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Management of Abnormal

Cervical Smears.
Sammy .K.
Facilitator: Patricia Muthaura

Objectives
Review HPV and its effects on
cervical epithelium.
Management of abnormal cervical
smears.
Value Addition in Pathological
Assessments.

Nonenveloped ds DNA
virus1

HPV
>100 types identified2
~3040 anogenital2,3
1520 oncogenic*,2,3
HPV 16 and HPV 18 types
account for the majority of
worldwide cervical
cancers.4

Nononcogenic** types
HPV 6 and 11 are most
often associated with
external anogenital warts.3
1. Howley PM, Lowy DR. In: Knipe DM, Howley PM,
eds.risk;
Philadelphia,
Pa: Lippincott-Raven; 2001:21972229.
*High
**
Low risk
2. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930934. 3. Wiley DJ, Douglas J, Beutner K, et al.
Clin Infect Dis. 2002;35(suppl 2):S210S224. 4. Muoz N, Bosch FX, Castellsagu X, et al. Int J Cancer.
2004;111:278285.
Reprinted from J Virol. 1994;68:45034505 with permission from the American Society for Microbiology
Journals Department.

Pathogenesis
HPV is epitheliotropic.
Episomal state
Integrated state

An important factor in
the early stages
following infection is
the individual's
susceptibility to
oncogenic HPV types,
which is determined by
the host's immune
system.

HPV Infection and Life


Cycle1

Shedding of VirusLaden Epithelial Cells

Cervical Surface
Mature
Squamous
Layer
Squamous
Layer

Parabasal
Cells

Viral Assembly
(L1 and L2)
Viral DNA Replication
(E6 and E7)
Episomal Viral DNA
in Cell Nucleus
(E1 and E2, E6 and E7)
Infection of Basal
Cells (E1 and E2)

Basal (Stem)
Cells
Basement Membrane

Normal
Epithelium

Infected
Epithelium

1. Frazer IH. Nature Rev Immunol. 2004;4:4654. Adapted with permission from Nature Reviews
Immunology 2004 Macmillan Magazines Ltd.

Cervical Anatomy

Location Of SCJ

American Cancer Society(ACS), American Society for Colposcopy and Cervical


Pathology (ASCCP), and American Society for Clinical Pathology (ASCP) have
similar guidelines.

The Abnormal Pap


Indicates possible presence of a
progressive neoplastic lesion that might
evolve to cancer.
Mild lesion: likely to regress spontaneously,
especially in young women. Does not
necessarily need treatment
High-grade lesion: considerable risk of
underlying severe dysplasia, with high
chance of progression to cancer

.Abnormal Screen
Result.
Classification

Management Strategies.

Bethesd
a

CIN

Dysplasi
a

ASCUS

Cellular
Atypia

Unspecifi
ed
cellular
changes

LGSIL

CIN 1

Mild
dysplasia

HGSIL

CIN 2,
CIN3

Moderate
/Severe
dysplasia

Availability of
resources
Treatment resources
Age
Fertility desires
Grade and extent of
lesion
Motivation for follow up
Expertise

1. Atypical squamous cells


-Atypical squamous cells of
undetermined significance (ASC-US)
-Atypical squamous cells cannot
exclude HSIL (ASC-H)
2. Low grade squamous intraepithelial
lesion (LGSIL or LSIL)
3. High grade squamous intraepithelial
lesion (HGSIL or HSIL)
4. Squamous cell carcinoma

5. Atypical Glandular Cells not


otherwise specified (AGC-NOS)
6. Atypical Glandular Cells, suspicious
for AIS or cancer (AGC-neoplastic)
7. Adenocarcinoma in situ (AIS)

AIMS of Colposcopy
1.To determine the precise geographical
anatomical position of the TZ
2.To confirm or refute the cytological
suspicion of cervical intraepithelial
neoplasia (CIN)
3.To recognize or rule out invasive cancer
4.To recognize or rule out glandular disease
5. To facilitate treatment of and monitor
progression or regression of CIN

Colposcopic features of CIN


Changes in the subepithelial angioarchitecture
Punctation: either fine or coarse depending on the
severity of the lesion.
Mosaic: either fine or coarse depending on the
severity of the lesion.
Atypical vessels: suggestive of associated
carcinoma

The degree of aceto-whiteness


Borders of the lesion

Satisfactory Colposcopy
Satisfactory colposcopy-indicates that
the entire SCJ and the margin of any
visible lesion can be visualized with
the colposcope
ECC-Endocervical evaluation by
cytology or curettage is sometimes
used when colposcopy is
unsatisfactory or when an
endocervical lesion is suspected

Colposcopy in Post
Menopause
Cervical and vaginal epithelium very
thin, allowing visualization of the
subepithelial capillaries, which may
appear red and atypical
Use of acetic acid is not as effective
in detecting premalignant disease
short course (34 weeks) of
intravaginal oestrogen cream

Colposcopy in Pregnancy
cervix is larger, oedematous and more
vascular
Cervix usually covered by mucus,
which is difficult to remove
Decidual changes of the cervical
epithelium can mimic cancerous
epithelium
vascular changes associated with
abnormality may be more pronounced

What is ASCUS?....
Atypical Squamous cells of
Undetermined Significance.
Lowest risk of developing into
cervical cancer(0.1 to 0.2%.)
Initial Approach:-3 pronged.
Repeat Cytology
HPV testing
Colposcopy

ASCUS
Reflex testing- Testing for HPV at initial screen
Prevalence of HPV DNA changes with age
among those with ASCUS
21 yrs and over
Effective in older women as less women will be
referred for colposcopy

Initial evaluation
2 repeat cytology exams six months apart
HPV testing
Colposcopy

Management Algorithm

Progression from mild -> severe


dysplasia =
1% risk, per year

From moderate -> severe dysplasia =


16% in 2 years
25% in 5 years

ASCUS in Special
populations
Pregnancy

Postmenopausal

Women aged 21 -24


years

Pregnancy-Defer
Colposcopy to 6 weeks post
partum, ECC is
unacceptable
Postmenopausal Managed
as general population
Women 21-24yr- Cytology
is preferred, Reflex testing
acceptable , if HPV neg
,cytology in 12 months.

ASCUS -H
Special (Where HSIL
cannot be ruled out)

Colposcopy advised
When CIN 2,3 not seen
at colposcopy HPV
testing at 12 months or
repeat cytology at 6
and 12 months
On repeat cytological
testing refer to
colposcopy if
HPV +
ASCUS and greater

LGSIL
Follow up
Cytological diagnosis
LGSIL (2%) of women
LGSIL is highly
predictive of HPV
infection
85% of patients with
LGSIL will have HPV
positve screen

Co- test at 12 months


and 24 months, if
negative re- test in 3 yrs,
if any test abnormalcolposcopy or ECC
If all are negative, routine
screening for 20 years
Post colposcopy ..in
absence of CIN
ablation/excision is
unacceptable

LGSIL

ASCUS/LGSIL Triage
Study (ALTS)
ALTS TRIAL

Result

ALTS was a clinical trial


designed to find the best
way to manage the mild
abnormalities that often
show up on Pap tests.
Women were divided into
ASCUS and LSIL diagnoses.
Patients in each category
were then assigned
randomly to one of three
groups or study armsColposcopy, Cytology, HPV

HPV testing is sensitive in


detecting underlying
precancerous lesions among
women with a Pap test
diagnosis of ASCUS
HPV testing is not useful for
women with a Pap test
diagnosis of LSIL
Colposcopically directed
biopsy is not completely
sensitive in detecting
precancerous lesions.The
sensitivity of the colposcopy
procedure is increased when
the colposcopist takes more
than one biopsy.

Stoler, M.H. and Schiffman, M., Interobserver Reproducibility of Cervical Cytologic and Histologic
Interpretations: Realistic Estimates From the ASCUS-LSIL Triage Study, Journal of the American Medical
Association, 285(11), Mar. 21, 2001.

HGSIL
0.45% of cytology
reports
75% will have biopsy
confirming CIN 2/3
1-2% invasive cancer
An immediate
LEEP/Colposcopy /or
ECC is acceptable
except in pregnancy

HGSIL

Atypical Glandular Cells


0.2% of pap results
High incidence of
underlying neoplasia
(9 -38% have
underlying neoplasia)
Cytology and HPV lack
Sensitivity to act
singly as a triage test

Categories
AGC NOS
AGC-favour neoplasia
AIS -Adenocarcinoma
in Situ

Frequently caused by benign


conditions- reactive changes and
polyps
not uncommonly associated with a
significant underlying neoplastic
condition including adenocarcinomas
of the cervix, endometrium, ovary, and
fallopian tube
(*CIN most common pathology)

Atypical Glandular Cells

Because of the spectrum of neoplasia


linked to AGC, initial evaluation must
include multiple testing modalities:
Colposcopy,
Endocervical evaluation and
sampling,
HPV testing,
Endometrial sampling

Endometrial Cells on Pap


Endometrial cells in keeping with the
stage of the cycle: no need for further
investigation
Endometrial cells not in keeping with the
stage of the cycle: no need for further
investigation in young women, but may
require assessment in older women
Endometrial cells in women with an IUD:
no need for further investigation

Normal appearing endometrial cells in


a postmenopausal woman: Always
warrant further assessment even if
the woman is using oestrogen
replacement therapy. Minimum TVS
Atypical endometrial cells or
cytological findings suggestive of
endometrial adenocarcinoma: refer for
ultrasound, hysteroscopy and biopsy
or diagnostic curettage

Part 1
A 21 year old girl has
HGSIL on cytology
Colposcopy satisfactory and
biopsy taken at 11 oclock
Result CIN2
Mgt:
a)LEEP
b)Pap Smear rpt at 6 and 12
months
c)Pap + Colpo in 6 and 12
months
d)HPVDNA in 12 months

Part 2
If her biopsy showed
CIN3 what would be
the next step
a)LEEP
b)Follow with Pap in 6
-12 months
c)Pap and colposcopy
in 6 -12 months
d)HPV DNA in 12
months

CIN2 ,3 IN TEENS AND YOUNG


WOMEN

Commercial Break..
A= Accurate , Little
Precision
B= Precise but not
accurate
C=No accuracy ,No
precision
D=Accurate and
Precise

LAST(Lower Anogenital
Squamous Terminology)
Basis of final Consensus

Buliding consensus for


reporting slides
Bethesda system
Two tier
Three tier

Limiting tiers
2 tier:- Higher Kappa
Statistic of 0.3 to 0.71
3 tier :-Kappa statistic
of 0.12 to 0.58.

.Basis Of Consensus.
Biomarkers
P16
Ki 67
Pro Exc
L1
HPV 16,18 m-RNA
Telomerase
HPV genotyping

Are Biomarkers The


solution?

Biomarkers
A lesion that was
problematic due to
somewhat tangential
sectioning was variably
called CIN1 as well as
CIN 2 on H&E (A).
Typical p16 positivity in
a continuous from the
bottom up pattern
indicative of high-risk
HPV E7 induction of p16
expression.

Clinical Application
New tier system
LGSIL=CIN1 AND
CIN2(P16 Negative)

HGSIL=CIN2 AND CIN3


(P16 Positive)

Thanx!