survival rates are dismal at
19-59% and 9-49% for patients with pT3 and pT4
disease, respectively [2, 3]. Although the causes
of failure are mainly distant metastases, local
recurrences are described in 23-51% of the cases.
In one series, rates of local recurrences were 6%,
18%, and 51% in patients with stage pT1, pT2,
and pT3 disease, respectively [4]. In another series
11%, 23%, and 31% of the patients developed local
recurrences within 5 years after radical cystectomy
[5]. The considerably high rate of local failures in
the various stages of bladder cancer suggests the
presence of residual micrometastasis in the pelvis,
either in the remaining pelvic lymph nodes or at
the site of the tumor bed. The median time to local
recurrence was 7=12 months whereas the median
time to the development of distant metastases was
16-20 months suggesting that local recurrences
might precede distant metastases [4-7]. It has been
demonstrated in some studies that local failures
besides pT stage and nodal metastases represent
an independent predictor of distant metastasis.
Furthermore, it has been shown that the presence
of local recurrences is associated with a poor
outcome and a median survival of 5-8 months
[4-7]. Based on these data, it seems reasonable to
sterilize microscopic metastasis or residues either by
preoperative or postoperative radiation therapy.
In another retrospective study, Granfors et al [9]

compared the outcome of 90 and 97 patients with
muscle-invasive bladder cancer who received
or did not receive neoadjuvant radiation therapy,
respectively. Neoadjuvant radiotherapy resulted in a
significant downstaging effect so that 7% and 57% of
patients without and with radiotherapy demonstrated
pT0 disease in the radical cystectomy specimen.
Among cT3 tumors, 0% and 56% of the patients
without and with radiotherapy achieved pT0 disease.
The progression-free survival was significantly
longer for patients who underwent neoadjuvant
radiotherapy (p<0.001); the disease-specific survival
time of patients with cT3 disease was significantly
higher after neoadjuvant radiotherapy as compared
to cystectomy alone (p = 0.007).
2. Preoperative Radiotherapy
Preoperative radiation therapy was used in the
1970s. However, conflicting results have been
produced over the years so that the concept of
preoperative radiotherapy to prevent intraoperative
tumor cell seeding and to eradicate microscopic
metastasis in the perivesical fat was not introduced
in daily routine.
b) Prospective Studies
a) Retrospective Studies
So far only 6 prospective randomized clinical trials

have been published with only one trial demonstrating
a statistically significant difference in the 2-year
disease-free survival [10-14].
Cole et al [8] and Pollack et al [8] published the largest

retrospective series on preoperative radiotherapy
and cystectomy versus cystectomy alone in muscleinvasive bladder cancer comprising 560 patients of
whom 338 and 232 patients received the combination
treatment of surgery alone, respectively. A mean total
dose of 49.3 Gy at 2 Gy per fraction was delivered 4
to 6 weeks prior to cystectomy. The median followup was 91 months and 54 months in the radiation
and the cystectomy alone groups, respectively. The
5-year local control rate in patients with stage T3b
was significantly improved in the radiation group
with 91% as compared to the cystectomy group
with 72% (p=0.03). Patients with T3b disease also
demonstrated a better 5-year outcome with regard
In one of the first trials, Slack et al [11] analyzed

the outcome of 234 patients with muscle-invasive
bladder who underwent preoperative radiotherapy
with 45 Gy and who underwent radical cystectomy
30 days after radiotherapy. The 5-year survival after
preoperative radiotherapy was 55% as compared to
only 32% in the cystectomy-only group. In another
prospective trial, Awwad et al [12] compared the
outcome of 36 and 17 patients with cT3 carcinoma
in bilharzial bladders who underwent preoperative
radiotherapy with 40-41 Gy followed by radical
310
cystectomy as compared to radical cystectomy. The

authors identified a significant 2-year survival benefit
of 53% in the radiotherapy group versus 19% in the
cystectomy group. However, the trial has several
drawbacks: (1) only patients with T3 disease were
included, (2) the patient numbers were small with only
53 recruited patients, and (3) patient numbers per arm
were not equally distributed, and (4) squamous cell
carcinoma of the bladder might have another clinical
course than urothelial cancer. Anderstrom et al [13]
evaluated the prognosis of a group of 44 patients
with cT1-3a urothelial bladder cancer of whom 22
received preoperative radiotherapy with 32 to 54 Gy.
The 3- and 5-year survival rates were 81% and 61%
in patients without radiotherapy and they were 81%
and 75% in patients with radiotherapy. Patients with
a complete response after radiotherapy (pT0) had
the best prognosis. Ghoneim et al [14] prospectively
randomized 93 patients with cT1-T4 bilharzial
bladder cancer to receive preoperative radiotherapy
with 20 Gy followed by radical cystectomy versus
cystectomy alone. After a minimum follow-up of 5
years, there was no statistically significant difference
between both groups with survival rates of 39%
and 32%. In the most recent study, Smith et al [15]
randomized a group of 140 patients with invasive
bladder cancer or rapidly recurring superficial high
grade tumors to receive 20 Gy of pelvic radiation
followed by cystectomy within 1 week or cystectomy
alone. The 5-year survival rate was 53% in the
combination group versus 43% in the cystectomy
group (p=0.23).
on the frequency and type of complications following

preoperative radiotherapy. Tomic et al [18] analyzed
the outcome of 103 patients who underwent radical
cystectomy after preoperative radiotherapy and
they observed intestinal complications in 39% of the
patients with an overall mortality rate in intestinal
complications in 3.3% of the cases. Reisinger et
al [19] described a 37% frequency of intestinal
complications with 67% of the patients requiring
salvage surgery and 20% of the patients dying
due to these complications. Cole et al [8] describe
a 2-month mortality rate of 3.6% which was higher
than the 2.1% rate in the cystectomy-only group.
However, the authors do not provide any long-term
data on treatment-associated complications and
mortality.
d) Postoperative Radiotherapy
c) Morbidity of Preoperative (Neoadjuvant)

Radiation Therapy
Postoperative radiotherapy has the benefit that the

group of patients who might benefit from radiotherapy can be better identified as compared to preoperative radiotherapy. Postoperative radiotherapy,
however, bears the significant problem that 2 doselimiting tissues are present in the pelvis: the intestinal epithelium on one hand, including intact loops of
bowel and also those of an orthotopic neobladder,
and the late responding connective tissues around
the anastomosis of the ureter, the urethra, and the
pelvis. In some reports, the frequency of radiation-induced obstruction of the small bowel was as high as
37% with 25% and 10% of the patients who required
surgery or died, respectively [19]. There are no prospective randomized clinical trials of postoperative
radiation therapy in patients with muscle-invasive
urothelial cancer of the bladder available. The only
prospective randomized clinical trial has been performed in patients with muscle-invasive carcinomas
in bilharzial bladders [20]. In this trial, 236 patients
with locally advanced cT3a to cT4 bladder cancer
were included and they received either postoperative radiotherapy multiple daily fractionation (MDF),
using 3 daily fractions of 1.25 Gy each, with 3 hours
between fractions, up to a total dose of 37.5 Gy in
12 days (75 patients); or postoperative radiotherapy
conventional fractionation (CF), for a total dose of 50
Gy/5 weeks (78 patients). Postoperative radiotherapy demonstrated a significant improvement with regard to 5-year disease-free survival which was 49%
and 44% for hyperfractionated and conventional
postoperative radiotherapy as compared to 25% for
cystectomy alone. The therapeutic benefit of postoperative irradiation was consistent for all tumor types,
histological grades, and pathological stages for both
the disease-free survival and local control in patients
with negative lymph nodes. Patients with nodal metastases demonstrated lower recurrence rates in the
postoperative radiotherapy groups, but this was not
associated with improved disease-free survival.
There are only a few studies available that concentrate
The only retrospective study on adjuvant radiation
A recent meta-analysis pooled the data from 5

randomized trials to compare 3- and 5-year survival
rates between patients who received preoperative
radiation therapy followed by cystectomy versus
patients who were treated by radical cystectomy
alone [16]. The corrected odds ratio was 0.94 (95%
CI 0.57-1.55) indicating a non-statistically significant
result. The clinical trial data achieved with this
meta-analysis do not support a significant role of
preoperative radiotherapy in patients with muscleinvasive bladder cancer, which was confirmed in
another recent systematic review in the role of
radiotherapy in bladder cancer [17]. However, it
is questionable if the data achieved in these trials
can be transferred into modern management of
bladder cancer in the 2000s for several reasons.
All of the randomized trials have been performed in
1970s and the 1980s and none of the trials could
consider modern high-precision techniques such as
intensity modulated radiotherapy or image-guided
radiotherapy. Therefore, there might be space for new
prospective randomized clinical trials in patients with
muscle-invasive bladder cancer without evidence of
distant metastases.
311
therapy in patients with urothelial bladder cancer

was published by Cozzarini et al [22], who analyzed
the oncological outcome of 150 patients. All men
received a total dose of 50 Gy to the pelvis and
achieved a disease-free survival rate and local
control rate of 44.6% and 88.4%, respectively. There
are, however, 3 updated reports from nonrandomized
postoperative radiotherapy studies in patients with
squamous cell and adenocarcinoma of the urinary
bladder [23-25]. The latest update comprised 216
patients who were treated with radical cystectomy
and pelvic lymphadenectomy with (82 patients)
or without (134) postoperative radiotherapy.
Postoperative radiotherapy was given to the whole
pelvis in a dose of 50 Gy/25 fractions over 5 weeks,
and started 4-10 weeks after surgery. Postoperative
radiotherapy improved the disease-free survival
significantly from 33 +/- 6% for cystectomy alone
to 58 +/- 6% for patients receiving postoperative
radiotherapy (P=0.002). The independent prognostic
factors for disease-free survival were the pathological
stage, histological subtypes, nodal involvement, and
the addition of postoperative radiotherapy.
References
1. Zaghloul MS. Adjuvant and neoadjuvant radiotherapy for
bladder cancer: revisited. Future Oncol. 2010 Jul;6(7):117791.
1,054 patients. J Clin Oncol. 2001 Feb 1;19(3):666-75
3. Dhar NB, Campbell SC, Zippe CD, Derweesh IH, Reuther
AM, Fergany A, Klein EA. Outcomes in patients with
urothelial carcinoma of the bladder with limited pelvic lymph
node dissection. BJU Int. 2006 Dec;98(6):1172-5. Epub
2006 Sep 6
4. Greven KM, Spera JA, Solin LJ, Morgan T, Hanks GE. Local
recurrence after cystectomy alone for bladder carcinoma.
Cancer. 1992 Jun 1;69(11):2767-70.
5. Visser O, Nieuwenhuijzen JA, Horenblas S; Members of the
Urological Oncology Working Group of the Comprehensive
Cancer Centre Amsterdam. Local recurrence after
cystectomy and survival of patients with bladder cancer: a
population based study in greater amsterdam. J Urol. 2005
Jul;174(1):97-102
6. Dhar NB, Jones JS, Reuther AM, Dreicer R, Campbell
SC, Sanii K, Klein EA. Presentation, location and overall
survival of pelvic recurrence after radical cystectomy for
transitional cell carcinoma of the bladder.BJU Int. 2008
Apr;101(8):969-72
Recommendations for Preoperative

Radiotherapy
Preoperative radiation therapy prior to radical
cystectomy results in a significant downstaging
effect on muscle-invasive bladder cancer (LE: 3,
GR: C)
7. Pejcic T, Hadzi-Djokic J, Acimovic M, Markovic B,

Maksimovic H, Milkovic B, Kajmakovic B. Local recurrence
of bladder cancer after cystectomy with orthotopic
bladder substitution and ileal conduit. Acta Chir Iugosl.
2007;54(4):63-7.
Preoperative radiation therapy results in a

significantly increased rate of pT0 tumors, which
is associated with a significantly improved local
control rate (LE 2b; GR: C)
8. Cole CJ, Pollack A, Zagars GK, Dinney CP, Swanson DA,

von Eschenbach AC. Local control of muscle-invasive
bladder cancer: preoperative radiotherapy and cystectomy
versus cystectomy alone. Int J Radiat Oncol Biol Phys.
1995 May 15;32(2):331-40
Preoperative radiation therapy should be

delivered with total dose of 49.3 Gy at 2 Gy per
fraction 4 to 6 weeks prior to cystectomy (LE: 2b,
GR 2)
9. Pollack A, Zagars GK, Dinney CP, Swanson DA, von

Eschenbach AC. Preoperative radiotherapy for muscleinvasive bladder carcinoma. Long term follow-up and
prognostic factors for 338 patients. Cancer. 1994 Nov
15;74(10):2819-27.
Preoperative radiation therapy does not result in

a significant survival benefit as compared to radical
cystectomy alone (LE: B, GR: ?)
10. Granfors T, Tomic R, Ljungberg B. Downstaging and survival

benefits of neoadjuvant radiotherapy before cystectomy for
patients with invasive bladder carcinoma. Scand J Urol
Nephrol. 2009;43(4):293-9.
Preoperative radiation therapy might be

associated with an increased risk of postoperative
intestinal complications and patients should be
informed accordingly (LE: 3, GR:C).
11. Blackard CE, Byar DP. Results of a clinical trial of surgery

and radiation in stages II and 3 carcinoma of the bladder. J
Urol. 1972 Dec;108(6):875-8.
12. Slack NH, Bross ID, Prout GR Jr. Five-year follow-up
results of a collaborative study of therapies for carcinoma
of the bladder. J Surg Oncol. 1977;9(4):393-405.
Recommendations for Postoperative

Radiotherapy
13. Awwad HK, Baki HA, El Bolkainy et al. Preoperative

irradiation of T3 carcinoma in Bilharzial bladder. Int J Radiat
Oncol Biol Phys 1979; 5: 787 794
Postoperative radiotherapy cannot be

recommended in patients with urothelial cancer of
the bladder (LE: 3, GR: C)
14. Anderstrm C, Johansson S, Nilsson S, Unsgaard B,

Wahlqvist L. A prospective randomized study of preoperative
irradiation with cystectomy or cystectomy alone for invasive
bladder carcinoma. Eur Urol. 1983;9(3):142-7.
Postoperative radiotherapy with a total dose of

50Gy to the whole pelvis improves disease-free
survival and local control in patients with locally
advanced, lymph node negative adenocarcinoma
of the bladder (LE: 2a, GR: B)
15. Ghoneim MA, Ashamallah AK, Awaad HK, Whitmore WF Jr.

Randomized trial of cystectomy with or without preoperative
radiotherapy for carcinoma of the bilharzial bladder. J Urol.
1985 Aug;134(2):266-8.
312
b) Background
16. Smith JA Jr, Crawford ED, Paradelo JC, Blumenstein B,

Herschman BR, Grossman HB, Christie DW. Treatment
of advanced bladder cancer with combined preoperative
irradiation and radical cystectomy versus radical
cystectomy alone: a phase III intergroup study. J Urol. 1997
Mar;157(3):805-7; discussion 807-8.
TUR monotherapy of invasive bladder cancers has

been discussed in the urologic literature since the
1940s[1]. Multiple groups evaluated the utility of
this approach either in isolation or in combination
with systemically administered poly chemotherapy.
[2-4] Comparing TUR to other standards of the day
including radical cystectomy, radiation monotherapy,
and combination therapy, Henry et al observed that
the 5-year survival rate for patients with T2 tumors
treated by TUR only was 63%.[5] In 1998, Solsona
and coworkers reported the results of a comparative,
non-randomized study of 133 patients with T2-3
bladder cancer treated by TUR. The clinical course
of these patients was compared to a concurrent
group of patients treated by radical cystectomy in
the same center.[6] These investigators reported
that for patients with negative TUR bed biopsies
following initial TUR, disease-specific survival was
equivalent to that observed in the cystectomy group.
Furthermore, patients in the TUR group with negative
muscle biopsies but with carcinoma in situ were found
to respond favorably to intravesical therapy. Herr et
al. reported on a similar experience in 155 patients
treated at a single institution with 10-year follow-up.
[7] Investigators form MD Anderson Cancer Center
reported that while TUR as monotherapy was
effective in appropriately selected individuals with
invasive bladder tumors, this approach was only
applicable to approximately 11% of the patients at
their center presenting with invasive bladder cancers.
[8] Recently, the Valencia group has updated its
experience with 15-year follow-up data. This most
recent report supports the authors contention that
in their hands at least, TUR monotherapy produces
high rates of disease-specific survival across all age
groups treated.[9]
17. Shelley MD, Wilt TJ, Barber J, Mason MD. A metaanalysis of randomised trials suggests a survival benefit for
combined radiotherapy and radical cystectomy compared
with radical radiotherapy for invasive bladder cancer: are
these data relevant to modern practice? Clin Oncol (R Coll
Radiol). 2004 May;16(3):166-71.
18. Widmark A, Flodgren P, Damber JE, Hellsten S, CavallinSthl E. A systematic overview of radiation therapy effects
in urinary bladder cancer. Acta Oncol. 2003;42(5-6):56781.
19. Tomic R, Granfors T, Modig H. Morbidity after preoperative
radiotherapy and cystectomy in patients with bladder
cancer. Scand J Urol Nephrol. 1997 Apr;31(2):149-53.
20. Reisinger SA, Mohiuddin M, Mulholland SG. Combined
pre- and postoperative adjuvant radiation therapy for
bladder cancer--a ten year experience. Int J Radiat Oncol
Biol Phys. 1992;24(3):463-8.
21. Zaghloul MS, Awwad HK, Akoush HH, Omar S, Soliman
O, el Attar I. Postoperative radiotherapy of carcinoma in
bilharzial bladder: improved disease free survival through
improving local control. Int J Radiat Oncol Biol Phys.
1992;23(3):511-7.
22. Cozzarini C, Pelegrini D, Fallini M, et al. Reappraisal of the
role of adjuvant radiotherapy in muscle-invasive transitional
cell carcinoma of the bladder. Int J Radiol Oncol Biol Phys
1999; 45: 221
23. Zaghloul MS, Mohran TZ, Saber RA, Agha N. Postoperative
radiotherapy in bladder cancer. J Egypt Nat Cancer Inst
2002; 14: 161 - 168
24. Zaghloul MS, Nouh A, Nazmy M, Ramzy S, Zaghloul
AS, Sedira MA, Khalil E. Long-term results of primary
adenocarcinoma of the urinary bladder: a report on 192
patients. Urol Oncol. 2006 Jan-Feb;24(1):13-20.
25. Zaghloul MS, El Baradie M, Nouh, Abdel-Fatah S, Taher A,
Shalaan M. Prognostic index for primary adenocarcinoma
of the urinary bladder. Gulf J Oncolog. 2007 Jul;(2):47-54.
VI. Bladder-sparing
Treatments for Localized
Disease
c) Indications
TUR monotherapy is appropriate, based on the
literature cited above, for the treatment of patients
with T2-T3 N0Mx bladder cancer in whom local
endoscopic resection is likely to produce complete
removal of the tumor exclusive of concomitant
non-invasive disease (i.e., CIS). Patients with
locoregional extension of disease as evidenced
by hydronephrosis or lymphadenopathy on axial
imaging are not considered good candidates for this
approach.
1. Transurethral Monotherapy for

the Treatment of Muscle-invasive
Bladder Cancer
a) Level of Evidence Reviewed
To date, no randomized studies have been performed
comparing transurethral resection (TUR) of invasive
(TNM stages T2-T4, No MX) bladder cancer as
monotherapy to other standard of care modalities
such as radical cystectomy or combined modality
therapy. The literature on this subject consists of
a few carefully performed clinical trials that are
observational in nature; these studies are generally
comparative, non-randomized, and uncontrolled
clinical experiences and are consistent at best with
level of evidence 2b, grade B.
c) Surgical Technique
Successful TUR of invasive bladder cancer is
confirmed by negative biopsies of the base and
periphery of the resection bed. In work cited above,
negative confirmatory biopsies correlated with longterm survival in those treated with TUR only.
313
d) Oncologic Outcome
8. Leibovici D, Kassouf W, Pisters LL, et al. Organ preservation

for muscle-invasive bladder cancer by transurethral
resection. Urology 2007;70:473-6.
TUR monotherapy should produce oncologic

outcomes equivalent to radical cystectomy in
appropriately selected patients according to longterm, single institution experiences reported by
Solsona and Herr (see bibliography). Bladder
preservation rates are also high in individuals with
small tumors completely resected with negative
follow-up biopsies.
9. Solsona E, Iborra I, Collado A, Rubio-Briones J, Casanova

J, Calatrava A. Feasibility of radical transurethral resection
as monotherapy for selected patients with muscle invasive
a) The Role of Partial Cystectomy
Partial cystectomy is an alternative form of therapy
for muscle-invasive disease that may be used in a
highly selected cohort of patients [1]. There is only
level 3 or 4 evidence regarding the appropriate use
of partial cystectomy for urothelial disease and it is
the treatment of choice for urachal adenocarcinoma,
which is not the subject of these guidelines. There are
no prospective phase II studies of partial cystectomy
nor are there prospective comparisons or randomized
trials assessing the relative efficacy of partial versus
radical cystectomy or radical transurethral resection
for invasive urothelial cancer.
Recommendations
1. TUR monotherapy is an alternative to radical
cystectomy in appropriately selected (see 2. below)
and counseled patients with T2-T3a N0Mx bladder
cancer (LE 2b, GR: B)
2. Patients most appropriate for this approach have
tumors that:
a. Are small
b. Are completely resectable
c. Have negative tumor bed and periphery
biopsies
A very small subset of patients (<5%) presenting with

muscle-invasive urothelial cancer will be eligible for
partial cystectomy when applying strict criteria. The
principal limiting factor is tumor location which should
be high on the dome or anterior wall away from the
bladder neck. Tumors on the posterior or lateral
walls may also be treated with partial cystectomy
if anatomically accessible [2, 3]. Tumors should be
primary rather than recurrent, and there should be
no CIS on bladder biopsies. A 2 cm circumferential
margin of normal mucosa is recommended and
tumors should be 3 cm or less in diameter.
d. Are not associated with upper tract compromise

(i.e., hydronephrosis)
e. Are not associated with radiographic evidence
of locoregional extension of disease (T3b, N+) at
the time of first treatment
3.
Should be discussed as part of the informed
consent process to patients contemplating
management options for invasive bladder tumors
(TNM Stages T2-3a, N0Mx; LE: 3, GR: C)
Partial cystectomy may also used in patients with a

tumor in a diverticulum in sites other than the dome
and may require ureteral re-implantation in select patients [4]. A recent series studied 39 patients treated
in a variety of ways, including partial cystectomy, for
tumor in a diverticulum [5]. Thirteen patients demonstrated T2 or greater disease and had a 45% 5-year
survival rate. Those patients with Ta and T1 disease
had better long-term survival (83% and 72%, respectively). A few small case series also report the
technical aspects and safety of laparoscopic/robotic
partial cystectomy for urothelial cancer and the use
of cystoscopy for tumor localization and initial identification of resection margins (LE 4C, GR C) [6, 7].
References
1. Flocks RH. The treatment of infiltrating carcinoma of the
bladder by transurethral resection. J Urol 1948;60:244.
2. Flocks RH. Treatment of patients with carcinoma of the
bladder. J Am Med Assoc 1951;145:295-301.
3. Barnes RW, Dick AL, Hadley HL, Johnston OL. Survival
following transurethral resection of bladder carcinoma.
Cancer Res 1977;37:2895-7.
4. Hall RR, Newling DW, Ramsden PD, Richards B, Robinson
MR, Smith PH. Treatment of invasive bladder cancer by
local resection and high dose methotrexate. Br J Urol
1984;56:668-72.
Several recent studies suggest that partial

cystectomy is over-utilized, particularly in nonacademic settings. In a population-based study
in Quebec, 30% of patients with invasive bladder
cancer underwent partial cystectomy over a 22-year
period [8]. Equally concerning is that only 23% of
patients had a pelvic lymphadenectomy and 24%
of patients required a salvage radical cystectomy.
Hollenbeck et al queried the SEER and National
Inpatient Sample databases from 1988-2000 and
5. Henry K, Miller J, Mori M, Loening S, Fallon B. Comparison

of transurethral resection to radical therapies for stage B
bladder tumors. J Urol 1988;140:964-7.
6. Solsona E, Iborra I, Ricos JV, Monros JL, Casanova J,
Calabuig C. Feasibility of transurethral resection for muscle
infiltrating carcinoma of the bladder: long-term followup of a
prospective study. J Urol 1998;159:95-8; discussion 8-9.
7. Herr HW. Transurethral resection of muscle-invasive
bladder cancer: 10-year outcome. J Clin Oncol 2001;19:8993.
314
found that in 2000, partial cystectomy was still

performed in 13-17% of patients and more commonly
in rural, non-teaching, low volume hospitals [9].
More recently, Fedeli and colleagues reviewed the
US National Cancer Database from 2003-2007 and
found a lower utilization that decreased over time
from 10% to 7% [10]. Capitanio et al reviewed the
SEER-9 database from 1988-2004 which included
7243 patients with stages pT1-4 N1-2 M0 disease
treated with partial (22%) or radical cystectomy [11].
They performed a matched analysis utilizing pT and
pN stage, grade, race, age, and year of surgery
and suggested that the use of partial cystectomy
did not undermine long-term cancer control. These
data should be interpreted with caution as within this
same database, 24% of patients did not appear to
have any node dissection and an additional 18% had
only 1-5 nodes removed, suggesting that surgical
quality was less that optimal regardless of the use of
partial or radical cystectomy.
many series in an effort to minimize the risk of wound

implantation, but there is no evidence to support their
routine use (LE 4C, GR C). Despite strict criteria of
cT1 or cT2 disease, 36% were upstaged to pT3 and
12% had node metastases, though only two-thirds of
patients underwent a pelvic lymphadenectomy. Fiveyear recurrence-free and disease-specific survival
probabilities were 62% and 84%, respectively, and
tumor size was the only variable associated with
recurrence. These data support a highly selective
use of partial cystectomy in patients with muscleinvasive bladder cancer (LE 3, GR B)
b) Partial Cystectomy after Neoadjuvant

Chemotherapy
Partial cystectomy has been incorporated into
bladder-sparing protocols after initial neoadjuvant
multi-agent chemotherapy in highly selected patients
with localized tumors. Sternberg et al reported on 13
patients among 104 treated with a bladder sparing
approach in mind who had partial cystectomy [12].
The 5-year survival for this select cohort was 69%.
In a separate report from MSKCC, 115 achieved
cT0 status after neoadjuvant chemotherapy and
28 underwent TUR alone and 15 underwent partial
cystectomy as definitive surgical management with
similar long-term survival of 74% for the combined
group with a median follow-up of 10 years [13]. There
may be a role for partial cystectomy as an alternative
to radical cystectomy following chemoradiation
therapy [14].
Two recent papers describe the contemporary

experiences from Memorial Sloan Kettering Cancer
Center and MD Anderson Cancer Center [2, 4]. The
former series described 58 patients with primary
non-urachal bladder cancer treated from 1995-2001
[4]. This represented 6.2% of patients presenting for
surgical therapy. All but 5 patients had a unilateral or
bilateral pelvic lymphadenectomy and 9 patients had
node metastases. A total of 7 patients had tumor in a
diverticulum. Of 5 patients with a final positive margin,
3 had negative intra-operative frozen sections of
the margins presumably due to sampling error.
On univariate analysis, CIS and multifocality were
associated with non-muscle-invasive recurrence
and lymph node metastases, and positive surgical
margins were associated with advanced recurrence.
CIS and node metastases were independent
predictors of advanced recurrence. Median followup was 31 months and 69% were alive and diseasefree while 22% died of disease.
Recommendations
Highly selected patients with focal invasive
cancers and cT0 or minimal residual disease after
neoadjuvant chemotherapy may be candidates
for bladder sparing with either TUR or partial
cystectomy (LE: 3, GR: C).
References
In the MD Anderson series, 37 patients underwent

partial cystectomy for curative intent between 1982
and 2003 [2]. All patients had pT2 or pT3 disease
and 14% had node metastases. Long-term cancer
control was achieved in 65% with an intact bladder
with a median follow-up of 53 months. Non-muscleinvasive recurrences occurred in 9 (24%) patients
and all were treated successfully. On multivariate
analysis, only pathologic tumor stage was associated
with recurrence-free survival.
1. Malkowicz SB, van Poppel H, Mickisch G, et al. Muscleinvasive urothelial carcinoma of the bladder. Urology. Jan
2007;69(1 Suppl):3-16.
2. Kassouf W, Swanson D, Kamat AM, et al. Partial cystectomy
for muscle invasive urothelial carcinoma of the bladder: a
contemporary review of the M. D. Anderson Cancer Center
experience. J Urol. Jun 2006;175(6):2058-2062.
3. Smaldone MC, Jacobs BL, Smaldone AM, Hrebinko
RL, Jr. Long-term results of selective partial cystectomy
for invasive urothelial bladder carcinoma. Urology. Sep
2008;72(3):613-616.
Smaldone et al reported a single surgeon series of 25

patients operated on over a 10-year period [3]. Their
protocol included 25 Gy of preoperative radiotherapy
delivered to the abdominal wall in 5 fractionated
doses, intraoperative intravesical Thiotepa, and
postoperative 6 weeks of intravesical BCG.
Preoperative radiotherapy and/or intra-operative
intravesical chemotherapy have been reported in
4. Holzbeierlein JM, Lopez-Corona E, Bochner BH, et al. Partial

cystectomy: a contemporary review of the Memorial SloanKettering Cancer Center experience and recommendations
for patient selection. J Urol. Sep 2004;172(3):878-881.
5. Golijanin D, Yossepowitch O, Beck SD, Sogani P, Dalbagni
G. Carcinoma in a bladder diverticulum: presentation and
treatment outcome. J Urol. Nov 2003;170(5):1761-1764.
6. Nerli RB, Reddy M, Koura AC, Prabha V, Ravish IR,
315
achieving local tumor control and patients are often

cured by contemporary cystectomy with major series
reporting 5-year pelvic control rates of 80-90%
and 5-year overall survival rates from 40% to 60%
[1-5]. It is this standard that treatment with bladderpreserving strategies must meet.
Amarkhed S. Cystoscopy-assisted laparoscopic partial

cystectomy. J Endourol. Jan 2008;22(1):83-86.
7. Mariano MB, Tefilli MV. Laparoscopic partial cystectomy in
bladder cancer -- initial experience. Int Braz J Urol. MayJun 2004;30(3):192-198.
8. Fahmy N, Aprikian A, Tanguay S, et al. Practice patterns
and recurrence after partial cystectomy for bladder cancer.
World J Urol. Aug;28(4):419-423.
Contemporary radiation-based bladder-sparing

therapy algorithms consist of: (1) maximal
transurethral resection of the tumor (TURBT),
(2) induction external beam radiation therapy
with concurrent chemotherapy, (3) cystoscopic
assessment of treatment response with prompt
cystectomy for non-responders, and (4) active
cystoscopic surveillance with a cystectomy at the
first sign of invasive recurrence. These algorithms
were developed as a result of the lack of adequate
local control of muscle-invasive urothelial carcinoma
treated by TURBT, by chemotherapy, or by
radiotherapy when used alone.
9. Hollenbeck BK, Taub DA, Dunn RL, Wei JT. Quality of

care: partial cystectomy for bladder cancer--a case of
inappropriate use? J Urol. Sep 2005;174(3):1050-1054;
discussion 1054.
Database, 2003 to 2007. J Urol. Jan;185(1):72-78.
11. Capitanio U, Isbarn H, Shariat SF, et al. Partial cystectomy
does not undermine cancer control in appropriately
selected patients with urothelial carcinoma of the bladder:
a population-based matched analysis. Urology. Oct
2009;74(4):858-864.
12. Sternberg CN, Pansadoro V, Calabro F, et al. Can patient
selection for bladder preservation be based on response to
chemotherapy? Cancer. Apr 1 2003;97(7):1644-1652.
b) External Beam Radiation Alone with Salvage

Cystectomy Reserved for Tumor Recurrence
13. Herr HW, Bajorin DF, Scher HI. Neoadjuvant chemotherapy

and bladder-sparing surgery for invasive bladder cancer:
ten-year outcome. J Clin Oncol. Apr 1998;16(4):12981301.
From the 1960s through the 1980s, the most common

type of bladder-sparing treatment was external
beam radiation therapy alone. Since the 1980s in the
United States radiation treatment has generally been
reserved for patients judged too unfit for cystectomy
on the basis of comorbid conditions or due to
disease extent. These negative selection criteria
may have contributed to the relatively poor results
achieved with radiation therapy alone compared
to cystectomy (see Table 5). Approximately 1015% of patients are excluded from treatment by
radical cystectomy at the time of operation because
previously unrecognized unresectable tumor spread
is found. Thus in cystectomy series, but not radiation
series, some of the patients with advanced local
spread tumor are excluded so this may be another
selection bias favoring cystectomy.
14. Koga F, Kihara K, Fujii Y, et al. Favourable outcomes of

patients with clinical stage T3N0M0 bladder cancer treated
with induction low-dose chemo-radiotherapy plus partial
or radical cystectomy vs immediate radical cystectomy: a
single-institutional retrospective comparative study. BJU
Int. Jul 2009;104(2):189-194.
3. Radiation-based Bladderpreserving Strategies: Radiation

Alone or Combined with Other
Modalities
a) Introduction
The treatment options for muscularis propria-invasive
bladder tumors can broadly be divided into those
that involve removal of the bladder and those that
spare it. There is a big difference among countries
in the path of care that they most often use to treat
these patients. For instance, in the United States
only a minority of the patients are offered radiation
therapy. However, in the United Kingdom, 60% of
eligible patients receive radical radiation therapy,
with surgery reserved for failures. The treatment of
many other cancers in North America, Europe, and
around the world, include organ-preserving therapy
as the, or one of the, current standards of care
for malignancies of the breast, larynx, anus, head
and neck, soft tissues (sarcoma), and prostate. In
each case, radical surgical extirpation can often
be avoided without compromising patient survival.
Improved radiotherapy techniques combined
with an enhanced understanding of the optimal
chemotherapeutic regimens have promoted multimodality therapy in selected patients with muscleinvasive bladder cancer as a viable alternative to
radical surgery alone. Cystectomy is effective in
In the 1960s, the Cooperative Surgical Adjuvant

Bladder Study group randomized 475 patients
with Stage T2-T4a bladder cancer to preoperative
radiation therapy (45 Gy) followed by open surgery
or surgery alone [13]. The study was large but
compromised by incomplete data collection and
follow-up. Of the 138 patients who completed
preoperative radiation therapy and surgery on
protocol, 34% had a complete pathologic response
of their bladder tumor (stage pT0). Furthermore,
those with a complete pathologic response at radical
cystectomy had a survival advantage of 55% versus
32% compared to those who had residual tumor at
the time of cystectomy. This led in the 1970s to 4
randomized trials comparing external beam radiation
therapy alone (60 Gy) with radical cystectomy
reserved for local recurrence to the standard group
receiving preoperative radiation therapy (40-50
Gy) with immediate radical cystectomy [6,10,14]
316
(Table 6). Three of these trials showed equivalent

overall survival with either approach. These studies
give Level 1b evidence that a bladder-preserving
approach with radiation therapy alone and salvage
radical cystectomy for local recurrence was not
significantly different in overall survival in this preneobladder era.
salvage cystectomy for the non-responders were

studied. The randomized trial from the United
Kingdom studied accelerated (twice-daily) radiation
monotherapy in 229 patients with muscle-invasive
urothelial carcinoma treated with radiation therapy
alone [15]. There was no advantage with the twicedaily schedule over the conventional once-daily
radiation schedule, and acute bowel and bladder
toxicities were higher. The biological rationale
underlying accelerated fractionation radiation therapy
in bladder cancer therefore remains unproven. Thus,
off protocol, the oncedaily radiation treatments
remain entirely reasonable.
Alternative radiation therapy fractionation schemes,

including the use of twice-daily radiation with the
potential advantage of improved biological effect to
better control of rapidly proliferating tumors, and with
the practical advantage of a more rapid completion
of radiation therapy and thus a shorter interval to
Table 5. (Section 5.3) Results of radical radiation therapy alone (Monotherapy): Muscle-Invading
Bladder Cancer
Study
M.D. Anderson Cancer Center [6]
National Bladder Cacer Group a
Eudinburgh [7]
London Hospital [8]
Princess Margaret Hospital [9]
Danish National Study [10]
Norway [11]
UK Cooperative Group [12]
Number
32
35
889
182
121
95
308
91
T2
40%
46%
59%
38%
5-year survival rates

T3(T4a)
All Stages
26%
35%
39%
23%
14%
28%
40%
36%
40%
45%
24%
SD Cutler, National Cancer Institute, Unpublished observations, 1983.

Modified from Zietman et al. Organ-Conserving approaches to muscle-invasive bladder cancer: future alternatives
to radical cystectomy. Ann Med 2000;32: 42-47
a
Table 6. (Section 5.3) Five year survival data from four randomized trials comparing preoperative radiation therapy (40-50 Gy) with immediate cystectomy to radiation therapy alone (60 Gy) with salvage
cystectomy recurence.
Study
No. of patients
5-year
Survival with
Pre-op RT and
cystectomy
(%)
Satistical
Significance
39
5-year
Survival with
RT and
Salvage
cystectomy
(%)
28
Urologie
Cooperative\
Group, UK
[14]
Danish
National
Cancer Group
[10]
National
Bladder
Cancer Group
(a)
MD Anderson
Cancer Center
[6]
189
183
29
23
none
72
27
40
none
67
45
22
significant
RT = radiation therapy
(a) SD Cutler, National Cancer Institute, unpublished observations, 1983
317
Notes
none
Large
T3
tumors
included
c) External Beam Radiation Therapy Combined

with Other Modalities and with Salvage
Cystectomy for Recurrence
of chemotherapy and radiation therapy combined

with TURBT. A study of 104 patients treated with
TURBT and M-VAC showed a T0 tumor response
rate of 49% and in these 52 patients the 5-year
survival rate was 67% [26]. However, 66% of the
104 patients required radical cystectomy, suggesting
a relatively low local bladder tumor control with
chemotherapy and TURBT alone. As described
below, modern trimodality therapy combining
radiation and chemotherapy with TURBT has led to
substantially higher T0 tumor response rates (6487%) and lesser need for salvage cystectomy. This
has tempered further interest in the treatment with
only chemotherapy and TURBT.
By the late 1980s, single institutions reported the

combination of a visibly complete TURBT followed
by radiation therapy lead to improved local control
[16, 17]. By 1994, the group from the University of
Erlangen referred to the visibly complete TURBT,
when followed by a tumor bed negative biopsy, as
an R0 resection [17]. The importance of the visibly
complete TURBT was also seen in many subsequent
cooperative group trials using radiation concurrent
with chemotherapy such as in RTOG 89-03 [18].
Combining external beam radiation beam therapy
with brachytherapy (for the delivery of precision
partial bladder radiation therapy) has been used by
some groups in Holland, Belgium, and in France.
Brachytherapy is done by an open cystotomy with
an implant using iridium-192 as low dose rate
irradiation to doses of 40 Gy combined with external
beam radiation doses of 30 Gy. The majority of the
reported series include patients who first underwent
maximal tumor resection by either partial cystectomy
or an open TURBT. The approach is reserved for
patients with solitary bladder tumors less then 5 cm
in diameter. The 5-year survival rates reported are
from 62-84% with a disease-specific survival rate
approaching 80% [19-21].
A second randomized trial comparing radiation

alone to radiation plus concurrent chemotherapy
with 5-fluorouracil (5-FU) and mitomycin C (MMC)
has been reported by a multi-center group led
from Birmingham, England, involving 360 patients.
The results showed no measurable differences in
toxicities. There was a significant increase in pelvic
disease-free rates at 2 years (67% free of recurrence
compared to 54% with radiation alone, P=0.02) and
at 5 years (62% and 51% respectively) [28]. The fiveyear overall survival rate was increased from 35% to
51%. Seventy-five percent of the patients treated
with 5-FU and MMC concurrent with radiation
therapy reported no late side effects. Of the 25%
who did report side effects, fewer then 5% reported
them as serious. Patients on this protocol underwent
urologic evaluation of their bladder capacity before
and after treatment. There was a median reduction
in bladder capacity of 10%, which was the same in
both groups.
1. E
xternal Beam Radiation Combined with
Concurrent Radiosensitizing Chemotherapy
Encouraging results were obtained when cisplatin
was first made available by the NCI to the National
Bladder Cancer Group in the early 1980s for
were unsuitable for radical cystectomy. In a protocol
combining the use of concurrent cisplatin with
conventional doses of radiation was carried out from
1981 to 1986 in 68 patients with muscle-invasive
bladder cancer, 64% of patients with clinical stage
T2 tumors and 22% of those with clinical stage
T3-T4a disease had long-term survival rates [22].
These promising findings of combining cisplatin
with radiation led to a randomized trial of radiation
therapy with or without concurrent cisplatin [23] in
99 patients with clinical stage T3 muscle-invasive
bladder cancer conducted by the National Cancer
Institute of Canada. This trial showed a significant
improvement in pelvic tumor local control at 5
years in patients treated with cisplatin and radiation
therapy (68%) versus radiation therapy alone (47%).
Similarly, early prospective studies at the MSKCC
that combined chemotherapy and TURBT resulted
in T0 tumor response rates nearly twice that of
chemotherapy alone, but these rates were less than
50% [24,25]. The results of combining TURBT with
chemotherapy but without radiation have not been as
successful in organ-preservation as the combination
Cooperative group and single institution trials

with concurrent chemotherapy and radiation
combined with TURBT. Over the last 25 years,
single institutions in North America and Europe and
multi-institutional cooperative groups including the
Radiation Therapy Oncology Group (RTOG) and the
Southwestern Oncology Group (SWOG) have enrolled
over 1000 patients with muscle-invasive bladder
cancer in bladder-preserving protocols. Several
variables have been tested including evaluating
more than cisplatin alone as the radiation-sensitizing
chemotherapy and evaluating alternative radiation
schemes. Beginning in the late 1980s some single
institutions and the RTOG were studying neoadjuvant
chemotherapy in addition to trimodality therapy for
the operable patients with muscle-invasive bladder
cancer (Table 7). Encouraging results led to the
opening of RTOG 8903, a Phase III trial comparing
neoadjuvant MCV chemotherapy, or not, prior to
concurrent cisplatin and radiation. This study was
closed prematurely after accrual of 123 of the planned
174 patients because there was an unexpectedly
high rate of leukopenia in the MCV arm [18]. With
a median follow-up of 5 years, the overall survival
rate was 48%, and was 49% in patients who were
318
Table 7. (Section 5.3) Results of tri modality treatment for muscle-invasive bladder cancer for selective
bladder preservation
5-year
survival
with intact
bladder
(%)
Study
loention
Multimodality therapy
used
Number of
patients
5-year
overall
survival
(%)
TURBT, MCV, external

beam
radiation + cisplatin
91
62 (4 yr)
44 (4 yr)
RTOG 8802
Tester et al.
[29]
TURBT, 5-FU, external

beam
120
63
NA
University of
Puris
Housset et.
[30]
TURBT, +/- MCV,

external beam
123
49
38
RTOG 8903
Shipley et al.
[18]
TURBT, external beam

radiation + cisplatin,
carboplatin, or 5-FU
and cisplatin
415
50
42
University of
Erlangen
Rodel et al.
[31]
TURBT, external beam

radiation + TAX and
cisplatin, adj. CEM
and cisplatin
80
56
47
RTOG 9906
Kaufman et al.
[32]
TURBT, MCV, external

beam
348
52
44
MGH
Efstathiou et
al. [33]
References
TURBT, transurethral resection of bladder tumor; tumor, 5-FU, 5-fluorouracil; MCV, methotrexate, cisplatin, vinblastine, TAX pactiaxel; GEM gemcitabine; RTOG, Radiation Therapy Oncology Group, MGH, Massachuscits General
Hospital; NA, not available.
randomized to the neoadjuvant MCV arm. Likewise,

there was no statistically significant difference in the
T0 tumor response rate, distant metastasis, or the
5-year survival with an intact bladder. Two European
phase III trials have studied the role of neoadjuvant
chemotherapy before radiation alone. The Danish
Group [36] treated patients with muscle-invasive
bladder cancer with neoadjuvant chemotherapy
before radiation and showed an insignificant 5%
decrease in 5-year survival compared to patients
treated with radiation alone (19% v. 24%). The
other phase III trial led in the United Kingdom by
the MRC Group studied neoadjuvant MCV before
radical radiation or radical cystectomy (34-35). In
the radical radiation sub-group of 415 patients, there
was an insignificant trend to better survival in those
treated with neoadjuvant MCV than those treated
with radiation alone. A meta-analysis of those 2
trials showed no significant difference in survival
(30.4% vs. 28.1%, P=0.334) with the addition of the
neoadjuvant chemotherapy [37].
therapy was reserved for those patients who had

a complete clinical response at the mid-point of
concurrent chemoradiation after radiation dosage of
40 (Gy). These patients then received consolidation
with additional chemotherapy and radiation for the
total dose of 64-65 Gy. Incomplete responders were
advised to undergo a radical cystectomy as were
patients whose invasive tumors recurred after the
full 64-65 Gy treatment. All patients were treated with
an aggressive TURBT, which was visibly complete
in 66% of patients. All patients were treated with
cisplatin concurrently with radiation therapy. With
the median follow-up for all surviving patients of 7.7
years, the 5-year, 10-year, and 15-year actuarial
overall survival rates were 52%, 35%, and 22%,
respectively (stage T2, 62%, 43%, and 28%; stage
T3-T4a, 41%, 27%, and 16%). The 5-year, 10-year,
and 15-year disease-specific survivals was 64%,
59%, and 57% (stage T2, 74%, 67%, and 63%; stage
T3-T4a, 53%, 49%, and 49%). The disease-specific
survival rates stratified by clinical stage are shown
in Figure 4, which demonstrates that there were
very few late recurrences at least up to 15 years.
These results are similar to those in contemporary
cystectomy series. In this series, the 5-year, 10year, and 15-year disease-specific survival for the
The Massachusetts General Hospital experience with

348 patients with muscle-invasive bladder cancer
who were entered on the successive prospective
trimodality protocols from 1986-2002 have recently
been updated [33]. Bladder-sparing trimodality
319
TURBT
Induction radiation and concurrent

chemotherapy
Repeat cystocopy with

transurethral biopsy
Complete Response
Incomplete Response
Consolidation chemotherapy and

radiation # adjuvant
chemotherapy AND long-term
cystoscopic surveillance
Radical cystectomy # adjuvant

chemotehrapy
Recurrent tumor
Figure 3. Current Schema for Trimodality Treatment of Muscle-invasive Bladder Cancer With Selective
Bladder Preservation.
Figure 4. Long-term Disease-specific Survival with Selective Bladder Preservation from the Massachusetts
General Hospital Experience (33).
320
102 patients undergoing cystectomy were 55%,

44%, and 44%, respectively. This indicates the
very important contribution of prompt cystectomy
for disease control in patients whose tumors recur.
A recent evaluation of patients undergoing salvage
cystectomy at the Massachusetts General Hospital
over these years indicates quite acceptable surgical
morbidity or mortality compared to major primary
cystectomy series. (Eswara & Heney, submitted
2010).
patients with tumors pathologic stage pT2-pT4, the

5-year overall survival rate was 36%[2]. The actuarial survival rate of all 269 patients with pathologic
stages ranging from pT0 to pT4 in this series was
45%. These results are similar to the Massachusetts
General Hospital Series [33] as well as those from
University of Erlangen (17,31) and RTOG [18]. The
similarity in survival is likely in part to the prompt use
of cystectomy when necessary for recurrence in the
bladder-preservation series.
d) Comparison of Survival Outcomes Following

Curative Therapy in Contemporary Series
by Cystectomy or by Bladder-preserving
Trimodality
Therapy
with
Cystectomy
Reserved for Recurrence
e) Quality of Life After Radiation-based

Bladder-preserving Therapy for Muscleinvasive Bladder Cancer
The instruments to assess quality of life have
been well established for prostate cancers and
gynecologic cancers, but not for bladder cancer.
The instruments that are currently used for bladder
cancer patients are adaptations and thus their
validity is somewhat uncertain. These studies are
also limited by incomplete sampling of all potential
participants which leaves unclear whether or not the
non-participants are those who have had a worse
outcome or who are the most satisfied. Despite
these limitations, some general principles can be
derived from this literature.
Comparing results of bladder-preserving therapy

to those of contemporary radical cystectomy series
is confounded by the discordance between clinical
staging (TURBT) and pathologic (cystectomy) staging. Clinical staging is more likely to underestimate
the extent of disease with regard to penetration into
the muscularis propria or beyond than is pathologic
(cystectomy) staging [38]. Thus if any favorable outcome bias exists among these selected, it is in favor
of the pathologically-reported cystectomy series. For
patients with muscle-invasive bladder cancer, the
overall survival outcomes following either contemporary radical cystectomy at major single institutions or
by trimodality therapy are shown in Table 8. The University of Southern California reported on 633 patients undergoing radical cystectomy with pathologic
stages T2-T4a with an overall survival rate at 5 years
of 48%, and at 10 years of 32% [1]. The Memorial
Sloan Kettering Cancer Center (MSKCC) contemporary radical cystectomy series showed that in 184
Minimal late pelvic toxicity is certainly required for

successful implementation of a selective bladderpreserving protocol. Long-term bowel and bladder
toxicity after chemoradiotherapy was investigated
in patients enrolled in prospective sequential RTOG
trials (8903, 9506, 9706, and 9906). One study
reported on 157 patients who underwent combined
modality therapy and who survived at least 2 years
from the start of treatment with their bladders intact.
The median follow-up was 5.4 years [39]. Seven
Table 8. (Section 5.3) Muscle-Invasive Bladder Cancer: Survival Outcomes Following Curative Therapy in
Contemporary Series
Series
Cystectomy:
U.S.C.
2001 [1]
M.S.K.C.C.
2001 [2]
SWOF/ECOG/CALGB*#
2002 [3]
Selective Bladder Preservation:
U. Erlangen*
2002 [17,31]
M.G.H.*
2009 [33]
R.T.O.G.
1998 [18]
Stages
Number
pT2-pT4a
633
pT2-pT4a
181
cT2-cT4a
317
cT2-cT4a
326
cT2-cT4a
348
cT2-cT4a
123
* These series include all patients by their intention-t-treat.

# 50% of patients were randomly assigned to receive 3cycles of neoadjuvant M-VAC.
321
Overall Survival
5 year
10 year
48%
32%
36%
27%
49%
34%
45%
29%
52%
35%
49%
--
percent of the patients experienced late grade 3 or

4 pelvic toxicity (5.7% GU and 1.9% GI). In only 1 of
9 patients, did a grade 3-4 GU toxicity persist. This
indicates that rates of late pelvic toxicity for patients
who undergo selective bladder preservation and
retain their native bladder are low.
dissatisfaction with their sexual lives. In the Swedish

and Italian series 38% and 25% of the men retained
functional erections as compared to 15% and 8% of
cystectomy controls. Use of sildenafil by patients in
the MGH series may have been the major reason for
better retained erectile function.
Zeitman and colleagues reported a study on patients

receiving TURBT, chemotherapy, and radiation
in the treatment of the bladder cancers at the
Massachusetts General Hospital (MGH) [40]. Of
221 patients with clinical stage T2-T4a cancer of
the bladder treated at the MGH from 1986-2000, 71
were alive with their native bladders and diseasefree in 2001. These patients were asked to undergo
a urodynamic study (UDS) and to complete a quality
of life questionnaire. Sixty-nine percent participated
in some component of the study with a median time
from the trimodality therapy of 6.3 years. This long
follow-up is sufficient to capture the majority of the late
radiation side effects. Seventy-five percent of patients
have normal functioning bladders by UDS. Reduced
bladder compliance, a recognized complication of
radiation, was seen in 22% of patients. However,
distressing bladder symptoms were seen only in
one-third of these patients. Two women showed
bladder hypersensitivity, involuntary contractions,
and incontinence. The questionnaires showed that
bladder symptoms were uncommon overall in both
sexes. However, 19% of women reported problems
with bladder control, and 11% of them wore pads.
The distress from urinary symptoms was only half as
common as symptom prevalence. Bowel symptoms
occurred in 22% of patients and caused distress in
14%. The majority of men retained sexual function
with or without use of sildenafil. Global healthrelated quality of life was high. The majority of the
patients treated by trimodality therapy therefore
retained good bladder function. It was concluded
that there is a small but detectable level of lasting
bowel dysfunction and distress and that this might
be judged as the additional price that these patients
have to pay to retain their bladders.
f) Translational Research: Prognostic or Predictive Molecular Tumor Markers as Predictors of Response to Radiation Treatment
Tumor suppressor genes such as p53 and pRB
have been studied in detail in bladder cancer, but
both markers have led to contradictory data in the
assessment of risk for disease--progression and
survival [43]. Cell-cycle regulatory proteins p27
and Ki-67 might predict recurrence and disease
progression but are not ready for routine clinical use
[44-46].
The bladder tumors pre-treatment apoptotic index or
altered expression of the RB1 or the BCL2 genes
might alter tumor response to radiation therapy [4749]. RTOG investigated the outcome of 73 patients
treated in 4 RTOG bladder-preserving protocols and
noted that among patients treated with transurethral
surgery and chemotherapy concurrent with radiationaltered expression of p53, CDKN2A, and pRB had no
prognostic significance but overexpression of Her-2
(ERBB2) correlated significantly with a reduced
complete response rate (50% vs. 81%, p=0.026).
The aim of targeted therapies is to interfere with
molecular events related to tumor proliferation [50].
Examples of these therapies are cetuximab, an antiEGFR monoclonal antibody; gefitinib and erlotinib,
EGFR-specific inhibitors; trastuzumab, an antihuman EGFR Type 2 (Her-2)-related monoclonal
antibody; and bevacizumab, a VEGF monoclonal
antibody [51]. Both EGFR and HER-2 are targets
identified on cancer cells, whereas VEGF is a target
that acts on the tumor microenvironment. Studies
have shown reduced complete response rates when
HER-2 is over expressed [51-53]. These results
have led to an ongoing RTOG protocol (RTOG0524) for patients with muscle-invasive bladder
cancer who are not fit for a cystectomy. This phase
I / II trial investigates paclitaxel and daily radiation
therapy with trastuzumab given to patients whose
tumors over express HER-2. This study is one of
the first examples of a molecular targeted therapy
being added to treatment for patients with localized
muscle-invasive bladder cancer. To date 55 patients
have been enrolled with the results still pending.
Recently the group in Leeds and in Oxford in the
United Kingdom, in collaboration with the Ontario
Cancer Institute in Toronto, have evaluated MRE
11 expression in patients with muscle-invasive
bladder cancer treated with radical radiation or with
cystectomy [55]. MRE 11 is one of a panel of DNA
Two cross-sectional questionnaire studies, one

from Sweden and one from Italy, have compared
the outcome following radiation with the outcome
following cystectomy [41-42]. The questionnaire
results for urinary function following radiation are
very similar to those recorded in the MGH study. Over
74% of the patients recorded good urinary function.
Both studies compared bowel function in irradiated
patients with that seen in patients undergoing
cystectomy. In both, the bowel symptoms were
greater for those receiving radiation than for those
receiving cystectomy (10% vs. 3% and 32% vs.
24% respectively), but in neither was this statistically
significant. In contrast to men who had been irradiated
for prostate cancer, the majority of the male bladdersparing patients reported adequate erectile function
(full or sufficient for intercourse) and only 8% reported
322
damage signaling proteins active in the process of

DNA double strand break repair. DNA double stand
breaks are the most lethal form of injury produced
by ionizing radiation and by some chemotherapy
agents. MRE 11 had been singled out as one
possible predictor of radiation treatment outcome.
The cohorts of patients treated with radical radiation
and a separate cohort of patients also treated in
Leeds by radical cystectomy have documented
that high MRE 11 protein expression by the tumor
predicts improved outcome with radiation therapy
but not in the cystectomy cohorts. Comparing the
high MRE 11 patients by treatment showed that the
patients treated with radiation have a significantly
higher disease-specific survival than those treated
with immediate cystectomy (P=0.02) while those
with low MRE 11 protein expression do insignificantly
better with surgery than with radiation. These results
tentatively identify MRE 11 overexpression as a
predictive molecular marker of improved causespecific survival following radiation therapy for
muscle-invasive bladder cancer.
and survival in selected patients comparable

to radical cystectomy, and affords a 70%
chance of maintaining a well-functioning native
bladder (see Table 8). Quality of life studies
have demonstrated that the retained native
bladder functions well and long-term toxicity of
chemoradiation to pelvic organs is low. These
reports support the acceptance of modern
bladder-sparing trimodality therapy for selected
patients as a proven alternative to cystectomy
(LE 3, GR C).
See Table 9 for
recommendations.
summary
of
these
Conclusion
In selected patients with muscle-invasive bladder
cancer, bladder-preserving therapy with cystectomy
reserved for tumor recurrence represents a safe
and effective alternative to an immediate radical
cystectomy. Cumulative published data of more
than 1000 patients in single institution and multiinstitution cooperative group trials demonstrate that
trimodality therapy results in excellent local control in
70% of patients with muscle-invasive bladder cancer
while preserving a native functional bladder without
compromising long-term survival. The 10-year
overall survival and disease-specific survival rates in
the bladder-sparing protocols are comparable to the
overall results reported with contemporary radical
cystectomy. Moreover, the 15-year results indicate
a plateau in disease-specific survival, suggesting
no evidence of increased rates of recurrence with
longer follow-up times. Life-long bladder surveillance
is essential. Prompt cystectomy for tumor recurrence
is necessary to prevent tumor dissemination. Thus,
bladder-preserving therapy is a bona fide option and
valid alternative to radical cystectomy in selected
patients. This approach should be discussed along
with all of the other treatment options during overall
initial treatment planning. This approach contributes
significantly to the quality of life of the patients so
treated and represents a unique opportunity for
urologic surgeons, radiation oncologists, and medical
oncologists to work hand-in-hand in a joint effort to
provide patients with the best treatment option for
this disease.
g) Levels of Evidence (LE) and Grades of

Recommendation (GR) for Radiation-based
Bladder-preserving Strategies for Muscleinvasive Bladder Cancer
1. Radiation therapy followed by salvage cystectomy
for tumor recurrence has comparable survival to
preoperative radiation therapy and cystectomy.
LE 1b, GR A).
2. Radiation therapy and chemotherapy result in
a higher rate of pT0 status than does radiation
therapy alone (LE 1b, GR A) .
3. Combined radiation and chemotherapy allow
good preservation of bladder function in the
great majority of patients. (LE 2a, GR B).
4.There is no clinical trial basis to indicate that
neoadjuvant chemotherapy prior to radiation
therapy improves survival. (LE 1a, GR A).
5. Complete TURBT, when possible, is associated
with higher rates of local tumor control and higher
cure rates than does incomplete initial tumor
resection for selected patients in trimodality
radiation/chemotherapy trials. (LE 2a, GR B).
6. Limited data suggests that high expression of
the molecular marker MRE 11 may be a putative
predictor for cause-specific survival following
radical radiation therapy for muscle-invasive
bladder cancer. (LE 3, GR B).
7. T
rimodality therapy consisting of TURBT plus
concurrent radio sensitizing chemotherapy and
radiation is judged safely possible, and, when
combined with early salvage cystectomy for
recurrence, this bladder-preserving treatment
approach offers a chance for long-term cure
323
Table 9. Summary of Recommendations

Treatment/
Comparison
Evidence
Level of
Evidence
Grade of
Recommendation
RT alone vs
40Gy+Cystectomy
3 of 4 RCTs report
similar survival
1b
ChemoRT vs
RT alone
1b
Neoadjuvant CT
with RT or ChemoRT
2 RCTs report significant

improvement in bladder
tumor eradication
3 RCTs and 1 meta-analysis
report no benefit
1a
ChemoRT preserves
good bladder function
3 QOL studies and RTOG protocols

report good tolerance
2a
Complete TURB
with ChemoRT
3 reports (1 phase III, 2 phase II)

show benefit
2a
Predictive Biomarkers
of outcome after RT
MRE 11 expression predicts

improved CSS (1 study)
Trimodality therapy vs
immediate cystectomy
Comparison of 3 contemporary
series of each report similar
5- and 10-yr survival
9. Gospodarowicz MK, Hawkins NV, Rawlings GA, et al.

Radical radiotherapy for muscle invasive transitional cell
carcinoma of the bladder: failure analysis. J Urol. Dec
1989;142(6):1448-1453; discussion 1453-1444.
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and cyclin E protein levels is associated with progression
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-cisplatin and bifractionated split course radiation therapy
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1997;16:319a.
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Group. Prognostic value of MIB-1 score, p53, EGFr, mitotic
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T1) bladder cancer; a prospective study. Eur Urol 1999;
136: 393400.
31. Rodel C, Grabenbauer GG, Kuhn R, et al. Combinedmodality treatment and selective organ preservation
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McDonnell TJ. Abnormal bcl-2 and pRb expression are
independent correlates of radiation response in muscleinvasive bladder cancer. Clin Cancer Res 1997; 3: 1823
29.
32. Kaufman DS, Winter KA, Shipley WU, et al. Phase I-II
RTOG study (99-06) of patients with muscle-invasive
bladder cancer undergoing transurethral surgery, paclitaxel,
cisplatin, and twice-daily radiotherapy followed by selective
bladder preservation or radical cystectomy and adjuvant
chemotherapy. Urology. 73:833-837, 2009.
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downstaging after preoperative radiotherapy for muscleinvasive bladder cancer. Int J Radiat Oncol Biol Phys
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of selective bladder preservation by combined-modality
49. Rodel C, Grabenbauer GG, Rodel F, et al. Apoptosis,
325
urologists and pathologists will see and need to be

familiar with: nested variant urothelial cancer, micro
papillary urothelial cancer, carcinogenesis (sarcoma
urothelial cancer), and urothelial cancer with small
cell, squamous, and carcinomas components. While
not all aspects of management of each variant will be
discussed, we will highlight recent information which
in most has significantly affected management.
p53, bcl-2 and Ki-67 in invasive bladder carcinoma:

possible predictors for response to radiochemotherapy and
successful bladder preservation. Int J Radiat Oncol Biol
Phys 2000; 46: 1213
50. Chakravarti A, Winter K, Wu CL, et al. Expression of the
epidermal growth factor receptor and Her-2 are predictors
of favorable outcome and reduced complete response
rates, respectively, in patients with muscle-invading bladder
cancers treated by concurrent radiation and cisplatinbased chemotherapy: a report from the Radiation Therapy
Oncology Group. Int J Radiat Oncol Biol Phys 2005; 62:
30917.
1. Nested variant urothelial cancer

It was originally identified as an aggressive entity
by Talbert and Young[5] who characterized the
tumor as one with a deceptively benign histologic
appearance. Small nests and tubules of urothelial
cells infiltrate through the lamina propria and usually
the muscularis. Its appearance can be mistaken for
a proliferative variant of von Brunns nests, a finding
present in many individuals. This entity can appear
as an isolated tumor or along with more classic
urothelial canceralmost invariably high grade,
in other portions of the bladder or adjacent to the
nested variant portion. It has been estimated to
represent 0.3% of all urothelial cancers.[6]. Little is
known about its response to non-surgical treatments.
This malignant variant has even a higher male
predominance than standard urothelial cancer (3:1
males to females in the United StatesSEER[7]).
Perhaps its most important clinical feature is mistaking
it for either a benign condition or a bland non-muscleinvasive urothelial cancer. Because these cancers
cannot be diagnosed without at least lamina propria
invasion, the standard treatment should be radical
cystectomy in the absence of distant metastases
and because the vast majority are more invasive
than this in the absence of distant metastases.
Whether neoadjuvant or adjuvant chemotherapy for
urothelial cancer is beneficial is unknown. Although
adjuvant radiation or chemotherapy have not been
shown to be beneficial, it is likely that the rarity of
this disease and the advanced nature of the cases
treated in such ways would leave this issue up for
further study.[8]
51. Press MF, Lenz HJ. EGFR, HER2 and VEGF pathways:
validated targets for cancer treatment. Drugs 2007; 67:
204575
52. Krger S, Witsch G, Bttner H, et al. HER2 overexpression
in muscle-invasive urothelial carcinoma of the bladder:
prognostic implications. Int J Cancer 2002; 102: 51418.
53. Jimenez RE, Hussain M, Bianco FJ, et al. Her-2/neu
analysis in primary and metastatic tumors. Clin Cancer Res
2001; 7: 244047.
54. Hussain MH, MacVicar GR, Petrylak DP, et al. Trastuzumab,
paclitaxel, carboplatin, and gemcitabine in advanced human
epidermal growth factor receptor-2/neu-positive urothelial
carcinoma: results of a multicenter phase II National Cancer
Institute trial. J Clin Oncol 2007: 25: 221824.
55. Choudhury, A, Nelson; Mark TW, et al: MRE 11 expression
is predictive of cause-specific survival following radical
radiotherapy for muscle-invasive bladder cancer. Cancer
research 70: 7017-7026, 2010.
VII. Treatment of Mixed

Histology Urothelial
Carcinoma
Urothelial carcinoma of the bladder represents by
far the most common histology of bladder cancer.
However, cancers classified as urothelial contain
non- urothelial components in 5-40% of cases.[1,2]
In general, the higher the grade of the urothelial
component and more invasive the cancer, the
more likely that non-urothelial components will be
found. Whether this is because such cancers are
less differentiated and more easily develop aberrant
histologic features or because the mixed urothelial
cancers are generally very aggressive and are
often not diagnosed until they are far advanced is
unknown.
2. Ur
othelial carcinoma with
micropapillary differentiation
It is another variant often considered to have bland
histology, was first described as part of the urothelial
carcinoma complex by Amin et al in 1994 [9]. It is
now considered to represent between 1 and 2%
of all urothelial cancers and has a strong male
predominance.[1,10,11] The histologic appearance
resembles micropapillary tumors arising in the ovary,
lung, breast, and other anatomic locations.[12] The
immunohistologic phenotype of these tumors has
been elegantly outlined.[12] All 13 of the cases
tested in that report[12] were positive for MUC1,
MUC2, CK7, PTEN, p53, and ki67. CK20 and
3BVE12 were negative in half the cases and Her/neu
was negative in 9 of the 13. In general, except for
p53 staining, at least 50% of cells were positive for
In general, however, molecular and genetic markers

of urothelial cancer are present in non-urothelial
as well as urothelial components, implying a clonal
origin.[3,4] Most of these cancers are fairly rare
and most information about them comes from case
series. However, for the two most common mixed
histologies, urothelial carcinoma with squamous
and/or carcinomas elements, some data from
randomized prospective studies existalthough
collected retrospectively. These will be reviewed. This
section is not meant to be encyclopedic, but instead
will focus on 6 urothelial carcinoma variants that all
326
the 6 markers present in every specimen. All of the

patients in this series and several of the others[10]
had at least muscle invading cancer and most had
disease beyond the bladder. In a recent review of
cases from MD Anderson Cancer Center, Kamat et
al[11] found that these cancers may be detectable
prior to muscle invasion and that cystectomy still is
recommended. The response to BCG was extremely
poor, with 18 of 27 patients experiencing progression
to stage T2 or greater at a median 8 months followup, one-third of whom had progressed to metastatic
disease. At 30 months median follow-up, only 5 of 29
patients were free of disease with an intact bladder.
[11] Neoadjuvant chemotherapy did not appear
superior to immediate cystectomy. The authors
recommended against such an approach unless
there was surgically unresectable (cN1 or cT4b)
disease. Following immediate cystectomy, 71%
of 32 cT4a or lower stage patients were alive at 5
years. In contrast, only 32% of 23 similar patients
treated with neoadjuvant chemotherapy followed by
cystectomy were alive at 5 years.
role of chemotherapy or radiation remains at best

anecdotal for this extremely aggressive malignancy;
even with disease confined to the bladder, 5- and 10year survival rates in the 25-35% range have been
reported.[18] However, since nearly 75% of patients
have more advanced disease at diagnosis,[18]
surgery alone is often not curative. Anecdotally good
responses of advanced cancers with combined
surgical treatment and chemotherapy have been
reported,19 but they remain the rarity. It should
be remembered that over 40% of these cancers
have multiple sites within the bladder[18] so that
careful bladder mapping in the rare circumstances
where partial cystectomy would seem feasible is
mandatory.
While the role of neoadjuvant chemotherapy is
unclear, Black et al13 reported downstaging to pT0
in 5 of 11 (45%) patients with clinical stage T2-T3
tumors using urothelial cancer-like regimens.
4. Small cell carcinoma

It can exist in a pure form, but, in the urinary tract over
50% have an epithelial component. Occasionally,
the epithelial component can be of non-urothelial
type such as squamous cell or adenocarcinoma, but
the vast majority of mixed tumors are with urothelial
cancers.[1]
3. S
arcomatoid carcinoma and
carcinosarcoma of the urinary
bladder
They consist of high grade cancers with malignant
epithelial and mesenchymal elements. While pathologists debate if there is a distinction between the
two, classically sarcomatoid carcinomas consist of
urothelial cancer with a spindle cell (mesenchymal)
component which retains expression of epithelial
molecular markers, while carcinosarcoma contains
recognizably more differentiated sarcomatous elements such as osteosarcoma.[13,14,15] As opposed
to nested variant or micropapillary urothelial cancers, the aggressive nature of this tumor is not overlooked because of bland histology. Extremely rarely,
this condition can be confused with other benign
conditions such as pseudosarcomatous, myofibroblastic proliferationsmost commonly postoperative
spindle cell nodules and pseudotumors.[1] The presence of outright urothelial carcinoma, however, usually makes the distinction quite obvious. Molecular
analyses including those for p53 indicate a common
clonal origin for both carcinomatous and sarcomatoid components.[16,17]
As opposed to other urothelial cancers with mixed

histologies which are generally treated as urothelial
cancers, it has been recognized by the World Health
Organization that any amount of small cell histology
should be regarded as a small cell carcinoma.[20]
This is presumably because this small cell component
determines the patients prognosis.
As with small cell carcinomas elsewhere, the majority
are positive for chromogranin A and synaptophysin,
and over 90% present with muscle invasion.[1] As
with carcinosarcoma, molecular analyses have
indicated similar genetic changes in the small cell and
coexistent urothelial carcinomatous components.
[1,21]
In general, mixed histology small cell carcinoma is
recognized as a systemic disease[1,3] and probably
should receive systemic chemotherapy aimed at
small cell carcinoma (e.g., cisplatin and etoposide
based therapy) along with extensive local treatment.
[1] In an MD Anderson series, the pT0 rate in patients
with cT2-4a mixed urothelial and small cell cancers
treated with neoadjuvant neuroendocrine regimens
was 10/12 (83%), compared with 3/9 (33%) with
a urothelial regimen.[13] Moreover, the diseasespecific survival at 5 years for these 21 patients
treated with neoadjuvant chemotherapy was 78%,
compared to 36% in 25 patients who underwent
immediate cystectomy.[22]
A review of data from the SEER cancer registry[18]

reported that between 1973 and 2004, this entity
represented 0.6% of all primary bladder cancers.
Nearly 75% of cases had regional or distant disease
at the time of diagnosis. Two-thirds of the patients
were male, actually a slightly lower percentage
than pure urothelial cancers and far lower than
micropapillary or nested variant cancers. In general
the treatment recommended is cystectomy even for
non-muscle-invasive carcinosarcomas, almost all
of which invade at least the lamina propria.[18] The
327
Bladder sparing approaches have also been reported.

Bex et al have published results for chemoradiation
that approach those for chemotherapy and
cystectomy,[23] although primarily only patients with
limited disease were reported.
Nested variant and micropapillary urothelial cancers

have deceivingly bland histologies and at times may
be confused for benign lesions. Even when detected
in non-muscle-invasive stages, these should be
treated with aggressive local extirpative therapy.
Endoscopic and intravesical management should be
discouraged.
5. The most common of the

mixed urothelial cancers are
those with squamous and/or
adenocarcinomatous elements
Carcinosarcomas and urothelial cancers with small

cell elements usually are diagnosed correctly, but
again are extremely aggressive malignancies.
Carcinosarcomas should be treated with local extirpative surgery. The role of additional systemic
chemotherapy is being explored and has received
some favorable reports.[19] Urothelial cancer with
small cell components should be treated as small
cell carcinoma with neoadjuvant cisplatin/etoposide
followed by aggressive local treatmentbe it extirpative surgery or chemoradiation. Muscle-invasive
urothelial cancers with squamous or adenocarcinomatous elements have responded particularly
well to multi-drug cisplatin-based urothelial cancer
regimens, especially M-VAC, and it would appear
that neoadjuvant chemotherapy should be used for
them before definitive surgery. Awareness of these
features of these common mixed urothelial cancers
by urologists and pathologists should assist in their
management.
They account for as many as 30% of patients

undergoing cystectomy for what has been termed
muscle-invasive urothelial cancer. In general,
these patients fare less well than those with pure
urothelial carcinoma even when stratified by stage.
[2] While no randomized prospective studies have
specifically addressed these cancers or any of the
other mixed variant urothelial cancers, because of
their high proportion, they have been included in
randomized prospective phase III trials of treatments
for invasive urothelial cancer and, at least in one
of the mature long-term studies of neoadjuvant
chemotherapy with cystectomy, results have been
analyzed.[24] In SWOG 8710, 59 (19.2%) of 307
patients with cT2-4a cN0 cM0 urothelial cancer had
squamous (N=37), adenocarcinomatous (N=20),
or squamous and adenocarcinomatous (N=2)
elements. Patients were randomized to receive 3
cycles of M-VAC chemotherapy before cystectomy
or undergo immediate cystectomy. There was
evidence of a survival benefit for patients with mixed
histology cancers who received M-VAC compared
to those who went directly to cystectomy (HR =
0.46, 96% CI 0.25-0.87) (p=0.02). This was so for
both clinical T2 and cT3-4a tumors (5-year survival
0.73 [M-VAC + cystectomy] vs. 0.54 [cystectomy
alone] for cT2; or 0.58% [M-VAC + cystectomy]
vs. 0.34 [cystectomy only] for cT3, 4a) and was far
better than the benefit of M-VAC for pure urothelial
cancers (HR=0.90, p=0.48). Not surprisingly M-VAC
also improved downstaging to pT0 compared to
cystectomy for mixed histology tumors (34% vs.
4%, p=0.004). The strengths of this study were its
randomized prospective design and the presence
of central histology review. The weaknesses were
the relatively small number of mixed histology cases
(N=59) and lack of quantification of the non-urothelial
cancer component. Despite these shortcomings,
until more information becomes available, patients
with cT2-T4a urothelial cancers with squamous or
adenocarcinoma elements should receive cisplatinbased combination chemotherapy before cystectomy
to optimize their chances of survival.
Recommendations
Nested variant and micropapillary urothelial
cancers, regardless of whether they are detected
in non-muscle-invasive or muscle-invasive
stages, should be treated with aggressive local
extirpative therapy (LE: 3, GR: B)
Carcinosarcomas should be treated if possible
with local extirpative surgery (LE: 3, GR: B)
Urothelial cancer with small cell components
should be treated with neoadjuvant chemotherapy
including neoadjuvant cisplatin and etoposide
followed by aggressive local treatment (LE: 3,
GR: B)
Muscle-invasive
urothelial
cancers
with
squamous or adenocarcinomatous elements
should be treated with neoadjuvant multi-drug
cisplatin-based urothelial cancer regimens before
definitive surgery (LE: 3, GR: C).
References
1. Amin MB. Histological variants of urothelial carcinoma:
diagnostic, therapeutic and prognostic implications.
Modern Pathology 22:S96-118, 2009.
In summary
2. Wasco MJ, Daignault S, Zhang Y, et al. Urothelial carcinoma

with divergent histologic differentiation (mixed histologic
features) predicts the presence of locally advanced bladder
cancer when detected at transurethral resection. Urology
70:69-74, 2007.
Mixed urothelial cancers with variant histologies

are generally found with only high grade urothelial
cancer and behave at least as aggressively as high
grade urothelial cancer and often even more so.
328
3. Chalasani V, Chin JL, Izawa JI. Histologic variants of

urothelial cancer and nontheatrical histology in bladder
cancer. Can Urol Assoc J 3:5193-8, 2009.
22. Siekfer-Radtke AO, Gee J, SHen Y, et al. Multi-modality

management of urachal carcinoma: The MD Anderson
Cancer Center Experience. J Urol 169:1295-8, 2003
4. Kipp BJ, Tyner H, Campion MB, et al. Chromosomal

alterations detected by fluorescence in situ hybridization in
urothelial carcinoma and rare histologic variants of bladder
cancer. Am J Clin Path 130:552-559, 2008.
23. Bex A, DeVries R, Pos F, et al. Long-term survival after

sequential chemoradiation for limited disease small cell
carcinoma of the bladder. World J Urol 27:101-106, 2009
24. Scosyrev E, Ely BW, Messing EM, et al. Do mixed
histological features affect survival benefit from neoadjuvant platinum-based combination chemotherapy
in patients with locally advanced bladder cancer? A
secondary analysis Southwest Oncology Group-Directed
Intergroup Study (8710). BJU 2010
5. Talbert ML, Young RH. Carcinoma of the urinary bladder

with deceptively benign-appearing foci: a report of three
cases. Am J Surg Path 13:374-381, 1989.
6. Holmang S, Johansson SL.
The nested variant of
transitional cell carcinoma. A rare neoplasm with poor
prognosis. Scan J Urol 35:102-105, 2001
7. Scosyrev E, Noyes K, Feng CY, Messing EMM. Sex
and racial differences in bladder cancer presentation and
mortality in the United States. Cancer, 1;115(1):68-74,
2009.
VIII. Follow-up
8. Dhall D, Al-Ahmadie, Olgac S. Nested variant of urothelial

carcinoma.
Archives Path Lab Med. 131:1725-1727,
2007
1. Distant Recurrences
Recently the long-term oncological outcome of
radical cystectomy was analyzed in a contemporary
series of 2287 patients who underwent radical
cystectomy between 1998 and 2008 [1], LE 3. The
mean and median follow-up was 35 and 29 months,
respectively. The 5-year overall, recurrence-free, and
cancer-specific survival rates were 57%, 48%, and
67%, respectively, with distant and local recurrence
rates of 37% and 6%, respectively. In another series,
Canter et al [2] reported on a 5-year recurrencefree survival and cancer-specific survival of 56.5%
and 59.5%, respectively, among 212 patients with a
mean follow-up time of 28 months, LE 3. Again, the
majority of patients developed distant metastases.
Contemporary cystectomy series have demonstrated
a 5-15% probability of pelvic recurrence. Most
recurrences manifest during the first 24 months,
often within 6-18 months after surgery. However,
late recurrences have occurred up to 5 years after
cystectomy.
9. Amin MB, JY Ro, el-Sharkawy T, et al. Micropapillary

variant of transitional cell carcinoma of the urinary bladder.
Histologic pattern resembling ovarian papillary serous
carcinoma. Am J Surg Path 18:1224-1232, 1994
10. Heudel P, El Karak F, Ismaili N, et al. Micropapillary
bladder cancer: A review of Leon Berard Cancer Center
experience. BMC Urology 9:5, 2009.
11. Kamat AM, Dinney C, Gee JR, et al. Micropapillary Bladder
Cancer: A review of the University of Texas MD Anderson
Cancer Center Experience with 100 Consecutive Patients.
Cancer 110:62-70, 2007.
12. Lopez-Beltran A, Montironi R, Blanca A, et al. Invasive
micropapillary urothelial cancer of the bladder. Human
Pathology 41:1159-1164, 2010.
13. Black PC, Brown GA, Dinney C. The impact of variant
histology on the outcome of bladder cancer treated with
curative intent. Urologic Onc: Seminars and Original
Invest. 27:3-7, 2007
14. Baschinsky DY, Chen JH, Vadmal MS, et al. Carcinoma
of the urinary bladder an aggressive tumor with diverse
histogenesis. A clinicopathologic study of four cases and
review of the literature. Arch Pathol Lab Med 124:1172-8,
2000.
The goal of all follow-up strategies is to detect

systemic metastases as early as possible to allow
adequate systemic treatment with or without
removal of metastatic lesions with a benefit in terms
of progression-free and cancer-specific survival.
To achieve the goal of an individualized follow-up
scheme, natural timing of recurrence, probability of
recurrences, functional deteriorations at particular
sites, and possible treatment options of a recurrence
should be considered [3].
15. Lopez- Beltran A, Pacelli A, Rothenberg HJ, et al.

Carcinosarcoma and sarcomatoid carcinoma of the
bladder: Clinicopathological study of 41 cases. J Urol
159:1497-503, 1998.
16. Sung MT, Wang M, MacLennan GT, et al. Histogenesis
of sarcomatoid urothelial carcinoma of the urinary bladder:
Evidence for a common clonal origin with divergent
differentiation.. J Path. 211:420-430, 2007
17. Armstrong AB, Wang M, Eble JN, et al. TP53 mutational
analysis supports monoclonal origin of biphasic
sarcomatoid urothelial carcinoma (carcinosarcoma) of the
urinary bladder. Mod Path 22:1113-118, 2009.
18. Wang J, Wang FW, LaGrange CA, et al. Clinical features
of sarcomatoid carcinoma (carcinosarcoma) of the urinary
bladder: Analysis of 221 cases. Sarcoma. Article ID
454792, 2010.
19. Damiano R, DAmiento M, Amorosi A, et al. Gemcitabine
and cisplatin following surgical treatment of urinary bladder
carcinosarcoma. Tumori 90:458-60, 2004
20. Eble JN, Sauter G, Epstein JI, et al eds. Path and Genetics
of Tumors, IARC Press: Lyon;359:2004
21. Abbosh PH, Wang M, Eble JN, et al. Hypermethylation of
tumor-suppressor gene CpG islands in small cell carcinoma
of the urinary bladder. Mod Path 21:355-362, 2008.
Recently, a nomogram based on 728 patients who

underwent cystectomy was presented. Standard
predictors were pathological stage of the primary
tumor (pTN) and nodal status (pN), LE 2b. The
prediction of recurrent disease increased by 3.2%
when the nomogram included: age, lymphovascular
invasion, CIS, neoadjuvant chemotherapy, adjuvant
chemotherapy, and adjuvant radiotherapy [4]. This
nomogram can be used to predict the individual risk
of systemic relapse and to develop a risk-adapted
follow-up protocol.
329
a) Distant Recurrences
87 were symptomatic and 87 were asymptomatic.

The 5-year cancer-specific and overall survival rate
was significantly higher in the group of patients
with asymptomatic metastasis so that the authors
recommend routine cross-sectional imaging of
the chest and the abdomen. On the other hand,
Volkmer et al [7] identified 444 out of 1270 patients
with recurrences after radical cystectomy, of which
154 and 290 were asymptomatic and symptomatic,
respectively. The overall survival rates at 1, 2, and
5 years were not significantly different between
both groups. The authors draw the conclusion that
symptom-guided follow-up might provide similar
results to a strict follow-up protocol at lower costs.
Distant recurrences are seen in up to 50% of patients

treated with cystectomy. Most recurrences are seen
in the first 24 months, although progression has
been observed after more than 10 years [5-8]. The
most likely sites for distant recurrences are the lungs,
liver, and bones [9]. Treatment of metastatic disease
with cisplatin-based combination chemotherapy with
either M-VAC or cisplatin and gemcitabine results in
a mean survival time of around 14 months.
Helical CT represents the standard imaging technique
of choice to detect lung metastases [9, 10]. Use of
a 5-mm contiguous reconstruction allows detection
of a minimum-sized lesion of 10 mm (LE 2b). For
the detection of liver metastases, CT should be
performed with native images as well as after using
nonionic, iodine-containing water-soluble contrast
agents; multidetector helical CT is todays standard
[11, 12]. For helical CT, 5 mm reconstructions should
be used, allowing a minimum-sized lesion of 10 mm
to be detected.
Recommendations
Postoperative follow-up after radical cystectomy
should be performed in a risk-adapted approach
using currently available nomograms (LE: 3, GR:
C)
Symptom-oriented follow-up might result in the
same long-term outcome as standardized followup protocols but at a lower cost (LE: 3; GR: C)
The majority of lymph node metastases originating

from urogenital cancer are located in the
retroperitoneum so CT scans of the abdomen and
the pelvis are the imaging procedures of choice
[13, 14]. On these cross-sectional modalities,
nodal metastases are usually suspected according
to location and size criteria, i.e. a maximum short
axis diameter 1cm is considered malignant [13].
However, CT scans of the abdomen and pelvis might
give false-negative results in up to 30% of cases due
to difficulties in the interpretation of lymph nodes
based on morphology and size alone [14]. Magnetic
resonance tomography (MRT) scans of the abdomen
and pelvis do not provide additional information and
should be restricted to patients with contraindications
to CT [10] (LE 2b). To date, PET has not been shown
to improve sensitivity in patients with metastatic
urogenital cancer overstaging by doing CT scanning
alone [15, 16], (LE 3). Bone scintigraphy (BS),
conventional radiographic techniques, computed
tomography, (18) FFDG PET/CT and whole body
MRI represent potential imaging studies to diagnose
and to monitor skeletal metastases [17-20].
Helical CT represents the imaging modality of

choice to identify lung, lymph node, and liver
metastasis (LE 2b; GR: B)
References
1. Yafi FA, Aprikian AG, Chin JL, Fradet Y, Izawa J, Estey
E, Fairey A, Rendon R, Cagiannos I, Lacombe L, Lattouf
JB, Bell D, Drachenberg D, Kassouf W. Contemporary
outcomes of 2287 patients with bladder cancer who were
treated with radical cystectomy: a Canadian multicentre
experience. BJU Int. 2010 Dec 16. doi: 10.1111/j.1464410X.2010.09912.x. [Epub ahead of print]
2. Canter D, Long C, Kutikov A, Plimack E, Saad I, Oblaczynski
M, Zhu F, Viterbo R, Chen DY, Uzzo RG, Greenberg RE,
Boorjian SA. Clinicopathological outcomes after radical
cystectomy for clinical T2 urothelial carcinoma: further
evidence to support the use of neoadjuvant chemotherapy.
BJU Int. 2011 Jan;107(1):58-62. doi: 10.1111/j.1464410X.2010.09442.x.
3. Malkowicz SB, van Poppel H, Mickisch G, Pansadoro
V, Throff J, Soloway MS, Chang S, Benson M, Fukui
I. Muscle-invasive urothelial carcinoma of the bladder.
Urology 2007 Jan;69(1 Suppl):3-16
However, based on 2 recent retrospective clinical

studies it appears questionable if early detection
of recurrences is associated with a survival benefit
when compared to recurrences that are detected
due to symptoms [6, 7], (LE 2b). In the first study,
479 patients who underwent radical cystectomy with
adjuvant therapy and who were followed according
to a standardized follow-up protocol were evaluated
to determine whether diagnosis of asymptomatic
recurrence after radical cystectomy by routine followup investigations conferred a survival benefit versus
symptomatic recurrence. After a median follow-up of
4.3 years, 174 recurrences were detected, of which
4. Karakiewicz PI, Shariat SF, Palapattu GS, Gilad AE, Lotan

Y, Rogers CG, Vazina A, Gupta A, Bastian PJ, Perrotte
P, Sagalowsky AI, Schoenberg M, Lerner SP. Nomogram
for predicting disease recurrence after radical cystectomy
for transitional cell carcinoma of the bladder. J Urol 2006
Oct;176(4 Pt 1):1354-61; discussion 1361-2.
5. Mathers MJ, Zumbe J, Wyler S, Roth S, Gerken M, Hofstdter
F, Klotz T. Is there evidence for a multidisciplinary followup after urological cancer? An evaluation of subsequent
cancers. World J Urol 2008 Jun;26(3):251-6.
6. Giannarini G, Kessler TM, Thoeny HC, Nguyen DP,
Meissner C, Studer UE. Do patients benefit from routine
330
2. Follow-up and Treatment of

Secondary Ureteral and Urethral
Tumors
follow-up to detect recurrences after radical cystectomy

and ileal orthotopic bladder substitution? Eur Urol. 2010
Oct;58(4):486-94.
7. Volkmer BG, Kuefer R, Bartsch GC Jr, Gust K, Hautmann
RE. Oncological followup after radical cystectomy
for bladder cancer-is there any benefit? J Urol. 2009
Apr;181(4):1587-93; discussion 1593.
a) Acquisition of Evidence
The recommendations given on follow-up and
treatment of secondary ureteral and urethral tumors
after radical cystectomy are based on an extensive
Medline search.
Regarding surgical treatment
of invasive bladder cancer, there is only limited
prospective, randomized data. Evidence obtained
from publications on this topic is mainly based
on retrospective multicenter series. Articles were
selected according to the following criteria: quality of
study evaluation, topic relevance, and presence of
intermediate and long-term outcome. Older studies
were only included if data were scarce in recent
publications. Generally, follow-up regimens for
ureteral and urethral recurrences should be adapted
according to the natural timing and probability of
recurrence, possible functional deterioration at
recurrence-specific sites, as well as the availability
of an efficient treatment option. The level of evidence
and grade of recommendation given are based as
outlined by the Oxford Centre for Evidence-based
Medicine [1].
8. Bochner BH, Montie JE, Lee CT. Follow-up strategies and

management of recurrence in urologic oncology bladder
cancer: invasive bladder cancer. Urol Clin North Am 2003
Nov;30(4):777-89
9. Heidenreich A, Albers P, Claen J, Graefen M, Gschwend J,
Kotzerke J, Krege S, Lehmann J, Rohde D, Schmidberger
K, Uder M, Zeeb H. Imaging studies in metastatic
urogenital cancer patients undergoing systemic therapy:
recommendations of a multidisciplinary consensus meeting
of the Association of Urological Oncology (AUO) of the
German Cancer Society. Urol Int 2010; 85: 1 - 10
10. Winer-Muram HT. The solitary pulmonary nodule. Radiology
2006; 239: 34 49 Wormanns D, Ludwig K, Beyer F,
Heindel W, Diederich S. Detection of pulmonary nodules
at multirow-detector CT: effectiveness of double reading to
improve sensitivity at standard-dose and low-dose chest
CT. Eur Radiol. 2005;15:14-22
11. Kanematsu M, Kondo H, Goshima S, Kato H, Tsuge U,
Hirose Y, Kim MJ, Moriyama N. Imaging liver metastases:
review and update. Eur J Radiol. 2006; 58:217-28
12. Khan SA. Imaging of liver cancer. World J Gastroenterol
2009; 15: 1289 1300
13. Barrett T, Choyke PL, Kobayashi H. Imaging of the lymphatic
system: new horizons. Contrast Med Mol Imaging 2006; 1:
230 - 245
b) Secondary Ureteral Tumors
14. Morisawa N, Koyama T, Togashi K. Metastatic lymph nodes

in urogenital cancers: contribution of imaging findings.
Abdom Imaging 2006; 31: 620 629
1. Incidence and Time to Ureteral Recurrence
15. Powles T, Murray I, Brock C, Oliver T, Avril N. Molecular

positron emission tomography and PET/CT imaging in
urological malignancies. Eur Urol 2007; 51: 1511 - 1521
According to recent series, secondary urothelial

tumors account for approximately up to 20% of all
recurrences after radical cystectomy for invasive
bladder cancer [2]. As opposed to local and distant
recurrences, metachronous upper urinary tract
recurrences after invasive bladder cancer are
considered late oncological events. Most ureteral
recurrences have been reported to occur after a
median time of 24-41 months after radical cystectomy
[3-7]. As a result of improved survival rates in
invasive bladder cancer, an increasing number of
patients will achieve long-term survival and will
therefore remain at risk for tumor recurrence in the
upper urinary tract. In numerous studies, the 5-year
rate of ureteral recurrences after radical cystectomy
is reported to range from 2-9% [2, 4, 6, 8-15]. In a
longitudinal study using landmark time analysis of a
total of 1329 patients treated with radical cystectomy,
it was shown that the risk of upper urinary tract
recurrence does not decrease over time with 3- and
5-year cumulative incidences of 4% (95% CI 3-6%)
and 7% (95% CI 5-8%) [15]. Furthermore, ureteral
recurrences have been reported to occur even 9
years after curative surgery, [6] which highlights the
importance of long-term surveillance of the upper
tracts after radical cystectomy.
16. Kibel AS, Dehdashti F, Katz MD, Klim AP, Grubb RL,
Humphrey PA, Siegel C, Cao D, Gao F, Siegel BA.
Prospective study of [18F]fluorodeoxyglucose positron
emission tomography/computed tomography for staging
of muscle-invasive bladder carcinoma. J Clin Oncol. 2009
Sep 10;27(26):4314-20. Epub 2009 Aug 3.
17. Pollen JJ, Gerber K, Ashburn WL, Schmidt JD. The value of
nuclear bone imaging in advanced prostate cancer. J Urol
1981; 125: 222 - 233
18. Ghanem N, Uhl M, Brink I, Schfer O, Kelly T, Moser E,
Langer M. Diagnostic value of MRI in comparison to
scintigraphy, PET, MS-CT and PET/CT for the detection of
metastases of bone. Eur J Radiol. 2005; 55: 41-55
19. Nakanishi K, Kobayashi M, Nakaguchi K, Kyakuno M,
Hashimoto N, Onishi H, Maeda N, Nakata S, Kuwabara M,
Murakami T, Nakamura H. Whole-body MRI for detecting
metastatic bone tumor: diagnostic value of diffusionweighted images. Magn Reson Med Sci. 2007; 6:147-55
20. Schlemmer HP, Schfer J, Pfannenberg C, Radny P,
Korchidi S, Mller-Horvat C, Ngele T, Tomaschko K,
Fenchel M, Claussen CD. Fast whole-body assessment
of metastatic disease using a novel magnetic resonance
imaging system: initial experiences. Invest Radiol. 2005;
40: 64-71
331
2. Rationale of a Risk-adapted Strategy for

Follow-up
10, 11, 17]. In two recent studies, the sensitivity and

specificity of frozen section analysis for the detection
of malignant ureteral margins was reported to
range between 74-75% and 98-99%, respectively,
with a positive predictive value of 94%, resulting in
an overall accuracy of 98% [4, 10]. On the other
hand, heterogeneous data exist on whether a
sequential resection of malignant ureteral margins
can unequivocally be advocated to reduce the risk
of a malignant anastomotic margin at cystectomy [4,
5, 10]. In two recent studies, the rates of converting
initially positive ureteral margins into negatives with
a sequential resection strategy were as high as 3941%, [4, 10] whereas in another study a conversion
rate of up to 82% was reported [5]. In this study, those
with initially positive but finally negative margins still
had a 4.4-fold increased risk as compared to those
patients with initially negative margins [5). However,
their risk decreased after conversion to a finally
negative ureteral margin since those patients with
positive anastomotic margins had an even higher
7.4-fold risk of recurrence [5].
Several clinical and pathological parameters have

been identified as risk factors for metachronous
upper urinary tract recurrence and should be taken
into consideration when addressing the patients
individual risk of recurrence. The rationale of a
risk-adapted strategy is supported by a recently
performed large retrospective analysis evaluating
the long-term risk of upper tract recurrence in
1420 patients who had undergone cystectomy[16].
In this study, a number of risk factors were shown
to potentiate the risk of upper tract recurrence.
Multivariate analysis revealed that patients with no
risk factors (history of carcinoma in situ (CIS) and
recurrent bladder cancer, high-grade pTa-T1 bladder
cancer, and distal ureteral malignancy at radical
cystectomy) had only a 0.8% risk of developing
ureteral recurrence 15 years after surgery whereas it
increased to 13.5% in patients with 3-4 existing risk
factors [16]. Furthermore, a recent large retrospective
single center series on 174 patients with recurrence
after radical cystectomy showed that the rate of
concomitant distant recurrences in patients with
secondary urothelial carcinoma was only 11%[2].
Since the incidence of malignant ureters at

cystectomy is highest in the distal ureters [18], some
authors have suggested resecting the ureters more
proximally at the crossing with the iliac vessels [11]. A
retrospective series among 755 patients undergoing
cystectomy reported CIS in the most proximally
resected ureters in only 1.2% of the patients [11]. In
this study, a considerable number of 17% of patients
with CIS on frozen section analysis had upper tract
recurrence and 80% of the patients with CIS at the
ureteral margin had also CIS of the bladder. The
authors suggested performing frozen section analysis
only in patients with known CIS of the bladder. This
may minimize the risk of ureteral strictures due to
ischemia of the distal part of the ureter and also be
beneficial for patients after prior pelvic irradiation
therapy, but makes the use of an afferent tubular
ileal segment for ureteral reconstruction necessary
[11].
Approximately 75% of upper tract recurrences are

detected when patients present with symptoms, such
as gross hematuria or flank pain. These symptoms
are often associated with locally advanced disease
and, consequently, are associated with poor
outcomes after radical nephroureterectomy [6].
Thus, new strategies for earlier detection of upper
tract recurrences while they are still localized
are necessary for effective treatment by radical
nephroureterectomy [6] given the opportunity of local
curative treatment [6]. Assessment of risk factors for
upper tract recurrence might help to identify high-risk
patients and tailor surveillance regimes according
to a risk-adapted strategy, thereby reducing the
need of unnecessary follow-up examinations and
surveillance costs in low-risk patients.
3. Risk Factors for Upper Urinary Tract

Recurrence
Carcinoma in situ of the Bladder

In patients with non-muscle-invasive bladder cancer
(pTa, pTis, pT1), the presence of CIS of the bladder
was found to be a risk factor for metachronous
upper tract carcinoma [10]. Conversely, in patients
with muscle-invasive disease, concomitant CIS
was not found to be independently associated with
upper tract recurrence [4, 6, 8, 14, 19], whereas
in patients with CIS-only disease at cystectomy, a
significantly higher rate of upper tract recurrences
was reported [20]. This finding may be artificially
skewed towards the patient cohort with low-stage
disease at cystectomy since a confounding effect of
survival differences between different tumor stages
has to be assumed.
U
reteral Margin and Frozen Section Analysis
Ureteral tumor involvement at final pathological
analysis of radical cystectomy specimens was found
in 4.8-13.0% of the patients and in 3.6-8.3% of the
examined ureters [4, 10, 11, 15, 17]. It has been
shown in various studies that tumor involvement of
the distal ureter at cystectomy is an independent
risk factor for upper tract recurrence [15, 16] with
an approximately 2.6-fold increase in the relative
risk [16]. While there is substantial evidence that
suggests that intraoperative frozen section analysis
is a reliable tool to detect malignant ureteral margins
at radical cystectomy, its role is controversial [4, 5,
332
T
umor Stage and Multifocality
patients with anastomotic tumor recurrence tended

to develop early progression to distant metastatic
disease, whereas patients with more proximal upper
tract recurrences showed improved recurrence-free
survival after radical cystectomy [25].
In several studies, tumor stage was investigated

as a possible risk factor of upper tract recurrence.
Approximately 65-100% of upper tract recurrences
occur in patients with organ-confined bladder cancer
(pT2bpN0M0 or lower stage disease) [8, 9, 14, 19,
21]. In one study, patients with pTa-T1 bladder cancer
were reported to have a 1.8-3.8 fold higher risk of
upper tract recurrence as compared to patients with
muscle-invasive disease [3]. Similar to the outcome of
patients with CIS-only disease at cystectomy, tumor
stage was not an independent risk factor for upper
tract recurrence, but was a rather strong predictor
of prolonged survival after radical cystectomy. These
data may be biased by the fact that patients with
high-stage disease were at considerably higher risk
for early local or systemic recurrence as compared to
patients with non-muscle-invasive disease [2, 22].
5. Diagnosis of Upper Tract Recurrence

R
adiological Imaging
According to current studies, patients diagnosed
with asymptomatic upper tract recurrence during
routine follow-up have a significantly higher survival
advantage than those with symptomatic recurrences
[6]. This stresses the importance of an early detection
of metachronous ureteral malignancy for a timely
initiation of a curative treatment.
In a recent analysis, the accuracy of a total of
1064 intravenous pyelography (IVP) studies of 322
patients, who underwent routine follow-up of the
upper tract at 1, 2, 3, 5, 7, and 10 years after radical
cystectomy, was investigated. Of these patients,
upper tract recurrence was detected in only 15
(4.7%), but only 8 of them had suspicious findings
on IVP. Patients with positive final ureteral margins
were at highest risk for recurrence. Therefore, the
authors concluded that routine excretory urography
should be limited to patients at high risk for upper
tract recurrence. Likewise, Slaton et al developed a
stage-specific surveillance protocol in patients after
radical cystectomy and suggested the use of upper
tract imaging every 1-2 years after radical cystectomy
for all tumor stages [26], but specific risk factors were
not taken into consideration in this study.
In a recent study, multifocality of the initial bladder

tumor was found to independently contribute to
a higher risk of ureteral involvement at radical
cystectomy and subsequent upper tract recurrence,
[4] which supports the results of a prior study [23].
Limited data exist as to whether or not urethral tumor
involvement predicts a higher likelihood for upper
tract recurrence [6, 14]. Urethral tumor involvement
in female patients has been significantly associated
with a higher risk for upper tract recurrence. Likewise,
in male patients, urothelial carcinoma of the prostatic
ducts invading the lamina propria was associated with
a higher risk for secondary ureteral tumors but not
for patients with a continuous expansion of urothelial
carcinoma into the prostate (classified as pT4a stage)
[6, 14]. Most presumably, this observation may also
be biased due to impaired survival rates in patients
with pT4a urothelial carcinoma of the bladder.
Although former studies reported similar sensitivity

rates of IVP and multidetector computed tomography
(MD-CT) urography for the detection of upper tract
recurrence ranging from 0-55%, [8, 9, 14, 19, 21, 26]
some current studies have adopted MD-CT urography
as the preferred diagnostic option compared to
conventional IVP for the detection of upper tract
tumors [27]. Contemporary series reporting on the
value of MD-CT derive mainly from series in which
patients had either primary upper tract tumors
or underwent upper tract imaging for a history of
microscopic or gross hematuria and are also limited
by a relatively small number of included patients. To
provide some recent aspects and developments in
this diagnostic field the results of the most current
studies will be outlined in the following.
4. Survival After Upper Urinary Tract

Recurrence
The 3-year survival rate for patients with upper
tract recurrence lies between 0 and 25%, but longterm survival of more than 9 years has also been
reported in some series [6, 19, 24]. Survival after
secondary ureteral recurrence is mainly predicted
by tumor stage and lymph node tumor involvement.
In a single-center series it was demonstrated that in
patients with pT3 or greater secondary upper tract
carcinoma, the median survival was only 1.3 years,
compared to 3.4 years in patients with pTa-T1 cancers
[6]. Similar results were seen in another series of 85
female patients who had an upper tract recurrence
rate of 2.4%. All recurrences were muscle-invasive
at nephroureterectomy [21].
In patients with primary upper tract tumors, MD-CT

urography shows a significantly higher sensitivity,
specificity, and test accuracy of 96%, 100%, and
99% as compared to IVP at 75%, 86%, and 85%,
respectively [27]. For MD-CT urography, the location
of the primary tumor seems to have a direct impact
on the detection accuracy. The sensitivity for the
detection of tumors in the renal pelvis was found
to range from 78-94% but decreased to 19-54% for
Some data suggest that tumor location also affects

survival in patients with upper tract recurrence
[25]. In some series, recurrence at the ureteroileal
anastomosis was found in up to 40-60% of the patients
with upper tract recurrence [4, 25]. Importantly,
333
tumor lesions in the ureter [28]. In a retrospective

series of 188 patients with a history of urothelial
carcinoma (using diagnostic ureterorenoscopy as the
diagnostic reference standard), MD-CT urography
showed a positive predictive value (PPV) of 63-67%
for the identification of a tumor lesion in the upper
tract [29, 30]. In both of these studies, characteristic
findings on MD-CT urography suspicious of an upper
tract tumor were filling defects and urothelial wall
thickening. Interestingly, when stratified by location,
urothelial wall thickening was more predictive of
tumors in the pelvicalyceal system (PPV 88%) than
in the ureter (PPV 33%). Conversely, filling defects
were more predictive in the ureter (PPV 88%) than
in the pelvicalyceal system (PPV 50%) [29]. MD-CT
was able to correctly predict the pTNM staging in
58-88% of the patients with upper tract malignancies
[28, 31]. However, even in contemporary series,
the main drawback of MD-CT urography is the low
positive predictive value for small tumors or urothelial
wall thickening (0-46%) [32].
cancer from intestinal epithelial cells [40]. Most

importantly, the additional use of urinary cytology
in established follow-up regimens (with radiological
and clinical examinations) does not significantly lead
to an earlier detection of upper tract recurrences
[40]. Selective ureteral urinary cytology results in an
improved positive predictive value of greater than
85% for high-grade muscle-invasive upper urinary
tract urothelial carcinomas, [41] but, for screening
purposes, invasiveness and additional costs have
to be considered.
Alternatively, urine-based markers have recently
become a popular tool to overcome the limitations of
conventional urinary cytology. Evidence in literature
derives mainly from patients with primary upper tract
tumors with relatively small numbers of included
patients. In a comparative analysis of 30 patients with
urothelial carcinoma of the upper tract, fluorescence in
situ hybridization (FISH) showed significantly higher
sensitivity rates as compared to urinary cytology
(77% vs. 36%) but not for specificity (95% vs. 100%),
and this has been confirmed in other studies [39, 42].
Moreover, FISH analysis, which uses gene-labeled
probes for the chromosomes 3, 7, 9, and 17, is less
interference-prone than urinary cytology [38]. For
immunocytology, a prior small study in 16 patients
with upper tract carcinoma reported a sensitivity rate
of 100% for the detection of low grade (G1-2) tumors
[43]. Altogether, due to their non-interference probe
analysis, FISH is a promising tool to contribute to a
more non-invasive diagnosis of high-grade upper
tract carcinomas. Nevertheless, taken together, there
is not enough evidence to support the routine use of
urinary cytology and urine-based markers alone for
the follow-up of the upper tracts [44].
The use of a split-bolus technique among 200

patients presented initially with hematuria was
prospectively assessed in a recent series [33].
Split-bolus techniques provide improved imaging
by simultaneous nephrographic and excretory CTphase acquisition. The corresponding sensitivity,
specificity, and PPV rates were 100%, 99%, and
99%, respectively [33]. Alternatively, in one study,
the use of MRI urography images was investigated
in 17 patients with a total of 23 upper tract lesions. A
sensitivity of 74% for the detection of small urothelial
carcinomas (2 cm or less) was reported [34].
Possible further technical improvements include
the acquisition of diffusion-weighted MRI images in
patients with upper tract obstruction due to upper
tract tumor lesions [35], but, still, these techniques
have failed to detect flat ureteral lesions [36].
U
reterorenoscopy
Ureterorenoscopy with biopsy using semirigid or
flexible instruments is the method of choice for the
histological diagnosis of an upper tract carcinoma [45].
Access to the upper tract after urinary diversion can
be particularly challenging and may require the use
of combined retrograde and antegrade techniques
[46]. For evaluating the local T stage, upper tract
biopsies are less reliable because of the limited
capability of biopsy instruments to retrieve adequate
tissue specimens sufficient for the evaluation of the
complete pelvicalyceal or ureteral wall [6]. This fact
is supported by a prior study that demonstrated that
even when lamina propria was present within the
specimens, almost 50% of the tumors were initially
misdiagnosed as superficial and were found to be
invasive in the final nephroureterectomy specimens
[47].
For local staging of the primary tumor lesion and

regional lymph nodes, magnetic resonance imaging
(MRI) has not proven diagnostic superiority to MDCT but is indicated in patients with contraindications
to MD-CT (iodine allergy, renal insufficiency) [34].
MRI remains contraindicated in patients with
pacemakers. Gadolinium infusion must be omitted
in patients with severe renal insufficiency (creatinine
clearance less than 30 mL/min) to avoid the risk of
subsequent nephrogenic systemic fibrosis. [37].
U
rinary Cytology and Molecular-based Urinary
Markers
Some authors have used urinary cytology at least
annually in patients after radical cystectomy [2, 13].
However, despite its high specificity (80-100%) the
sensitivity of voided urine cytology for the detection
of upper tract tumors is low (36-60%) (38, 39). After
urinary diversion, the detection of malignant cells
in voided urine samples is significantly hampered
because of the difficulty in distinguishing urothelial
6. Treatment of Upper Urinary Tract Recurrence

R
adical Nephroureterectomy
Radical nephroureterectomy is the standard treat-
334
ment for patients with invasive upper tract recurrence [6, 13, 21]. Eligibility of patients (in terms of
performance status and tumor extent) to undergo
open radical nephroureterectomy is a predictive factor for improved survival. A prior study demonstrated
that while the overall median survival of patients with
upper tract recurrence was only 10 months, those
who were eligible for radical nephroureterectomy
had a median overall survival of 26 months [8].
survival. Interestingly, in this study, patients who

did not receive any lymphadenectomy at the time of
surgery had comparable survival rates to those with
pathologically confirmed node-positive disease at
radical nephroureterectomy. By contrast to patients
with upper tract recurrence, the rate of lymph-node
positive disease in primary upper tract carcinoma
was only 25% [52, 53]. Moreover, the ideal anatomic
template of regional lymphadenectomy according
to the primary site of recurrence has not been
established, which is mainly due to the inconsistent
lymphatic drainage in the retroperitoneum in
urologic malignancies [54]. Altogether, given the
lack of evidence for a therapeutic benefit of regional
lymphadenectomy, its role in patients with upper tract
recurrence remains unclear and therefore currently
is considered as a diagnostic procedure.
Increasing experience with laparoscopic radical

nephroureterectomy suggests that it is oncologically
equivalent to open surgery for tumors of equal
grade, stage, and lymph node status. These
data derive mainly from patients with primary
upper tract carcinoma. A recent study comparing
retrospectively the outcomes of patients treated
with open (N=704 patients) and laparoscopic radical
nephroureterectomy (N=70 patients) for primary
upper tract urothelial carcinoma found no significant
differences in 5-year cancer-specific survival
between both the open and laparoscopic groups [48].
One limitation of this analysis is that patients treated
with laparoscopic radical nephroureterectomy had
significantly less likelihood for lymph node tumor
involvement at the time of surgery as compared to
patients treated with open surgery, which might have
biased the final survival analysis. Nonetheless, given
the lack of data and the challenging postoperative
anatomy in the retroperitoneum and pelvis after radical
cystectomy and urinary diversion, with the need to
enter and reconstitute the ureteroileal anastomosis,
laparoscopic
radical
nephroureterectomy
in
secondary upper tract recurrence has still to be
regarded as an investigational treatment option.
A
djuvant Chemotherapy
The role of adjuvant chemotherapy in node-positive
upper tract recurrence has only been addressed in
a few studies [13]. In locally advanced upper tract
carcinoma, the results of adjuvant chemotherapy
remain poor as only 5% or fewer of the patients will
achieve long-term survival [13]. The low incidence
of upper tract recurrences makes it unlikely that
randomized prospective studies on the role of
adjuvant therapy can be performed. Controlled
observational and registration type multi-institutional
studies with pooling of data are encouraged.
C
onservative Treatment for Upper Tract Recurrence
Conservative treatment options for patients with
upper tract recurrence after invasive bladder
cancer include endoscopic and percutaneous
resections. Indications for performing renal-sparing
treatment in patients with upper tract recurrence
are bilateral tumors, solitary kidney, or severe renal
insufficiency, and tumor features of small size,
low grade, and low stage. Studies reporting on
outcomes after endoscopic treatment of upper tract
carcinomas derive almost exclusively from patients
with primary carcinomas who have a significantly
improved prognosis as compared to patients with
metachronous tumors. Approximately 50-75% of the
patients with upper tract recurrence present initially
with high-stage, high-grade disease compared to
only about 30% of the patients with de novo urothelial
carcinoma of the upper tract [6, 8, 9, 19, 21, 24, 55,
56]. Moreover, in patient series performing radical
nephroureterectomy and regional lymphadenectomy,
lymph node tumor involvement has been reported
in 32-83% [6, 8, 14]. These data indicate that upper
tract recurrences are more aggressive malignancies
than primary urothelial cancers. Optimal indications
for conservative nephron-sparing treatment of
secondary upper tract tumor recurrences remain to
be defined.
L
ymphadenectomy
The role and extent of regional lymphadenectomy at
radical nephroureterectomy in patients with upper tract
recurrence has not been well-defined and remains
controversial. Open radical nephroureterectomy was
accompanied by regional lymphadenectomy only in
a few retrospective series [6, 8, 14]. In these series,
the rate of locally advanced disease (pT3-T4) ranged
from 54-66% with lymph-node positive disease found
in 32-83% of the patients.
Similar to the increasing evidence for a therapeutic
benefit of extended lymphadenectomy for invasive
bladder cancer, [49, 50] there is recent evidence that
also suggests that extended lymphadenectomy in
invasive upper tract carcinoma is a strong predictor
for improved disease-free and cancer-specific
survival [51]. A retrospective series on 132 patients
with primary muscle-invasive upper tract urothelial
carcinoma showed that pathological tumor stage and
lymph node tumor involvement were independent
risk factors for disease-free survival [52]. Moreover,
the number of removed lymph nodes and the
extent of lymphadenectomy was an independent
risk factor for recurrence-free and cancer-specific
335
Recommendations for Follow-up and

Treatment of Secondary Ureteral
Tumors
63]. Patients with symptomatic urethral recurrences

have no significantly different median time to
diagnosis as compared to patients diagnosed by
cytological abnormalities [58]. Urethral recurrences
in superficial tumor stages (pTa, pTis) are diagnosed
in many cases by abnormal cytology (59-100%) as
opposed to invasive tumors (pT1-T4), which are
often detected after patients have developed local
symptoms (~79%) such as gross hematuria, bloody
urethral discharge, palpable mass, change in voiding
habits, or local pain [58, 64].
Surveillance regimens should be based on a riskadapted strategy (LE: 3, GR: B).

T
he number of risk factors potentiates the risk
of recurrence. Risk factors include: (a) positive
ureteral margin, (b) carcinoma in situ of the
bladder and ureter, (c) tumor multifocality, (d)
urethral tumor involvement, and (e) male gender
(LE: 3, GR: B).
2. Risk Factors in Male Patients

In a large, retrospective single-center series of 729
male patients treated with radical cystectomy with
a median follow-up of 38 months, independent risk
factors for urethral recurrence were found to be a
history of non-muscle-invasive bladder cancer,
prostatic urethral involvement, and NMIBC (pTa,
pTis, pT1) at radical cystectomy. In this study,
superficial prostatic involvement (pTa, pTis) was a
stronger predictor for urethral recurrence compared
to invasive prostatic involvement [58)]. Similar
findings were found in another large, retrospective,
single-center series of 768 male patients with a
longer median follow-up of 13 years in which prostatic
urethral involvement, but not tumor multifocality
or bladder CIS, was an independent risk factor for
urethral recurrence. By contrast to the prior report
[58], patients with invasive prostatic involvement
had a higher risk for urethral recurrence compared
to patients with superficial prostatic urethral tumors
[57].
Patients with final positive ureteral margins in

the definitive pathology report at surgery are at
increased risk of ureteral recurrence. Frozen
section analysis for this finding has a high
sensitivity and specificity for the detection of
malignant ureteral margins (LE: 3, GR B).
Ureterorenoscopy with biopsy is the diagnostic
procedure of choice for the diagnosis of a
metachronous upper tract recurrence after
radical cystectomy (LE: 3, GR: C).
Cytology and urine-based markers such
as fluorescence in situ hybridization and
immunocytology are indicative of upper tract
recurrence, but their sole use cannot be
recommended for exclusive follow-up of the
upper tracts (LE: 3, GR: B).
From an oncologic standpoint, routine upper
tract imaging is only indicated in patients with
high risk or clinical symptoms suspicious of a
metachronous upper tract recurrence and the
optimal interval for follow-up imaging is unclear
(LE: 3, GR: C).
3. Urinary Diversion and Urethral Recurrence

Some series suggest that patients with orthotopic
diversion have a decreased risk for urethral
recurrence as compared to patients with
supranational diversions [57, 61, 65]. However,
other comparable series did not find orthotopic
diversion to be a significant independent risk factor
compared to cutaneous diversions [58]. Prior studies
have hypothesized that the continued exposure
of the remnant urothelium to urine in orthotopic
diversions may have a protective effect against the
development of a urethral recurrence [66]. These
conflicting results may also be due to a patient
selection bias since patients with lower tumor stages
might rather be treated with orthotopic diversion than
patients with locally advanced disease [58].
Nephroureterectomy is the treatment of choice

for invasive upper tract recurrence, providing
prolonged survival (LE 3, GR: B).
Based on scarce data, regional lymphadenectomy
in patients undergoing radical nephroureterectomy
is of limited diagnostic value, and its therapeutic
role is undetermined. (LE: 3, GR: C).
c) Secondary urethral tumors

1. Incidence of Urethral Recurrences after
Radical Cystectomy
According to contemporary series, the risk of urethral
recurrence is low, occurring after a median time of 1424 months in 3.7-8.1% of male patients undergoing
radical cystectomy for bladder cancer, [57-62] with a
resulting 5-year urethral recurrence-free probability
after radical cystectomy of approximately 95% [57,
60]. Most urethral recurrences are detected by
evaluation of symptoms (57-61%), whereas 31-39%
are detected by abnormal urethral cytology [58,
4. Preoperative Prostatic Biopsy and Frozen

Section Analysis
In one study, preoperative prostatic urethral biopsies
showed a high negative predictive value of 99%
compared to final urethral margin status whereas a
positive finding correlated in only 68% of the cases
with a positive final urethral margin status [67].
Confirmatory results of the relatively low positive
336
predictive value of transurethral loop biopsies at

the level of the verumontanum as to the final results
of cystoprostatectomy specimens were reported in
246 patients. The sensitivity and specificity was only
53% and 77%, resulting in a positive and negative
predictive value of 45% and 77%, respectively [68].
By contract, in this study, sensitivity and specificity
of frozen section analysis was 100% [67]. A recent
retrospective study of 294 patients confirmed that
a positive urethral margin status is the strongest
independent risk factor for urethral recurrence as
compared to prostatic urethral and stromal invasion
[60)]. This strengthens the importance of achieving a
tumor-free urethral margin at radical cystectomy.
of the urethral margin for frozen section analysis

[73]. Altogether, the present data underscore the
value of the intraoperative frozen section analysis
for the detection of urethral malignancy at radical
cystectomy. Furthermore, they add to the growing
body of evidence that patients with invasive bladder
cancer at the bladder neck should not be excluded
from an orthotopic approach in advance unless
the intraoperative frozen section analysis reveals
evidence of malignancy at the distal urethral margin
[73].
6. Survival after Urethral Recurrence

The 5-year disease-specific and overall survival after
urethral recurrence is reported to be only 35% and
52%, with a median overall survival after diagnosis of
28-54 months [58, 60, 63]. There are heterogeneous
results in the current literature whether bladder or
urethral recurrence pathology is the most important
factor for overall survival after urethral recurrence.
While Huguenot et al found no differences in survival
[58], Lin et al reported in 24 patients with urethral
recurrence that bladder pathology determined
predominantly their survival [77]. Conversely,
Clark et al found among 47 patients with urethral
recurrence that stage of urethral recurrence but
not bladder cancer pathology was more predictive
for overall survival [63]. Possible explanations for
these contradictory observations may be different
patient selection criteria and the different use of
prophylactic urethrectomies at radical cystectomy
which may have biased the survival analyses of
both studies. Second, the number of patients with
pT0 disease after urethrectomy differs considerably
in the 2 studies. Lin et al included 9 patients (37%)
with pT0 disease [77], whereas Clark et al excluded
all pT0 patients from final survival analysis [63].
In their analysis, Huguet et al found none of the
patients to have pT0 stage at urethrectomy [58],
and, most importantly, 26% of their patients with
urethral recurrence had upper tract recurrence, [58]
which tends to be high stage and high-grade disease
at initial diagnosis [6]. Third, survival in patients
with urethral recurrence and concomitant distant
metastases is mainly determined by the presence of
metastatic disease [2]. In conclusion, it remains still a
matter of debate whether urethral or bladder cancer
pathology is more predictive for overall survival after
urethral recurrence.
5. Risk Factors in Female Patients

In female patients undergoing radical cystectomy,
the rate of urethral recurrence was reported to range
between 0.8-4.3% [21, 69-71]. By contrast to the low
rate of concomitant urethral malignancy in females
with primary bladder cancer (~2%), [72] a higher
rate of urethral malignancy at radical cystectomy of
12% has been reported [73]. A history of multifocal
or recurrent bladder cancer was found to contribute
to an increased risk for urethral recurrence [21].
Furthermore, the risk of tumor involvement of the
distal urethra at radical cystectomy is significantly
higher in patients with bladder neck or vaginal
involvement and preoperatively enlarged inguinal
lymph nodes [74-76]. A pathological reevaluation
of 67 female cystectomy specimens showed that
concomitant urethral tumors were exclusively
located in the proximal or mid portion of the urethra.
Moreover, women with urethral tumors often showed
localization of the primary tumor at the bladder neck.
These tumors were of higher grade and stage and
harbored a higher risk of node-positive disease
[75]. Stein et al prospectively evaluated 71 female
cystectomy specimens and reported that tumor
localization at the bladder neck and urethra was
present in 19% and 7%, respectively. The presence
of a bladder neck tumor significantly correlated with
the highest risk of concomitant urethral malignancy.
Conversely, approximately 60% of the patients with
malignancy at the bladder neck had no evidence of
tumor involvement of the proximal urethra. In this
study, frozen section analysis of the distal urethral
margin showed a 100% sensitivity and specificity for
detection of a positive urethral margin as compared
with the final pathological analysis [74]. Another study
on 85 female patients confirmed the usefulness of
frozen section analysis with a sensitivity of 100%
for the detection of a malignant urethral margin
[21]. Nonetheless, one must remember that
urethral recurrence may occur even in patients
with negative final urethral margins possibly due
to a submucosal extension of the primary bladder
tumor into the urethra with unaffected urothelial
layer at frozen section analysis [76]. This highlights
the importance of an adequate full-thickness biopsy
7. Diagnosis and Staging of Urethral Recurrence

Given the low rate of urethral recurrence, there is
little data or agreement on the optimal follow-up of
the asymptomatic patient with a retained urethra
after radical cystectomy. All patients with urethral
bleeding, pain, or mass should be evaluated
promptly. The follow-up regimens described in
current literature derive mainly from different highvolume centers and are based on urinary cytology,
337
urethral washings, urethroscopy, and different

imaging modalities [57, 59, 61, 62, 77, 78]. In terms
of frequency of follow-up, some authors suggest the
routine use of urinary cytology, urethral washings,
and urethroscopy on a quarterly basis for the first
2 years continued semiannually afterwards, [61]
whereas others only conduct clinical follow-up [58].
It seems therefore reasonable to tailor surveillance
regimens according to the patients individual risk
profile. Urinary cytology is certainly a useful
and noninvasive diagnostic tool to detect urethral
recurrence but its sensitivity is considerably reduced
in patients after urinary diversion [40]. Controversial
data exist to the question whether the routine use of
urethral washings in patients with a retained urethra
after cystoprostatectomy is of prognostic advantage.
Among 24 patients with a median follow-up of 28
months after urethrectomy, a significant impact on
disease-free survival was not observed between
those who routinely received urethral washings and
those who did not [77]. Urethroscopy with biopsy is
certainly the method of choice for the histological
diagnosis of urethral recurrence but the use of
urethroscopy on a regular basis has not appear to
provide any survival benefit [9, 57, 59, 60, 62]. For
local staging after detection of a urethral malignancy,
there is increasing evidence that magnetic resonance
imaging is superior to MD-CT in patients with urethral
malignancy in terms of staging accuracy[78].
urethrectomy at the time of urethral recurrence [58,

61]. Similar results were obtained from a recent
analysis of the SEER database investigating the
timing of urethrectomy as a possible predictor for
improved survival among 2401 male patients who
underwent radical cystoprostatectomy for bladder
cancer. A total of 195 men (8.1%) developed urethral
recurrence and were treated with either concurrent
or salvage urethrectomy. The use of concurrent
urethrectomy at radical cystoprostatectomy versus
salvage urethrectomy was not found to confer any
significant independent survival benefit (HR=0.775,
95% CI 0.592-1.014, p=0.0632). Interestingly, by
contrast to patients treated at urban non-teaching
hospitals, patients treated at teaching hospitals were
more likely to undergo salvage urethrectomy for
recurrence versus immediate urethrectomy. In this
study, tumor stage at radical cystectomy was the only
independent variable that predicted performance
of concurrent urethrectomy [62]. Furthermore,
complication rates and intraoperative blood loss
are not significantly different in patients treated
with delayed or immediate urethrectomy [79]. In
female patients, given the overall low rate of urethral
recurrence, the use of prophylactic urethrectomies
without evidence of invasive malignancy at the
urethral margin does not have a significant impact
on the oncological long-term outcome after radical
cystectomy [72, 80, 81]. As for upper tract recurrence,
adjuvant treatment modalities for urethral recurrence
have yet to be addressed sufficiently in the literature
and should be performed only within prospective
randomized trials.
8. Management of Urethral Recurrence

Non-invasive Urothelial Tumors (pTa-pTis)
In patients with a non-invasive urethral recurrence, a
urethra-preserving strategy can be attempted using
transurethral resection of the tumor lesion [64].
However, in a series with high-grade pTa urothelial
carcinoma of the urethra after radical cystectomy
treated with TUR, only 3 of 4 patients with recurrence
progressed to invasive disease. After recurrence,
all were managed with salvage urethrectomy and
remained disease-free after a median time of 2444 months [64]. The authors concluded that an
additional adjuvant local treatment, i.e., BCG, in high
grade tumors may have reduced the risk of further
recurrence [64]. In a prospective analysis of patients
with carcinoma in situ in the urethra after radical
cystectomy, the use of intraurethral BCG perfusion
weekly for 6 weeks showed a complete remission rate
of 80% but did not show any therapeutic response in
patients with papillary or invasive disease [59].
Recommendations for Follow-up and

Treatment of Secondary Urethral
Tumors
Risk factors for urethral recurrence in male
patients are prostatic tumor involvement (either
superficial or invasive) and bladder neck
involvement in female patients (LE: 3, GR: B).
Intraoperative frozen section analysis has a
high sensitivity and specificity for the detection
of a malignant urethral margin for both male and
female patients (LE: 2b, GR: B).
Patients with positive urethral margins in the final
pathology report are at increased risk of urethral
recurrence (LE: 3, GR: B).
T
he use of routine surveillance urinary cytology,
urethral washings, and diagnostic urethroscopy in
asymptomatic patients has not shown a survival
benefit (LE: 3, GR: B).
Invasive Urothelial Tumors (pT1-pT4)

Urethrectomy is the treatment option of choice in
male patients with invasive urethral recurrence
providing long-term survival [62]. In 2 recent studies,
the use of prophylactic urethrectomies in male
patients with invasive prostatic tumor involvement
at radical cystectomy was not found to confer any
survival benefit compared to patients treated with
Urethrectomy is the preferred treatment in patients

with invasive carcinoma at the urethral margin at
radical cystectomy or at a later recurrence (LE
3, GR B)
338
Local conservative treatment is an option in

patients with non-invasive tumor(s) or carcinoma
in situ of the urethra (LE: 3, GR: C).
14. Sved PD, Gomez P, Nieder AM, Manoharan M, Kim SS,

Soloway MS (2004) Upper tract tumour after radical
cystectomy for transitional cell carcinoma of the bladder:
incidence and risk factors. BJU Int 94, 785-789
In patients with urethral recurrence and

concomitant distant recurrence outside the
urinary tract, systemic chemotherapy is indicated
(LE: 3, GR: C).
15. Tran W, Serio AM, Raj GV, Dalbagni G, Vickers AJ,

Bochner BH, Herr H, Donat SM (2008) Longitudinal risk
of upper tract recurrence following radical cystectomy for
urothelial cancer and the potential implications for longterm surveillance. J Urol 179, 96-100
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341
342
Committee 7
Urinary Diversion
Chairs:
Bjoern G. Volkmer
Members:
Hassan Abol-Enein, Thomas Davidsson, Sigurdur Gudjonsson,
Stefan H. Hautmann, Henriette V. Holm, Cheryl T. Lee,
Fredrik Liedberg, Stephan Madersbacher, Murugesan Manoharan,
Wiking Mansson, Robert D. Mills, David F. Penson,
Eila C. Skinner, Raimund Stein, Urs E. Studer,
Joachim W. Thueroff, William H. Turner
Corresponding Author:
Professor of Urology
University of Ulm
Boschstrasse 4 a
89231 Neu-Ulm
Tel.: +0049 731 153 8750
FAX +0049 731 153 8752
e-mail: richard.hautmann@uni-ulm.de
343
Table of Contents
III. TYPES OF URINARY DIVERSION
I. INTRODUCTION
1. ORTHOTOPIC BLADDER SUBSTITUTION

IN MEN
II. GENERAL ASPECTS OF URINARY

DIVERSION
2. ORTHOTOPIC DIVERSION IN FEMALES

3. C
ONTINENT CUTANEOUS URINARY
DIVERSION
1. URINARY DIVERSION AND RENAL

FUNCTION
4. CONDUIT URINARY DIVERSION
2. SECONDARY TUMORS AFTER URINARY

DIVERSION
5. URETEROSIGMOIDOSTOMY
3. COMPLICATIONS
6. PALLIATIVE URINARY DIVERSION
4. URINARY DIVERSION AFTER PELVIC

IRRADIATION
7. U
RINARY DIVERSION IN THE PEDIATRIC
AGE GROUPSPECIAL CONSIDERATIONS
IV. RECOMMENDATIONS
5. PREGNANCY AND URINARY DIVERSION
344
Urinary Diversion
Richard E. Hautmann, Bjoern G. Volkmer
Hassan Abol-Enein, Thomas Davidsson, Sigurdur Gudjonsson ,
Stefan H. Hautmann, Henriette V. Holm, Cheryl T. Lee,
Fredrik Liedberg, Stephan Madersbacher, Murugesan Manoharan,
Wiking Mansson, Robert D. Mills, David F. Penson,
Eila C. Skinner, Raimund Stein, Urs E. Studer,
Joachim W. Thueroff, William H. Turner
recommendations given are again of Grade C
only [1]. Grade C recommendation is given when
expert opinion is delivered without a formal analytical
process. In order to check the power of the expert
opinion and the validity of the consensus reached
by the diversion group, each committee member
disclosed the experience, surgical volume, and types
of diversions used at his or her home institution. The
results are presented in Table 1.
I. Introduction
Radical cystectomy and urinary diversion have
been assessed the highest relative value in terms
of difficulty of the surgery for any procedure in urology. They are also the most difficult laparoscopic or
robotic procedures and more so if the diversion is
performed totally intracorporeally. The risk of cystectomy and urinary diversion is based not only on
the technical challenges of the procedure but also
on the nature of the patients need. The incidence
of bladder cancer increases continually with advancing age; thus, the responsibility of providing optimal
surgical treatment for elderly and possibly frail patients is common among urologists. Improvement in
patient rehabilitation is noteworthy through continent
cutaneous diversions and neobladders and better
enterostomal therapy support. In this context, there
must remain continued emphasis on refining the surgical technique of radical cystectomy and urinary diversion to provide utmost safety for the patient.
Our expert opinion is based on almost 16,000

diversions and radical cystectomies performed in 3
continents (Africa, USA, Europe). This committee
represents a well-balanced combination of pioneering
institutions of any type of diversion, high volume
centers and surgeons, as well as data from low
volume institutions, plus a leading pediatric urology
institution and the Swedish registry for bladder
cancer, which reports any case from Sweden,
including treatment, that has been observed in the
respective period.
Some conclusions from Table 1 are:
Only 3/11 institutions have experience with any
The International Consultation on Urological

Diseases (ICUD) has looked at published evidence
and produced recommendations at various levels.
For proper assignment to levels of evidence,
one has to consider study design (prospective,
retrospective), number of patients enrolled, if the
study cohort consists of all patients available or
not, type of assessment tool and its psychometric
properties
(validity/reliability),
and
response
rate. Unfortunately, not a single randomized
controlled study within the field of urinary
diversion exists. Consequently, almost all studies
used in this report are of Level 3 evidence good
quality retrospective studies or case series or
Level 4 evidence including expert opinion based on
first principles research. Therefore, the grades of
type of diversion.
A
nal diversions play no role in the US, but are of
value in pediatric patients and in the third world.
Continent cutaneous diversions play a secondary
role; even former pioneering institutions (LA) use it

with decreasing frequency.
Conduit (42.2%) and neobladder (38%) are the

standard diversions at large centers.
T
ruly population-based data from the USA [2] and
from the Swedish Bladder Cancer Registry (S.

Jahnson, Linkping, Sweden) show a neobladder
rate in the range of 15%; with increasing hospital
volume the neobladder/continent diversion rate
345
approaches 75%, addressing the impact of hospital

volume on the use of continent reconstruction and
the question of continent diversion being a new
parameter for measurement of quality of care. Our
group considers these data a further argument for
the centralization of radical cystectomy and urinary
diversion.
hospital case load. We need realistic criteria! Our

committee considers a minimum annual case load
of 25 radical cystectomies done by not more than
two surgeons, to be the basis of a high volume
center.
A
nother major difficulty the committee had to master
was the lack of standardized reporting in the

urological literature. Recently Donat emphasized
the need for standardized reporting of outcomes
and complications, especially in urological
oncology, because of the mostly elderly population
and the associated comorbidities [3]. Radical
cystectomy and urinary diversion are 2 steps of
one operation. However, the literature uniformly
reports the complications of radical cystectomy
while ignoring that the majority complications are
diversion-related. While this may seem semantic,
it is not [4].
A
detailed analysis of Table 1 brings us to the key
question for criteria used to define the limits for

low, intermediate, and high annual hospital and
surgical case load. In most publications, one single
radical cystectomy per year was defined as low
annual surgical case load, 2 radical cystectomies
per year are intermediate, and 3 or more radical
cystectomies per year as high. Even though 2
cases per year represent 100% more than one
radical cystectomy per year, from a practical point
of view, these surgeons have a very low case load.
On the other end, a surgeon who performs 3 or 4
radical cystectomies is already defined as a high
volume surgeon. So, the limits appear to be chosen
totally arbitrarily. The same applies to the annual
Until recently, significant disparity in the quality of

surgical complication reporting as well as the lack of
universally accepted reporting guidelines, definitions,
Table 1. Numbers and Types of Urinary Diversions (%) performed by the Authors
Period
Neobladder
Cont.Cut.
643
95-04
45.1
1.4
53.5
962
00-09
40.0
2.0
58.0
0.9
611
85-99
51.5
1.5
42.5
1.6
2.5
0.4
Ann Arbor
Bern
Conduit
UC
Anal
TUUC
No
diversion/ others
unknown
No. RCX
708
00-10
51.0
8.0
39.0
1.5
0.5
0.1
Kassel
765
94-10
30.2
6.8
60.5
0.7
2.0
0.1
Los
Angeles
1359
71-01
51.6
25.8
22.3
0.3
1012
00-10
74.2
5.3
20.2
0.3
119
00-04
28.6
31.1
40.3
134
04-09
6.0
30.6
63.4
335
68-80
55.0
45
593
81-90
2.0
33
41.0
15
982
91-00
6.0
39
41.0
12
1023
01-10
15.0
24
53.0
Mansoura
3157
80-04
39.1
3.5
34.4
23.1
246
02-09
10.6
89.4
158
1997
19.0
19
55.0
221
2003
17.0
12
70.0
208
2006
9.0
80.0
Lund
Mainz
Norwich
Swedish
Registry
229
2008
15.0
81.0
1613
86-09
66.0
0.4
22.0
10.0
1.3
0.2
Vanderbilt
789
00-07
35.5
0.4
63.5
0.1
0.5
15867
38.0
10.4
42.2
1.2
7.5
0.1
0.8
Ulm
Total
346
and grading systems have made it impossible to

compare the surgical morbidity and outcomes in
patients who have undergone cystectomy. There
is a clear case for reporting of complications in a
standardized way. The Clavien system provides
such a straightforward and validated instrument, and
it has already been successfully adopted by several
urological centers [4, 5].
stenosis; stone formation; and reflux of infected

urine.
The pathological changes seen with varying
etiologies are the same, and thus the cause at the
time of detection may not be obvious. As well a
natural age-related decline, estimated to be 1 mL/
min each year over the age of 50 [8], may occur, and
there may be many non-urologic causes for declining
renal function including hypertension, diabetes, and
drugs.
This article discusses the reconstructive options

after radical cystectomy due to bladder cancer or
other conditions, the criteria for selection of the
most appropriate procedure, and the outcomes and
complications associated with the available diversion
options.
Many studies that report on renal function after

urinary diversion are small with limited follow-up
and report retrospectively on serum creatinine with
or without ultrasound or intravenous urography
(IVU) appearance. This is unfortunate as the serum
creatinine remains within normal limits until there has
been approximately a 50% reduction in GFR and the
presence of upper tract dilation does not necessarily
equate to a reduction in renal function.
II. General Aspects of

Urinary Diversion
1. Urinary Diversion and Renal
Function
Ideally, for an accurate assessment of function

we should rely on serial isotopic GFR. 51 Cr-EDTA
is used frequently as it is freely filtered through
glomeruli and minimally reabsorbed from intestinal
segments. Measurement of pre- and postoperative
renal function using radioisotope studies would
provide the best information on the safety of lower
urinary tract reconstruction with regard to the upper
tracts.
a) Preoperatively
Renal function has an important bearing on outcome
following urinary reconstruction as there is an
increase in acid load as a result of absorption of
urinary constituents through the bowel mucosa. The
larger the surface area of bowel and the greater the
contact time with urine, the greater the acid load will
be. Thus, continent reconstruction poses a greater
potential problem than conduit urinary diversion. In
the presence of normal renal function, most patients
with a continent reservoir are able to compensate,
provided the reservoir is emptied to completion at
regular intervals. In the presence of renal impairment,
the ability to cope with the increase in acid load is
reduced, which may result in a metabolic acidosis.
Kristiansson et al reported 10-year follow-up using

51
Cr-EDTA isotopic GFR on patients who were
randomized to an ileal (n=18) or colonic (n=20)
conduit as well as a refluxing or non-refluxing
ureteroileal anastomosis [9]. Thirty-four percent
of patients had a drop in GFR of more than 25%,
40% in the colonic group and 28% in the ileal group.
There was no difference in GFR reduction between
refluxing and non-refluxing ureteroileal anastomoses,
although renal scarring and bacteriuria were more
common with a refluxing anastomosis. Ureteroileal
strictures developed up to 14 years postoperatively.
In these patients, ureteric reimplantation improved
renal function in 6 of 7 renal units, and balloon
dilation improved renal function in 1 of 5 renal units.
There is no exact renal function cutoff below which

continent urinary reconstruction should not be
performed, but, as a general guide, in the presence
of a serum creatinine >150 mol/l or glomerular
filtration rate (GFR) < 50 mL/min, one should avoid a
continent diversion [6].
One proviso is in the presence of obstructive renal
impairment, drainage may be performed to allow
renal function to recover before a final decision is
made. Continent urinary diversion has also been
performed as a staged procedure in preparation for
renal transplantation in patients with end-stage renal
disease [7].
b) Postoperatively
More recently, Samuel and colleagues using serial

isotope GFR have reported follow up of more than 4
years in 178 patients who had an ileal conduit with
freely refluxing ureteroileal anastomoses [10]. Fiftytwo (29%) demonstrated a worsening GFR of more
than 5% (mean 31%) at a mean of 8.2 years. In 33
(18%), there was no identifiable obstruction as a
cause for deteriorating GFR.
There are many potential reasons for deterioration in

renal function following urinary diversion including:
transmission of high pressure to the upper urinary
tract secondary to obstruction, physical or functional,
at any sitein particular ureteroileal and stomal
In a single center non-randomized retrospective

comparison of 275 patients with minimum follow-up
of 12 months (mean 52) who underwent ileal conduits
or orthotopic bladder substitution, Song et al reported
hydronephrosis in 1.4%, 8.3%, and 6.3% following
347
ileal conduit (n=78), orthotopic bladder substitution

with refluxing anastomoses (n=86), and orthotopic
bladder substitution with antirefluxing anastomoses
(n=11), respectively [11]. Chronic renal failure
(defined as creatinine above 3.0 mg/dL) occurred in
7.7% of those in the conduit group compared with
3.5% of those with a refluxing anastomosis and 2.7%
of those without in the orthotopic bladder substitution
groups. The mean preoperative serum creatinine
was significantly higher in the conduit group and
all of those in the conduit group who progressed
to chronic renal failure were thought to have renal
deterioration unrelated to the urinary diversion.
Pyelonephritis was significantly more common in the
orthotopic bladder substitution groups.
They concluded that ureteroileal obstruction was

the leading cause of renal deterioration following
orthotopic bladder substitution and that it is less
prevalent with refluxing anastomoses to a low
pressure afferent limb detubularized ileal reservoir.
e) Ureterocolonic Diversion
As a result of significant complications, the popularity
of ureterosigmoidostomy declined once conduit
urinary diversion became established. Deterioration
in renal function as a result of high pressure reflux
of infected urine was one of the main concerns.
Modifications in technique have made colonic
diversion a much safer procedure; however, its
popularity remains modest.
c) Continent Cutaneous Diversion

Following continent cutaneous diversion, Kristjansson
and colleagues, using 51 Cr-EDTA isotopic GFR,
reported a decrease in renal function of more than
25% total GFR in 28% of 18 patients 11 years after a
cecal reservoir [9].
Conclusions
Urinary diversion into bowel segments is not
inherently damaging to the kidneys. In general, renal
function after diversion into continent detubularized
reservoirs compares favorably with ileal conduit
diversion. However, the literature is insufficient to
recommend one form of diversion over another.
There remains a long-term risk of renal deterioration,
which is often asymptomatic, and thus close followup is necessary for all patients who have undergone
urinary diversion in order to identify correctable
causes early.
In another paper, Jonsson reported follow-up on

126 patients up to 25 years (median 9.5) post Kock
pouch [12]. They recorded a reduction in 51 Cr-EDTA
GFR from 6 years onwards, but this was equivalent
to that expected in relation to aging. It was concluded
that renal function was not affected by the diversion
as long as obstruction was recognized early and
managed appropriately.
Those with renal pathology prior to surgery seem to

be at greatest risk of postoperative renal deterioration.
Serum creatinine is an imprecise measure of renal
function. Isotopic GFR measurement will detect
renal function deterioration most accurately and at
an early stage. The latter, however, is not available
to all patients. In these situations, follow-up with
serum creatinine and ultrasound should be followed
by diuresis renography if upper tract dilation is
seen. Early intervention for physical obstruction
often results in a sustained improvement in renal
function.
Fontaine et al reported over 10 year follow-up of a

heterogeneous group of 53 patients with bladder
exstrophy 37 continent cutaneous diversions and
16 with the urethra as the continence mechanism
[13]. Using 51 Cr-EDTA clearance, they found no
deterioration in renal function in 43 of the 53. In
the remaining 10 (19%), which consisted of 8 with
a Mitrofanoff combined with either ileal or sigmoid
augmentation or pouch, 1 with a Kock pouch, and 1
with an ileocecal patch and reconstruction onto the
native urethra, GFR fell by 20% or more.
d) Orthotopic Bladder Substitution
2. Secondary Tumors after Urinary

Diversion
As with other types of reconstruction, there are

few long-term reports of GFR following orthotopic
reconstruction. Thoeny and colleagues reported a
prospective analysis in 76 patients with a median
follow-up of 84 months (range 60-155) after a low
pressure ileal afferent limb bladder substitute [14].
a) U
rinary Diversion
Segments
in
Isolated
Bowel
Our review included the patient data presented by

Austen and Klble in their paper published in the
Journal of Urology [15] and in their reply to a letter to
the editor of that journal [16]. Those data had been
obtained through a MEDLINE search up to October
2004. We used the same headings as Austen and
Klble (i.e., urinary diversion and carcinoma), and,
similar to those investigators, we analyzed the data
on latency period, histological findings, tumor location
(ureterointestinal anastomosis vs. distance to the
anastomosis), initial diagnosis leading to urinary
diversion (malignant vs. benign), and treatment of
Preoperative mean serum creatinine +/- 1 SD was 98

+/- 19 mol/L and at 10 years thereafter was 83 +/- 27
mol/L. Twelve (16%) of 76 patients had increased
serum creatinine, 5 of whom had preoperative
dilation or obstruction. In this prospective study,
renal deterioration was seen only in the presence
of pre-existing renal pathology or postoperative
obstruction; however, more precise assessment of
GFR is not available.
348
the secondary tumors. We also included 4 patients

from Lund and Oslo.
20 years ago [19]. All 15 adenocarcinomas appeared

in patients who had undergone surgery due to bladder
exstrophy. Median latency was 37 years (range 1356 years). In 3 patients, conversion to other forms
of diversion had been performed after 8 months,
14 years, and 18 years, respectively, but it was not
reported whether the ureterocolic anastomoses were
removed in those cases.
Table 2 shows the total number of tumors found

in isolated bowel up to August 2010, including the
cases reported by Austen and Klble [15, 16] and 2
cases from Lund. During the period 2004 to August
2010, 15 carcinomas after ureterosigmoidostomy
were described.
It is likely that the etiology of tumor development

after ureterointestinal diversion is multifactorial.
There is evidence of the involvement of increased
levels of N-nitrosamine and/or free oxygen radicals
in response to infection and chronic inflammation.
Until recently, all risk calculations were severely

hampered by the absence of easily accessible hard
data on the total number of procedures performed. As
a courtesy, Klble et al. provided some information
of the first multicenter study that allows us to relate
the number of secondary tumors with the number of
various types of urinary diversions done [18].
Conclusions
Patients who have undergone conduit diversion,
continent cutaneous diversion, or orthotopic bladder
substitution do not seem to be at increased risk of
secondary malignancy. By comparison, the risk is
slightly higher after cystoplasty, albeit not increased
enough to support endoscopic surveillance.
However, the present knowledge regarding gastric
cystoplasty is insufficient, and hence patients should
be followed after such surgery. Furthermore, yearly
colonoscopy is recommended in cases involving
ureterosigmoidostomy, beginning 10 years after the
procedure.
They analyzed the operative records of 44 German

hospitals for urinary diversions performed from
1970-2007 and registered all reported tumors till
2009. In 17,758 urinary diversions, 32 secondary
tumors occurred (Table 3). The tumor risk in
ureterosigmoidostomy (2.58%) and cystoplasty
(1.58%) was significantly higher than in other
continent forms or urinary diversion (p<0.0001).
The risk in orthotopic (ileo)colonic neobladders
(0.97%) was significantly higher (p=0.0001) than in
ileal neobladders (0.05%). The difference between
ileocecal pouches (0.18%) and ileal neobladders
was not significant (p=0.46), and the tumor risk with
ileal conduits was minimal (0.02%), (Table 4).
3. Complications
Any critical analysis and comparison of urinary
diversion technique centers around the questions:
Is there a perfect solution? or: Which diversion
technique is the best? or: Which one has the lowest
complication rate? At this point our committee must
disappoint the readers of this report and rather
explain why it is absolutely inappropriate to ask
these questions.
b) Ureterosigmoidostomy
Since 2004, there have been reports of 15
adenocarcinomas
and
8
adenomas
after
ureterosigmoidostomy (a reference list can be
obtained from the present authors), and descriptions
of more than 200 cases had already been published
Table 2. Secondary tumors after diversion using isolated gut segments

Ileum
Colon
Ileocecal
Stomach
Total no.
15+1*
22
Continent cutaneous
14**
14
Neobladder
Rectal bladder
Cystoplasty
41
15
10
68
Total
60
42
10
114
Conduit
From publications by Austen and Klble (15,16), since 2004, and 4 Lund cases.
* This case was transferred from continent cutaneous diversion using colonic segment.
**Includes 2 Lund cases (described in this paper) but excludes a case (17) from Austen and
Klble, that is now transferred to the ileal conduit group.
349
Table 3. Numbers of Secondary Tumors in 17,758 Urinary Diversions

no.
secondary
tumors
no. diversions
%
median
latency period
(years)
Neobladder Ileal
4190
(0.05 %)
3.0
6.3
Neobladder Ileocoecal
239
(1.26 %)
4.0
13.6
Neobladder Colonic
70
(1.43 %)
6.0
9.9
Pouch Ileocoecal
2181
(0.18 %)
12.0
8.8
Ileocystoplasty
233
(1.71 %)
21.5
10.5
Colocystoplasty
20
Conduit Ileal
8637
(0.02 %)
11.0
8.9
Conduit Colon
430
(0.23 %)
40.0
24.4
Ureterocutaneostomy
1138
Ureterosigmoidostomy
16
620
(2.58 %)
32
17,758
Total
mean time
operation to
analysis
(years)
4.9
10.3
26.0
18.9
Klble 2011
Table 4. Tumor Risk in Continent and Incontinent Urinary Diversion

Ileum
(ileo-)colon
total
Conduit
0.02%
0.23%
0.03%
p=0.84
p=0.0091
Pouch/Neobladder
0.05%
0.28%
0.13%
Total
0.03%
p=0.00001
0.08%
p<0.0001
Cystoplasty
0.27%
1.71%
0.00%
1.58%
2.58%
p=0.46
Klble 2011
350
Muscle-invasive bladder cancer occurs in a
data on long-term complications that consider

their time-dependency will be comparable.
Otherwise, complications that occur early are
overrepresented, while those occurring late might
be underrepresented, since the number of patients
will decrease over time [20].
comorbid population with a mean age of 65-69

years in contemporary radical cystectomy series.
The incidence of early complications, defined as
occurring either during the hospital stay or within 90
days of surgery, has been reported in the range of
20-57% [5]. Therefore, accounting for the impact of
surgical morbidity on patient outcome is essential
for treatment planning, for clinical trial design, and
for assessing new surgical techniques.
An ideal methodology for reporting adverse events

related to surgical therapy should include 10
established basic reporting criteria [5]: (1) a clear
description of the method of data acquisition, (2)
an indication of the duration of follow-up, (3) an
indication of whether or not outpatient complication
data are included, (4) definitions/inclusion criteria
of at least one complication, (5) an indication of the
mortality rate and cause of death, (6) an indication
of the morbidity rate (number of patients and the
total number of complications recorded), (7) an
indication of procedure-specific complications, (8)
the utilization of a grading system to clarify severity
of complications, (9) an indication of the median
or mean length of stay, and (10) an indication of
the methodology utilized to assess patient risk
stratification (e.g., Charlson-Romano index, ASA
scoring).
A recent evaluation of the urologic oncology

literature revealed that the majority of series that
reported on radical cystectomy morbidity had not
employed a formal complication reporting system,
had not utilized grading systems other than
categorizing them into major versus minor, had
not accounted for comorbidities, or had not defined
complications. This makes it impossible to compare
data and most certainly leads to an underestimation
of morbidity for the procedure. In addition, the
incidence of perioperative complications have
often been utilized as surrogate measures of
surgical competency, institutional quality of care,
success of new surgical techniques, and have
even been suggested as benchmarks for financial
reimbursement [5].
Recently, efforts have been made to standardize

the reporting of early complications. The Clavien
system in the Memorial Sloan-Kettering Cancer
Center modification has proven to be a useful tool to
classify these complications according to domains
(e.g., genitourinary, gastrointestinal, infectious)
and grades [5]. Unfortunately, this system is less
suitable for reporting long-term complications [20].
T
he difficulty in comparing complications across
series is manifold. The lack of standardization is

hampering the progress of reducing morbidity and
complications associated with radical cystectomy.
Radical cystectomy and urinary diversion are two
steps of one operation. However, the literature
notoriously reports on complications of radical
cystectomy, ignoring that the vast majority of
complications are diversion-related. This may
seem semantic, but it is not [4]. This is of particular
importance for this consensus report.
The recent literature on urinary diversion shows a

trend to the increasing use of standardized reporting
of complications in urologic oncology, in particular of
complications of urinary diversion (4, 5, 20]. Table
5 presents a representative example of adequate
reporting: It is the summary of neobladder-specific
early ( 90 days) complications in 1013 patients
with neobladders. Table 6 presents an attempt
to compare diversion-related complications in a
realistic way [20, 21, 22].
Until recently, any publication on cystectomy and
urinary diversion complication rates has reported

the rates by simply dividing the absolute number
of events by the total number of patients treated,
irrespective of the time to the complication onset.
Early complications occur in a short and well-defined
interval of 90 days postoperatively. Stratification of
complication rates to the first, second, or third month
postoperatively is not meaningful. In contrast, longterm complications may occur decades later. Since
most complications develop time-dependently,
they should be reported using the Kaplan-Meier
method for time-dependent events in analogy to
reporting tumor recurrence. This can easily be
explained by the example incisional hernias.
We observed 41 hernias in 923 patients (4.4%).
In contrast, the Kaplan-Meier method revealed a
rate of 6.4% at 10 yearsa 45% higher rate than
that published usually. Standardization of reporting
long-term complications does not only impact on
definitions but also an statistical analysis. Only
Conclusions
Surgical morbidity following urinary diversion is
significant and, when strict reporting guidelines
are incorporated, higher than previously published.
Accurate reporting of postoperative complications
after radical cystectomy is essential for counseling
patients, combined modality treatment planning,
clinical trial design, and assessment of surgical
success. Specific diversion related complications,
i.e., neobladder-vaginal fistula or hypercontinence
following orthotopic bladder substitution in women
are reported in the respective sections.
351
Table 5. Neobladder specific complications within 90 days of surgery by category in 1013 patients with
neobladders
no
complication
category
Grade
1
Grade
2
Grade
3
Grade
4
Grade
5
complications
38
146
35
12
236 (23.3%)
Total
infection
777 (76.7%)
abscess
988
20
25
UTI
837
38
138
176
sepsis
978
15
12
35
genitourinary complications
843 (83.2%)
100
64
170 (16.8%)
renal failure
995
11
18
ureteral obstruction
965
16
31
48
urinary leak
948
44
21
65
urinary fistula
1002
11
urinary retention
985
23
28
miscellaneous
918 (90.6%)
95 (9.4%)
metabolic acidosis despite treatment

surgical
1007
985 (97.2%)
28 (2.8%)
1010
incisional hernia
Grade 1: oral medications

Grade 2: intravenous medications
Grade 3: interventional radiology or operation
Grade 4: lasting disability or organ resection
Grade 5: death
Hau J Urol, 2010
Table 6. Diversion-specific (not cystectomy) long term complications * using non-standardized reporting
f.u. median
patients
Conduit
Bern
Neobladder
Ulm
Mayo
(years):
8.1
6.3
6.0
(n=)
131
1,057
923
complications
(n=)
192
1453
---
patients with
(n=):
87/131
643/1057
376/923
patients with
(%):
66.0
61.0
40.8
within years:
5:
45
50
10:
50
68
15:
54
70
Reoperation rate (%):
20:
94
40
80
6
Complications (pts/%):
bowel
32
(24%)
215
(20.3%)
31
(3.4%)
(5.0%)
UTI
30
(23%)
174
(16.5%)
46
stoma
32
(24%)
163
(15.2%)
anastomosis
18
(14%)
122
(11.5%)
102
(11.5%)
(0.2%)
urolithiasis
12
(9%)
162
(15.3%)
renal function
35
(27%)
213
(20.2%)
* Bern :
Mayo:
Ulm:
> complications 3 months ; > 5 years follow-up
Madersbacher J Urol, 2003
> 30 days of surgery
Shimko
J Urol, 2011
> 3 months of surgery
Hautmann
J Urol, 2011
352
4. Urinary Diversion after Pelvic

Irradiation
another method to increase or boost the dose to the

prostate. While such dose escalation may improve
local control of the prostate cancer, any salvage
surgery may become that much more difficult.
Earlier detection of treatment failure using PSA may
increase the pool of patients potentially suitable for
salvage surgery, but it is uncertain if earlier and more
aggressive surgery will translate into better results
with acceptable morbidity. Bladder preservation
strategies will also provide a greater challenge for
salvage surgery. Fortunately, the dose of external
radiation therapy to the pelvis for bladder cancer
is less than that delivered for prostate cancer ( 60
Gy).
Tumor recurrence of a urologic, gynecologic or

gastrointestinal tumor or a defunctionalized bladder in
patients who had received definitive radiation therapy
may be followed by salvage radical cystectomy.
Historically, these patients have been considered to
have a risk of significant postoperative morbidity and
unsatisfactory functional results. Complications have
been attributed to radiation damage to the ureter and
bowel, resulting in increased rates of anastomotic
problems, upper urinary tract obstruction, and
infection. Therefore, most centers use supravesical
urinary diversion with a transverse colonic segment
[23-29) or cutaneous ureterostomy.
During pelvic radiotherapy for cancer, the cecal pole

as well as parts of the ascending colon, appendix,
and ileum are exposed to considerable doses of
radiation. Since these segments of bowel are used
for reservoir and afferent segment construction, it
is plausible that the high complication rate that was
observed was secondary to radiation damage of the
intestinal segments.
In a series of patients with urinary diversion after

pelvic irradiation [30], 58.5% of these patients
experienced one or more complications occurring
within a 90 day period from the date of surgery.
Seventy-seven percent
of the
patients with
neobladders versus 52.2% of the patients without
neobladders had complications. The rate of grade
3-5 (major) complications, according to the modified
Clavien system of the Memorial Sloan-Kettering
Cancer Center, was 28% in patients with neobladders
and 31.9% in patients without neobladders. The
majority of these complications were classified
as genitourinary or infection-related. In-hospital
mortality was 0% for patients with neobladders and
11.6% for patients without neobladders . In 10 of 25
patients with orthotopic reconstruction, serious and
highly unusual late complications were observed,
e.g., spontaneous ileal perforation, ileal stenosis,
stenosis of the descending colon, spontaneous
neobladder perforation, and neobladder-vaginal
fistula.
Limited data are available on the outcome of

continent urinary diversion in patients with previous
pelvic irradiation [23, 24, 26, 31].
Bochner et al [32] reported the outcome of
orthotopic ileal urinary diversion during salvage
cystoprostatectomy after failed radiation for
bladder and prostate cancers. They noted a total
of 6 complications (33%) in 18 patients, including
prolonged urinary leakage in 2, and afferent nipple
stenosis, ureteral stenosis, enteropouch fistula,
and urinary retention in 1 each. The reoperation
rate during the mean 28 month follow-up was 17%.
Of the patients, 33% were incontinent during the
day and 44% were incontinent at night. Gheiler et
al [33] reported a similar experience. Brand [34]
described cecal rupture after Indiana ileocecal
continent diversion as a postoperative complication,
underlining the vulnerability of the irradiated cecal
region. Other than this report, all published studies
of the results of continent cutaneous and orthotopic
urinary diversion in irradiated patients have an
average follow-up of only 1-2 years. Nevertheless,
alarmingly high open reoperation rates of up to 25%
have been reported during this limited follow-up.
Comparing results in early publications [35, 36] with
subsequent data published many years later by the
same groups clearly demonstrates that conclusions
based on small series with limited follow-up may be
misleading.
This series confirms the high morbidity of radical

cystectomy in a comorbid population with
experienced surgeons in a high volume institution.
Salvage treatment after failure of the initial therapy
for localized cancer is always more difficult. These
patients are an adversely selected group because
the first attempt of curative treatment had failed.
Judgment is required to decide who should have a
surgical resection after previous radiation therapy,
and then technical expertise is needed to do the
operation with acceptable success. This series adds
to the evidence that salvage surgery for bladder
and prostate cancer, as well as gastrointestinal and
gynecologic cancers, can be done safely. Overall
complication rates are higher than those noted in
patients without previous radiation therapy [30].
In the future, the problems with salvage are likely
to increase. Dose escalation for prostate cancer
radiation therapy is a potential reason. Currently,
the dose to the prostate with conformal radiation
therapy is 74-78 Gy. Implant radiation, either by
itself or combined with external radiation therapy, is
Since radiation damage is historically known to

increase with time, these aspects are especially
important when evaluating complications of surgical
procedures in irradiated patients. Proper patient
selection for salvage surgery has also contributed
to the improvements in long-term outcome [37].
Selection of appropriate surgical candidates for
353
salvage therapy depends on several factors:

recurrent prostate or bladder cancer versus
gastrointestinal or gynecologic cancer, extent of
recurrent disease, and existence of fistula formation.
It is believed that patients with more advanced local
disease, refractory voiding symptoms related to a
fibrosed non-functional bladder, or severe symptoms
related to other complications associated with the
prior irradiation will be better served with cystectomy
and lower urinary tract reconstruction. Based on the
published long-term experience, salvage surgery
(cystoprostatectomy, anterior exenteration) with
orthotopic lower urinary tract reconstruction is a
safe, effective procedure that can provide a potential
curative intervention and a functional lower urinary
tract for properly selected patients in whom previous
definitive radiation therapy has failed, with results
only marginally worse as compared to non-irradiated
patients, at least in high volume centers [38].
diversion [39].
There are no contraindications against a Cesarean
section.
Cesarean section
cautiously in:
should
be
performed
very
patients with intraperitoneal hydrocephalus shunts

patients with pouches, enterocystoplasties, or
neobladders
c) Special Aspects
1. W
hich form of urinary diversion should be
recommended in young patients who plan to have
children?
Our review of the literature shows a successful

course of pregnancy is possible with all types of
urinary diversion. We therefore strongly recommend
that the choice of the type of urinary diversion should
consider first the individual situation and needs of
the patient, but with secondary respect to a potential
pregnancy.
5. Pregnancy and Urinary Diversion

Fertility-sparing cystectomy is restricted to children or
premenopausal women with benign diseases. Once
the problems associated with urinary incontinence
have been solved and the patients have reached
puberty, sexuality and fertility become more
significant. At this time the medical responsibility
shifts from the pediatrician and pediatric urologist to
the gynecologist and general practitioner. However,
these colleagues rarely have major experience with
the psychological aspects of sexuality, fertility, and
pregnancy in these patients. Meanwhile, all functions
of female sexuality can be preserved, if a fertilitysparing cystectomy and urinary diversionincluding
a neobladderis performed. Consequently, the
patients desire for a normal sexual life has to be
respected.
2. Is simultaneous sterilization an option?

In the twentieth century, the majority of patients with
urinary diversion had simultaneous sterilization. The
first patient who became pregnant following urinary
diversion did so despite previous sterilization.
Nowadays, sterilization of patients undergoing
urinary diversion is not performed routinely, since
pregnancy is not considered contraindicated in
patients with urinary diversion.
3. Are there medical indications for an

interruption?
In 1972, Olesen recommended a therapeutic
abortion if the renal function was abnormal when
pregnancy was diagnosed [40]. Since the difficulties
of saving the renal function during pregnancy
have been ameliorated, we think that this general
recommendation should be obsolete in 2011.
a) Childbirth
In all patients with urinary diversion, the form of
delivery must be planned considering many relevant
aspects: potential damages to the urinary diversion
by the Cesarean section, potential damages to the
pelvic floor by vaginal delivery, special anatomic
problems of the mother, and, last but not least, the
health of the child.
4. W
hat examinations are recommended before,
during and following pregnancy?
Richmond et al suggest that whenever possible,
counseling of patients with myelomeningocele
should be done before conception, when radiological
pelvimetry and renal function assessment could be
carried out without risk to the fetus in utero [41].
Vaginal delivery should be performed with caution

in:
patients with ureterosigmoidostomy

patients with malpresentation
All pregnant women with any type of urinary

diversion should be assessed (ideally antepartum)
by an multidisciplinary team of experts, involving
the obstetrician (perinatologist), urologist, obstetric
anesthesiologist, general surgeon, neonatologist,
and nursing staff who work together to develop
(tailor) the optimal peripartum plan on a case-bycase basis [42].
patients with cervical prolapse

b) Cesarean section:
Hensle et al consider the elective scheduling of a
Cesarean delivery before the onset of labor the
preferred method in patients with urinary diversion,
in particular in those with orthotopic continent urinary
354
patients with ureteral reflux,
Kennedy et al recommend an initial screening

maternal ultrasound examination at 20 weeks of
gestation to look for maternal hydronephrosis.
Follow-up maternal renal ultrasound examinations
should be performed if hydronephrosis is noted
initially or for recurrent episodes of pyelonephritis
[43].
patients with impaired renal function,

patients requiring catheterization, and patients with
ureterosigmoidostomy.
7. Pregnancy following urinary diversion and

renal transplantation
In Germany, the patient is seen by the obstetrician

every 4 weeks during the first 4 months of gestation,
every 3 weeks during the next 3 months, every 2
weeks during the next 2 months, and then in weekly
intervals until delivery. We strongly recommend
that the patient be seen by a urologist at the same
intervals until delivery. The urologist should perform
urinalysis, microbiologic controls of the urine, renal
ultrasound (including estimation of the resistive
index, when hydronephrosis is present), and controls
of the storage function and emptying of the urinary
diversion.
The first successful pregnancy after renal

transplantation ended in 1958 with the delivery
of a healthy child [45]. Since that time, a growing
number of reports on successful pregnancies have
been published. Problems like immunosuppression,
impaired renal function, and obstructive uropathy
may lead to a much less favorable prognosis as for
pregnancy in patients with urinary diversion alone.
Until today, only 3 pregnancies in women with a kidney
transplanted to an ileal conduit were reported. In 2
cases, pregnancy had to be terminated in the tenth
and twenty-second weeks, respectively, because of
progressing renal failure from compression of the
ileal loop [46]. The only successful pregnancy was
published by Hein et al [47]. Their patient had a
neurogenic bladder caused by an occult spina bifida.
At the age of 14, an ileal conduit was created. Nine
years later, the patient suffered from progressive
renal failure caused by chronic pyelonephritis. She
underwent bilateral nephrectomy. At the age of 26
years, a living donor kidney transplantation was
performed. Four months later, the patient became
pregnant. In the thirty-fifth week, an intermittent
obstruction of the left ureter was noted, leading to the
decision of terminating the pregnancy. Delivery of a
healthy male was accomplished by a low segment
Cesarean section because of a narrow pelvic cavity.
The postoperative course was uneventful.
5. What information on reconstructive urology

does an obstetrician need?
The obstetrician needs complete information on
the anatomic situation of the patient with urinary
diversion. The knowledge of all reports on surgical
procedures performed in the particular patient in
the past is compulsory. Precise information on the
fixation points of the urinary diversion and of the
course of the ureters is necessary. Urological input
at the time of surgery helps identification of the lower
urinary tract anatomy, prompt recognition of any
inadvertent urinary tract injury, and assistance in the
repair of any damage.
6. Is long-term antibiotic prophylaxis required

during pregnancy with a urinary diversion?
8. Pregnancy tests in patients with urinary
Symptomatic urinary tract infection is a problem

encountered in a large proportion of patients with
urinary diversion. Contributing factors to urinary
tract infections are urinary stasis, difficulty with
clean intermittent catheterization, and ureteric
compression.
diversions
In a recent study, Nethercliffe and coworkers

analyzed urine of patients with urinary diversion
using the Clearview pregnancy test (Unipath
Ltd. Bedford, England) [48]. Although all of these
patients were not pregnant, positive pregnancy tests
were found in 8 women and 5 men (false-positive
rate: 57%). The authors suggest that the mucus
produced in enterocystoplasties may interfere with
the pregnancy test. Patients and doctors have to be
aware of this [49] .
Twenty-one percent of the patients reviewed had

premature labor, presumably related to the high
incidence of lower urinary tract infections and acute
episodes of pyelonephritis. The authors advocated
aggressive antibiotic therapy for all urinary tract
infections in this group of patients [44]. Therefore,
Hensle et al considered it advisable to keep all these
women on antibiotic prophylaxis through pregnancy
[39].
III. Types of Urinary Diversion
We think that a low-dose antibiotic prophylaxis is at

least advisable in the following patients:
1. Orthotopic Bladder Substitution

in Men
patients with a history of febrile UTI during
a) Indications and Tumor Stage
patients with hydronephrosis,
The indication for cystectomy is almost always

bladder cancer. The extent of pelvic disease has little
pregnancy,
355
bearing on the appropriateness of orthotopic bladder

substitution. If pelvic recurrence does develop, it
does not usually have a significant impact on the
function of an orthotopic bladder substitute, and
patients who have positive pelvic nodes can achieve
good functional results with orthotopic bladder
substitution [50, 51].
chance of maintaining erectile function. In men with

an orthotopic bladder substitute, who had attempted
nerve-sparing, nighttime continence was better
than in those who did not [54]. The rate at which
nighttime continence was achieved and the final
nighttime continence rate were both improved. This
results from preservation of the afferent intrapelvic
anatomic sensory nerve supply to the pelvic floor
and external urethral sphincter [55] with preserved
urethral sensation. An impaired urethral sensation
is associated with poorer continence [56]. Nerve
sparing also preserves the efferent autonomic
innervation to the sphincteric smooth muscle, which
may mediate resting pressure generation (tonus).
The risk of urethral recurrence after orthotopic

bladder substitution is generally 5-10% and it usually
occurs in the first 3 years when it does happen. A
high risk is a contraindication to orthotopic bladder
substitution, but prediction of risk is not simple.
Reported risk factors for urethral recurrence include
multifocal disease, carcinoma in situ, prior intravesical
chemotherapy, ureteric disease, and urothelial
cancer in the distal prostatic urethra. Furthermore,
prostatic urothelial carcinoma is common. If whole
mount pathologic assessment of the prostate is done
after cystoprostatectomy, detection rates are nearly
50% [52, 53]. Most patients with prostatic disease,
however, do not develop urethral recurrence. So,
unless there is obvious disease in the prostatic
urethra, we perform distal prostatic urethral biopsies
before surgery and then construct an orthotopic
bladder substitute if these are negative. Paraffinembedded biopsies are more reliable than an
intraoperative frozen section. Nevertheless, an
intraoperative frozen section of the resection margin
is considered sufficient by many centers. Biopsies
done before cystectomy also enable discussion of
the result with the patient, who then has greater
certainty that orthotopic bladder substitution will be
possible at the time of cystectomy.
If tumor characteristics permit, then nerve sparing

should be attempted. This can be bilateral if disease
is not muscle-invasive, or unilateral if there is
lateralized muscle-invasive disease. In men, the
nerves are at particular risk dorsolateral to the
seminal vesicles, in the vesicoprostatic angle, and in
the region of the prostatic apex.
e) Reservoir Configuration
An orthotopic bladder substitute must be a lowpressure reservoir of adequate capacity (allowing a
socially acceptable voiding interval without urinary
leakage) and must empty to completion. If this is
so, the upper urinary tracts will be preserved, and
metabolic disturbance will be minimal. Many surgical
techniques have been reported but some key factors
are alike. Detubularization and a spherical shape
ensure that an orthotopic bladder substitute has low
pressure and maximum volume for the length of bowel
used. A spherical reservoir has 4 times the capacity
and a quarter of the pressure compared to a cylinder
made from the same length of bowel. The use of
less bowel reduces the reservoirs surface area and
therefore the chance of absorptive complications,
but larger reservoirs have lower end-filling pressures
[57] and better continence, particularly in the early
postoperative period. This advantage is short-term,
though, and the functional capacity of an orthotopic
bladder substitution that is made from a shorter
segment increases rapidly from 150 mL to 400-500
mL [58]. The use of excessive length of bowel may
produce low-pressure floppy reservoirs that empty
less effectively. Larger reservoirs have a greater
chance of rupture, because when they are allowed
to fill to capacity, the wall tension at a given pressure
is greater. The use of 40-45 cm of ileum is sufficient
for the reservoir itself. Popular techniques include
an ileal afferent limb orthotopic bladder substitute
using 55 cm of distal ileum, preserving the 25 cm of
terminal ileum, and the W-shaped bladder substitute
[59, 60].
b) Age and Motivation

Although there is no age cut-off for orthotopic bladder
substitution, in practice many patients over the age
of 70 years will opt for a simpler conduit urinary
diversion as the postoperative course is less arduous
and urinary incontinence is less likely. The motivation
of the patient is probably the most important factor
when considering their suitability for an orthotopic
bladder substitute, although it is difficult to assess
this objectively. Patients must be prepared to commit
to the long-term follow-up program necessary. There
is no point in the surgeon being enthusiastic if the
patient is not; this will result in poor function and the
risk of complications.
c) Sphincter Function
Urinary continence after orthotopic bladder
substitution depends, amongst other factors, on
adequate urethral sphincter function. Caution should
be exercised before offering orthotopic bladder
substitution in patients with significant urethral
strictures.
f) Minimally-invasive Surgery
d) Surgical Technique
There is increasing interest in laparoscopic and

robotic cystectomy, with either intracorporeal or
Nerve-sparing cystectomy does not just increase the
356
extracorporeal formation of ileal conduit or the

orthotopic bladder substitute [61-64]. Whether
reports with intermediate follow-up suggesting
equivalent pathologic and oncologic outcome will be
confirmed remains to be determined [65]. But there
are advantages in terms of blood loss, transfusion
rate, postoperative pain, and return of bowel function
[64]. In most reported series, cases have been highly
selected; it remains to be seen what the limitations
of minimally-invasive surgery might be in terms of
tumor size and bladder mobility. With regard to the
reconstruction, although there are a number of reports
of intracorporeal surgery, most surgeons currently
prefer to perform an extracorporeal technique as this
is faster. However, to do this, the ureters must be
kept long and there is concern about an increased
risk of ureteroileal stenosis [61]. Once a reservoir
has been constructed the urethral anastomosis
may be carried out by an open technique or by reestablishing a pneumoperitoneum. The technology
will probably need to improve before intracorporeal
reconstruction becomes standard practice.
delaying voiding when the patient feels that the urge

to void is irresistible and that leakage may occur. A
rapid increase in reservoir capacity following surgery
allows daytime continence to be achieved. Nighttime
continence is established less quickly. During sleep,
a detrusor-sphincter reflex normally increases outlet
pressure as the bladder wall stretches during filling;
this reflex is lost after cystectomy. As the reservoir
fills at night, therefore, additional outlet contraction
is not recruited, and when the rise in reservoir
pressure exceeds outlet pressure, leakage occurs.
This tendency to leak is normally compounded
because vasopressin is secreted at night, and urine
is therefore concentrated. However, the intestinal
wall of the bladder substitute will secrete water
into the reservoir, to try to render its contents isoosmolar, and so overnight urine output is greater
after orthotopic bladder substitution than before
cystectomy [68].
Men achieve self-assessed continence by day and
by night in 92% and 76% of cases, respectively.
Attempted
nerve-sparing
improves
daytime
continence, and increasing age worsens it [54]. Men
with type II diabetes gained daytime continence
more slowly than controls and were less likely to
achieve nighttime continence. Urinary tract infection
also worsens continence [69], and an unexpected
deterioration in continence should prompt exclusion
of infection and residual urine. Urine infection should
be uncommon.
g) Functional Aspects
1. Voiding
The mechanism of voiding for patients with an
orthotopic bladder substitute is well-described [57,66]
in case of an ileal reservoir (not cecal!). A passive
pressure rise occurs in the reservoir during filling,
and this stretches the reservoir wall, activating the
intestinal stretch receptors, resulting in a sensation
of filling. The patient learns this new sensation
during postoperative voiding rehabilitation. For an
ileal reservoir, voiding occurs by reducing outlet
pressure and pelvic floor and sphincter relaxation,
perhaps combined with slight straining. If straining
occurs, the upper urinary tracts and the reservoir
are equally subjected to the resulting abdominal
pressure rise, and so no pressure gradient is created
from the reservoir towards the upper tracts. In the
early postoperative period, men should sit to void, to
help them to learn how to empty the reservoir. Late
voiding difficulty occurs in 20% of men [67] within the
first 10 postoperative years for a variety of causes,
but almost all of these men void normally after
endoscopic assessment and relief of the underlying
bladder outlet obstruction.
3. Upper Urinary Tract Preservation

Voiding with an orthotopic bladder substitute
cannot produce reflux; this has been confirmed
scintigraphically [70]. Long-term upper tract
outcomes are excellent: as few as 2.7% of patients
should develop ureteroileal stricture, if a direct endto-side ureteroileal anastomosis is used [71, 72].
The use of stents in ureteroileal anastomosis after
orthotopic bladder substitution has been shown
to improve outcomes [73]. Up to half of patients
who develop a short ureteroileal stricture can be
successfully managed endourologically [72].
These data are consistent with the outcome of a
randomized surgical trail done to determine the effect
of different afferent mechanisms with an orthotopic
bladder substitute. This showed clearly that the use
of an antireflux nipple valve was associated with a
worse outcome than a dynamic isoperistaltic afferent
tubular ileal segment [74]. This was confirmed in
another randomized study recently [75]. In the longterm, the upper tracts are well preserved, and upper
tract calculi are rare [76].
2. Continence
Continence is achieved when outlet pressure
exceeds reservoir pressure. This requires careful
preservation of the urethral sphincter and the
formation of a low pressure reservoir, by doubly
cross-folding detubularized ileum (see above) to
achieve the desired reservoir volume of 400-500 mL.
The reservoir is constructed with an initial volume
of around 150 mL, and in the first postoperative
weeks, the patient has to work actively to stretch
the reservoir. Stretching the reservoir is done by
Table 7 presents specific long-term complications

when standardized reporting is used [20].
4. Postoperative Management
Of paramount importance is the active postoperative
357
management and regular long-term follow-up of

patients with an orthotopic bladder substitute. The
key issues [77] are achieving a capacity of 400-500
mL, residual free voiding of sterile urine, and the
treatment of any outlet obstruction.
are at higher risk of incontinence but some of them

will have excellent neobladder function (unpublished
data). Medical comorbidities, cardiac and pulmonary
function, and cognitive function are all important
factors that should be considered, along with the
patients social support and patient preference.
2. Orthotopic Diversion in Females

a) Patient Selection: Patient-related Factors
b) Patient Selection: Oncologic Factors
There are both patient-related and cancer-related

factors influencing the appropriateness of continent
orthotopic diversion in women (Table 8). The
patient-related factors are generally based on the
recommendations of surgeons performing these
diversions rather than on evidence-based studies.
A number of the contraindications to continent
diversion are identical for men and women. These
include the basic requirements of adequate renal
function, available healthy bowel, and a functional
urethral sphincter. Preexisting incontinence is a
relative contraindication for women considering a
neobladder. Some bladder cancer patients experience
urge incontinence due to the tumor itself, which
may be expected to improve after the cystectomy.
A woman with stress urinary incontinence may be
willing to continue to wear pads rather than deal with
a stoma, or may be considered for a sling or Burch
procedure at the time of diversion with planned selfcatheterization.
Prior to the wide adoption of orthotopic diversion for

females, it was necessary to show that it was safe
to preserve the urethra during the cystectomy. De
Paepe et al initially reviewed 22 female cystectomy
specimens and found urethral involvement in
36% [80]. Coloby and colleagues evaluated 47
consecutive cystectomy specimens with step
sectioning through the urethra, finding only 7% with
urethral involvement, all of whom also had bladder
neck involvement [81]. Stenzl had similar findings in
a review of 356 specimens with localized invasive
cancer, as did Marlani and Chen [82-84]. Finally,
Stein and colleagues evaluated 67 specimens with
13% urethral involvement. Again only bladder neck
involvement and anterior vaginal wall invasion
predicted urethral involvement, though 50% of those
with bladder neck tumor had no tumor in the urethra
[85]. In most of these studies, tumor involvement of
the trigone, the presence of carcinoma in situ (CIS),
or multifocal primary tumors did not predict urethral
recurrence.
Age alone is not a criterion for offering continent

diversion [78, 79]. The impact of age on outcomes
with orthotopic diversion has not been fully examined
in females. In our experience, women over age 75
It is now standard to require a negative frozen

section of the urethral margin prior to proceeding
with neobladder construction in women [78, 86, 87,
88, 89, 115]).
Table 7. Diversion specific long-term complications (> 3 months post-op) at 10 years in 923
patients with neobladder operated between
1986-2008 using the Kaplan-Meier method
Table 8. Contraindications For Orthotopic

Diversion In Women
Absolute contraindications:
R enal insufficiency (estimated creatinine

clearance of < 35-40)
ureteroileal stenosis13.80%
refluxing anastomosis (Wallace) 6.40%

non-refluxing (Le Duc)17.00%
urinary retention (female) 42.20%
subneovesical obstruction in men 8.20%
(correctable)
functional obstruction in men 5.10%
(clean intermittent catheterization required)
incisional hernia 6.40%
(41 in 923 patients = 4.4%)
Hautmann, J Urol 2011
Cancer invading the anterior vagina
Positive frozen section at the urethral margin
Inadequate available bowel
Relative contraindications:
Invasive cancer at the bladder neckon TURBT

S evere co-morbidities requiring very short
operative time
Significant stress incontinence
L ocally extensive disease at surgery (stage

T4)
Prior pelvic radiation

358
preservation [95]. However, others have routinely

dissected the presacral tissue as part of the node
dissection without a clear reduction of continence
[97, 101], To date, no randomized comparison of
these 2 techniques has been performed.
In summary, it is reasonable to advise against

neobladder reconstruction for a woman with invasive
bladder neck involvement or suspected invasion of
the vaginal wall or cervix. However, such patients
may be considered for neobladder diversion if
intraoperative frozen section of the urethral margin
is negative. It appears that overall 60-70% of
women undergoing cystectomy might be reasonable
candidates for continent diversion (88).
d) Complications
Most of the early and late complications of women
undergoing radical cystectomy and neobladder are
identical to those of men and are managed in a
similar fashion [20, 102, 103]. Two complications are
different in female patients:
c) Anatomic Basis of the Preservation of

Continence in Women
Orthotopic neobladder was introduced as an option
for women in the 1990s. Prior to that time, it was
generally believed that the primary continence
mechanism in women was located in the bladder
neck itself [90].
1. Pouch-vaginal Fistula
This complications occurs in 1-5% of patients even
in experienced hands [86, 101, 104]. Awareness of
this potential complication is important at the time
of surgery. When possible, the anterior vaginal wall
should be left intact, taking a strip of vagina only
in cases with close approximation of the tumor.
Any vaginal incision should be carefully closed in
a watertight manner with absorbable suture. An
omental flap may be transposed to the pelvis and
tacked to the pelvic floor on either side of the urethral
stump [79, 97].
However, it was ultimately recognized that the urethra

alone could provide continence if the sphincter
mechanism was carefully preserved [91].
Colleselli and colleagues did elegant cadaver
studies showing that the primary rhabdosphincter in
adult women is an omega shaped structure under
the pubic symphysis deep to the endopelvic fascia
surrounding the distal third of the urethra. The main
nerves supplying this sphincter are the somatic
pudendal nerves which run under the endopelvic
fascia. The autonomic nerves coursing through the
pelvic plexus and along the lateral vagina supply the
smooth muscle of the bladder neck and urethra. The
smooth muscle extends throughout the length of the
urethra [92]. Similar findings had been described
by others [93]. The distal urethra was found to
correspond to the area providing continence on
videourodynamic studies performed in women
who had undergone orthotopic reconstruction
after cystectomy [94]. There is consensus that
preservation of the rhabdosphincter function is critical
to maintaining continence in women undergoing
neobladder reconstruction [79, 86, 87, 95-97].
Avoiding dissection into or below the endopelvic
fascia surrounding the urethra helps ensure that this
muscle and its nerve supply are not disturbed [96].
Stenzl, Studer, and others suggest that preservation
of this plexus in a nerve-sparing approach is crucial
to maintaining urethral tone and may decrease the
risk of late urinary retention due to spasticity of the
denervated smooth muscle of the urethra [93, 98100]. Stenzl compared 66 patients from 3 centers
who had bilateral nerve preservation to 28 who had 1
side preserved and 7 who had no nerve preservation
(due to tumor infiltration or scarring). The report
does not indicate how these data were collected or if
there was a difference in follow-up or other variables
between the groups. Self-catheterization was
required in only 9% of the first group (66 patients)
compared to 0% of the group with 1 nerve spared
(28 patients) and 72% of the 7 patients without nerve
These fistulae rarely heal spontaneously except

in the first few weeks after surgery. Therefore, a
prolonged trial of catheter drainage or more proximal
diversion is probably not warranted. Vaginal
estrogen supplementation may help healing prior
to such a repair. Repair can be attempted vaginally,
with a Martius labial fat pad flap or muscle flap from
the leg interposed between the layers in difficult or
irradiated cases. When attempts to repair a vaginal
fistula have failed, the patient may be better served
by conversion to a cutaneous diversion.
2. Urinary Retention
Urinary retention is clearly more common in women
than men undergoing orthotopic diversion (Table 9).
Such retention may occur early, but often appears
after a year or more of good neobladder function
and emptying. In the Ulm series of 116 women,
the rate of retention increased steadily over time to
approximately 50% by 5 years [78]. The etiology has
been debated, but most authors believe it is due to
a mechanical kink in the uretha-pouch anastomosis
as the full pouch falls posteriorly during Valsalva
maneuver [79, 97, 103, 110-112]. This can often
be documented on a lateral straining cystogram.
However, not all patients with retention have this
finding. Other suggested etiologies include autonomic
denervation of the urethral stump or disordered reinnervation resulting in inability to relax the sphincter
[78, 94, 113, 114].
Since the first description of this potentially undesirable
late complication of orthotopic bladder substitution
in women [109] in 1996, a number of authors have
359
suggested modifications in surgical technique to try

to prevent this problem and have presented data to
suggest improved outcomes [79, 95, 97, 110, 112].
However, all are consecutive series and because
the complication may appear late, such reports may
be biased by shorter follow-up in the new group.
Nevertheless, some attempt to fill the posterior
pelvis and re-establish anterior and superior fixation
of the new bladder seems to be warranted. At the
University of Southern California, a sacrocolpopexy
with mesh and omental transposition laid between
the bladder and vagina have been routinely
performed [79]. Ali-el-Dein described anchoring the
vaginal apex to the preserved round ligaments and
also used an omental flap [97]. However, others
believe these maneuvers are unnecessary [118],and
recent results suggest that they have not prevented
retention (see below). Studer has suggested that
the location of the urethral opening in the pouch is
an important variable [115]. A recent study from the
group in Ulm suggested that patients in whom the
bladder neck itself is preserved (for example those
with non-urothelial tumors) have a higher risk of
retention than those in whom the urethra is divided
just below the bladder neck [108]. Preservation of the
uterus and its supporting ligaments when possible
may be an effective way to help prevent retention,
though again this question has not been subjected
to a prospective or randomized trail [116].
It is clear that every woman undergoing neobladder

reconstruction should be advised that intermittent
catheterization may be required for adequate
emptying and must be willing and able to learn
how to perform this. Many women who are dry but
require self-catheterization seem quite happy with
the diversion in spite of this [117].
e) Continence (Table 9)
Continence results in the literature are difficult
to compare between series because of a lack of
consensus on definitions, varied follow-up periods,
and varied mechanisms of data collection. Some
of the larger series reporting continence results
with neobladders have not separated out patients
by gender [86, 110, 115]. Few studies have used
the gold standard of a validated, anonymous
questionnaire to evaluate continence. In addition,
urinary retention may develop as a late event, so
follow-up time is an important variable in these
reports. In one of the largest series, Ali-el-Dein and
associates reported on a total of 136 women who
underwent a radical cystectomy and orthotopic
substitution, with 100 patients evaluable at a mean
follow-up of 36 months. Overall, 95% of the women
were continent in the day, 86% were continent at
night, 2 were completely incontinent, and 16% were
in chronic retention [102].
Stein and colleagues completed a mailed questionnaire
study using the validated Bladder Cancer Index with
56 women returning the questionnaire (64% of the 87
surviving women). Significant daytime incontinence
was reported in 23% of the women and nighttime
incontinence in 34%. Somewhat surprisingly, 61%
Treatment of retention is intermittent catheterization.

Alpha blockers are not effective [97]. Transurethral
resection of a urethral fold and open reduction of the
pouch size with anterior fixation to the abdominal
wall have also been described [97, 116].
Table 9. Continence In Reported Series Limited to Females

Follow-up
Author
Hautmann
# pts
(mos -mean)
Daytime
Nighttime
Continence % Continence%
Self Catheterize
%
(1996)
(2000)
116
60
83
83
50
(2006)
Granberg
(2008)
59
29
90
57
35
Nesrallah
(2005)
29
37
97
86
10
Ali-el-Dein
(2008)
192
51
92
72
16
Stenzl
(2001)
83
26
82
72
11
Stein
(2002)
81
78
78
N/A
33
Stein
(2009)#
56
103
87
66
61
# Anonymous validated questionnaire
360
reported that they catheterized at least once per day

and 39% always voided by self-catheterization. Only
18% of the women who catheterized reported that it
was a moderate bother and 56% reported it was no
bother at all [117].
because of the risk of a false negative report from

the pathologist. Urothelial cell carcinoma located in
the urethra or involving prostatic ducts or stroma is
the main indication for urethrectomy.
In female patients, biopsies should also be obtained
f) Sexual Function and Quality of Life
from the bladder neck, and, if positive, urethrectomy

should be performed. Furthermore, it is necessary
to exercise caution if there is a tumor close to
the bladder neck, as well as in cases involving
widespread CIS. Optimal knowledge regarding the
urothelial pathology of the lower urinary tract is of
importance when informing and discussing with the
patient preoperatively.
Only a few studies have examined the postoperative

sexual function of women undergoing cystectomy
and urinary diversion [118-122]. Results suggest that
sexual dysfunction is common and may be potentially
improved by leaving the uterus intact when possible
and preserving the autonomic nerves lateral to the
vagina [119, 120]. Comparisons of most aspects of
quality of life in both men and women between types
of urinary diversion have been limited but do not
show any convincing differences [122,123, 124].
Some patients may prefer continent diversion to

orthotopic reconstruction because of the risk of
urine leakage after the latter procedure.
Conclusion
c) Prerequisites
Orthotopic neobladder reconstruction is an attractive

option for selected women undergoing radical
cystectomy for bladder cancer. Oncologic outcomes
appear to be excellent with appropriate selection
criteria. Careful attention to patient selection, surgical
technique, and follow-up are all important to optimize
functional results.
Although antirefluxing ureteric anastomosis is not

necessary in orthotopic bladder substitution, it is
required in continent cutaneous diversion because
the efficient outlet mechanism can allow high
intrareservoir pressure. Both ileum and the right
colon can be used for construction of the pouch.
Different types of inlet, pouch, and outlet have
been combined. The stoma is usually in the right
lower quadrant or in the umbilicus. In this review,
the techniques that are most widely used today are
described. The majority of these were developed in
the 1980s and 1990s, although a few new methods
were also reported in the last decade.
Additional studies are necessary to allow surgeons

to minimize incontinence and urinary retention in
these patients.
3. Continent Cutaneous Urinary

Diversion
a) Introduction
d) The Outlet
The modern era of continent urinary diversion began 30

years ago with the introduction of continent cutaneous
diversion, which at that time was represented by
the Kock pouch. Since then, numerous techniques
for this type of diversion have been described, but
some of these appeared only once in the literature,
indicating that they were associated with technical
problems, high complication rates, and suboptimal
functional results. Today, only a handful of methods
are in use, and, in general, they are the second
choice after orthotopic bladder substitution for
patients undergoing radical cystectomy.
T
he intussuscepted ileal nipple valve
T
he Kock pouch: The Kock pouch was the
first method to be accepted by the urologic

community after it was described by Kock and
refined by Skinners group in the 1980s [125,
126]. However, the initial enthusiasm about this
procedure was soon dampened by increasing
reports of complications, including the following:
the afferent ileal nipple valve was prone to stenosis
with subsequent upper tract dilatation and risk of
renal impairment; the efferent counterpart was
subject to erosion by mesh, pinhole fistula, sliding,
and prolapse with risk of urine leakage and/or
difficulties in catheterization. The risk of afferent
nipple stenosis is estimated to be 30% after 5
years [127]. Because of the technical complexity
of the Kock pouch and the high complication rate,
this procedure is no longer used in routine clinical
practice. A modified technique for constructing the
efferent nipple [128] has been described, but no
further information is available in the literature from
the past 5 years.
b) Indications
In patients with bladder cancer undergoing radical
cystectomy, the main indication for continent

cutaneous diversion is when urethral removal is
deemed necessary due to a high risk of recurrence
of urothelial carcinoma. This risk can be estimated
based on the pathology report from the preoperative
transurethral resection biopsies of the prostate.
Such biopsies should be taken from the bladder
neck to the verumontanum on both sides before
cystectomy. Relying on frozen sections of the
urethra obtained during surgery may be dangerous
361
T
he Mainz pouch I: The ileal nipple valve was also
nocturnal continence in 74%, and 22% indicated

having satisfactory continence [135].
used in the first Mainz pouch that was described

[129] but modifications were subsequently
introduced due to the above-mentioned problems.
Today, the appendix is the first choice, but if it
missing or unsuitable, a nipple valve is configured
and fixed to the ileocecal valve and the reservoir
wall with staples [130]. In terms of complexity, the
Mainz pouch I with an intussuscepted nipple valve
cannot be considered inferior to the Kock pouch.
T
he Lundiana pouch: In the Lundiana pouch, the
ileum is also stapled, and the ileocecal valve is then
incorporated into the outlet in such a way that it
adds to the efferent length and closure mechanism
[136]. In Lund, 200 patients received this type
of diversion in the years 1992-2007, 160 at time
of cystectomy and 40 to treat benign disease.
Early (90-day) mortality was 2.5%. Evaluation of
191 of the patients who started intermittent selfcatheterization revealed that continence was
achieved in 177 (93%). Revision of the outlet due
to incontinence and/or difficulties in catheterization
was done in 13 patients, and revision of the stoma
was performed in 14 (unpublished). In one patient,
conversion to an ileal conduit was necessary after
unsuccessful attempts to revise the outlet. At last
follow-up, 14 patients reported that they had had
one or more episodes of difficult catheterization.
T
he appendix: Advantages of using the appendix
are that it is ready made and a smaller portion

of bowel is used. Inasmuch as the appendix is not
always available or suitable, it is necessary to be
familiar with other methods for continent cutaneous
diversion. The main problem associated with using
the appendix is the tendency towards stomal
stenosis. In the Mainz study [131], 63 (32%) of 196
patients underwent a total of 107 interventions.
Using a similar technique, other investigators [132]
observed 28% stenosis within a mean follow-up of
only 33 months. More recently, it was found that 6
of 52 patients needed early operative intervention
to revise the stoma, and late stomal complications
occurred in 12 of 52 [133]. This clearly offsets the
excellent continence (100%) reported in several
publications.
T
he serous-lined extramural valve/T-pouch:
The serous-lined extramural valve as a continent

urinary outlet was first described by the Mansoura
team, and soon thereafter a similar technique
was reported by the Los Angeles group (double
T-pouch). The principle of both these methods is
the creation of a serous-lined trough in which a
tapered ileal segment is placed. Two articles have
described the use of this technique in Europe [137,
138]. As correctly stated by the authors of this
report, construction of the pouch is sophisticated.
Indeed, this is the main drawback of the method
and represents a serious obstacle to general
acceptance.
T
he
tapered/stapled ileal outlet: Several

variations of the tapered/ stapled ileal outlet have
been described, all of which comprise a narrowed
ileal segment that creates passive resistance. A
true intraluminal closure mechanism is absent in
most, which may have an impact on continence.
The advantage of this approach is its simplicity.
e) Stone Formation
T
he Indiana pouch: In this procedure, the ascending
Stone formation is a common phenomenon after

urinary tract reconstruction, and its etiology is
multifactorial, including residual urine, chronic
bacteriuria, mucus, and foreign material such as
staples [139]. Although an incidence as high as
44% has been reported [140], most reports indicate
rates of 5-20%. In the series of 191 Lundiana outlets,
pouch stones occurred in 22 (12%) patients, and
in 18 of those patients, the stones were removed
endoscopically (unpublished data). the importance
of regular pouch irrigation has been recognized and
should be encouraged.
colon patched with an ileal segment constituted the

pouch, the outlet being a 10-cm plicated or stapled
ileal segment. Some modifications in fashioning
the outlet were also introduced, such as stapling
the ileum with a gastrointestinal anastomosis
(GIA) stapler and metallic staples, and using only
the right colonic segment. In addition, Lambert
sutures were placed at the angulated portion
of the ileocecal valve so as to roll cecal tissue
around the ileocecal valve and narrow it; this was
done to increase outflow resistance. However, in
a series of 125 patients in which the technique
had been modified to some extent with regard to
the ileocecal valve [134], the vast majority had
complications, 73 of which were related to the
efferent limb, such as incontinence, parastomal
hernia, difficult catheterization, or stomal stenosis.
These problems resulted in 31 reoperations. The
final outcome with regard to continence was not
stated. The last published study concerning the
Indiana pouch indicated that complete daytime
continence was achieved in 96% of patients and
f) Perforation/Rupture
The risk of this complication is higher after continent
cutaneous diversion than after orthotopic bladder
substitution, because the former lacks a pop-off
mechanism [141]. In the series of 191 Lundiana
pouches (unpublished data), this complication was
seen in 8 patients; 6 of these individuals underwent
open surgery, whereas 2 were cured by antibiotics
and drainage.
362
g) Other Important Aspects
complication rates [145]. It is likely that ileum is

used more commonly because it is the technically
simplest conduit to perform. Acknowledging this,
there are still settings where it is preferable that
colon, as opposed to ileum, be used. Specifically,
in the setting of patients with short bowel syndrome
or in patients who have had prior irradiation of the
ileum or distal ureters, a colonic conduit should be
considered. Another setting where a sigmoid colon
conduit should be considered is in the patient who is
undergoing en bloc resection of the colon or rectum,
as this may eliminate the need for an additional
bowel anastomosis.
There is virtually 100% bacterial colonization after

intestinal urinary diversion, but, provided the flow
of urine is not obstructed, clinical symptoms are
exceedingly rare. This is discussed in another review
published by Wullt and co-workers [142].
Conclusion
Continent cutaneous diversion has a place as an
option for reconstruction of the urinary tract in patients
who undergo cystectomy. The main indications
seem to be in patients in whom urethrectomy has to
be performed and in those in whom the prospect of
possible urine leakage after orthotopic neobladder is
repugnant. Multiple techniques have been described.
However, many of them are too complicated to gain
widespread acceptance. Simplicity characterizes
the appendiceal outlet and the outlet of the different
modifications of the Indiana pouch, and excellent
functional results can be obtained. However,
complications from the pouch and the outlet are not
infrequent and lifelong surveillance of these patients
is necessary.
Ileum or colon are the preferred intestinal segments

for use in urinary conduit diversion. Jejunum is
technically feasible, but should be used as a
last resort, given the higher rate of metabolic
abnormalities. A recent Cochrane review of the
available evidence comparing ileal conduit to colonic
conduit failed to show significant differences in upper
urinary tract infection or ureterointestinal stenosis
[147]. This review did not specifically look at rates
of stomal stenosis or metabolic abnormalities,
but others have noted similar rates of these longterm complications when comparing ileal to colonic
conduit [145, 146]. To this end, the choice of ileum
versus colon in conduit diversion should be based
upon surgeon preference and patient characteristics,
as discussed earlier.
4. Conduit Urinary Diversion

The conduit is still the most commonly performed
urinary diversion today [2, 143]. This is also confirmed
by our group (Table 1). Nevertheless, there is very
little new information in the literature and a lack of
hard data, including standardized reporting. Recent
efforts to overcome this dilemma at least in part are
the 2003 and 2011 series published by Madersbacher
et al and Shimko et al.
a) C
omplications Following Conduit Diversion
The discussion of complications again is hampered
by insufficient standardized reporting.
The introduction of continent urinary diversion

minimized the impact of urinary diversion on body
image and allowed the patient to live a more normal
life. Despite these potential benefits of continent
urinary diversion, ileal loop conduit has remained the
more commonly used form of urinary diversion, likely
due to the fact that it is technically simpler to perform.
Rarely conduits are formed from large bowel. Whether
or not this last point regarding complications is true
remains a point of debate. Large bowel surgery has a
higher infectious complication rate than small bowel
surgery, the mesocolon is shorter, and the vascular
supply more critical, depending on the segment
used. Advantages are, for example, a bigger stoma!
The metabolic abnormalities associated with jejunal
conduits provide a compelling reason to limit the
use of jejunal conduits to patients who, for whatever
reason (i.e., prior irradiated bowel or distal ureters
and/or inflammatory bowel disease) cannot undergo
either an ileal or colonic urinary conduit.
Short-term Complications
A recent review of complications in 1057 patients
undergoing ileal loop diversion at the Mayo clinic
documented a 3.6% incidence of abscess at
the bowel anastomosis and a 2.7% incidence of
enteric fistula formation, although some of these
complications occurred more than 3-6 months after
surgery [22]. Given that bowel leak, abscess, and/or
fistula formation are potentially lethal complications,
meticulous surgical technique should be employed
when performing the ileoileal bowel anastomosis
[147].
The other short-term complication that is highly
relevant to urinary conduit diversion is urine leak
at the ureteroileal anastomosis. Estimated to occur
in 2-5.5% of patients [145, 148], this complication
was associated with an astonishingly high rate of
mortality in early ileal conduit series [149, 150].
While more recent reports do not demonstrate such
high mortality rates with this complication [146], this
is still a complication that should be avoided with the
use of proper surgical technique and placement of
ureteral stents. A recent randomized clinical trial of
Urinary conduit using ileum is the most commonly

performed conduit procedure [144]. Studies
comparing ileal or colonic urinary conduit diversion
have documented fairly similar long- and short-term
363
54 patients undergoing either ileal loop conduit or

ileal neobladder documented more frequent urine
leak on postoperative day 1 in the unstented group,
although no differences were noted on postoperative
days 3 and 7. Importantly, stenting reduced the risk
of early upper tract dilatation and was associated
with improved bowel function. Stenting was not
associated with an increased risk of ureteroileal
stricture or upper tract infection [147]. To this end, we
recommend routine ureteral stenting in all patients
undergoing ileal loop conduit.
rate with a median time to stricture of 1.1 years [22].

It has been suggested that the individual end-toside ureteroileal anastomosis technique described
by Bricker may have a higher rate of stricture when
compared to using a conjoined (Wallace) technique
[149]. However, 2 recent retrospective series failed
to document any difference in the rate of ureteral
stenosis between the 2 different types of reimplant
[152, 153]. The choice of ureteral reimplant, therefore,
should be based on individual patient characteristics
and surgeon preference.
Long-term Complications
Long-term complications associated with the urinary

stoma are not infrequent occurrences following ileal
loop conduit. Stomal stenosis has been reported
to occur in 2-4% of patients undergoing ileal loop
diversion, with a median time to diagnosis of 9.2
years in one study [22, 148]. Chechile et al noted
a stomal revision rate of 5.5% in their patients
undergoing ileal loop and, importantly, noted no
difference in the re-operative rates between patients
undergoing end versus loop type stomas [154). The
incidence of parastomal hernia following ileal loop
varies from 3.7-13.9% [22, 148] and was noted to
occur at a median of 2.4 years after surgery.
Ileal conduits have been used for many years.

However, standardized and detailed information
is only rarely available regarding the incidence of
complications. Madersbacher et al for example,
reported on a cohort of 131 patients undergoing
ileal conduit diversion who survived at least 5 years,
where an overall complication rate of 66% was
observed [21]. In fact, many patients experienced
more than one complication during the first 5 years,
and complications can continue to develop even
beyond 15 years; 24% of patients developed stoma
problems, 24% had bowel complications, 23% had
symptomatic urinary tract infection (UTI), and 27%
had deterioration of renal function.
Table 6 presents a comparison of conduit versus

neobladder The data must be interpreted with
caution. The neobladder long-term complication rate
seems to be much lower (40% vs. 60%!) .
In the Mayo series, 19% of patients undergoing ileal

loop diversion developed new onset chronic renal
insufficiency (defined as a serum creatinine greater
than 2.0 mg/dL) at a median of 2.3 years after
surgery [22].
The conduit complication rate seems to be endless!

As expected, the UTI rate favors the neobladder
(5% vs. 25%) and the ureteroileal anastomosis
complication rates are identical.
There are a number of reasons why these patients

experience deterioration in renal function. One
common etiology is renal scarring secondary to
infection. Reported long-term pyelonephritis rates
following ileal loop conduit vary from 6-23% [151,
21]. In the Mayo series, 12% of patients reported a
pyelonephritis episode at a median of 2.3 years after
surgery. The overall infectious complication rate in
this series was 16.5% [22]. There has been some
debate concerning the value of nonrefluxing ureteral
anastomoses in conduit surgery, but the available
evidence does not support the use of nonrefluxing
reimplants in the setting of urinary conduit. Given
that refluxing ureters allow easier radiologic followup of the upper tracts, as loopograms should allow
free reflux of contrast facilitating assessment of the
remaining urothelium, refluxing ureteral reimplants
should be routinely performed at the time of ileal
conduit.
Conclusion
Ileal conduit diversion remains the most commonly
used method for reconstructing the urinary tract in
conjunction with radical cystectomy. It is probably
technically easier than continent reconstruction.
However, the complications, early as well as late, are
legion. Several studies confirm a high incidence of
upper tract complications, probably increasing with
length of follow-up.
It is difficult to draw definitive comparisons with other
diversion techniques as surgical techniques have
improved markedly over the last 25 years, and few
series report comparable long-term outcomes ( 20
years) in patients with neobladders.
5. Ureterosigmoidostomy
Regarding this type of diversion, there is really
no new information. This corresponds to conduit
diversion.
Another potential cause of long-term renal

insufficiency is ureteroileal anastomotic stricture.
This is thought to occur primarily due to distal
ureteral ischemia and is associated with a high reoperation rate. A recent systematic review of the
literature noted an 8.2% incidence of anastomotic
stricture following ileal conduit [148]. The group at
the Mayo clinic reported a 10% anastomotic stricture
a) Preoperative Considerations
The success of ureterosigmoidostomy depends
on patient selection. Factors are anal sphincteric
function, renal function, liver function, degree of
364
- Urine Leakage
ureteral dilation, history of prior radiation therapy,

primary colonic disease, and patients compliance with
long-term medications [155]. Paramount to success
is an adequate anal sphincter mechanism. This
should be assured both by history and preoperative
testing using large volume enemas with the patient
assuming normal activities. Inability of the patient
to retain 400 to 500 mL in the upright position for 1
hour is a contraindication to ureterosigmoidostomy
[155]. Patients with neurogenic bladder are not
suitable candidates for ureterosigmoidostomy, as
there may be associated anal sphincter dysfunction
[156]. Preoperative evaluation of the patient
selected for ureterosigmoidostomy should include
studies for bowel disease that might contraindicate
the operation. The presence of diverticulitis or colon
polyps may be investigated by barium enema or
colonoscopy [155]. Compromised renal function
results in accentuation of hypercritical acidosis that
results from ureterosigmoidostomy. Consequently,
patients should have normal renal function to avoid
this complication. Inability to handle the excess
ammonia absorption has been reported to lead
to hyperglycemia encephalopathy. Therefore,
ureterosigmoidostomy should be avoided in patients
with liver disease [157]. In the presence of ureteral
dilation, creation of a nonrefluxing anastomosis may
be difficult to achieve. Compliance with long-term
medication, such as antibiotics and bicarbonate, is
mandatory in patients with ureterosigmoidostomy
[155].
Leakage of urine occurs as an early complication

of ureterosigmoidostomy with a reported incidence
of 3.5% after combined technique of ureterocolic
anastomosis [161]. Small leaks usually seal
spontaneously. Extensive leaks, especially those
associated with prolonged ileus or signs of peritonitis,
are indications for immediate reoperation. Bilateral
percutaneous nephrostomy tubes and defunctioning
colostomy are viable conservative therapeutic
options [162].
- Pelvic Abscess
This diagnosis should be considered if a
patient develop otherwise unexplained fever.
Ultrasonography and computed tomography with
or without aspiration establish the diagnosis in most
cases. Once diagnosed, open or percutaneous
drainage should be carried out [162].
e) Late complications
- Reflux
Reflux is rare except after the Nesbit technique
of direct mucosa-to-mucosa anastomosis [163].
The incidence is high with dilated ureters, so
if one or both ureters are significantly dilated,
ureterosigmoidostomy should not be considered
[164]. Allen interposed an ileal nipple valve between
the dilated ureters and the sigmoid colon to solve
this problem [165].
b) Preoperative preparation
An adequate bowel preparation is mandatory
prior to ureterosigmoidostomy to avoid infectious
complications. The regimen includes a low residue
diet, oral laxatives, cleansing enemas, and oral
intestinal antiseptics for 3 days preoperatively [155].
- Pyelonephritis
Pyelonephritis is one of the most common and most
dangerous complications of ureterosigmoidostomy,
even with the combined or transcolonic techniques.
Wear and Barquin reported an incidence of 81% with
the older refluxing techniques of Coffey [166] and
Nesbit [167], as compared with an incidence of 5.7%
after the Leadbetters [168] combined technique
[164]. Williams et al reported an incidence of 45%
with the Goodwin transcolonic technique [169, 170].
Zincke and Segura reported an incidence of 20% with
the combined technique of ureterosigmoidostomy
[171]. The combination of high bacterial counts
inside rectal contents and the high rectosigmoid
pressure during voiding might be responsible for the
high incidence of pyelonephritis. Thus, long-term
antibacterial suppressive therapy is recommended
for patients with ureterosigmoidostomy [172].
c) Advantages
In 1973, Wear and Barquin enumerated the following
advantages of ureterosigmoidostomy over Brickers
ileal loop: voluntary sphincteric control of urination
without an external stoma and its complications, no
indwelling tubes or external collecting device, shorter
operating time and easier technique, ability to stage
the operation, ability to perform via intraperitoneal
or extraperitoneal approach, requirement of 2 rather
than 5 suture lines, and better acceptance by the
patient and his relatives [158, 159].
d) Early Complications
- Postoperative Anuria
The most serious immediate complication from
ureterosigmoidostomy is anuria if the anastomosis
is not stented. Anuria after removal of the ureteral
stents indicates bilateral obstruction caused by tissue
edema. In both cases, percutaneous nephrostomy
tubes should be placed, especially in case of fever
or flank pain [160].
- Ureterocolic anastomotic stricture

Ureteral obstruction at the ureterocolic anastomotic
site may occur as a late complication in 32% of patients
when the Leadbetter technique [160] is used and in
49% with other types of ureterocolic anastomosis
[164]. The incidence of upper tract dilatation after
365
ureterosigmoidostomy with a submucosal tunnel

was 12.845% [161, 173, 174, 175, 176].
cystectomy in geriatric patients. Several reports

have documented feasibility and oncological efficacy
of cystectomy in the elderly.
- Incontinence
Although perioperative mortality was substantially

higher in the advanced age group (5.3% vs. 1%),
postoperative morbidity was similar (34% in those <70
years, 39% in those 70 years [186]. The Memorial
Sloan-Kettering Cancer Center retrospectively
analyzed 44 octogenarians who underwent radical
cystectomy [187]. Postoperative mortality was 4.5%
and 29 patients (66%) had to be hospitalized acutely
after surgery, emphasizing the considerable mortality
and morbidity of this procedure in octogenarians
[187]. The major advantage of radical cystectomy is
the avoidance of local problems caused by locally
advanced disease; following radical cystectomy, the
rate of local recurrences is small [188]. One has to be
aware, however, that in contrast to younger patients,
the oncological superiority of radical cystectomy
compared to bladder-sparing approaches in elderly
patients is not convincingly demonstrated [189].
Incontinence after ureterosigmoidostomy is a

drastic social problem. It can be attributed to high
rectal pressure. Patients should be advised to
empty on a regular basis, including once or twice
during the night [166]. Imipramine hydrochloride
at bedtime is indicated for those with persistent
nocturnal enuresis [177]. Daytime continence rates
for ureterosigmoidostomy range from 8397% [161,
173, 174, 175, 176] and nighttime continence rates
from 58-92%.
Conclusion
Although the mortality and initial morbidity following
ureterosigmoidostomy have been significantly
reduced, some inherent chronic complications
remain problematic.
f) The sigma rectum pouch (Mainz Pouch II)
b) Types of Palliative Urinary Diversion
The sigma rectum pouch is another low pressure

modification of ureterosigmoidostomy. The procedure
was introduced by the Mainz group in 1993 [178].
The procedure entails single folding and antimesenteric splitting of the rectosigmoid colon to improve
the urodynamic characteristics of the reservoir. The
Goodwin technique is utilized for ureteral reimplantation [179]. In 1996, the same group reported on
their experience with the sigma rectum pouch in 73
patients [180]. Stenosis at the ureteral implantation
site was encountered in 5 patients (6.8%). Daytime
continence was achieved in 95% of patients. Nocturnal enuresis was encountered in only 2% of patients.
All patients were on prophylactic alkalinization. Similar satisfactory short-term results were reported [181
- 183]. However, no long-term results were reported
following this technique.
Cutaneous Ureterostomy
This is the most popular form of alternative nonbowel form of diversion in elderly patients or in a
palliative setting [190, 191]. In a recent series of
72 patients 80 years of age or older undergoing
radical cystectomy and urinary diversion, cutaneous
ureterostomy was performed in 87.5% [191].
Operative time is short, and renal function is not a
selection factor. Construction of a single stoma in the
lateral or midline position is generally feasible and
ensures easy care with minimal patient discomfort.
Stenting is usually necessary to avoid stomal
stenosis. Saika et al assessed health related quality
of life in elderly patients (75 years) who underwent
radical cystectomy and received either an ileal
conduit, cutaneous ureterostomy, or orthotopic
bladder substitution [190]. After a follow-up of over 3
years, no relevant differences in any area of quality
of life was seen in the 3 groups, underlining the role
of cutaneous ureterostomy in frail, elderly patients
[190].
6. Palliative Urinary Diversion

The issue of palliation and urinary diversion centers
around 2 issues: (1) management of elderly/geriatric
patients with muscle-invasive bladder cancer in whom
radical cystectomy/urinary diversion is associated
with a considerable morbidity and mortality, and
(2 patients with tumor-induced upper urinary tract
dilatation and renal insufficiency in a palliative setting.
A recent analysis of the SEER-database revealed
a peak age incidence of bladder cancer around 85
years [184]. Due to demographic changes with a
3-fold rise in the number of octogenarians expected
in the next 25 years, a substantial increase of elderly
patients with bladder cancer can be expected [185].
Defunctionalization of the Contralateral Renal

Unit
If only 1 kidney is diverted and urine continues

to flow downstream, it may be necessary to
defunctionalize the latter [192]. These patients
are usually poor candidates for nephrectomy. In a
previously obstructed kidney, ligation of the ureter
usually causes significant pain and spontaneous
ureteral recanalization [192]. In these cases, renal
arterial embolization should be considered.
a) Bladder sparing or radical cystectomy with

urinary diversion in elderly patients?
Palliative Treatment of Ureteral Obstruction
There exists no randomized study to compare

a bladder-sparing strategy versus palliative
Common causes of malignant compression of the
366
7. Urinary Diversion in the Pediatric

Age GroupSpecial Considerations
ureterovesical junction and the prevesical ureter

are locally advanced bladder, prostate, and cervical
cancers. Malignant obstruction of the mid- and upper
ureter is usually caused by metastatic lymphatic
spread. Indication for treatment should be considered
very carefully [192]. Septic episodes are rare in
malignant ureteral obstruction if there has been no
retrograde endoscopic manipulation. The insertion
of a regular double J stent or percutaneous catheter
will result in frequent consultations to change the
catheters, even under anesthesia. Any manipulation
carries the risk of infection and dislocation, and
quality of life should be the main treatment goal.
In the pediatric age group, continent and incontinent

types of urinary diversion can be applied, each
with specific advantages and disadvantages [197].
Bladder augmentation and heterotopic continent
cutaneous diversion are the options for continent
urinary diversion in patients with and without
neurogenic deficits. Orthotopic bladder substitution
and continent anal diversion [198] should be offered
only to patients with competent urethral or anal
sphincters. For incontinent urinary diversion, a
colonic conduit is the preferred solution in children
[199].
Percutaneous Nephrostomy
Drainage of an obstructed upper urinary tract caused
by a locally advanced or metastatic urothelial cancer
leads to an ethical dilemmais such drainage
going to facilitate treatment with chemotherapy or
radiotherapy, or is it perpetuating and allowing other
problems to develop? Aravantinos et al concluded,
based on an analysis of 270 cases, that only patients
with specific cancers (e.g., prostate cancer) that
progress slowly by nature may substantially benefit
from the procedure [193]. Bilateral nephrostomies
are generally poorly tolerated and usually only the
renal unit with the better function should be diverted
by nephrostomy.
Indications for urinary diversion in childhood include

neurogenic bladder, functional or anatomical
loss of the lower urinary tract, radical surgery for
malignancies, and failure of reconstruction of the
lower urinary tract (e.g., failure of primary bladder
closure in patients with bladder exstrophy).
a) Postoperative Considerations
The level of the neurological defect is a crucial aspect
in patients with myelomeningocele. This determines
whether a patient is ambulatory or wheelchair-bound,
and whether she or he will be able to adequately
perform clean intermittent catheterization (CIC). An
important aspect is the transition from ambulatory to
a wheelchair-bound state with aging and increasing
obesity [200].
Pyelovesical Bypass
Desgrandchamps et al introduced a technique of
pyelovesical bypass with a composite prosthesis
[194]. In the initial series, 21 patients were treated
with a success rate of over 90% [194]. The authors
concluded that subcutaneous pyelovesical diversion
ensures a better quality of life than classical
percutaneous nephrostomy in cancer patients at the
palliative stage [195]. Similar encouraging data were
reported by others [196].
Urine storage at low pressures in an adequate

capacity reservoir for preservation of the upper
urinary tract and achieving urinary continence are the
main goals of bladder augmentation or substitution
in childhood.
b) Surgical Techniques
Ureteral Stenting
1. Bladder Augmentation and Substitution
These data suggest that in patients with a limited life

expectancy permanent stents might be an option.
Bladder augmentation is indicated in patients who

are incontinent due to an overactive detrusor and/
or a low-compliance bladder or small contracted
bladder after radiation or multiple surgeries. Patients
should be able to perform CIC via the urethra. If this
is impossible for anatomic or orthopedic reasons,
a Mitrofanoff cutaneous stoma is preferable for
catheterization [201].
Conclusion
The decision regarding bladder sparing or radical
cystectomy in the elderly/geriatric patient with
invasive bladder cancer should be based on tumor
stage and comorbidity best quantified by a validated
score, such as the Charlson score. Chronological
age is of limited relevance. Cutaneous ureterostomy
is the most popular non-bowel urinary diversion in
this setting, providing adequate quality of life. The
issue of decompression of an obstructed urinary
tract in a patient with advancing pelvic malignancy
(particularly bladder cancer) remains a difficult
clinical situation. The indication for drainage should
only be made when the views and wishes of the
patient and caregivers are taken into account. The
prognosis remains very poor.
Gastric segments, small and large bowel, and the

ureter can be used for bladder augmentation. The
bladder is opened widely (clamtechnique)
to prevent an hourglass phenomenon of the
bladder, with the augmented segment becoming a
diverticulum at the bladder dome.
In patients, who are unable to perform CIC via the
urethra, the presence of the appendix is a distinct
advantage. The appendix can be used as a continent
367
cutaneous stoma of an augmented bladder. The

appendix is embedded in the taenea libera in a
similar manner as in heterotopic continent cutaneous
pouches [202]. The ileocecal valve can be used
as an antireflux mechanism for ureters, which are
implanted into the terminal ileum, which works even
for severely dilated or short ureters [203, 204]. Nondilated ureters can be implanted into the large bowel
by the submucosal tunnel technique [205].
popular form of urinary diversion until the latter half

of the last century [242-245]. In the long run, high
postoperative complication rates and deterioration of
the upper urinary tract became evident. Electrolyte
imbalances, upper urinary tract infections, chronic
renal failure, and uremia were common in the
past [243, 244, 246-250]. However, refinements in
surgical techniques, improved antibiotic treatment,
and better suture materials allowed a revival of
this surgical strategy as an attractive alternative
for continent urinary diversion [245, 251, 252]. This
is especially true for developing countries where
cultural and economic difficulties are encountered
in accepting and obtaining catheters for intermittent
self-catheterization of a continent cutaneous urinary
diversion and external appliances for incontinent
urinary diversion [253]. Both a previous dilated
upper urinary tract and an insufficient anal sphincter
are contraindications [254].
Complications from the use of gastric segments

are hyponatremic, hypochloremic alkalosis and
hematuria-dysuria syndrome in up to 37% of patients
[206, 207]. A further late complication is development
of secondary malignancies starting from the tenth
postoperative year [208-211]. Therefore, the use of
the stomach for bladder augmentation has become
obsolete.
Ureterocystoplasty avoids most of the adverse
effects of intestinal cystoplasties. However, the
association of a small contracted bladder with a
severely dilated ureter of a non-functioning kidney
is rare. In 1973, Eckstein described the technique of
ureterocystoplasty [212]. Its success depends very
much on patient selection. A reaugmentation rate of
up to 73% is reported [213-216].
The rectosigmoid pouch (Mainz Pouch II) is based

on the classic ureterosigmoidostomy but applies
the principles of detubularization and spherical
reconfiguration of bowel to eliminate high-pressure
peristaltic contractions and create a low pressure,
high capacity rectosigmoid reservoir [198]. In a series
of 35 children with a mean follow-up of 112 months,
all were continent during the day and 3 (9%) had
nighttime incontinence requiring pads. Ten (15%) of
69 ureters required reimplantation (7 for obstruction
and 3 for reflux) [255]. Most of the submucosally
imbedded ureters that required reimplantation were
already preoperatively dilated. Implanting dilated
ureters in a serosa-lined extramural tunnel provides
better results [255-257]. The augmented and valved
rectum, and the double-folded rectosigmoid bladder
are further modifications of the ureterosigmoidostomy
strategy with excellent continence rates [258260]. However, as the surgery of the augmented
and valved rectum technique is quite complex and
requires temporary colostomy, the technique did not
find wide acceptance.
In patients with bladder exstrophy, bladder

augmentation with or without closure of the bladder
neck with a Mitrofanoff stoma is an option after
failure of primary reconstruction [217-220]. In the
long-term, these patients become continent with
their Mitrofanoff stoma. However, the complication
rate is high at 40% [220-222].
2. Continent Cutaneous Diversion

When there are irreparable sphincter defects, small
bladder capacity, obstruction of the upper urinary
tract, patients being unable to perform transurethral
CIC, and impossible reconstruction of the bladder
neck, continent cutaneous diversion is a reasonable
alternative to bladder substitution. Ileum [223-227],
the ileocecal segment [228-235], and colon can be
used for the construction of a continent pouch [236238].
4. Incontinent Diversion
For patients who are either physically or mentally
unable to perform CIC and for patients with chronic
renal failure, incontinent urinary diversion remains
the diversion of choice. Ileum [261-263], the ileocecal
segment [264, 265], transverse colon [266, 267], and
sigmoid colon can be used for incontinent diversion
[268, 269].
High continence rates are the advantage of

continent cutaneous diversion as compared to
bladder augmentation only. Using the embedded
appendix or an ileal intussusception valve as the
continence mechanism, more than 90% of patients
were continent [239]. If the appendix is not available,
the Yang-Monti technique is a viable option for the
creation of a continent catheterizable tube [240,
241].
In 1937, Seifert described incontinent urinary diversion

by a jejunum conduit and Bricker popularized the use
of the ileal conduit in 1950 [261, 263]. Early results
were promising and hence the procedure was also
commonly used for urinary diversion in children.
However, the number of reported complications
increased with the length of follow-up [270].
Deterioration of the upper urinary tracts and renal
function, calculus formation, and stoma stenosis
3. Continent Anal Diversion in Children (see also

III. 5)
Ureterosigmoidostomy was the first form of continent
urinary diversion to be performed and became a
368
resulted in late complication rates of 19-86% [250,

271-278]. In the 1970s, Hendren and Middleton
concluded that this operation should be abandoned
in children or any patient with potential longevity
[273, 279]. The alternative form of incontinent urinary
diversion is the colonic conduit introduced by belhr
in 1952 and popularized by Mogg in the early 1960s
[268, 269]. Elder and coworkers suggested that it
had the same long-term complications as the ileal
conduit [280]. However, they used an isoperistaltic
and refluxing conduit. Using an isoperistaltic colonic
conduit with a antirefluxive ureter implantation, good
results after a mean follow-up period of more than 16
years were reported (range 5-26 years) [199].
failure of primary reconstruction, dilatation of the

upper urinary tracts is common when lower urinary
tract reconstruction is indicated. Implantation of these
ureters into the bowel has a higher complication rate
as compared to normal ureters [197, 205]. Using a
submucosal tunnel implantation into large bowel,
16% of the renal units required reimplantation. Using
the serosa-lined extramural tunnel technique [293]
in dilated ureters, the reimplantation rate was much
lower (3%) [239].
Recently, the necessity of antirefluxing ureteral
implantation in children has been discussed
controversially [299-302]. Clearly, there is a need
for a prospective randomized study assessing the
impact of reflux from a potentially contaminated
diversion. Until evidence is obtained that even lowpressure reflux will not harm the kidney in the long
run, in young patients with a long life expectancy
the kidneys should be protected by an appropriate
antirefluxing technique.
c) Surgical Complications
The use of bowel segments for urinary tract
reconstruction in children is challenging and surgical
complications are common [197, 281-284]. After
bladder augmentation, Herschorn et al reported a reoperation rate of 36% over 6 years [285]. Using the
ileocecal segment for bladder augmentation and a
cutaneous stoma for for CIC (Hemi-Indiana pouch),
Husman and Cain reported a re-operation rate of
48% in 62 patients [186]. Using the Kock pouch in
20 children and adolescents, Abd-el-Gawad et al
reported pouch-related complications after a followup of 6.5 years in 10 (88%) of 13 children and in 3
(43%) of 7 adolescents [287, 288]. In a series of 91
patients with bladder exstrophy, Surer and colleagues
observed stomal stenosis or stomal prolapse in 24,
calculus formation in 24, bowel obstruction in 3,
fistulae in another 3, and bladder perforation in 2
patients [283].
2. Stomal Stenosis
In continent urinary diversion, stomal stenosis is the
most frequent single complication, with an incidence
of up to 32% [148, 239, 283, 284, 303].
It is treated by simple excision or incision of the
scar at skin level. In children with an ileal conduit,
stenosis of the stoma occurred in up to 42% [273278]. In patients with a colonic conduit, the incidence
was 16% after a mean of 119 years (range 520)
postoperatively [304].
3. Bone Density
Among other mechanisms, chronic acidosis may play
a major role in a decrease of bone mineral density
after bladder augmentation or urinary diversion.
1. Ureterointestinal Stenosis
Ureteral implantation is a crucial point in urinary
diversion. For implantation of the ureter into a bowel
segment, refluxive and antirefluxive techniques
are available [227, 289-293]. The incidence of
ureterointestinal stenosis for refluxive techniques
(e.g., Nesbit or Wallace technique) is between 2%
and 7%, and for antirefluxive techniques (Le Duc,
submucosal tunnel, serosa lined tunnel, afferent
nipple valve) is between 2% and 8% [205, 294298].
4. Growth Retardation
It is very unlikely that the changes in position on
the growth curve after enterocystoplasty are a
consequence of enterocystoplasty. It seems to be a
non-specific phenomenon that must be considered
in any clinical population of similar size and age
distribution after a similar time period [305].
5. Vitamin B12
In a recent review article, Somani and co-workers

demonstrated that the average incidence of
ureterointestinal stenosis in patients with an
ileal conduit was 11% in prospective and 8% in
retrospective studies. In patients with a continent
cutaneous diversion, the stenosis rate was 7% in
prospective and 8% in retrospective studies, and in
bladder substitution it was 7% in prospective and 5%
in retrospective studies [148]. Most of these studies
were performed in patients with bladder cancer and
normal upper urinary tracts.
About 1% of orally administered vitamin B12 is

absorbed by an additional, yet unknown pathway
[306, 307]. Studies, unlike older textbooks suggest,
demonstrate that the terminal ileum can not be
considered the only site of vitamin B12 absorption
[306-311].
After urinary diversion with ileal segments, substitution
therapy is performed in up to 35% of patients [312,
313, 314, 315. 316]. However, in the literature there
are only reports of 5 patients with clinical symptoms
(1 with neurological symptoms) seemingly related to
vitamin B 12 deficiency [314, 316, 317].
In patients with neurogenic bladder or in those after
369
A randomized study demonstrated that oral therapy

(2 mg per day) is as effective as parenteral application
(1 mg intramuscularly) of vitamin B12 in patients with
cobalamin deficiency [307]. Hence, oral treatment of
low vitamin B12 levels may be considered especially
in children.
Based on these, our committee strongly

recommends that this type of surgery only be
performed at high volume hospitals. Our committee
also considers a minimum annual case load of 25
surgeries, done by not more than 2 surgeons, to be
the definition of a high volume center.
6. Bowel Dysfunction
V. References
There are relatively few reports in the literature

concerning bowel dysfunction after urinary diversion.
An increased stool frequency was reported after ileal
or colonic conduit diversion in 4-33% of patients, after
bladder augmentation, in 7-59% after substitution, and
after continent cutaneous diversion in 3-23% [296,
318-324]. On the other hand, stool incontinence is
in epidemiological studies surprisingly common with
an estimated prevalence of up to 20% depending on
age, gender, and population [325, 326].
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378
Committee 8

Prostate
Chairs:
Joan Palou,
David Wood
Members:
H. Al-Ahmadie,
B. Bochner,
Henk van der Poel,
Ofer Yossepowitch
379
Table of Contents
I. INCIDENCE
III. Urothelial Carcinoma

Prostatic Stromal Invasion
1. Carcinoma in Situ
1. Incidence
2. Papillary Lesions
2. Mechanisms of Stromal Invasion
3. Stromal Invasion
3. Diagnosis
4. Cystectomy Specimens
4. P
redicting Prostatic Stromal
Invasion
II. Diagnosis of Superficial

Urothelial Carcinoma or CIS
in the Prostatic Urethra
5. Treatment and Outcome Analyses
IV. RECOMMENDATIONS
1. Diagnosis
2. Treatment
3. Follow-up of the Prostatic
Urethra
380
Urothelial Carcinoma of the Prostate

Joan Palou, David Wood
H. Al-Ahmadie, B. Bochner,
Henk van der Poel, Ofer Yossepowitch
a tumor in the prostatic urethra is associated with

urothelial cancer elsewhere in the urinary tract
[14]. Mungan et al reported multiplicity as the only
risk factor of PU involvement in patients with nonmuscle-invasive bladder cancer [18]. Although in
cystoprostatectomy specimens the incidence of
urothelial carcinoma of the prostatic urethra has
been reported as high as 43% (27), most of these
series consisted of patients with larger, muscleinvasive bladder cancer [19].
I. INCIDENCE
1. Carcinoma in Situ
In 1952 Melicow and Hollow described Bowens
disease of the prostatic urethra [1]. Ortega et al were
the first to describe carcinoma in situ (CIS) of the
prostatic urethra in 1953 (Level 3)[2]. In approximately
90% of the cases, CIS is associated with a papillary
or solid bladder tumor [3]. However, in about 10%
of cases, it may present as an isolated lesion. It is
often diagnosed in the context of multifocal disease
of the bladder (Level 3)[2]. Prostatic urethra (PU)
involvement by CIS is relatively rare (Level 3)[4].
Its prevalence and significance has been clarified
by the use of routine random biopsies including the
prostatic urethra in patients with superficial bladder
tumors or positive urine cytology. In 1529 patients
with primary bladder tumors who had random
biopsies, 19% had carcinoma in situ, and 2.7%
had CIS in the prostatic urethra (Level 3)[5]. The
presence of PU CIS increased with the duration of
bladder cancer: secondary tumor involvement of
the prostatic urethra and ducts in bladder cancer
may be detected in 10-15% of patients with highrisk superficial bladder disease within 5 years and
in 20-40% within 15 years (Level 3)[6-8] (Fig.1).The
majority of patients also relapse in the bladder (Level
3) [8].
Figure 1. Urothelial carcinoma in situ involving prostatic

urethra. Markedly atypical and pleomorphic tumor cells
undermining urethral lining (highlighted in inset).
3. Stromal Invasion
Stromal invasion is present in 37-64% of men with
prostate involvement at cystoprostatectomy for
invasive bladder cancer [19;20] (Fig. 2). It was
generally shown to be a sign of poor prognosis [2022]. Survival in men with PU involvement without
stromal invasion was more than 60% 5 years after
the cystoprostatectomy, whereas less than 30% of
men survived when stromal invasion into the prostate
was present [20]. Stromal invasion into the prostate
was shown to be associated with an increased risk
of nodal metastases [21].
The most frequently reported risk factors for PU CIS

are multifocality of bladder cancer and CIS in the
bladder [9-12]. Others found bladder neck location
of the bladder cancer predictive of PU CIS [13;14].
2. Papillary Lesions
Primary papillary lesions in the prostatic urethra do
occur in only 1-4% of cases [15-17]. In most cases
381
Figure 2. Left: Urothelial carcinoma in situ involving prostatic ducts (UC) without stromal invasion. Note
adjacent normal prostatic ducts that are free of tumor involvement (NP). Right: Urothelial carcinoma with
invasion of prostatic stroma (arrows). Note adjacent ducts involved by in situ disease.
Besides stromal invasion, a distinction can be made

between contiguous and non-contiguous tumor
growth into the prostate. The former describes direct
invasion of the bladder tumor into the prostate,
whereas the latter refers to synchronous presence
of PU tumors. In a series of 320 cystoprostatectomy
specimens, Ayyathurai et al describe contiguous
tumor growth into the prostate in 9% of cases,
and non-contiguous in 15% [20]. Several studies
showed worse prognosis for contiguous versus noncontiguous growing tumors [20;23;24].
involvement in 143 of 489 cystectomy specimens

(Level 3)[23]. Nineteen cases showed direct
penetration from bladder to prostate and had a bad
prognosis. The remaining 124 patients had different
stages of indirect prostatic involvement. Thirty-seven
had low grade tumor or CIS and 29 had prostatic
disease involving the ducts only; these patients had
a relatively good prognosis. Wood et al reported
a 43% incidence of urothelial carcinoma of the
prostate in cystectomy specimens (Level 3)[14]. In
this series, 94% of those with prostatic involvement
had disease present in the prostatic urethra,
including 67% with CIS of the prostatic ducts or
acini. Risk factors included CIS of the bladder neck
or trigone, prior intravesical therapy, and ureteral
involvement by urothelial carcinoma. In a prospective
pathologic assessment, Revelo et al reported
results of 121 consecutive cystoprostatectomy
specimens analyzed by whole mount (Level 3)[28].
Of 121 prostates, 58 (48%) had urothelial carcinoma
involving the prostatic urethra, of which 19 (33%)
had apical involvement. All patients with prostatic
apical involvement by urothelial carcinoma uniformly
had involvement of more proximal (toward the base)
portions of the prostate. These results validate the
concept of cystoprostatectomy. Nixon et al reviewed
192 consecutive radical cystectomy specimens and
noted prostatic urethral involvement in 30 (15.6%)
specimens (Level 3)[11]. Of patients with CIS in
the bladder specimen, 31.3% (25/80) had prostatic
urethral involvement. Similarly, 34.7% (25/72) with
multifocal urothelial carcinoma of the bladder had
prostatic urethral involvement. Multivariate analysis
revealed the risk of prostatic urethral involvement to
4. Cystectomy Specimens
Most reports of prostatic urethral involvement at the
time of radical cystectomy are not only retrospective
but lack careful pathologic assessment of the prostate
and thus are likely to underreport the true incidence
of involvement with urothelial carcinoma. However,
the incidence of prostatic urethral involvement
approaches 50% in series where detailed pathologic
assessment of the prostate is performed [25;26].
In a prospective histopathologic study by Sakamoto
et al, 31 of 134 cystoprostatectomy specimens in
patients with primary bladder cancer revealed prostatic involvement (Level 3)[27]. They differentiated
between superficial (periurethral) and deep prostatic glands and demonstrated that there was prostatic urothelial carcinoma involvement of superficial
glands around the verumontanum in 93% of the cases, and at 5 and 7 oclock in 84%; only 1 patient had
deeper gland involvement without superficial gland
involvement.
Esrig et al analyzed their findings of prostatic
382
be 12- to 15-fold higher if CIS or multifocal urothelial

carcinoma of the bladder was present. More recent
data showed a prostatic tumor location in 38% of 248
cystoprostatectomy specimens [25]. In the majority
of men with prostatic involvement of urothelial
cancer, the cancer originated from the urothelial
mucosa, whereas in 4% the tumor extended through
the bladder wall into the prostate [29].
lesions in the prostate (Level 3)[35]. Donat et al

reported a 39% rate of prostate relapse in patients
with superficial bladder cancer (Level 3)[33]. They
recommended a systematic transurethral loop
biopsy extending through the bladder neck, trigone,
and prostatic urethra, and ultrasound-guided biopsy
of the prostate to evaluate patients with high grade
superficial disease; they do not justify the proposed
timing or frequency.
Predictors of PU involvement in cystoprostatectomy

specimens are:

a. multiplicity [11;18;25].
b. bladder neck tumor location [19;26].
c. bladder carcinoma in situ [11;19].
The staging of bladder carcinoma should include

independent evaluation and staging of any prostatic
lesion (Tables 1-4) (Level 3)[22]. Involvement of
the prostate by CIS is almost always associated
with bladder CIS (Level 3)[3]. Superficial disease
in the prostate is sometimes evident as a papillary
tumor. More commonly, it is silent and insidious with
no evidence of macroscopic disease. Once stromal
invasion is detected, the management changes
completely (see Section III. Prostatic Stromal
Invasion). Cystoscopy is a valuable measure of
prostatic urethral involvement in macroscopic
lesions, with a sensitivity of 83.3% and specificity of
95.1% (Level 3)[11]. But it is not always a valuable
tool; in patients with recurrent superficial urothelial
disease after BCG treatment, when considering
suspicious or visible lesions, Orihuela et al had a
48% negative biopsy rate (Level 3)[36]. CIS in the
prostatic urethra is common in high-risk superficial
bladder cancer (9-25%), and can evolve to prostatic
stromal disease (Level 3)[37]. Rikken et al stress
the need to perform a biopsy of the prostatic urethra
in every patient with high grade superficial bladder
cancer, with the intention of identifying patients with
tumors in that location to allow better therapeutic
planning (Level 3)[31]. Eight of 9 patients with
CIS of the prostatic urethra have coexistent CIS
in the bladder. Resectoscope loop biopsies of the
prostatic urethra are taken from the lateral lobes
and floor beginning distal to the bladder neck and
extending just proximal to the verumontanum. In
1 study, 76.5% of 17 prostatic urethral biopsies
contained identifiable prostatic ducts, and ductal
urothelial carcinoma was identified in 7 [33]. Hillyard
et al recommended taking a biopsy of the prostatic
urethra with the resectoscope loop from the lateral
lobes distal to the bladder neck and performing a
complete resection of the prostatic urethra (Level 3)
[38]. Bretton et al also recommended performing a
complete resection with 1 to 3 passes and separate
identification to determine the extent of prostatic
involvement (Level 3)[39].
II. Diagnosis of Superficial

Urothelial Carcinoma or CIS
in the Prostatic Urethra
1. Diagnosis
Urothelial carcinoma of the prostate is often
understaged; correct diagnosis has to be achieved in
order to avoid progression due to undetected stromal
invasion (Level 3)[8;23]. Interestingly, prostatic
involvement of urothelial cancer was the only
predictor of understaging in recurrent high risk nonmuscle-invasive bladder cancer: 53% understaging
in men with prostate involvement versus 20% in
men without. This suggests that prostatic sampling
plays a role in management of non-muscle-invasive
bladder cancer [30]. Cystoscopy was described as
a valuable tool to diagnose PU involvement [11].
However, Rikken et al showed that cystoscopically
hard to detect lesions, such as carcinoma in situ, can
be expected in around 10% of men with (a history
of) non-muscle-invasive bladder cancer at prostate
biopsy diagnosis [31].Transurethral resection of
the PU had highest accuracy for detecting stromal
invasion when compared to FNA or core-biopsy
prostate sampling [32]. Still detection of TUR biopsies
in the PU for stromal invasion was reported to be
only 56% [33]. Even at cystoprostatectomy specimen
pathology, an accurate protocol is required to prevent
undersampling of the prostatic urethra [34].
The only way to approach 100% accuracy would
be to perform an extensive transurethral resection
of the prostate, an impractical approach for routine
staging of patients with bladder cancer (Level 3)
[35]. Multiple random biopsies of the bladder and
prostatic urethra are not recommended as a normal
routine in superficial bladder cancer. There is a very
low incidence of CIS in that location, but this means
that CIS of the prostate will be undetected in patients
with primary bladder tumors (Level 3)[35]. Solsona
et al recommended a prostatic biopsy in patients
with positive cytology or in those with macroscopic
Survival is optimized if radical treatment precedes

stromal invasion (Level 3)[8]. The detection
of prostatic relapse, particularly early stromal
invasion, is difficult. That is why frequent and
lifelong biopsies of the bladder neck and prostate
are recommended in patients with recurrent high
grade papillary and in situ tumors of the bladder
(Level 3)[8].
383
Table1. Classification of Prostatic Urothelial Carcinoma According to Chibber et al [49]
Group 1 CIS of prostatic urethra and ducts, with or without similar disease in the bladder
Group 2 Superficial papillary bladder tumor of prostatic urothelium and major ducts with similar bladder
tumor
Group 3 Invasive tumor of bladder base and neck with prostatic extension
Table 2. Classification of Prostatic Involvement According to Hardeman and Soloway [70]
Stage 1 Tumor confined to prostatic urothelium

Stage 2 Invasion of ducts and acini, but confined to the basal membrane
Stage 3 Stromal invasion
Table 3. TNM (2001) Classification of Prostatic Urothelial (Transitional Cell) Carcinoma (71)
Tis pu CIS, affecting prostatic urethra

Tis pd CIS, affecting prostatic ducts
T1 Tumor invading subepithelial connective tissue
T2 Tumor invading prostatic stroma, spongiosum body, or periurethral muscle
T3 Tumor invading cavernous body prostatic capsule or bladder neck (extraprostatic extension)
T4 Tumor that invades surrounding organs
Table 4. TNM Classification (2009) of T4 Urothelial (Transitional Cell) Carcinoma of the Bladder (72)
T4 Tumor invades any of the following: prostate stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal
wall
T4a Tumor invades prostate stroma, seminal vesicles, uterus, or vagina
T4b Tumor invades pelvic wall or abdominal wall
2. Treatment
of urothelial neoplasms that cannot be managed

with intravesical therapy. Since Morales introduced
bacillus Calmette-Gurin (BCG) as intravesical
therapy of superficial urothelial carcinoma of the
bladder, several authors have evidenced its efficacy
both on bladder CIS and on CIS of the prostatic
urethra (Level 3)[22;42-45]. Superficial tumors of
the prostate can be treated conservatively if they are
completely resected and treated with intravesical
instillations. TUR with intravesical BCG provides a
significantly better prophylaxis of tumor recurrence
in Ta and T1 bladder cancer than TUR alone (Level
2)[46]. However, topical antineoplastic agents
may neither gain sufficient access to the prostatic
urothelium nor are incubated upon it for sufficient
duration of time (Level 3)[47]. In a few patients, there
is contact of the chemotherapeutic agent with the
prostatic urethra, but in the majority it is only during
micturition. In a non-randomized study comparing
BCG and epirubicin, there seemed to be a better
prostate response to BCG (Level 3)[47]. Hillyard et al
advocated radical surgery in patients with ductal and
stromal involvement; however, this is not justified with
numbers (Level 3)[38]. Solsona et al also advocated
radical surgery in patients with ductal involvement
a) General Comments
Local resection and staging of the often present
bladder tumor are essential for management of PU
urothelial cancers. Often the bladder cancer dictates
treatment, in particular in the cases with a muscleinvasive bladder tumor. Management of superficial
(non-stroma-invading) and non-superficial (stromal
or contiguous) PU tumors will be discussed.
b) Management of High Grade or CIS PU

Cancers
The prognostic implications of detecting CIS of
the prostatic urethra are defined by the risk of
progression (Level 3)[37]. Some authors feel that
this finding mandates the need to offer radical
cystoprostatectomy as primary therapy (Level 3)
[40;41]. Esrig et al analyzed their findings of prostatic
involvement at radical cystectomy; 37 of their patients
with low grade tumors or CIS and 29 with ductal only
prostatic disease had a relatively good prognosis
(Level 3)[23]. Both the prostatic urethra and distal
ureter have been considered extravesical locations
384
(Level 3)[48]. Although it seems that these patients

do worse with conservative treatment, this is likely
due to selection bias.
to BCG. In fact, treatment of CIS of the prostatic

urethra associated with superficial bladder tumor
has resulted in complete response rates of 70-100%
in the prostatic urethra and 47-72% when both the
bladder and prostate are considered (Table 6). In
the series of Bretton et al, therapeutic failure has
always been evidenced as disease progression in
the bladder; they believe that transurethral resection
of the prostate contributed significantly to the
successful control of tumor in the prostatic urethra
(Level 3)[39]. Hillyard et al described 2 cases in
which radical cystoprostatectomy was performed
to treat tumor progression in the prostatic urethra
or due to progression in the bladder (Level 3)[38].
Schellhammer et al reported an update of the
series of Hillyard et al and described persistence
or recurrence of disease in 9 of 17 patients (Level
3, [33]). Seven were treated with radical surgery.
Four presented with recurrence or progression in
the bladder, 1 in the prostate and 2 in both bladder
and prostate. They obtained good results in 8 of
10 patients with mucosal carcinoma and in 4 of 7
patients with ductal involvement. Therefore, a more
aggressive approach is warranted in cases with
ductal or acinar involvement.
c) BCG Penetration in the Prostatic Urethra

There is not complete agreement on the degree of
BCG penetration of the prostatic urethra in bladder
instillations. Some authors propose a primary
resection of the bladder neck to obtain direct
contact between the drug or immunotherapy and
the prostatic urothelium [43;49]. Several studies
on the prostatic tissue of patients who received
BCG without prior resection of the prostate have
demonstrated the presence of granulomas,
indicating that BCG penetrates into the prostate
(Level 3)[50-52]. Oates et al performed biopsy in
13 of 32 patients who received BCG because a
prostatic nodule or enhanced consistency of the
gland was palpated, and granulomas were found in
all of them (Level 3)[52]. Mukamel et al diagnosed
granulomas in 40% of the patients and distinguished
an early period (1.5-3 months after BCG) during
which these granulomas formed caseum (Level 3)
[51]. At a later stage (4-14.5 months after BCG), they
did not. Hillyard et al performed several cystograms
in patients without resection of the bladder neck or
prostate and only occasionally observed contrast
medium in the prostatic urethra (Level 3)[38].
However, patients with previous TUR of the prostate
show good opening of the bladder neck on the one
hand, and reflux to the prostatic ducts on the other.
Both changes could facilitate the penetration of BCG
into the prostatic gland.
In selected cases, a disease-specific survival of

89% was reported at 7.5 years follow-up for 28
patients with CIS of T1 or lower grade PU cancers
[55]. However, 28% required a cystectomy for local
recurrence or progression. In a series of 33 patients,
general progression of disease was evidenced in 8
cases, 3 of them at the prostatic urethra (Level 3). The
therapeutic response of this form of disease reaches
70%, while the global vesicoprostatic response is
only 40%. Palou et al showed an 82% response rate
of BCG for intraprostatic duct CIS even without TURP
[54]. Therefore, the results support the view that
BCG is a valid option to treat carcinoma in situ of the
prostatic urethra even without previous transurethral
resection and that it achieves an improved response.
However, with longer follow-up, disease progression
occurs in 24% of the cases. These patients have a
high disease-specific mortality.
BCG instillations were shown to result in lower local

recurrences in patients after TURP compared to men
without TURP [18;39;46;53-55].
Leibovici et al found a clinically significant elevation
of prostate specific antigen (PSA) in 41.6% of the
patients receiving BCG therapy, which reverted
to normal in 3 months (Level 3)[56]. The variation
of PSA levels following instillation of BCG was
evaluated (Level 3)[57]. The variation was higher in
patients who had previously undergone TUR of the
prostate (Table 5), which may be related to better
penetration of BCG into the prostate. Given these
results, resection of the bladder neck or prostate
is advisable, with separate superficial and deep
sampling at 5 and 7 oclock on both sides of the
verumontanum. This allows better initial staging
and gives the best chance to detect prostatic duct
involvement. This maneuver will also facilitate
penetration of BCG in the prostate.
Table 5. Total PSA Values During BCG Instillations

in Patients With and Without TURP [57]
TURP No TURP
Before BCG
1.2 2.1
1st instillation
7.7 3.4
2nd instillation
10.9 3.5
3rd instillation
8.8 3.8
d) BCG Treatment
4th instillation
7.1 4.5
The response rate of bladder CIS to BCG

immunotherapy is approximately 70%. When only
the mucosa of the prostatic urethra is involved, this
form of prostatic involvement should also respond
5th instillation
6.2 4.7
One month
5.3 4.7
Three months
3.5 3.2
385
Table 6. Conservative treatment of CIS in the prostatic urethra with BCG with or without TUR
Reference
Number of
patients (%)
Pathology
TURP
Bretton et al
(39)
Ovesen et al
(73)
Gofrit et al
(53)
Palou et al
(46)
Taylor et al
(55)
Mungan et al
(18)
23 (8.7)
CIS
10 (23.8)*
20
33 (20.7)*
28
14
Follow-up
(months)
Yes
Global/
prostate
response
56/100
CIS
Yes
-/ 80
26
CIS and
exophytic
CIS
Yes
46.5/95.3
58.5
No
39.4/69.6
64
CIS and
exophytic
CIS and
exophytic
No
35.7/50
90
No
NA/64
66
42
* Incidence in patients with bladder CIS
A good staging should be initially performed,

comprising a transurethral resection of the prostate,
together with strict follow-up and aggressive
management of recurrence or persistence of
ductal disease. Very few cases of recurrence in the
prostatic urethra after BCG failure have been treated
conservatively. Orihuela et al treated 5 patients,
and only 2 patients with papillary lesions sustained
complete response (Level 3)[36]. The other 3
patients with CIS or high grade tumors recurred
and progressed. Initial management of superficial
prostatic urethral disease with intravesical treatment
with BCG has reasonably good results with a
response rate of approximately 70%.
noninvasive and in 38% there was stromal invasion.

Solsona et al strongly recommend frequent random
biopsies of the prostatic urethra during initial and
repeated cystoscopic examinations (Level 3)[35].
Details of frequency and technique were not provided.
For patients with positive cytology in follow-up in the
absence of macroscopic bladder carcinoma, it is
mandatory to evaluate the bladder and the prostatic
urethra with multiple biopsies (Level 3)[35]. With a
positive cytology during the first 6 months of followup after conservative management of a superficial
bladder carcinoma, bladder recurrence is most likely
to be the cause (Level 3)[58]. The prostatic urethra
should be considered if there has been associated
carcinoma in situ, tumor near the bladder neck,
or multifocal disease (Level 3)[11;39]. If positive
cytology appears in longer term follow-up, the upper
urinary tract should be evaluated (Level 3)[59].
Patients who progress and those with urothelial

carcinoma of the bladder undergoing radical
cystectomy should be considered for prostatectomy
as well, given the high degree of prostatic involvement
(Level 3)[11;14;28].
Summary
3. Follow-up of the Prostatic

Urethra
Superficial urothelial cancers of the prostate are rare

and most often associated with bladder cancers. In
radical cystectomy specimens, the incidence of prostatic stromal invasion by urothelial carcinoma of the
prostate may be related to the extent of pathologic
evaluation and is associated with poor prognosis.
Most reports of prostatic urethral involvement at the
time of radical cystectomy are not only retrospective,
but lack careful pathologic assessment of the prostate. Underreporting of the true incidence of prostatic
involvement is common. Series of patients who underwent cystectomy for urothelial carcinoma of the
bladder report an incidence of urothelial carcinoma
of the prostate from 12-48% with stromal invasion in
7.6-16.6% [8;11;14;22-24;28;60-62]. Transurethral
resection of the prostate may improve response to
instillation therapy such as BCG. Careful follow-up
is required since recurrence in the prostate predicts
prognosis in non-muscle-invasive bladder cancer.
With increasing numbers of patients receiving initially

longer courses of intravesical therapy for high grade
superficial bladder cancer or CIS rather than radical
surgery, there will be an increased number of patients
at risk of developing urothelial carcinoma of the
prostate. Urothelial carcinoma of the prostate may
occur in 8-48% of patients (Level 3)[11;14;36;39].
Prostatic urethral involvement tends to be more
common in patients with CIS of the bladder, as well
as those with multifocal tumors and involvement of
the bladder neck (Level 3)[11;14;36;39].
In the series of Herr and Donat, with a minimum
follow-up of 15 years, 39% of patients with superficial
bladder cancer (72% with associated CIS treated with
BCG) relapsed in the prostate at a median follow-up
of 28 months (Level 3)[39]. In 62%, the tumors were
386
specimens, Ayyathurai et al describe contiguous

tumor growth into the prostate in 9% of cases
and non-contiguous in 15% [20]. Several studies
showed worse prognosis for contiguous versus noncontiguous growing tumors [20,23,24](Table 7).
III. Urothelial Carcinoma

1. Incidence
Table 7. Classification of Involvement of the Prostate

According to Pagano et al [24]
Adequate specimen processing by whole

mount sectioning of the prostate is essential for
determining the true incidence and pattern of
stromal invasion. Using this technique, several
contemporary cystoprostatectomy series provide
evidence suggesting prostatic stromal invasion is
more common than generally appreciated. Stromal
invasion is present in 37-64% of men with prostate
involvement at cystoprostatectomy for invasive
bladder cancer [19,20]. Shen et al studied 214
consecutive cystoprostatectomy specimens and
found invasive prostatic urothelial carcinoma in 39
patients (18%) [63] A similar incidence of stromal
invasion was observed by Richards et al (19%)[26]
and by Pettus et al (20%)[19]. It should be noted
that the prostatic stroma might be involved not only
in those with invasive bladder cancer but also in
men with non-invasive bladder cancer previously
managed by transurethral resection and intravesical
therapy. Herr and Donat evaluated 186 consecutive
men with superficial bladder cancer and found a
total of 14% to subsequently relapse with prostatic
stromal involvement [8].
Stage
Patients (%) Survival (%)
Contiguous
44 (61)
7%
Noncontiguous
28 (39)
46%
Urethral mucosa
100%
Ductal/acinar
14
50%
Stromal
40%
Extracapsular invasion 0
A third pattern has been described as tumors

located at the bladder neck trigone extending into
the prostatic stroma through thin lamina propria of
the bladder neck without histological evidence of
extravesical or intraurethral spread [33], but the
prognostic significance remains unknown.
3. Diagnosis
In men diagnosed with invasive urothelial carcinoma,
accurate determination of prostatic involvement
prior to cystoprostatectomy remains hampered by
inadequate diagnostic tools. Wood et al were first to
assess the diagnostic yield of transurethral prostate
biopsies, needle biopsies of the prostate, and fine
needle aspiration of the prostate to identify prostatic
involvement in 25 consecutive patients [14]
Stromal invasion is generally considered a sign of

poor prognosis [20-22]. Survival in men with PU
involvement without stromal invasion was more than
60% 5 years after the cystoprostatectomy, whereas
less than 30% of men survived when stromal invasion
was present [20]. Stromal invasion into the prostate
was shown to be associated with an increased risk
of nodal metastases [21].
While superficial prostate involvement was

accurately identified in the majority of patients, the
overall diagnostic accuracy for stromal invasion was
poor with only 2 of the 5 patients being identified by
TUR biopsies. In a more recent study from the same
group, 6 of 35 cystectomy specimens (17%) harbored
urothelial carcinoma involving the prostatic stroma
(either tumor extension from the bladder involving
periprostatic tissue or direct extension via the urethra)
[64]. In the 5 patients who had a TUR biopsy prior to
surgery, the diagnostic yield of prostatic involvement,
including superficial urethral and stromal invasion,
was 100%. Donat et al evaluated 246 male patients
undergoing cystectomy for bladder cancer and
analyzed the ability of transurethral loop biopsies
to adequately determine the presence and extent of
prostatic involvement [65]. Biopsies were obtained at
the 4 and 8 oclock positions from the bladder neck
to the verumontanum. With a sensitivity of 53%,
specificity of 77%, and positive predictive value of
45%, the authors concluded that transurethral biopsy,
while remaining the primary diagnostic modality, is
an imperfect tool for detecting stromal invasion by
2. Mechanisms of Stromal Invasion

Prostatic stromal invasion is defined by the
presence of irregular invasive tumor nests or single
cells within the dense fibromuscular stroma of the
prostate or admixed within benign prostate glands.
Accompanying ductal/acinar carcinoma in situ and a
desmoplastic inflammatory response often coexists.
Besides stromal invasion, a distinction can be made
between contiguous and non-contiguous tumor
growth into the prostate. The former describes
direct invasion of bladder tumor into the prostate
as an extravesical tumor extension (stage pT3b or
greater) penetrating into the stroma directly through
the prostatic capsule whereas the latter refers to
synchronous presence of PU tumors as a pagetoid
spread of urethral tumor into the stroma via the ducts
and acini. In a series of 320 cystoprostatectomy
387
4. Predicting Prostatic Stromal

Invasion
While lacking support from level l evidence, the

importance of extended lymph node dissection in the
context of stromal invasion cannot be overstated. It
has been well acknowledged that the more extensive
the dissection and the more nodes removed,
the higher the staging accuracy and therapeutic
benefit to patients.[65,67,68] Mapping studies have
provided important data regarding the incidence
and location of node metastases in patients with
bladder cancer, specifically pT4 disease. Dangle et
al have recently demonstrated that extending the
lymph node dissection to include the presacral and
common iliac nodes changed the pN stage from pN0
to pN1 in 69% of cases and from pN1 to pN2 in 33%
of patients [65]. These findings reiterate results from
an earlier mapping study by Leissner and colleagues
who demonstrated that 7% of patients with Iymph
node spread had node metastases in the common
iliac or presacral regions only [69].
Given the lack of accurate diagnostic tools,

clinical factors that might help clinicians predict
stromal invasion would be particularly useful. Most
studies, however, assessing predictors of prostatic
involvement by urothelial carcinoma have combined
superficial urethral involvement and stromal invasion
into a single endpoint in their multivariate analyses.
Wood et al identified carcinoma in situ (CIS) involving
the trigone, bladder neck, periurethral structures,
and ureter, and the use of intravesical instillations
as predictors of prostatic urethral involvement [14].
Similarly, Pettus and colleagues found prostatic
urothelial carcinoma in 77 of 235 cystoprostatectomy
specimens (stromal invasion present in about half) and
identified CIS at the trigone as a significant predictor
of prostatic involvement (OR 6.3) [19]. In fact, only
6% of the patients with a bladder tumor proximal to
the trigone and no associated CIS had pathological
evidence of urothelial cancer involving the prostate.
In a more recent series of 96 cystoprostatectomy
specimens, Richards et al found prostatic stromal
involvement in 18 patients (19%) [26]. After adjusting
for clinical stage, Iymphovascular invasion, and
tumor multifocality, the presence of carcinoma in
situ (OR 3.2) and location of tumor at or below the
trigone (OR 3.3) were the only independent clinical
predictors of stromal invasion. Taken together, even
in the absence of positive findings on transurethral
loop biopsies, the presence of cancer, in particular
CIS, at the bladder neck trigone should be considered
a strong risk factor for prostatic stromal invasion.
Recently, in another study by Arce et al, they found
in multivariate analysis of a series of 717 cystectomy
specimens the presence of solitary T2-T3 bladder
tumor at the trigone or bladder neck was predictive
of invasive prostatic involvement [66].
In addition to lymph node status, it has been

suggested that the outcome of men with stromal
invasion can be stratified by the pattern and depth
of stromal invasion as aforementioned. Spread of
urothelial carcinoma into the ducts via the urethra
may not be as ominous as extravesical tumor
extension into the prostate or silent invasion into
the stroma emanating directly from a bladder neck
tumor. The recent study published by Barocas and
colleagues demonstrated the overall survival of men
with carcinoma in situ involving the prostatic urethra
or involvement of prostatic ducts to be similar to the
overall survival of men with no prostatic involvement
[21]. The outcome of those with stromal invasion was
uniformly poor irrespective of the mode of spread.
IV. RECOMMENDATIONS
Non-invasive Urothelial Carcinoma of the
Prostate
5. Treatment and Outcome Analyses

The
application
of
neoadjuvant
systemic
chemotherapy followed by radical cystoprostatectomy
with extended pelvic lymph node dissection is the
standard of care for men with prostatic stromal
invasion by urothelial cancer. Ample evidence is now
available to attest that prostatic stromal invasion is
associated with a higher likelihood of lymph node
metastases and a profound negative impact on
survival independent of lymph node status. Shen
and colleagues, for example, detected lymph node
metastases in 74% of the patients with stromal
invasion; the 5-year survival in this group was 32%
[63]. Similar findings were reported by Barocas et
al who found lymph nodes metastases in 74% of
men with bladder tumor extending into the stroma
and estimated the 3-year overall survival of men
with stromal invasion with and without lymph node
involvement to be 7% and 17%, respectively [21].
1. Macroscopic evidence of superficial bladder

cancer in the prostatic urethra is highly specific.
TUR of any macroscopic or suspicious lesion
is required for determination of the stage and
grade of tumors in the prostatic urethra. Once a
non-muscle-invasive high-grade tumor or CIS of
the bladder has been diagnosed, careful followup of the prostatic urethra is mandatory (grade
C).
2. High- and low-grade non-invasive urothelial
carcinoma and CIS of the prostate should be
treated with intravesical BCG (grade C).
3. Evidence (level 3) shows that TUR may improve
contact of BCG with the prostatic urethra and it
looks that response rates to BCG are increased
(grade C).
4. CIS or tumor in the prostatic ducts warrants
388
further study because very few patients have

been treated. It is advisable for the clinician to
perform radical surgery if there is any doubt, to
avoid understaging in patients with prostatic duct
involvement (grade C).
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392
Committee 9
Chemotherapy for Metastatic

Chair:
CN. Sternberg
Members:
D. Bajorin,
R. Dreicer,
M. Galsky,
D. George,
M. Milowsky,
D. Quinn,
G. Sonpavde,
WM. Stadler,
D. Theodorescu,
D. Vaughn
Correspondence:
Cora N. Sternberg, MD, FACP,
San Camillo and Forlanini Hospitals
Padiglione Flajani
Circonvallazione Gianicolense 87
00152 Rome, Italy
Phone: +39 06 6641 8008
Fax: +39 06 6630771
E-mail:cstern@mclink.it
393
Table of Contents
I. Background and
Introduction
VIII. Combination Therapy

IX. Level of Evidence and
for Second-line and Salvage
Therapy
II. First-line Treatments

III. Modifications of M-VAC
X. Novel Agents for Advanced

IV. Doublet Chemotherapy

V. Triplet Drug Combination
with Platinum Analogues
XI. New Trial Designs and the

Development of Tailored
Therapy
VI. Cisplatin-ineligible Patients
XII. Predictive Models
VII. Second-line Treatments/

Salvage Chemotherapy
Monotherapy
XIII. Abstract
394
Chemotherapy for Metastatic

CN. Sternberg,
D. Bajorin, R. Dreicer, M. Galsky,
D. George, M. Milowsky, D. Quinn,
G. Sonpavde, WM. Stadler, D. Theodorescu, D. Vaughn,
I. Background and
Introduction
III. Modifications of M-VAC

Several phase II trials have evaluated administration
of dose-dense M-VAC (DD-M-VAC) with either GMCSF (granulocyte macrophage colony stimulating
factor) or G-CSF (granulocyte colony stimulating
factor). These studies have demonstrated the
possibility of increasing the doses as much as 60%
[7]. Unfortunately, in some of these trials, toxicity
was also significantly increased [8-10].
Bladder cancer is a major health problem as defined

by incidence, mortality, and cost of care. While
a major part of the expense is directed towards
treatment of non-muscle-invasive and organconfined bladder cancer, the major morbidity and
mortality is a result of recurrent and/or metastatic
disease. Although urothelial cancer is typically a
chemo-sensitive disease, only a small sub-set of
patients with advanced disease achieve long-term
disease-free status.
The European Organisation for Research and

Treatment of Cancer (EORTC) conducted a
randomized trial comparing DD-M-VAC given on
an every 2 week schedule with classic M-VAC.
With DD-M-VAC, it was possible to deliver higher
doses of doxorubicin and cisplatin as compared to
classic M-VAC. Although there was not a significant
difference found in median survival (approximately
15 months in both arms), 21.8% were alive on the
DD-M-VAC arm versus 13.5% on the M-VAC arm
at 5 years (HR=0.76, P=0.042). There was also
a significant difference in favor of DD- M-VAC in
response rate (72% vs. 58%, P=0.016), complete
response rate (25% vs. 11%, P=0.006) and median
progression-free survival (9.5 vs. 8.1 months,
P=0.017) [7;11].
II. First-line Treatments

Cisplatin combinations such as M-VAC (Methotrexate,
Vinblastine, Adriamycin, Cisplatin) were extensively
studied in the 1980s and yielded partial and complete
remissions in patients with metastatic disease, with
long-term survival reported in complete responders
[1;2]. Patients with nodal disease only and a good
performance status have a 35% complete response
rate, with the majority enjoying long-term survival
and apparent cure [3].
On the basis of trials comparing M-VAC to cisplatin
chemotherapy [4;5] and to CISCA (cisplatin,
cyclophosphamide,
Adriamycin)
combination
therapy, M-VAC became the standard of care for the
treatment of metastatic bladder cancer in the 1990s
with reproducible response rates in the range of 4070% and a median survival of approximately 1 year
in several series [2;4;6].
A phase III randomized trial comparing M-VAC plus

prophylactic G-CSF with docetaxel-cisplatin (DC) plus
G-CSF was reported by the Hellenic Cooperative
Oncology Group [12]. Two hundred twenty patients
were randomly assigned to M-VAC (109 patients) or
DC (111 patients). The overall response rate (54.2%
vs. 37.4%; P=0.017), median time to progression
(TTP; 9.4 vs. 6.1 months; P=0.003) and median
survival (14.2 vs. 9.3 months; P =0.026) favored
the M-VAC regimen. After adjusting for prognostic
factors, the difference in time to progression
Nevertheless, the toxicity of the M-VAC regimen,

without grouth factor support, consisting mainly of
myelosuppression and mucositis, with a low but
consistent therapy related death rate, has challenged
routine use.
395
remained significant, whereas the survival difference

was non-significant at the 5% level. M-VAC caused
more frequent grade 3 or 4 neutropenia (35.4% vs.
19.2%; P=0.006), thrombocytopenia (5.7% vs. 0.9%;
P=.046), and neutropenic sepsis (11.6% vs. 3.8%;
P=0.001), but toxicity of M-VAC was considerably
lower than that previously reported for M-VAC
administered without G-CSF. It can be concluded
from this study that not only was M-VAC supported
by G-CSF more effective than DC but that it was
also better tolerated than classic M-VAC as first-line
treatment in advanced urothelial carcinoma (level of
evidence 1b).
survival was 7.7 months for GC and 8.3 months

for M-VAC, with a hazard ratio of 1.09. The 5-year
progression-free survival rates were 9.8% and
11.3%, respectively (P=0.63). On the basis of a more
favorable risk-benefit ratio, many consider the GC
regimen as a new standard treatment in metastatic
urothelial cancer (level of evidence 1b).
Several phase II trials explored the combination
of paclitaxel and cisplatin [19;20] with an overall
response rate of approximately 50%. At least three
trials evaluated the combination of docetaxel and
cisplatin with complete responses ranging from
19- 26% and partial responses from 34-58%. [2123]. The toxicity of these regimens was considered
moderate with neutropenia and neurotoxicity being
most common. As noted above, a phase III trial
demonstrated that this regimen was inferior to
M-VAC plus G-CSF [12].
These trials confirm that classic M-VAC with

appropriate hematopoietic growth factor support
is an effective treatment. DD-M-VAC is another
excellent option that may potentially lead to higher
long-term cure rates.
Several phase II trials have studied the combination

of paclitaxel with varying doses (150-225 mg/
m) and carboplatin (AUC 5-6) reporting overall
response rates of 14-65%, with complete responses
in 0-40% [24-28]. This regimen is well-tolerated with
predominantly mild hematologic and neurologic
toxicities.
IV. Doublet Chemotherapy

Several phase II trials in both pretreated and
untreated patients evaluated the combination of
cisplatin and gemcitabine (GC). Different schedules
and dosages in locally advanced and/or metastatic
bladder cancer have been conducted [13] with
overall response rates ranging from 41- 57% and
complete response from 18- 22% [14-16]. Toxicity
was generally acceptable and median survival rates
were 12.5, 14.3, and 13.5 months, respectively.
A phase III trial conducted by the ECOG compared

M-VAC with paclitaxel-carboplatin [29]. Patients with
previously untreated metastatic urothelial carcinoma
were randomized to either standard M-VAC or
paclitaxel 225 mg/m plus carboplatin AUC 6 every
3 weeks. After 2.5 years, the study was closed due
to slow accrual. Of the planned 330 patients, only 85
were enrolled. Compared with carboplatin-paclitaxel,
patients treated with M-VAC had more severe
myelosuppression, mucositis, and renal toxicity.
Interestingly, a quality of life evaluation revealed
non-significant differences between the two arms.
At a median follow-up of 32.5 months, there was
no significant difference in response rate (35.9%
M-VAC vs. 28.2% PC, P=0.34) or median survival
(15.4 months M-VAC vs. 13.8 months PC, P=0.41)
between the two arms. Definitive conclusions
are not possible, given that the trial was severely
underpowered.
These results led to a large industry-sponsored

randomized trial of GC versus M-VAC. When first
published, at a median follow-up of 19 months,
overall survival in the M-VAC group was 14.8 months
as compared to 13.8 months in the GC group [17].
This trial was not designed as an equivalency trial,
and many more patients would have been needed
to prove that the two regimens were equivalent in
efficacy.
The toxicity profile was different in the two arms,
with lower rates of grade 3-4 neutropenia (72% vs.
84%), neutropenic fever (2% vs. 14%), and grade
3-4 mucositis (1% vs. 22%) in the GC arm, and a
lower rate of thrombocytopenia and anemia in the
M-VAC arm. It is possible that some of the toxicities
in the M-VAC group could have been avoided with
the prophylactic use of G-CSF, which was not
routinely prescribed. The quality of life profile was
similar for both arms with the exception of a nonstatistically significant improvement in fatigue in the
GC group.
The combination of gemcitabine and pemetrexed has

been tested in 64 chemo-naive patients with locally
advanced and/or metastatic urothelial carcinoma. The
overall response rate among 47 patients evaluable
for response was 28% and overall response rate for
the intention-to-treat population was 20%. Median
response duration was 11.2 months and median
overall survival 10.3 months. There was one toxic
death due to neutropenic sepsis. The efficacy was
not superior to that of single-agent gemcitabine
[30].
In an update of this trial [18], overall survival was

similar in both arms with median survival of 14.0
months for GC and 15.2 months for M-VAC. The
5-year overall survival rates were 13.0% and 15.3%,
respectively (P=0.53). The median progression-free
The combination of gemcitabine and paclitaxel has

been evaluated in both pretreated and untreated
396
patients with different doses and schedules [31-35]

with responses in the range of 35-55%.
investigated non-cisplatin-based chemotherapy

regimens in cisplatin-ineligible patients, however,
these trials have generally included heterogeneous
eligibility criteria due to a lack of consensus
regarding what actually constitutes cisplatinineligibility. Recently, a working group surveyed a
large group of medical oncologists in an attempt to
develop a uniform definition of patients unfit for
cisplatin that could be used to standardize eligibility
criteria for clinical trials in this patient population
moving forward [42;43]. Based on the survey
results and the available literature regarding the
safety of cisplatin in patients with urothelial cancer
and other solid tumors, a consensus definition was
generated. According to this definition, patients are
deemed cisplatin-ineligible if they meet at least
one of the following: ECOG performance status
of 2, creatinine-clearance less than 60 mL/min,
common terminology for adverse events (CTCAE)
grade 2 or greater hearing loss, CTCAE v4 grade 2
or greater peripheral neuropathy, or New York Heart
Association Class III heart failure. These criteria are
rooted in common clinical practice, are designed
to optimize the general population of patients with
urothelial cancer who are eligible for clinical trials,
and may lead to a greater likelihood of developing a
viable strategy for regulatory approval of therapeutic
regimens for this important patient subset.
Given the activity observed in several two-drug

combinations, partially non-overlapping toxicities,
and different mechanisms of action, combination
therapy in three-drug regimens was the next logical
step.
V. Triplet Drug Combination

with Platinum Analogues
Investigators have attempted to enhance treatment
efficacy by adding a third drug to the doublet
combinations. Data emerging from the phase II
studies have suggested that triplet regimens might
produce higher response rates and improve median
survival [36-38].
To elucidate the role of paclitaxel when added to
GC, a large international Intergroup Study EORTC
30987 compared the triplet paclitaxel-cisplatingemcitabine (PCG) with the conventional GC doublet
in 627 chemo-naive patients with locally advanced
or metastatic urothelial carcinoma. The study was
designed to identify a 4-month difference in median
survival between the two treatment groups. Overall
response rate was 57.1% for PCG (CR 15%)
and 46.4% for GC (CR 10%, P=0.02). Median
progression-free survival was 8.4 months and 7.7
months for PCG and GC respectively (P=0.10).
Median survival was 15.7 months for PCG and 12.8
months with GC, with no significant difference in
overall survival (P=0.10). Both treatments were welltolerated, with more thrombocytopenia and bleeding
on GC (12% vs. 7%) and more febrile neutropenia
on PCG (13% vs. 4%). In a retrospective subgroup
analysis, a survival benefit was seen in patients with
the bladder as their primary tumor site and in those
with no risk factors or one factor (risk factors were
the presence of visceral metastases and a WHO
performance status of 1) [39].
The most commonly used non-cisplatin-based

combination chemotherapy regimen in patients
with advanced urothelial cancer is gemcitabine and
carboplatin. This combination has been evaluated as
first-line treatment in phase II trials [44;45] .
In one of the gemcitabine-carboplatin trials, 60
unselected patients with advanced urothelial
carcinoma were treated with carboplatin AUC 5
day 1 and gemcitabine 1000 mg/m2 days 1 and 8
every 21 days in a study of the Hellenic Cooperative
Oncology Group [46] . The objective response rate
was 38.4% with 11.7% complete responses and
26.7% partial responses. The median time to disease
progression was 7.6 months and the median overall
survival was 16.3 months. The median survival was
comparable to that reported for the combination of
M-VAC according to the Memorial Sloan-Kettering
Cancer Center prognostic model (3) based on similar
baseline prognostic features.
In light of the results, this triplet regimen cannot be

recommended as first-line therapy (level of evidence
1b).
VI. Cisplatin-ineligible Patients
The authors concluded that the combination of

gemcitabine and carboplatin appears to have
considerable activity as the first-line treatment
of unselected patients with advanced urothelial
carcinoma with manageable toxicity, and that it
deserved further evaluation in this setting.
As the majority of patients with advanced urothelial

cancer are older (median age 68 years) and renal
function declines with age, alternative non-cisplatinbased therapy is needed [40]. In fact, approximately
40% of patients with advanced urothelial cancer are
cisplatin-ineligible due to renal dysfunction alone
[41], and the proportion of cisplatin-ineligible patients
is likely much higher when including treatmentlimiting factors such as poor performance status
and comorbidities. Several phase II studies have
The University of Michigan led a phase II trial

of carboplatin, gemcitabine, and paclitaxel for
advanced urothelial cancer in patients with advanced
urothelial malignancy of any histology, no previous
chemotherapy for metastatic disease, Southwest
397
Oncology Group performance status of 2 or less,

and serum creatinine levels of 2 mg/dL or less [38].
Of 49 patients accrued, 15 (32%) experienced a
complete response while 17 (36%) patients had
a partial response. Febrile neutropenia occurred
in only 1.4% of patients while grade 3 neuropathy
occurred in 4 patients. The median survival was
14.7 months. The trial was notable for significant
responses and good median survival with a noncisplatin regimen, including responses in patients
with squamous histology, who historically tend to
be resistant to cytotoxic therapy. On that basis, this
regimen has been widely used for subjects who are
not cisplatin-ideal even though it has never been
formally compared to cisplatin-containing regimens.
study 30986, a phase III trial comparing M-CAVI

versus GCa in patients with advanced urothelial
cancer unfit for cisplatin-based chemotherapy,
were presented [50;51]. Eligibility criteria for this
trial included a WHO performance status 2 and/
or impaired renal function (GFR greater than 30
but less than 60 mL/min). Overall survival was not
different between the two arms [8.1 months versus
9.3 months; HR 0.94 (95% CI, 0.72-1.22); P=0.64].
However, severe acute toxicity (defined as grade
3-4 mucositis, grade 4 thrombocytopenia associated
with bleeding, grade 3-4 neutropenic fever, grade
3-4 renal toxicity, death) was substantially greater
for M-CAVI than GCa (21.2 % vs. 9.3%). This
trial provides level 1 evidence for the use of GCa
chemotherapy in patients deemed ineligible for
cisplatin-based chemotherapy; however, adoption
of a standard definition of cisplatin-ineligible and
additional randomized studies of chemotherapy
and novel agents in this patient population are
desperately needed [42].
A randomized trial in patients with surgically

incurable advanced bladder cancer evaluated
whether the carboplatin-based regimen M-CAVI
(methotrexate, carboplatin, and vinblastine) offered
an advantage over the cisplatin-based regimen
M-VAC (methrotrexate, vinblastine, doxorubicin,
and cisplatin) [47]. In this 47 patient trial, the overall
response rates were 39% for M-CAVI and 52% for
M-VAC (P=0.3) with 3 complete responses among
the patients receiving M-VAC and none in the
M-CAVI group. The median disease-related survival
was 16 months with M-VAC versus 9 months with
M-CAVI (P=0.03). The authors concluded that
M-CAVI was less toxic but less active than M-VAC
and the M-CAVI regimen should be reserved for noncisplatin candidates.
VII. Second-line Treatments/

Salvage Chemotherapy
Monotherapy
Vinflunine, a microtubule inhibiting vinca alkaloid
is the most thoroughly investigated agent in the
second-line setting. One phase II trial recruited 51
patients, most of whom had progressed within 12
months, and demonstrated an 18% response rate
and a median duration of response of 9.1 months
[52] . Another phase II trial accrued 175 patients with
disease progressing within 12 months of platinumbased chemotherapy and demonstrated a response
rate of 15% and median duration of response of 6
months [53]. Subsequently, a randomized phase III
trial accrued 370 patients and compared vinflunine
plus best supportive care (BSC) to BSC alone as
second-line therapy [54]. This trial accrued patients
progressing after frontline platinum-containing
chemotherapy for metastatic disease, and those
who had received prior peri-operative chemotherapy
only were excluded. More than 80% had progressed
within 6 months after prior chemotherapy and greater
than 70% of patients had visceral disease. An
extension of survival, the primary endpoint, was not
demonstrated by an intention-to-treat (ITT) analysis
(6.9 vs. 4.6 months, P=0.287), but there was a
statistical improvement in response rate (8.6 vs. 0%)
and median progression-free survival (3.0 vs. 1.5
months). Approximately 30% of patients in both arms
received subsequent systemic therapy, which may
have confounded survival. Multivariate Cox analysis
adjusting for prognostic factors demonstrated a
significant extension of survival with vinflunine
(P=0.036), reducing the risk of death by 23%. In
another analysis of only the eligible population
A second randomized phase II study evaluated the

cisplatin-containing regimen M-VEC (methotrexate, vinblastine, epirubicin, and cisplatin) and the
carboplatin-containing regimen M-VECa (methotrexate, vinblastine, epirubicin, and carboplatin) in 57
patients with recurrent or metastatic bladder cancer
[48]. The overall clinical response rate was 71% (with
25% complete responses) in the M-VEC group and
41% (with 11% complete responses) in the M-VECa
group (P=0.04).
In a third randomized phase II trial comparing the
toxicity and efficacy of gemcitabine plus cisplatin
(GP) and gemcitabine plus carboplatin (GCa) in
patients with advanced urothelial cancer, the median
survival times were 12.8 months and 9.8 months,
respectively [49]. Although the trial was not designed
with sufficient power to detect significant differences
in efficacy between the arms, there is the suggestion
of a better outcome in the cisplatin arm. The
authors concluded that the GCa combination might
be considered as an alternative to GP in selected
patients such as those with renal dysfunction. The
trial only included patients with a creatinine clearance
equal to or greater than 60 mL/min and a Zubrod
performance status of 0-2.
More recently, the updated results of the EORTC
398
(n=357), the median survival was significantly

longer for vinflunine with BSC compared to BSC
(6.9 vs. 4.3 months, P=0.04). Based on this study,
vinflunine was approved by the European Medicine
Agency (EMA) and is the only agent approved by a
regulatory agency for this indication. The key grade
3 or 4 toxicities for vinflunine were neutropenia
(50%), febrile neutropenia (6%), anemia (19%),
fatigue (19%), and constipation (16%). A recent
retrospective analysis of patients who received
second-line vinflunine identified ECOG performance
status greater than 0, hemoglobin less than 10 g/dL,
and liver metastasis as poor prognostic factors [55].
gemcitabine-paclitaxel with continuation beyond 6

cycles until progression [72]. None of the patients
had received previous paclitaxel, and approximately
half had received previous gemcitabine. The median
disease-specific survival was 7-8 months and the
median progression-free survival was approximately
3.5 months in both groups. The strategy of a
fixed number of cycles versus continuation until
progression could not be evaluated since a mean of
only 4 cycles were delivered in both groups.
Table 1. Reported Phase II Trials of Second-line
Therapy for Metastatic Urothelial Carcinoma
Numerous other chemotherapeutic and targeted

agents have been evaluated as second-line therapy
in non-randomized phase II trials and modest
or marginal activity has been demonstrated for
some agents (Table 1). Eligibility criteria for these
reported phase II trials have been highly variable
and heterogeneous, enrolling patients treated with
peri-operative chemotherapy followed by frontline
therapy for metastatic disease or enrolling those who
had received peri-operative chemotherapy alone
and with no requirement for a defined treatmentfree interval after frontline therapy. Prior treatment
may not be clearly defined. This renders comparison
of outcomes across trials difficult; the corollary is
that going forward, it might be important to enroll
homogeneous patients in predefined chemosensitive
or chemoresistant strata. Generally, these trials
report response rates of 5-25%, median progressionfree survival of 2 to 3 months and median survivals
of 6 to 9 months (Table 1) [56-70].
Taxanes (paclitaxel, docetaxel, nanoparticle-albuminbound paclitaxel) have been evaluated following firstline GC, while gemcitabine and the taxanes, alone
or in combination have been employed following
M-VAC. Second-line pemetrexed, a multitargeted
antifolate and active as first-line therapy, illustrates
the degree of heterogeneous outcomes in previouslytreated patients. One study demonstrated modest
activity of 8% and did not attain the level of activity
required to continue accrual to the second stage in
another trial (60;64). Conversely, another phase II
trial in presumably comparable patients employed
pemetrexed in the second-line setting of metastatic
urothelial carcinoma and demonstrated a response
rate of 28% [71].
VIII. Combination Therapy

Combination regimens have also been evaluated
as second-line therapy in phase II trials (Table 1),
although a potential incremental benefit compared
to monotherapy remains undefined. A German
randomized phase II trial of 102 patients compared
the strategy of administering 6 cycles of second-line
Drug
N
56
RR
%
20
PFS
(mo)
2.4
OS
(mo)
5.5
Ifosfamide (62)
Gemcitabine (66)
30
11
4.9
8.7
Gemcitabine (67)
35
22.5 -
5.0
Weekly Paclitaxel (68)
31
10
2.2
7.2
Docetaxel (65)
30
13
9.0
Nab-paclitaxel (70)
35
44
Paclitaxel-Gemcitabine
41
(31)
Ifosfamide-Gemcitabine
34
(105)
Carboplatin-Paclitaxel (73) 44
60
14.4
21
4.0
9.0
16
4.0
6.0
Pemetrexed (60)
47
27.7 2.9
9.6
Pemetrexed (64)
12
Ixabepilone (58)
42
11.9 2.7
8.0
Oxaliplatin (61)
18
1.5
7.0
Vinflunine (53)
175 15
2.8
8.2
Vinflunine (52)
51
18
3.0
6.6
Irinotecan (57)
40
2.1
5.4
Topotecan (69)
44
9.1
1.5
6.3
Gefitinib (106)
31
3.0
Lapatinib (63)
59
4.5
Sorafenib (80)
27
6.8
Sunitinib (77)
45
2.4
6.9
Pazopanib (79)
18
22
Index: (-)=Not available or stipulated in publication; N=number of patients; RR=response rate;

PFS=progression-free survival; OS=overall survival
399
Another trial evaluated carboplatin-paclitaxel

following prior cisplatin-based chemotherapy not
including paclitaxel, and reported a response rate of
16%, median progression-free survival of 4 months,
and median survival of 6 months [73]. A phase I/II trial
evaluated a combination of salvage weekly cisplatin,
gemcitabine, and ifosfamide in a heterogeneous
group of patients who had received previous
platinum-based chemotherapy [74]. The response
rate was 40.8% but hematologic toxicities appeared
prohibitive. Similarly, the combination of pemetrexed
and gemcitabine has demonstrated moderate activity
coupled with substantial myelosuppression [30;75].
Scant data support re-administration of secondline M-VAC following prior first-line M-VAC in those
with an excellent previous quality of response and
relatively prolonged time to progression [76]. M-VAC
appears to have activity after GC, although this has
not been formally reported.
Akt/mTOR, Ras), immune modulation (CTLA-4

antagonists), and strategies to target the putative
tumor initiating stem cells. Given the rapid proliferation
that characterizes metastatic urothelial carcinoma,
chemotherapeutic agents targeting DNA replication
and/or cell division may continue to play a role even
in the era of biologic agents (Table 2). While early
disease appears to segregate into two molecular
pathways (papillary tumors are characterized by
gain-of-function mutations affecting oncogenes such
as RAS and FGFR3, and carcinoma in situ (Tis)
and invasive tumors are characterized by loss-offunction mutations affecting tumor suppressor genes
p53, RB, and PTEN). A critically important driver of
urothelial carcinogenesis in the setting of advanced
disease remains elusive.
1. Chemotherapy
Eribulin is a synthetic derivative of the marine
sponge product halichondrin-B that inhibits
tubulin polymerization, and is being evaluated as
monotherapy in the first- or second-line setting,
and in combination with GC. Novel anti-mitotic
agents that inhibit the kinesin spindle protein (AZD4877), the polo-like kinase (BI-6727) and a potent
methotrexate analogue, pralatraxate are all being
evaluated in the second-line setting (Table 2). Nabpaclitaxel is being evaluated as a single agent in
previously treated patients and in combination with
carboplatin and gemcitabine as neoadjuvant therapy
preceding radical cystectomy.
IX. Level of Evidence and

for Second-line and Salvage
Therapy
Since a survival benefit was not demonstrated with
vinflunine by intention-to-treat analysis in the only
phase III trial conducted in this setting and modest
efficacy (that appears similar to activity of other
available agents), in our opinion, these data represent
level 2a evidence and a grade B recommendation.
Additionally, other agents that have been evaluated
in smaller numbers of patients in phase II trials
also represent level 2a evidence and a grade B
recommendation. Given the poor outcomes with
currently available agents and regimens and the
palliative nature of such therapy, clinical trials should
remain the preferred option for the second-line and
salvage therapy of metastatic urothelial carcinoma
(Tables 2 and 3). Given the observation that these
patients progress rapidly and poor performance might
frequently preclude systemic therapy, the strategy of
early second-line therapy in patients with stable or
responding disease after first-line chemotherapy is
being investigated (Table 3).
2. Angiogenesis-targeting Agents
Modest activity has been demonstrated in phase II
trials of the multi-targeted VEGFR tyrosine kinase
inhibitor, sunitinib as frontline or salvage therapy
of metastatic urothelial carcinoma [77;78]. In the
salvage setting of a heavily pretreated population
that received sunitinib 50 mg daily for 4 of 6 weeks
or 37.5 mg daily, a partial response was seen in 3
of 45 patients, and in 1 of 32 patients respectively.
Clinical regression or stable disease was achieved
in 33 of 77 (43%) patients. The median progressionfree survival (2.4 months) and overall survival (6-7
months) were disappointing. There were substantial
toxicities with one treatment-related death and 47
patients experiencing grade 3 or 4 toxicities.
While sunitinib has demonstrated modest activity in
the salvage setting (described earlier), a frontline trial
enrolled cisplatin-ineligible patients with a creatinine
clearance of 30-60 mL/min and ECOG performance
status 1 or greater to receive sunitinib 50 mg daily
for 4 weeks of every 6 weeks [77]. Of 14 evaluable
patients, 2 partial responses (14.3%) were obtained,
and 9 patients (64.3%) had SD lasting greater than
3 months and the median progression-free survival
was 6 months. This agent is under further study in
combination with GC as neoadjuvant treatment and
as maintenance therapy in patients experiencing
X. Novel Agents for Advanced

A better understanding of the molecular biology of
urothelial carcinoma is yielding promising, albeit
unvalidated results. Molecular targets including
angiogenic pathways (VEGF, angiopoietin/Tie2,
FGFR3), growth factor tyrosine kinase receptors
(EGFR, Her2, Met, IGF-1R), cytoplasmic signaling
pathways of survival and proliferation (PI3K/
400
complete response, partial response, or stable

disease after first-line therapy.
dose reduction [82]. Based on these promising results, the CALGB has launched a critically important
first-line phase III trial that compares GC with GCbevacizumab. Another phase II trial is evaluating the
combination of carboplatin, gemcitabine, and bevacizumab for cisplatin-ineligible patients [83]. Separate phase II trials are evaluating neoadjuvant GC
or DD-M-VAC plus bevacizumab followed by radical
cystectomy with a goal of improving pathologic complete remissions and long-term outcomes.
Another single institution Italian experience with

pazopanib (a multi-targeted VEGFR tyrosine kinase
inhibitor) pre-treated patients was reported at the
ESMO meeting in October 2010. Of 18 heavily
pre-treated patients with a median of 5 (312)
prior regimens, 4 (22%) patients obtained a partial
response and 11 (61%) had stable disease [79].
Sorafenib did not demonstrate significant activity
as first- or second-line therapy by itself, but its
evaluation in combination with frontline gemcitabine
plus carboplatin is ongoing (Table 2) [80;81].
Aflibercept (VEGF-trap), a VEGF receptor fusion

protein that has greater affinity for VEGF than
bevacizumab and also targets placental growth factor
(PlGF), demonstrated poor activity as second-line
monotherapy [84]. Based on preliminary evidence
for activity in a phase I trial, a randomized phase
II trial in the second-line setting will evaluate the
value of adding AMG-386 (angiopoietin neutralizing
peptibody) to carboplatin-paclitaxel [85]. Another
randomized phase II trial is planning the secondline evaluation of a combination of docetaxel with
monoclonal antibodies against either VEGFR1 (IMC18F1) or VEGFR-2 (IMC-1121B) (Table 3).
A randomized phase II trial is evaluating salvage

docetaxel alone or with vandetanib (a VEGFR and
EGFR targeting agent) in patients who have received
up to 3 prior regimens (Table 3).
Dovitinib, a multitargeted inhibitor of VEGF and
FGF receptors is being evaluated in the secondline setting after evaluation of FGFR-3 expression
(Table 2 and 3). A phase II trial evaluating first-line
GC plus bevacizumab for metastatic urothelial carcinoma demonstrated promising activity (overall response rate 58%, median progression-free survival
8.2 months, median overall survival 19.1 months),
accompanied by a significant rate of venous thromboembolism that was ameliorated with gemcitabine
3. EGFR and Her2-targeting Agents

Disappointingly, gefitinib alone or in combination with
GC demonstrated poor or no activity [86;87]. Erlotinib
has demonstrated biologic activity in the neoadjuvant
setting and further evaluation may be warranted in
TABLE 2. Key Ongoing or Planned Non-randomized Trials Employing Novel Agents for Urothelial
Carcinoma*
Line of Therapy
Drug/Regimen
Molecular Target
First or second
First
Neoadjuvant
First (cisplatin-ineligible)
Neoadjuvant
First
Neoadjuvant, first-line
Neoadjuvant
First-line
Neoadjuvant
Second
Second
Second
Second
Second
Second
Second
First-line cisplatin-ineligible,
second-line
First-line
Eribulin
GC-Eribulin
GCa-Nab-paclitaxel
GCa-Bevacizumab
DD-MVAC-bevacizumab
GCa-Sorafenib
GC-Sunitinib
GC-Sorafenib
GC-lenalidomide
Dasatinib
AZD-4877
Pralatrexate
Volasertib
Pazopanib
Dovitinib
Tamoxifen
Everolimus
Everolimus-Paclitaxel
Tubulin
Tubulin
Tubulin
VEGF
VEGF
VEGFR, PDGFR, Raf
VEGFR, PDGFR
VEGFR, PDGFR
Immune-modulation, angiogenesis
Src
Kinesin spindle protein
Folate
Polo-like kinase
VEGFR, PDGFR
VEGFR, PDGFR, FGFR
Estrogen receptors
mTOR
mTOR and tubulins
GC-Temsirolimus
mTOR
Index: *- From www.ClinicalTrials.Gov accessed 20 October 2010 (107), GC=gemcitabine plus cisplatin,
GCa=gemcitabine plus carboplatin, Nab-paclitaxel=nanoparticle albumin bound paclitaxel, DD-MVAC= dose dense
M-VAC
401
selected patients. An ongoing randomized phase II

trial is evaluating the combination of cetuximab with
front-line GC.
treated with first-line trastuzumab in combination

with paclitaxel, carboplatin, and gemcitabine in a
phase II trial [88]. Thirty-one (70%) of 44 patients
responded (5 complete responses and 26 partial
responses), although it is unclear if these patients
unequivocally had Her2-driven tumors since gene
amplification was infrequent. Median time to
progression and survival were 9.3 and 14.1 months,
respectively. Disappointingly, a randomized phase II
trial that attempted to compare GC with or without
trastuzumab as front-line therapy and another phase
II trial that attempted to evaluate trastuzumab as
second-line monotherapy for Her2 over-expressing
metastatic urothelial carcinoma closed early
due to a lower than expected frequency of Her2
overexpression. Also, a phase II trial is evaluating
trastuzumab in combination with paclitaxel and
radiotherapy as a bladder-conserving regimen in
patients with localized/locally advanced urothelial
carcinoma of the bladder.
In a phase II trial of patients with EGFR and/or Her2

expression, lapatinib demonstrated partial responses
in 3% and response plus stability 16 weeks or longer
in 12% of patients with a trend towards apparent antitumor effect in those with EGFR or Her2 expression
2+/3+ by immunohistochemistry (IHC) [63]. A
randomized British trial is evaluating maintenance
lapatinib or placebo in patients with EGFR and/or
Her2-expressing tumors with stable or responding
disease after frontline chemotherapy (Table 3).
In the EORTC Genitourinary Group, escalating
doses of lapatinib in combination with GC are under
evaluation in a dose-finding study.
In one study, patients with metastatic urothelial or
squamous carcinoma whose tumors expressed
Her2/neu (by IHC, serology, or fluorescence in situ
hybridization) in the primary or metastatic site were
Table 3. Key Ongoing or Planned Randomized Trials of Systemic Therapy*

Target
Line of
therapy
Phase
Eligibility
Group 1
Group 2
First-line
III
Chemo-naive or 1 year after

peri-operative chemotherapy
GC
GC-Bevacizumab
First-line
II
Chemo-naive or 1 year after

peri-operative chemotherapy
GC
GC
Cetuximab
Cisplatin-ineligible
GCa
GCa-Vandetanib
Docetaxel
Docetaxel Cetuximab
EGFR
Placebo
Sunitinib
VEGFR, PDGFR
Placebo
Lapatinib
Her2, EGFR
Cetuximab Paclitaxel
Docetaxel Vandetanib
EGFR
VEGFR, EGFR
Sunitinib
VEGFR, PDGFR
Docetaxel-IMC18F1
VEGFR2,
VEGFR1
First-line
Second-line
II
II
Second-line
II
Second-line
II
Second-line
II
Salvage
II
Consolidation following
response/stability after
frontline therapy
frontline therapy
frontline therapy
Progression after frontline
regimen
Progression after 3 prior
regimens
Progressive disease,
intolerant or ineligible for
cisplatin
First or secondline
II
Second-line
II
Progressive disease
Second-line
II
Progressive disease
Cetuximab
Docetaxel
Placebo
DocetaxelIMC1121B
Carboplatinpaclitaxel
Carboplatinpaclitaxel- AMG386
VEGF
EGFR
VEGFR, EGFR
Angiopoietin/Tie2
Index: * From www.Clinicaltrials.gov accessed October 20, 2010, GC=gemcitabine plus cisplatin, GCa=gemcitabine,
carboplatin, IMC1121B=monoclonal antibody against VEGFR2, IMC18F1=monoclonal antibody against VEGFR1
402
4. Other Molecular Targets
would potentially be extremely beneficial and advance the field. Several studies have made progress
towards this end. In the neoadjuvant setting, Takata
et al have employed a cDNA microarray platform to
profile gene expression from biopsies of 27 patients
with invasive bladder cancer who were subsequently treated with M-VAC neoadjuvant chemotherapy
[100]. Based on supervised analyses designed to
discover genes differentially expressed between
14 M-VAC responders (defined as downstaging to
T1 or less) and 13 non-responders (defined as T2
or greater stage), a set of 50 genes was identified,
25 overexpressed and 25 underexpressed, that differed significantly between these groups. Splitting
their data into an 18 sample learning and 9 sample
test set, they developed a 14-gene M-VAC response
classifier based on the learning samples that correctly classified 8 of 9 test set samples. Quantitative
RT-PCR to assess expression of these genes for
classification purposes was used to validate these
results [100]. However, such signatures are of much
greater potential value if they are independently and
prospectively validated on novel test sets. To that
end, the same group performed a validation study of
their predictive platform on 22 additional cases, profiled as before [97]. The signature correctly predicted
response in 19 of 22 additional cases, providing a
sensitivity of ~100% with a specificity of ~73%. Most
importantly, in terms of potential application of this
classification scheme for patients with invasive bladder cancer, in this independent test set, the positive
predictive value for the assay was approximated at
~79% (11 of 14 cases), while the negative predictive value was approximated at ~100% (8 of 8 nonresponders identified).
Expression of the IGF-1R appears to increase with

stage and correlate with poor outcomes [89]. A phase
II trial is planning the evaluation of combination GC
and cixutumumab, a fully human monoclonal IgG1
antibody against IGF-1R, as first-line therapy for
metastatic urothelial carcinoma.
Based on ER- expression in urothelial carcinoma
and the inhibitory effect of selective estrogen
receptor modulators in preclinical models, salvage
therapy with oral tamoxifen is being evaluated (Table
3) [90;9].
The mTOR inhibitors, everolimus and temsirolimus
are being evaluated as monotherapy or in combination
with chemotherapy (Table 2). Immune-modulation
with ipilimumab, a monoclonal antibody against
CTLA-4 has demonstrated immune-modulating
activity in the neoadjuvant setting, and a trial is being
planned in combination with frontline chemotherapy
(Table 2) [92]. Lenalidomide is another agent with
immune-modulating and anti-angiogenic activity
and is being evaluated in combination with frontline
combination chemotherapy (Table 2). Src inhibitors
have demonstrated preclinical activity, and a trial is
evaluating dasatinib as neoadjuvant therapy with
correlative endpoints [93;94].
XI. New Trial Designs and the

Development of Tailored
Therapy
Innovative clinical trial paradigms may enable the
rapid evaluation and approval of novel agents. The
consolidation second-line strategy following frontline
therapy in stable or responding patients employing
biologic agents is being pursued with sunitinib and
lapatinib. Neoadjuvant therapy before surgery in
localized disease permits rapid in vivo assessment
of pathologic response and biologic activity.
A second study examined cisplatin-based

combination chemotherapy (M-VAC and GC) in 30
patients with locally advanced or metastatic invasive
bladder cancer (T4b, N2-3, or metastatic M1). An
oligonucleotide microarray platform was used to
profile the gene expression of tumors from these
patients and related it to survival [98]. A set of 55
genes was differentially expressed between these
groups; interestingly, all 55 were underexpressed
in patients with long-term survival. No difference in
the genes correlated with survival between patients
treated with M-VAC versus GC was noted, suggesting
that gene expression differences may underlie
the similar efficacy of these regimens. To answer
the question whether any of these genes might
be adaptable to traditional immunohistochemical
validation, they selected two, emmprin and survivin,
for immunohistochemistry, and found that they were
highly significantly associated with overall survival
singularly or in combination (all cases P 0.001).
Lastly, addressing the issue of specificity of these
genes to response of these drugs as opposed to
some other survival parameter, they found that
emmprin positive and negative tumors exhibited
The goal of personalized therapy may be

attainable. Factors predictive of response may
facilitate personalized therapy and enable judicious
patient selection even in the early stages of drug
development. Low levels of DNA-repair genes
(ERCC1 and BRCA1) and tumor gene expression
profiling or genomics based on in vitro drug
sensitivities in the NCI-60 cancer cell line panel
appear to be associated with better long-term
outcomes [95-99]. A vigorous and multidisciplinary
international effort to validate these observations will
enable more rapid advances.
XII. Predictive Models

Selection of patients with a high likelihood of benefit
403
differential response rates of 39% versus 74%,

while survivin positive and negative tumors exhibited
response rates of 47% and 70%, respectively. Double
negative tumors exhibited a high response rate of
82%, whereas double positive tumors exhibited a
response rate of only 27%. This resulted in an odds
ratio for response in double negative tumors of
11.9 (95% CI, 3.2-42.3). Based on these findings,
the authors proposed that if emmprin and survivin
immunohistochemical detection were independently
validated in large patient cohorts and staining were
inter-institutionally standardized, these markers
might be used to stratify patients into high and low
likelihood of response groups, with likely responders
treated by traditional cisplatin-based methods and
likely non-responders assigned to investigational
therapies [98].
gene expression-based or immunohistochemicaldetected biomarkers could become part of the

diagnostic workup and management in the future
(level of evidence 2b, Grade of recommendation: Not
recommended outside a clinical trial or biomarker
study). Unfortunately, the majority of these promising
biomarkers have not yet undergone appropriate
assay validation in prospectively collected samples
so that full biomarker qualification studies can be
performed. Implementation of molecular markers
on which to base treatment decisions in bladder
cancer lagged behind other diseases but it is hoped
that the strategies discussed above can be validated
in prospective studies in order to move the field
forward.
In the adjuvant setting, a study [101] assessed the

gene expression of the chemotherapy response
modifiers multidrug resistance gene 1 (MDR1) and
excision repair cross-complementing 1 (ERCC1) to
determine if they are useful in identifying a group
of patients benefiting from cisplatin-based adjuvant
chemotherapy. Formalin-fixed paraffin-embedded
tumor samples from 108 patients with locally
advanced bladder cancer, who had been enrolled
in AUO-AB05/95, a phase III trial randomizing
a maximum of 3 courses of adjuvant cisplatin
and methotrexate (CM) versus methotrexate,
vinblastine, epirubicin, and cisplatin (M-VEC), were
included in the study. Tumor cells were retrieved by
laser-captured micro-dissection and analyzed for
MDR1 and ERCC1 expression using a quantitative
real-time reverse transcription-polymerase chain
reaction assay. Importantly, expressions of MDR1
and ERCC1 were independently associated with
overall progression-free survival. The correlation of
high MDR1 expression with inferior outcome was
stronger in patients receiving M-VEC, whereas
ERCC1 analysis performed equally in the CM and
M-VEC groups.
Combination cisplatin regimens are a standard of
Recommendations
care for patients with a Grade A recommendation
for first-line advanced urothelial cancer with
adequate renal function.
In patients with renal impairment, advanced

age or poor performance status, carboplatin
and gemcitabine is a grade A recommendation
and for patients with renal impairment only use
of gemcitabine/carboplatin/paclitaxel can be
considered (Grade C).
U
se of triplet regimens adding paclitaxel
to
gemcitabine
recommended.
plus
cisplatin
is
not
F
or second-line therapy after a platinum-based
treatment, vinflunine has been adopted as a

standard in Europe but not in North America.
U
se of vinflunine is a grade B recommendation.
N
ovel agents and approaches are urgently needed
in the treatment of urothelial cancer and clinical
trial accrual needs to be actively encouraged by
urologists, medical oncologists, and radiation
oncologists. In this regard, the standard of care
for a majority of patients with advanced bladder
cancer is the best clinical trial available.
Gene expression-based predictive models may

not only be predictive of single drug therapeutic
response, but could also be combined to successfully
predict combination responses [99;102-104].
This approach uses a novel algorithm term CoeXpression ExtrapolatioN (COXEN), which uses
expression microarray data as a Rosetta Stone for
translating between drug activities in a cancer cell
line panel to drug activities in a set of clinical tumors.
This technique has been used in bladder cancer and
has also successfully predicted clinical outcome in
breast and ovarian cancer. More than 500 patients
have been evaluated, of which 233 patients were
enrolled in clinical studies.
XIII. Abstract
Advanced metastatic urothelial carcinoma of the
bladder and other bladder cancers are responsive to
chemotherapy. Cisplatin-containing chemotherapy
regimens such as M-VAC, dose dense M-VAC
(DD-M-VAC) and cisplatin with gemcitabine can
improve quality of life and overall survival. Cisplatinbased regimens can produce complete responses
in approximately 15% of patients, which can be
durable. Major unmet needs exist for patients who
In summary, while not yet extensively validated

in a sufficient number of samples obtained from
prospective clinical trials, there is the potential that
404
fail first line standard cisplatin-based regimens, are

precluded from cisplatin treatment because of renal
impairment, or are not suitable for cisplatin due to
comorbid conditions or advanced age. For cisplatinineligible patients, the combination of carboplatin
with gemcitabine has emerged as a standard of care.
For patients with platinum-refractory cancer, several
chemotherapeutic agents have demonstrated activity.
These include: vinflunine, taxanes, ifosfamide, folate
modulators, and anthracyclines; of these, only
vinflunine has been compared to best supportive
care in a phase III trial. Novel targeted agents under
investigation may be of interest in the second line or
maintenance setting. To date, no second line agent
has yet demonstrated definitive clinical benefit in
a randomized controlled trial. Therefore, a clinical
trial remains an excellent option for all patients with
advanced urothelial cancer.
or without recombinant human granulocyte-macrophage

colony-stimulating factor for the initial treatment of advanced
malignant urothelial tumors: results of a randomized trial. J
Clin Oncol 1995;13(9):2272-7.
11. Sternberg CN, de Mulder P, Schornagel JH et al. Seven
year update of an EORTC phase III trial of high dose
intensity M-VAC chemotherapy and G-CSF versus classic
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408
Committee 10
Non-urothelial Cancer of the

Urinary Bladder
Chair:
Bruce R Kava,
Members:
Hassan Abol-Enein,
Jack Baniel,
Adrienne Carmack,
Alexandra Coquhoun,
William Turner
Address all Correspondence

Bruce R Kava,
Associate Professor of Urology
Interim Chair, University of Miami Miller School of Medicine
Chief of Urology, Department of Veterans Affairs Medical
Center, Miami
PO Box M016960 (M814)
Miami, Florida, USA
409
Table of Contents
I. Non-urothelial Bladder
Cancer
IV. Adenocarcinoma
1. Epidemiology
2. Primary Adenocarcinoma
II. SCC Not Associated with

Schistosomiasis
3. Urachal Adenocarcinoma
4. Adenocarcinoma in Bladder
Exstrophy
1. Epidemiology
5. Secondary (Metastatic) Bladder

Adenocarcinoma
2. A
ssociation with Spinal Cord
Injury (SCI)
3. Smoking
V. Small Cell Carcinoma
4. Etiology
1. EPIDEMIOLOGY
5. Clinical and Pathologic Features
2. Clinical Features
6. Treatment
3. Pathologic Features
4. Treatment
III. Squamous Cell Carcinoma

in Association with
Schistosomiasis (Bilharziasis)
VI. Other Bladder Tumors

1. Bladder Sarcoma
1. Epidemiology
2. C
arcinosacroma and arcinomatoid
Tumors
2. Etiology
3. Paraganglioma and Pheochromocytoma

4. Treatment
4. Bladder Pseudotumors
5. Melanoma
6. Lymphoma
410
Non-urothelial Cancer of the Urinary

Bladder
Bruce R Kava,
Hassan Abol-Enein, Jack Baniel, Adrienne Carmack,
Alexandra Coquhoun, William Turner
and treatment recommendations are different. Each

will be discussed separately in the sections below.
I. Non-urothelial Bladder
Cancer
II. SCC Not Associated with

Schistosomiasis
Non-urothelial bladder cancer refers to a

heterogeneous group of malignancies, which are
considerably less prevalent than urothelial carcinoma.
Data from several contemporary epidemiologic
studies highlighting the relative percentage of the
various histological subtypes of bladder tumors by
geographic region is depicted in Figure 1 [1,2].
1. Epidemiology
Often referred to as non-Bilharzial SCC, this
represents the most common non-urothelial bladder
malignancy, accounting for 2-5% of cases in most
contemporary cystectomy series [4-8]. These tumors
are most often diagnosed during the seventh decade
of life.
The relative scarcity of these tumors has precluded

the development of large-scale prospective clinical
trials. In a recent review of the National Cancer
Institutes Surveillance Epidemiology and End
Results (SEER) database, [3] slightly more than
3700 non-urothelial tumors were identified over a
34-year period from over 125,000 cases of bladder
cancer. Of these non-urothelial tumors, only small
cell carcinoma appears to have demonstrated a
slight increase in incidence during that time period
(Figure 2).
The incidence of SCC demonstrates less of a male

predominance than does urothelial carcinoma.
Compiling data from 915 patients in 10 series
of patients with SCC, Johansson and Cohen [9]
reported that the ratio of males to females was 1.4:1.
Similar to urothelial carcinoma, however, women
are more likely than men to present with advanced
disease [10]. Data from the Netherlands Cancer
Registry [11] corroborates this higher incidence of
T3 and T4 tumors noted in women relative to men
(21.7% vs. 14.5% in T3, and 14.5% vs. 8.4% in T4).
As a result of these data, the level of evidence

provided regarding screening recommendations,
staging, and treatment strategies of non-urothelial
malignancies is limited. Nevertheless, the clinician
must be aware of these tumors, which often
warrant a different clinical approach than urothelial
carcinoma. Each of the tumors will be addressed
individually, and evidence-based recommendations
will be provided when applicable.
Data from Surveillance, Epidemiology, and End

Results (SEER) program conducted between 1973
and 1997 [12] shows that there is a large racial
disparity in the incidence of SCC. With an annual
incidence of 1.2 per 100,000 person-years, African
Americans were twice as likely to develop these
tumors as Caucasians, who had an annual incidence
of 0.6 per 100,000 person-years.
Squamous Cell Carcinoma (SCC)

SCC may occur de novo, or in individuals who
have been infected with the parasite Schistosoma
hematobium. It is important to recognize the
distinction between these two populations of
patients, because the epidemiology, natural history,
2. A
ssociation with Spinal Cord
Injury (SCI)
In the United States, patients with SCI represent
the largest cohort of patients affected by SCC. This
411
Figure 1. Percentage and histologic subtype of non-urothelial bladder cancers seen in various tumor
registries worldwide (1,2).
Figure 2. Age-adjusted incidence rates of nonurothelial bladder cancer by histological subtypes in the USA,
nine SEER registries, 1973-2007 (3).
412
condition is believed to arise as a result of chronic

urinary tract inflammation, a factor which may
contribute to the higher likelihood of SCC in patients
with chronic cystitis, persistent calculi, and bladder
diverticula [13].
tobacco abuse. Any history of hematuria should be

evaluated.
3. Smoking
The relationship between SCC and cigarette
smoking is not clear; Johansson and Cohen [9]
found a higher incidence of SCC in smokers. SEER
data support a direct correlation between quantity
of cigarettes smoked and relative risk of developing
SCC [23]. Indirect evidence from the Swedish
Cancer Registry [24], however, does not support an
association between SCC and smoking. A review
of this data, which plotted trends in bladder cancer
in Sweden between 1960 and 1993, revealed that,
despite a rising incidence of urothelial carcinoma in
Swedish women (which correlated with an increased
prevalence of smoking), the incidence of SCC
remained relatively constant.
Historically, the incidence of bladder cancer in

patients with SCI was believed to be as high as 2.310%, with most cases representing SCC [14-16].
SCI patients with indwelling catheters were found to
have the highest risk for the development of SCC;
up to 10% of these individuals developed SCC at
10 years [14]. Interestingly, studies determined
that patients performing clean intermittent selfcatheterization were significantly less likely to
develop SCC than those SCI patients with indwelling
catheters [17, 18].
Recently, these concepts have been scrutinized by
data emerging from several contemporary series. A
United States Department of Veterans Affairs review
of admission data from 33,560 SCI patients identified
only 130 patients with bladder cancer, for an overall
incidence of 0.39% [19]. Some 42 patient records
were available for review, including 23 (55%) with
urothelial carcinoma, 14 (33%) with SCC, and 4
(10%) with adenocarcinoma. It is noteworthy that in
26 patients with indwelling catheters, the incidences
of SCC and urothelial carcinoma were equal,
implicating chronic inflammation and tobacco abuse
as competing risk factors.
4. Etiology
Because urinary tract infections are more common
in women, a relationship between squamous
metaplasia, leukoplakia, and the development of
SCC was proposed by Connery [25] and by Holly
and Mellinger [26]. In a series of 20 patients with
long-standing leukoplakia, OFlynn and Mullaney
[26] observed the development of 5 cases of SCC.
Although squamous metaplasia is not considered
a premalignant lesion, it is often found in areas
adjacent to SCC [13]. Many studies, however,
have confirmed that there is a high prevalence of
squamous metaplasia in the general population, and
that it is not necessarily implicated in the development
of SCC [28].
In another study of 2900 SCI patients from several

centers in the southwest United States, bladder
cancer was detected in only 8 (0.32%) patients, none
of whom had an indwelling catheter [20]. Another
study evaluated 15 SCI patients with SCC, who were
followed over a 24-year period from a VA Center in
Northern California [21]. Interestingly, the majority of
these patients had never had an indwelling catheter.
Finally, in the largest study to date, Pannek et al. [22]
evaluated 43,561 SCI patients from multiple urologic
centers in Eastern Europe. In all, 48 patients with
bladder cancer were identified, for an overall
incidence of 0.11%. Only 7% of patients in this series
had indwelling catheters, and the prevalence of SCC
was only 0.02%.
A few case reports have documented associations

between cyclophosphamide, bacille CalmetteGurin (BCG), human papillomavirus, and SCC
of the urinary bladder [29, 30]. Other studies have
revealed possible genetic and chromosomal changes
that may be associated with SCC. Abnormalities of
chromosomes 3, 8, 10, 13, and 17 have been detected
in SCC [31]. Studies on uroplakin II gene expression
found a significant difference in expression between
urothelial carcinoma and SCC, with expression
being greater in SCC. Uroplakins are the major
differentiation products of the urothelium that control
the various pathways of urothelial differentiation [8].
Based upon these epidemiologic data, guidelines

regarding the necessity, frequency, and the diagnostic
testing needed for bladder cancer screening in the
SCI patient population cannot be determined. Initial
reports, in which a high percentage of patients
with spinal cord injury developed SCC are flawed,
primarily related to the retrospective manner in which
data were obtained, small patient cohorts, and less
rigorous statistical evaluation than would be expected
for a more contemporary evaluation. Although the
incidence of SCC in a contemporary SCI population
appears to be less than 1%, it is recommended that
these patients should be monitored, particularly if
they have indwelling catheters or have a history of

The presenting symptoms in patients with nonschistosoma-related SCC are not distinguishable
from urothelial carcinoma. Hematuria is the main
clinical feature in 63-100% of patients. Irritative
bladder symptoms are seen in two-thirds of patients.
Weight loss, back or pelvic pain, and frank obstructive
symptoms are less common and suggest advanced
disease [4-6,32]. A urinary tract infection is present
in 30-93% of patients at the time of diagnosis
[4-6,33,34], and symptoms have often been present
413
b) Radical Surgery
for a prolonged period of time before the diagnosis

is made [4,4,8,33].
While most of the surgical series are subject to

selection bias, radical cystectomy seems to offer
some advantages in patients with SCC. Richie et
al [37] reported a 5-year survival rate of 48% in 25
patients treated with radical cystectomy. While the
investigators stated that this compared favorably with
results in patients with urothelial carcinoma, they did
not include in the analysis 3 patients (9%) who died
during the perioperative period and an additional 5
patients in whom insufficient pathologic or follow-up
data were obtained. Given the small cohort of study
patients, and adjusting for these cases, the 5-year
survival rate is significantly lower than was reported.
Tumor stage was identified as the most important
predictor of outcome.
Relatively few series of patients from Europe and the

Americas have addressed pure SCC. Most of these
are retrospective observational series that are more
than 10 years old, and use older staging and grading
systems. Despite this, we know that the majority
of patients present with a bulky, solitary tumor that
extensively involves the bladder wall. These tumors
are sessile lesions, often with ulceration and areas of
squamous metaplasia adjacent to the primary tumor.
A predilection for the trigone has been noted, but
SCC can arise anywhere within the bladder. Tumors
may occupy a bladder diverticulum and have been
described in association with bladder calculi [35].
SCC is often locally advanced at the time of
diagnosis. Debbagh et al [36] reported that 10 of 14
(71%) patients in their series had a palpable tumor on
rectal examination, and 11 (79%) had upper urinary
tract obstruction. Pretreatment imaging studies may
demonstrate hydronephrosis in 33-59% of cases
[5,6,8]. Of 114 patients with SCC of the bladder in
one series, 92% had T2 to T4 disease at the time
of diagnosis, and most tumors were high grade [5].
As with urothelial carcinoma, clinical understaging is
seen in as many as 73% of patients [6,37].
Similarly Serretta et al [8] reported on 19 patients

with pure SCC of the bladder undergoing radical
cystectomy. With a mean follow-up of 52 months,
63% had died of local recurrence, with only one
patient developing distant metastases.
Emerging data on the surgical management and
outcome of treated SCC continues to be derived from
relatively small single center series. In a recent series
of 45 patients [38], in which 67% presented with T3
tumors, 37% of patients were alive without disease
and 29% had died of disease at a median followup of 15 months following cystectomy. Similarly,
Kassouf et al [39] reported a 50% recurrence in 10
of 20 patients who had undergone cystectomy at
only 5 months. The majority of patients who died of
SCC had isolated pelvic recurrence in the absence
of disseminated metastases, emphasizing the
importance of local surgical control.
6. Treatment
Pure SCC of the bladder has a poor prognosis,
with most patients succumbing within 1 to 3 years
of diagnosis.
Failure to provide loco-regional
control is the hallmark of the difficulty in managing
these patients. In a series of 120 patients from the
Royal Marsden Hospital, the overall 5-year survival
rate was 16%, with only 8% of patients developing
metastatic disease [33].
c) P
rognostic Comparison with Urothelial
Carcinoma
a) Radiation
Irrespective of whether radiation is used as
neoadjuvant or as primary treatment, results have
been uniformly poor [6,32]. In a report by Quilty
and Duncan [34], 51 patients were treated with
radical radiotherapy, delivered with a 3-field beamdirected technique, covering the entire bladder, to a
prescribed dose of 55 Gy over 4 weeks. Patients
were treated prone, immediately after emptying
their bladders. Only 4 patients in this series had T2
cancer, with a median survival of 14.3 months, and
a 3-year survival of 26.8%. Of 48 patients treated
with radiation therapy by Rundle et al [6], the 5-year
survival for patients with T2 and T3 disease was
16.7% and 4.8%, respectively. No patient with T4
disease was alive beyond 11 months. Similarly, in
a series of 17 patients with T2 and T3 tumors who
were treated with radiation therapy alone, Johnson
et al [5] reported a 20% 5-year survival rate, which
was not statistically different than the 34.6% 5-year
survival rate seen in 7 patients in which preoperative
radiation was followed by radical cystectomy.
Several large contemporary cystectomy series in the

literature have compared outcomes in patients with
urothelial carcinoma with those in patients with SCC.
In a large series from Japan [40], evaluating 1042
patients treated with urothelial carcinoma and 89
patients with SCC, there was no significant difference
observed in 5-year post-cystectomy survival (68.0%
urothelial carcinoma vs. 60.8% SCC). In a review of
SEER data between 1988 and 2003 [41], patients
with SCC had worse outcomes than those with
urothelial carcinoma except for those patients with
localized cancers who were treated by cystectomy.
d) Neoadjuvant Radiation
Several studies have retrospectively evaluated the
efficacy of pre-cystectomy irradiation. Data is limited
because of the small number of patients studied, and
the lack of randomized clinical trials. Johnson et al
[5] integrated preoperative radiation therapy followed
414
Recommendations
by cystectomy and reported a 5-year survival rate of

34%. Swanson et al [42] reported similar results with
the same approach. Patients with T2 disease showed
the highest survival figures. Given the relative rarity
of these tumors, the advanced stage of presentation,
and the overwhelmingly poor overall survival with
these tumors, it would be difficult to devise clinical
trials of sufficient power to demonstrate a difference
in the outcome between the two groups.
In summary, non-schistosoma-related SCC

is an uncommon form of bladder cancer that
usually presents at an advanced stage, generally
recurs loco-regionally, and has an extremely
poor prognosis. Death is most often related to
loco-regional failure, and not to disseminated
metastasis.
e) Impact of Urinary Diversion
The current literature supports cystectomy as the

treatment of choice, when possible (grade B) [53].
The impact of the type of urinary diversion in patients

with SCC is the subject of some discussion in the
literature. In a series of 19 patients undergoing radical
cystectomy and urinary diversion, all 3 patients with
an orthotopic ileal neobladder developed recurrence
at the anastomosis between the neobladder and the
urethra [43]. In another series reported by Stenzl et
al [44], intraoperative frozen section biopsies were
obtained from the bladder neck before orthotopic
reconstruction. No local recurrences occurred in the
5 female patients in this series.
III. Squamous Cell Carcinoma

in Association with
Schistosomiasis (Bilharziasis)
1. Epidemiology
This type of cancer is prevalent where urinary
Schistosoma hematobium is endemic. It is often
referred to as schistosoma-related SCC or bilharzial
SCC. The highest incidence of SCC of the bilharzial
bladder occurs in Egypt [1]. In a report by Ghoneim et
al [54], SCC accounted for 59% of 1026 cystectomy
specimens. A high incidence of SCC is also found
in Iraq, the Jizan region in southern Saudi Arabia,
Yemen, and Sudan. In Africa, the disease has been
reported in the Gold Coast region and in South
Africa. However, the incidence in these countries
is lower because Schistosoma hematobium is
less endemic and less severe [55]. With a mean
age at presentation of 46 years, the mean age of
schistosoma-related SCC patients is 10 to 20 years
younger than that seen with non-schistosomarelated SCC [56]. In areas in which schistosomiasis
is endemic, some 80% of cancer specimens have
shown histologic evidence of bilharzial infestation
[55]. A lag period of approximately 30 years has been
reported between infection with the parasite and
subsequent development of the disease. The maleto-female ratio is 5:1 [57]. This male predominance
is attributed to sustained contact with infected water
supplies that laborers often endure while working in
various outdoor environments (Figure 3).
f) Chemotherapy
The role of neoadjuvant or adjuvant chemotherapy in
the treatment of patients with pure SCC of the bladder
is uncertain. SCC is considerably less responsive to
standard chemotherapy regimens used for urothelial
carcinoma [45, 46]. Neoadjuvant M-VAC has
been tried with no objective response [47]. Newer
combination regimens consisting of gemcitabine,
paclitaxel, and docetaxel, when combined with a
platinum compound, may yield sustained disease
remission in up to 50% of cases; these hold promise
for the future [48].
g) Prevention and Early Detection

Several screening protocols have been advocated
in an attempt to diagnose these tumors earlier,
thereby improving outcomes. Broecker et al [49]
recommended annual cystoscopy and urine cytology
in patients with SCI. Others have suggested routine
random bladder biopsies every 1 to 2 years. Navon
et al [50] advocated urine cytology or random
bladder biopsies in patients with spinal cord injuries
for more than 10 years or in those with recurrent or
chronic urinary tract infection. Celis et al [51] showed
that psoriasin, a calcium-binding protein expressed
by squamous epithelia, is a potential marker for
SCC. Other biomarkers, such as SCC antigen and
bcl-2 and p53 oncoproteins, may have a possible
role in early diagnosis [52]. The role of these new
markers in the early detection and follow-up of
bladder SCC requires further study before they can
be recommended.
Contemporary epidemiological studies have

demonstrated a decline in the incidence of bilharzial
SCC, as public health efforts have been successful
in eradicating schistosomiasis in many areas of the
Nile delta and in rural Egypt [58-62]. Interestingly,
despite the decline in SCC, the incidence of bladder
cancer remains high. This is believed to be a result
of the high prevalence of tobacco use that has now
created a significant rise in the incidence of urothelial
cancer. Figure 4 depicts some of these trends [63].
415
2. Etiology
metaplasia of the bladder epithelium and the

predominance of SCC in patients with bilharziasis.
Evidence from animal models suggests that the

biogenesis of bladder cancer is a multistage process.
It involves initiation by carcinogens, followed by
promotion of tumor growth [64]. Schistosomarelated bladder cancer may be initiated by exposure
to an environmentally or locally-produced chemical
carcinogen that is excreted in urine. This carcinogen
reacts with the mucosal surface of the bladder to
produce irreversible and potentially carcinogenic
changes in the DNA of some urothelial cells. Chronic
bacterial infection, which commonly complicates
urinary schistosomiasis, has been implicated in the
production of nitrosamines, which are well-known
potent carcinogens derived from precursors in the
urine. Additionally, bacterial infections may induce
the secretion of beta-glucuronidase, which has been
shown to split conjugated carcinogens to yield free
carcinogenic products [65,66].
Recent laboratory studies have shown that

overexpression of cyclooxygenase-2 is associated
with increasing pathological stage and grade and
a worse outcome after radical cystectomy [67,68].
Abdulamir et al found that bilharzial and nonbilharzial SCC have different molecular profiles of
tumor development of progression [69].

Patients usually present with symptoms of cystitis,
including painful micturition, frequency, and
hematuria. A diffuse, irregular filling defect is usually
detected on cystogram. Computed tomography (CT)
scanning or magnetic resonance imaging (MRI) is
helpful for diagnosis and staging, which relies on
cystoscopy, biopsy, and bimanual examination under
anesthesia [70].
The possibility that carcinogenic products may be

of parasitic origin is not supported by several recent
investigations [55]. However, local mechanical
irritation by Schistosoma eggs appears to be an
important promoting factor [66]. Vitamin A deficiency
may explain the high frequency of squamous
Urine cytology may provide valuable diagnostic

information in patients with schistosoma-related SCC
[71]. In fact, cytokeratin shedding in urine has been
used as a biologic marker for the early detection of
SCC [72].
Figure 3. Gender disparities in stage of bladder SCC at diagnosis. Data derived from the Netherlands Cancer
Registry (11).
From Felix, et al : Cancer Causes Control (2008):19,421-9

Figure 4. Changing Patterns of Egyptian Bladder CancerData abstracted from NCI- Cairo (4).
416
Most patients present for treatment at an advanced

stage, and 25% of cases are inoperable when
first seen [56]. This is because of the nonspecific
symptoms of schistosoma-related SCC, which often
mimic simple bilharzial cystitis.
circumvent the physiologic and social inconvenience

of urinary diversion and the possible loss of sexual
potency. Once again, local resection is feasible only
in select cases. Solitary tumors must not involve
the trigone, and their size must allow resection with
adequate oncologic margins; the rest of the bladder
mucosa must be free of any associated precancerous
lesions. These strict criteria are met in only a minority
of cases. El-Hammady et al. [79] found partial
cystectomy feasible in only 19 of 190 (10%) patients.
Additionally, augmentation cystoplasty was required
in 5 of these patients, in order to increase residual
bladder capacity. The 5-year survival rate was 26.5%,
and patients with low-grade tumor had approximately
twice the survival as those with high-grade disease.
Less favorable results with partial cystectomy were
reported by Omar et al [80] in a series of 22 cases.
All patients except 1 developed tumor recurrence
within 2 years. This different outcome may be related
to the wide variability of selection criteria.
Similar to urothelial bladder cancer, clinical

understaging occurs in a high percentage of cases
[70] and schistosoma-related SCC is often locally
advanced at the time of diagnosis. In a study of 608
patients with schistosoma-related SCC, pT1 disease
was found in 2.6%, pT2 in 10.5%, pT3 in 80.0%,
and pT4 in 6.9% [54]. Lymph node metastases were
only present in 18.7% of cystectomy specimens.
Interestingly, the vast majority of tumors were low
and medium grade (49.7% and 33.2%, respectively),
a factor that may account for the low incidence of
lymph node positivity [73].
Grossly, tumors are generally of the nodular,
fungating type and are located in the dome or
posterior or lateral walls of the bladder. Five gross
types have been identified: nodular (60%), ulcerative
(23%), verrucous (7%), papillary (7%), and diffuse
(3%) [55]. A variety of atypical changes in the
bladder mucosa, including metaplasia, dysplasia,
and, rarely, carcinoma in situ, may be associated
with the disease [74].
d) Radical Cystectomy
Radical cystectomy and urinary diversion provides
a logical treatment approach for patients with
resectable tumors [81, 82]. In an early series of
138 cases, Ghoneim et al [82] reported a high
perioperative mortality rate of 13.7%. This was
primarily due to peritonitis, intestinal obstruction, and
liver failure. Cardiopulmonary complications were
uncommon among this relatively young group of
patients. In this older series, overall 5-year survival
was 32.6%. Patients with pT1 and pT2 disease
had a 43% overall 5-year survival, which compared
favorably with 30% in patients with pT3 and pT4
tumors. Low-grade tumors were associated with a
46% overall 5-year survival, and high-grade disease
was associated with a 5-year survival of 21%.
Lymph node metastases were associated with a
poor outcome, and reduced the 5-year survival rate
to 20% [81].
4. Treatment
a) Radiation
The growth characteristics of carcinoma of the
bilharzial bladder have been studied with the goal
of evaluating its potential response to radiation
therapy [74]. Two growth features were noted: [1]
high cell mitotic rate with a potential doubling time of
6 days, and [2] an extensive cell loss factor. Tumors
with such growth characteristics were expected to
exhibit a better response to radiation therapy [75].
Nevertheless, early experiences with external beam
radiation therapy for definitive control of these tumors
were disappointing [76]. Factors that interfered with
the efficiency of radiation treatment in these cases
included coexisting Schistosoma-related urologic
lesions, which interfere with local tissue tolerance,
and considerable tumor bulk, which reduces local
tumor control. Furthermore, the presence of radioresistant hypoxic tumor cells is suspected in light of
the capillary vascular pattern of this cancer [77].
A more contemporary report evaluating 1026

cystectomy patients from an area in which
schistosomiasis is endemic [54] found that 59% of
tumors were SCC. Bilharzial ova were identifiable
in 88% of specimens. Interestingly, extravesical
extension was not significantly different among
patients with SCC or urothelial carcinoma (13.5%
and 14.9%, respectively). Overall the 5-year survival
rate with SCC was 50.3%. Only tumor stage, grade,
and lymph node involvement had independent
significant effects on survival.
b) Endoscopic Resection
In view of the usual high tumor volume and its
advanced stage, transurethral resection is not
definitive treatment in the management of this
disease. Endoscopic resection should be used only
for obtaining a biopsy specimen for histopathologic
diagnosis.
e) Neoadjuvant Radiation
As discussed above, schistosoma-related SCC
is often understaged. Unlike urothelial cancer,
recurrences in patients undergoing radical surgery
for schistosoma-related SCC often occur locally.
The aim of preoperative radiation is to eradicate
microextension of tumor into the perivesical tissues
and lymphatics.
c) Segmental Resection (Partial Cystectomy)

Segmental resection is an attractive alternative to
417
Awaad et al [83] compared the results of cystectomy

after preoperative administration of 40 Gy radiation
therapy with outcomes in a control group treated
with cystectomy only. Reported 2-year survival
rates were significantly improved in the irradiated
group. Ghoneim et al [84] compared the results
of cystectomy after preoperative irradiation using
20 Gy with those of cystectomy alone. Ninety-two
patients were divided into 2 groups, and followed
for 60 months. Patients who received preoperative
radiation showed a trend towards longer survival,
although this was not statistically significant. In lowstage tumors, regardless of grade, survival was not
influenced by preoperative irradiation, as it was in
high-stage tumors.
Secondary prevention includes early detection

with urine cytology and selective screening of the
population at risk. The yield of a single screening
study done in a rural area in Egypt was 2 per 1000
individuals [71]. Such a detection rate would not
justify regular screening.
Recommendations
In summary, bilharzial SCC is the most common
form of bladder cancer in endemic areas. It most
often presents at an advanced stage but with low
grade cells. Cystectomy is the standard treatment,
but long-term survival remains disappointing
(grade B). Limited evidence (Grade B) supports
a potential role of neoadjuvant chemotherapy
and radiation therapy, but it is not yet sufficient to
facilitate a recommendation.
The presence of a large proportion of hypoxic

cells within bulky tumors could explain the modest
improvement that was observed after this regimen.
To enhance the therapeutic value of irradiation,
misonidazole, a hypoxic cell sensitizer, was
given before the radiation regimen was delivered
[84,85]. A prospective trial was divided into 3 arms:
cystectomy only, 20 Gy of preoperative radiation
followed by cystectomy, and preoperative radiation
followed by cystectomy with misonidazole added
as a radio-sensitizer. The addition of misonidazole
did not provide any additional survival advantage to
patients who were given preoperative radiotherapy
(level 1 evidence).
IV. Adenocarcinoma
1. Epidemiology
Adenocarcinoma of the bladder is the third most
common histologic type of bladder carcinoma. In
regions in which schistosomiasis is not endemic, it
comprises 0.5- 2.0% of all bladder tumors [89-91].
The incidence in areas where schistosomiasis is
endemic is higher, at 5.2-11.4% [54, 92,93].
f) Chemotherapy
Annual incidence rates for adenocarcinoma are

correspondingly very low. One study from the United
States using SEER data identified just 32 patients
(0.7%) with adenocarcinoma from 4045 patients with
newly diagnosed bladder cancer over a 1- year period
(1977-1978) [94]. Similar to urothelial carcinoma,
adenocarcinoma shows a male predominance. In a
total of 11 series comprising 247 patients, the gender
ratio between males and females was 2.7:1 [9].
Several agents have been evaluated by Gad-elMawla et al [86] in order to treat patients who are
initially not believed to be surgically resectable.
All trials were phase 2 studies in which a single
agent was used, and the optimal results were
obtained with epirubicin. Neoadjuvant and adjuvant
epirubicin chemotherapy were used in a prospective,
randomized study involving 71 patients with invasive
cancer in bilharzial bladders. Two-thirds of treated
patients had SCC. Disease-free survival rates were
73.5% and 37.9%, favoring the chemotherapy group
[87]. Additional long-term follow-up results have not
been published.
The relative rarity of this tumor makes determination

of risk factors difficult [94]. Nevertheless, there appears to be a higher likelihood of developing adenocarcinoma in patients with a history of schistosomiasis, endometriosis, bladder augmentation, and other
irritative conditions of the urinary bladder [95,96].
Adenocarcinoma also carries the unique distinction
of being the most common tumor arising in the bladder of patients with exstrophy. Such patients carry a
4% lifetime risk of developing adenocarcinoma [97].
Bilharzial SCC does not appear to be responsive

to chemotherapy that has traditionally been used
for urothelial carcinoma. In a recent multicenter
study that consisted of 120 patients treated with
neoadjuvant cisplatin and gemcitabine [88], patients
with SCC had no survival benefit over those who
underwent cystectomy alone.
Adenocarcinoma of the urinary bladder is classified as either: primary adenocarcinoma, urachal

adenocarcinoma, or secondary (metastatic) adenocarcinoma. Secondary tumors are indicative of local
extension of a primary colonic, prostatic, or ovarian
cancer [98]. Primary, urachal, exstrophy-associated,
and metastatic adenocarcinoma will be discussed
separately.
g) Prevention and Early Detection

Bilharzial SCC is a preventable malignant disease.
Primary prevention entails control of bilharziasis
through snail control (the intermediate host of the
parasite) and mass treatment of the rural population
with oral antibilharzial drugs such as praziquantel.
418
2. Primary Adenocarcinoma
poor prognosis regardless of the treatment modality

utilized. Five-year survival varies from 11-57%; the
small number of patients in each series precludes
individual comparison of treatment undertaken.
Consistently reported independent prognostic
factors for survival include age, stage, grade, and
lymph node involvement [92,93,96,99,100,105].
a) Epidemiology
El-Bolkainy and associates reported an incidence of
8.1% in a series of 229 cases of bladder cancer [56].
Between 1970 and 1995, 1870 cystectomies were
carried out in the Urology and Nephrology Center of
Mansoura. Of these, 185 cases (9.9%) proved to be
primary non-urachal adenocarcinoma of the bladder
on histopathologic examination [55]. Similarly,
between 1994 and 2003, 3659 cystectomies were
performed at the National Cancer Institute, Cairo and
Minia Oncology Centre, Egypt. Of these, 192 (5.2%)
were for primary non-urachal adenocarcinoma of the
bladder [92]. In addition to these 2 large schistosomaassociated series of patients, two recent series from
the United States have been evaluated. Using the
SEER database, Wright et al identified 1374 cases
of primary adenocarcinoma of the bladder recorded
between 1973-2002 [99]. Lughezzani et al [100] also
evaluated SEER data and found a total of 306 (2.5%)
primary adenocarcinoma patients among 12,003
bladder cancer patients undergoing cystectomy
between 1988 and 2006.
c) Pathological features
In order for a diagnosis of primary adenocarcinoma
of the bladder to be made, it must be clearly
distinguished from urothelial carcinoma with areas of
glandular metaplasia. The pathogenesis of primary
non-urachal adenocarcinoma is based on the ability
of the urothelium to undergo metaplastic changes
[108]. Mostofi [109] proposed that the metaplastic
potential of the urothelium has 2 distinct patterns.
Progressive invagination of hyperplastic epithelial
buds into the lamina propria (von Brunns nests) leads
to the formation of cystitis cystica. Subsequently,
metaplasia of the urothelial lining of these cysts,
which become columnar mucin-producing cells,
results in the production of cystitis glandularis, which
is a premalignant lesion. As a result, careful follow
up of patients with cystitis glandularis is necessary
[109]. Chronic bladder irritation and infection are the
predisposing factors for these changes [107,110].
This explains, at least partly, the higher incidence of
these tumors among patients with cystitis resulting
from schistosomiasis.
b) Clinical features
Primary adenocarcinoma of the bladder presents
with hematuria in most patients, which may be
associated with irritative voiding symptoms and,
occasionally, mucus passage in the urine [89, 93,101104]. Cystoscopically, the tumor is usually sessile,
but can be papillary [103]. It can arise anywhere
along the lateral walls, trigone, dome, and anterior
wall of the bladder [93,101,103,104]. Multiple tumors
are present approximately 50% of the time [54,101].
Adenocarcinoma is virtually always invasive with
only 1 series documenting 2 non-invasive tumors
[105]. Interestingly, both patients were alive at 51
and 61 months following TUR alone.
Histologically, adenocarcinoma may be non-mucinproducing or mucin-producing. Most of these tumors

are mucin-producing, but the gross passage of mucus
during micturition remains uncommon [105,110].
This is because most of the mucus is secreted into
the extracellular (interstitial) matrix of the urinary
bladder, rather than into the bladder lumen [93].
Occasionally, mucin is secreted within the lumen
of the acini. In other cases, mucin accumulates
within the intracellular space displacing the nucleus
to a peripheral crescent, giving the cells a signet
ring appearance. It is generally accepted that this
histological subtype denotes a poor prognosis [111114].
Similar to urothelial carcinoma, the in situ form of

adenocarcinoma appears to portend a poor prognosis.
Chan et al [106] reviewed all the case files for a series
of 19 patients who had bladder biopsies performed
at Johns Hopkins Hospital between 1984 and 2000
confirming the presence of adenocarcinoma in situ.
Nearly 80% of these patients also exhibited some
form of concomitant urothelial carcinoma in situ.
Although none of the patients progressed to develop
primary adenocarcinoma of the bladder, 74%
ultimately received treatment for invasive carcinoma
(often for an aggressive histological subtype: 5 cases
of small cell and 4 cases of micropapillary urothelial
carcinoma). Clearly, it is difficult to determine whether
the urothelial or adenocarcinoma component of the
in situ disease determined prognosis, but certainly
the co-existence of both entities mitigated a poor
outcome.
No uniformly accepted grading system for

adenocarcinoma of the bladder exists. On the
basis of histopathologic findings, Anderstrom
et al classified vesical adenocarcinoma into 5
patterns: glandular with columnar, sometimes
entericappearing cells; colloid carcinoma; papillary
adenocarcinoma; signet ring cell carcinoma; and
clear cell carcinoma [96]. Several other histologic
subtypes have been described, including mucinous,
enteric (colonic) type, adenocarcinoma not otherwise
specified (NOS), clear cell, hepatoid, and mixed type
[104]. Unfortunately, no clear data exists regarding
the impact of these different histologic patterns on
survival or prognosis. The exception is signet ring
cell carcinoma, which usually follows a very rapid
Primary adenocarcinoma of the bladder has a very
419
course, resulting in death in the majority of patients

within 6 months [111].
Others have found no correlation between DNA

ploidy and outcome [93,12] whereas Song et al [124]
showed that DNA ploidy significantly correlated with
tumor progression and subsequent poor outcome.
In short, there are no molecular markers predictive
of outcome for primary adenocarcinoma that have
been validated in an independent patient cohort.
d) Treatment
Several treatment strategies have been used in the
management of primary adenocarcinoma of the
bladder. In general, the available series are too
small to permit meaningful comparisons between
differing treatment approaches.
2. Radiation Therapy
Adenocarcinoma is not a radioresponsive disease,
with 5-year survival rates of less than 20% in
patients treated by external beam irradiation alone
[91,106,114]. The addition of preoperative irradiation
to partial cystectomy did not improve the survival in
2 early studies [91,96]. One of the 2 large Egyptian
cystectomy series for adenocarcinoma did assess
the benefit of adjuvant radiation treatment [93].
Patients receiving adjuvant radiation experienced
improved outcome (61% vs. 37% 5-year survival),
but the study was not a randomized trial and patient
selection may have accounted for the survival
differences.
1. Surgical Resection
Surgical strategies include transurethral resection
(TUR), partial cystectomy, and radical cystectomy.
The therapeutic yield after TUR, with or without
adjuvant radiotherapy, is poor (19-31% 5-year
survival) [102,115]. Partial cystectomy for localized
disease in a mobile part of the bladder has been
advocated by several authors, including a series of
15 patients who had a 5-year survival of 54% [96].
Other series however, have shown poorer 5-year
survival rates of 16-37% following partial cystectomy
[91,116].
The reported 5-year disease-free survival in several
cystectomy series range from 0-80% in several
historical series [91,96,115-120]. Contemporary
series quote more consistent 5-year survival rates,
ranging from 35-55% [92,93,99,100]. Such survival
rates are not dissimilar to those of patients with either
urothelial or squamous cell carcinoma [54,121].
Indeed, Lughezzani et al [100] showed that while
patients with primary bladder adenocarcinoma are
significantly more likely to present with high stage
disease, stage and grade, the adjusted survival
was equivalent to that of patients with urothelial
carcinoma.
3. Chemotherapy
A number of factors have been shown to have

independent prognostic significance in patients with
adenocarcinoma of the bladder. Those consistently
reported include age, stage, grade and lymph
node involvement. Potential molecular prognostic
factors have also been assessed. El Sobky et
al [122] assessed the prognostic significance
of markers of angiogenesis in bilharzial primary
bladder adenocarcinoma. Fifty-five cases of
primary bladder adenocarcinoma were assessed
for immunohistochemical markers of angiogenesis
(anti-CD31), microvessel density (MVD) and DNA
ploidy in relation to survival. Only lymph node
involvement and MVD were independent prognostic
factors for survival. However, previously defined
clinical prognostic factors (stage and grade) did not
predict survival in this series suggesting possible
selection bias in the series (only 55 cases were
assessed from a previously reported larger cohort
of 185 patients). The prognostic significance of
DNA ploidy has been assessed by other groups with
conflicting results. Shaaban et al [123] showed that
DNA ploidy did not correlate with tumor stage or
grade but was predictive of lymph node metastases.
Urachal carcinoma is extremely rare and represents

less than 1% of all bladder tumors [121,131-133].
Previous reports consistently suggested that 33%
of bladder adenocarcinomas were urachal in
origin [105,118,120,131]. More recently, literature
suggests that just 10% of such tumors are urachal
[99]. Tumors present at a significantly younger age
(median age at presentation 47-56 years) and the
male:female distribution is less pronounced than
for other forms of bladder adenocarcinoma at 1.3:1
[99,103,132-134].
Reports of the use of chemotherapy in the treatment

of primary bladder adenocarcinoma are limited. The
literature is confined to case reports or very small case
series. The most successful chemotherapy regimens
utilize 5-fluorouracil (5-FU), which is extrapolated
from its use for gastrointestinal malignancies. Most
of the published series involve small numbers and
the response is universally unsatisfactory [126-130].
3. Urachal Adenocarcinoma
a) Epidemiology
b) Clinical and pathological features

Due to the frequent extravesical location of the
tumor, presentation is often late. The most common
presenting symptoms are hematuria, dysuria, and
frequency. Less common symptoms and signs
include mucosuria, abdominal pain, abdominal
mass, and, rarely, umbilical discharge [133,134].
Cross sectional imaging can be a useful diagnostic
tool (Figure 5). CT appearances consistent with
urachal adenocarcinoma include a mixed solid/
cystic midline mass, an unencapsulated caudal
tumor component involving the bladder wall with
420
a cystic encapsulated supravesical portion, mass

calcification, and presence of low attenuation areas
(consistent with mucin content) [135,136].
of glandular or polypoid proliferation, presence

of urachal remnants within the tumor, extension
of tumor into the bladder wall with involvement of
the space of Retzius, anterior abdominal wall, or
umbilicus, and no evidence of a primary neoplasm
elsewhere. These criteria are felt to be too strict
by many, who have adopted the more pragmatic
approach of the group at the MD Anderson Cancer
Center of considering all adenocarcinomas located
at the bladder dome or midline as adenocarcinoma
until proven otherwise [131].
There are no known risk factors for development of

urachal adenocarcinoma. The presence of a urachal
anomaly per se does not increase the risk of urachal
adenocarcinoma [137] However, patients with a
urachal mass who experience hematuria or are over
55 years of age, have a 17- and 3-fold increased
likelihood of urachal carcinoma, respectively [138].
The histological appearance of urachal carcinoma is
indistinguishable from enteric type adenocarcinoma
[131,139]. Recognized histological forms include:
enteric, mucinous, signet cell, and adenocarcinoma
not otherwise specified [140]. Two theories propound
as to the origin of these unique tumors. According
to Begg et al [141], this type of tumor arises from
enteric rests left behind following cloacal closure
during embryological development. The alternative
theory suggests development along a metaplastic
pathway [110,131].
Sheldon et al initially described the staging system

that is still widely used for urachal carcinoma [131]:
Stage I - tumor confined to the urachal mucosa
Stage II - local invasion confined to the urachus
Stage III - local extension into A) bladder, B)
abdominal wall, C) peritoneum, or D) local viscera
Stage IV - metastases to A) regional lymph nodes or
B) distant sites
Several diagnostic classification systems exist for

urachal adenocarcinoma. Sheldon and Mostofi
[110,131] listed several strict criteria for diagnosis
including tumor located at the dome of the bladder,
absence of cystitis cystica or cystitis glandularis,
predominant invasion of the muscularis or deeper
tissues with a sharp demarcation between the
tumor and surface bladder urothelium that is free
The Mayo clinic group proposed a simpler staging

system (Stage 1, confined to urachal mucosa,
stage 2, extending beyond the urachus/bladder,
stage 3, regional lymph node metastasis, stage 4,
distant metastasis) [138]. Given the similar survival
between patients with stage 3 and 4 disease, the MD
Anderson group suggested consolidation of these
Figure 5. 59 year old woman with urachal adenocarcinoma. The

anterior bladder wall is thickened (red arrows), with mild perivesical
fat stranding, and prominence of the urachus (blue arrows). A large
discrete mass is not noted here.
421
2 stages to create a simplified three tier staging

system [133]. Notwithstanding these modifications,
the Sheldon staging system is still the most widely
used system in current practice.
total urachectomy should be undertaken as part of

surgical treatment of all urachal tumors.
c) Treatment
A number of chemotherapeutic regimens have been

assessed in patients with either metastatic disease
at presentation, or high risk of disease recurrence
following surgical resection (positive surgical margins
or presence of lymph node metastases). Most reports
involve single patients or very small case series. In
common with primary bladder adenocarcinoma, the
most promising regimens appear to be 5-FU based
[127,133]. Of 20 patients receiving chemotherapy in
the MD Anderson Cancer Center series for metastatic
disease, there were only 4 patients with significant
objective responses, of whom 3 had received a 5-FU
based regimen. Subsequently the group is presently
performing a multi-center phase II clinical trial, using
5-FU, gemcitabine, cisplatin, and leucovorin [146].
2. Chemotherapy
1. Surgical Resection
Correct identification that a bladder tumor is urachal
in origin is imperative as this dictates modification
of standard bladder cancer surgical techniques,
to include complete excision of the urachus and
umbilicus. Surgical treatment options include
either 1) partial cystectomy with en bloc excision
of the urachus, posterior rectus fascia, peritoneal
reflections, and umbilicus, or 2) radical cystectomy
with en bloc excision of the urachus/umbilicus.
There are no randomized trials comparing these
surgical techniques, but durable results appear
achievable with either approach. Reported 5-year
survival rates following partial cystectomy with en
bloc urachal/umbilical excision range from 31-83%
[91,96,99,105,118,120,132-134,138,139,142]. The
more contemporary series estimate a 40-50% 5year survival with either partial or radical cystectomy
[132,138]. Some authors emphasize the need to
utilize frozen section at the time of surgery to ensure
negative surgical margins are achieved when
performing a partial cystectomy [133,138].
There are no diagnostic tumor markers for urachal

adenocarcinoma. However, elevated Ca19-9 and
CEA levels have been reported by a number of
authors [133,147,148]. These tumor markers have
been shown to correlate well with response to
chemotherapy [133].
4. Adenocarcinoma in Bladder
Exstrophy
a) Epidemiology
There are currently no data to support the therapeutic

benefit of bilateral pelvic lymphadenectomy as part
of the surgical management of urachal tumors.
Lymphadenectomy undoubtedly allows more
accurate disease staging and thereby provides
prognostic information. However, in the absence of
effective adjuvant therapies, its routine use cannot
be endorsed.
Adenocarcinoma is the most common bladder

cancer in patients with bladder exstrophy. Patients
with exstrophy have a reported 4% lifetime risk of
developing this type of malignancy [97]. In a review
of 40 patients with untreated bladder exstrophy,
McIntosh and Worley [149] found that 33 cases were
adenocarcinoma, the mean age at diagnosis was
44 years, and two-thirds of the patients were male.
Even with the advent of urinary diversion surgery, the
risk of developing carcinoma in the bladder remnant
is significant. Smeulders et al reported on a series of
102 patients born with bladder exstrophy, who were
followed for a minimum of 35 years [97]. There were
4 cases of bladder cancer, which was calculated to
be 694 times greater than the risk in the normal adult
population. Three of the 4 patients had undergone
a simple cystectomy before the age of 5, and all
were males. This implies that there was retention
of a portion of the bladder in these individuals, which
is speculated to become malignant in the presence
of sperm or secretions from the male genitourinary
tract.
There is very little available information describing

the feasibility or oncologic outcome associated
with minimally-invasive approaches (laparoscopic
or robotic) for urachal tumors [143-145]. None of
the follow-up data from these case reports are
mature enough to compare outcomes with those of
conventional open surgery.
Survival rates for patients with urachal adenocarcinoma appear to be superior to those of patients
with non-urachal adenocarcinoma [99,105]. Factors
predictive of disease recurrence following surgical resection include positive surgical margins and
high disease stage [133,138]. The Mayo clinic series
showed low stage, low pathologic grade, the undertaking of total urachectomy, and negative surgical
margin status to be associated with improved outcome on univariate analysis. Interestingly, stage and
undertaking total urachectomy no longer retained
statistical significance on multivariate analysis [138].
The authors (probably correctly) attribute this to the
low number of patients studied and emphasize that
b) Pathology and clinical features

The histopathology of the bladder in exstrophy
patients has been well-described [150]. The
development of adenocarcinoma of these bladder
remnants is thought to arise from either metaplasia
of the urothelium, which is exposed to inflammatory
422
stimuli, or as a result of the displacement of ectopic

colonic or rectal epithelium that occurs during
division of the cloaca. The fact that the majority of
the bladder malignancies occur during the fifth and
sixth decades of life and that adenocarcinoma has
been found to arise in other conditions resulting in
defunctionalized bladders and after augmentation
enteroplasty favors the metaplasia theory [151153]. The prognosis of these tumors is poor as a
result of late presentation. As a result, all patients
with exstrophy who have retained their bladders
should be followed closely, although no specific
follow-up regimen can be recommended based upon
the existing literature.
urinary bladder being one of the most common

organs involved [161,162]. Talamonti et al reported
on a series of 70 patients undergoing en bloc
bladder resection for colorectal carcinoma [163].
There were 58 primary and 12 recurrent tumors
in the series. Median survival was 34 months in
patients with negative surgical margins and 11
months for patients with positive margins. There
were no 5-year survivors. A more recent series
by Carne et al [164], retrospectively evaluated 53
patients who had secondary involvement of the
bladder with a colorectal cancer over a 15-year
period. The most common site of the primary tumor
was the sigmoid colon [46/53], with the remainder
invading from the rectum [2/53], the ascending colon
[4/53], and the transverse colon [1/53]. All 4 patients
undergoing blunt dissection of the tumor from the
bladder, without resection of the involved bladder,
developed local recurrences and subsequently died
of their disease. There were no local recurrences
in 4 patients undergoing total cystectomy and 3 of
the 4 patients with follow-up were alive, 2 without
and 1 with disease. Finally, in the 45 patients who
underwent partial cystectomy, there were a total of 8
(19%) local recurrences. The authors emphasized
the importance of obtaining frozen sections of the
resection margins at the time of partial cystectomy.
However, whether frozen sections were taken in
the patients who had local recurrences was not
reported.
5. Secondary (Metastatic) Bladder

Adenocarcinoma
Secondary bladder adenocarcinomas are tumors
that involve the bladder by either direct extension
from adjacent organs, reimplantation from adenocarcinoma located higher up within the urinary tract, or
lympho-hematogeneous spread. A retrospective review of surgical specimens collected over a 90-year
time period [154] showed that secondary bladder
tumors comprised 2.3% of 5533 surgical specimens
assessed. The most common sites of secondary tumor origin were, in order of their occurrence, colonic,
prostatic, rectal and cervical. Over 50% of tumors
assessed were adenocarcinomas. Indeed, secondary adenocarcinoma of the bladder is more common than primary adenocarcinoma [155]. Some of
these secondary adenocarcinomas are histologically
distinct, allowing rapid identification of tumor origin,
such as prostatic tumors. However, many present
the clinician with a diagnostic challenge when trying to determine tumor origin, which is clearly of importance in planning subsequent disease management. In the first instance, the clinical history, endoscopic exams, and radiological studies are valuable
in identifying tumor origin. When such studies are
not informative, immunohistochemical staining of
tumor biopsy specimens may be undertaken. Two
groups have reported that lack of CDX2 and villin
staining indicates that an adenocarcinoma sampled
from the bladder is unlikely to be colorectal in origin
[156,157]. Positive PSA staining is pathognomonic
of prostatic origin and vimentin staining indicates
endometrial/ovarian origin [158]. Many other immunostains have been assessed, including CK7, CK20,
CEA and Ca19-9, however, most lack the specificity
to confidently discriminate tumor origin [158]. Similarly, assessment of mucin produced by the tumor
has failed to add clarity when assessing tumor origin
[159]. Urine cytology can be useful at identifying tumors of secondary origin, for example, prostatic or
colonic, although it lacks sensitivity in the diagnosis
of primary bladder adenocarcinoma[160].
Treatment Recommendations
The treatment of adenocarcinoma depends upon

its subclassification. Primary adenocarcinoma is
poorly responsive to radiation and chemotherapy
and should be treated with radical cystectomy
(Grade B).
Urachal adenocarcinoma should be treated with
en bloc resection of the urachus and umbilicus with

partial or radical cystectomy (Grade B).
The incidence of adenocarcinoma is much higher
in exstrophy patients. Any patient with bladder

exstrophy who has retained his or her bladder
should be closely followed, though an exact
regimen cannot be defined based on currentlyavailable evidence (Grade C).
Patients with metastatic primary or metastatic

urachal adenocarcinoma of the bladder should be
considered for enrollment into a clinical trial using
5-FU based chemotherapy (Grade C).
In patients with locally advanced colonic or

rectal tumors that secondarily involve the bladder,
patients may undergo complete resection of the
involved portion of the bladder, either with partial
cystectomy and verified negative margins or radical
cystectomy (Grade B).
Approximately 10% of colorectal adenocarcinomas

will be attached to adjacent structures, with the
423
nuclei. This gives a characteristic appearance of

round blue cells under the microscope with routine
hematoxylin and eosin staining. Frequent mitotic
figures and extensive necrosis are common in
small cell carcinoma, and are indicative of its often
aggressive behavior [176]
V. Small Cell Carcinoma

1. EPIDEMIOLOGY
Primary small cell carcinoma is a neuroendocrine
tumor that is rare, with just under 300 cases reported
in the English-language literature. Despite this, this
histologic subtype accounts for 0.48-0.7% of all
cases of primary bladder tumors [165-169].
The diagnosis of small cell carcinoma may be confirmed by immunohistochemical stains for neuronspecific enolase, chromogranin A, and synaptophysin [168, 177]. In more complex cases, additional
immunohistochemical stains for pan-cytokeratin and
p63 may be needed to distinguish it from urothelial
carcinoma [177].
The incidence of small cell carcinoma appears to

be increasing in the United States. A recent review
of SEER data identified 642 cases of small cell
carcinoma of the urinary bladder between 1991
and 2005 [169]. During that time period, there was
a 300% increase in the incidence of this tumor,
from 0.05 to 0.14 cases per 100,000 population.
Additionally, relative to all other bladder tumors,
small cell carcinoma increased from 0.3% to 0.6% of
all histologic types of bladder cancer,
A number of studies have shown that small cell

carcinoma exists as either pure small cell carcinoma
or in combination with urothelial carcinoma [170172]. Rarely, small cell carcinoma may coexist with
squamous cell carcinoma or adenocarcinoma [171,
178]. The implications of this are that in pure small
cell carcinoma, the chemotherapeutic regimen should
be specifically directed to small cell carcinoma.
Extremely poor responses have been noted in those
patients treated with regimens that are specific for
urothelial carcinoma (MVAC or taxol, methotrexate,
and cisplatin) [179].
2. Clinical Features
Most of the data regarding the clinical features of
small cell carcinoma of the bladder is derived from
only a few series and case reports. The vast majority
of patients diagnosed with small cell carcinoma are
male, with a propensity for it to affect patients in
their late 60s and early 70s [169-171]. Caucasians
account for 90% of patients with small cell carcinoma
in the SEER-cancer registry [169].
4. Treatment
Local treatment with either radiation therapy [170]
or surgery alone [170, 171,179] yields very poor
results in patients with clinically localized small cell
carcinoma of the bladder. Based upon the treatment
paradigm developed for small cell lung cancer,
primary chemotherapy followed by either radiation
therapy or cystectomy seems to provide the optimal
means of managing patients with this tumor [180184]. Based upon the chemotherapeutic regimen
used for small cell lung cancer, the agents used are
etoposide and cisplatin, possibly alternating with
ifosfamide and doxorubicin.
Similar to other bladder malignancies, hematuria is

the presenting complaint in close to 90% of patients
[171,172]. On occasion, paraneoplastic syndromes
may herald the diagnosis [173,174].
Small cell carcinoma usually cannot be visually distinguished from urothelial carcinoma on cystoscopy.
Urine cytology may be helpful in providing a suspicion of small cell carcinoma. A retrospective analysis of 29 urine specimens from patients diagnosed
with small cell carcinoma showed that 56% could be
diagnosed by urinary cytopathology [175]. The other
cases were interpreted as high grade urothelial carcinoma. Five patients had both small cell carcinoma
and urothelial carcinoma.
a) Chemotherapy and cystectomy

In the small series reviewed by Sved et al [170],
13 of 18 patients who underwent cystectomy plus
chemotherapy were alive at a mean of 27 months.
Similarly, Walther [165] reported favorable response
rates in seven patients treated with systemic etoposide and cisplatin in neoadjuvant and adjuvant protocols. In a retrospective analysis from MD Anderson Cancer Center, median and 5-year disease-free
survival was significantly improved in patients who
received preoperative chemotherapy [179]. In this
study, 5-year survival was 36% for 25 patients who
underwent cystectomy alone compared with 78% in
those who received preoperative chemotherapy. Interestingly, an evaluation of the surgical specimens
indicated that 10/12 patients receiving a regimen
directed towards small cell carcinoma (either etoposide and cisplatin or ifosfamide and doxorubicin)
had no residual tumor in the bladder versus 3 of 9
At the time of presentation, 90% of patients with

small cell carcinoma have muscle-invasive disease,
approximately 50% have T3 or T4 disease [169],
and 24-67% have metastases [169,170]. Small cell
carcinoma metastasizes most commonly to lymph
nodes, liver, bone, lung, and brain [170].
3. Pathologic Features
Microscopically, small cell carcinoma of the bladder
resembles small cell carcinoma of the lung. The tumor
is comprised of a population of relatively uniform
cells with scant cytoplasm and hyperchromatic
424
patients receiving chemotherapy directed towards

urothelial cancer (MVAC or taxol, methotrexate, and
cisplatin).
hematuria, and the diagnosis is made early. The

majority of the tumors are high grade and may attain
very large size before recognition (see Figure 6).
Tumor grade is established on the basis of mitotic
rate and proliferation indices rather than nuclear
atypia [190]. The preferred treatment for localized
disease is radical cystectomy with negative margin
resection. In the largest series to date, encompassing
10 patients, the 5-year survival rate was 80%.
Metastatic sarcomas are treated with multimodality
protocols. Doxorubicin and ifosfamide are the most
active single agents available [191].
b) Chemotherapy and radiation therapy

Radiation therapy has been used as an alternative to
cystectomy in many centers, and seems to provide
comparable results when used with neoadjuvant
chemotherapy. In the largest series to date, 17
patients with localized small cell bladder cancer
were treated over a 14-year period using platinumbased chemotherapy followed by radiation therapy
to 56-70 Gy [184]. The median overall survival was
32.5 months, with 88% of patients showing an initial
complete response. In another retrospective study
evaluating 10 patients, the 2- and 5-year survival
rates in patients treated with chemotherapy and
radiation were 70% and 44%, respectively [185].
Of note, local recurrences warranting surgery have
occurred with this approach [184]
2. C
arcinosacroma and
carcinomatoid Tumors
Carcinosarcoma is a rare type of primary tumor
composed of an admixture of malignant epithelial
(carcinoma) and malignant soft tissue elements
(sarcoma). The term sarcomatoid has been used to
describe a malignant spindle cell tumor with epithelial
differentiation [192]. In a series of 41 patients,
Lopez-Beltran reported that both carcinosarcoma
and sarcomatoid tumors had similar presentations
[192]. The most common epithelial component was
urothelial in both types. Most patients had locally
advanced tumors at the time of diagnosis. Despite
aggressive surgical management, the outcome is
poor. Treatment failure occurs within 1 to 2 years
following treatment [192]. Metastatic disease showed
a favorable response to cisplatin and gemcitabine
[193].
c) Chemotherapy alone
This is primarily used in patients with metastatic
disease. Similar to small cell lung cancer, there is
an initial response seen in most patients. In a phase
II trial evaluating 30 patients with metastatic small
cell bladder cancer [185], 72% of patients had a
complete response, and 28% of patients had a
partial response. The durability of the responses is
short-lived, however, as the median overall survival
with this disease is between 5 and 13.3 months
[184,186].
3. Paraganglioma and Pheochromocytoma
Second line therapy has been evaluated in isolated

case reports using vinorelbine [187]. Prophylactic
brain irradiation has also been evaluated, but limited
data is available. [185,188]
These are extra-adrenal neoplasms derived from

neural crest cells. Bladder pheochromocytoma
accounts for 0.05% of bladder tumors. It may be
derived from embryonic rests of chromaffin cells in
the detrusor sympathetic plexus. It accounts for 10%
of extra-adrenal pheochromocytoma. Malignancy
was demonstrated in 10% and characterized by
local invasion, regional lymph node metastases, or
distant spread.
Conclusions
Small cell carcinoma of the bladder is an aggressive
disease that often presents in advanced stages.
Because of the rarity of this lesion, evidence is
limited. Aggressive multimodal therapy is warranted,
yet altogether this subtype of bladder cancer carries
a dismal prognosis.
Bladder pheochromocytoma may be hormonally

active and presents with attacks of paroxysmal
hypertension, headaches, palpitations, blurred vision,
and sweating associated with the act of micturition
[194]. If the disease is suspected, cystoscopy should
be performed under adrenergic blockade in the
operating room. The gross appearance is often a
solitary, submucosal, or intramural nodule. Biopsy
should be avoided. The diagnosis depends on CT
scan or MRI for anatomical location and the extent
of the lesion. Isotopic scanning using 131iodine
metaiodinebenzylguinidine (MIBG) is the study of
choice for localizing small pheochromocytomas with
more than 90% specificity [195]. Positron emission
tomography was recently used with high sensitivity
as well [194].
VI. Other Bladder Tumors

1. Bladder Sarcoma
Malignant soft tissue tumors represent the most
common histologic type of the non-epithelial
bladder tumors. Half of bladder sarcomas are
leiomyosarcoma, 20% are rhabdomyosarcoma, and
the remainder are angio-, osteo-, and carcinosarcoma
[189]. The histological pattern of leiomyosarcoma
is characterized by interwoven bundles of spindleshaped cells. The incidence is higher in patients
with previous local radiation treatment or systemic
chemotherapy [190]. Most patients present with
425
Figure 6. 62 year old male with leiomyosarcoma of the

urinary bladder. The mass fills the entire urinary bladder
and pelvis, leaving only a small area in which urine can
accumulate (arrows). Despite its massive size, the patient
underwent cystoprostatectomy with cancer- free surgical
margins and remains disease free at 5 years.
The standard treatment is local excision via partial

cystectomy combined with pelvic lymph node
dissection. The surgery is employed under the same
precautions as in adrenal pheochromocytoma with
controlled adrenergic blockade.91
urethra more than the bladder. Secondary melanoma

of the bladder was found in patients with widespread
metastatic melanoma of the skin [190, 198]. The
patients history and careful examination of the skin
is essential to confirm the primary nature of the
tumor. The histologic picture of bladder melanoma
is similar to other melanomas. It is composed of
large malignant cells arranged in nests with variable
amounts of pigments. The cell origin of bladder
melanoma is undefined. Treatment of primary
bladder melanoma is radical surgery. The prognosis
is poor [199, 200].
It may be difficult to distinguish benign and malignant

lesions if the disease is localized. Lifelong follow-up is
important as the malignant pheochromocytoma may
show local recurrence with or without metachronous
metastases.
4. Bladder Pseudotumors
6. Lymphoma
Bladder pseudotumors are rare and may resemble

malignancy. The etiology and histogenesis
remain unclear. Some of these lesions present
as postoperative spindle-cell tumors. It may be
difficult to distinguish them from leiomyosarcoma
on a histopathologic basis [196]. However, absence
of significant nuclear atypia, less than three mitotic
figures per high power field, and presence of spindle
cells with myxoid degeneration and eosinophilic
cytoplasm favor pseudotumor. Some tumors may
show a fascicular growth pattern with deposition of
interstitial collagen [197]. Local recurrence or distant
metastases are rare following tumor excision. If the
diagnosis is clear, transurethral resection or partial
cystectomy is sufficient. Radical cystectomy may be
required if the diagnosis is difficult to distinguish from
bladder sarcoma.
Bladder lymphoma is usually a part of metastatic

spread of systemic disease. Primary lymphoma
is very rare. Microscopic analysis shows diffuse
infiltration of lymphoid cells into the normal structures
of the bladder [201]. Primary lymphoma is more
common in women [202]. It is mostly localized
and of low grade with good prognosis [201]. Local
irradiation is the recommended treatment with a high
recurrence-free survival [201, 202].
VIII. summary of the recommendations

Squamous Cell Carcinoma
5. Melanoma
Patients with SCI should be aware of the risk of

development of SCC. A surveillance schedule,
however, cannot be determined from the currently
available evidence. (Grade D)
Primary bladder melanoma is very rare. It affects the
Cystectomy is the best primary therapy for SCC,
426
Paraganglioma and Pheochromocytoma
whether it is related to schistosomiasis or is not

associated with schistosomiasis (Grade B).
The standard treatment for patients with

paraganglioma and pheochromocytoma is partial
cystectomy with pelvic lymphadenectomy, with
the same precautions taken as for any other
pheochromocytoma with preoperative adrenergic
blockade (Grade C).
Neoadjuvant chemotherapy or radiation therapy

prior to cystectomy for SCC is not advisable, given
the information available to date (Grade D).
In patients with metastatic disease, epirubicinbased chemotherapy regimens offer a higher
likelihood of an initial complete response than other
agents. The long-term survival benefits remain to
be determined (Grade A).
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ICUD Guidelines on Bladder Cancer:

Diagnosis and Evaluation
Ashish M. Kamat
(MD Anderson Cancer Center, Houston, TX)
Paul K. Hegarty
(Guys Hospital , London, UK)
Guidelines
A group of 17 experts from 5 countries
thoroughly assessed 125 references related to diagnosis
and screening of bladder cancer
> 250 page document
No new level 1 or 2 studies since last ICUD

guidelines published
Most reports level 3 or 4, few level 2b
Most recommendations are Grade C

some B and D
Screening Recommendations
Bladder cancer screening is not helpful in
improving survival (Grade C)
If undertaken, screening should be confined to
high risk patients (Grade C).
Screening in high-risk can consist of annual
cytology & dipstick (Grade C).
Further studies of screening are warranted
Hematuria
No correlation between degree of hematuria &
diagnosis of bladder cancer (Grade B).
Microscopic hematuria is variable & intermittent in
bladder cancer
Lack of hematuria on a single urinalysis does not

exclude bladder cancer (Grade C).
Evaluation
Imaging of the upper tracts necessary in
investigation of hematuria (Grade B).
For asymptomatic microscopic hematuria without
risk factors for urothelial carcinoma, urine cytology
or cystoscopy can be used (Grade B).
In patients with irritative voiding symptoms and
hematuria, carcinoma in situ (CIS) must be ruled out
(Grade C).
Cystoscopy and Cytology

Cystoscopy alone is the most cost effective
method to detect recurrence of bladder cancer
(Grade C).
Among urinary markers, urine cytology is the
gold standard for surveillance (Grade B).
Cytopathologists should use uniform
nomenclature (Grade C).
Cystoscopy and Cytology

Bladder wash cytology provides better
diagnostic yield than voided urine cytology
(Grade B).
At cystoscopy minimal manipulation should be
performed prior to bladder wash. Residual urine
mixed with bladder lavage specimen should be
sent for cytology (Grade D).
Cytology
For follow-up urine cytology is most useful for
diagnosis of high-grade tumor recurrence (Grade B).
Cytology valuable for differentiating high-grade
from low- grade urothelial carcinomas (Grade B).
No consensus on other urinary markers in the
diagnosis of bladder cancer (Grade D).
Markers eg FISH may be most useful in the
setting of a negative cystoscopy and atypical
cytology. (Grade C).
Endoscopic Techniques
White light cystoscopy (WLC) is the gold standard
for evaluation of the lower urinary tract (Grade B).
Fluorescence cystoscopy
improves the rate of detection of CIS (Grade B).
decreases risk of residual tumor after TURBT (Grade B).
useful for positive cytology but negative findings on WLC
(Grade C).
Imaging
Imaging of the upper tracts necessary in
investigation of haematuria (Grade B).
CT urography most useful
intravenous urography, regular CT, ultrasound & MRI
are options (Grade C).
Imaging for staging should be obtained prior to

TURBT
or >2 weeks after TURBT to avoid artifacts (Grade C).
Imaging
CT & MRI not accurate for staging of primary
bladder tumors but may be demonstrate metastatic
disease (Grade B).
With invasive bladder tumors, metastatic work-up
includes chest radiography, liver function tests, and
alkaline phosphatase measurement (Grade C).
Bone scan for patients with bone pain or elevated
alkaline phosphatase concentration (Grade B)
Technique
Insufficient information to support specific
energy modality for TURBT (Grade D).
Patients undergoing TURBT should be given
appropriate prophylactic antibiotics (Grade B).
Technique of TURBT
Document shape, size & location of the tumor
(Grade C).
Document appearance base of the tumor (Grade C).
these details provide important prognostic information
Obtain separate tumor base & margin biopsies for

larger tumors (Grade C).
Attempt complete tumor resection except in
patients with diffuse CIS (Grade C).
Technique
If ureteral orifice is resected,
cutting current should be used.
Functional study should be performed 3-6 weeks
later (Grade C).
Diverticulum
Aggressive resection risks perforation.
Low-grade, noninvasive tumors may be treated TUR
or fulguration with or without intravesical therapy
(Grade C).
Technique
A second TURBT should be performed in all
patients with a high-grade T1 lesion or select HG
Ta lesion (Grade B).
The optimal timing of repeat TURBT is 4-6 weeks
after the first resection (Grade C).
Technique: Random Biopsies

Not routinely recommended (Grade C).
Indicated in
Patients with positive findings on urine cytology &
normal cystoscopy (Grade B).
Candidates for partial cystectomy (Grade C).
Prostatic Urethral Biopsy

Indicated in cases of multifocal urothelial
carcinoma of the bladder, CIS & visible
abnormalities of the prostatic urothelium (Grade
B).
Prostate biopsy not useful in counselling patients
for neobladder, but useful in indentifying cT4
disease (Grade C).
Contributors
AM Kamat (USA)
PK Hegarty (UK)
JR Gee (USA)
S Rawal (India)
Clark (USA)
JD Davies (USA)
SS Chang (USA)
A Patel (UK)
M Manoharan (USA)
TS OBrien (UK)
J Fan (China),
RS Svatek (USA)
M Arianayagam (Australia)
P Black (Canada)
NJ Hegarty (Ireland)
R Sanchez-Salas (France)
INTERNATIONAL CONSORTIUM FOR UROLOGIC

DISEASES EUROPEAN ASSOCIATION OF UROLOGY
INTERNATIONAL CONSULTATION ON BLADDER
CANCER 2011:
CONSENSUS GUIDELINES BY THE PATHOLOGY OF
BLADDER CANCER WORK GROUP
Mahul B. Amin, MD, Victor E. Reuter, MD
And
Vienna Austria, March 18, 2011
35 Urologic Pathologists from 13 Countries
Participants
Hikmat A. Al-Ahmadie, MD (New York, NY, USA)
Ferran Algaba, MD (Barcelona, Spain)
Isabel Alvardo-Caberrera, MD (Mexico City, Mexico)
Liang Cheng, MD (Indiana, IN, USA)
John C. Cheville, MD (Rochester, MN, USA)
Glenn Kristiansen, MD (Zurich, Switzerland)
Richard J. Cote, MD (Miami, FL, USA)
Brett Delahunt (Wellington, New Zealand)
John N. Eble, MD (Indianapolis, IN, USA)
Mahmoud Elbaz, MD (Cairo, Egypt)
Elizabeth Genega, MD (Boston, MA, USA)
Christian Gulmann, MD (Dublin, Ireland)
Arndt Hartmann, MD (Erlangen, Germany)
Participants
Cord Langer, MD (Graz, Austria)
Antonio Lopez-Beltran, MD (Cordoba, Spain)
Cristina Magi-Galluzzi, MD, PhD (Cleveland, OH, USA)
Jorda Merce, MD, PhD (Miami, FL, USA
George J. Netto (Baltimore, MD, USA)
Esther Oliva, MD (Boston, MA, USA)
Priya Rao, MD (Houston, TX, USA)
Jae Y. Ro, MD, PhD (Seoul, S. Korea)
John R. Srigley, MD (Toronto, ON, Canada)
Satish K. Tickoo, MD (New York, NY, USA)
Toyonori Tsuzuk, MD, PhD (Nagoya, Japan)
Saleem A. Umar, MD (Miami, FL, USA)
Theo Van der Kwast, MD (Toronto, ON, Canada)
Robert H. Young, MD (Boston, MA, USA)
Whats New in this Consensus Offering?:

An Update on:
The knowledge of the histoanatomy of the bladder

as it pertains to the diagnosis and staging of
bladder cancer
The prognostic significance of histologic grading
by the WHO (2004)/ISUP system, its contributions,
shortfalls and opportunities for refinement
The information needed from the clinicians by the
pathologist in order to provide optimal pathologic
reporting of bladder cancer
On nomenclature for inverted lesions of the
bladder
Whats New in this Consensus Offering?:

An Update on:
The histologic types of bladder cancer and the

variants of urothelial cancer, some relatively
recently described, with a focus on definition for
diagnosis and their implied clinico-pathologic
significance
Role of immunohistochemistry and molecular
studies in contemporary routine practice diagnosis,
prognostication or predicition of bladder cancer
The reporting of bladder cancer in transurethral
resection of bladder tumors (TURBT) and
cystectomy specimens
Urothelial denudation
Seen with
instrumentation with
CIS
Extensive or complete
denudation in a bladder
biopsy should be
reported as correlation
with concurrent
cytology results may
yield a positive
diagnosis of
malignancy in the
patient
Urothelial hyperplasia
Papillary or flat
Thickened urothelium
without cytologic atypia
Flat hyperplasia may be
seen adjacent to low
grade papillary tumors
Papillary hyperplasia is
suggested to be a
precursor lesion for a
subset of papillary
urothelial neoplasms
Squamous Metaplasia
Should be reported and

specified whether
keratinizing or not and
whether focal or
multifocal
Current evidence does
not support any
precursor potential with
focal changes, although
multifocal and/or
extensive lesions
precede or may be
associated concurrent
with neoplasia
Glandular
Metaplasia
Cystitis cystica &

cystitis cystica
glandularis are
proliferative lesions
They may be associated

with intestinal metaplasia
Glandular metaplasia
is not a risk factor for
adenocarcinoma or
UCa
Multifocal disease
Metaplasia with dysplastic
changes
- Associated with risk for
adenocarcinoma
pT1 invasion into

the lamina propria
pT1
pT2
pT3
67-75% 5-year survival
pT2 invasion into

the m. propria
pT3 invasion into

the perivesical fat
pT4 invasion of
adjacent organs
10-25% 5 year survival
Muscularis Mucosae Muscle
Hyperplastic Muscularis Mucosae:
Patterns frequently observed but exceed thickness of

previously described MM
To avoid confusion in diagnosis, documentation

of MM-only invasion by carcinoma is not
recommended in the main pathologic diagnosis,
and should be reported as urothelial carcinoma
with lamina propria invasion (at least pT1)
Involvement of MM may be included in a comment
to provide information on depth/extent of invasion
M. mucosae muscle patterns
Typical
Variant
Wispy or thin muscle bundles
Hypertrophic MM muscle
Muscularis Propria
Several terms are currently being used to describe

both MP (deep muscle, muscle proper or detrusor
muscle) and MM (superficial muscle). These terms
are not recommended and use of standardized
nomenclature of MP muscle bundles is
recommended
It is important to document the presence or
absence of MP in a biopsy irrespective of
involvement
Some institutions recommend not mentioning the
presence or absence of MP in low grade tumors
and require documentation in high grade tumors
only
Muscularis Propria
In cystectomy specimens, a
more objective and
reproducible anatomical or
extent of disease criterion
is needed between pT2a
and pT2b subcategories
Substaging of pT2 disease
and recognition of pT3
disease is not tenable in
TURBT specimens
Documenting Amount of
Muscularis Propria in Specimen
Formal studies are lacking
Amount of MP included in the specimen (isolated and rare versus

established groups)
MP in the area of the tumor or not in the vicinity
Information may be useful in the management of

invasive cancer
Inclusion of the information is optional but may be
communicated in a multidisciplinary setting
Muscle Involved by
UCa, Indeterminate
Type
Muscle bundles
indeterminate between
MM and MP should be
reported with terminology
such as "invasive
urothelial carcinoma with
invasion of muscle,
indeterminate type" to
prompt the urologist for a
restaging biopsy
procedure
Adipose Tissue
Adipose tissue is frequently present in the LP and

MP of the urinary bladder, usually scant in the
former and abundant in the latter
Involvement of adipose tissue by tumor in biopsy or
TURBT specimens should not be automatically
interpreted as pT3 disease
There is limited reliability of pT3a vs pT3b
subcategorization as gross involvement of
perivesical fat (extravesical fat) may not always be
readily recognizable and may be mimicked by
reactive changes
Assessment of pT2 vs. pT3 cystectomy alone
Lamina Propria Invasion
There are problems with interobserver

reproducibility in the diagnosis of early
LP invasion
When early invasive urothelial carcinoma
is suspected, diagnosis through
examinational of additional levels, or in a
consensus manner either with other
pathology colleagues or thru quality
assurance meeting is encouraged
Microinvasive Urothelial Carcinoma
To diagnose early invasion, stringent criteria such

as: only focal invasion, less than 1 high power
field, or 0.5 mm from the nearest basement
membrane, should ideally be employed
Studies are needed to establish a clinically
significant definition of microinvasive urothelial
carcinoma. Until there is understanding of the
definition, it is recommended that only stringent
criteria be used or the term microinvasive
carcinoma not be used
Substratification or Substaging of
Lamina Propria Invasion (pT1)
Depth of invasion may be established either:
Up to MM: pT1a or beyond the MM or vascular plexus: pT1b;

Up to MM: pT1a, in to MM: pT1b, or beyond the MM or vascular
plexus: pT1c
Currently substaging is not recommended due to the lack

of widely accepted and reproducible criteria although there
is much need for such studies
It is recommended for the pathologist to provide an
estimate of the LP invasion in pT1 tumors with respect to
depth and/or quantity of invasion (e.g. focal, multifocal,
extensive, etc.)
Minimal (micro) invasion
Extensive invasion
Grading of Urothelial Carcinoma
The non-invasive urothelial lesions and neoplasms

can be flat, papillary (exophytic) and inverted
(endophytic). All 3 growth patterns may be seen in
a single tumor
The World Health Organization (WHO) (2004) /
International Society of Urologic Pathologists
(ISUP) classification system is the recommended
system. It has also been endorsed by the WHO
2004 Blue Book, the 4th Series Armed Forces
Institutes of Pathology Fascicle on Bladder and the
7th edition AJCC Cancer Staging Manual
WHO (2004)/ISUP Grading System

Flat Lesions:
Normal
Hyperplasia
Reactive
Dysplasia
CIS
Atypia of
unknown
significance
Papillary Lesions:
Non invasive
Papilloma
PUNLMP
Low grade
High grade
Invasive
Inverted Lesions:
Non invasive
High grade
Low grade (rare)
Papilloma
PUNLMP
Low grade
High grade
Invasive
High grade
WHO (2004)/ISUP Classification

The diagnosis of
neoplasia is made
on the basis of the
presence of a
fibrovascular core
Grading is
performed
Based primarily on
cytology
& some architectural
features
N
O
R
M
A
L
D
Y
S
P
L
A
S
I
A
H
Y
P
E
R
P
L
A
S
I
A
C
A
I
N
S
I
T
U
P
A
P
I
L
O
M
A
L
O
W
G
R
A
D
E
L
M
P
H
I
G
H
G
R
A
D
E
Inverted Neoplasms
Papillary tumors may be associated with a variable

degree of inverted growth patterns; although focal
areas of inverted growth are not uncommon,
prominent or exclusive inverted growth is much
rarer and when encountered may pose problems
related to grading or assessment of invasion
From the clinical standpoint during cystoscopy,
inverted tumors made be polypoid, dome-shaped
or frequently raise the suspicion of invasive
Courtesy R. Montironi, Italy
Exophytic tumor
Inverted tumor
I
N
V
P
A
P
I
L
O
M
A
I
N
V
L
M
P
I
N
V
I
N
V
L
G
H
G
Inverted High Grade without

invasion
Inverted High Grade with

invasion
Urothelial Dysplasia
Overall features are those of a neoplastic

atypia but which fall short of the criteria for
CIS; dysplasia is not further graded
There is some evidence, largely genetic, that
dysplasia shares some abnormalities with CIS
and therefore likely represents a precursor
lesion
Few studies, most dated, indicate a 5-19% risk
of developing cancer
Urothelial Dysplasia
The diagnosis of de novo dysplasia (i.e. in a

patient without history of bladder neoplasia)
should not be made or should be made with
great caution as the vast majority of patients,
in the limited studies, do not progress to
cancer
While dysplasia likely represents a marker of
urothelial genetic instability, the diagnosis
should not by itself invoke any therapy;
continued surveillance is recommended
UROTHELIAL DYSPLASIA
Urothelial CIS
Biologically, therapeutically and prognostically

significant flat lesion
There is a spectrum of nuclear and architectural
atypia. CIS defined by WHO (2004) / ISUP
includes cases diagnosed previously as severe
dysplasia and even some cases previously
diagnosed as moderate dysplasia
Development of invasion is seen in 20 to 30% of
the cases
WHO (2004) /ISUP : Prognostic Significance

Papillom PUNLMP
a
LG pap
ca
HG
pap ca
34-78
(50)
7-12
34-74
Recurrence
9-18
Grade
progression
2%
17-62
(34)
11
Stage
progression
0-4
3-18
27-61
100
93-100
82-96
65-90
Survival
Does not predict risk at individual patient level

Need for incorporation with other clinical parameters in
nomograms to provide personalize risk stratification
Contributions of WHO (2004) /ISUP
Establishment of uniform terminology and common

definitions for papillary neoplasms
Establishment of detailed criteria of various preneoplastic
conditions and various grades of tumor
Correlation with urine cytology terminology, facilitating
cyto-histologic correlation and making it easier for
urologists to manage patients
Creation of a category of tumor that identifies a tumor with a
negligible risk of progression (PUNLMP), whereby patients
avoid the label of having cancer which has psychosocial
and financial implications. Neither is a benign lesion
(papilloma) diagnosed in these patients, so they may still be
followed up closely
Contributions of WHO (2004) /ISUP
Identification of a distinct group of patients

(high-grade papillary UCa) who would be
ideal candidates for intravesical therapy
Removal of ambiguity in diagnostic
categories in WHO 1973 system (e.g., TCC
grade 1-2, TCC grade 2-3)
Stratification of bladder tumors into
prognostically significant categories
Emergence of molecular correlates for high
grade tumors and tumors at the low-grade
end of the spectrum which may help provide
ancillary grading tools, and possibly guide in
future refinements of the current grading
system
Grading Papillary Urothelial Neoplasm

with Histologic Heterogeneity
Grade heterogeneity is not uncommonly

encountered in papillary urothelial neoplasia.
There are studies showing that pure HG
papillary U Ca has a higher disease
progression rate than tumors with mixed highgrade and low-grade areas.
The WHO (2004)/ISUP system recommends
grading of heterogeneous tumors to be based
on the highest grade present in a tumor

There is no current widely acceptable

definition or criteria to provide quantitative
estimate of size of smallest focus required
to upgrade a lesion.
Studies are needed to establish
quantitative/semi-quantitative criteria that
need to be present to alter assignment of
grade in tumors with grade heterogeneity

The distinction between PUMLMP and low grade papillary U

Ca is not that critical in an individual patient
Distinction of low grade from high grade carcinoma is more
important
When assigning the tumor grade in tumors with borderline
grade histology, other tumor parameters such as
multifocality, previous grade of the tumor, size of lesions,
frequency of recurrence, presence of concurrent CIS,
positive cytology may be factored in the grading
Currently, no reliable or acceptable IHC or molecular
markers to assist in grading
Papillary Hyperplasia with Cytologic

Atypia
Terminology used when criteria of papillary

neoplasia are not fulfilled but there is a
background of cytologic atypia
Dysplasia with early papillary formations

CIS with early papillary formations
Usually occurs in the backdrop of treatment

setting
These terms are only descriptive diagnoses and
outcome studies are not available
Epstein, Reuter, Amin Bladder Biopsy

Interpretation,
2nd edition
CIS with early

papillary features
Dysplasia with early

papillary features
Grading Invasive Cancer
Practice in the United States
Almost all cases, once diagnosed as
invasive, are called high grade

Exceptionally rare cases are called
low grade including variants such as
nested variants
Most studies show that once invasive,
depth of invasion is more important
Grading Invasive Cancer
Practice in the Europe
Further grading of high grade (WHO 2004/ISUP

system)
G2 and G3 categories (of WHO 1973 system)
Incorporated into algorithms such as the EORTC
system
Criteria for distinction of G2 versus G3 not well
defined but studies show prognostic significance
in at least pT1 tumors
Conventional Urothelial Ca
Histologic Variants of Bladder Cancer

Prognosis:
Aggressive
Micropapillary
Small cell
Sarcomatoid
With rhabdoid
features
Signet ring
adenocarcinoma
Giant cell carcinoma
Favorable
Pure LELC
Verrucous Ca
Carcinoid tumor
Therapy:
Sarcomatoid Ca
Small cell
Large cell
neuroendocrine
Lymphoepitheliomalike
Micropapillary
Diagnosis
Nested variant
UCa with small
tubules
Plasmacytoid UCa
UCa with clear cell
features
Bladder carcinoma can demonstrate many different

morphologies; major categories include urothelial
carcinoma, squamous cell carcinoma,
adenocarcinoma and small cell carcinoma
All forms of bladder carcinoma originate from
changes in the overlying urothelium
Urothelial carcinoma is the most common category
of bladder carcinoma, comprising approximately
95% of all bladder carcinomas
Urothelial carcinoma may be subdivided into
conventional and variant subtypes
Variant forms include the 15 subtypes; it remains unclear

what percentage of variant form impacts survival in most
cases
Most variants often admixed with conventional UCa,
squamous or glandular differentiation
Level I evidence is limited for most bladder carcinoma
variants, given their relative rarity. Prospective or
consecutive cases studies in large series evaluating the
impact of various histologic variants on outcome or therapy
have not yet been performed

The percentage of variant component required to
make a diagnosis of a particular variant is not defined
When mixed with conventional or other variants of U
Ca, the relative percentages of the different histologies
must be specified
e.g. U Ca with micropapillary histology (40%),
conventional U Ca histology (50%) and with
squamous differentiation (10%)
Papillary tumor
Micropapillary U Ca
Micropapillary UCa
Sarcomatoid UCa
Small cell Ca
Nested UCa
Microcystic UCa
Plasmacytoid UCa
Lipoid-rich UCa
UCa with Squamous and Glandular

Differentiation
Controversial and limited data
Some studies have shown a worse prognosis when
compared with pure urothelial cancer
Others show no differences between stage matched
cohorts
The presence of divergent differentiation in a TURBT
may predict locally advanced cancer at cystectomy
Invasive squamous cell carcinoma

Schistosomal
Non-schistosomal
Verrucous carcinoma
Should be pure in morphology

If associated with destructive invasion,
should be classified as squamous cell
carcinoma invasive with verrucous
features
Molecular Subtyping of UCa
There are promising emerging tests which have the

potential to impact prognostication and prediction
to therapy in U Ca
Prospective studies determining their efficacy and
best practices for performing the tests are
underway (e.g. the UROMOL study in Europe
investigating and validating gene expression
profile)
Further studies need to be defined for professional
and technical quality assurance and optimal
patient care
IHC Markers
in Staging UCa
Smoothelin
- Contractile protein
- Fully differentiated muscle
cells
- Hyperplastic muscularis
mucosae (-) to weak
- Diffuse positivity in muscularis
propria
Caution: Susceptible to variation in antibody titer

Must be interpreted in the context of morphology
Reporting of Bladder Cancer
Guidelines : CAP and European Society of

Uropathology etc.
Reporting in synoptic pattern is preferred
Clinical information important for pathology
diagnosis
Cystoscopic impression
Previous history of bladder cancer
Previous history of therapy (intravesical or systemic)
History of stones, indwelling, catheter, etc.
A deeper bite for assessment of MP involvement in

TURBTs should be preferably submitted separately,
for larger tumors
Reporting at Cystectomy
No residual cancer in cystectomy:

? pT0 or pT2 (if TURBT showed muscle
invasive disease)
By AJCC 6th edition: pT2
Studies in literature have shown pT0 (no
tumor at cystectomy) have better prognosis
than pT2 tumor at cystectomy
Need conference multidisciplinary input to
resolve reporting tumor (-) cystectomies
Reporting of Bladder Cancer
Minimum number of lymph nodes in cystectomy

not established
Size of largest metastatic focus and extranodal
extension, if present should be documented
Frozen section is not an optimal method for a
primary diagnosis of invasive urothelial carcinoma
or to perform pathologic staging prior to a
cystectomy
Chapter 3: Biological Markers

Shahrokh F. Shariat
Bernd J. Schmitz-Drger
Michael Droller
Vinata B. Lokeshwar
Yair Lotan
MLiss A. Hudson
Bas van Rhijn
Michael Marberger
Yves Fradet
George P. Hemstreet
Per-Uno Malmstrm
Osamu Ogawa
Pierre Karakiewicz
Weill Cornell Medical College, New York, NY, USA

EuromedClinic, Frth, Germany
Mount Sinai School of Medicine, New York, NY, USA
University of Miami School of Medicine, Miami, FL, USA
UT Southwestern Medical Center, Dallas, TX, USA
Washington University, St. Louis, Missouri, USA
Netherlands Cancer Institute, Amsterdam, Netherlands
Medical University of Vienna, Vienna, Austria
Laval University, Laval, Quebec, Canada
University of Nebraska, Omaha, Nebraska, USA
University Hospital, Uppsala, Sweden
Kyoto University, Kyoto, Japan
University of Montreal, Montreal, Quebec, Canada
Disclosures
Patents
Method to determine prognosis after therapy for prostate
cancer
Granted 2002-09-06
Methods to determine prognosis after therapy for bladder
cancer
Granted 2003-06-19
Prognostic methods for patients with prostatic disease
Granted 2004-08-05
Soluble Fas urinary marker for the detection of bladder
transitional cell carcinoma
Granted 2010-07-20
Definition of Biological Marker

NIH definition: a characteristic that is objectively measured and
evaluated as an indicator of normal biological processes, pathogenic
processes, or pharmacologic responses to a therapeutic intervention
For our purposes: a biomarker is the end result of a bioassay,
a laboratory technique for processing biological material from humans,
expressed quantitatively or categorically
Imaging results could also be included as a biomarker if we interpret
bioassay broadly enough
Measurement outcome of a biomarker:
binary (e.g., positive or negative)
categorical (e.g., high, medium, low)
quantitative (e.g., the level of some urine/serum protein), or
more complicated (e.g., a genomic signature or metagene)
Clinical Uses of Biomarkers

Clinical practice
Determine the risk of developing disease
Early detection/screening
Establish diagnosis
Diagnostic
Markers
Determine prognosis
Predict response to therapy
Therapeutic target
Monitor disease/treatment response

Clinical Trials
Stratifying study populations
Conducting interim analysis of efficacy/safety
Applied toward regulatory approval
Prognostic
Markers
Biomarker Conundrum for Bladder Cancer
Number of published articles
PubMed Search on bladder cancer AND (biomarker OR biomarkers OR

molecular marker OR molecular markers) yields 4125 hits (3/17/2011)
Number of biomarkers routinely used by urologists: cytology

Why havent biomarkers lived up to their promise?
A variety of issues and

barriers can affect the
movement of clinical tests
from research to clinical

practice.
Shariat et al., Eur Urol 2007
Analytical and regulatory barriers to the
application of biomarkers
Status of intellectual property protection
Availability of standard reference materials for the assay
Complexity of assay format
Implementation of quality control to assure reproducibility and accuracy
Sufficient market testing size to assess methods of commercialization
Lack of clear guidelines for good manufacturing/laboratory practice and
quality control requirements for all phases of biomarker development
Cost and effort required to accumulate clinical data under appropriately

designed, Institutional Review Board-approved prospective trials
The interval required for resolution of patent issues, assay
standardization, validation, testing, and regulatory approval
Why havent biomarker studies led to translation?
Biomarker research done in context of usual clinical care, not

clinical trials
Biomarker assays not standardized
Most biomarkers findings not reproducible
Biomarkers that appear biomedically and statistically
significant at one center - NOT significant in other centers
Lack of minimal set of CDEs, use cases, metadata
Pre-analytical variation not controlled or annotated
Usually small, single institution studies
Bringing the ideal marker to clinical practice
Easier: performed easily and promptly in a

clinical environment
Better: does the biomarker add to established

predictors?
Faster: available in an efficient and timely
manner
Cheaper: cost-effectiveness
Modification of the structured phase-approach to the

systematic discovery, evaluation, and validation of biomarkers
PHASE
GOALS/AIMS
EXPERIMENTATION
SAMPLE DETAILS
Preclinical
Exploratory; nominate
Preclinical study
Possible bias: small size and
Testing
and rank candidate
for hypothesis generation
convenience sampling
biomarker profiles
0
Develop an assay with
Reproducibility and robustness
clinically reproducible results
of assay; No assessment of
benefit
II
Test on small sample to
Marker optimization, establish
Sample population assay
determine benefit
prediction rules, determine cut-
developed from candidate
offs
biomarker profile
Retrospective design
Sample population should be
Determine operating
characteristics & internal
the target population
validation
III
External validation
Retrospective or prospective,
Generaliziability, Impact on
clinical decision-making
IV
Assess whether biomarker

reduces the burden of disease
Post-approval reporting and

testing for other disease
processes or disease stages
Multi-institutional, large study
Reporting
recommendations
for tumor marker
prognostic studies
(REMARK)
NCI-EORTC
McShane et al.,2005
Levels of evidence for grading clinical utility of biomarkers: Tumor
Marker Utility Grading System (TMUGS)
Hayes et al. JNCI 1996
Predictive modeling - Personalized medicine

The only useful function of a statistician is to make predictions,
and thus to provide a basis for action.
W.E. Deming
Modeling strategies
Logistic regression
Cox proportional hazards regression (caveat: competing risks
lead to overestimation of the probability of an event)
Recursive partitioning and regression trees
Artificial neural networks
Shariat et al., Cancer 2008
To determine the value of a new biomarker
It is NOT sufficient to show that it is:

1. significantly related to the outcome
2. statistically significant in a multivariate model including the
standard clinical and pathologic factors
3. more significant than the standard clinical and pathological
factors in a multivariate model
A variable that is statistically significant in a multivariate model
might not improve the models predictive accuracy
- Odds ratio and hazard ratio do not meaningfully describe a
biomarkers ability to classify patients
- Neither the p-value
Gain in predictive accuracy
It is necessary to show that adding a biomarker to an

existing model based on the most important clinical and
pathologic factors improves the predictive accuracy of
the model.
Does the biomarker add predictive/prognostic information to the
current risk group classification?
Does the classifier improve the predictive inaccuracy and proportion

of explained variation?
Does the classifier improve the Area Under the ROC Curve (AUC)
or C-index (Concordance Index)?
Clinical validation of biomarker-based model
A biomarker is optimal for the patients in the training set

used to develop it (overly optimistic results)
Therefore biomarker-based models need to be validated
on data not used to develop it:
- Internal validation on original dataset
- External validation on independent dataset (best!!!)
Statistics in marker research

Attention to sound statistical practice
- should be delivered as early as possible
- will help maximize the promise of biomarkers for patient care
Studies should include a measure of predictive accuracy
External validation using data from a completely different study
provides the highest irrefutable evidence that a model is valid
Other issues such as over-reliance on statistical significance
tests, over-fitting of models, small sample sizes, and lack of prespecification of the validation process continue to be problematic
Statistical methodology is an area of research
Shariat et al., Urol Oncology, 2010
Clinical States Model of Bladder Cancer

Death From Other
Causes
Initial Bladder
Evaluation: No
Cancer Diagnosis
Non-invasive
UCB
Invasive
UCB
Metastatic
UCB
Death From UCB
Urinary Markers for Screening and Monitoring

Death From Other
Causes
Initial Bladder
Evaluation: No
Cancer Diagnosis
Non-invasive
UCB
Death From UCB
Potential indications for marker use

Screening (Voiding symptoms, hematuria, risk populations e.g.,
occupational exposure/life style)
Reflex testing
Follow-up of patients with bladder cancer
Why are new markers attractive?

Cystoscopy gold standard for diagnosis and
surveillance
Invasive, expensive, time consuming
Up to 10% of significant lesions still missed by

cystoscopy
NCCN UCB Surveillance Protocol

Cystoscopy
0-2 years Every 3 months
2-4 years Every 6 months
5 years + Annually
Cytology
Obtained at time of cystocopy
Butonly 40% complete recommended surveillance
protocol
Cytology
Cells readily available in urine
Relies on abnormal cellular morphology

Reasonable specificity (87-95%)
Poor sensitivity (12-48%)
Higher sensitivity for high grade disease
Useless: infection during intravesical Rx
Need for highly trained cytopathologist

Interpreter dependent
Accuracy affected by:
Low inter- and intra-observer
Collection technique
Pelvic radiation, intravesical
therapy, instrumentation
Cytopathologist
reproducibility
Variability of urinary cytology is very high

Positive in 38% to 65% of recurrent UCB
Sensitivity for grade 3:
33% to 95%
Sensitivity for stage T2:
37% to 100%
Accuracy from poor (63%) to excellent (89%)
even after adjusting for age and gender

regardless of tumor stage and grade
Gold Standard?
Sensitivity of Cytology
(Review of Literature)
Grade 1
37%
Grade 2
75%
Grade 3
94%
After 1990
11%
31%
60%
All studies
21%
53%
78%
Before 1990
Halling et al JUrol 2002
Ideal Tumor Marker

Potential to replace, delay, or complement cystoscopy and/or
cytology
Characteristics
- Non-invasive - Rapid - Objective - Reproducible - Cost-effective
- Easy to perform and interpret - High sensitivity and specificity

For monitoring, two different paradigms:
- Low risk tumors: reduction of diagnostic cystoscopies
- High risk tumors: recognition of tumor recurrence as early as

possible and prevention of progression
Commercially available bladder tumor markers

Test/
marker
Cytology
Marker detected/
Marker type
Tumor cells
Hematuria
detection
BTA-Stat
A: Hemoglobin
B: Red blood cells
Complement factor Hrelated protein (and also
Complement factor H)
Complement factor Hrelated protein (and also
Complement factor H)
Nuclear mitotic apparatus
protein
Nuclear mitotic apparatus
protein
Nuclear matrix protein
BTA-TRAK
NMP-22
NMP-22
BLCA-4
Survivin
Specimen
Assay type
FDA approval
Voided urine
Barbotage specimen
A: Voided urine
B: Voided urine
Voided urine
Microscopy
n.a.
Voided urine
Sandwich ELISA
Diagnosis, follow- Bard/Bion

up
Diagnostics
Voided urine
Sandwich ELISA
follow-up
Matritech, Inc.
Voided urine
Point-of-care device
Matritech, Inc.
Voided urine
ELISA (using a rabbit

polyclonal antibody)
Bio-dot test
Diagnosis high
risk, follow-up
-
A member of inhibitors of
apoptosis gene family
UBC
Cytokeratin 8 and 18
(cytoskeletal proteins)
CYFRA 21-1 Cytokeratin 19 (a
cytoskeletal protein)
DD23
185-kDa tumor
associated Antigen
Voided urine
uCyt+
UroVysion
Carcinoembryonic
antigen, 2 bladder tumor
cell-associated mucins
Alt in chromosomes 3, 7,
17 and 9p21
Voided urine
A: Dipstick, B: Interference- microscopy /RBC analyzer

Dipstick immunoassay
Diagnosis, followup
Manufacturer
A: Bayer
Corp. B: Bard/Bion
Diagnostics
Eichrom
Technologies
Fujirebio
Diagnostics
IDL Biotech.
Sandwich ELISA or a point

of care test
Immunoradiometric assay
or ELISA
Immunocytochemistry
Bio Int; Roche

Diag
UroCor Labs
Voided urine,
Exfoliated cells
Immunocytochemistry
Follow-up
Scimedx, Inc.
Voided urine,
Exfoliated cells
Multi-colored, multi-probe
FISH
Diagnosis, follow- Abbott, Vysis

up
Voided urine
Exfoliated cells
Urine Biomarkers for Detection and Surveillance

Marker
# Studies
# Pts
Sensitivity
Range
Specificity
Range
BTA
BTAstat
BTAtrak
NMP22
FDP
5
17
4
15
4
436
1377
360
838
168
48
58
71
71
54
32-58
29-74
60-83
47-100
47-68
92
73
66
73
61
91-92
56-86
60-79
55-98
25-80
ImmunoCyt
Cytometry
Quanticyt
Hb-dipstick
Lewis X
6
5
5
2
3
276
364
129
117
95
67
60
58
40
75
52-100
45-85
45-65
37-41
68-79
75
82
76
87
85
62-82
50-92
68-87
87
67-86
FISH
Telomerase
Microsatellite
CYFRA21-1
4
3
6
3
165
146
108
156
79
39
82
85
70-86
29-66
75-92
75-88
70
Na
89
82
66-93
Na
79-100
73-95
Cytology
26
2213
35
13-75
94
85-100
Shariat et al., Minerva Urol, 2009
Marker Sensitivity and Specificity: Meta-analyses

Marker
Cytology
Cytology
Cytology
Cytology
Median Sensitivity Median Specificity

(range)
(range)
55 (48-62)*
94 (90-96)*
34 (20-53)
99 (83-99)
35 (13-75)
94 (85-100)
44 (38-51)*
96 (94-98)*
Total Number
of Patients
3,444
2,767
5,545
14,260
BTA stat
BTA stat
BTA stat
70 (66-74)*
71 (57-82)
58 (29-74)
75 (64-84)*
73 (61-82)
73 (56-86)
1,160
2,534
3,461
NMP22
NMP22
NMP22
NMP22
NMP22 BladderChek
67 (60-73)*
73 (47-87)
71 (47-100)
68 (62-74)*
65 (50-85)
78 (72-83)*
80 (58-91)
73 (55-98)
79 (74-84)*
81 (40-87)
2,290
2,413
2,041
10,119
2,426
Immunocyt
Immunocyt
This assessment
67 (52-100)
84 (77-91)*
81 (42-100)
75 (62-82)
75 (68-83)*
75 (62-95)
959
3,041
4,899
FISH (Urovysion)
FISH (Urovysion)
This assessment
72 (69-75)*
76 (65-84)*
72 (23-100)
83 (82-85)*
85 (78-92)*
80 (40-100)
2,477
3,101
2,852
Sensitivity of Select Markers Based on Tumor Grade and Stage

Marker
# studies
Grade 1
Grade 2
Cytology
Cytology
8
9
0.12 (.04-.31)
0.17
0.26 (.17-.37) 0.64 (.38-.84)

0.34
0.58
BTA stat
BTA stat
8
7
0.47 (.38-.56)
0.45
0.73 (.59-.83) 0.94 (.55-.99)

0.6
0.75
NMP 22
0.41
NMP 22
0.61(.35-.81)
Immunocyt
0.78
0.9
FISH (Urovysion)
0.56
0.78
0.95
0.53
Grade 3
0.8
0.71 (.41-.90) 0.79 (.63-.89)
Marker
# studies
Ta
T1
>T2
TIS
Cytology
.15 (.09-.25)
.46 (.34-.59)
.55 (.35-.73)
.63 (.29-.87)
BTA stat
.57 (.47-.67)
.82 (.63-.92)
.91 (.74-.97)
.66 (.42-.83)
NMP 22
.60 (.42-.76)
.85 (.27-.97)
.89 (.50-.98)
.73 (.54-.86)
NMP22 improves prediction of UCB

in high risk patients
May improve referrals from PCP

May improve timing of cysto in systems with limited resources
Lotan and Shariat, BJU Int. 2009
AUC for detection: 74% (95% CI: 72-76%)

Range across institutions: 68 to 89%
Question: (How) can molecular markers support screening of

patients at risk of having or developing bladder cancer?
Statement:
Feasibility of bladder cancer screening has been demonstrated in several

prospective trials. The results from one study using dip-stick testing for
hematuria suggests a survival benefit of individuals undergoing
hematuria screening. Despite these encouraging reports validation of the

results and improved definition of risk populations suited for screening is
required.
Recommendation:
Bladder cancer screening using urine for testing is promising but
cannot be recommended at present.
LoE: 1b
Grade: B
Agreement: 100%
Question: (How) can molecular markers support follow-up of

patients with non-muscle invasive low risk bladder cancer?
Statement:
Marker-guided follow-up of patients with superficial low risk tumors
appears feasible. However, studies proving the efficacy of this concept

and demonstrating an added value for the patients or the health system
are lacking.
Recommendation:
Marker-guided follow-up of patients with non-muscle invasive low
grade bladder cancer appears attractive, however, based upon the
current level of evidence this procedure cannot be recommended
at present
LoE: 1b
Grade: B
Agreement: 100%
Question: (How) can molecular markers support follow-up of

patients with non-muscle invasive high risk bladder cancer?
Statement:
Molecular markers detect high grade bladder cancer with high

sensitivity. At this stage it remains unclear how molecular markers can
support surveillance of patients with high grade bladder cancer.
Recommendation:
A use of molecular markers in surveillance of patients with high
grade bladder cancer cannot be recommended.
LoE: 2b
Grade: B
Agreement: 100%
Question: (How) can molecular markers be used in reflex testing for

bladder cancer?
Statement:
At present experience with reflex testing is very limited (mostly restricted to
FISH technique) and therefore does not permit a definite statement. reflex
testing should be exploited in more detail within prospective controlled

studies.
Recommendation:
Reflex testing is considered experimental at present and should be
investigated further.
LoE: 2b
Grade: B
Agreement: 100%
Summary I
All test sensitivities > cytology (low grade!)
All test specificities < cytology
CIS sensitivities surprisingly low
No single marker has demonstrated superior clinical utility

over cytology and cystoscopy
There is no ideal marker
We will have to select appropriate markers according clinical needs

Screening setting: high specificity
Follow-up setting: sensitivity
Diagnostic strategy affects selection of a marker
Summary II
Despite numerous publications, the utility of markers in
clinical decision-making remains limited
meanwhile the first prospective trials on a marker-guided
follow-up in bladder cancer patients are underway.
In addition, several screening studies could demonstrate
the feasibility of molecular markers in this setting.
Probably no single assay will be sufficient because of the
molecular heterogeneity of bladder cancer
Clinical states of advanced UCB
Determine prognosis
Predict response to therapy
Therapeutic target
Monitor disease/treatment response
Clinically
Advanced Disease
Clinically
Non-muscle
Invasive Disease
Death from
Disease
Local and/or
Distant
Recurrence
Clinical
Metastases
Death from
Other Causes
Clinical Needs
Accuracies of prognostic models (i.e., nomograms) not perfect

there may be markers that help improve outcome prediction
Molecular markers established as independent predictors of disease
recurrence and survival in pts treated with bladder cancer
Novel markers may identify patients with biologically and
clinically aggressive BCa and thereby help improve current
staging and prognostic models
Tumors are heterogeneous
Potential Role for Biomarkers

Identify high risk patients (staging and prognosis)
Advanced disease at cystectomy
Recurrence after cystectomy
Predict response to chemotherapy
Identify pathways for targeted therapy
Shariat et al, 2009
PROMISING TISSUE-BASED PROGNOSTIC MOLECULAR MARKERS

Cell cycle related markers
p53, pRB, p21, p27, cyclin E1, cyclin D1, Ki67
Apoptosis
Fas (CD95), Caspase-3, Survivin, Bcl-2
Angiogenesis
Microvessel density, Thrombospondin-1, VEGFR, bFGF
Signaling proteins
ERBB family receptors, RAS, PI3K pathway genes, FGFR3
Hormone receptors
Her2, AR, ER, PR
PROMISING BLOOD-BASED PROGNOSTIC MOLECULAR MARKERS

Plasma-insulin growth factor binding protein-1 and -3
Transforming growth factor-1
Interleukin-6 and its receptor

Soluble E-cadherin
Urokinase plasminogen activation axis (uPA, PAI-1, PAI-2, uPAR)
Matrix metalloproteinase
HIGH-THROUGHPUT TUMOR PROFILING (DNA microarray, metabolomics, etc)
Investigated pathways
Cell Cycle regulation
p53
inhibits G1/S progression
pRb
sequesters E2F, inhibits cell cycle progression
p21/p16/p27
cyclin-dependent kinase inhibitors
Cyclin D1/cyclin E cell cycle control at G1/S transition

KI-67
cell proliferation
Apoptotic pathway
p53
induces apoptosis or DNA repair
Bcl-2
inhibits caspase activation
Bax
activates cytochrome C release and apoptosis
Caspase 3
induces apoptosis
Survivin
protects from apoptosis and regulates mitosis
Angiogenesis pathway
TSP1
inhibits angiogenesis
VEGF
promotes angiogenesis through NOS
uPA
degrades extracelullar matrix
bFGF
growth factor stimulating angiogenesis
Is one marker optimal?
Combined cell-cycle biomarkers

Shariat et al., J Clin Oncol 2003
Combined apoptosis biomarkers

Karam et al., Lancet Oncol 2007
Nomograms
Recurrence
BCa-specific Death
Competing-risk nomograms for prediction of clinical

outcomes in patients with pT1-2 N0 UCB
after radical cystectomy
Recurrence
Points
Age at surgery
P. Grade
10
20
30
40
50
60
Cancer-specific Survival
70
80
90
100
Age at surgery
30 40 50 60 70 80 90
2
Lymphova
3
1
Lymphova
Total Points
1(Y)REC-Free.Surv.
2(Y)REC-Free.Surv.
3(Y)REC-Free.Surv.
5(Y)REC-Free.Surv.
7(Y)REC-Free.Surv.
0
0
2
20
0 .9 9 5
40
0 .9 9
0 .9 9
60
20
30
40
50
60
70
30
40
50
60
70
80
1
80
4
100
120
0 .9 8 0 .9 7 0 .9 50 .9 3 0 .9 0 .8 6 0 .8
0 .9 8 0 .9 7 0 .9 50 .9 3 0 .9 0 .8 6 0 .8
140
160
0 .7 0 .6 0 .5 0 .4
180
Total Points
1(Y)BCa-Spec.Surv.
20
0.998
2(Y)BCa-Spec.Surv.
40
0.995
0.995
0.99
60
0.99
80
0.98 0.97
0.98 0.97
4
100
120
0.95 0.93 0.9 0.86 0.8
0.95 0.93 0.9 0.86 0.8
140
160
0.7 0.6
0.7 0.6 0.5 0.4 0.3
0.995
0.99
0.98 0.97
0.95 0.93 0.9 0.86 0.8
0.7 0.6 0.5 0.4 0.3 0.2
0 .7 0 .6 0 .5 0 .4 0 .3 0 .2 0 .1
0.99
0 .7 0 .6 0 .5 0 .4 0 .3 0 .2 0 .1
7(Y)BCa-Spec.Surv.
0 .9 8 0 .9 7 0 .9 50 .9 3 0 .9 0 .8 6 0 .8
100
5(Y)BCa-Spec.Surv.
0 .9 8 0 .9 7 0 .9 50 .9 3 0 .9 0 .8 6 0 .8
90
0 .7 0 .6 0 .5 0 .4 0 .3 0 .2
3(Y)BCa-Spec.Surv.
0 .9 8 0 .9 7 0 .9 50 .9 3 0 .9 0 .8 6 0 .8
80
90
No. of Markers
0
1
No. of Markers
10
Points
0 .7 0 .6 0 .5 0 .4 0 .3 0 .2 0 .1 0 .0 3
0.99
0.98 0.97
0.98 0.97
0.95 0.93 0.9 0.86 0.8
0.95 0.93 0.9 0.86 0.8
0.7 0.6 0.5 0.4 0.3 0.2
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.03
Shariat et al., J Urol, 2011
Ongoing clinical trials at UT

Southwestern Dallas, Texas
1. Prospective staining of
all TUR and cystectomy
specimens for markers
2. Prospective, randomized
single center study:
adjuvant chemotherapy after
radical cystectomy in patients
with pT1-3 N0 who have 3
markers altered
UCB Molecular Pathways- Opportunities for Targeted

Therapies
Non Invasive LG UCB pathway: HRAS or FGFR3 mutant proteins
Inhibition of RTK-as signaling pathway
e.g. Receptor tyrosine kinase inhibitors: gefitinib, erlotinib
ErbB2 blocker: trastuzumab
EGFR blocker: cetuximab
Invasive High Grade UCB pathway:
Restoration p53/RB function: gene therapy/small molecules
Inhibition VEGF/VEGFR: Sorafenib, sunitinib, pazopanib,
bevacizumab
Inhibition of anti-apoptotic molecules (survivin)
Summary
Currently NO prognostic marker is ready for integration
into clinical decision-making
Bladder cancer develops along multiple molecular pathways
multiple molecular markers to capture biological
potential of tumor
Molecular medicine holds the promise that clinical outcomes
will be improved by directing therapy toward tumor
mechanisms and targets
The advent of high-throughput technologies is allowing
comprehensive identification of molecular targets and
molecular markers
The Future: integration of molecular panels

Improve prognosis of heterogeneous disease (UCB)
e.g. early cystectomy in pT1HG
Improve selection and thereby increase use of current
chemotherapy
Prediction of response to current chemoRx
Therapeutic response indicator
e.g. select patients who achieve pT0 after neoadjuvant
chemotherapy for bladder preservation
Target for therapy (combination therapies)
Questions?
57
ICUD-EAU 2011
Recommendations of committee
on LG Ta disease
Badrinath Konety (USA), Willem Oosterlinck
(Belgium), Paul Sved (Aus), Raj Pruthi (USA),
Sam Chang (USA), Eduardo Solsona (Spain),
Sigurdur Gudjonsson (Sweden), Mark
Soloway (USA)
Levels of Evidence used

(modified from Sackett et al. OCEBM 2001)
Level
Type of evidence
1a
Evidence obtained from meta-analysis of randomized trials
1b
Evidence obtained from at least one randomized trial
2a
Evidence obtained from one well designed, controlled study

without randomization
2b
Evidence obtained from at least one other type of well designed,

quasi-experimental study
Evidence obtained from well designed non-experimental studies

such as comparison studies, correlation studies and case reports
Evidence obtained from expert committee reports or opinions or

clinical experience of respected authorities
Grade of recommendation
Grade
Nature of recommendation
Based on clinical studies of good quality and consistency addressing the

specific recommendations and including at least one randomized trial
Based on well conducted clinical studies but without randomized clinical

trials
Made despite the absence of directly applicable clinical studies of good

quality
Grade classification (WHO-ISUP)

Papilloma
PUNLMP
Low grade
High grade
Incidence of LG Ta SEER-Medicare
2000-2005
Year of Diagnosis
Stage I Disease
2000
2001
2002
2003
2004
2005
807 (19.28)
814 (19.28)
797 (18.33)
835 (17.37)
930 (17.96)
848 (18.06)
LG Ta
Progression rates are low <20%
Cancer specific survival is extremely high
>95%
PUNLMP more likely to recur but
progression extremely rare
Lifelong risk of recurrence with late
recurrence following years of no tumor
Overall survival LG Ta
Kaplan-Meier Estimate for Overall Survival
1.00
Survival Distribution Function
0.75
0.50
0.25
0.00
0
10
20
30
40
50
60
70
survival_months
STRATA:
gradecat=High Grade
gradecat=Undifferentiated Grade
Censored gradecat=High Grade

Censored gradecat=Undifferentiated Grade
gradecat=Low Grade
gradecat=Unknown Grade
Censored gradecat=Low Grade

Censored gradecat=Unknown Grade
80
Cancer specific survival LG Ta

1.00
0.75
0.50
0.25
0.00
0
10
20
30
40
50
60
survival_months
STRATA:
gradecat=High Grade
gradecat=Low Grade
gradecat=Undifferentiated Grade
gradecat=Unknown Grade
Censored gradecat=High Grade

Censored gradecat=Low Grade
Censored gradecat=Undifferentiated Grade
Censored gradecat=Unknown Grade
70
80
Prior recommendations
Oosterlinck et al. 2005
Lesions >0.5cm, multiple (>5),
papillonodular and positive cytology need
further evaluation (B)
Routine upper tract studies not
recommended during follow up (B)
To be considered in symptomatic patients and
those with positive cytology (A)
Random biopsy for positive cytology (B)

Oosterlinck et al. Urology 2005
Previous recommendations
Immediate post TUR intravesical chemo recommended
(A)
MMC (40mg or Epirubicin (50mg) (A)

Avoid chemo if perforation present (D)
Instillation same day as TUR (B)
Adjuvant intravesical chemo for multiple tumors (A)
Intravesical chemo first line (B)

BCG second line (A)
Cysto at 3 months if negative next at 9 months (C)
Office fulguration acceptable (C)
Urine cytology or markers not needed at diagnosis (A)
or follow up (B)
Literature review
PubMed search conducted
Search terms used
Bladder cancer; bladder neoplasm, low grade, low
stage, diagnosis, intravesical therapy; cystoscopy,
smoking, prevention, observation, expectant
management, CT urography, intravenous
pyelogram/IVP, cytology, urinary markers, fluorescent
cystoscopy, transurethral resection, surveillance, BCG,
Mitomycin.
Human, 25 years
Other association guidelines (AUA, EAU, BAUS, Int.
Consultation on bladder tumors/SIU)
Urinary tumor markers

Recommendation
BTA has little role in diagnosis of LG Ta
tumors
NMP22 has better sensitivity than
cytology but cannot replace cystoscopy
ImmunoCyt has good sensitivity for LG Ta
tumors and can be used to prolong
intervals between cystoscopy
UroVysion/FISH has no role in diagnosis
of LG Ta tumors
Level of
evidence
2b
Grade of
recommendation
B
1b
2a
2b
Performance characteristics of
markers
Marker
UroVysion
Microsatellite analysis
Gene microarray
Immunocyt/ uCyt+
Nuclear matrix protein 22
BTA stat
BTA TRAK
Cytokeratins
Survivin
Sensitivity
Specificity
30-72
58
80-90
76-85
49-68
57-83
53.8-91
12.1-85
53-90.4
63-95
73
62-65
63-75
85.8-87.5
68-85.7
28.3-83.9
75-97.4
88-100
Upper tract evaluation and surveillance

Recommendation
Level of evidence
Grade of
recommendation
Routine upper tract studies are not

recommended for patients with LG Ta
tumors at diagnosis of index tumor
Upper tract evaluation in patients with
LG Ta UC is recommended in the
presence of:
o gross hematuria
o unexplained positive urine cytology
2b
2b
Routine upper tract studies surveillance is

not recommended for patients with LG
Ta tumors during follow up
2b
Expectant management
Recommendation
Level of
Grade of
evidence recommendation
Expectant management should be pursued only in

patients with established history of LG Ta UC
Optimal tumor characteristics include low tumor burden
Particularly applicable to those with advanced age or

co-morbidity but can be offered to younger patients
after careful and thorough discussion
Surveillance includes periodic cystoscopy and cytology
Patients who demonstrate increase in size, number or

appearance of tumor(s) or develop positive urine
cytology should cease expectant management and
undergo formal TUR and further evaluation
Office fulguration is a good option for patients with small
LG Ta UC. This can be followed by post fulguration
instillation of intravesical chemotherapy
Intravesical chemotherapy
Recommendation
Initial step in management is complete
TUR
Immediate post-TUR instillation of
intravesical chemotherapy in the form of
Mitomycin C or epirubicin is
recommended to prevent recurrences
Induction chemotherapy with or without
maintenance has unclear but potential
benefit
The risks of repeated courses of
intravesical chemotherapy have to be
weighed against the benefit
Level of
evidence
2b
Grade of
recommendation
A
1a
2b
Intravesical immunotherapies
Recommendation
Intravesical BCG is not appropriate as initial

intravesical therapy for patients with LG Ta UC
Intravesical BCG could potentially be used in
patients with recurrent LG Ta UC who have not
responded to courses of intravesical
chemotherapy
Secondary immunomodulating therapies do not
have a role in management of LG Ta UC at this
time
Level of
evidence
Grade of
recommendation
High grade Ta, T1 and CIS
ICUD update session

dr. Max Burger, Regensburg
prof. Fred Witjes, Nijmegen
March 18, 2011
Radboud University Nijmegen Medical Centre
The Netherlands
Members committee 4
Marko Babjuk, Prague

Maurizio Brausi, Modena
Chris Cheng, Singapore
Eva Comperat, Paris
Jay Shah, Colin Dinney, Houston
Joachim Throff, Wolfgang Jger, Mainz
Wolfgang Otto, Max Burger (co chair), Regensburg
Fred Witjes (chair), Nijmegen
The Netherlands
Dr Max Burger
The Netherlands
High grade Ta
The Netherlands
Ta HG recommendation 1
Ta HG should be suspected if
papillary tumour is seen in cystoscopy
urinary cytology is positive
The assessment Ta HG should be based on
multiplicity
tumour size
early recurrence
concomitant CIS
LOE 3, recommendation grade B

The Netherlands
Ta HG recommendation 2
Ta HG should be completely resected
photodynamic diagnostic may be considered
uncertain radicality should prompt re- TURB
Ta HG should undergo instillation therapy

effect of early instillation uncertain
BCG should be given
duration of BCG should exceed one year
LOE 2, recommendation grade A

The Netherlands
CIS
The Netherlands
CIS recommendation 1
If CIS is suspected clinically
cytology, cystoscopy, upper tract imaging
TURBT in CIS:
PDD considered in pos. cytology/ neg. cystoscopy
LOE 1a, recommendation grade A

The Netherlands
Cystectomy in CIS:
provides excellent survival
however, overtreatment in 50%
The Netherlands
Intravesical therapy
immediate instillation may be considered
should follow complete resection of pap. tumours
should be based on BCG
LOE 1a, recommendation grade A

Maintenance therapy
required, best schedule unkown, >1 year

The Netherlands
Treatment response
should be assessed at 3 months

if no response: cystectomy or further BCG
BCG: another 6 wk. course or 3 wkly boosters
Unknown when best to abandon conservation
The Netherlands
Follow up
white light cystoscopy and cytology
every 3 months for 2 years

every 4 months in 3rd year
every 6 months in 4th/ 5th year
once per year thereafter
imaging of upper tract yearly
LOE NA, recommendation grade C
The Netherlands
Q&A
The Netherlands
Dr Witjes
The Netherlands
T1 disease
The Netherlands
T1 recommendation 1
The assessment T1 BC should be based on
tumour grade and size

early recurrence
Multiplicity
concomitant CIS
UC involving the prostatic mucosa or ducts
depth of lamina propria invasion
LOE1a, recommendation grade A

The Netherlands
Prediction of prognosis
impossible on an individual level
The Netherlands
Other potential prognostic factors

Response to intravesical therapy
Tumor at 3 months after BCG: up to 80% progression
Insufficiently validated in clinical trials are:

LVI??
Markers
P53, p27, Ki67
The Netherlands
T1 recommendation 2
The use of one immediate postoperative
instillation of chemotherapy is not supported
by consistent data and therefore it should not
be recommended as standard practice
The Netherlands
New literature on immediate instillation

Hendricksen (2008):
course of epirubicin with or without one instillation
Gudjonsson (2008), Berrum-Svennung (2008):

epi versus nothing
only effect in very low risk tumors
Bhle (2009):
Gemcitabin versus placebo
20 hrs contineous bladder irrigation
Brausi (2010):
data in high risk very limited
The Netherlands
EAU guideline 2011
The Netherlands
EAU guideline 2011
The Netherlands
T1 recommendation 3
Patients with high risk and with recurrent or
persistent disease after BCG immunotherapy
should be offered cystectomy
The Netherlands
Who already initial cystectomy

Especially consider immediate cystectomy
in patients with 2 of the following factors:
Tumor multifocality
Size > 3 cm
Associated CIS
Obviously non responders to BCG

3 or 6 months
The Netherlands
Why cystectomy
No RCTs, risk of overtreatment, but.
Frequent understaging
Up to 30% in T1
Up to 50% in high grade T1
Better survival after surgery

QOL: pts seem to accept surgery and the
consequences for better survival
The Netherlands
Why cystectomy
Prognosis in case of progression is bad
The Netherlands
T1 recommendation 4
If a bladder sparing approach is desired, a
secondary TURB should be performed and
followed by intravesical BCG therapy
LOE3, recommendation grade B
The Netherlands
BCG
Some kind of maintenance schedule should
be used
Impact on progression unclear
BCG has more toxicity
The Netherlands
BCG failure
The Netherlands
BCG failure recommendation 1

In any BCG nonresponse or failure
cystecomy is recommended
LOE 2a, recommendation grade A.
The Netherlands
BCG failure recommendation 2

The threat of progression remains real but
comfortably low enough within the first 6
months of beginning BCG to consider
alternatives to cystectomy for those patients
unfit or refusing this standard management
option
The Netherlands
Progression
comfortably low enoughmeans
<5% within 12 months
Usually exceeds 12 months
The Netherlands
Know the different BCG failures

Refractory:
disease free not achieved within 6 mths (persistence,
recurrence, progression)
Resistant:
recurrence of persistence at 3 months, free at 6 months
Relapsing:
disease after 6 months nd after CR
Intolerant:
disease after less than adequate therapy
The Netherlands
BCG failure recommendation 3a

Alternative treatment options
repeat resection and repeat BCG (LOE 1a, Gr.A)
More than 2 cycles BCG seems ineffective
possibly combine with IFN- (LOE 2, grC)

Gemcitabin has shown effectivity, but more
studies are needed (2 recent trials)
Thermo-chemotherapy has shown effectivity, but
more studies are
The Netherlands
BCG failure recommendation 3b

No alternative treatment options
There is no reported evidence of significant

efficacy using
current intravesical chemotherapy

IFN- monotherapy
photodynamic therapy
radiation therapy.
The Netherlands
Q&A
The Netherlands
ICUD-EAU International Consultation on

Bladder Cancer
Committee #6
Muscle-invasive bladder cancer
26th EAU Congress, Vienna, 2011

Eberhard-Karls University Tuebingen
Committee Members
Joaquim Bellmunt
Michael S. Cookson
Georgios Gakis
Khurshid A. Guru
Axel Heidenreich
Seth P. Lerner
Edward M. Messing
David I. Quinn
Mark P. Schoenberg
William U. Shipley
Arlene O. Siefker-Radtke
Arnulf Stenzl (Chair)
Cora Sternberg
Contents
1. OVERVIEW
2. INDICATIONS AND ALGORITHM OF TREATMENT
3. RADICAL CYSTECTOMY
1. Removal of the tumor bearing bladder
1. Timing and delay of cystectomy
2. Technique
3. Lymphadenectomy
4. Laparoscopic and robotic-assisted lap. cystectomy
2. Surgical outcome: morbidity and mortality
3. Oncological outcome of radical surgery according to TNM
staging
4. PERIOPERATIVE CHEMOTHERAPY
1. Neoadjuvant chemotherapy
2. Adjuvant chemotherapy
Contents contd.
5. PERIOPERATIVE RADIOTHERAPY
6. BLADDER-SPARING TREATMENT FOR LOCALISED DISEASE
1. Transurethral monotherapy
3. External beam radiotherapy
4. Multimodality treatment
7. TREATMENT OF MIXED HISTOLOGY UROTHELIAL CARCINOMA
8. FOLLOW-UP
1. Site of recurrence
1. Distant recurrences
2. Follow-up and treatment of secondary ureteral and urethral
tumors
Timing and delay of cystectomy

Minimally invasive techniques including robotic assisted
laparoscopic radical cystectomy have been reported in
increasing numbers. Shortterm outcomes, pathologic findings
and assessments of morbidity compared to the open technique
have been reported. Continued research with these techniques
is required and specifically results of several randomized trials
underway should be reported prior to accepting this as an
equivalent option to open radical cystectomy (Level 2a Grade
C).
Cystectomy is also indicated as palliation for intractable pelvic
pain and bleeding from locally advanced or metastatic bladder
cancer (Level 4 Grade C)
Timing and delay of cystectomy

Delay in cystectomy for muscle-invasive disease is
associated with significantly reduced overall and cancer
specific survival.
(level of evidence: 3, grade of recommendation: B)
Radical cystectomy in patients with muscle-invasive

bladder cancer should be performed within 3 months
after initial diagnosis of stage localized T2 T4 disease.
(level of evidence: 3 grade of recommendation: C)
Treatment of mixed histology urothelial

carcinomas
Nested variant and micropapilary urothelial cancers regardles
of detected in non-muscle invading or muscle-invading stages
should be treated with aggressive local extirpative therapy
(Level of Evidence 3, Grade of recommendation B)
Carcinosarcomas should be treated if possible with local
extirpative surgery
(Level of Evidence 3, Grad of recommendation B)
Urothelial cancer with small cell components should be treated
with neoadjuvant chemotherapy including cisplatin and
etoposide neoadjuvantly followed by aggressive local treatment
(Level of Evidence 3, Grade of recommendation B)
Radical Cystoprostatectomy
apex-sparing
Urethra
Bladder
P
D
Rhabdosphincter
SV
enucleation
Neurovascular bundle
seminal vesicle sparing

LK
Technique
Preservation of the anterior and membranous urethra

including parts of the prostate and seminal vesicles for
reasons of fertility, potency and continence are technical
variations to the nerve-sparing approach which may improve
patients quality of life but must be attentively judged
against possible oncological risks.
(level of evidence 3, Grade C)
Cystectomy in FemalesIndications and extent
Urethra
T2-T4a, N0-NX, M0 B
high-risk pTa-T1
BCG Non-responder
Transurethrally uncontrollable
pTa-disease
Prostate (GR B)
Sphincter
Uterus
Bladder
Vagina
Pelvic Lymphadenectomy
Technique
In female patients standard anterior pelvic exenteration
includes the entire urethra, adjacent vagina, uterus, distal
ureters and respective lymph nodes
(level of evidence: 3, Grade: C)
The urethra + supplying autonomous nerves can be

preserved in case of a planned orthotopic neobladder
(level of evidence: 3, Grade: C)
Oncology
Function
Laparoscopic and robotic-assisted

laparoscopic cystectomy (RALC)
Minimally invasive approach to radical cystectomy has a significant
role in management of locally advanced bladder cancer (level 3,
grade C)
Immediate oncologic results are acceptable and comparable to

open radical cystectomy. Meanwhile long-term oncological data is
still awaited and will define its permanent role in urologic oncology.
(level 2b, grade B)
Laparoscopic and robotic-assisted

laparoscopic cystectomy (RALC) - contd
Centers across the world with expertise in minimally invasive
surgery especially surgical expertise should presently be offering
these options for bladder cancer. (level 3, Grade C)
High-volume centers with dedicated minimally invasive surgical

teams have shown better and safe results. (level 3, Grade B)
Cystectomy:
Short/long costs of BCa/UUT Ca
Hospital/Surgeon Volume vs. costs
Konety et al, J Urol, 2004
Cystectomy:
Hospital/Surgeon Volume vs. Mortality
Hospital volume
Surgeon volume
% Mortality
5
4
3
2
1
0
<3
3-10
11-25
26-50
>50
Cystectomies per year

Barbieri et al, J Urol, 178:1418-22, 2007
Mc Cabe et al, Postgrad Med J, 83:556-60, 2007
Surgical outcome-morbidity and mortality

Surgical complications associated with radical cystectomy and urinary
diversion should be reported in a uniform grading system. The currently
best adapted graded system for cystectomy is the Clavien grading
system (level of evidence: 2, grade of recommendation B).
Surgical complications associated with radical cystectomy and urinary
diversion should include the length of follow-up for the patient cohort,
and a minimum of 30-day but preferable for 90-day reported outcome
(level of evidence 3, grade of recommendation C).
ASA score, age, previous treatment for bladder cancer or other pelvic
diseases, surgeon and hospital volume of radical cystectomy, and type
of urinary diversion influence surgical outcome (level of evidence: 3,
grade of recommendation: C)
Reduction in blood loss and blood transfusion is afforded by meticulous
technique, use of modern surgical devices, and improved understanding
of pelvic anatomy. (level of evidence: 3, grade of recommendation C)
Follow-up and treatment of secondary

ureteral tumours
Ureterorenoscopy with biopsy is the diagnostic procedure of
choice for the diagnosis of a metachronous upper tract
recurrence after RC (Level 3, Grade C).
The use of cytology and urine-based markers, i.e. fluorescence
in-situ hybridization and immunocytology, cannot be
recommended for routine follow-up of the upper tracts so far
since their use has only been evaluated in patients with primary
upper tract cancers (Level 3, Grade B).
Routine upper tract imaging is only indicated in patients with
clinical symptoms suspicious of a metachronous upper tract
recurrence (Level 3, Grade B).

ureteral and urethral tumours
Nephroureterectomy is the treatment of choice for

invasive upper tract recurrence providing prolonged
survival.
(Level 3, Grade B)
A regional lymphadenectomy in patients undergoing

radical nephroureterectomy is only of diagnostic value.
(Level 3, Grade C).
Spare for discussion only
Oncological outcome according to TNM

staging
The AJCC substratifications in node-negative pT2 and pT3
bladder cancer are of prognostic value (Level 3, Grade B)
Nomograms provide improved prognostic information
oncological outcomes after radical surgery as compared to
pTNM staged predictions. However, its general applicability
not been established sufficiently by external validation so
(Level 3, Grade B)
for
the
has
far
In patients older than 80 years, radical cystectomy is associated

highest risk reduction on cancer-related and non-cancer related
mortality (Level 3, Grade B).
Oncological outcome
Radical cystectomy is the mainstay of treatment in muscleinvasive bladder cancer providing long-term survival
(Level 2b, Grade B).
The AJCC substratifications in node-negative pT2 and pT3
bladder cancer are of prognostic value (Level 2b, Grade B)
In patients older than 80 years, radical cystectomy is associated
highest risk reduction on cancer-related and non-cancer related
mortality (Level 3, Grade B).
Based on the scarce data available the routine use of molecular
markers for primary risk assessment in invasive bladder cannot
be recommended so far (Level 3, Grade B).

ureteral tumours
Surveillance regimens should be based on a risk-adapted strategy
(Level 3, Grade C).
The number of risk factors potentiates the risk of recurrence: (a)
positive ureteral margin (b) carcinoma in situ of the bladder and
ureter, (c) tumor multifocality, (d) urethral tumor involvement
and (e) male gender (Level 3, Grade B).
Patients with finally positive ureteral margins at surgery are at
increased risk of ureteral recurrence. Frozen section analysis has
a high sensitivity and specificity for the detection of malignant
ureteral margins (Level 2b, Grade B).

urethral tumours
Risk factors for urethral recurrence in male patients are
prostatic tumor involvement (either superficial or invasive) and
bladder neck involvement in female patients (Level 3, Grade B).
Intraoperative frozen section analysis has a high sensitivity and
specificity for the detection of a malignant urethral margin for
both male and female patients (Level 2b, Grade B).
Patient with positive final urethral margins are at increased risk
of urethral recurrence (Level 3, Grade B).
Prophylactic urethrectomy is not justifiable in patients with
carcinoma in situ at the urethral margin (Level 3, Grade C).

urethral tumours
The use of urinary cytology, urethral washings and diagnostic
urethroscopy for follow-up has not proven to provide a survival
benefit (Level 3, Grade B).
Urethrectomy should be considered in patients with invasive
carcinoma at the urethral margin at radical cystectomy or in
case of invasive urethral recurrence (Level 3, Grade B).
Local conservative treatment is an option in patients with noninvasive tumor(s) or carcinoma in situ of the urethra (Level 3,
Grade C).
In patients with urethral recurrence and concomitant distant
recurrence outside the urinary tract systemic chemotherapy is
indicated (Level 3, Grade C).
ICUDEAU GUIDELINES ON BLADDER CANCER
Committee 7: Urinary diversion

Richard E. Hautmann, Hassan Abol-Enein,
Thomas Davidsson,
Sigurdur Gudjonsson
Stefan H. Hautmann
Henriette V. Holm
Cheryl T. Lee
Fredrik Liedberg
Stephan Madersbacher Wiking Mansson
Murugesan Manoharan Robert D. Mills
David F. Penson
Eila C. Skinner
Raimund Stein
Urs E. Studer
Joachim W. Thueroff
William H. Turner
Bjoern G. Volkmer
ICUD-EAU GUIDELINES BLADDER CANCER
RCX AND URINARY DIVERSION

Highest relative value
in terms of difficulty of the surgery for
any procedure in urology
They are also the most difficult laparoscopic or robotic
procedures and more so if the diversion is performed
totally intracorporeally.
Risk of procedure is based
not only on the technical challenges
but also on the nature of the patients needing.
RCX AND URINARY DIVERSION (UD)

ARE 2 STEPS OF ONE OPERATION
Literature uniformly reports the
complications of RCX
While ignoring that the majority of
complications are diversion related (75%)!
This may seem sematic, but it is not
Hautmann, J Urol 2010
ICUD-EAU GUIDELINES ON BLADDER CANCER
COMMON MEASURES
FOR SURGICAL OUTCOMES OF RCX AND UD
Estimated blood loss

Operative time
Analgesic use
LOS
Time to return to work
Perioperative death
Complication rates
Hospital costs
FEW STUDIES ON RCX AND UD

REPORT ON
Readmission rates
Reoperation rates
Intensive care stays
Additional interventional radiologic
procedures
DONAT, UROLOGY, 2007
ICUDEAU GUIDELINESS ON BLADDER CANCER
THE MAJORITY OF RCX SERIES ON MORBIDITY HAD:
NOT defined complications

NOT utilized a grading system other
than categorizing into
major versus minor
NOT accounted for comorbidities
NOT employed a formal complication
reporting system
Shabsigh EUR Urol 2009
CONCLUSIONS
The lack of consistency in the method used to
accrue, define, and report complication data
makes it impossible to compare morbidity rates
among different surgical techniques, surgeons
or institutions
Improved surgical outcome reporting
(f.i. Clavien system) will allow more meaningful
comparisons when randomized trials are sparse
and f.i. for comparison between open and
minimaly invasive techniques
DONAT, UROLOGY, 2007
ICUD-EAU GUIDELINES OF BLADDER CANCER
EVIDENCE AND URINARY DIVERSION
Not a single randomized study *

Almost all studies used in this report are of
Level 3 or Level 4 evidence including
expert opinion based on first principles
research
The grades of recommendations given are
mostly of Grade C
* except studies on ureteroileostomy
Table 1: Numbers and Types of Urinary Diversions (%) performed by the Authors
No
diversion/
Anal unknown others
No. RCX
Period
Neobladder
Cont.Cut.
Conduit
UC
TUUC
643
95-04
45.1
1.4
53.5
962
00-09
40.0
2.0
58.0
0.9
611
85-99
51.5
1.5
42.5
1.6
2.5
0.4
708
00-10
51.0
8.0
39.0
1.5
0.5
0.1
765
94-10
30.2
6.8
60.5
0.7
2.0
0.1
1359
71-01
51.6
25.8
22.3
0.3
1012
00-10
74.2
5.3
20.2
0.3
119
00-04
28.6
31.1
40.3
134
04-09
6.0
30.6
63.4
335
68-80
55.0
45
593
81-90
2.0
33
41.0
15
982
91-00
6.0
39
41.0
12
1023
01-10
15.0
24
53.0
Mansoura
3157
80-04
39.1
3.5
34.4
23.1
Norwich
246
02-09
10.6
89.4
158
1997
19.0
19
55.0
221
2003
17.0
12
70.0
208
2006
9.0
80.0
229
2008
15.0
81.0
Ulm
1613
86-09
66.0
0.4
22.0
10.0
1.3
0.2
Vanderbilt
789
00-07
35.5
0.4
63.5
0.1
0.5
Total
15867
38.0
10.4
42.2
1.2
7.5
0.1
0.8
Ann Arbor
Bern
Kassel
Los Angeles
Lund
Mainz
Swedish
Registry
No. RCX
Period
643
95-04
45.1
1.4
53.5
962
00-09
40.0
2.0
58.0
0.9
611
85-99
51.5
1.5
42.5
1.6
2.5
0.4
708
00-10
51.0
8.0
39.0
1.5
0.5
0.1
765
94-10
30.2
6.8
60.5
0.7
2.0
0.1
1359
71-01
51.6
25.8
22.3
0.3
1012
00-10
74.2
5.3
20.2
0.3
119
00-04
28.6
31.1
40.3
134
04-09
6.0
30.6
63.4
335
68-80
55.0
45
593
81-90
2.0
33
41.0
15
982
91-00
6.0
39
41.0
12
1023
01-10
15.0
24
53.0
Mansoura
3157
80-04
39.1
3.5
34.4
23.1
Norwich
246
02-09
10.6
89.4
158
1997
19.0
19
55.0
221
2003
17.0
12
70.0
208
2006
9.0
80.0
229
2008
15.0
81.0
Ulm
1613
86-09
66.0
0.4
22.0
10.0
1.3
0.2
Vanderbilt
789
00-07
35.5
0.4
63.5
0.1
0.5
Total
15867
38.0
10.4
42.2
1.2
7.5
0.1
0.8
Ann Arbor
Bern
Kassel
Los Angeles
Lund
Mainz
Swedish
Registry
Cont.Cut.
Conduit
UC
TUUC
No
diversion/
Anal unknown others
Neobladder
others
Period
643
95-04
45.1
1.4
53.5
962
00-09
40.0
2.0
58.0
0.9
611
85-99
51.5
1.5
42.5
1.6
2.5
0.4
708
00-10
51.0
8.0
39.0
1.5
0.5
0.1
765
94-10
30.2
6.8
60.5
0.7
2.0
0.1
1359
71-01
51.6
25.8
22.3
0.3
1012
00-10
74.2
5.3
20.2
0.3
119
00-04
28.6
31.1
40.3
134
04-09
6.0
30.6
63.4
335
68-80
55.0
45
593
81-90
2.0
33
41.0
15
982
91-00
6.0
39
41.0
12
1023
01-10
15.0
24
53.0
Mansoura
3157
80-04
39.1
3.5
34.4
23.1
Norwich
246
02-09
10.6
89.4
158
1997
19.0
19
55.0
221
2003
17.0
12
70.0
208
2006
9.0
80.0
229
2008
15.0
81.0
Ulm
1613
86-09
66.0
0.4
22.0
10.0
1.3
0.2
Vanderbilt
789
00-07
35.5
0.4
63.5
0.1
0.5
Total
15867
38.0
10.4
42.2
1.2
7.5
0.1
0.8
Ann Arbor
Bern
Kassel
Los Angeles
Lund
Mainz
Swedish
Registry
Conduit
Anal
No. RCX
Cont.Cut.
UC
TUUC
No
diversion/
unknown
Neobladder
No. RCX
Period
643
95-04
45.1
1.4
53.5
962
00-09
40.0
2.0
58.0
0.9
611
85-99
51.5
1.5
42.5
1.6
2.5
0.4
708
00-10
51.0
8.0
39.0
1.5
0.5
0.1
765
94-10
30.2
6.8
60.5
0.7
2.0
0.1
1359
71-01
51.6
25.8
22.3
0.3
1012
00-10
74.2
5.3
20.2
0.3
119
00-04
28.6
31.1
40.3
134
04-09
6.0
30.6
63.4
335
68-80
55.0
45
593
81-90
2.0
33
41.0
15
982
91-00
6.0
39
41.0
12
1023
01-10
15.0
24
53.0
Mansoura
3157
80-04
39.1
3.5
34.4
23.1
Norwich
246
02-09
10.6
89.4
158
1997
19.0
19
55.0
221
2003
17.0
12
70.0
208
2006
9.0
80.0
229
2008
15.0
81.0
Ulm
1613
86-09
66.0
0.4
22.0
10.0
1.3
0.2
Vanderbilt
789
00-07
35.5
0.4
63.5
0.1
0.5
Total
15867
38.0
10.4
42.2
1.2
7.5
0.1
0.8
Ann Arbor
Bern
Kassel
Los Angeles
Lund
Mainz
Swedish
Registry
Cont.Cut.
Conduit
UC
TUUC
No
diversion/
Anal unknown others
Neobladder
Ann Arbor
No. RCX Period

643
95-04
962
00-09
Neobladder
45.1
40.0
Cont.Cut. Conduit
1.4
53.5
2.0
58.0
UC
TUUC
-
No
diversion
/
Anal unknown others
0.9
-
611
85-99
51.5
1.5
42.5
1.6
2.5
0.4
708
00-10
51.0
8.0
39.0
1.5
0.5
0.1
765
94-10
30.2
6.8
60.5
0.7
2.0
0.1
1359
71-01
51.6
25.8
22.3
0.3
1012
00-10
74.2
5.3
20.2
0.3
119
00-04
28.6
31.1
40.3
134
04-09
6.0
30.6
63.4
335
68-80
55.0
45
593
81-90
2.0
33
41.0
15
982
91-00
6.0
39
41.0
12
1023
01-10
15.0
24
53.0
Mansoura
3157
80-04
39.1
3.5
34.4
23.1
Norwich
246
02-09
10.6
89.4
158
1997
19.0
19
55.0
221
2003
17.0
12
70.0
208
2006
9.0
80.0
229
2008
15.0
81.0
Ulm
1613
86-09
66.0
0.4
22.0
10.0
1.3
0.2
Vanderbilt
789
00-07
35.5
0.4
63.5
0.1
0.5
Total
15867
38.0
10.4
42.2
1.2
7.5
0.1
0.8
Bern
Kassel
Los Angeles
Lund
Mainz
Swedish
Registry
others
Period
643
95-04
45.1
1.4
53.5
962
00-09
40.0
2.0
58.0
0.9
611
85-99
51.5
1.5
42.5
1.6
2.5
0.4
708
00-10
51.0
8.0
39.0
1.5
0.5
0.1
765
94-10
30.2
6.8
60.5
0.7
2.0
0.1
1359
71-01
51.6
25.8
22.3
0.3
1012
00-10
74.2
5.3
20.2
0.3
119
00-04
28.6
31.1
40.3
134
04-09
6.0
30.6
63.4
335
68-80
55.0
45
593
81-90
2.0
33
41.0
15
982
91-00
6.0
39
41.0
12
1023
01-10
15.0
24
53.0
Mansoura
3157
80-04
39.1
3.5
34.4
23.1
Norwich
246
02-09
10.6
89.4
158
1997
19.0
19
55.0
221
2003
17.0
12
70.0
208
2006
9.0
80.0
229
2008
15.0
81.0
Ulm
1613
86-09
66.0
0.4
22.0
10.0
1.3
0.2
Vanderbilt
789
00-07
35.5
0.4
63.5
0.1
0.5
Total
15867
Ann Arbor
Bern
Kassel
Los Angeles
Lund
Mainz
Swedish
Registry
Conduit
Anal
No. RCX
Cont.Cut.
UC
TUUC
No
diversion/
unknown
Neobladder
38.0 10.4 42.2
1.2 7.5 0.1
0.8
UD AND RENAL FUNCTION
Age related GFR decline: 1 ml /min/year age 50

Serum creatinine remains normal until GFR < 50 %
Ideal: Isotopic GFR (51Cr-EDTA)
Cut off for continent diversion:
Serum creatinine
> 150 mol/l
GFR
< 50 %
Upper tract dilatation:
Does not equate to
reduction of renal function
Preexisting renal pathology: Greatest risk of postop
renal deterioration
Urinary diversion into bowel segments
is not inherently damaging to the kidneys
Table 2: Secondary tumours after diversion using isolated gut

segments
Ileum
Colon
Ileocecal
Stomach
Total no.
15+1*
22
Continent Cutaneous
14**
14
Neobladder
Rectal bladder
Cystoplasty
41
15
10
68
Total
60
42
10
114
Conduit
From publications by Austen and Klble (15,16), since 2004, and four Lund cases.
This case was transfered from continent cutaneous diversion using colonic segment.
** Includes 2 Lund cases (described in this paper) but excludes a case (17) from
Austen and Klble, that is now transferred to the ileal conduit group.
Mansson 2011
Table 3: Secondary Tumors in 17,758 Urinary Diversions

no.
secondary
tumors
no.
diversions
median
latency period
(years)
mean time:
operation to analysis
(years)
Neobladder Ileal
4190
(0,05 %)
3,0
6,3
Neobladder Ileocecal
239
(1,26 %)
4,0
13,6
Neobladder Colonic
70
(1,43 %)
6,0
9,9
Pouch Ileocecal
2181
(0,18 %)
12,0
8,8
Ileocystoplasty
233
(1,71 %)
21,5
10,5
Colocystoplasty
20
Conduit Ileal
8637
(0,02 %)
11,0
8,9
Conduit Colon
430
(0,23%)
40,0
24,4
Ureterocutaneostomy
1138
16
620
Total
4,9
10,3
(2,58 %)
32 17,758
26,0
18,9
Klble 2011
Table 4: Tumor Risk in Continent and Incontinent Diversion
Ileum
Conduit
(ileo-)colon
0,02%
0,23%
p = 0.84
Pouch/Neobladder
Total
0,03%
p = 0.0091
0,05%
0,03%
total
p = 0.00001
0,28%
0,13%
0,27%
0,08%
p < 0.0001
Cystoplasty
1,71%
0,00%
1,58%
p = 0.46
2,58%
Klble 2011
SECONDARY TUMORS AFTER DU

CONCLUSIONS
Ureterosigmoidostomy, cystoplasty and
probably (ileo)colonic OBS bear a
significantly increased tumor risk and
require regular endoscopic evaluation
beginning at the 5th postop year
After OBS and conduits regular endoscopy is
not mandatory
In ileocecal pouches, it is recommended in
the presence of symptoms such as
hydronephrosis, chronic urinary infection,
and hematuria
IDUC-EAU GUIDELINES ON BLADDER CANCER
ORTHOTOPIC BLADDER SUBSTITUTION

IN MEN (OBS)
INDICATION AND TUMOR STAGE

Extent of pelvic disease
little bearing on appropriateness
Pelvic recurrence
no impact on OBS function
LN + patients
achieve good functional results
HAUTMANN, J UROL, 1999
OBS INDICATION AND TUMOR STAGE
NO CONSENSUS
PREOPERATIVE DISTAL PROSTATIC
BIOPSIES
Paraffin-embedded biopsies more reliable
Discuss result with patient before surgery
FROZEN SECTION OF THE RESECTION

MARGIN AT THE TIME OF SURGERY
FUNCTION PRESERVING CANCER SURGERY
OBS WITH NERVE SPARING RCX
If tumor characteristics permit

Chance of maintaining erectile function
Preserved urethral sensation
Improved resting pressure
Better night time continence
KESSLER, J UROL, 2004

HUGONNET, J UROL, 2001
OBS - AGE AND MOTIVATION

No age cut off for OBS
In practice: Many patients > 70 years will opt
for a simpler conduit as the postoperative
course is less arduous and incontince is less
likely
Motivation of the patient is the most
important factor when considering suitability
for an OBS, although it is difficult to assess
this objectively
Patients must be prepared to commit to the
long term follow up program necessary
OBS - UPPER TRACT PRESERVATION

Voding with OBS cannot produce reflux
Antireflux nipple worse
than isoperistaltic tubular segment
2 RANDOMIZED SURGICAL TRIALS !
Low anastomotic stricture rate (<2,7 %)
Stented uretero-ileal anastomosis improves outcomes
WAIDELICH
STUDER
STUDER
SHAABAN
BJU
J.UROL
J.UROL
BJU
1998
2006
1996
2006
ICUD-EAU GUIDELINES O BLADDER CANCER
OBS POSTOPERATIVE MANAGEMENT

OF PARAMOUNT IMPORTANCE:
Active postoperative management

and regular long term follow-up
Key issue is achieving a capacity of 400-500 ml
Residual free voiding of sterile urine
Treatment of any outlet obstruction
THURAIRAJA BJU 2008
OBS IN FEMALES
PATIENT SELECTION: ONCOLOGIC FACTORS
It is reasonable to advise against OBS for invasive
bladder neck involvement or suspected invasion of
the vaginal wall or cervix
Such patients may be considered for OBS if
intraoperative frozen section of the urethral margin
is negative
Overall 60-70% of women are resonable candidates
for OBS.
STEIN, UROLOGY 1998
OBS IN FEMALES:
ANATOMIC BASIS OF THE PRESERVATION OF CONTINENCE
Prior to the 1990s the primary continence mechanism

was located in the bladder neck itself
The urethra alone could provide continence if the
sphincter mechanism was carefully preserved
The primary rhabdosphincter is an OMEGA shaped
structure surrounding the distal third of the urethra
The main nerves supplying this sphincter are the
somatic pudendal nerves which run under the
endopelvic fascia. The autonomic nerves coursing
through the pelvic plexus and along the lateral vagina
supply the smooth muscle of the bladder neck and
urethra
THANAGHO
HBNER
BJU
1966
BHATTA
EUR.UROL 2007
EUR.UROL 1993 COLLESELLI J UROL
1998
OBS IN FEMALES SURGICAL BASIS OF NERVE SPARING

NO CONSENSUS
NERVE SPARERS:
Avoiding dissection below the endopelvic fascia surrounding the
urethra helps insure that this muscle and its nerve supply are not
disturbed
Nerve sparing aproach is crucial to maintaining urethral tone
and may decrease the risk of retention due to spasticity of the
denervated urethra
MECHANICS:
Routine dissection of presacral tissue as part of the node
dissection without clear reduction of continence
To date no randomized comparison of these two techniques has
been performed
STENZL
TURNER
ALI-EL-DEIN
STEIN
J.UROL 1995
J.UROL 1997
J.UROL 2002
J.UROL 1997
TABLE 9: Continence In Reported Series Limited to Females

(78, 79, 102, 105 - 109 )
# pts
Author
Hautmann
Follow-up
Daytime
Nighttime
(mos -mean)
Continence
%
Continence
%
Self
Catheterize
%
(1996)
(2000)
(2006)
116
60
83
83
50%
Granberg
(2008)
59
29
90
57
35
Nesrallah
(2005)
29
37
97
86
10
Ali-el-Dein
(2008)
192
51
92
72
16
Stenzl
(2001)
83
26
82
72
11
Stein
(2002)
81
78
78
N/A
33
Stein
(2009)#
56
103
87
66
61
# Anonymous validated questionnaire
CONTINENT CUTANEOUS DIVERSION (CCD)
Second choice after OBS

Indications in 2011
Simultaneous urethrecomy
TCC lower urinary tract
TCC prostatic ducts (?)
Patient preference
Risk of leakage after OBS
Patient refuses labor intensive rehabilitation
Pediatric age group
CCD PRINCIPAL DISADVANTAGES

No leak point (pop off)
Need for antireflux mechanism
NO CONSENSUS
Pouch pioneers
+
Pediatric urologists +
Risk of complications
CCD
Rupture
10 %
Stone formation
10-20 %
Bacterial colonization
100 %
>
OBS
<1%
<1%
15%
CCD - OUTLET
Nipples abandoned
Appendix: Ready made
Availability, suitability
Stomal stenosis (1020%)
Tapered/plicated/stapled ileum: Simplicity
Serous lined extramural valve (T-pouch)
Sophisticated
No general acceptance
CONDUIT
AND URETEROSIGMOIDOSTOMY
No / very little new information

Lack of hard data
No standarized reporting
Recent efforts to overcome this dilemma
Table 6: Diversion specific (not RCX) long term complications *

using non-/ standardized reporting
Conduit
Bern
f.u. median
(years):
patients
Neobladder
Mayo
Ulm
8.1
6.3
6.0
(n=)
131.0
1,057.0
923.0
complications
(n=)
192.0
1453.0
---
patients with
(n=):
87/131.0
643/1,057.0
patients with
(%):
66.0
61.0
within years:
5:
45
50
10:
50
68
15:
54
70
20:
94
80
Reoperation rate
(%):
40%
376/923.0
40.8
6%
Complications
(pts/%):
bowel
32
(24%)
UTI
30
(23%)
stoma
32
(24%)
anastomosis
18
(14%)
12
(9%)
35
(27%)
urolithiasis
renal function
*Bern :
Mayo:
Ulm:
> complications 3 months ; > 5 years follow up

215
(20.3%)
31
(3.4%)
(16.5%)
46
(5.0%)
163
(15.2%)
122
(11.5%)
102
(11.5%)
(15.3%)
(0.2%)
(20.2%)
174
162
213
Madersbacher J.Urol. 2003

Shimko
J.Urol. 2011
Hautmann
J.Urol. 2011
Table 6: Diversion specific (not RCX) long term complications *

using non-/ standardized reporting
Conduit
Bern
f.u. median
(years):
patients
Neobladder
Mayo
Ulm
8.1
6.3
6.0
(n=)
131.0
1,057.0
923.0
complications
(n=)
192.0
1453.0
---
patients with
(n=):
87/131.0
643/1,057.0
patients with
(%):
66.0
61.0
within years:
5:
45
50
10:
50
68
15:
54
70
20:
94
80
Reoperation rate
(%):
40%
376/923.0
40.8
6%
Complications
(pts/%):
bowel
32
(24%)
215
(20.3%)
31
(3.4%)
UTI
30
(23%)
174
(16.5%)
46
(5.0%)
stoma
32
(24%)
163
(15.2%)
18
(14%)
(11.5%)
102
(11.5%)
urolithiasis
12
(9%)
162
(15.3%)
(0.2%)
renal function
35
(27%)
213
(20.2%)
anastomosis
*Bern :
Mayo:
Ulm:
> complications 3 months ; > 5 years follow up

122
Madersbacher J.Urol. 2003

Shimko
J.Urol. 2011
Hautmann
J.Urol. 2011
CONDUIT - CONCLUSION
Remains the most commonly used diversion in
conjunction with RCX
Technically easier than continent reconstruction
Complications, early as well as late, are legion
Incidence of upper tract complications increasing
with length of follow up
Comparisons with other techniques are difficult as
surgical techniques have improved markedly over
the last 25 years
Few series report comparable long-term outcomes
(>20 years) in patients with neobladders
PEDIATRIC DIVERSION: INDICATIONS

Neurogenic bladder
Functional or anatomical loss of the lower
urinary tract
Failure of primary reconstruction of the
lower urinary tract (bladder exstrophy)
Radical surgery for malignancies
PEDIATRIC DIVERSION GOALS
Urine storage at low pressures in

an adequate capacity reservoir for
preservation of the upper tract
Achieving urinary continence
URINARY DIVERSION IN THE PEDIATRIC AGE GROUP

SPECIAL CONSIDERATIONS
Options for continent diversion in patients

with and without neurogenic deficits:
Augmentation and CCD
Anal diversion should be offered only to
patients with competent anal sphincters
Preferred solution for incontinent
diversion: colonic conduit
Table 7: Diversion specific long term complications (> 3 month

post-op) at 10 years in 923 neobladder pts operated
between 1986-2008 using the Kaplan-Meier method
Uretero-ileal stenosis
refluxive anastomosis (Wallace)
non refluxive
(Le Duc)
13,80 %
6,40 %
17,00 %
Urinary retention (female)
42,20 %
Subneovesical obstruction in men

(correctable)
8,20 %
Functional obstruction in men (CIC)
5,10 %
Incisional hernia
(41 in 923 pts = 4,4 %)
6,40 %
Hautmann, JUrol 2011
Table 5: Neobladder specific complications within 90 d of surgery

by category in 1013 patients (modified CLAVIEN)
category
no complication
infection
777 (76,7%)
abscess
988
UTI
837
Sepsis
978
GU complications
843 (83,2%)
renal failure
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
38
146
35
12
20
38
complications
Total
236 (23,3%)
25
176
138
6
15
12
35
100
64
170 (16,8%)
995
11
18
ureteral obstruction
965
16
31
48
urinary leak
948
44
21
65
urinary fistula
1002
11
urinary retention
985
23
28
miscellaneous
918 (90,6%)
metabol. Acidosis
despite TX
1007
incisional hernia
1010
Grade 1:oral medications

Grade 2: intravenous medications
Grade 3: interventional radiology or operation
Grade 4: lasting disability or organ resection
Grade: 5: death
95 (9,4%)
6
3
Hautmann JUrol.2010
COMPLICATIONS OF UD
Conclusions:
Surgical morbidity following UD is significant and,
when strict reporting guidelines are incorporated,
higher than previously published
Accurate reporting of postoperative
complications after RCX is essential for:
counseling patients
combined modality treatment planning
clinical trial design
assessment of surgical success
COMMITTEE 7
FINAL RECOMMENDATION FOR RCX AND UD
Centralisation / regionalization
High volume surgeons / hospitals
Annual case load of 25 procedures
Not more than 2 surgeons
PROSTATE INVOLVEMENT BY UROTHELIAL CELL

CARCINOMA
Joan Palou (Chair)

David Wood (co-chair)
Bernie Bochner
Henk van der Poel
H. Al-Ahmadie
Ofer yossepowitch
UROTHELIAL CELL CARCINOMA AND CARCINOMA

IN SITU OF THE PROSTATIC URETHRA
INCIDENCE
Primary bladder tumours: from 0.5 to 28 %
Depending on the population screened.

Palou et al, Urology 1995
The incidence of prostatic UCC in patients with superficial or invasive

bladder cancer oscillates between 12 and 48%, and between 7.6 and
16.6% of stromal invasion.
UROTHELIAL
CELL
CARCINOMA
IN SITU OF THE PROSTATIC URETHRA
AND
CARCINOMA
INCIDENCE
CIS
First described by Melicow in 1952
Rarely present as an isolated lesion

In a series of 1529 pats. with NMIBC it was 19 % bladder CIS and
2.7% CIS in PU (Millan et al, J Urol 2000)
It may be detected from 15 to 40 % in the followup of High grade
NMIBC (Herr HW et al J Urol 1999; Davis JW et al, J Urol 2002)
PAPILLARY UROTHELIAL CELL CARCINOMA

OF THE PROSTATIC URETHRA
INCIDENCE
Papillary lesions
Primary papillary lesions occur from 1-4 %

Bates HR,Jr, J Urol 1969
Multiplicity as a risk factor
Mungan MU et al, Eur Urol 2005
INCIDENCE OF PROSTATIC UC IN CYSTECTOMY SPECIMENS
Publication
Year
Patients
TCC in prostate (%)
J Urol
1977
300
12
Coutts et al
Brit J Urol
1985
43
36
Wood et al
J Urol
1989
84
23
Reese et al
J Urol
1992
115
29
Pagano et al
J Urol
1996
570
13
Esrig et al
J Urol
1996
489
29,2
Herr et al
J Urol
1999
186
39
Ngninkeu et al
J Urol
2003
283
27
Revelo et al
J Urol
2004
121
48
Nixon et al
J Urol
2002
192
15,6
Author
Schellhammer et al
STROMAL INVASION BY UROTHELIAL CELL CARCINOMA
INCIDENCE
Stromal invasion
Is present in 37-64 % of men with prostate involvement at

cystoprostatectomy
The differences of incidence between the different studies are
related to a careful pathologic assessment (whole mount section)

There is an increase risk of nodal metastases
Pagano et al, J Urol 1996
HISTOPATHOLOGY AND SURVIVAL

Stromal invasion
Stage
Patients (%)
Survival (%)
Contiguous
44 (61)
Not contiguous
28 (39)
46
Urethral mucosa
100
Acinal/ductal
14
50
Stromal
40
Extracapsular invasion
Donat et al, et al, J Urol 2000
STAGING OF UCC OF THE PU
Stage 1
Tumour confined to the

prostatic urothelium
Stage 2
Duct and acini invasion,

but confined to the basal
membrane
Stage 3
Stromal invasion
Hardeman and Soloway, Worl J Urol 1988
CLASSIFICATION OF THE UCC OF THE PU
TNM BLADDER: Pt4a (Stromal invasion)

TNM PROSTATIC URETHRA:
Tis pu CIS, affecting the prostatic urethra

Tis pd CIS, affecting the prostatic ducts
T1
Tumour invading the connective subepithelial tissue
T2
Tumour invading the prostatic stroma, the corpus spongiosum
or
the periurethral muscle
T3
Tumour invading the prostatic capsule of the corpus
cavernosum or the bladder neck (extraprostatic extension)

T4
Tumour invading the neighbouring organs
ANATOMICAL AND HISTOPATHOLOGICAL HISTORY

RECOMMENDATION
TNM : pT4a only in cases of stromal invasion.

For the rest, the stage of the bladder tumour and of the PU
should be indicated using suffix Tis pu or Tis pd, meaning extension
towards prostatic urethra or towards prostatic ducts.
Extravesical invasion of the seminal vesicles is a sign of locally

advanced disease.
Volkmer et al, J Urol 2003
Daneshmand et al, J Urol 2004
DIAGNOSIS OF UCC OF THE PU
Macroscopic evidence of superficial bladder cancer of the prostatic

urethra is highly specific.
Nixon et al, J Urol 2002
CONSIDERATIONS:
Correct sampling of the PU: extensive TUR not feasible in all the
patients
Biopsy with the resectoscope loop from the lateral lobes distal to the
bladder neck until the verum montanum
In any suspicious lesion and recurrent high grade or bladder CIS
DIAGNOSIS OF UCC OF THE PU
Prostatic sampling plays an important role in the management of the

urothelial cell cancer
Prostatic involvement may become a predictor of understaging in BCG

failure in NMIBC.
Huguet et al, Eur Urol
2005
Eur Urol 2006
Huguet et al, Eur Urol 2006
Huguet et al, Eur Urol 2006
TREATMENT OF CIS OF THE PU (TIS PU)
BCG
Palou J, et al: Urology, 47: 482, 1996
Hillyard RW, et al: J Urol, 139: 290, 1988
BCG PENETRATION IN THE PU
Granulomas in the prostate up to 40 % after intravesical BCG

Mukamel et al, J Urol 1990
Increase of PSA after BCGin 41.6 % of the patients

Leibobici et al, J Urol 2000
Higher increase of PSA in BCG treated patients after TUR of the

prostate.
Palou et al, BJU Int 2000
EFFECT OF BCG ON PSA SERUM LEVELS
mo
TURp:
Yes
No
mos
Palou et al, BJU 2000
TREATMENT
MESSAGE:
High- and low-grade non-invasive UCC or CIS of the prostate should be
treated with endovesical BCG.
The TUR seems to improve BCG contact with the PU.
It seems that TUR improves efficacy of BCG endovesical treatment.
SUPERFICIAL UCC OF THE PROSTATE

(mucosa involvement)
LOW GRADE
HIGH GRADE or CIS
BCG
BCG
No recurrence
Recurrence
LOW GRADE
2nd COURSE
OF BCG
No recurrence
HIGH GRADE
or
CIS
Progression
Recurrence
CYSTOPROSTATECTOMY
Consider
TREATMENT OF CIS OF THE PROSTATIC URETHRA,

WITH PROSTATIC DUCT INVOLVEMENT (TIS PD)
BCG ?
TREATMENT OF CIS OF THE PU

WITH PROSTATIC DUCT INVOLVEMENT (TIS PD)
Soloway MS, et al. : J Urol, 167: 1573, 2002

Hardeman SW, et al. : World J Urol, 6: 170, 1988
TREATMENT PROSTATIC DUCTS
Palou et al, Urology 2007
Palou et al, Eur Urol 2006
RESULTS
BCG is a feasible therapeutic option for this kind of patients with TCC
affecting the prostatic ducts.
In this trial:
73% of the patients had bladder preservation
Only one death by tumour was observed
It is obvious that these patients need to be strictly followed with cystoscopy

and cytology to detect any recurrences and/or progression.
Palou et al, Eur Urol 2006
SUPERFICIAL UCC OF THE PROSTATE

Duct involvement
TUR + BCG
Re-TUR at 3 mos
NO TUMOUR
FOLLOW-UP
CYSTOPROSTATECTOMY
TUMOUR
PROSTATIC URETHRA FOLLOW-UP
Patients
Prostatic urethra
tumour
Follow-up
Herr and Donat,

1999
186
39 %
62 % not invasive
38 % stromal inv.
15 years
Hardeman et al.
1988
63
16 %
43 months
Solsona et al.
1991
276
13.3 %
34.3 months
Tumour incidence in the prostatic urethra when following-up superficial bladder

carcinoma.
TREATMENT: TIS IN PU AFTER BCG TREATMENT
Mean age: 72 years (63-82)

Mean follow up: 47 months (12-84)
PROSTATIC URETHRA FOLLOW-UP

Secondary tumours: In high-risk superficial bladder cancer it occurs in
some 10-15% at 5 years and some 20-40 % at 15 ys.
Herr et al, J Urol 1999
RECOMMENDATION
In patients with high-risk superficial bladder UCC and/or CIS, particularly
with bladder neck involvement and multifocality, the prostatic urethra

should be monitored.
Be careful with understaging
RECOMMEDATIONS
1. Macroscopic evidence of superficial bladder cancer in the prostatic urethra is
highly specific.
TUR of any macroscopic or suspicious lesion is required
Once a
non-muscle invasive high-grade tumor or CIS, careful follow-up of the prostatic
urethra is mandatory
(grade C).
2. High- and low-grade non-invasive urothelial carcinoma and CIS of the prostate
should be treated with intravesical BCG (grade C).
3. Evidence (level 3) shows that TUR may improve contact of BCG with the
prostatic urethra and it looks that response rates to BCG are increased (grade C).
RECOMMEDATIONS
4. CIS or tumor in the prostatic ducts warrants further study. It is advisable for the
clinician to perform radical surgery if there is any doubt, to avoid understaging
(grade C).
5. Patients with non-invasive urothelial carcinoma in whom conservative therapy
fails should be considered for cystoprostatectomy (grade C).
6. Patients with intermediate- to high-risk superficial urothelial carcinoma of the
bladder or CIS, especially with involvement of the bladder neck and multifocality,
require monitoring of the prostatic urethra (grade B or C).
PROSTATIC STROMAL INVASION

DIAGNOSIS
Transurethral biopsies of the prostatic urethra have shown to be efficacious for

identifying prostatic involvement, but they do not reliably determine the extension of
such involvement, particularly regarding stromal invasion.

53 % sensitivity and 77 % specificity in the diagnosis of stromal invasion.
New methods are necessary to detect prostatic stromal invasion.
Wood et al, J Urol 1989
Donat et al, J Urol 2001
PROSTATIC STROMAL INVASION

PREDICTIVE FACTORS
CIS at the trigone

Tumor multifocaclity
Location of the tumour at or below the trigone (or at the bladder neck)
Lymphovascular invasion
Pettus et al, Eur urol 2008
Richards et al, Urology 2010

Arce et al, Canad J urol 2011
TREATMENT
ROLE OF CYSTECTOMY
RECOMMENDATION
Grade C
Radical cystoprostatectomy with lymphadenectomy, with or without
urethrectomy, is the choice treatment for loco-regional control in patients
with prostatic invasion.
TREATMENT
ROLE OF LYMPHADENECTOMY
FACTS
There is a 40-50 % incidence of positive nodes in a pT4a tumour.
Data exist that show lymphadenectomys potential impact on survival.
See: Invasive bladder cancer
RECOMMEDATIONS: STROMAL INVASION
1. The incidence of prostatic urothelial carcinoma in men with superficial or

invasive bladder cancer ranges from 12% to 48%, and 7.6% to 16.6% have
stromal invasion. The prostate is a site of relapse for patients with non-muscle
invasive bladder cancer (grade C).
2. Transurethral biopsy of the prostatic urethra is effective in identifying prostatic
involvement but does not accurately reveal the extent of stromal invasion
(grade C).
3. Retrospective and prospective studies are needed to determine better
prognostic factors for prostatic stromal invasion (grade C).
4. Radical cystoprostatectomy is the treatment of choice for locoregional control in

patients with prostatic stromal invasion (grade B).
5. In patients with pT4 disease, the incidence of positive nodes ranges from 40%
to 50%, and node mapping studies indicate that multiple sites are involved (grade
C).
6. Data show that the extent of lymphadenectomy may have an impact on survival
(grade C).
7. The number of patients with prostatic stromal invasion treated in radiation

therapy trials is too small to allow definitive conclusions regarding survival
outcome (grade C).
8. Although the data are limited and the number of patients with prostate stromal
invasion cannot be determined from the literature, the use of radical cystectomy
as a salvage procedure does not appear to diminish disease-specific or overall
survival probability (grade C).
Chemotherapy for metastatic transitional cell

carcinoma of the urothelium
Cora N. Sternberg, San Camillo Forlanini Hospital, Rome, Italy
Guru Sonpavde, US Oncology Baylor College, Webster
Walter M. Stadler, University of Chicago, Chicago
Dean Bajorin, Memorial Sloan Kettering Cancer Center, New York
Robert Dreicer, Cleveland Clinic, Cleveland
Daniel George, Duke University School of Medicine, Durham
Matthew Milowsky, Memorial Sloan Kettering Cancer Center New York
Dan Theodorescu, University of Colorado Cancer Center, Denver, Colorado
David Vaughn, University of Pennsylvania, Philadelphia
Matthew D. Galsky, Mount Sinai, New York
David Quinn, University of Southern California, Los Angeles
ICUD March, 2011
First line randomized trials in

advanced transitional cell carcinoma
Author
Treatment
RR (%)
MDS (mo)
Best arm
Loehrer
M-VAC
CDDP
126
120
39
12
12.5
8.2
M-VAC >CDPP
Logothetis
M-VAC
CISCA
65
55
65
46
12.6
10.0
M-VAC >CISCA
Von der Maase
M-VAC
GC
202
203
46
49
14.8
13.8
M-VAC ~ GC
HD-MVAC
M-VAC
134
129
62
50
14.5
14.1
HD-M-VAC >
M-VAC
Bamias
M-VAC
DC
109
111
54
37
14.2
9.3
M-VAC > DC
Dreicer
M-VAC
PC
44
41
36
28
15.4
13.8
M-VAC > PC
PCG
GC
312
315
57.1
46.4
15.7
12.8
PCG ~ GC
Sternberg
Bellmunt
MDS: median duration of suvival. M-VAC: cisplatin, methotrexate, adriamycin, vinblastine. CDDP: cisplatin.
CISCA: cisplatin, adriamicin, cyclophosphamide. GC: gemcitabine, cisplatin. HD-MVAC: high dose M-VAC. DC:
docetaxel, cisplatin. PC: Paclitaxel, carboplatin. PCG: paclitaxel, cisplatin, gemcitabine.
Better patient selection, earlier diagnosis and screening, better

supportive care (growth factors)
High Dose M-VAC vs M-VAC

Study design (n=263)
Classic M-VAC
Stratify
Who PS
R
A
N
D
O
M
I
Z
E
MTX: 30mg/m2 DAYS 1, 15, 22

VLB: 3mg/m2 DAYS 2, 15, 22
ADM: 30mg/m2 DAY 2
CDDP: 70 mg/m2 DAY 2
Q 28 d
HD- M-VAC + G-CSF

MTX: 30mg/m2 DAY 1
VLB: 3mg/m2 DAY 2
ADM: 30mg/m2 DAY 2
CDDP: 70mg/m2 DAY 2
Q 14 d
Sternberg CN, J Clin Oncol 2001;19(10):2638-1646
High Dose M-VAC vs M-VAC

7 Year update of Overall Survival
100
90
Unadjusted p=0.0417
HR=0.76 (0.58 0.99)
80
70
35% survival
60
50
40
HD-M-VAC: median 15.1 months
30
20
10
M-VAC: median 14.9 months
25% survival
0
0
O N
112129
101134
Number of patients at risk :

32
15
11
45
29
23
10
(years)
12
Treatment
4
8
2
0
M-VAC
HD M-VAC
Sternberg CN, Eur J Cancer 2006 Jan;42(1):50-4
M-VAC with G-CSF support

Hellenic trial of M-VAC vs docetaxel and cisplatin:
classic M-VAC with appropriate hematopoietic
growth factor support is an effective treatment.
(level of evidence 1b)
EORTC trial of HD-MVAC vs M-VAC is another
excellent option that may potentially lead to higher
long term cure rates.
Doublet chemotherapy
GC vs M-VAC - 5 year update
Overall Survival
GC
14.0 months (12.3-15.5 )
M-VAC
15.2 months (13.2-17.3 )

HR: 1.09 (0.88-1.34)
Von der Maase H, J Clin Oncol 2005 Jul 20;23(21):4602-8
EORTC30987/Intergroup study design
T4bN0M0 or TxN2-3
or M1 TCC of
urothelium
No prior
chemotherapy
R
a
n
d
o
m
i
s
e
Gemcitabine: 1000 mg/m2 days 1, 8 and 15

Cisplatin :
70 mg/m2 day 1 or 2
Arm 1 is given as a 4 week cycle (28 days)
Every 21 days if d15 is withheld or missed
Paclitaxel
Cisplatin
Gemcitabine
80 mg/m2 on days 1 and 8

70 mg/m2 on day 1
1000 mg/m2 on days 1 and 8
Arm 2 is given as a 3 week cycle (21 days)
Opened in May 2001. Closed in June 2004

Centres activated: 107. Patients entered/required: 627/610
Treatment: until disease progression; a max. of 6 cycles
Bellmunt J, et al. J Clin Oncol 2007;25 (Suppl 18): 242s. Abst LBA5030
Median FU = 3.2 years
Overall Duration of Survival
Maximum FU = 5.5 years
100
90
Gem/Cis
247/315
12.8 mo
Pac/Cis/Gem
239/312
15.7 mo
0.86 (0.72-1.03)
80
Overall Logrank test: p=0.10

70
60
14% r. reduction risk of death (n.s.)
50
40
30
20
10
(years)
O
247
N
315

159
76
34
239
312
185
86
35
13
6
Treatment
0
2
Gem+Cis
Gem+Cis+Pac
Survival for all patients grouped according to

number of risk factors present at baseline
n=199
Risk factors:
0= KPS > 80, no visceral mets
1= KPS < 80 or visceral mets
2= KPS < 80 and visceral mets
33.0 m.
13.4/13.6 m.
9.3 m.
Bajorin, D. F. et al. J Clin Oncol; 17:3173-3181 1999

Copyright American Society of Clinical Oncology
First line chemotherapy for platinum

eligible patients
Recommended as first line therapy
M-VAC, HD-MVAC and GC
Triplet PCG not recommended as first line
therapy (level of evidence 1b)
Cisplatin ineligible patients

The majority of patients with advanced urothelial
cancer are older (median age, 68 years)
Renal function declines with age
Alternative non-cisplatin based therapy is needed

Approximately 40% of patients with advanced
urothelial cancer are cisplatin-ineligible due to renal
dysfunction alone
The proportion of cisplatin-ineligible patients is much
higher when including treatment-limiting factors such
as poor performance status and comorbidities
Defining cisplatin-ineligible
patients with metastatic bladder
cancer
M. D. Galsky, N. M. Hahn, J. E. Rosenberg, G.
Sonpavde, W. K. Oh, R. Dreicer, N. J. Vogelzang, C.
N. Sternberg, D. F. Bajorin, J. Bellmunt, CisplatinIneligibility in Bladder Cancer Working Group
28% of all patients had CrCl < 60 ml/min

40% of patients > 70 had CrCl < 60 ml/min
40
60
68
36
20
16
7
Proportion ineligible
80
100
A large proportion of patients are unfit for cisplatinbased therapy
Age < 60
Age 60-70
Age 70-80
Age 80+
Dash et al, Cancer, 2006
EORTC 3098
Randomize
At least one of the following:

WHO PS 2
CrCL > 30 mL/min and <
60 mL/min
VINCENT
Randomize

NYHA Class III-IV CHF
CrCL of 60 mL/min
Gemcitabine
Carboplatin
Methotrexate
Carboplatin
Vinblastine
Vinflunine
Gemcitabine
Placebo
Gemcitabine
Hypothesis
Tremendous variability exists in the definition

of unfit patients
A uniform definition of unfit patients will lead
to:
more uniform clinical trials
a greater likelihood of developing a viable
strategy for regulatory approval
Types of Definitions
Pick and Choose

WHO PS 2
Creatinine clearance of <
60 mL/min
Traditional
inclusion/exclusion
All of the following:

Karnofsky performance
status 60%
Creatinine clearance 30
mL/min
Cardiac ejection fraction
40%
Survey of GU Medical Oncologists

Survey sent on three occasions over 3 weeks
65/120 (54%) completed survey

The majority (62%) cited prior involvement with
clinical trials in unfit patients
What renal function threshold should be used?
N=65
How should renal function be measured?
N=65
How should renal function be measured?
N=65
What age threshold should be used?
N=65
What PS threshold should be included?
N=65
What comorbidities should be included?

(neuropathy)
N=65
Proposed eligibility criteria for clinical trials

enrolling unfit patients
1. ECOG PS of 2 (KPS of 60-70)
2. Creatinine clearance < 60 ml/min

3. CTCAE v4 Grade 2 audiometric hearing loss
4. CTCAE v4 Grade 2 peripheral neuropathy
5. NYHA Class III heart failure
Conclusions
Substantial heterogeneity exists among criteria
defining unfit patients
A simple and concise definition of unfit is

proposed for use as eligibility criteria for clinical
trials moving forward.
Randomized phase II/III study assessing

gemcitabine/carboplatin (GC) and
methotrexate/carboplatin/vinblastine (M-CAVI)
in previously untreated patients (pts)
with advanced urothelial cancer unfit for
cisplatin based chemotherapy:
phase III results of EORTC study 30986
M. De Santis 1, J. Bellmunt 2, G. Mead 3, J.M. Kerst 4, M. Leahy 5,
G. Daugaard 6, T. Gil 7, P. Maroto 8, S. Marreaud 9, R. Sylvester 9
1 Kaiser
Franz Josef - Spital and ACR-ITR VIEnna, Vienna; 2 Hospital Vall d'Hebrn, Barcelona;
3 Royal South Hants Hospital, Southampton; 4 Netherlands Cancer Institute, Amsterdam;
5 St James Hospital, Leeds; 6 Rigshospitalet, Copenhagen; 7 Institut Jules Bordet, Brussels;
8 Hospital Santa Creu, Barcelona; 9 EORTC Data Center, Brussels
Phase II/III EORTC randomized trial in

unfit metastatic bladder patients
GCa; gemcitabine & carboplatin
M-CAVI; methotrexate, carboplatin & vinblastine
Performance status WHO 2 and/or
Impaired renal function
(30 ml/ min GFR < 60 ml/min)
De Santis M et al, J Clin Oncol 2010 (suppl: abstr LBA 4519)

De Santis M et al, J Clin Oncol 2009, 27, no. 33, 5634-5639
Phase III results of EORTC study 30986
First valid PFS data in this patient population

100
90
80
70
60
%
50
40
30
20
10
0
0
O N
113 119
115 119
HR=1.04 (95%CI: 0.80, 1.35)

p=0.78
4.2 months (95%CI: 3.7, 5.9)

5.8 months (95%CI: 4.8, 6.9)
(years)
1
2
3
4
5
20
5
5
3
1
15
3
3
2
2
6
1
1
8
Treatment
1
M-CAVI
1
GC
Phase III results of EORTC study 30986
First valid OS data in this patient population

100
90
80
70
60
%
50
40
30
20
10
0
0
O N
108 119
110 119
HR=0.94 (95%CI: 0.72, 1.22)

p=0.64
8.1 months (95%CI: 6.1, 10.3)

9.3 months (95%CI: 7.6, 11.3)
(years)
1
2
3
4
5
37
13
7
3
1
44
15
5
2
2
1
1
8
Treatment
1
M-CAVI
1
GC
GCa vs M-CAVI in poor PS or CrCl< 60 ml/min

The first randomized phase III - trial comparing
GCa and M-CAVI in cisplatin ineligible patients
Patients ineligible for cisplatin, benefit from
carboplatin based combination chemotherapy
although toxicities were important
Both combinations were active in this well defined
group of unfit patients, although toxicity was
higher on the M-CAVI arm
Patients with CrCl 40-60 and those with poor PS
could be evaluated separately
Sternberg CN, ASCO discussion 2010
GCa vs M-CAVI in poor PS or CrCl< 60 ml/min
This trial provides level 1 evidence for the use

of GCa chemotherapy in patients deemed
ineligible for cisplatin-based chemotherapy,
Adoption of a standard definition of cisplatinineligible and additional randomized studies
of chemotherapy and novel agents in this
patient population are desperately needed
2nd line chemotherapy: single agent phase II trials

Author and year
of publication
Molecule
No. of
patients
evaluated
ORR
(%)
Median
survival time
in months
Blumenreich, 1982
Vinblastine
37
18
NR
Pronzato, 1997
Ifosfamide
20
0.8
Witte, 1997
Ifosfamide
56
20
5.1
Mc Caffrey, 1997
Docetaxel
30
13
9.0
Papamichael, 1997
Paclitaxel
14
NR
Vaughn, 2002
Paclitaxel
31
10
7.2
Joly, 2009
Paclitaxel
6.8
Lorusso, 1998
Gemcitabine
31
23
5.0
Gebbia, 1999
Gemcitabine
24
29
13.0+
Albers, 2002
Gemcitabine
28
11
8.7
Witte, 1998
Topotecan
44
6.3
Dodd, 2000
Pyrazoloacridine
14
9.0
Roth, 2002
Piritrexim
27
7.0
Wulfing, 2009
Lapatinib
59 (34)
4.0
Moore, 2003
Oxaliplatin
18
NR
Sridhar, 2005
Bortezomib
11
NR
Gomez-Albuin, 2007
Bortezomib
19
3.8
Rosenberg, 2008
Bortezomib
25
5.7
Dreicer, 2007
Epothilone B
45
12
Sweeney, 2006
Pemetrexed
47
28
9.6
Galsky, 2007
Pemetrexed
12
NR
Gallagher, 2007
Sunitinib
45
NR
Dreicer, 2009
Sorafenib
27
6.8
45 (37)
Phase III trial of Vinflunine plus Best Supportive

Care vs BSC alone (n=370)
2nd line
T4bN0M0 or
TxN2-3 or M1
Progression after 1st
line Platinum
treatment
Stratify
Center
Refractory vs. nonrefractory
R
A
N
D
O
M
I
Z
E
VFL+BSC (PS 0: 320mg/m, q3w; PS

0 with previous pelvic irradiation
and PS1: 280mg/m (n=253)
BSC with treatment upon

progression permitted (n=117)
2:1
Primary endpoint: Overall survival

Secondary Endpoints: ORR, PFS, Disease control, QOL and Clinical Benefit
Bellmunt J, J Clin Oncol. 2009 Sep 20;27(27):4454-61
Phase III trial of Vinflunine plus Best Supportive

Care vs BSC alone: OS
N=357
N=370
ITT population
Eligible patients
Overall Survival: Intent to Treat Population (N= 370)
7 month median survival is a benchmark in the second line setting!

VFL + BSC
N= 253
BSC
N= 117
No. of events
204
103
No. censored (%)
49 (19.4)
14 (12.0)
Median OS
(months)
(95% Cl)
6.9
(5.7, 8.0)
4.6
(4.1, 7.0)
VFL + BSC
BSC
Hazard ratio (95%

CI)
0.88 (0.69, 1.12)
p value *
0.2868
Overall survival (months)

* Stratified log rank test
Vinflunine - second line therapy

Based on this study, vinflunine was approved by the
European Medicine Agency (EMA)
The only agent approved by a regulatory agency for this
indication.
A retrospective analysis of patients that received
second-line vinflunine identified ECOG performance
status >0, hemoglobin <10g/dL and liver metastasis as
poor prognostic factors
Bellmunt J, J Clin Oncol 2010;28(11)1850-5
Combination therapy as second-line therapy

Paclitaxel and gemcitabine:
German randomized phase II trial of 102 patients
compared 6 cycles of second-line gemcitabinepaclitaxel with continuation beyond 6 cycles until
progression
Italian trial of every 2 week gemcitabine-paclitaxel
Carboplatin-paclitaxel following prior cisplatinbased chemotherapy
Albers P, Ann Oncol. 2011 Feb;22(2):288-94.
Sternberg CN, Cancer; 2001 Dec 15;92(12):2993-8.
Vaishampayan UN, Cancer 2005, 104(8):1627-32
Second-line chemotherapy
Vinflunine: Level 2a and Grade B
recommendation
Clinical trials should remain the preferred option
Novel agents: ongoing or planned phase II trials of

salvage therapy for metastatic TCC
Drug/Regimen
Molecular target
Institution
Nab-paclitaxel
Tubulin
Canadian
AZD-4877
Kinesin spindle protein
Multicenter
Pralatrexate
Folate
Multicenter
Pazopanib
VEGFR2, PDGFR
Italy, NCI (US)
Tamoxifen
Estrogen receptors
Baylor
Everolimus
mTOR
Belgian
Everolimus-Paclitaxel
mTOR and tubulins
SWOG
Aflibercept
VEGF, PlGF
NCI (US)
TKI-258 (Dovitinib)
VEGFR, PDGFR, FGFR
Multicenter
Vorinostat
HDAC
California
Docetaxel-ASA404
Tumor and endothelial tubulin
Mt. Sinai/HOG
BI-6727
Polo-like kinase
Multicenter (US)
Phase II trials with HER 1/2 inhibition

Author
Regimen
Results
Comments
Petrylak 2003
(SWOG)
2nd line Gefitinib N=29, 3%RR 4%

PFS at 6 mos
Minimal effect
with single agent
Gefitinib
Philips 2008
(CALGB)
Fixed Dose-Rate
Gemcitabine,
DDP + Gefitinib
No better than
GC with
excessive
toxicity
Hussain 2007
HER 2 positive
N=44/57 70% RR, No Phase III trial
Trastuzumab,
OS 14.1 mos
Paclitaxel, Carbo
+ Gemcitabine
Wlfing, 2009
2nd line
Lapatanib
N=25, 36% RR
OS 11.1 mos
N=59, 1.7% OR,

SD 31% med
TTP 8.6 wks, OS
17.9 wks
Clinical benefit
correlated with
EGFR and HER-2
overexpression
Modified from Sternberg C, ASCO Education 2008
Trials with HER 1/2 Inhibition

Advanced Disease
Maintenance or
Consolidation
Lapatinib + GC
phase I (EORTC)
Lapatinib (Powles)
GC +/- Cetuximab
(Hussain)
Docetaxel +/- Gefitinib

(Siefker-Radtke,
MDACC)
Neo adjuvant
Erlotinib (SiefkerRadtke, MDACC)
Cetuximab +/Paclitaxel (Fox

Chase)
Stage IV bladder cancer

4-8 cycles of
1st line chemotherapy
HER1/HER2
status
Negative
(European Consortium)
Maintenance
HER1/HER2 positive
Responders
Randomized
Selected
Positive
Exclusion criteria
Response to
chemo
PD
Increase PFS from the

time of completion of
chemo. from 6 to 9 mos
CR/PR/SD
Randomisation
Lapatinib
n=204
Placebo
Progression free survival (primary end point)

Follow up for survival
Coordinator, T Powles
Targeting angiogenesis in urothelial cancer

VEGF, bFGF and IL-8 levels correlate with stage and
outcome
MVD: predictor of progression, vascular inv, N+, recurrence,
and S in invasive TCC
VEGF levels in the metastatic setting appears to correlate

with poor DFS
VEGF mRNA levels and MVD independent prognostic factors

for recurrence and M1 in neoadjuvant M-VAC
Elfiky AA and Rosenberg JE, Curr Oncol Rep. 2009 May;11(3):244-9
Single Agent Angiogenesis Inhibition in TCC

Presented
Advanced
Ongoing
Advanced
Bellmunt
ASCO GU 2008
1st line Unfit

Sunitinb
14.3% PR, 78.6%
benefit and 6 mos
TTP
Necci ESMO
2010)
Pili ( ASCO GU)
2nd and 3 line

Pazopanib (TKI)
Gallagher ASCO
2008/ 2009*
2nd line Sunitinb

7% PR, 24% Stab
but 17% PFS > 3
mos. Cont dose:
less activity*
California
Cancer
Consortium
2nd line
VEGF Trap (antiVEGF antibody
with broad
activity)
Dreicer (ECOG)
ASCO 2008
2nd line Sorafenib

no significant
activity
Hussain
Consortium
ASCO 2009
Maintenance
Randomized
Phase II Sunitinib
Advanced Combination Chemotherapy and

Anti-angiogenesis Trials
Presented
Phase II
Ongoing
Phase II/III
Hahn (HOG)
ASCO 2009
Cisplatin +
Gemcitabine +
Bevacizumab
Choueiri
(DFCI)
2nd line
Docetaxel +/ZD6474
(Zactima)
Bajorin
(MSKCC)
ASCO 2009
(tox)
Carbo + Gem +
Bevacizumab
Kelly (Jefferson)
Carboplatin +
Gem+Sorafenib
Rosenberg
(CALGB)
Phase III
Cisplatin +
Gemcitabine +/Bevacizumab
Personalized therapy using emerging

technologies
Pharmacogenomics (blood, tumor)
Genomic profiling (molecular profiling)
Genomic profiling/drug sensitivity: i.e. CO-XEN

Mutational analysis (high-throughput)
Proteomics still in its infancy

Micro RNA
Circulating tumor cells
Pharmacogenomics in bladder cancer

Differences in DNA repair capacity modify
individual susceptibility to carcinogenesis, but
also affect individual response to therapy
Nucleotide excision repair (NER) is one of the
major DNA repair pathways ( ERCC1, BRCA1)
The product of ERCC-1 gene functions in the
NER pathway and is a molecular marker of
platinum resitance
Predictive factors of response:ERCC1

Nucleotide excision repair
Excision repair cross
complementing 1 (ERCC1)
predicts response and
resistance to cisplatin
57 patients with advanced TCC,

Rx with GC or the triplet
containing paclitaxel and GC
High mRNA
Low mRNA
Significant correlation
between relative gene
expression levels > 7 and
decrease in survival (p=
0.035)
Bellmunt J, Ann Oncol. 2007 Mar;18(3):522-8
Co-expression extrapolation (COXEN)

algorithm
Predicting clinical outcomes by using
molecular signatures (i.e. breast cancer)
Incorporates gene profiling with drug sensitivity
Validates the clinical setting with patient

outcomes
Forecasts drug responses
Lee JK, Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13086-91
Resistant
Evaluation of COXEN treatment response

biomarkers in human bladder cancer
REFERENCE Sets
2
3
2
3
1
2
2
3
1
1
2
575A
1
2
BLA-40 is 40 Expression
Human Bladder Profiling
Cancer Cell Lines
mRNA profiled
1
3
2
1
2
1
2
1
3
2
IC50 for Test

Compounds
1
2
1
2
1
2
2
1
2
1
1
2
1
2
1
2
Sensitive
1
x
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
Resistant
1
2
Bladder Tumor
samples
from patients
GI50
Actual
Resistant:
log(GI50)
resistent
resistant
Prediction
COXEN
Resistant:
predicted
resistent
resistant
1.0
0.8
Predicted non-responders
(P-value
= 0.021)
(p-value
= 0.021)
0.0
COXEN Score
Predicted responders
0.6
Prediction
COXEN
Sensitive:
predicted
sensitive
0.4
(p-value = 0.016)
GI50
Actual
Sensitive:
log(GI50)
sensitive
0.2
umuc9
X253jp
slt4p3
X253jbv
umuc14
crl7833
fl3p10
ku7
umuc3
umuc3e
rt4
crl7193
crl2169
ht1197
X575a
cubIII
mghu3
jon
kk47
bc16.1
Bladder
Tumors
Fraction Disease-Free
BLA-40 Cell line Cisplatin normalized log(GI50) & MiPP prediction scores
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
Predict: in vitro
Drug Sensitivity
50
100
150
Survival
time
Time
(months)
Standardized log(GI50)
Standardized COXEN Score
VALIDATION Sets
Resistant
1
2
1
2
1
2
Drug Response Prediction Model

(Gene Expression)
Evaluation of Model on
Cells or Tumors
(RT-PCR)
2
1
Predict: Therapy
Response
Focus on the subset of probes that consititutes a signature of drug sensitivity!
1
2
SW1710
x
COXEN
Bladder
Cell Lines
1
2
KK47
Resistant
CRL2742
x
1
2
1
2
1
2
2
1
VMCUB1
2
1
Resistant
x
2
1
2
1
1
2
1
2
UMUC1
Sensitive
1
2
2
1
Sensitive
x
1
2
UMUC3
HTB9
Sensitive
x1
3
2
2
1
x
2
1
NCI-60 Panel
3
2
1
2
1
J82
Sensitive
2
1
2
1
RT4
1 Sensitive
2
3
x 1 1
1
2
2
1
3
1
2
3
1
2
1
2
3
2
3
Resistant
Sensitive
x
1
Sensitive
1
x
2
Sensitive
x
1
3
2
2
3
1
1
2
1
2
1
2
1
2
Validation of new drug effectiveness in human

bladder cancer cells: 45,545 compounds tested
1
2
3
RT4
1 Sensitive
2 1 1
x3
2
3
1
1
x
2
1
2
2
1
1
2
1
2
575A
1
2
1
3
2
1
2
1
3
2
1
2
1
2
2
1
2
1
2
1
2
1
1
x
1
2
1
2
Resistant
1
2
1
2
1
2
2
1
1
2
2
1
1
2
1
2
Resistant
1
2
Resistant
1
2
SW1710
1
2
1
2
1
2
2
1
2
1
CRL7193
Resistant
x
1
2
1
2
1
2
CRL7833
2
1
2
1
1
2
1
2
1
2
253J-P
Resistant
1
2
1
2
1
2
KK47
1
2
Resistant
x
1
2
1
2
Resistant
CRL2742
Resistant
1
2
2
1
1
2
1
2
HT1376
1
2
1
2
1
2
1
2
1
2
Resistant
1
2
Resistant
x
1
2
253J-BV
Resistant
1
2
1
2
2
1
T24
1
2
x
UMUC13D
UMUC1
2
1
1
2
1
2
1
2
1
2
2
1
1
2
1
2
1
2
KU7
1
2
2
1
1
2
1
253JLaval 2
Resistant
1
x
2
1
1
2 2
Resistant
x
2
1
VMCUB1
1
2
1
2
Sensitive
Sensitive
1
2
1
2
1
2
UMUC9
Resistant
UMUC3
1
2
2
1
Sensitive
x
1
2
2
1
CUBIII
1
2
2
1
1
2
Sensitive
HTB9
Sensitive
x1
3
2
2
1
1
2
Sensitive
MGH-U4
1
2
J82
x2
1
1
2
x
1
Sensitive
2
3
60 100
2
3
1
Sensitive
1
2
3
2
1
1
2
HU456
2
1
1
2
1
2
Sensitive
1
2
1
2
1TCCSUP 1
2
Sensitive
2
x
1 1
2
1
MGH-U3
1
2
1
2
1
2
Resistant
1
2
2
1
2
UMUC2
1
2
x
1
1
2
1
2
3
Sensitive
x
1
3
2
20
with C-1311
Sensitive
SLT4
2
3
1
BC16.1
x
1
2
1
2
1
2
Sensitive
1
2
1
2
1
2
1
2
3
2
3
Bladder Cancer Clinical Trial
1
2
1
2
3
UMUC14
T24T
1
2
3
2
1
3
1
2
Sensitive
x
2
1
3
1
2
3
1
2
3
3
2
2
3
1
1
2
40 human bladder
cancer cell lines
(BLA-40)
2
1
3
2
3
NSC 637993
Percent of cell counts
2
3
2
1
JON
2
1
Sensitive
1
2
1
2
3
Sensitive
x
2
3
1
x
1
2
3
1
UMUC6
Sensitive
1
3
2
2
3
VMCUB3 1
1
2
3
1
2
3
1
2
3
1
3
2
1
2
3
3
2
1
2
1
2
HT1197 1
Sensitive
1
2
1
2 2
1
1
2
1
2
Sensitive
VMCUB2
2
3
1
2
1
3
FL3
Sensitive
2
3
3
2
1
1
2
1
2
-8 -7 -6 -5 -4
Log base 10 of molar concentration of NSC 598354

637993
Courtesy of D. Theodorescu
51
Gene expression
model
Genome-wide gene expression profiling

Predicting response to neoadjuvant M-VAC
Takata R, Aktuelle Urol. 2010 Jan;41 Suppl 1:S41-5

Takata R Clin Cancer Res 2005;11, 2005
Genetic signatures
associated with
.
aggressive behavior
High
throughput
DNA
microarrays
identify
biomarkers for
bladder cancer
Sanchez-Carbayo M, J Clin Oncol. 2006 Feb 10;24(5):778-89
Gene expression based or immunohistochemical

detected biomarkers
Promising biomarkers have not yet been
extensively validated in sufficient numbers in
prospective clinical trials
Could become part of the diagnostic workup
and management in the future
Grade of recommendation: Not
recommended outside a clinical trial or
biomarker study (level of evidence 2b)
Conclusions for first line therapy

First-line advanced urothelial cancer with adequate renal
function: combination cisplatin regimens are the standard
of care (Grade A recommendation).
Use of triplet regimens adding paclitaxel to gemcitabine
plus cisplatin is not recommended.
Unfit patients: renal impairment, advanced age or poor
performance status: carboplatin and gemcitabine
(Grade A recommendation).
Renal impairment only gemcitabine/carboplatin/paclitaxel
can be considered (Grade C).
Conclusions for second line therapy

For second line therapy after a platinum based
treatment, vinflunine has been adopted as a
standard in Europe but not in North America.
(Grade B recommendation).
Novel agents and approaches are urgently needed

and clinical trial accrual needs to be actively
encouraged.
The standard of care for a majority of patients with
advanced bladder cancer is the best clinical trial
available.
Non-urothelial cancer of the Bladder

Bruce R. Kava (USA) sub committee chair
Jack Baniel (Israel)- presentation
Hassan Abol-Enein (Egypt)

Alexandra J Colquhoun (USA)
William H Turner (UK)

Adrienne J. K. Carmack (USA)
Non-urothelial Bladder Cancer

TCC is the most prevalent bladder tumor (superficial
and invasive)
The other end of bladder tumors:
Adenocarcinoma
Small cell carcinoma
Others
(Level 3 evidence)
Worldwide Incidence
Urothelial and Nonurothelial Bladder Cancer
Squamous Cell Carcinoma (SCC)

Two main categories:
SCC in western countries (non-bilharzial)
SCC in the bilharzial bladder
(Rundle,1982) (Level 3 evidence)
Non-bilharzial SCC of the Bladder

Epidemiology
2nd bladder malignancy
age 70 years
2-5% in contemporary cystectomy series
Black to white 2:1
Male to female ratio 1.4:1
Presents at advanced stage
(Serratta,2000) (Level 3 evidence)
Non Bilharzial SCC of The Bladder

Gender Differences
In USA:
incidence of urothelial ca in men >3x women
incidence of non-urothelial ca in men =1.4x women
(Johansson SL and Cohen SM 1997: compiled data from 915 patients in 10 series)
Level 3
Women present with more advanced stage tumors:
Mungan AL, et al (2000):

Data derived from the
Netherlands Cancer Registry:
Level 3

Etiology
Relation to cigarette smoking is not clear.
*Chronic inflammatory disorders.
*Calculi, diverticula, indwelling catheters.
Spinal cord injury patients.
Squamous metaplasia is common.
(Thorn,1997) ( Level 3 evidence)
(- *Level 4 evidence)

Association with Spinal Cord Injury
Incidence of SCC in Spinal Cord Injured patients:
2.3- 10% in early, small retrospective reports
Kaufman et al (1977), Locke et al (1985), Bejany, et al (1987)
Level 3
West et al (Urology 1999):US Dept of Veterans Affairs Admissions

Data:
33,560 patients with SCI identified
130 (0.39%) patients with Bladder cancer identified
of: 42 records available for review:
May reflect: increase in cigarette
23 (55%) Urothelial ca
smoking and reduced indwelling
13 (33%) SCC
catheters
Level 3
4 (10%) Adenoca

Association with Spinal Cord Injury
Bickel et al (1991): report on 3 Louisiana medical centers
8/2900 (0.32%) SCI patients developed bladder cancer
2/8 SCC, 6/8 Urothelial ca
Level 3
Pannek J (2002): by questionnaire sent to Urology Depts in
Eastern Europe
43,561 SCI patients identified
Only 7% of patients had indwelling catheters
48 (0.11%) patients developed bladder cancer
19% of the patients with bladder cancer were SCC
Level 3
SCC of the Bladder in

Spinal Cord Injury
Recommendations:
(Grade B)
The incidence is less than 1%
Monitoring of patients with indwelling catheters is

important
Hematuria should be evaluated
Frequency of surveillance and diagnostic work up
can not be determined

Pure SCC (Clinico-pathologic features):
Usually present with hematuria
30-90% have associated infection irritative

symptoms
Latent period from symptoms to diagnosis

Superficial SCC is rare, majority are muscle- invasive
(Jones, 1980; Rundle, 1982; Quilty, 1986)
(Level 3 evidence)

Pure SCC (Clinico-pathological features):
Solitary large tumor
Sessile lesion with ulceration surrounded with
metaplasia
Trigone, but can occur in other areas
May develop in diverticula, associated with stones
Imaging and work-up the same as for TCC
(Costello, 1984; Sereta, 2000)
(Level 3, 4 evidence)
Non-bilharzial SCC of the Bladder:

Treatment
Prognosis is generally poor (most die 1-3 years after dg.)
Radical surgery is the most effective treatment
5-year survival rates range from (16-48%)
Treatment failure is usually due to local pelvic
recurrence
Incidence of distant mets 8-10%
(Jones, 1980)
(Level 3 evidence)
Non-bilharzial SCC of the Bladder: Treatment
Radiotherapy Alone:
5-year survival 16-26%
The response was more in T2 disease.
T3 disease (4.8%) 5 years.
(Quilty, 1986; Johnson, 1976; Rundle, 1982)
(Level 3 evidence)
Non-bilharzial SCC of the Bladder:

Treatment
Preoperative radiotherapy?
Some improvement 5 years 48% (many patients
had been excluded).
No reliable randomized studies to draw a
conclusion.
(Richie,1976)
(Level 3 evidence)
Non-bilharzial SCC of the Bladder: Treatment

Chemotherapy ?
Role is uncertain
Effective chemotherapy protocol has not been found
Neoadjuvant M-VAC no response
(Khaled, 2000)
(Level 3 evidence)
The results of new combination regimens (paclitaxelgemcitabine-cisplatin) are awaited.

(Level 4 evidence)
Bilharzial SCC of The Bladder

Pathogenesis
Latent period up to 30 years.
Locally produced chemical carcinogen
DNA changes
Bacterial infections (Nitrosamines)
Metaplasia (Mechanical irritation)
Level 4
Changing Patterns of Egyptian Bladder Cancer

Data abstracted from NCI- Cairo
From Felix, et al : Cancer Causes Control (2008):19,421-9

Clinical presentation
Latency period of approx 30
years between infestation
and development of cancer
Similar symptoms between
bilharzial cystitis and
malignant cystitis. Painful
and frequent voiding, with
hematuria
many cases have advanced
disease when first seen
Diagnostic work-up is the

same as TCC (CK in the urine)
Level 3 and 4
Life cycle of
Schistosomiasis
Retrospective Egyptian Cystectomy Series

Pathologic Stage and Prognosis
Tumor grade:
GI: 50%
GII: 32%
GIII: 18%
Understaged in 33%
Ghoneim MA, et al (J Urol 1997): Level 3

Clinico-pathological features:
Most of the tumors are located in posterior or lateral walls
5 types based upon gross appearance
Nodular fungating: 60%
Ulcerative 23%
Verrucous 7%
Papillary 7%
Diffuse 3%
Atypical changes - Metaplasia, dysplasia, leukoplakia are
common but CIS is rarely seen.
Very rare to invade the ureters or the urethra

EUA/Endoscopic Resection
In many cases, limited to biopsy
Not a known tool for treatment because of bulky
disease.
In case of complete endoscopic excision, follow up
cystoscopy and deep biopsy is required
Level 4

Partial cystectomy
Indications limited:
Low grade, solitary lesion
Small tumor allows good safety margin
Away from the trigone.

These criteria were present in 19/190 pat. (10%).
Augmentation cystoplasty needed in 25%.
5 year survival in 26.5%.
Local recurrence was high.
El-Hammady, (1975): Level 3

Radical Cystectomy
608 patients with SCC.
5 year survival = 50.3%.
Tumor stage, grade and LN involvement were
independent prognostic factors.
Cystectomy as single modality is inadequate
Ghoneim (1997): Level 3

Neoaduvant Radiation Therapy
20 cGy prior to cystectomy vs cystectomy alone
Prospective, randomized trial evaluating 90
patients.
60 months follow-up
Trend in favor of irradiation but not statistically
significant.
Ghoneim, et al (1985): Level 1

Radiation Therapy alone:
Few studies
Poor response
Tumor bulk with hypoxic cells

Bilharzial cystitis (intolerance)
Level 4
cystectomy vs. 20 rad + cystectomy vs. 20 rad + misondzl +

cystectomy - Addition of misonidazole as a radiosensitizer
did not alter survival advantage.
Ghoneim 1985
Level 1

Chemotherapy
Phase II studies showed some activity of epirubicin.
Level 4
Neoadjuvant epirubicin showed an initial promising

results in one study but was not reproducible.
Level 2
In recent multicenter trial using neoadjuvant

cisplatin + gemcitabine, patients with SCC did not
show survival advantage. Level 2
New chemotherapy protocol has to be identified.

Grade B:Recommendations
Non-Bilharzial SCC:
Predominantly single center, retrospective series
Radical Cystectomy appears to offer the best survival in localized
disease
Bilharzial SCC:
Predominantly single center, retrospective series
Radical Cystectomy appears to offer the best survival in
localized disease
Adenocarcinoma of the bladder
Adenocarcinoma of The Bladder
Primary
Urachal
Metastatic
Adenocarcinoma of the Bladder

Incidence
0.5-2%
Western series
(Bennet, 1984) (Level 3 evidence)
8-11%
In Endemic Bilharzial areas

(El-Mekresh, 1998) (Level 3 evidence)
Exstrophy 4% life time risk

Male to female: 2.7:1
(Level 3 evidence)

Urachal Carcinoma:
Rare tumor (1 in 1400)
Younger age (49 years vs. 58 nonurachal)

Male to female 4:3
(Dandeker, 1997)
(Level 3 evidence)

Urachal Carcinoma:
Location (bladder dome)
Extravesical extension
Sharp demarcation
Not associated with cystitis glandularis
Indistinguishable from enteric adenocarcinoma
(Johnson, 1985)
(Level 4 evidence)

Urachal Carcinoma:
Staging (Sheldon, 1984)
I: Urachal mucosa
II: Invasion to the urachus
III: Invasion to the bladder, abdominal
wall, local viscera
IV: regional nodes or distant metastases

Urachal Carcinoma:
Treatment:
Wide excision of the umbilicus,
urachus, and partial cystectomy
Survival:
40% at 5 years (MD Anderson)
Prognosis:
Lymph node involvement
Positive surgical margin
(Level 3 evidence)

Urachal Carcinoma:
systemic treatment:
Chemotherapy
5-fluorouracil and cisplatin

No benefit
(Level 3 evidence)
Radiotherapy
Not enough trials seems poor
(Level 4 evidence)

Adenocarcinoma in bladder exstrophy:
The most common malignancy in the retained bladder
More in males
(McIntoch and Woly 1955) (Level 3 evidence)
4/102 patients followed for more than 35 years
700 times risk > normal population
(Smeulder, 2001)
(Level 3 evidence)
metaplasia of the urothelium d/t defunctionalised

bladder and bowel augmentation
(Level 4 evidence)

Primary adenocarcinoma
Chronic vesical irritation, metaplastic changes
Virtually always invasive
(Dandekar,1997)
Mucin or non-mucin producing

Stage, Grade, LNs are the prognostic factors
(El-Mekresh,1998)
(Level 3 evidence)

Primary adenocarcinoma
Treatment
TUR
(19% -5 years)
(Kramer,1979)
Partial cystectomy
(dismal ~25%)
(Abenoza,1987)
Radical cystectomy
(0-80%)
(El-Mekresh,1998)
Radiotherapy
(<20%)
(Thomas,1971)
Preoperative irradiation (No benefit) (Anderstrom,1983)
Chemotherapy
(Dismal)
(Hatch,1989)
(Level 3 evidence)

Secondary adenocarcinoma
Direct extension
Lymphohematogeneous spread
Colon 21%
Prostate
19%
Rectum
12%
Cervix 11%
(Bates and Baithun,2000) (Level 3 evidence)
Deleted in Colon Cancer protein (DCC) immunostain +ve may
differentiate primary from 2 (Yossepowitch, urology 2004) level 3
Adenocarcinoma of the Bladder

Secondary adenocarcinoma
Treatment:
Wide excision with a wide safety margin is required
(20% recurrence)
Bladder-sparing surgery (100% recurrence)
The treatment failure depends on the stage of the
primary disease
(Carne,2004) (Level 3 evidence)

Rare tumor (neuroendocrine tumor in the lungs)
+/- 300 cases reported
0.4 0.7% of all bladder tumors
Age above 60, 80% are males
Pathological diagnosis is difficult
Usual appearance at stage T2
Metastatic disease in 67% (LN, liver, bone, lung and brain).
(Sved et al.,2004)
(Level 3 evidence)

Treatment: multimodal therapy
Lung small cell chemotx. cis+etoposide/ifos+doxo,
median survival 10-14 months
MDA experience (JUrol,2004) 46 pts. 5-year survival:
cystectomy + post-op chemo 36%
neoadjuvant chemo + cystectomy -78% (chemo
directed to small cell and not MVAC/gemzar+cis)
2009, 2 studies (UK+North Africa) survival 7-33 months
(Siefker-Radtke et al.,2004)
(Level 3 evidence)

GRADE B RECOMMENDATION:
Cure is most likely with a combined multimodality
approach including neoadjuvant chemotherapy
and local therapy
Bladder Sarcoma
Leiomyosarcoma (50%)
Hematuria early diagnosis
Radical cystectomy in early cases (80% survival)
(Rosso,1992) (Level 3 evidence)
Multimodal treatment in metastatic disease

(Level 4 evidence)
Rare Bladder Malignancies

Carcinosarcoma
Aggressive disease (41 cases)
Poor outcome following cystectomy alone
(Lopenz-Beltran,1998) (Level 3 evidence)
Multimodal treatment
(Froehner,2001) (Level 4 evidence)
Paraganglioma, pheochromocytoma
Paroxysmal symptoms with micturition
Cystoscopy under precaution (Biopsy !!!)
Local excision with lymphadenectomy
May be difficult to distinguish (benign or malig)
(Klingler,2001) (Level 3 evidence)
Melanoma:
Primary is rare
Secondary from the skin is more prevalent
Clinical picture and biopsy are diagnostic urethra and not so

much in the bladder
Treatment is radical surgery
Prognosis is poor
(De Torres, 1995) (Level 3 evidence)
Lymphoma:
Part of metastatic spread
More in women
Localized disease has good prognosis
Local irradiation is satisfactory
(Kempton,1997) (Level 3 evidence)
Bladder Pseudotumors
Rare
Resemble malignancy
Postoperative spindle cell tumors
Can mimic leiomyosarcoma
Absence of mitotic figures
TUR or partial resection is enough
Cystectomy if the diagnosis is difficult

(Jones, 1993) (Level 3 evidence)

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BLADDER CANCER

MARK SOLOWAY - SAAD KHOURY

2nd International Consultation on Bladder Cancer - Vienna

5 Boulevard Flandrin - 75016 Paris - FRANCE

The great tragedy of science :

EVIDENCE BASED MEDICINE OVERVIEW OF THE MAIN STEPS FOR

2.2 How papers are analysed?

The International Consultation on Urological Diseases (ICUD)

Papers published in peer reviewed journals have differing

The Agency for Health Care Policy and Research

- Systematic reviews and meta-analysis of randomised

The ICUD proposes that future consultations should use a

The use of standard check lists is recommended to insure

1. 1st Step: Define the specific questions or statements

The objective of the check list is to give a quality rating for

The analysis of the literature is an important step in preparing

how well the study was reported

2.1 What papers should be included in the analysis?

The ICUD has adopted the CONSORT statement and its

Papers published, or accepted for publication in the peer

ICUD has modified the Oxford Center for Evidence-Based

Papers published in non peer reviewed supplements will

An exhaustive list should be obtained through:

II. the table of contents of the major journals of urology and

Having completed a rigorous and objective synthesis of the

It is expected that the highly experienced and expert

available external clinical evidence from systematic research.

6.2 Grades of Recommendation

5. 5th Step: Final Grading

Grade A recommendation usually depends on consistent

The grading of the recommendation is intended to strike an

Grade B recommendation usually depends on consistent

The grades of recommendation have not been reduced and a

All interventions should be judged by the body of evidence

Grade D No recommendation possible would be used

6.1 Levels of Evidence

7. Levels of Evidence and Grades of Recommendation

Firstly, it should be stated that any level of evidence may be

From initial discussions with the Oxford group it is clear that

The ICUD recommend, that, as a minimum, any test should

Level 2 evidence (incorporates Oxford 2a, 2b and 2c)

good quality retrospective case-control studies where

good quality case series where a complete group of patients

There are aspects to the ICUD system that require further

(Chairs are underligned)

First Affiliated Hospital of Xian,

Lahey Clinic Medical Center

Consultant Urologic Surgeon

William Bill Turner,

Department of Pathology &

Director of Urologic Oncology

University of British Columbia,

Department of Pathology &

Vanderbilt University Medical

Vanderbilt University Medical

Vanderbilt University Medical

Guys and St Thomas Hospital,

Guys and St Thomas Hospital,

UT Health Science Center San

Director of Surgical Oncology

Department of Pathology, Memorial Sloan-Kettering Cancer Center,

Department of Pathology, Stanford University School of Medicine,

1. 1st Step: Define the specific questions or statements

Papers published, or accepted for publication in the peer

Papers published in non peer reviewed supplements will

II. the table of contents of the major journals of urology and

Grade A recommendation usually depends on consistent

Grade B recommendation usually depends on consistent

Grade D No recommendation possible would be used

Level 2 evidence (incorporates Oxford 2a, 2b and 2c)