BLADDER CANCER

Urothelial Carcinoma
UC represents over 90% of all bladder cancers diagnosed in the US 68,000 new cases are diagnosed per year

>90% diagnosed are older than 55 13,000 deaths annually 500,000 survivors currently in the US

3:1 male to female, with incidence rising in all groups Lifetime risk of 1/28

Bladder cancer:
Incidence: Mortality:

Epidemiology

20/100000/year (Europe) 8-9/100000/year

Fourth most common cancer in men

Incidence: 31.1 Incidence: 9.5 mortality: 12.1 mortality: 4.5

Seventh most common cancer in women

At diagnosis >70%: > 65 y of age

Bladder Anatomy

The urinary bladder has 3 distinct histologic layers

Urothelium Lamina Propria Detrusor (Muscularis Propria)

Bladder Urothelial Carcinoma

Smoking is the #1 risk factor Amines, 4-aminobiphenyl & analines are the culprits
Aromatic amines in dyes, solvents, paints, combustion products, rubber, and textiles are also risk factors Hairdressers, mechanics, truckers Phenacetin derived analgesics Not coffee and artificial sweeteners Rarely familial syndrome with DNA mismatch repair (Lynch II) Slow acetylators (40% higher) vs fast acetylators

Bladder Urothelial Carcinoma

The vast majority of bladder UC are the result of environmental exposuretobacco Endogenous molecular factors play a role Cyclophosphamide & ifosfamide chemo A. fangchi herbs & arsenic Radiation therapy Prostate, anal, cervix

Bladder Urothelial Carcinoma

The entire urothelium is susceptible to carcinogenic insult and thus, to malignant transformation A field change disease Tumorgenesis separated by time and space Cells migrate and implant vs. multifocal carcinogenesis

Urothelial Carcinoma

The urinary bladder is the reservoir of urine and therefore has a prolonged face-time with renally excreted carcinogens

UC has a long latency from exposure to cancer development supporting the theory of a carcinogenic cumulative effect on malignant transformation of the urothelium 48,000 Men over 10 years- UC incidence re: fluid intake

1.5L of water/day << less than 240mL

Bladder cancer:
90-95%

Histology

transitional-cell carcinoma

3% 2% <1%

squamos-cell carcinoma adenocarcinoma small-cell carcinoma

Pathology
MACROSCOPIC ASPECT: the balder tumors are mainly situated around the
orifices of the bladder: urethral and ureteral The repartition of the tumor implantation on the bladder walls -lateral and posterior walls 70 %, -trigone and bladder nec 20 %, -anterior wal andcalota 10 %.

Pathology
Bladder cancer manifest in a variety of patterns of tumor growth

pediculate papillary sessile infiltrating nodular mixed

For urothelial cancers or transitional cell carcinomas

Tumor grading Broders

G I - over 75 % differentiated cells Well-differentiated

G II - between 50 75 % differentiated cells Moderately differentiated G III - between 25 50 % differentiated cells Poorly differentiated

G IV - under 25 % differentiated cells High-grade urothelial carcinoma

The T element
pTx pT0 pTa pTis pT1 - it is not possible to determine the infiltration tumoral degree - free of malignant histological pattern - non invasive papilary carcinoma - flat, in situ carcinoma - carcinoma with invasion of lamina propria

pT2a - carcinoma with invasion in first superficial layers of smooth muscle pT2b - carcinoma with invasion of the whole muscular thickness pT3a - carcinoma with microscopic invasion of perivesical fat pT3b - carcinoma with macroscopic invasion of perivesical fat pT4a invading the pelvic viscera: prostatic stroma, rectum, uterus, vagina pT4b extending to the pelvic sidewalls or abdominal wall

Bladder cancer:

Entities

75-85% superficial bladder cancer pTa, pTis, pT1

10-15% muscle-invasive bladder cancer pT2, pT3, pT4 5% metastatic bladder cancer

N+, M+

Bladder cancer:
Stage
0 I II III IV

Stage and Prognosis

5-y. Survival
NoMo NoMo NoMo NoMo NoMo >85% 65-75% 57% 31% 24%

TNM
Ta/Tis T1 T2a-b T3a-4a T4b

each T each T

N+Mo M+

14% med. 6-9 Mo

The N element
-N1 single positive node less than or equal to 2 cm in diameter -N2 one or more positive nodes less or equal to 5 cm in diameter -N3 positive nodes greater than 5 cm in diameter

The M element

-M0 no metastases -M1 distant metastases

Non-Muscle Invasive UC

Historically known as superficial bladder cancer Wide range- Low-grade papillary to high grade T1 with CIS 70-75% are amenable to bladder sparing treatments

Grade 1,2,3 vs. Low/High Grade- regardless of invasion or CIS presence

All tumors that have not invaded the detrusor

Tumor Grading

Ta denotes a papillary (LG or HG) tumor confined to the urothelium T1 is a papillary, sessile or nodular tumor invading the lamina propria (LG or HG)

Anything beyond the urothelial basement membrane until the detrusor.

Signs and Symptoms

Hematuria - painless hematuria, the most common sign, occurs in about 60 70 % of patients : grossly in papilary tumors, if it is intense at the end of the voiding, it is a sign of bladder hematuria ; Piuria it is rare as a unique sign ; associated with hematuria : piohematuria. Polachiuria bladder irritability and urinary frequency, late sign of diffuse carcinoma or infiltrative tumor. Tumoral cystitis the most sever form of cistitis Disuria it is a sign of the bladder neck involvement, the tumor engagement on the urethra can produce acute urinary retention. Pelvic pain occurs rarely at the beginning of the disease, and grow during urinating, irradiates in the genital organs Fever, Seizure, Lumbar (flank) pain in the infiltrative forms of the tumors with ureteral obstruction and pielonefritys. Metastatic signs fractures on pathological bone, cerebral acute ischemia, pulmonary embolii Paraneoplazic signs weight loss, fatigue, anemia, loss of appetite , etc. Renal failure phenomena

DIAGNOSIS & Staging

Ultrasonography noninvaziv method, good specificity and sensitive,
repeatable

Cistoscopy All patients suspected of having bladder cancer should have careful
cystoscopy and bimanual examination under spinal anesthesia Abnormal areas should be biopsied. Random or selected-site mucosal biopsy specimens may also be obtained. Retrograde pyelography should be performed if the upper tracts are not adequately visualized on the excretory urogram. can diagnose the bleeding source (bladder or upper urinary tract), the number, size and macroscopical aspect of the tumor

Urography indicated in all patients with signs and symptoms suggestive of

bladder cancer is not a sensitive method of detecting bladder tumors -it is useful in examining the upper urinary tracts for associated urothelial tumors -Large tumors may appear as filling defects in the bladder on the cystogram -Ureteral obstruction caused by a bladder tumor is usually a sign of muscle invasive cancer and can lead to a nonfunctional obstructed kidney.
-

Examples of Cystoscopic Tumor

Examples of Cystoscopic Tumor

Cystoscopy

Tumor Grading

CIS is a flat, high-grade, tumor confined to the urothelium. No lamina propria invasion.

Velvety, erythematous and easily missed on cystoscopy Severe atypia and nuclear aplasia with disorderly architecture Can be multicentric and often occur with high-grade tumors Ominous CIS undermining of adjacent healthy urothelium

Tumor Grading

CIS is a flat, high-grade, tumor confined to the urothelium. No lamina propria invasion.

Velvety, erythematous and easily missed on cystoscopy Severe atypia and nuclear aplasia with disorderly architecture Can be multicentric and often occur with high-grade tumors Ominous CIS undermining of adjacent healthy urothelium

Carcinoma in Situ

DIAGNOSIS & Staging

Pulmonary and skeletal radiography ;for eventual metastasis, should be
performed before proceeding to pelvic lymphadenectomy

Computed Tomography Scan in addition to assessing the extent of the

primary tumor, CT scanning also provides information about the presence of pelvic and para-aortic lymphadenopathy and visceral metastases To accurately assess the depth of penetration, CT scanning should be done before transurethral resection

Magnetic Resonance Imaging Good and accurate results for can be

obtained with MRI

Lymphadenectomy

Pelvic lymphadenectomy is the most accurate way of determining regional lymph node involvement. Some patients have only limited nodal metastases below the bifurcation of the common iliac arteries, and without invasion of adjacent organs they may be cured by pelvic lymphadenectomy. The primary regions of lymphatic drainage of the bladder are the perivesical, hypogastric, obturator, external iliac, and presacral lymph nodes

The evolution of the bladder tumors

The urothelial tumors have a natural evolution to extension, infiltration and

dissemination to the lymphatic nodes, first of all in the pelvic lymph nodes and then, very quickly in the other nodes, including the mediastinal and supraclaviculary ones. The dissemination in the other organs is most of all hematogenous. The common sites of vascular metastases are bones (pelvic bones, lumbar vertebra, ribs) liver, lung, adrenal glands, the kidneys, testicles. Any other organ may be involved The evolution depends on the superficial or invasive aspect of the tumor, the degree of differentiation and the genetic aspect of the tumor Almost 25% of patients with newly diagnosed bladder cancer have muscleinvasive disease, the vast majority being tumors of high histologic grade. Most patients (85% to 92%) with muscle-invasive bladder cancer already have this level of invasion at the time of initial diagnosis. Almost 50% of patients with muscle-invasive bladder cancer already have occult distant metastases.

Endoscopic Management

Office-based cystoscopy is the mainstay of diagnosis and surveillance.

Entire urethra, prostate, bladder neck, and bladder Quality of efflux from each ureteral orifice

Extent, location, number, and nature of tumors as well as UO proximity, mucosal irregularities or urethral involvement should be recorded and/or photographed. Urine cytology is encouraged for baseline and may encourage future random biopsies if positive

Endoscopic Management

TURBT is the initial treatment for visible lesions. Performed under regional or general anesthesia Need bimanual exam before prep and drape and after case for staging. Cytology with cystoscopy can be helpful as a baseline marker for future surveillance and treatment monitoring

Examples Bladder Tumor Resection

Endoscopic Management

Essential to resect all of tumor ultimately to a depth of the detrusor for accurate staging Separating superficial and muscle swipes may aid the pathologist in identifying muscularis propria from muscularis mucosa An increase in abdominal fullness or girth requires a cystogram to r/o intraperitoneal perforation A cystogram is required prior to post-TURBT intravesical instillation

Endoscopic Management

Conservative treatment of diverticular tumors Should be sampled rather than resected A minority advocate purposeful perforation Partial cystectomy Random biopsies would be warranted in preop planning
TURBT should proceed without worry of the UO Pure cut across UOs minimizes scarring Stenting to manage oedema and healing

Endoscopic Management Complications

Obturator reflex perforation Bleeding TUR Syndrome UO Obstruction Unrecognized disease Perforation

Extraperitoneal Intraperitoneal

Why Do Patients Recur?

(and later, what can the urologist do about it)

Nature of the tumor Poor Protoplasm Missed tumors at TURBT Incomplete TURBT resection Implantation of shed tumor cells at TURBT A de novo tumor due to a tumor-sensitized, atrisk urothelium

Field change disease and the urothelium will dedifferentiate at its leisure

Endoscopic Management 2nd Look (Restage) TURBT

When tumor volume, inaccessibility, and intraoperative medical instability warrant a second look for patient safety. Recommended 2-6 weeks after all HGTa & T1 tumors OR if no muscle present
40% positivity of re-staging sites of HG tumors and 20-50% likelihood of T-upgrade to MI disease

Intravesical Therapy
Goal is to treat residual or unresected disease

Prevent future recurrences and progression

Delay the need for more aggressive surgical intervention Prevent tumor implantation

Immunotherapy BCG

Bacillus Calmette-Guerin

Live, attenuated Mycobacterium bovis Developed by Albert Calmette and Camille Guerin at the Pasteur Institute Used initially as a Tb vaccine Massive local immune response all reflecting a Th1 process driven by Direct binding of fibronectin within the bladder wall

Immunotherapy BCG

Use in CIS

CIS is often diffuse preventing complete tumor resection 80% response rate 50% durable at 4 yrs and 30% at 10 yrs Higher efficacy compared with intravesical chemo Induction vs. induction + maintenance

BCG Scheduling
6 week induction alone is insufficient to achieve optimal response Lamm and SWOG Maintenance

(after 6 week induction)

@ 3 months- 3 weekly instillations @ 6 months- 3 weekly instillations then every 6 months for 3 years

18 more instillations

Contraindications

Absolute

Immunosuppressed and immunocompromised Immediately after TURBT/TURP, gross hematuria or traumatic foley (disrupted urothelium) Hx of BCG Sepsis

Relative

Active UTI Total incontinence Liver disease Hx of TB Poor performance status or advanced age

BCG Toxicity Treatments

Moderate Irritative Symptoms, hematuria, afebrile (<48hrs)

Get urine culture Anticholinergics, pyridium, analgesics & NSAIDS

Severe Irritative Symptoms, Fevers, or >48hrs

Urine Culture, CXR, LFTs ID Consult

Isoniazid and rifampin until symptoms resolve

Dose reduction when instillations resume

BCG Toxicity Treatments Serious Complications

Hemodynamic changes (BCG Sepsis), highgrade fevers, allergic reactions, solid organ involvement with fevers & rigors
Blood and Urine Cultures, CXR, LFTs Steroids, antihistamines, broad-spectrum antibiotics ID Consult

Isoniazid, rifampin, ethambutol, for 3-6 months

University of Chicago BCG Treatment and Surveillance Protocol for HGTa

Initial TURBT After 4 weeks, Re-TURBT (bc HG Ta and all T1 disease) *After 6 weeks, BCG x 6 weeks (induction) Cystoscopy surveillance at 3 month mark* 3 Weeks of BCG Cystoscopy surveillance at 6 month mark* 3 Weeks of BCG Cystoscopy surveillance at 9 month mark* 3 Weeks of BCG Cystoscopy surveillance at 12 month mark*

*from 1st dose of BCG induction All in all, 1 year's worth of cancer treatment induction + maintenance + 4 surveillance cystoscopies

Intravesical Chemotherapy

Mitomycin C
An antibiotic derivative that inhibits DNA synthesis via alkylation A larger molecule

systemic absorption rare unless perforation

Reduces recurrence and progression, although inferior to BCG induction & maintenance Attractive due to much less toxic than BCG 20-40mg/20-40mL of sterile water

Palmar Desquamation

MMC Chemical Cystitis

Intravesical Chemotherapy
Doxorubicin, Valrubicin & Epirubicin
Doxorubicin Inhibits topoisomerase II and thus inhibits protein synthesis Shown to prevent recurrence but not progression Valrubicin Approved for treatment of BCG refractory CIS who refuse or are unfit for radical cystectomy 20% complete response Epirubicin Decreases recurrence when compared to TUR alone Not FDA approved in US

Intravesical Chemotherapy Thiotepa & Others

Only agent approved for treatment of papillary urothelial bladder cancer

The original and cheapest intravesical agent

Alkylating agent that is >50% absorbed

Myelosuppression

Gemcitabine & docetaxel intravesically currently being investigated

Early Cystectomy
Should be considered in patients who Micropapillary Variant!
Do not tolerate intravesical therapy Failed attempts at disease control with TURBT +IVT

Lesions not amenable to endoscopic resection Failure of TURBT and intravesical therapy
Recurrence at higher grade and multifocality Progression on intravesical therapy (Grade Progression) Invasion into detrusor (T progression) Especially in HGTa or CIS

Future Fluorescent Cystoscopy

5-aminolevulinic acid (5-ALA)

A precursor to heme biosynthesis is instilled into the bladder

Taken up by neoplasms Blue light excites the agent and can detect otherwise unseen CIS on white light Many false + due to inflammatory lesions

Fluorescent Cystoscopy

Fluorescent Cystoscopy

Long-Term Investigation

Laser ablation therapy for known low-grade papillary tumors

Argon, KTP, Holmium, & Neodynium-YAG In select lower and upper tract tumors with close surveillance No obturator nerve stimulation Not appropriate for new lesions or initial TURBT Collateral damage

Office Fulguration

In low risk and recurrent LGTa papillary tumors or papillomas

Surgical Management of Invasive Bladder Cancer

Indications for radical cystectomy

- Infiltrating muscle-invasive bladder cancer without evidence of metastasis or with low-volume, resectable locoregional metastases (stage T2-T3b) - Superficial bladder tumors characterized by any of the following:

Refractory to cystoscopic resection and intravesical chemotherapy or immunotherapy

Extensive disease not amenable to cystoscopic resection Invasive prostatic urethral involvement

- Stage-pT1, grade-3 tumors unresponsive to intravesical BCG vaccine therapy

- CIS refractory to intravesical immunotherapy or chemotherapy - Palliation for pain, bleeding, or urinary frequency - Primary adenocarcinoma, SCC, or sarcoma

Radical Cystectomy
Radical Cystectomy
Removal of bladder with surrounding fat Prostate/seminal vesicles (males) Uterus/fallopian tubes/ovaries/cervix (females) + Urethrectomy

Pelvic Lymphadenectomy
More is better

Urinary Diversion
Ileal conduit Continent cutaneous reservoir Orthotopic neobladder

Radical Cystectomy

- Midline incision - Thorough intraabdominal exploration (rule out metastatic disease) - Assess resectability of bladder

Step 1: mobilize the urachus from the umbilicus

Step 2: mobilize the bladder from the bowel

Step 3: isolate and transect ureters

Step 4: complete lymph node dissection

Step 5: separate bladder from sigmoid colon

Step 6: complete posterior dissection and cut off bladder blood supply

Step 7: complete anterior dissection and isolate urethra

Step 8: transect urethra and remove specimen

Impact of Surgical Technique on Outcomes

More extended lymph nodes dissection = better outcomes More lymph nodes removed = better outcomes Lower positive margin rate = better outcomes More experienced surgeons = better outcomes

Pelvic Lymphadenectomy
~25% have LN involvement at cystectomy

Accurate staging
Assessment of prognosis Adjuvant therapies (chemotherapy, clinical trials)

Therapeutic benefit
Removal of micrometastatic disease

Pelvic Lymphadenectomy

Modifications in technique
Nerve sparing for potency Prostate sparing Gynecologic organ sparing Anterior vaginal wall sparing Urethral sparing in women Urethral sparing in men

Urinary Diversion
Use of intestinal segment to bypass/ reconstruct/ replace the normal urinary tract Goals:
Storage of urine without absorption Maintain low pressure even at high volumes to allow unobstructed flow of urine from kidneys Prevent reflux of urine back to the kidneys Socially-acceptable continence Empties completely

Ideal diversion has yet to be discovered

Types of Urinary Diversion

ILEAL CONDUIT

(incontinent diversion to skin)

CONTINENT CUTANEOUS RESERVOIR

ORTHOTOPIC NEOBLADDER

(continent diversion to skin)

(continent diversion to urethra)

Figures from www.clevelandclinic.org/health/health-info/docs

Ileal Conduit
15-20 cm of small intestine (ileum) is separated from the intestinal tract

Intestines are sewn back together (reestablish intestinal continuity)

Ileal Conduit
Ureters are attached to one end of the segment of ileum Natural peristalsis of intestine propels urine through the segment Other end is brought out through an opening on the abdomen

Ileal Conduit

Ileal Conduit

Ileal Conduit
ADVANTAGES Simplest to perform Least potential for complications No need for intermittent catheterization Less absorption of urine DISADVANTAGES
Need to wear an external collection bag Stoma complications Parastomal hernia Stomal stenosis Long-term sequelae Pyelonephritis Renal deterioration

Continent Cutaneous Reservoir

Many variations (same theme)
Indiana Pouch, Penn Pouch, Kock Pouch

All use various parts of the intestine

ileum, right colon most commonly

Reservoir
Detubularized intestine- low pressure storage

Continence mechanism
Ileocecal valve (Indiana) Flap valve (Penn, Lahey) Intussuscepted nipple valve (Kock)

Continent Cutaneous Reservoir

INDIANA POUCH

Appendix removed

Right colon is opened lengthwise and folded down to create a sphere

Continent Cutaneous Reservoir

INDIANA POUCH
Ureters attached to back of reservoir (not shown)

RESERVOIR

EFFERENT LIMB (to skin)

Continence maintained by ileocecal valve

Continent Cutaneous Reservoir INDIANA POUCH

Continent Cutaneous Reservoir

DISADVANTAGES ADVANTAGES Most complex No external bag Need for regular Stoma can be covered intermittent with bandaid catheterization Potential complications: Stoma stenosis Stones Urine infections

Orthotopic Neobladder
Currently the diversion of choice
Studer, T-Pouch, Hautmann, Ghoniem, etc.

COMPONENTS: Internal reservoir detubularized ileum Connect to urethra (efferent limb)

Urethral sphincter provides continence

Afferent Limb ureteral connection

Antirefluxing (T-Pouch, Kock) Low pressure isoperistaltic limb (Studer)

Orthotopic Neobladder

Ureters attached

15-20 cm

44 cm

Ileum detubularized
Reservoir Connect to urethra

STUDER ILEAL NEOBLADDER

Orthotopic Neobladder
Isolation of ileal segment

22 cm

22 cm

15-20 cm

Orthotopic Neobladder
Afferent Limb

Detubularization of ileum

Orthotopic Neobladder
Afferent Limb

Reservoir

Opening to urethra

Orthotopic Neobladder

Orthotopic Neobladder
ADVANTAGES No external bag Urinate through urethra May not need catheterization DISADVANTAGES Incontinence (10-30%) Retention (5-20%) Risk of stones, UTIs Need to train neobladder

Choice of Urinary Diversion

Disease Factors
Urethral margin

Patient Factors
Kidney function / liver function Manual dexterity Preoperative urinary continence/ urethral strictures Motivation

Surgeon Factors
Familiarity with various types of diversions

Urinary Diversions
Enterostomal therapist is CRITICAL for success Urinary diversions require lifelong follow-up
Imaging (kidneys/ureters/diversion) Labs (electrolytes, acid-base, B12 levels) Cancer follow-up (surveillance imaging, cytology)

Conclusions
Surgery is the cornerstone of treatment for invasive bladder cancer Accurate staging (after surgery) is the most important determinant of prognosis A properly performed lymph node dissection makes a difference Choice of urinary diversion must be individualized for optimal outcomes

New Frontiers
Laparoscopic cystectomy Robotic cystectomy with intracoporeal diversion