Premalignant and malignant conditions of

the cervix
Kindu Y, Lecturer

06/27/2021 Kindu.Y 1
 Session objectives
 At the end of this session, students will be able to:
o Review the anatomy of the cervix
o Explain the natural history of neoplasia and cervical cancer
o Describe methods of cervical cancer screening
o Describe clinical presentation of cervical cancer
o Describe diagnostic and staging modalities of cervical
cancer
o Describe management of CIN and cervical cancer

06/27/2021 Kindu.Y 2
 Anatomy of the cervix

06/27/2021 Kindu.Y 3
06/27/2021 Kindu.Y 4
 Cervical intraepithelial neoplasia
o Cervical intraepithelial neoplasia (CIN) is a premalignant
condition of the uterine cervix.
o The ectocervix is covered in squamous epithelium.

o And the endocervix, including the cervical canal, is covered

with glandular/columnar epithelium.
o CIN refers to squamous abnormalities/metaplastic changes.

06/27/2021 Kindu.Y 5
 Squamocolumnar Junction? New and old?

 Squamous Metaplasia? What is the underlying cause?

 Risk ages of metaplasia?

 Transformation zone?

06/27/2021 Kindu.Y 6
 Basic virology of human papillomavirus

 Double stranded DNA virus with a protein capsid unique to each viral
type

 More than 150 serotypes

 More than 40 serotypes can infect the LAGT

 Causes 99.7% cervical neoplasia, nearly all

 primarily infects human squamous or metaplastic epithelial cells

 six "early" (E) genes govern functions early in the viral life cycle,
including DNA maintenance, replication, and transcription.

06/27/2021 Kindu.Y 7
 Basic virology of HPV…
 Early genes are expressed in the lower squamous epithelial layers

 The two "late" genes encode the major (Ll) and minor (12) capsid proteins.

 These proteins are expressed in the superficial epithelial layers late in the
viral life cycle and during the assembly of new, infectious viral particles.

 Sequential HPV gene expression is synchronous with and dependent on

squamous epithelial differentiation.

 Completion of the viral life cycle takes place only within an intact, fully

differentiating squamous epithelium

06/27/2021 Kindu.Y 8
 Basic virology of HPV…

 A new infection is initiated when the Lt and L2 capsid proteins bind

to the epithelial basement membrane or basal cells, which permits
entry of HPV viral particles into host cells

06/27/2021 Kindu.Y 9
 Basic virology of HPV…

 The human papillomavirus life cycle is completed in synchrony with squamous epithelium
differentiation. Early genes. Including the E6 and E7 oncogenes, are expressed most strongly within
the basal and parabasal layers.

 The late genes encoding capsid proteins are expressed later in the superficial layer. Intact virus is shed
during normal desquamation of superficial squames. Late genes are not strongly expressed in high-
grade neoplastic lesions

06/27/2021 Kindu.Y 10
 HPV serotypes
1) hrHPV
2) lrHPV
 6,11,16,18,31,33,35,45,52,56,58,59,68
 hrHPV infection docs not cause neoplasia in most infected women,
and additional host, viral, and environmental factors determine
progression to LAGT neoplasia.

06/27/2021 Kindu.Y 11
 Epidemiology

 Genital HPV-M/C STD

 High prevalence among women aged 14 to 59 – 40 %

 hrHPV infection is common after sexual initiation

 Most common in women younger than 25

 Highest prevalent among 20-24 years old – 45%

 Prevalence decreases with age

 Simultaneous or sequential infection with multiple HPV types is

common

06/27/2021 Kindu.Y 12
 Epidemiology

 number life time and recent sexual partners and early age of

first sexual intercourse-most important

 Cervical hrHPV infection generally requires penetrative intercourse

 Congenital HPV infection

06/27/2021 Kindu.Y 13
o Infection by one of the HPV genotypes is necessary but not sufficient.

o Contributing factors include HPV subtype, persistence of infection,

immune status….

o Over 150 subtypes of HPV

o At least 80% of sexually active women will have acquired a genital

HPV infection by age 50

o 90% of new HPV infections will have resolved within 2-5 years

06/27/2021 Kindu.Y 14
 Infection Outcomes and Natural History

 Latent or expressed/productive or neoplastic infection?

 Temporally, HPV infection can be transient (spontaneous resolution,

clearance) or persistent.

 High-grade neoplasia (CIN 3, AIS, or cancer) is the least common

outcome of genital HPV infection and requires HPV expression and
persistence.

06/27/2021 Kindu.Y 15
 Infection Outcomes and Natural History

Neoplastic infections

 The E6 and E7 oncoproteins produced interfere with the function of

and accelerate degradation of p53 and pRb, respectively, key host
tumor-suppressor proteins which leaves infected cells vulnerable to
malignant transformation by loss of cell-cycle control, cellular
proliferation, and accumulation of DNA mutations over time

06/27/2021 Kindu.Y 16
 Outcome of Genital HPV infection

06/27/2021 Kindu.Y 17
 normal epithelial differentiation becomes disrupted and incomplete.

 The degree of disruption is used to grade LAGT histology as low-

grade or high-grade SIL?

 low-grade lesions are generally acute, transient, and not oncogenic

06/27/2021 Kindu.Y 18
 Infection diagnosis

 clinically suspected based on lesions or results of cytology, histology,

and colposcopy, all of which are subjective and often inaccurate

06/27/2021 Kindu.Y 19
 Summary
 M/c HPV subtype associated with Ca cervix?
 2nd M/c HPV subtype associated with Ca cervix?
 3rd M/c HPV subtype associated with Ca cervix?
 HPV subtype most specific to Ca cervix is?
 HPV subtype mostly associated with Squamous cell carcinoma?
 HPV subtype mostly associated with adenocarcinoma

06/27/2021 Kindu.Y 20
 Group discussion
o Could a woman get HPV without being sexually active?

o Is it possible to prevent HPV using condom?

o Does HPV will cause cancers other than cervical cancer?

06/27/2021 Kindu.Y 21
CERVICAL INTRAEPITHELIAL NEOPLASIA

06/27/2021 Kindu.Y 22
 Risk factors CIN
Demographic risk factors
Low socioeconomic status
Increasing age
Behavioral risk factors
Early coitarche
Multiple sexual partners
Male partner with multiple prior
sexual partners
Tobacco smoking
06/27/2021
Dietary deficiencies
Medical risk factors
Cervical high-risk human
papillomavirus infection
Exogenous hormones (COC)
Parity
immunosuppression
Inadequate screening
Kindu.Y 23
 Natural History

 Preinvasive lesions can spontaneously regress, remain stable, or

Progress

 LSILs are thought to be manifestations of acute HPV infection, and

approximately 90 % regress within a few years.

 High-grade lesions are less likely to regress. 40 % of CIN 2 cases

show spontaneous regression within 2 years.

 This is even more frequent (>60 percent) in young, healthy women

06/27/2021 Kindu.Y 24
 Natural History of Cervical intraepithelial Neoplasia (CIN)
Lesions

06/27/2021 Kindu.Y 25
 Epidemiology of CIN
 CIN-M/C in 20-30 years
 CIS-M/C in 30-35 years
 Ca of cervix – Bimodal peak, 35-39 and 56-60 years

06/27/2021 Kindu.Y 26
06/27/2021 Kindu.Y 27
 Natural history of Cxal CA

06/27/2021 Kindu.Y 28
 Grades of cervical intraepithelial neoplasia
o CIN 1 is a low-grade lesion and refers to mildly atypical cellular
changes in the lower third of the epithelium.

o CIN 2 is considered a high-grade lesion and refers to moderately

atypical cellular changes confined to the basal two-thirds of the
epithelium. There is considerable variability in this category.

o CIN 3 is a high-grade lesion and it refers to severely atypical cellular

changes encompassing greater than two-thirds of the epithelial
thickness and includes full-thickness lesions

06/27/2021 Kindu.Y 29
 Cervical cancer screening

 Screening of high risk woman is very crucial for the better

prevention of cervical cancer.

 Because:
 Long preinvasive state (10-15yrs)
 Effective screening methods
 Effective treatment
 Purpose: to identify of intraepithelial lesion

06/27/2021 Kindu.Y 30
 Types of Screening

1. Population Based Screening- Screening asymptomatic patients at the

community level.

2. Selective screening – screening high risk women, Example

screening for ovarian cancer in women with family History.

3. Opportunistic Screening- Screening women who present with

symptoms to the hospital or the health facility.

06/27/2021 Kindu.Y 31
 Characteristics of screening methods
o Disease should have a detectable pre-cancerous stage.

o Disease should have significant impact on public health.

o The screening method should be highly sensitive and highly specific.

o Test procedure should be acceptable to the community and financially

affordable.

o Facilities for definitive diagnosis and subsequent treatment should be

readily available.

06/27/2021 Kindu.Y 32
 Screening test for pre-invasive cervical cancer
o Cervical Cytology (Pap Smear)

o HPV testing

o Combined Test/Cotesting

o Visual Inspections

06/27/2021 Kindu.Y 33
 Cervical Cytology
o The Pap test's specificity - 98%

o False-negative Pap test results may derive from sampling errors that
fail to collect abnormal cells or from screening errors where the
screener overlooks or misclassifies abnormal cells.

o Suboptimal management of abnormal results by providers and poor

patient compliance also contribute to avoidable cases of cervical
cancer.

06/27/2021 Kindu.Y 34
 Cervical Cytology
 Initiated at 21 years of age regardless of age of coitarche
 Women age 21-29 every 3 years routine
 Women age 30-65 every 5 years – routine co-testing
 Stop after 65 if no Hx of moderate or severe dysplasia or cancer and
they had have either three negative Pap test results in a row or two
negative Co-test results in a row with in 10 years, with the most recent
test performed with in the past 5 years.
 Women with CIN2, CIN3, AIS- continue for at least 20 years
 Women underwent total hysterectomy with no Hx of HSIL or Ca CX?
 Q 3 yrs. For 20 years after initial 3 pap test with in the first 2 years of
post hysterectomy if the have Hx of HSIL or Cx Ca
 Instruments used- Ayers spatula and endocervical brush

06/27/2021 Kindu.Y 35
 Cervical Cytology

1. Ayers spatula
2. Endocervical brush
3. Plastic broom

06/27/2021 Kindu.Y 36
 Prerequisites for pap smear
o Abstain from vaginal intercourse

o Avoid douching

o Avoid vaginal tampon use

o Avoid intravaginal medicinal or contraceptive creams for a minimum

of 24 to 48 hours before tested

o Patient should not be menstruate

o Treatment of cervical infections prior to the test

06/27/2021 Kindu.Y 37
 Cervical Cytology

06/27/2021 Kindu.Y 38
 hrHPV testing
o A role for HPV testing in cervical cancer screening is attractive
because of its greater immediate sensitivity for CIN 3 or cervical
cancer and the objectivity of its result.

o HPV testing is usually performed from the residual liquid based

cytology pap smear after the cytology slide is prepared.

06/27/2021 Kindu.Y 39
 Co-testing
o The combination of HPV testing with cytology (co-testing) raises the
sensitivity of a single screening test for high-grade neoplasia and
leads to earlier detection and management of HSIL.

o Co-testing offers a nearly 100 % negative predictive value for high-

grade neoplasia.

o Cytology-negative and HPV-positive test results will occur in < 10

percent of screened patients. In such cases, co-testing is repeated 12
months later.

06/27/2021 Kindu.Y 40
 Visual inspection methods

o Indicated for women for whom cervical cancer screening is

recommended and for whom these methods are the best
screening option
 (i.e. women who do not have access to cervical cytology
and HPV testing).

o  Visual inspection can be performed during pregnancy

 but cervical biopsies are relatively contraindicated in

pregnant women unless invasive cancer is suspected.
06/27/2021 Kindu.Y 41
 Visual inspection with acetic acid (VIA)

Procedure

o Vaginal speculum

o Light source that can illuminate the cervix

o 5% acetic acid or 5% Lugol's iodine Large cotton swabs

o Sterile pot for acetic acid

o Sponge holding forceps for application of acetic acid and iodine

o Medical waste receptacle

06/27/2021 Kindu.Y 42
 Cont…
 Inspection - Visual inspection is performed using the naked eye, as follows

o Position the patient in the dorsal lithotomy or frog leg position

o Insert a speculum into the vagina and visualize the cervix

o Inspect the cervix and note any lesions

o Ensure that the entire cervix is visible and that the SCJ is visible in its entirety

o Apply either acetic acid or Lugol's iodine using a cotton swab, wait for one
minute

o Inspect the cervix again and note any lesions or color changes

o Document the findings

06/27/2021 Kindu.Y 43
 Cont…
o Positive test is characterized by opaque, dense, well-defined
acetowhite areas that touch the SCJ or are close to the external OS, or
by the presence of a cervical lesion that turns aceto-white.

o The absence of color change is a negative test.

06/27/2021 Kindu.Y 44
 Poisitive result for VILI?

06/27/2021 Kindu.Y 45
 Follow-up of abnormal findings
o Areas with abnormalities and gross cervical lesions should be
biopsied.

o Biopsy is important to identify or exclude invasive cancer.

o Lesion that involves three or four quadrants of the TZ, extends into
the cervical canal or vaginal walls, and bleeds easily on contact may
suggest invasive cancer.

o Detection of CIN is enhanced by obtaining multiple biopsies from the

most abnormal appearing area

06/27/2021 Kindu.Y 46
 Flow chart for screening and treatment

06/27/2021 Kindu.Y 47
 Treatment options
o Excisional treatments

 Cervical conization

 LEEP

o Ablative treatments

 Cryotherapy

 Laser ablation

06/27/2021 Kindu.Y 48
 LEEP

06/27/2021 Kindu.Y 49
 Cryotherapy

06/27/2021 Kindu.Y 50
 Laser ablation

06/27/2021 Kindu.Y 51
 Cont…
o Women with CIN 1: management is guided by the results of the preceding
cytologic test.
 CIN 1 with a prior cytologic sample reported LSIL), or normal cytology in the
presence of HPV 16 or 18, recommended follow-up is co-testing at one year.

o CIN 2,3 with an adequate colposcopy, we suggest treatment with excision

rather than ablation.
 LEEP is preferred over CKC because it can be performed in the office setting.

o Histologic diagnosis of persistent CIN 2,3, either a repeat diagnostic

excisional procedure or hysterectomy is appropriate.

06/27/2021 Kindu.Y 52
 Prevention of CIN and cervical cancer

 Primary prevention: the primary approach to the

prevention of cervical CIN is vaccination against oncogenic
HPV infection.

 Secondary prevention: secondary prevention is aimed at

cervical cancer rather than CIN itself.
 For women with CIN, appropriate monitoring and treatment are
used to prevent progression to malignant disease.

06/27/2021 Kindu.Y 53
 Cervical cancer

o Worldwide, cervical cancer is common, and it ranks 4th among

all malignancies for women.

o Compared with other gynecologic malignancies, cervical cancer

develops in a relatively younger population.

o In 2018, global cervical cancer estimates include

 nearly 570,000 new cases
 and more than 311,000 deaths

o In general, 85% cervical cancer belongs to developing counties..

06/27/2021 Kindu.Y 54
 Risk factors

 in addition to demographic
o parity- 7 -4x 1 or 2 2x
o lack of regular screening?
o Number of sexual partners ?
o HPV-99.7%
o Immunosuppression
o HPV infection (type)
o cigarrate smoking current &
o HSV2
former - 2-3x
o Early coitarche?
o Long term COC use 4x-
reduces after cessation

06/27/2021 Kindu.Y 55
 Pathophysiology

06/27/2021 Kindu.Y 56
 Histologic types of cervical cancer
o Squamous Cell Carcinoma

 make up approximately 70 percent of all cervical cancers, and arise

from the ectocervix.

 Over the past 30 years, the incidence of squamous cell cancers has
declined, whereas that of cervical adenocarcinoma bas risen.

 These changes may be attributed to an improved method of screening

for early squamous lesions of the cervix

06/27/2021 Kindu.Y 57
 Adenocarcinoma
o Make 25 % of cervical cancers and arise from the endocervical
mucus-producing columnar cells.

o Because of this origin within the endocervix, adenocarcinomas are

often occult and may be advanced before becoming clinically evident.

o They often give the cervix a palpable barrel shape during pelvic
examination.

06/27/2021 Kindu.Y 58
 Diagnosis of cervical cancer
o Symptoms

 Postcoital bleeding

 Bleeding after douching

 Watery vaginal discharge

o Physical examination

 Cervical ulceration

 polypoid mass

06/27/2021 Kindu.Y 59
 Papanicolaou Test and Cervical Biopsy
o Histologic evaluation of cervical biopsy is the primary tool to
diagnose cervical cancer.

o If abnormal Pap test results are noted, colposcopy is often performed.

o And adequate cervical and endocervical biopsies are obtained.

06/27/2021 Kindu.Y 60
 Staging of cervical cancer

06/27/2021 Kindu.Y 61
 Laboratory and imaging

06/27/2021 Kindu.Y 62
 Treatments

06/27/2021 Kindu.Y 63
 Hysterectomy
o Women with FIGO stage IA2 through IIA cervical cancer, that is,
those without obvious parametrial involvement, may be selected for
radical hysterectomy

o plus pelvic lymph node dissection and with or without paraaortic

lymph node dissection.

o Surgery is appropriate for those who are physically able to tolerate an

aggressive surgical procedure,

o those who wish to avoid the long-term effects of radiation therapy,

and/or those who have contraindications to pelvic radiotherapy
06/27/2021 Kindu.Y 64
 Cervical cancer during pregnancy
o Survival rates between pregnant and non-pregnant women with
cervical cancer do not differ when matched by age, stage, and year of
diagnosis.

o Diagnosis

 A Pap test is recommended for all pregnant patients older than 21 at

the initial antenatal visit.

 If Pap test results adenocarcinoma in situ, or suspected malignancy,

colposcopy is performed and biopsies are obtained. However,
endocervical curettage is excluded to prevent amniotic sac rupture.
06/27/2021 Kindu.Y 65
 Stages I and II Cancer in Pregnancy

o Women with microinvasive squamous cell cervical carcinoma

found during conization that measures <3 mm
 and contains no LVSI(lymphovascular space involvement)
(stage IAl) may deliver vaginally and reevaluated after 6 weeks
postpartum.

o Given the outcomes, a planned treatment delay is generally

acceptable for women who are 20 or more weeks' gestational age at
diagnosis with stage I disease
 and who desire to continue their pregnancy.
06/27/2021 Kindu.Y 66
 Advanced Cervical Cancer in Pregnancy
o Women with advanced cervical cancer diagnosed prior to fetal
viability are offered primary chemo-radiation.

o Spontaneous abortion of the fetus tends to follow whole-pelvic

radiation therapy.

o For women who decline pregnancy termination, systemic

chemotherapy can be administered.

o If cancer is diagnosed after fetal viability is reached and a delay until

fetal pulmonary maturity is elected, then a classical cesarean delivery
is performed.
06/27/2021 Kindu.Y 67
 Thank you !

06/27/2021 Kindu.Y 68