CIN & Cervical Screening

Plan
Part 1: Incidence, pathogenesis, and
prevention
Part 2: Cervical Screening
Part 3: Grading, treatment, and Follow up
Part 1: Incidence, pathogenesis,
and prevention
Introduction
Premalignant condition of uterine cervix
Ectocervix is covered by squamous epitheiam
Endocervix including cervical canal covered by
glandular epithelium
CIN refers to squamous abnormality
Adenocarcinoma in situ, and adenocarcinoma
CIN can be low grade or high grade.
Women with low grade CIN have minimal
potential for developing cervical malignancy
Incidence
4 % in US for CIN 1, 5% for CIN2, 3
High grade lesion are typically diagnosed in
women 25-35 years old
Invasive cancer is commonly after age of 40
Typically 8-13 years afer a diagnosis of a high
grade lesion
Premalignant disease of the cervix
HPV
infection
CIN I
CIN II
CIN III
Cervical
cancer
Normal cervix
Pathogenesis
Role of human papillomavirus (HPV)
Major etiologic agent
Strong association
Necessary for development of neoplasia
Not sufficient alone to cause such disorders cause
many HPV infected women do not develop it
HPV subtype, and persistence of virus
Enviromental (eg, cigarette smoking)
Immunlogic influences
HPV Subtype
Over 100 subtype
40 types specific for anogenital epithelium
Distribution varies by geographic region
Infection with more than one subtype is common
Acquisition of one subtype and clearance of
another are independent events
Subtype determines manifestation of infection
and oncogenic potential of virus
Oncogenic HPV
Low Risk & High Risk Subtypes
Low risk e.g., HPV 6 and 11
do not integrate into host genome
Only cause CIN 1 (10%)
benign condylomatous genital warts (90%)
High risk e.g., HPV 16 and 18
Associated with CIN 2, 3, persistence, and invasive
cancer, can also cause low grade
Low grade (25%), high grade (50-60%)Cancer(70%)

Persistence
HPV is transient and occur in young women
Persistency is a key factor for development of high
grade
Unknown why it persists
The likelihood of persistence
Older age - > 55 years of age (50%)
Duration of infection long infection = long clearance
High oncogenic HPV subtype the longer it persists
Sexual transmission
HPV transmitted sexually
Endemic amongst sexually experienced
individuals
At least 75-85% of sexually active women will
have acquired genital HPV by age 50

Cervical Transformation Zone
Transformation Zone vs SCJ
SCJ where the squamous epithelium meets the
cervical of ectocervix meets columnar epithelium of
endocervix.
Transformation zone is dynamic entity of metaplasia
throughout a womens life, which is the area of
glandular epithelium has been replaced by squamous
epithelium
Transformation zone comprises SCJ + larger area
Primary site of carcinogenic HPV-related CIN& CN
Cuboidal cells at Squamouscolumnar Junction
Molecular Mechanism
Epitheliotropic, once epithelium is infected, the virus
can either persist in cytoplasm or integrate into the
host genome
Remains episomal nonintegrated state
Low-grade cervical lesion
Becomes integrate into human genome
High grade lesion and cancer may develop
Integration into host cell disruptions of viral
regulatory oncoproteins, where E6 binds to p53, and
E7 binds to Retinoblastoma, and suppress their
function, the latter activates IL5&IL6 which are
important in progression of CN 2,3 to over malignancy..
Co-factor in Pathogenesis
Immunosupression cervical cancer is one of
AIDS related malignancy in women
Cigarette smoking with HPV have synergistic
effects on development of CIN and CN
Breakdown products of nicotine cotinine and NNK are
concentrated in cervical mucus and cause cellular
abnormalities
HSV and Chlamydia surrogate marker for
exposure of HPV rather than a causal factor
OCP long term use, as a surrogate marker
Prevention
Primary HPV vaccination
Secondary for cervical cancer rather than
CIN, through appropriate treatment and
prevent progression to malignant disease
Part 2
Cervical Screening
Cervical screening
Prevention of cervical cancer
Early detection by:
Pap smear
HPV test

Pap Smear
George Papanicolaou (1883-1962)
The Pap test aims to identify abnormal cells
sampled from the transformation zone, the
junction of the ecto- and endocervix, where
cervical dysplasia and cancers arise.

Guidelines
ACOG
Start at 21 years
21-29: Pap smear every 3 years
30-65: Pap smear every 3 years OR HPV co-
test every 5 years
Stop at 65 years
Annual screening not recommended
How to prepare?
Before the pap test, patient should avoid:
Having intercourse
Using tampon
Douching
Preferably not during menstruation
Speculum
Insert lubricated speculum
Methods Of Interpretation
For conventional Pap smears, cervical samples
obtained by brush and spatula are plated on a
microscope slide and preserved with fixative.
Thin layer (or liquid-based) cytology, an
alternative to conventional cytologic sampling,
has been widely implemented in the US.
Testing involves transferring samples from the brush
and spatula into a liquid fixative solution; the cytology
lab subsequently traps the loose cells onto a filter
from which they are plated in a monolayer onto a
glass slide
Spatula
Insert spatula and rotate
Smear on a slide
Cytobrush
Insert brush and rotate
Smear on slide
Fixation
Alcohol

Liquid Media

Bethesda
Specimen type (conventional, liquid-based, etc)
Specimen adequacy
Satisfactory for evaluation (note presence/absence of
endocervical/transformation zone component)
Unsatisfactory for evaluation (specify reason)
Specimen rejected/not processed (specify reason)
Specimen processed and examined, but unsatisfactory
for evaluation of epithelial abnormality because of
(specify reason)

Bethesda
General Categorization (Optional)
Negative for intraepithelial lesion or malignancy
Epithelial cell abnormality
Other
Interpretation/result
Negative for intraepithelial lesion or malignancy
Organisms (e.g. trichomonasvaginalis)
Reactive cellular changes associated with inflammation,
radiation, intrauterine contraceptive device
Atrophy
Bethesda
Epithelial cell abnormalities
Squamous
Atypical squamous cells
ASC-US (undetermined significance)
ASC-H (cannot exclude HSIL)
Low grade squamous intraepithelial lesion (LSIL) - mild
dysplasia/CIN I
High grade squamous intraepithelial lesion (HSIL)
moderate and severe dysplasia/CIN II/III
Squamous cell carcinoma
Bethesda
Epithelial cell abnormalities
Glandular
Atypical
Endocervical
Endometrial
NOS
Atypical favor neoplastic
Endocervical
NOS
Endocervical adenocarcinoma in situ (AIS)
Adenocarcinoma
Part 3
Classification and Treatment
CIN Classification
Low-grade squamous intraepithelial lesion
(LSIL)
CIN I (Mild dysplasia) 50%, 30%, 20%, 1-5%
High-grade squamous intraepithelial lesion
(HSIL
CIN II (Moderate dysplasia)
CIN III (Severe dysplasia) 33%, 60-74%



CIN Classification
Diagnosis:
Pap tests
Colposcopy
Endocervical curettage
Cone biopsy or loop electrosurgical excision
procedure (LEEP) which are performed to rule
out invasive cancer
Adequacy of Colposcopy

Must evaluate the entirety of the lesion

Must evaluate the entirety of the SCJ

Failure of either criteria is an inadequate
colposcopy and leads to changes
TREATMENT
Mainstays of treatment of high-grade cervical
intraepithelial neoplasia (CIN) are excision or
ablation
Excisional treatments are:
referred to as cone biopsies or cervical conization
Ablative treatments
use an energy source (eg, cryotherapy, laser) to
destroy the transformation zone
Laser
TREATMENT
What to choose
Factors affect:
Efficacy: the efficacy rate for both ablation and excision is
approximately 90 to 95 percent
Diagnostic specimen: no specimen is removed in ablative. For
this reason, an excisional procedure is required for diagnostic
purposes in the following situations:
High risk of invasive disease
Glandular disease is present
Diagnostic uncertainty
Future obstetric risks Excision has been associated with an
increased risk of adverse obstetric outcomes
Morbidity Excisional methods are typically thought to be
associated with greater morbidity than ablative therapy.
However, the meta-analysis of randomized trials found no
significant difference in adverse effects

What to choose?
For women with CIN 2,3 and an adequate
colposcopy, either an excisional treatment or
an ablative treatment is appropriate.
For women with an inadequate colposcopy,
recurrent CIN 2,3, an excisional procedure is
preferred

What to choose?
For young women with CIN 2,3 and an
adequate colposcopy, either observation or
treatment is acceptable. If treatment is
performed, either excision or ablation may be
used.
What to choose?
Women with CIN 1 Most women with CIN 1
are managed with follow-up testing, and
treatment is only indicated if CIN 1 persists for
longer than two years.
Hysterectomy for:
1. CIN 2,3 with a positive conization margin
2. who have completed childbearing
3. who would benefit from a definitive
procedure
4. women who are not willing or able to comply
with long-term follow-up
Outcome:
The rate of recurrent or persistent CIN is 5 to 17 percent
despite therapy with any of the excisional or ablative
techniques

Higher rates of persistent disease are associated with:
Large lesion size (eg, greater than two thirds of the surface of the
cervix)
Endocervical gland involvement
Positive margin status
Continuing human papillomavirus (HPV) DNA positivity (especially
with HPV 16) six months or more post-treatment

The prognosis after treatment of CIN differs based upon the
presence of CIN at the margin of a conization specime
FOLLOW-UP AFTER TREATMENT:
After treatment with excision or ablation, women with
CIN 2,3 should be followed with:
Human papillomavirus (HPV)/cervical cytology co-testing in
12 and 24 months.
If both co-tests are negative, co-testing should be repeated in
three years.
If there is abnormal cytology or a positive HPV test during follow-
up, colposcopy with endocervical sampling should be performed.
If CIN 2,3 is identified at the margins of an excisional
procedure or post-procedure endocervical curettage
(ECC), cytology and ECC at four to six months is
preferred.