Screening for

Female Genital
Tract Malignancy
By
Helmy A. Rady
Screening Generally
Is to seek about
certain problem in
certain high risk
gp.
Concept
Prevention is better than
cure.
 Phases of Tumourgenesis
Normal cells Dysplasia Invasive
asymptomatic
As cancer ovary
Cancer cx.
End. C.

Invasive
symptomati
 Most Cancers Develop
In The Unscreened
And The Underscreened.
 World Health Organization
Criteria for a Screening Program
1.The condition sought should be
an important health problem.

2.There should be accepted

treatment for patients with
recognized disease.

3.Facilities for diagnosis and

treatment should be available.
4.There should be a recognizable
latent or early symptomatic
stage.

5.There should be a suitable test

or examination.

6.The test should be acceptable

to the population.
7.The natural history of the
condition, including
development from latent to
declared disease, should be
adequately understood.

8.There should be an agreed

policy on whom to screen.
9.The cost of case finding
(including diagnosis and
treatment of patients
diagnosed) should be
economically balanced in
relation to possible expenditure
on medical care as a whole.

10.Case finding should be a

continuing process and not a
Incidence of Gynecologic
Cancers in Egyptian Women with
cancer
25
20

Percent 15
10
5
0
Breast Cervical Ovarian Uterine
Cancer Cancer Cancer Cancer
Source: GLOBOCAN 2000.
Endo. cancer
 Risk factors
DM(CCS)
Early
Hypertension(CCS)
menarche(<12yrs)
HRT
Tamoxifen
Late White race
menopause(>52 COC use has a
yrs) protective effect
Long history of Endometrial
infertility hyperplasia(simple
Anovulation and 2%; Atypical
PCOS glandular 23%)
Obesity especially
truncal
Endometrial Cancer Screening
 Routine Papanicolaou's (Pap) test is
inadequate and endometrial cytology is
too insensitive and nonspecific to be
useful in screening for endometrial
cancer even in a high-risk population.
 Transvaginal ultrasound examination of
the uterus and endometrial biopsy are
too expensive to be employed as
screening tests

Screening of high-risk individuals could at

best detect only half of all cases of
endometrial cancer.
 Most patients who have endometrial cancer
present with abnormal perimenopausal or
postmenopausal uterine bleeding early in the
development of the disease, when the tumor
is still confined to the uterus.

Application of an appropriate and accurate

diagnostic test in this situation usually results
in early diagnosis, timely treatment, and a
high cure rate.
Papanicolaou Test
50 % of women with endometrial cancer will have
normal findings.

Liquid-based cytology appears to increase the

detection of glandular abnormalities .

Benign endometrial cells are recorded

occasionally on a routine Pap smear in women 40
years and older.

Postmenopausal women with such findings have

nearly a 3- to 5 % risk of endometrial cancer.
Endometrial Sampling
Preferred for the initial evaluation of women
with bleeding suspicious for malignancy.
if sampling techniques fail to provide sufficient
diagnostic information, D&C may be required
to clarify the diagnosis.
Transvaginal ultrasound

The first step in woman presenting with

abnormal uterine bleeding.
Normality for TVU is defined as a thin
symmetrical endometrial line of less than 45
mm double endometrial thickness.
If the biopsy shows endometrial cancer,
treatment is needed.
If the biopsy sample is normal or non-
diagnostic or if the uterine cavity is inaccessible
in a woman with an abnormal endometrium on
TVU colour doppler TVU and saline-infusion
sonography or outpatient hysteroscopy.
Transvaginal ultrasound

The value of TVU in symptomatic

premenopausal women and those using
hormone-replacement therapy is lower
because the normal endometrial thickness
varies with circulating concentrations of female
steroid hormones.
Endometrial cytology
has a lower sensitivity to detect endometrial
cancer than endometrial biopsy.
33% of endometrial carcinomas are falsely
classified as hyperplasia.
Laboratory Testing
serum CA125 level
Preoperatively, an elevated titer indicates the
possibility of more advanced disease.
useful in patients with advanced disease or
serous subtypes to assist in monitoring
response to therapy or during post treatment
surveillance.
Imaging Studies
Chest radiograph.
Computed tomographic (CT) scanning or
magnetic resonance (MR) imaging usually is
not necessary .
However, MR imaging occasionally can help to
distinguish an endometrial cancer with cervical
extension from a primary endocervical
adenocarcinoma.
 FIGO Surgical Staging
System
Tumor limited to endometrium IA
Tumor invades less than 50% of myometrium IB
Tumor invades at least 50% of the myometrium IC
Tumor extends to the glandular epithelium of the endocervix IIA
Tumor extends to the stromal connective tissue of the cervix IIB
Tumor involves serosa and/or adnexa (direct extension or IIIA
metastasis) and/or cancer cells in ascites or peritoneal washings
Vaginal involvement (direct extension or metastasis) IIIB
Pelvic and/or paraaortic lymph node metastasis IIIC
Tumor invades bladder mucosa and/or bowel mucosa IVA
Distant metastasis (i.e., inguinal nodes, omentum) IVB
CX
Epidemiology of Cervical Cancer

Magnitude of the Problem: -

500,000 new cases identified
each year
80% of the new cases occur in
developing countries
At least 200,000 women die of
cervical cancer each year
Cervical cancer is the third most
common cancer worldwide
Epidemiology of Cervical
Cancer cont.

Most common female

cancer in developing
countries:
leading cause of cancer death
in women.
80-85% cases seen at late
incurable stages.
 Epidemiology of Cervical
Cancer cont.
High risk patients:
High parity?!!
1)Exo cx: Multiple partner
Genital infections
HPV & HSV II
Smoking
Sexual behaviour of
womens partner
 Epidemiology of Cervical
.Cancer cont
Age
2. Endo cx Obesity
Like endometrial D.M.
C. Hypertension
Nulligravida &
Virgin
Low parity
Tamoxifen
 HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68
Infection with oncogenic HPV types is the most
significant risk factor in cervical cancer etiology.
HPV is a main cause of cervical cancer.
Analysis of around 10,000 specimens from women
in 22 countries indicated prevalence of HPV DNA
in cervical cancers worldwide = 99.7%.
 Pathogenesis of CIN
Metaplasi
St.sq.
Columner a
Dysplasi epith.
epith. a
CIN
Chlamydia
Dysplasia H.S.V. - H.P.V-
by oncogen Sperm TV.
Ptn.
Histones &
protamines
Morphological Changes of
Cervical Cancer
Prevention of Cervical Cancer
Cervical cancer is a preventable disease
Primary prevention:
Education to reduce high risk sexual behaviour
Measures to reduce/avoid exposure to HPV and
other STIs
Secondary prevention:
Treatment of precancerous lesions before they
progress to cervical cancer (implies practical
screening test)
Now : HPV vaccines.
 Secondary Prevention of
Ca.Cx.
Key Point is to detect

precancerous lesions BY
A good screening method

PAP smear test is considered to be

the gold standard Has limitations ?
Alternatives to Pap Smear What are
they?
Why screening for
cervical cancer?
1. Is relatively common in
unscreened women.
2. Has a relatively good
prognosis if found early stage in
its natural course of disease.
3.Has a characteristic natural
course that is a slow progression
through a premalignant stage.
 Why screening for
cervical cancer? Cont
4. A premalignant stage can be
detected by noninvasive means (the
Pap smear &VIA).
5. There are effective treatment
modalities to eradicate premalignant
lesions and early invasive cervical
cancer.
 Screening by Pap. Cx. Smear
:a. Importance unscreened female have ten fold
risk > screened female

b. To
whom : sexually active female (18-35 y)
- Every
- Specially, high risk group.
:c. When
- Annually up to the age of 35y
- No need to extend screening > 35y if smear is N.
- At each pregnancy
- If new risk factors appear after 35y.
d- If + ve smear colposcopy
 Alternatives to Cytology
Visual Inspection of the cervix:
Unaided: Downstaging.
Aided with acetic acid: VIA:
Naked eye
Aided with acetic a and magnification( VIAM)
Colposcopy
Automated pap smear
HPV DNA test
Infrared Spectroscopy & Laser Fluorescence
Limitations of Pap Smear
Complex laboratory test
Requires trained cytotechnician for reading
and pathologist for review
Continuous monitoring needed to maintain
high-quality results
Reports often take minimum 1-2 weeks to
obtain
Follow-up of women is difficult
Usually available only in large cities in many
countries
COMPARISON BETWEEN
SCREENING METHODS
Effective Safe Practical Affordable Available
Visual Yes Yes Yes Yes Yes
Inspection:
AA
Visual No Yes Yes Yes Yes
Screening:
Unaided
Automated Yes? Yes ? No No
Pap Screening
HPV Yes Yes ? ? Yes
Screening
Cervicography Yes? Yes ? ? Yes
HPV Vaccine ? ? Yes ? No

Source-Program for Appropriate Technology in Health [PATH] 1997.

VIA ..represents a proven,
simple means of identifying
cervical intraepithelial neoplasia
in developing countries.

Commentary: P. Blumenthal. Detection of

cervical intraepithelial neoplasia in developing
countries. The Lancet March 13, 1999
Comparison between :
VIA and Cytology

Sensitivity(%) Specificity (%)

Cytology 47--62 60-95

VIA 76-84 79-83

VIA& PAP SMEAR
Recent studies have demonstrated
that "VIA is a safe, simple and
effective adjunct to the Papanicolaou
smear for cervical cancer screening
and can be helpful in reducing
referrals for colposcopy without
compromising quality of care.
MEANING OF Acetowhite
All acetowhite patches are not
cancer:
Any of these epithelial changes can
become acetowhite:
Healingor regenerating epithelium
Congenital transformation zone
Inflammation
Immature squamous metaplasia
MEANING OF
Acetowhite cont.
HPV infection
CIN
Adenocarcinoma
Invasive squamous
cell carcinoma
 Early Detection Works!

A precursor lesion of cervical cancer

develops slowly, over one or two
decades, and can be easily treated
Therefore . . . screening (detection of
the precursor lesions) and effective
treatment cure.
 Symptoms (ca cx)

Spotting (post-coital), intermittent

painless bleeding
Pain
Smelling discharge (foul,)
Dysuria, rectal bleeding
Leg edema
Distal metastasis
Janvier 2009
Burden of
cervical
cancer in
Egypt
2713 new cases of
cervical cancer / year
2178 deaths with
cervical cancer / year
Prevalence of HPV or
genital warts : No
data
WHO Information Centre on HPV and
Cervical Cancer 2007

49
Prevention Levels of Cervical Cancer
Level

I II III IV

Normal Communication & Information Death

PV e

ive
t H al

t H iv

tic
PV

as
ien ic

as

sta
ns og

r s i nv

I nv
n

ta
T ol

ste
Pe e-i
Bi

Me
ra

Pr

Stage
50
 PAP
smear

51
Bethesda 2001 Cervical
Cytology Classification
Negative for squamous intraepithelial lesion or malignancy

Epithelial cell abnormalities: Squamous Cell

- Atypical Squamous Cells of undetermined significance (ASC-US)
- Atypical Squamous Cells, cannot exclude HSIL (ASC-H)
- Low-Grade Squamous Intraepithelial lesion (LSIL)
encompassing: HPV/ mild dysplasia (CIN1)
- High-Grade Squamous Intraepithelial lesion (HSIL)
encompassing: moderate and severe dysplasia (CIN2/CIN3/CIS)
or with features suspicious of invasion (if invasion is suspected)
- Squamous Cell Carcinoma

52
Bethesda 2001 Cervical
Cytology Classification

Epithelial cell abnormalities: Glandular Cell

- Atypical Glandular Cells (AGC)
endocervical cells (NOS)
endometrial cells (NOS)
glandular cells (NOS)
- Atypical Glandular Cells (AGC), favor neoplastic
(endocervical, glandular)
- Endocervical Adenocarcinoma in situ
- Adenocarcinoma
. endocervical . endometrial
. extrauterine . Not otherwise specified (NOS)

53
 HPV DNA testing
Testing for high-risk HPV types has been proposed both
as a primary screening modality (in concert with, or instead
of, cervical smear testing) and as a method to triage Pap
smear results that are equivocal or show low-grade
abnormalities.

The high costs of HPV testing, including high

infrastructure costs, continue to be a barrier for large-scale
implementation.

New research is focusing on development of low-cost

HPV diagnostic assays for use in resource limited settings.
54
 Alternative Screening
Methods
The operational difficulties in organizing and implementing quality community-
based screening programs using the Pap smear have given rise to an increasing
interest in evaluating and implementing alternative screening strategies that may
be easier to apply, and are lower in cost and technology.

VIA (Visual Inspection using Acetic acid)

VILI (Visual Inspection using Lugols Iodine)

See and Treat Protocols

55
 VIA procedure
Patients will be examined in the lithotomy position.
Careful inspection of the external genital organs including the vulva, perineum and

perianal regions.
Introduction of a Cusco vaginal speculum without the use of lubricants, but may be

moistened with tap water.

Careful inspection of the cervix and vaginal walls with identification of the

Transformation Zone (TZ) after clearing any secretions using a cotton-tipped swab.
Application of acetic acid 3-5% on the cervix using a cotton-tipped swab and

inspection of the cervix 30-60 seconds later.

Identification and description of any acetowhite lesion on the cervix with detailing

of the following:
-Size and location of the lesion in relation to the TZ.
-Degree of acetowhiteness (translucent, shiny or opaque).
-Borders (well or ill-defined).
-Surface (flat or raised).
-Vasculature (punctation, mosaicism or abnormal-shaped vessels).
All identified lesions will be documented on the patients sheet using diagrammatic

illustrations for the cervix as well as for the external genitalia.

56
 Interpretation
The patient will be described as having a VIA negative
test if:
-No acetowhite lesions could be seen on the cervix, or
-Presence of physiologic metaplasia described as
translucent acetowhite areas with confluent ill-defined
borders located within the TZ.

VIA positive test will be considered if any acetowhite

lesion is identified on the cervix excluding physiologic
metaplasia.

Any lesions involving the external genitalia or the vaginal

walls will be reported separately on the patients sheet.
57
Further management
directed biopsies if necessary.

Histopathological examination of the biopsy specimens

the descriptive findings of:

-Pre-invasive lesions (CIN 1, 2 or 3).

-Invasive cancer (squamous cell carcinoma,
adenocarcinoma or others).
-No identifiable pathological lesions.

58
Further management
Patients having a VIA positive test with no identifiable
pathological lesions in the biopsy specimen will be further
investigated using Colposcopic examination and HPV testing.

VIA positive patients with pathological documentation of pre-

invasive lesions will be managed according to the American
Society for Colposcopy and Cervical Pathology (ASCCP)
guidelines.

VIA positive patients with pathological documentation of invasive

cancer will be managed according to the National Comprehensive
Cancer Network (NCCN) guidelines.

59
HPV and Cervical Cancer

All Women
HPV and Cervical Cancer

About 80% of Women

will be infected with
HPV in their lifetime
 HPV and Cervical Cancer
About 7% of
Women will
have an
abnormal Pap
test
 HPV and Cervical Cancer
will have a % 30~
high grade
precancerous
lesions
 HPV and Cervical Cancer
About 10,000
Women (per
year in the
United States)
will develop
cervical cancer
 Established and Potential Cofactors
Involved in HPV Carcinogenesis
Coinfection
With Other
Sexual History Sexually
Transmitted
Infections
OCs
HPV Diet
Smoking

Endogenous
HIV Hormones

Cervical Genetic
Cancer Factors

.Castellsagu X, Muoz N. J Natl Cancer Inst Monogr. 2003;31:2028

HPV
Nonenveloped double-
stranded DNA virus
>100 types identified

~3040 anogenital

~20 oncogenic*
? Most common
Nononcogenic**
types
? Most common
Estimated World Burden of HPV-Related Diagnoses Focus on Cervical Disease and Genital
Warts

Cervical Cancer: 0.5 million

cases/year
High-grade precancerous lesions:
10 million

PV
cH Low-grade cervical lesions: 30

V
HP
million
ni
ge

ic
en
pe co

Genital warts: 30
og
ty on
s

million
pe n c
to

ty no
le

s
no
ab

to
ut
b

HPV infection: 660

tri

bl

million
ta
At

bu
tri
At

. World Health Organization, Geneva, Switzerland: World Health Organization; 2005:138 .1

. World Health Organization. Geneva, Switzerland: World Health Organization; 1999:122 .2
.World Health Organization. WHO Office of Information. WHO Features. 1990;152:16 .3
 HPV Types 6, 11, 16, and 18 in Cervical
Cancer and Other Anogenital Diseases
Prevalence
of HPV
Type

Clifford GM, Rana RK, Franceschi S, et al. Cancer Epidemiol Biomarkers Prev. 2005;14:1157-1164. 2. Clifford GM, Smith JS, Aguado T, et al. Br J Cancer.. 1
2003;89:101-105. 3. Muoz N, Bosch FX, de Sanjos S, et al. N Engl J Med. 2003;348:518527. 4. Clifford GM, Smith JS, Plummer M, et al. Br J Cancer.
.2003;88:6373. 5. Gissmann L, Wolnik L, Ikenberg H, et al. Proc Natl Acad Sci USA. 1983;80:560563
Spectrum of Changes in Cervical Squamous Epithelium Caused by
HPV Infection
Normal /HPV Infection /CIN 2 / CIN 3
Cervix CIN 1 Cervical Cancer

Adapted from Goodman A, Wilbur DC. N Engl J Med. 2003;349:15551564. Copyright 2003
. Massachusetts Medical Society. All rights reserved. Adapted with permission
 Mechanisms of HPV Transmission
and Acquisition
Sexual contact
Through sexual intercourse
Genitalgenital, manualgenital, oralgenital
Genital HPV infection in virgins is rare, but may result from
nonpenetrative sexual contact.
Proper condom use may help reduce the risk, but is not fully
protective against infection.
Nonsexual routes
Mother to newborn (vertical transmission)
Undergarments, surgical gloves, biopsy forceps
Hypothesized but not well documented; would be rare
Most infected individuals are unaware that they are
infected and may unknowingly spread the virus.

Kjaer SK, Chackerian B, van den Brule AJ, et al. Cancer Epidemiol Biomarkers Prev. 2001;10:101106. 2. Winer. 1
RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Am J Epidemiol. 2003;157:218226. 3. Fairley CK, Gay NJ,
Forbes A, Abramson M, Garland SM. Epidemiol Infect. 1995;115:169176. 4. Herrero R, Castellsagu X, Pawlita M,
et al. J Natl Cancer Inst. 2003;95:17721783. 5. Manhart LE, Koutsky LA. Sex Transm Dis. 2002;29:725735. 6.
Smith EM, Ritchie JM, Yankowitz J, et al. Sex Transm Dis. 2004;31:5762. 7. Ferenczy A, Bergeron C, Richart RM.
Obstet Gynecol. 1989;74:950954. 8. Roden RBS, Lowy DR, Schiller JT. J Infect Dis. 1997;176:10761079. 9. Anhang
PATIENT INSTRUCTION
No intercourse during the 24 hours prior to the test
No douching during the 24 hours prior to the test
 Technique
Visualize entire cervix if possible
Carefully remove any obscuring discharge
Sample ectocervix first with spatula
Sample endocervix with gentle cytobrush rotation
Apply material uniformly to slide
Fix rapidly with spray or liquid fixative
 Technique
Hold spray fixative 10 inches away from slide
Collect cells before bimanual exam
Avoid contamination with lubricant
Test for GC and Chlamydia after pap smear
INTERPRETATION/RESULT
Negative for Intraepithelial Lesion or Malignancy
Organisms
Trichomonas vaginalis
Fungal organisms morphologically consistent with Candida
species
Shift in flora suggestive of bacterial vaginosis
Bacteria morphologically consistent with Actinomyces species
Cellular changes consistent with herpes simplex virus
INTERPRETATION/RESULT (Cont.)
Negative for Intraepithelial Lesion or
Malignancy
Other non-neoplastic findings (Optional to report; list
not comprehensive)
Reactive cellular changes associated with
Inflammation
Radiation
Intrauterine contraceptive device
Glandular cells status post hysterectomy
Atrophy
INTERPRETATION/RESULT (Cont.)
Epithelial Cell Abnormalities
Squamous cell
Atypical squamous cells (ASC)
ASC-US
ASC-H
Low-grade squamous intraepithelial lesion (LSIL)
Encompassing: human papillomavirus/mild dysplasia/cervical
intraepithelial neoplasia (CIN) 1
High-grade squamous intraepithelial lesion (HSIL)
Encompassing: moderate and severe dysplasia, carcinoma in situ;
CIN 2 and CIN 3
Squamous cell carcinoma
INTERPRETATION/RESULT (Cont.)
Glandular cell
Atypical glandular cells (AGC) (specify endocervical,
endometrial, or not otherwise specified)
Atypical glandular cells, favor neoplastic (specify
endocervical or not otherwise specified)
Endocervical adenocarcinoma in situ (AIS)
Adenocarcinoma
Endocervical
Endometrial
Extrauterine
Not otherwise specified (NOS)
THE WHO AND BETHESDA SYSTEM
TERMINOLOGY

WHO histological terms Bethesda Cytological Terms

CIN 1/ Mild Dysplasia LSIL

CIN 2 / Moderate Dysplasia HSIL

CIN 3 / Severe Dysplasia HSIL

CIN 3 / Carcinoma in Situ HSIL

ASCCP Management Guidelines
ASC-US

Repeat Cytology
mos X 2 6@ HPV DNA Testing

Colposcopy

When liquid-based cytology is used, or when co-collection

for HPV DNA testing can be done, "reflex" HPV DNA
testing is the preferred approach

Wright TC Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ, for 2001 ASCCP-Sponsored Consensus
Conference. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities.
.JAMA. 2002;287:2120-2129
Patient Management Using HPV Triage

ASCUS

HPV TEST

Low Risk + or + HPV

HPV

COLPOSCOPY
Repeat Pap and/or
HPV Test in 12 mo.
or return to routine
screening at
discretion of
High-grade Squamous Intraepithelial
Lesion (HSIL)
0.45% of cytology reports
75% will have biopsy-confirmed CIN II-III
1-2 % invasive Cervical Ca
An immediate Leep or Colposcopy/ECC is
acceptable (except in pregnancy or adolescents)
Recommended Management of Women with HSIL

All should have Colposcopy

Managing Women with HSIL
UNACCEPTABLE STRATEGIES
Ablation is unacceptable in the following
circumstances:
Colposcopy has not been performed
CIN II-III is not identified histologically
ECC identifies CIN of any grade

Triage utilizing either of the following is

unacceptable
Repeat cytology
HPV DNA testing
AGC frequency and association with CIN

Mean frequency of AGC 0.3 %

Associated CIN 1, 2, or 3 9 - 54 %
AGC assoc. with AIS 8%
AGC assoc. with carcinoma 9%

Jones and Davey Arch Pathol lab Med 2000,124:672

Jones and Novis. Arch Pathol Lab Med 2000;124:665
Ronnett et al, Hum Pathol 1999;30:816
Veljovich et al, Am J Obstet Gynceol 1998;179:382
Soofer and Sidaway Cancer 2000;90:207
Recommended Management of Women with AGC

All should have

Colposcopy
ECC
Conclusion
MANAGEMENT OF CIN
TERMINOLOGY
LEEP
LEEP
LONG-TERM COMPLICATIONS OF THE
TREATMENT
Cervical stenosis
The risk correlates with the size of the cone and
menopausal status
Stenotic cervix impairs the ability to examine the
transformation zone and endocervical canal
Increases the difficulty of office procedures
Concerns in labor
Hematometra or pyometra can occur

Gynecol Oncol 2005 Mar;96(3):771-5

LONG-TERM COMPLICATIONS OF
THE TREATMENT
Infertility
Treatment of CIN does not appear to impair fertility
Pregnancy loss and preterm birth
Treatment of CIN is associated with preterm birth

Lancet. 2006 Feb 11;367(9509):489-98

The Squamocolumnar junction
Before puberty SCJ is a sharply demarcated line and is
.situated at or just inside external cervical os

+ E2
TZ
TZ

Before At Squamous After

puberty puberty metaplasia menopause
 Anatomically TZ is situated at
external os extending a bit wider
onto ectocervix below.
TZ is the cancer-bearing area of
cervix with >90% of cervical cancer
taking origin from metaplastic
squamous epithelium of TZ.
Early coitarche exposes TZ at early
age to oncogenic viruses.
 Neoplasia can be regarded as a complex
failure of cellular hemostasis resulting in
uncontrolled cellular proliferation in a
population of cells that do not
communicate normally with the
surrounding tissues with subsequent
expansion, local invasion and distant
metastasis.

Human genome contains genes with the

potential of causing cancer ( Oncogenes) ,
as well as genes having the ability to block
malignant growth ( Tumor suppressor
genes).
 HPV (16, 18) DNA
The initiating event
in cervical dysplasia
and carcinogenesis is Integrated into
likely to be infection host DNA
with HPV.
HPV infection has E6 & E7 in the
been detected in up viral genome
to 99% of women
with squamous
Protein byproducts
cervical carcinoma.
Subtypes, 16 and 18,
are found in up to P53, Rb
62% of cervical
carcinomas
Unchecked
cellular growth
 Endocx Columnar
Epithelium
At puberty and During pregnancy

Exposure to low
pH of the vagina

Physiological squamous
Risk factors
metaplasia Coitus-
No risk factors HPV-
Atypical Metaplasia
.Normal T.Z
NL immunity
.Abnormal T.Z
No progression-
Regression- Immune
Suppression

Invasive CIN
Carcinoma CIS
Nomenclature & Classification
 Cervical Intraepithelial Neoplasia [CIN]
Syn:
Pre-invasive cancer
Pre-clinical Cancer
(FIGO) Stage [0] Carcinoma of the Cervix

Def:
Spectrum of intraepithelial cellular changes
(dysplasia or atypia) suggestive of neoplasia
 :Dysplasia

Loss of normal maturation, stratification and

differentiation of squamous epithelium of cervix (mainly
metaplastic squamous epithelium of T.Z.).

Dysplastic (atypical) cellshave the following criteria:

Dyskaryosis (Mild, moderate, severe)

MitosIs
Pleomorphism** (Anisocytosis, Anisonucleosis, Polychromasia)
 :Grades of CIN

According to the degree of dysplasia;

CIN I = mild dysplasia
CIN II = moderate dysplasia
CIN III = severe dysplasia or carcinoma in situ (CIS)
Cervical Intraepithelial Neoplasia [CIN]

I II

III
 Recent nomenclature of CIN
(Bethesda System)
Used in USA, It is simple and has better clinical
correlation.

CIN I = Low grade squamous intraepithelial

lesion (LG/SIL) This includes HPV
.changes
CIN II
High grade squamous intraepithelial
CIN III
lesion (HG/SIL)
CIS
 :Significance of CIN

Not all cases of dysplasia of the cervix signify cervical

neoplasia.
Mild degrees of dysplasia (CIN I/II) may occur in some
benign conditions as:
1. Cervical infections:
a. HPV infection
b. Chlamydia trachomatis
c. Trichomonas vaginalis

2. Pregnancy: cervical cell dysplasia reverts to normal

after the end of pregnancy (after puerperium).
3. Oral contraceptives: long term use causes dysplastic
changes which regress after pill discontinuation.
 :Progress of CIN to invasive cancer

CIN I may revert to normal if left untreated in a minority

of cases. However most cases undergo progress to
higher grades CIN II/III.
Risk of invasion of CIN I/II is not clearly defined.
CIN III mostly develops from CIN I and II, however in
some cases of CIN III, lesions probably arise as such.
90% of CIN III progresses to invasive cancer over 10-15
years if left untreated.
CIN III should be promptly treated once diagnosed.
Diagnosis of CIN
CIN is a pre clinical entity; with no
symptoms or signs, and it is hence
detected in the context of
Screening for Cervical
Malignancy or During
Cytological or Colposcopic
examination of the cervix for other
indications
 I. Cervical Cytology
Microscopic examination of the exfoliated
cervical epithelial cells has been first
.advocated by papnicolauo in 1943
He also advocated a classification system
based on the nature of the cells found on the
.cytology specimen
I. Cervical Cytology
 I. Cervical Cytology

Class Diagnostic terminology

I normal
II A Inflammatory atypia
B or R Squamous atypia
C HPV
III CIN I/ CIN II/ CIN III
IV CIS
V Squamous cell carcinoma
I. Cervical Cytology
 I. Cervical Cytology

Indications of pap test

Screening
Inflammatory and infectious cervical lesion
Follow up after CIN treatment
Suspicious cervical lesion
I. Cervical Cytology
 I. Cervical Cytology

Sensitivity of 65% and

Specificity of 60% to 90% in
recent reviews
in detecting CIN II and III
Detect 30% of new cancer cases
each year
This is due errors of sampling,
fixation, or interpretation.
 I. Cervical Cytology
Sampling error; the lesion too small to
exfoliate cells or the device did not pick
up the cells and transfer them to the
glass slide.
Preparation error; poor fixation on the
glass slide, leading to air-drying and
inability to interpret results. The slide
may be too thick or obscured by vaginal
discharge, blood or mucus.
Interpretation error; occurs when the
cells are there but not identified.
 I. Cervical Cytology

Liquid ewas FDA approved to avoid

interpretation errors.
I. Cervical Cytology
I. Cervical Cytology
I. Cervical Cytology
 I. Cervical Cytology

The cytologic diagnosis of ASC-US is

associated with a 10 to 20% incidence of CIN
I and of 3 to 5% risk for CIN II or III.

Management options include; Repeat

cytology every 4 to 6 months with referral
for coloposcopy if any subsequent
abnormality is detected, immediate
Coloposcopy and HPV testing.
 I. Cervical Cytology

Immediate coloposcopy is assumed to be

the most sensitive method for detecting CIN
II or III.
Several studies, however, have documented
the usefulness of HPV testing in the
assessment of ASC-US pap test.
HPV testing can identify 90% of the patients
with CIN II or III.
 I. Cervical Cytology

ASC-US/LSIL Triage Study (ALTS)

concluded that
HPV triage is highly sensitive in
identifying CIN II
and III and it cuts the rate of referral
to
coloposcopy by 50%.
It concluded that LSIL should be
referred for
 .Colposcopy

The colposcope is simply a light source and a

magnifying lens.
The power of magnification is about 5 to 40 times.
 .Colposcopy
: Normal findings. 1

The transformation zone (TZ) including the

grape-like translucent pink columnar
epithelium (the upper limit of the TZ), the
smooth pale pink stratified squamous
epithelium and sheet, tongues of metaplastic
epithelium.
Gland openings and Nabothian follicles are
normal findings.
Colposcopy
 Colposcopy
: Abnormal findings. 2

Aceto-white epithelium: after application

of acetic acid (3%).
Leukoplakia (before acetic acid) which
may hide any lesion till CIS.
Punctuations: proliferation of the rete
pegs.
Mosaics.
 Colposcopy

Abnormal shaped vessels: only in

invasive cancer. Vessels appear short,
bizarre with abnormal course make sudden
curves, bends, appear as commas, earth
worms, spaghetti or cork screw.
Colposcopy
Colposcopy
 Colposcopy
3. Unsatisfactory colposcopy; inability to
visualize the upper limit of the TZ or even the
whole TZ.
ECC or Cervical Cone biopsy should be done.
Endocervical Curettage
ASCCP guidelines do not require
endocervical curettage. In cases when an
endocervical sample is needed, a cytobrush
is sufficient for sampling the endocervical
canal.
CAUSES OF NON-CORRELATION BETWEEN
CYTOLOGY AND COLPOSCOPY
Cervical lesion is in the endocervical canal, or not in
the
cervix.
Colposcopic findings are not apparent to the
examiner,
although the lesion is present. (eg. Severe atrophy
obscures the
colposcopic findings).
The biopsies performed did not include the visualized
lesion.
The laboratory did not identify the lesion within the
submitted
biopsies. (Orientation of the biopsy, initial sections of
the
paraffin embedded tissue did not include the lesion.)
.Cervical cone biopsy
 .Cervical cone biopsy
Conization is indicated for the diagnosis
in women with HSIL;

Limit of the lesion cannot be clearly

visualized with colposcopy.
The SCJ is not seen at colposcopy.
Lack of correlation between cytology,
biopsy and colposcopy.
Micro-invasion suspected
Atypical Glandular Cells are an important
issue in the cervical cytology.
They carry a risk of development to
adenocarcinoma in situ and invasive
adenocarcinoma
The term micro-invasive does not hold true in
adenocarcinoma of the cervix.
Once confirmed in cytology, cervical brush
cytology, endocervical curettage or
conization are advocated.
 MANAGEMENT OF ASC-H

Refer directly to colposcopy*

Do not perform HPV testing*

Wright et al, 2001 Consensus Conference, submitted

MANAGEMENT OF ASC-US
Acceptable Options:
* Follow-up with repeat cervical cytology in 6 and
12 months; if ASC-US or more severe, refer to
colposcopy.

* Perform HPV DNA testing for high-risk HPV

types;
- if HPV negative: return to screening in 12 mon
- if HPV positive: repeat cervical cytology in
6 & 12 months, if ASC-US or more severe, refe
to
colposcopy. Use of HPV DNA testing in late
 HPV Triage for ASC-US Pap test

| ________
____________

| |
HPVHPV positive
negative
| |
repeat papcolposcopy or
12
.mos
.repeat pap at 6 & 12 mos
Manos MM, et al, JAMA 281:1605-10, 1999
 MANAGEMENT OF LSIL

Recommend option:
* Refer directly to colposcopy.

* If colposcopy and biopsies fail to identify

CIN,
follow-up with repeat cytology at 6 and 12
months,
refer to colposcopy if repeat is ASC-US or
more severe.

* acceptable option to follow with Pap in 6

and 12 months with referral as above, in
special circumstances.
Wright et al, 2001 Consensus Conference, submitted
 MANAGEMENT OF HSIL
Recommend option:
* Refer directly to colposcopy.

* If colposcopy and biopsies fail to identify

CIN,
review of the original cytology, biopsy and
colposcopy findings are recommended.
* If the above review confirms HSIL, a
diagnostic
excisional procedure, such as electro-loop
excision,
of the transformation zone is recommended
in
 MANAGEMENT OF AGC
:Recommend option
* Refer directly to colposcopy.
* Colposcopy should include endocervical
sampling.

*In symptomatic women, and women over 35

years
of age, endometrial sampling should also be
performed.

* A diagnostic cervical cone biopsy may be

needed,
and referral to a clinician experienced in
MANAGEMENT OF CIN 1
Risk of follow up of CIN 1 -
1. Invasive cancer already exists and
was missed by Pap, colpo and biopsy.
2. Invasive cancer develops between
follow up visits.
3. Patient lost to follow up and develops
invasive cancer.
FOLLOW-UP: OBSERVATION VS. THERAPY

Patients with Pap smears interpreted as LSIL

may
have colposcopy directly
if reliable and have the ability to be followed,
may be followed by repeat smears at 4 to 6
months.

A meta-analysis of women with LSIL Pap

tests had
a pooled rate of regression reported as
47.39%, with a very low risk of invasive
carcinoma, varying from 0.00% to 0.74% of
FOLLOW-UP: OBSERVATION VS. THERAPY

Should the Pap return as ASCUS, LSIL or

HSIL,
the patient should have colposcopy done,
with
directed biopsies if needed. If colposcopy
is
performed, and a lesion is identified,
colposcopic
directed biopsies are indicated to
establish the
diagnosis.
OBSERVATIONAL FOLLOW-UP, CIN 1
If the patient has a follow-up Pap smear
that is
within normal, or benign cellular
changes,
repeat follow-up at 4 to 6 month
intervals
should continue. If the smears remain
within
normal, or benign cellular changes, the
patient
may return to annual yearly screening if
four
 TREATMENT VS. OBSERVATION
The treatment decision on such patients is
dependent upon the pathologic findings.
Individuals that have CIN 2 and CIN 3,
require
appropriate treatment for cervical
intraepithelial
neoplasia. Patients with CIN 1 may have
observational follow-up by cytology if
acceptable
to the patient and physician.
ACOG Committee Opinion, No 195, Nov. 1997; Gold M et al,
1996; Ferris DG et al, 1996
 TREATMENT VS. OBSERVATION
Grossly visible lesions of the cervix
require
cervical biopsy for pathologic
evaluations.
Grossly visible CIN 2 and CIN 3 lesions
may
be associated with invasive squamous
cell
carcinoma, usually microinvasion, and
rarely
he see and treat approach using electro-
op excision of any visible lesion is generally
ot recommended due to common treatment
non CIN lesions, and the potential
nnecessary excision of part of the
ervix.

OG Committee Opinion, No 195, Nov. 1997; Gold M et al, 1996; Ferris DG

 TREATMENT OUTCOMES FOR CIN
A systemic review of controlled and
randomized trials in women with CIN 1 (low
grade lesions), or CIN 2 or CIN 3 (high grade
lesions) determined that the outcomes as far
as recurrence of CIN, or non-recurrence of CIN
between cone biopsy, cryotherapy, laser
ablation, or electro-loop excision demonstrated
no substantive difference in outcomes.
Nuovo et al. Int J Gynecol Obst 2000;68:25.
 METHODS TO TREAT CIN

There are a variety of accepted methods

therapy to treat CIN, including:
cryosurgery ablation,
laser ablation or excision,
electro-loop excision,
cone biopsy
ACOG: 1997; Nuovo et al, 2000; Wright et al, 1995
 MANAGEMENT OF CIN
Ablative therapy is not recommended if the SCJ
and/or the limits of the lesion cannot be seen
colposcopically.
A negative ECC prior to ablative therapy has

been suggested by experts.

An ECC at the time of LEEP/cone may indicate

an increased risk of residual disease but may

not influence post-LEEP/cone management.
See and treat approach for low-grade

lesions leads to a significant number of

patients with negative histology.
 MANAGEMENT OF CIN
Ablative therapy is not recommended if the SCJ
and/or the limits of the lesion cannot be seen
colposcopically.
A negative ECC prior to ablative therapy has

been suggested by experts.

An ECC at the time of LEEP/cone may indicate

an increased risk of residual disease but may

not influence post-LEEP/cone management.
See and treat approach for low-grade

lesions leads to a significant number of

patients with negative histology.
SCREENING OF OVARIAN
MALIGNANCY
A woman's risk at birth of having ovarian
cancer sometime in her life is 1% to
1.5%, and that of dying from ovarian
cancer almost 0.5%
 Successful screening is defined as an

intervention that results in reduction in

the mortality of the screened population

relative to the unscreened population.

 Screening requires high sensitivity and
specificity.

High sensitivity maximizes the potential for

influencing survival, whereas high
specificity reduces the chances of false
positives that result in unnecessary
operations.
 Compounded by the fact that ovarian
cancer is a relatively rare condition,
around 99.6% specificity is required to
detect one case of ovarian cancer in
every 10 women testing positive (10%
positive predictive value).
 There is no evidence that screening of

the general population or of targeted at-

risk populations achieved reduction in

mortality.
 Large randomized controlled trials are
now underway for screening in ovarian
cancer.

The endpoint in these trials is cause

specific mortality reduction in the
screened population.
 Transvaginal
Ultrasonography & CA-
125
 TV-US
Transvaginal ultrasonography have been
shown to have a very high (>95%)
sensitivity for the detection of early-stage
ovarian cancer

Transvaginal color-flow Doppler to assess

the vascularity of the ovarian vessels has
been shown to be a useful adjunct to
ultrasonography , but it has not been
shown to be useful in screening
 CA-125
Regarding the sensitivity of the test,
CA125 can detect 50% of patients with
stage I disease

Data suggest that the specificity of

CA125 is improved when the test is
combined with transvaginal
ultrasonography or when the CA125
levels are followed over time
Proteomics
 A new approach is the use of proteomic
patterns to identify ovarian cancer

In a study using this technology, the

sensitivity for predicting ovarian cancer
was 100% with a specificity of 95% and a
positive predictive value of 94%.

This technology is in the early phases of

development and validation, and its
efficacy has yet to be demonstrated in
large population-based studies.
Single nucleotide
polymorphism
 Another new approach is the
measurement of plasma DNA levels and
allelic imbalance by a technique known
as digital single nucleotide polymorphism
(SNP) analysis.
Genetic risk for ovarian
malignancy
 Most epithelial ovarian cancer is sporadic,
with familial or hereditary patterns
accounting for 5% to 10% of all
malignancies.
Hereditary ovarian cancers in general
occur in women approximately 10 years
younger than those with nonhereditary
tumors.
 In the past, it had been thought that
there were two distinct syndromes
associated with a genetic risk,
site-specific hereditary ovarian cancer
hereditary breast-ovarian cancer syndrome.

However, it is now believed that these

groups essentially represent a continuum
of mutations with different degrees of
penetrance within a given family
 Most hereditary ovarian cancer is
associated with mutations in them BRCA1
gene, located on chromosome 17.
A small proportion of inherited disease is
associated with germline mutations in
another gene, BRCA2, located on
chromosome 13 .
The mutations are inherited in an
autosomal dominant fashion
 HNPCC syndrome, which includes
multiple adenocarcinomas, involves a
combination of

familial colon cancer (known as the Lynch I

syndrome)
Ovarian
Endometrial
Breast cancer
Other malignancies of the gastrointestinal and
genitourinary systems
 ROMA
RMI
OTHERS
 The risk of breast cancer in women with a
BRCA1 or BRCA2 mutation may be as high as
56% to 87%.

Important data demonstrates that

prophylactic oophorectomy irrespective of
screening in those with BRCA1 and BRCA2
germline mutations:

essentially abolishes the incidence of ovarian

cancer
and also markedly reduces the incidence of breast
cancer in the oophorectomized population as
compared with controls
 This is increasingly considered the
approach of choice where the high-risk
patient is able to rationalize the
cost/benefit equation.
 In general, where it is recommended,
prophylactic bilateral salpingo-
oophorectomy is performed with
completion of childbearing.

Hormone replacement therapy is

commenced thereafter until a point that
appropriately corresponds to natural
menopause, that is, around 50 years
Current recommendations for management of
women at high risk for ovarian cancer are
summarized as follows

Genetic counseling +/- genetic testing for

BRCA1and BRCA2

Women who wish to preserve their

reproductive capacity can undergo
screening by transvaginal
ultrasonography every 6 months

Oral contraceptives should be

recommended to young women
 Women who do not wish to maintain their
fertility or who have completed their families
should be recommended to undergo
prophylactic bilateral salpingo-
oophorectomy

In women who also have a strong family history

of breast or ovarian cancer, annual
mammographic screening should be
performed beginning at age 30 years.

Women with a documented HNPCC syndrome

should be treated as above, but in addition, they
should undergo periodic screening
mammography, colonoscopy, and
 It is entirely unclear whether it will ever

be feasible,effective or cost-effective to

screen the general population for ovarian

cancer.
 Furthermore, with the clear impact of
prophylactic oophorectomy for targeted
groups, it is also unclear whether
screening of targeted groups even if
effective will approach the definite
benefits to be obtained by removal of
ovaries after completion of childbearing
VAGINAL
INTRAEPITHELIAL
NEOPLASIA
VaIN
 Vaginal cancer is rare
Approximately 90 percent of
vaginal cancers are squamous and
develop slowly from precancerous
epithelial changes
 VaIN is rarely found as a primary lesion,
and most often develops as an extension
of CIN, mainly in the upper third of the
vagina
 definition
A condition where neoplastic cells are
within the boundaries of surface
epithelium of the vagina
 Classification
VaIN I :- mild dysplasia; lower 1/3
VaIN II :- mod. dysplasia; lower 2/3
VaIN III :- severe dysplasia; > 2/3
Risk Factors
Although the natural history of VaIN is less
understood than that of CIN, risk factors for VaIN
are thought to be similar to those for CIN,
suggesting similar etiology.
This disease is primarily found in
postmenopausal women with an average age of
64 years. However, with recent increases in HPV
infection of the LGT being seen in a younger
population, VaIN is now being diagnosed in
younger women.
Cervical or vulvar neoplasia increases the risk
for VaIN and vaginal squamous cancer.
 Demographic risk factors
Ethnicity (Latin American countries, U.S.
minorities)
Low socioeconomic status
Age
Behavioral risk factors
Infrequent or absent cancer screening Pap tests
Early coitarche
 Multiple sexual partners
Male partner who has had multiple sexual
partners
Tobacco smoking
Dietary deficiencies
Medical risk factors
Cervical high-risk human papillomavirus
infection
Parity
Immunosuppression
 Diagnosis
Generally, VaIN is asymptomatic.
If present, symptoms may include
vaginal bleeding, discharge, and odor.
Abnormal cytology is most often the first
indication of VaIN
subsequent colposcopic examination of
the lower genital tract frequently locates
a vaginal lesion for biopsy.
 Vaginal Colposcopy
Because of redundant vaginal tissue, vaginal
colposcopy may be difficult. A clear plastic
speculum may aid visualization of all quadrants
of the vagina.
By applying 3- to 5-percent acetic acid to
vaginal mucosa, acetowhite changes consistent
with neoplasia are identified.
Half-strength Lugol solution applied to the
vagina delineates nonstaining areas, which are
likely to contain abnormal epithelium.
Biopsy may be obtained
 Treatment of VaIN
high-grade VaIN is believed to be a
precancerous lesion and requires eradication
Management of VaIN depends on the grade of
neoplasia and may include observation,
excision, ablation, topical antineoplastics, or
rarely, radiation therapy.
Management strategies are determined by
colposcopic and histologic findings along with
comprehensive patient counseling.
 Low-Grade Vaginal
Intraepithelial Neoplasia VaIN 1
observational approach after biopsy
resulted in regression in 88 percent with
VaIN 1.
no VaIN 1 lesion progressed to high-
grade VaIN or invasive cancer.
This lesion most likely represents atrophy
or transient HPV infection.
High-Grade Vaginal Intraepithelial
Neoplasia VaIN 2 and 3
The treatment modality choice for
patients with high-grade VaIN is
influenced by the location and number of
lesions, whether the patient is sexually
active, vaginal length, previous radiation
therapy, previous treatment modalities in
patients with recurrent VaIN, and clinician
experience.
 Excision
Wide local excision of a high-grade unifocal
lesion or partial vaginectomy for multifocal
lesions may be used.
Excisional procedures have the advantage of
providing a surgical specimen for which resected
margins can be examined and the presence of
invasive vaginal cancer excluded.
Moreover, partial vaginectomy has the highest
cure rate and fewest recurrences for high-grade
disease
 Wide local excision carries less morbidity than
vaginectomy, but both modalities may be
complicated by bladder or rectal injury and
hemorrhage. Subsequent vaginal scarring and
stenosis may compromise vaginal intercourse or
cause dyspareunia.
As an alternative excisional modality, CO2 laser
causes significant thermal damage to the tissue
specimen and is not recommended. Likewise,
LEEP has poor depth control and carries a
substantial risk of thermal damage to underlying
pelvic structures, including the bladder and bowel.
 Medical Ablation
Before medical treatment the possibility
of invasive cancer must be excluded.
Persistent VaIN 1 or 2 and selected VaIN
3 lesions may be medically treated using
5-percent fluorouracil (5-FU) cream
 A 3-mL dose of cream is placed in the vaginal
vault by plastic vaginal applicator every other
day for 3 days during the first week of treatment
and once weekly thereafter for up to 10 weeks
Patients selected for this treatment require
counseling, effective contraception and close
monitoring.
Surveillance should include vaginal cytology and
colposcopy 2 months after treatment is
completed
 Carbon Dioxide Laser
Ablation
Laser ablation is well-suited for
eradication of multifocal lesions and
causes less scarring and blood loss than
excisional modalities. Rarely, excessive
bleeding and thermal damage to the
bladder and bowel can occur
 Radiation Therapy
There is a role for radiation treatment of high-
grade VaIN, but it carries significant morbidity
and should be reserved for select cases.
significant complications may occurred like:
vaginal stenosis, adhesions, ulceration, necrosis,
and fistula formation
Furthermore, radiation treatment compromises
subsequent cytologic, colposcopic, and
histologic interpretation.
Disease recurrence often necessitates radical
surgery.
 Prognosis

excision and CO2 laser ablation had

similar cure rates of 69 percent.
Topical 5-flurouracil cream was curative in
46 percent of cases
Patients with any grade of vaginal
neoplasia require long-term monitoring,
as the recurrence rate for high-grade
disease is significant.
VULVAR
INTRAEPITHELIAL
NEOPLASIA
VIN
 Incidence
Vulvar cancer is rare
less than 3 to 5 percent of all gynecologic
cancers and less than 0.5 percent of all cancers
in women
Ninety percent of vulvar cancer is squamous
and in some cases develops slowly through
precancerous epithelial changes called vulvar
intraepithelial neoplasia (VIN).
 Pathophysiology
Although HPV DNA has been found in 72
percent of VIN lesions, HPV is less
commonly associated with vulvar cancer,
with most studies showing approximately
40-percent HPV DNA positivity
The progression of vulvar carcinoma in
situ to invasive cancer has been strongly
suggested, although not confirmed
conclusively.
 Original Terminology
Terminology for squamous VIN was
introduced by the International Society
for the Study of Vulvar Disease (ISSVD) in
1986. Under this classification, VIN
grades 1, 2, and 3 were defined by
abnormal cellular changes found to
varying thickness within the squamous
epithelium as in the case of CIN
New Modified Terminology
Classification of VIN has recently been simplified
The older designation of VIN 1 has been
eliminated, whereas VIN 2 and 3 categories
have been combined.
This redefinition reflects whether lesions are
likely to be premalignant or not, and therefore
whether or not lesions require therapy.
The VIN 1 category has been eliminated
because evidence is lacking that such lesions
are cancer precursors.
The term VIN is now applied only to
histologically high-grade squamous cell lesions
and combines the previous categories of VIN 2
and 3
 Vulvar Intraepithelial Neoplasia:
Terminology and Characteristics
usual type (Warty, Basaloid AND
Mixed) : Formerly VIN 2, VIN 3, vulvar CIS
Younger women
Multicentric disease
Oncogenic HPV infection
Smoking,
other STIs,
immunosuppression
 VIN, differentiated type:
210% of former VIN 3 lesions
Older, postmenopausal women
Oncogenic HPV infection uncommon
VIN, unclassified type: Rare pagetoid
lesions
 Diagnosis
Vulvar intraepithelial neoplasia may be
asymptomatic and discovered during
routine gynecologic examination or
during evaluation of abnormal cervical or
vaginal cytology. When present, signs
and symptoms may affect a patient's
sexuality and quality of life
 Pruritus
Pain or burningVulvar soreness
Bleeding
Discharge
Urination discomfort
Persistent ulcerSkin area that has a different
color or texture from surrounding tissue
Existing nevus
change in symmetry or color
Lump or wart-like growth
 Colposcopy
A histologic diagnosis is necessary before high-
grade VIN is managed.
This is best accomplished by magnification of the
vulva, usually by use of a colposcope, with
biopsy of the most abnormal-appearing areas.
Vulvar epithelial changes are enhanced by
applying a 3- to 5-percent acetic acidsoaked
gauze pads to the vulva for 5 minutes prior to
colposcopic examination.
Vulvar intraepithelial neoplasia, usual
type varies in clinical appearance.
Some lesions are raised,
hyperkeratotic, and pigmented
whereas others are flat and white.
Often, lesions appear bulky, resemble
condylomata, and are multifocal with
extensive involvement of the
perineum and adjacent skin.
Vulvar intraepithelial neoplasia, differentiated type
is generally unifocal and associated with lichen
sclerosus or vulvar hyperplasia. A lesion may
appear as an ulcer, warty papule, or
hyperkeratotic plaque.
Any lesion suspicious for invasive carcinoma
should be biopsied, particularly lesions that are
slightly elevated, roughened, nodular, or
ulcerated. This is especially true in older
women.
 Management
Vulvar Intraepithelial Neoplasia 1
As previously stated, the progression of
VIN 1 to VIN 3 has not been established
and the modified terminology has
eliminated the VIN 1 category entirely.
Lesions reported as VIN 1 may be
reassessed annually and generally
resolve without treatment.
Vulvar Intraepithelial Neoplasia
2 and 3
Treatment objectives should include:
(1) improving patient symptoms,
(2) preserving the appearance and function of
the vulva, and
(3) excluding invasive disease.
Standard treatment of high-grade lesions of the
vulva can be achieved by local destruction or
excision. Medical management with topical
immune modulators or systemic agents is
currently investigational. Treatment of VIN 2 or 3
is individualized and based on lesion location,
size, and clinician expertise. Many patients are
best treated by combined excisional and
ablative procedures.
 Excisional Surgery
Extensive vulvar surgery for VIN is not always
necessary if patients undergo close monitoring
for disease progression or recurrence.
Carcinoma in situ or large lesions in which
invasive carcinoma cannot be excluded by
simple biopsy are best managed by wide local
excision (WLE) with a surgical margin that
includes at least 5 mm of normal tissue Because
disease recurrence is related to surgical margin
status, frozen section histology of the specimen
margins should be evaluated intraoperatively
 Ablative Treatment
Although providing good cosmetic results, lesion
ablation with CO2 laser does not allow histologic
evaluation of a surgical specimen. Therefore, the
presence of invasive carcinoma must be
excluded beforehand. Although generally less
disfiguring than WLE, laser ablation can result in
prolonged and painful healing and in prolonged
wound discharge. Recurrence of VIN has been
reported more commonly following laser
vaporization than after WLE
 Cavitational ultrasonic surgical aspiration (CUSA)
may be used in the treatment of high-grade VIN
confined solely to non-hair-bearing vulvar skin.
Ultrasound is used to cause cavitation and
disruption of affected tissue, which is then
aspirated and collected This technique provides the
advantages of laser ablation with less scarring or
pain and also provides a histologic specimen.
However, the tissue specimen is severely
fragmented during the process and lacks the
diagnostic accuracy of surgically excised tissue for
ruling out the presence of invasive cancer.
 Topical Treatment
Topical treatments are currently under
investigation and have not yet become
recommended clinical therapy. These
agents include imiquimod 5-percent
cream (Aldara) cidofovir emulsion
(Vistide), and 5-percent fluorouracil
cream.
Photodynamic therapy (PDT) using
topical 5-aminolevulinic acid (5-ALA) has
been used as tissue-conserving treatment
for vulvar carcinoma in situ. Although
PDT preserves tissue without scarring or
disfigurement, it has a low response and
high recurrence rate
Prognosis and Prevention
There are accumulating case reports supporting
the invasive potential of untreated, high-grade
VIN .
It is currently not possible to predict high-grade
VIN lesion behavior.
Regardless of the treatment modality chosen,
recurrence is common, particularly in patients
with multifocal disease and
immunocompromise.
Surveillance for persistent and recurrent LGT
disease is advisable.
Thank you