Cervical ca (precancerous and invasive)

HALE TEKA, M.D,
OB/GYN RESIDENT,
MEKELLE UNIVERSITY
Friday, June 21, 2019 HALE TEKA, M.D., RESIDENT PHYSICIAN 1
Preinvasive and Invasive Lesions of the
Cervix
12:47 pm, Jul 26, 2019

Part – I: Preinvasive Lesions of the Cervix

•Contents
1. The Squamocollumnar Junction
2. Squamous Metaplasia
3. Human Papillomavirus
4. Cervical Intraepithelial Neoplasia
5. Differential Diagnosis and Evaluation of Cervical Lesions
6. Management of Cervical Intraepithelial Neoplasia
HALE T., M.D., RESIDENT PHYSICIAN
Friday, December 30, 2016 3

The Squamocolumnar Junction (SCJ)

• During embryogenesis:
✓upward migration of stratified squamous epithelium from the
urogenital sinus and vaginal plate is thought to replace müllerian
epithelium
✓This process usually terminates near the external cervical os,
forming the original (congenital) squamocolumnar junction
(SCJ)

• When visible on the
ectocervix, the SCJ is a pink,
smooth squamous epithelium
juxtaposed against the red,
velvety columnar epithelium
surrounding the external
cervical os

•The location of the SCJ varies with age and hormonal status
•It everts outward onto the ectocervix during
1. Adolescence,
2. Pregnancy, and
3. With the use of combination hormone contraceptives

•It regresses into the endocervical canal with low estrogen states
such as
1. Menopause and
2. Prolonged lactation
3. Use of progestin-only contraceptives,
4. Natural process of squamous metaplasia

The SCJ is located on the
ectocervix and is fully visualized
The SCJ is located within the
endocervical canal and is not
visible
The location of the squamocolumnar junction (SCJ) is variable

Friday, December 30, 2016 HALE T., M.D., RESIDENT PHYSICIAN 10

Squamous Metaplasia

•Lower vaginal pH is the suspected stimulus for squamous
metaplasia
✓Ongoing replacement of columnar epithelium by squamous
epithelium on the cervix

•Undifferentiated reserve cells are the precursors of the new
metaplastic cells, which differentiate further into squamous
epithelium
•This normal process creates a progressively widening band of
metaplastic epithelium termed the transformation zone (TZ), lying
between the original SCJ and the present columnar epithelium

•Cervical reserve and immature metaplastic cells appear particularly
vulnerable to the oncogenic effects of HPV and cocarcinogens
•Squamous metaplasia is most active during adolescence and
pregnancy
•This may explain why early age at sexual activity onset and at first
pregnancy are known risk factors for cervical cancer

Schematic describing relevant
cervical landmarks

HUMAN PAPILLOMAVIRUS

•Human Papilloma Virus
✓Double-stranded DNA virus with a protein capsid
✓Cause of genital and extragenital cancers
✓Responsible for approximately 5 percent of all cancers
✓Approximately 150 genetically distinct HPV types have been identified
✓Of these types, 40 primarily infect the lower anogenital tract

•Two types of genes
✓Early genes
oSix “early” (E) genes govern functions early in the viral life cycle, including DNA
maintenance, replication, and transcriptions
✓Late genes
oThe two “late” genes encode the major (L1) and minor (L2) capsid proteins and
are expressed in the more superficial layers
oThese proteins are needed late in the viral life cycle to complete assembly into
new, infectious viral particles

•HPV gene expression occurs in synchrony with and is dependent upon
squamous epithelial differentiation
•Therefore, completion of the viral life cycle takes place only within an
intact, fully differentiating squamous epithelium
•The completely assembled viral particles are shed within the superficial
squames

•HPV is a nonlytic virus, and therefore infectiousness depends upon
the normal desquamation of infected epithelial cells
•A new infection is initiated when the L1 and L2 capsid proteins
bind to the epithelial basement membrane and/
or basal cells, permitting entry of HPV viral particles into new host
cells

•HPV Types
✓150 types
✓40 anogenital
✓High risk (oncogenic)
o 15-20 oncogenic types
o 16, 18, 31, 33, 35,39, 45, 51, 52 and 58
o 16 the most oncogenic type mainly because of its persistence
✓Low risk (nononcogenic)
o 6, 11, 40 42, 43, 44, and 54

•Together, HPVs 16 and 18 account for approximately
✓70 percent of cervical cancers worldwide,
✓68 percent of squamous cell carcinomas, and
✓85 percent of adenocarcinomas

•Infection with high risk HPV does not result in neoplasia in most
infected women
•This indicates that additional host and environmental factors
determine whether or not high risk HPV will cause neoplasia

•HPV Transmission
✓Transmission of genital HPV results from direct, usually sexual, contact
with the genital skin, mucous membranes, or body fluids of a partner
with either warts or subclinical HPV infection
✓Little is known regarding the infectivity of subclinical HPV, but it is
assumed to be high, especially in the presence of high
viral counts

•The most important risk factors for the acquisition of genital HPV
infection are:
✓the number of lifetime and recent sexual partners and
✓early age at first sexual intercourse

•HPV gains access to the basal cell layer and basement
membrane through microabrasions of the genital epithelium
during sexual contact
•Once infected, these basal cells become a viral reservoir

•Genital HPV infection is multifocal, involving more than one lower
reproductive tract site in most cases
•Therefore, neoplasia at one genital site increases the risk of neoplasia
elsewhere within the lower genital tract, although the cervix appears
most vulnerable
•Also, simultaneous or sequential infection with multiple HPV types is
common

•Most genital HPV infections result from sexual intercourse.
•High-risk HPV cervical infection is generally limited to women who have
experienced penetrative sexual contact
•Oral-genital and hand-genital HPV transmissions are possible but are much
less common than with genital-genital transmission
•Sexually naïve women occasionally test positive for nononcogenic types at
the vulva or vagina, perhaps due to vaginal tampon use or digital
penetration

• Genital HPV is the most common sexually transmitted disease (STD) in the
United States, and most sexually active adults are infected at some time
• Most incident HPV infections develop in women younger than 25 years
• The point prevalence in U.S. females
✓aged 14 to 59 years is 27 percent
✓aged 20 to 24 years (45 percent) and
✓ becomes less prevalent with increasing age

•Women prior to coitarche can become infected with high-risk types as
well, but this is uncommon
✓Fomite transmission, known to occur
with nongenital warts, is unproven but likely explains some of these
cases
•The role of nonsexual transmission of HPV remains unclear and requires
further study

•have rates of HR HPV positivity, abnormal cervical cytology, and
high-grade cervical neoplasia similar to those of heterosexual
women, but undergo cervical cancer screening less often
•Women with or without past sexual experiences with men have a
similar risk, implying that digital, oral, and perhaps object contact
places them at risk of HR HPV infection

•Women who have sex with women have rates of
✓high risk HPV positivity,
✓abnormal cervical cytology, and
✓high-grade cervical neoplasia similar to those of heterosexual
women, but undergoes cervical cancer screening less often
•Those who have never had sex with men appear to be at similar risk,
implying that digital, oral, and object contact places them at risk of
HPV infection

•Therefore, all women who are sexually active should undergo
cervical cancer screening according to current recommendations
regardless of sexual orientation

•Congenital HPV Infection
✓Uncommon
✓Not related to the presence of maternal genital warts or route
of delivery
✓Manifestations
oConjunctival, laryngeal, vulvar, or perianal warts present at
birth or that develop within 1 to 3 years of birth

•Indications for cesarean section
✓Large genital warts that would likely obstruct delivery or
✓Warts that would avulse and bleed with cervical dilation or
vaginal delivery
✓Otherwise CS not always indicated in HPV infection and for the
presence of warts

•Warts in pediatric age group
✓Sexual abuse
✓Fomite
✓Nonsexual contact,
✓Autoinoculation

The natural history of genital human
papillomavirus (HPV) infection varies
between individuals and over time.
Most infections are subclinical.
Spontaneous resolution is the most
common outcome.
Neoplasia is the least common
manifestation of HPV infection,
developing as the result of persistent
infection with integration of HPV
DNA.

•3 possible outcomes of HPV infection
✓Latent HPV infection
oVirus not integrated and its oncogenes not expressed
✓Productive HPV infection
oLow level oncogene expression but no integration
oManifestations
➢Subclinical infection
➢Genital warts ➔ Condyloma acuminata
✓Neoplastic HPV infection

✓Neoplastic HPV infection
oHPV genome integrates with the host genome
oEarly genes supress p53 and pRB
oInfected cells vulnerable to malignant transformation by loss of
cell-cycle control, cellular proliferation, and accumulation of
DNA mutations over time

✓HPV infection is a marker of the initiation of sexual activity and is not necessarily
evidence of promiscuity
✓Most HPV lesions, whether clinical or subclinical, spontaneously regress, especially in
adolescents and young women
✓The risk of progression to high-grade neoplasia increases with age, as HPV infection
in older women is more likely to be a persistent infection
Natural History of HPV Infection

•HPV Prevalence
✓Genital HPV is the most common sexually transmitted infection.
✓Inapparent (subclinical) infection is far more common than
clinically apparent infection

•Risk Factors for HPV Infection
✓The most important risk factors for the acquisition of genital HPV
infection are the number of lifetime and recent sexual
partners and early age at first sexual intercourse

Diagnosis of HPV Infection
✓A sure diagnosis can be made only by the direct detection of
HPV DNA
✓ Methods
oin situ hybridization,
onucleic acid amplification testing (NAAT),
opolymerase chain reaction (PCR)

• Indications for HPV DNA testing
1. Cotesting with cervical cytology screening in women aged 30
years or older,
2. Triage or surveillance of certain abnormal cytology results and
untreated CIN, and
3. Posttreatment surveillance

Treatment of HPV Infection
✓Indications for treatment
oSymptomatic warts that cause physical or psychologic
discomfort,
oHigh-grade neoplasia, or
oInvasive cancer

Prevention of HPV Infection
✓Behavioral interventions
oSexual abstinence,
odelaying coitarche, and
olimiting the number of sexual partners

✓Condoms
oCondoms do not cover all potentially HPV-infected anogenital
skin
oTherefore, condoms may not be completely protective but are
likely to reduce acquisition and transmission of HPV

Immunology of HPV Infection
✓How does the HPV evade the immune system?
1. Limitation of the infection to the epithelium and therefore
absence of a viremic phase
2. Low level expression of early genes;
3. The nonlytic, noninflammatory nature of the infection; and
4. Delayed production of the highly immunogenic capsid proteins
within the superficial squames

•Prophylactic HPV Vaccines
✓They prevent the establishment of new and
persistent infection and subsequent development of neoplasia
✓They do not prevent transient HPV positivity or resolve preexistent infection
✓Three types FDA approved
oCervarix (HPV2) is a bivalent vaccine against HPVs 16 and 18.
oGardasil(HPV4) is a quadrivalent vaccine against HPV types 6, 11,16, and 18
oGardasil 9 (HPV9) : HPV4 plus types 31, 33, 45, 52, and 58.

• Efficacy
✓ HPV 2 and HPV 4 ➔ 65% prevation of SIL and Ca
✓ HPV9 ➔ 80% prevention of SIL and Ca
✓ Three of the vaccines ➔ Nearly 100% protection of SIL and Ca
from the covered HR HPVs

• Start vaccination
✓ 9 – 12 years
✓ include women who are not previously vaccinated aged 13 –
26 years

•Vaccines are expected to prevent approximately 70 percent
of cervical cancers, but they will not protect against the
approximately 30 percent caused by oncogenic HPV types
not covered in the vaccine
•HPV vaccination, therefore, does not negate the need for
cervical cancer screening

•In Ethiopia
✓ Vaccination started on
✓ Age at start
✓ Coverage

•Therapeutic Vaccines
✓Todate no therapeutic vaccine has developed for established
HPV infection

• The following are not necessary
✓ Booster doses
✓ Screening for HPV before vaccination
✓ Excluding women who are sexually active or HPV DNA
possotive
✓ Management of male partner

CERVICAL INTRAEPITHELIAL NEOPLASIA

Risk Factors for Cervical Neoplasia

•The two most important risk factors
✓Multiple sexual partners
✓Early coitarche

•Dietary deficiencies
✓Although data are inconclusive, dietary
deficiencies of certain vitamins such as A, C, E, beta carotene and
folic acid may alter cellular resistance to HPV infection and
thus may promote viral infection persistence and cervical neoplasia

•Exogenous hormones
✓There is an increased risk of cervical cancer in current users of
combination oral contraceptives (COCs) that is related to duration of
use.
✓Moreover, the relative risk nearly doubles at 5 years of COC use
✓The increased risk declines after COC use ceases, and risk returns to
that of nonusers 10 years after use stops

•Parity
✓Increasing parity has been correlated with cervical cancer risk, but it is
unclear if this is related to earlier sexual activity, a progestin exposure effect,
or other factors
✓Immune suppression during pregnancy, hormonal influences on cervical
epithelium, and physical trauma related to vaginal deliveries have been
suggested as etiologic factors associated with the development of cervical
neoplasia

•Immunosuppression
✓Immunosuppressed women in general show
o increased severity,
o multifocal lesion pattern,
o treatment failure,
o persistence, and
o recurrence of lower genital tract disease compared with those who are immunocompetent
✓ These includes
o Human immunodeficiency virus (HIV)-positive women
o Transplant recipients
o Women on immunosuppressive medications

•Inadequate screening
✓Cervical cancer prevention requires identification and eradication of
precursor or early invasive lesions through cytologic screening
✓Lack of screening is a major contributor to higher rates of cervical
cancer in socioeconomically disadvantaged women

•Tobacco smoking
✓The biologic plausibility of a link between
tobacco and cervical neoplasia is supported by several points:
1. Cervical mucus of smokers contains carcinogens and is mutagenic;
2. Genetic alterations in the cervical tissue of smokers are similar to those
seen in smoking-related neoplasias at other sites;
3. Risk is dose-dependent, increasing with both
duration and amount of tobacco use; and
4. Risk decreases with cessation of smoking

Natural History

Differential Diagnosis and Evaluation of Cervical Lesions
✓Cervical Cytology
oPap test screening test of choice in asymptomatic women
oPap test’s specificity is consistently high, approximating 98 percent
oHowever, estimates of its sensitivity are lower and more variable (45 – 65%)
oPap test being less sensitive for the detection of adenocarcinomas than for
squamous lesions, rate of adenocarcinoma and adenosquamous
carcinoma is increasing
oSCC decreasing

✓False-negative Pap test results
may be caused by
oSampling error, in which abnormal cells are not present in the Pap test;
oScreening error, in which the cells are present but missed by the screener; or
oInterpretation error, in which abnormal cells are misclassified as benign

Performing a Pap Test
✓Patient Preparation
oAvoid menstruation
oAbstain from vaginal intercourse, douching, and use of vaginal
tampons and medicinal or contraceptive creams for a
minimum of 24 to 48 hours before a test
oTreatment of cervicitis or vaginitis prior to Pap testing is optimal

• Appearance of squamous cells varies with menstrual cycle and hormonal status
• Thus note the following
✓ date of LNMP
✓ current pregnancy
✓ exogenous hormone use
✓ Menopausal status
✓ complaints of abnormal bleeding
✓ prior abnormal test results, CIN or other LGT neoplasia
✓ IUD (can cause reactive cellular changes)

✓Location
oSampling of the transformation zone is paramount to the sensitivity of the
Pap test
✓Sampling devices
oSpatula, the broom, and the endocervical brush
oA spatula predominantly samples the ectocervix.
oAn endocervical brush samples the endocervical canal and is used in
combination with a spatula.
oA broom samples both endo- and ectocervical epithelia simultaneously,
but can be supplemented by an endocervical brush

✓Conventional slide collection
o Avoid air drying of cells, which is a leading cause of poor slide quality
o The spatula sample should be held while the endocervical brush sampling
immediately follows.
o The spatula sample is then quickly spread as evenly as possible over one half to
two thirds of a glass slide
o The endocervical brush is firmly rolled over the remaining area of the slide, after
which fixation is quickly carried out by spraying with or immersing in fixative

•Liquid-Based Test Collection
✓Currently, two liquid-based Pap tests are FDA approved
oBD SurePath
oThinPrep

Cytology with HPV Co-testing
• Cotesting
✓ cytology + HPV DNA testing for women above 30 year old
✓ For HR HPVs only
✓ Sample for the DNA can be the residue of LBC or a separate
sample taken in a different container
✓ sensitivity nearly 100%
✓ enables early detection and management

• Management of cotesting result
✓ Both negative ➔ repeat screening after 5 years
✓ Cytology +ve but HPV negative ➔ follow cytology +ve mgt protocols
✓ Cytology negative but HPV +ve
oOptions of management
➢ repeat cotesting after 1 year, if repeat HPV +ve ➔ use colposcopy
or
➢ reflex genotyping for HPVs 16 and 18 ➔ if +ve ➔ Colposcopy

Primary HPV Testing
• Paradigm shift in cervical cancer screening
✓ simultaneous testing of 16 types of HR HPVs
✓ Pap test assumes secondary role
✓ Double sensitivity
✓ Less specificity
✓ to counter balance the specificity issue, reflex cytology testing for non
– 16 or 18 HR HPVs
✓ Increased colposcopy referrals but earlier detection of HSIL

Cervical Cancer Screening Guidelines
•Initiation of Screening
✓Screening should begin at age 21 years regardless of sexual history
✓Exceptions to this
o Immune compromise, including
➢HIV infection,
➢Use of immunosuppressive medications, and
➢Organ transplantation
o In such cases, screening should begin at sexual activity onset, even if before age 21,
and should consist of two Pap tests at 6-month intervals during the first year, then
annually

•Screening Interval
✓ACOG recommendation
o Between ages 21 and 29, ACOG (2009) recommends Pap testing at 2-year intervals using
either conventional or liquid-based methods
o At age 30, women at average risk for cervical cancer can be screened at 3-year
intervals if three previous, consecutive, Pap tests have been documented as negative
o Every 5 years if co – testing

✓Women with HIV infection should receive annual screening for
life
✓Women with prior treatment for CIN 2, CIN 3, AIS, or cervical
cancer should receive annual screening for at least 20 years as
they remain at increased long-term risk of cervical cancer

•Discontinuation of Screening
✓Screening may be stopped at age 65 or 70 in women with average risk
for cervical cancer after three consecutive, negative Pap results
during the prior 10 years
✓ACOG (2009) alone recommends that older women who are sexually
active and have multiple partners continue routine screening because
it is unclear if the postmenopausal cervix remains at increased risk of
neoplasia when exposed to new HPV infection

•Screening after hysterectomy
✓For supracercial hysterectomy
✓Women with histories of high-grade cervical neoplasia or
cancer

The Bethesda System

The 2014 Bethesda System Cytology
Report Components

The 2001 Bethesda System: Epithelial Cell Abnormalities

• Bethesda System
✓ Standardized cervical cytology reporting
o Speciment adequacy
➢ Satisfactory
▪Slide cellularity, no obscuring blood or inflamation
➢Unsatisfactory
▪ Lack of cellularity, obscuring blood or inflamation

• Unsatisfactory results
✓ repeat after 4 – 6 months
✓ if still unsatisfactory ➔ colposcopy

• ASC – US
✓ Most common cytologic abnormality
✓ if ASC – Us alone (Age < 25)
o repeat testing after 1 year
o repeat test abnormal ➔ colposcopy
✓ Age above 25
o ASC – US with negative HR HPV ➔ cotest after 3 years
o ASC – US with +ve HR HPV ➔ Colposcopy

•LSIL
✓ Cytologic features of HPV infection + CIN
✓ Carries 15 – 30% of risk of CIN – 2/CIN3 similar to HR HPV +ve ASC – US
✓ Colposcopy is indicated
✓ With HR HPV
o Negative ➔ cotesting after 1 year (but immediate colposcopy is
acceptable)
o +ve ➔ colposcopy immediately

✓ Postmenopausal women
o repeat cytology result at 6 – 12 months
o HPV testing
o colposcopy
✓ Young (Aged 21 – 24)
o avoid immediate colposcopy, high rates of resolutions up untill the next
scheduled cytology
o schedule cytology after 1 year

•Atypical Squmous Cells, Cannot exclude HSIL
✓ Colposcopy required regardless of HPV cotest result
✓ Inadequate colposcopy ➔ diagnostic excision

• HSIL
✓ Colposcopy
✓ see and LEEP appraoch
✓

• Glandular Cell abnormalities
✓ Colposcopy and endometrial sampling
✓ Reflex HPV testing not recommended

Colposcopy

•Colposcopy
✓This is an outpatient procedure that examines the lower anogenital
tract with a binocular microscope
✓The colposcope consists of a stereoscopic lens or digital imaging
system that has magnification settings ranging from 3- to 20-fold and
that is attached to a moveable stand

• Sensitivity: 50 – 80%
• Gree (red free) light fliter adds contrast to adid vascular pattern
evaluations
•

Clinical Considerations
Directing Colposcopy

•Solutions
✓Normal saline
oUsed at the beginning of the colposcopic examination, saline helps
remove cervical mucus and allows initial assessment of vascular
patterns and surface contours
oAbnormal vessels, especially when viewed with green-filtered light,
may be more prominent than after acetic acid application

Use of a blue-green (red-free) light filter
provides higher contrast and definition of
vascular patterns.
Benign surface vessels viewed through a
colposcope using usual white light source

✓Acetic Acid
oAcetic acid 3- to 5-percent is a mucolytic agent that is thought to
exert its effect by reversibly clumping nuclear chromatin
oThis causes lesions to assume various shades of white depending on
the degree of abnormal nuclear density.
oApplying acetic acid to abnormal epithelium results in the
acetowhite change characteristic of neoplastic lesions as well as
some nonneoplastic conditions.

Cervix after application of acetic acid.
Several areas of acetowhite change adjacent
to the squamocolumnar junction are apparent

✓Lugol Solution
oLugol iodine solution stains mature squamous epithelial cells a dark brown
color in estrogenized women as a result of high cellular glycogen content
oDue to poor cellular differentiation, dysplastic cells have lower glycogen
content, fail to fully stain, and appear various shades of yellow
oLugol solution should not be used in patients allergic to iodine, radiographic
contrast, or shellfish.

Same cervix after application of Lugol iodine
solution.
Nonstaining of the lesions at the 10 to 11 o’clock
positions is seen (black arrow), while there is partial
iodine uptake of acetowhite areas along the
posterior SCJ (white arrow).

oThis solution is particularly useful when abnormal tissue cannot
be found using acetic acid alone
oIt is also used to define the limits of the active transformation
zone, as immature squamous metaplasia does not stain as
strongly as mature (fully differentiated) squamous epithelium

• Examination
✓ Cervical visualization
owhether the cervix is fully seen or whether the evaluation is
limited by inflammation, bleeding, scarring, or other obscuring
causes
✓ Thus evaluation can be noted as adequate or inadeaute

• SCJ visibility
✓ Completely, partially or not visible
✓ Adeaute
o Full visualization of SCJ + upper limits of all lesions
✓ Types of TZ
o Type 1➔ Entirely ectocervical
o Type2 ➔ endocervical component that can be fully visualized
o Type 3 ➔ endocervical component that cannot be fully visualized

• Lesion Grading
✓ Normal squamous epithelium
o Featureless, smooth, pale pink surface
o blood vessles absent or seen only as fine capillary network
✓ Columnar epithelium
o red

Reid Colposcopic Index

Low-grade squamous
intraepithelial lesion (LSIL).
After 5-percent acetic acid
application, LSIL is often multifocal
and bright white with irregular
borders.

High-grade squamous intraepithelial lesion
(HSIL).
After 5-percent acetic acid application, HSIL
demonstrates off-white dull color and coarse
vascular pattern.

Colposcopy shows a large high-grade
lesion with cuffed crypt openings (arrow)
and atypical vessels (arrowheads) that are
worrisome for invasive cancer.

Biopsy

•Excissional Biopsy
✓Ectocervical biopsy
✓Endocervical sampling

1. Endocervical curette,
2. Endocervical speculum,and
3. Cervical biopsy forceps.

Endocervical sampling is currently recommended during
colposcopy in the following situations

Management of CIN

CIN -1
• Treatment
✓ No need of agressive treatment
✓ Observe indefinitely, if diagnosed after:
o ASC – US
o LSIL
o Negative Pap with +ve HR HPV 16/18

✓Treat if it persists for greater than 2 years
✓ no need of treatment for those who are younger than 25 years
even if persistent
✓ Observation consists of
o cotest after 12 months of CIN – 1 diagnosis
o For those age < 25 years ➔ Only Pap after 12 and 24 months

✓ Persistent CIN – 1 may be treated by
o Ablation
➢Adequate colposcopic examination
➢Endocervical sampling lacks HSIL (CIN2/3) or ungraded CIN
oExcision
➢ Inadequate colposcopic examination
➢ ungraded CIN
➢ HSIL (CIN 2/3)

✓ CIN – 1 diagnosed after ASC – H or HSIL Pap test
o age 25 or older
➢ cotesting at 12 and 24 months
➢ diagnostic excision
o age 21 – 24
➢ colposcopic and cytology at 6 months intervals

✓ Regardless of age group
o excision is recommended if
➢ persistent unexplained HSIL cytology after 24 months
➢ Inadequate colposcopy
➢ Possotive endocervical samples

CIN – 2 and CIN – 3
• Management
✓ Indications for diagnostic excision
o Inadeaute colposcopy
✓Indicaitons for direct treatment
o unequivocal diagnosis of CIN – 3
✓ Hysterectomy
o Not primary management
o reserved only excision is not feasible or HSIL persists or recurs

✓ Young ladies with low parity
o either treatment or observation are acceptable if colposcopy is adequate
o observation consists of
➢ repeat cytology and colposcopy after 6 months
o treatment
➢ inadequate colposcopy
➢ CIN -3 specified
➢ CIN 2/3 persits after 24 months follow up

Adenocarcinoma in Situ
• Diagnostic excision is required to exclude invasive cancer with
maximum cetainity
• Cold – knife conization or LEEP, if margins are free and if the
woman has completed her family size, simple hysterectomy
• Residual cancer 80% with possotive margins, thus, repeat excisions
if hysterectomy is not advisable because of motivation for bearing
more kids

Cervical Cytology:
Initial Management of Epithelial Cell Abnormalities

Surveillance of Abnormal Cervical Cytology in the Absence of Histologic
High-Grade Neoplasia

•Treatment of CIN
✓Ablative procedures
o Cryosurgery,
o Electrofulguration, and
o Carbon dioxide (CO2) laser
✓Excisional procedures
o Cold-knife conization
o Laser conization
o LEEP

Ablation
• Not indicated in
✓ HIV patients
✓ CIN – 3
✓ AIS
✓ AGC

Excision
• LEEP
✓ primary outpatient management tool for HSIL
• CKC
✓Prefered for patients at high risk of invasive cancer
• CO2 laser ablation
✓ Expensive, require extensive training, thermal compromise of
speciment margins

✓Hysterectomy
oRecurrent high-grade cervical disease if childbearing has been completed
or
oWhen a repeat cervical excision is strongly indicated but technically not
feasible
o AIS
oOtherwise unacceptable as primary therapy for CIN 1, 2, or 3

Part – II: Cervical Cancer

•Contents
1. Incidence
2. Risk Factors
3. Pathophysiology
4. Histologic Types
5. Diagnosis
6. Staging
7. Workup
8. Management
9. Prognosis

Introduction
•Incidence
✓Cervical cancer is the most common gynecologic cancer in women
and is mostly attributed to HPV infection
✓Compared with other gynecologic malignancies, cervical cancer
develops in a younger population (median age at diagnosis 48 years
of age) of women and screening should begin in young adulthood

•Mostly early cancers are asymptomatic
•Symptoms of advanced cancer include
✓Bleeding
✓Watery discharge
✓Sings associated with venous, lymphatic, neural or ureteral
compression

•Biopsy is diagnostic
•Staging is clinical and it dictates the management and is the most important
indicator of long term survival
✓Early stages
oEffectively erradicated surgically by either conization or radical
hysterectomy
✓Late stages
oChemoradiation is primarily selected

✓Cervical cancer is common worldwide and ranks third among all
malignancies for women
✓In general, higher incidences are found in
developing countries, and these countries contribute 85 percent of
reported cases annually and this high incidence is attributed to lack of
screening

•Risk Factors
✓Invasive cervical cancer shares the same risk factors as cervical preinvasive
lesions
o HPV infection
➢99.7% of cervical cancers are associated with an oncogenic HPV subtype
➢HPV 16 accounts for 57% and HPV 18 for 16% of cervical cancers
o Lower socioeconomic predictors
➢Lower educational attainment, older age, obesity, smoking, neighborhood
poverty and lack of screening

✓Cigarette Smokign
o Increases the risk of SCC
o May alter high risk HPV clearance
✓Reproductive behavior
o Multiparity
o Use of combined oral contraceptives
✓Sexual activity
o Early coitarche
o Multiple sexual partners

Pathophysiology
•Tumorigenesis
✓HPV infection to the cells of SCJ ➔ dysplastic lesion ➔ SCC of
the cervix
✓HPV oncoproteins are critical component of continued cancer
cell proliferation
oHPV infection ➔ E1 and E2 (early replication proteins) enable
the virus to replicate within cervical cells ➔ LSIL

✓E7 bind to Rb (retinoblastoma tumor suppressor protein)
✓E6 bind to p53 tumor suppressor protein
✓In both instances bidning leads to degradation of these
suppressor protiens and immortalization of cervical cells

Tumor Spread
Paracervical and parametrial LNs➔
Obturator LN ➔ Internal, external
LN➔ Common illiac LN ➔
Paraaortic LN
In contrast, lymphatic channels from
the posterior cervix course
through the rectal pillars and the
uterosacral ligaments to the rectal
lymph nodes. These nodes are
encountered during radical
hysterectomy and are removed with
the uterosacral ligaments

•Lymphovascular Space Involvement
✓As tumor invades deeper into the stroma, it enters blood capillaries
and lymphatic
channels
✓Not included in staging
✓Poor prognostic indicator
✓Indication for radiation therapy

•Local and Distant Tumor Extension
✓With extension through the parametria to the pelvic sidewall,
ureteral blockage frequently develops, resulting in
hydronephrosis
✓Additionally, the bladder may be invaded
by direct tumor extension through the vesicouterine ligaments
(bladder pillars)

• The rectum is invaded less often because it is anatomically separated
from cervix by
the posterior cul-de-sac
• Distant metastasis results from hematogenous dissemination, and the
lungs, ovaries, liver, and bone are the most frequently affected organs

Histologic Types

•The two most common histologic subtypes of cervical cancer are
squamous cell and adenocarcinoma

SQUAMOUS CELL CARCINOMA
75% of cervical cancers
Arise from ectocervix
3 histologic types
◦ Keratinizing
◦ Nonkeratinizing
◦ Papillary
ADENOCARCINOMA OF CERVIX
Trends in increasing incidence of
adenocarcinoma
20-25% of cervical cancers
Arises from endocervix
Poorer overall survival

Diagnosis
•Symptoms
✓Usually asymptomatic
✓Early symptoms
oWatery discharge
oBlood tignged vaginal discharge

•Symptoms of advanced diseases
✓ Compression symptoms
o Compression of lymphatic drainage
➢ Lower extremity edema
o Sciatic nerve compression
➢ Low back pain
o Uretral compression
➢ Hydronephrosis and uremia
➢ Ureteral stenting or percutaneous nephrostomy
tube insertion are usually required

✓Hemorrhage
oCan be uncontrolled if from a tumor bed
oCan be treated with
➢Packing
➢Monsel solution
➢Topical aceton
➢Radiation
➢Hypogastric artery ligation

•Tumor invasion to local organs
✓Bladder
oHematuria
oSymptoms of vesicovaginal fistula
✓Rectum
oSymptoms of rectovaginal fistula
oConstipation

•Physical Examination
✓Most have a normal general physical exam findings
✓With advancing disease
o Enlarged supraclavicular or inguinal lymphadenopathy,
o Lower extremity edema,
o Ascites, or
o Decreased breath sounds with lung auscultation may indicate metastases
✓Cervical growth can be exophytic or endophytic

•During bimanual examination,
✓a clinician may palpate an enlarged uterus resulting from tumor invasion and growth
✓Alternatively, hematometra or pyometra may expand the endometrial cavity
following obstruction of fluid egress by a primary cervical cancer
✓In this case, the uterus may feel enlarged and boggy
•Advanced cervical cancer cases may have vaginal involvement, and the extent
of disease can be appreciated on rectovaginal examination

•In such cases, palpation of the rectovaginal septum between the
index and middle finger of an examiner’s hand reveals a thick,
hard, irregular septum.
•The proximal posterior vaginal wall is most commonly invaded
•In addition, during digital rectal examination, parametrial,
uterosacral, and pelvic sidewall involvement may be palpated.

•Either one or both parametria may be invaded, and involved
tissues feel thick, irregular, firm, and less mobile
•A fixed mass indicates that tumor has probably extended to the
pelvic sidewalls
•However, a central lesion can become as large as 8 to 10 cm in
diameter before reaching the sidewall

•Pap Smear
✓Its use for suspicious lesions is discouraged
✓Sesitivity of a single Pap test
oFor high grade lesions ➔ 55-80%
oFor low grade lesions ➔ 30-50%
✓Thus, the preventive power of Pap smear testing lies in regular serial
screening

•Colposcopy and Biopsy
✓If abnormal Pap smear findings are noted, colposcopy is often
performed
✓Cervical punch biopsies or conization specimens are the most
accurate for allowing assessment of cervical cancer invasion

1. Cervical leiomyoma,
2. Cervical polyp,
3. Prolapsing uterine
leiomyoma or sarcoma,
4. Vaginitis,
5. Cervical eversion,
6. Cervicitis,
7. Threatened abortion,
8. Placenta previa,
9. Cervical pregnancy,
10.condyloma acuminata,
11.Herpetic ulcer, and
12.Chancre
Differential Diagnosis

Staging
•Cervical cancers are staged clinically
•Allowable components of staging include
✓Cold knife conization,
✓Pelvic examination under anesthesia,
✓Cystoscopy,
✓Proctoscopy,
✓Intravenous pyelogram
✓Computed-tomography [CT] scan), and
✓Chest radiograph

MRI for Cervical Ca evaluation
ADVANTAGES
•Measures tumor size precisely even for
endocervical lesions, and for
delineating cervical tumor boundaries
and surrounding invasions commonly
performed in patients being
considered for fertility-sparing radical
trachelectomy
LIMITATIONS
1. Less accurate for diagnosing
microscopic or deep cervical
stromal invasion or identifying
minimal parametrial extension
2. False-negative findings occur with
small volumes of disease and with
tissue foci in which cancer cannot
be differentiated from other tissues
such as scar or necrosis

CT for Cervcail Ca Evaluation
ADVANTAGES
Can aid detection of enlarged lymph
nodes, ureteral obstruction, or distant
metastasis
High-resolution depiction of anatomy,
especially when used with contrast
evaluate tumor size and bulky
extension beyond the cervix
LIMITATIONS
CT is not accurate for assessing subtle
parametrial invasion
or deep cervical stromal invasion
This is because of its poor soft-tissue
contrast resolution and thus its difficulty
in enhancing local tumor invasion from
normal parametrium
Internal node architecture is often
poorly defined by CT

Work up

Treatment

Simple and Extended Hysterectomy

•Early Stage
✓Stage IA1
oConization
oType I hysterectomy
oRadical trachelectomy with pelvic LN dissection if they desire fertility
✓Stage IA2 – IIA
oRadical hysterectomy (Type III ) and pelvic lymphadenectomy

•Adavanced Stage Primary Disease
✓ ➔ Stage IIB -IVA
o Radical surgery at times pelvic exenteration
o Radiation therapy
➢ External beam radiation
➢ Extended field radiation
➢ Brachytherpay ➔ Intracavitary radiation
o Chemoradiation
•IVB
✓ Palliation

•Palliative Care
✓Gastrostomy tube for persistent N & V
✓Surgery for bowel obstruction
✓Percutaneous nephrostomy tubes for urinary fistulas or urinary
tract obstruction
✓Pain management

Chemotherapy Regimens and Response Rates of
Cervical Cancer

Prognosis
•Prognostic Factors
✓Stage of the disease
✓Nodal involvement
✓Histologic grade
✓Histologic type of the tumor

Management during Pregnancy
•Diagnosis
✓Pap screening similar to the nonpregnant population
✓If Pap results show HSIL or suspected malignancy ➔
colposcopic–directed biopsy should be obtained
✓If colposcopic-directed biopsy fails to show malignant cells ➔
Cold-knife conization should be performed in the second
trimester

•Management in early stage
✓ IA1-IIA
o Intentional delay of treatment till 6 weeks postpartum doesn’t pose harm
o IA1
➢ Vaginal delivery
o IA2-IIA1
➢ Delivery via C/S
•Management in advanced stage
✓ IIB-IVB
o Chemoradiation
o Classical C/S

References
1. F. Gary Cunningham, 2016. Williams Gynecology, 3rd Edition, The McGraw-
Hill Companies, Inc.
2. James R. Scott, 2008. Danforth’s Obstetrics and Gynecology, 10th edition
3. UpToDate 21.8

Cervical ca (precancerous and invasive)

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