Premalignant disease of the

cervix
Dr shameem R. ALaasam
Introduction
Carcinoma of the cervix is the second commonest cancer among
women worldwide, with only breast cancer occurring more commonly.

While the natural history of breast cancer is poorly understood, cervical

cancer is a preventable condition and considerable effort goes into
detecting and treating the preinvasive disease
CERVICAL INTRAEPITHELIAL
NEOPLASIA
CIN (formerly cervical dysplasia) refers to premalignant changes in the
cervical epithelium that have the potential to progress to cervical
cancer.

CIN is most commonly diagnosed in women in their 20s; CIS is

diagnosed most commonly in women of age 25 to 35 years; and
invasive cancer is typically diagnosed after the age of 40.
pathophysiology
• The cervix is composed of the columnar epithelium, which lines the
endocervical canal, and squamous epithelium, which covers the
exocervix.
• The point at which they meet is called as squamocolumnar junction
(SCJ).
• The SCJ rarely remains restricted to external os. Instead, it is a
dynamic point that changes in response to puberty, pregnancy,
menopause, and hormonal stimulation.

• In neonates, SCJ is located on the exocervix. At menarche, the

production of estrogen causes the vaginal epithelium to fill with
glycogen. Lactobacilli act on the glycogen and lower the pH,
stimulating the subcolumnar reserve cells to undergo metaplasia.
Metaplasia advances from the original SCJ inward, toward the internal
os and over the columnar villi.
This process establishes an area called the transformation zone (TZ).
The TZ extends from the original SCJ to the physiologically active SCJ.
These metaplastic cells are more susceptible to oncogenic factors;
therefore, CIN most commonly occurs during menarche and after
pregnancy when metaplasia is most active.
The transformation zone (TZ) is the site where premalignancy and
malignancy develop.
Normal cervix with transformation zone.
Risk factors for CA cervix/CIN:

a. Young age at first intercourse (<16 years)

b. Multiple sexual partners
c. Cigarette smoking
d. Race
e. High parity
f. Low socioeconomic status
g. Human papillomavirus (HPV) infection
h. HIV
i. Immunosuppression
• HPV is now accepted as the primary causative agent in CIN and
cervical cancer. DNA fragments of HPV have been found incorporated
into the DNA of cells from 80% of all CIN lesions and 90% of all
invasive cervical cancers.
• There are more than 100 different serotypes of HPV. Serotypes 6 and
11 are among the types with the lowest oncogenic potential. They
are responsible for causing 90% of condylomas. Serotypes 16 and 18
and 31 and 41 are of higher oncogenic potential. These so-called
“high risk” types of HPV are responsible for about 70% (types 16 and
18) and 5% to 10% (types 31 and 45) of cervical cancers.
• We are now able to test for high-risk HPV types in Pap smear specimens.
This testing allows providers to more accurately predict which
precancerous lesions have the potential to progress to cancer if left
untreated and which will most likely spontaneously regress.
• Moreover, HPV vaccines are now available (e.g., Gardasil and Cervarix)
that prevent HPV infections and reduce the risk of cervical cancer by 70%.
• Gardasil immunizes against types 6, 11, 16, and 18.
• Cervarix immunizes against types 16, 18, 31, and 45.
• Both are given as three injections over 6 months to males and females
age 9-26.
Classification of CIN
CIN can be divided into low-grade (CIN 1) and high-grade disease (CIN 2
and 3).
CIN I: Cellular dysplasia confined to the basal third of the epithelium
(formerly mild dysplasia)
CIN II (formerly moderate dysplasia), two-thirds of the epithelium is
involved.
CIN III (formerly severe dysplasia), more than two-thirds of the
epithelium shows abnormal changes. The atypical cells in CIN III can
expand the full thickness of the epithelium (formally CIS or carcinoma
in situ).
Histologic classification of cervical intraepithelial neoplasia (CIN).
DIAGNOSIS
Pap Smear Screening

Because cervical dysplasia is otherwise asymptomatic, the Pap smear

has revolutionized our ability to identify, monitor, and treat
premalignant cervical changes before cancer arises.

The goal of cytologic screening is to sample the TZ, the area where
transformation from squamous epithelium to columnar endocervical
epithelium takes place and where dysplasia and cancer arise.
The Pap smear involves scraping endocervical and ectocervical cells
from the external os of the cervix with a spatula to sample cells from
the TZ .
Because the squamocolumnar junction (SCJ) may be in the endocervical
canal, it is important to also sample the endocervical canal with a
cytobrush. The sample is then placed directly on a glass slide
(conventional Pap smear) or into a liquid-based medium that is then
used to make a slide. The prepared slides are then examined by a
cytopathologist with or without aid of an automated cytology
Performing a Pap. (A) Spatula. (B) Endocervical brush.
Abnormal Pap Smear Management

• Pap smear reports may show findings consistent with normal cellular
material, inflammatory changes, infection, dysplasia, or cancer.

• the major classes of epithelial abnormalities as they are reported

using the 2001 Bethesda classification system.
Major Classes of Epithelial Cell Abnormalities Found on Pap Smears
• the ASC category has been divided into two groups:
• ASC-US (atypical squamous cells of unknown significance) and ASC-H
(atypical squamous cells—cannot rule out high-grade lesion).
• Patients in the ASC-H category should be evaluated with colposcopy.
Patients with ASC-US should undergo HPV testing to determine
whether colposcopy is indicated or not.
• Patients who receive an ASC-H, low-grade squamous intraepithelial
lesion (LSIL), or high-grade squamous intraepithelial lesion (HSIL) Pap
smear result should proceed directly to colposcopy
Management of Abnormal Pap Smear Results in Adult Women a
• Fortunately, many epithelial abnormalities found on Pap smears will
regress to normal over 6 months to 2 years. Some of the
abnormalities will persist at their current level, and the remainder
will progress to more serious lesions or cervical cancer .
• ASC and LSIL lesions usually represent a transient infection with HPV,
so the majority will regress spontaneously over time.
• However, HSIL lesions are more likely to be associated with persistent
infection and progression to cancer. Therefore, patients who receive
an ASC-H, LSIL, or HSIL Pap smear result should proceed directly to
colposcopy
Natural History of Cervical Intraepithelial Lesions
HPV Testing

• With the advent of HPV DNA testing, it is now recommended that

women with an ASC-US result be tested immediately for the presence
of high-risk HPV subtypes. This process is known as reflex HPV testing.
• “Reflex” testing can be achieved using either the residual liquid from
the liquid-based Pap test or a separate sample collected at the time of
the initial Pap for HPV testing.
• The HPV results are added to the initial Pap smear interpretation. This
eliminates the need for the patient to return for repeat testing, and it
allows the clinician to predict a patient’s risk for a high-grade lesion
with more accuracy and to better direct the plan of care.
• If the woman with an ASC-US Pap test is positive for a high- risk HPV
type, she should be evaluated with colposcopy , where directed
biopsies can be performed if indicated.
• However, if the patient with an ASC-US Pap test is negative for a high-
risk HPV type, she can continue with routine screening appropriate
for her age
COLPOSCOPY AND CERVICAL BIOPSY

• Once a cytologic diagnosis of epithelial abnormalities has been made

on Pap smear, a histologic examination is needed to make the
diagnosis of cervical dysplasia or cancer.

• This histologic evaluation can be achieved during colposcopy with

directed biopsies to determine the severity of dysplasia and to
identify any invasive carcinoma.
• Colposcopy is the outpatient examination of the magnified cervix
using a light source . It is used for both diagnosis and treatment.
• After a history and counselling, the woman undresses and places her
legs in the semi-lithotomy position. A speculum is passed and the
cervix examined with the light source under magnification (5 to 20 X).
Usually 5 per cent acetic acid and iodine are applied to the cervix and
biopsies taken when necessary.
• Acetic acid causes nucleoproteins within cells to coagulate temporarily,
therefore areas of increased cell turnover, for example in CIN will appear
white at colposcopy .
• Areas of CIN lack the presence of intracellular glycogen and therefore stain
yellow as opposed to the normal squamous epithelium which will stain
brown when iodine is applied.
• Changes may include acetowhite epithelium, mosaicism, punctations, and
atypical vessels
• These lesions should be biopsied, and the specimens should be sent to
pathology where more definitive histologic diagnoses can be made
 Cervix with acetic acid.

Cervix with cervical intraepithelial neoplasia (CIN) and new

Colposcope. vessels.
Colposcopic view of the cervix. Abnormalities shown include
acetowhite epithelium, punctations, and mosaic patterns.
Treatment of Cervical Dysplasia

• When the diagnosis of CIN is made on cervical biopsy, several

treatments may ensue.
• CIN I is commonly followed with repeat Pap smears (every 6 months
for 12 months) or HPV testing in 1 year. If either the repeat Pap
smears are abnormal or if the testing for high-risk HPV is positive, the
patient should have a repeat colposcopy and biopsy if indicated.
• If the repeat Pap smears are all within normal limits or if the patient is
found to be HPV negative, the patient can return to routine cervical
screening appropriate for her age
• Women with CIN I that persists for more than 2 years or with CIN II
may be treated with cryotherapy or surgical excision.
• An alternative to treatment in young women with CIN II is
observation with colposcopy and Pap testing every 6 months for 24
months.
• Women with CIN III are treated with surgical excision. Historically, a cold-
knife conization (CKC) was performed, which removes a wedge-shaped
portion of the cervical stroma and endocervical canal
• This is no longer the standard of care for CIN. The loop electrosurgical
excision procedure (LEEP) or large-loop excision of the transformation
zone (Lletz) is now more commonly performed to treat CIN II and CIN III.
• LEEP, loop, and Lletz all refer to the same procedure that involves removing
a cone-shaped piece of cervical portio (conization), typically with a
cauterized fine-wire loop or with a laser .
• The LEEP can be performed as an office procedure under local anesthesia
and is quicker and has less blood loss than the CKC.
Cold-knife cone of the cervix.
LEEP/Lletz conization procedure.
• In general, cervical excision procedures remove cervical tissue
without causing extensive damage to the stroma of the cervix,
although scarring of the endocervical canal may still ensue. Infrequent
complications include cervical stenosis, cervical in- sufficiency,
infection, or bleeding.
• The persistence rate is about 4% for CIN II and CIN III and the recurrence rate is
10% and 15%, respectively.
• Therefore, after surgical conization, patients should be followed every 6 months
with a repeat Pap smear or repeat Pap smear and colposcopy for 1 year. If the
results all remain normal, the patient can return to routine screening for at least 20
years.
• Alternatively, after a cervical conization with unsatisfactory colposcopy, the patient
can be followed with HPV testing every 6 months for 1 year after the procedure. If
not high risk, the patient can return to routine screening for at least 20 years.
• In either scenario, any abnormal cytology or the presence of high-risk HPV should
result in repeat colposcopic examination and cervical biopsies if indicated.
cervical cancer screening
• The new guidelines recommend that all women should begin cervical
cancer screening at age 21 regardless of risk factors, including age of
onset of sexual activity.
• Women aged 21 to 29 should have Pap testing every 3 years.
• The preferred option for women aged 30 and above is to screen with
both a Pap test and an HPV test, and if both are negative, to re-screen no
sooner than every 5 years.
• Co-testing with a Pap and an HPV test is 95% to 100% sensitive for CIN III.
• If HPV testing is unavailable, screening with pap smear alone every 3
years is acceptable for women 30 and over.
• It is reasonable for women over age 65 to 70 to stop cervical cancer
screening if they have had three or more normal Pap tests in a row
have not had CIN 2/3 or higher in the past 20 years, or if a woman has
had a total hysterectomy (removal of both the uterine corpus and
cervix) for benign indications (such as bleeding or fibroids) and she
does not have a history of CIN 2/3 or higher, she may stop pap
screening at the time of her hysterectomy.
• Women with a history of CIN II or III who undergo hysterectomy may
safely discontinue Pap smear screening after three consecutive
negative screening tests (either the three most recent Pap smears
prior to the hysterectomy or three consecutive screening exami-
nations subsequent to the hysterectomy).
• Importantly, women who have undergone a supracervical
hysterectomy and have an intact cervix still need to continue routine
Pap smear screening appropriate for their age.