Natural History of Cervical Cancer

Invasive
EXPOSURE Normal Precursors Cancer
Cells

Co Factors

HPV Normal Cells Persistent Integration of

Infection HPV Infection Viral DNA

Co Factors
Transformation of
Cell

Cancer Dysplasia: CIN

Non Infected Life time risk of 80 – 90% 5 – 15% persist

women infection 80% regress in 36
months

?
?

Latency

< 5% progress to
Median Duration of New Infection is 8 months CIN
Epidemiology

 There are 466 000 new cases each year worldwide

 There are 231 000 deaths worldwide due to cervical cancer each year
 80% of the deaths are from developing countries

HPV is the primary cause for cervical cancer (HPV is a common sexually transmitted infection)

 HPV infects the columnar epithelium or the basal cells of the squamous epithelium either
through an aberration/ulceration in the epithelium or at the squamo-columnar junction
 Preventing HPV transmission is very difficult. Barrier contraceptive methods are only
partially effective because the virus can exist throughout most of the anogenital area
(including areas not covered by male condoms) and can remain infectious for years
 Within 3 years of sexual debut, a high risk of HPV infection is observed
 HPV cannot be treated and in majority of cases it will become undetectable. In smaller
proportion of cases it will become a precancerous lesion called dysplasia
 In 80 – 90% of infected persons, the infection clears within 2 years
 Only in 5 – 15% the infection persists for long time and cervical neoplasia may develop
 1/10 000 of women infected with HPV may develop cervical neoplasia in their lifetime
o HPV 16 – 60 – 70% of cervical cancers
o HPV 18 – 10 – 15% of cervical cancers
 Detectable HPV infection is common among young women rising up to a peak prevalence of
20% at 20 – 24 age group. It becomes 8 – 10% for the women aged > 30 years
 Among the few who develop dysplasia, majority will likely develop mild dysplasia, which
usually regress or does not progress particularly under the age of 35. Few who develop
dysplasia will progress to cervical cancer
 Progression to detectable pre-cancerous lesion will take as long as 10 years
 Risk of progression from moderate to severe form is around 32% for 10 years
 Women aged 35 or older with precancerous lesions are at high risk of developing cancer
 Cervical cancer develops after 40 and most frequent in fifties and sixties
 Risk Factors
o Tobacco Use
o Young Age at first birth
o Use of OCP
o Hormonal and Physical implications of high parity
 Women with at least one previous negative cervical smear have low rates of invasive cancer
for ten or more years
 Even screening women just once for the lifetime at age 35 could reduce cervical cancer
mortality by 26%
HPV Low-grade Cervical High-grade Cervical Invasive
Infection Dysplasia Dysplasia Cancer

Characteristics: Characteristics: Characteristics: Characteristics:

HPV infection is extremely
common among women of
reproductive age.
HPV infection can remain
stable, lead to dysplasia,
or become undetectable.
Management:
While genital warts
resulting from HPV
infection may be treated,
there is no treatment that
eradicates HPV.
Primary prevention
through use of condoms
offers some protection.
Low-grade dysplasia
usually is temporary and
disappears over time.
Some cases, however,
progress to high-grade
dysplasia.
It is not unusual for HPV
to cause low-grade
dysplasia within months
or years of infection.
Management:
Low-grade dysplasia
generally should be
monitored rather than
treated since most lesions
regress or do not progress.
High-grade dysplasia, the
precursor to cervical
cancer, is
significantly less common
than low-grade dysplasia.
High-grade dysplasia can
progress from low-grade
dysplasia or, in some
cases,
directly from HPV
infection.
Management:
High-grade dysplasia
should be treated, as a
significant proportion
progresses to cancer.
Women with high-grade
dysplasia are at risk of
developing invasive
cancer; this generally
occurs slowly, over a
period of several years.
Management:
Treatment of invasive
cancer is expensive and
often not effective in
advanced stages.

Cervical cancer is a rare long term outcome of persistent infection with one of the high risk Human
Papilloma Virus Types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82)

Natural History of Cervical Cancer Precursor Lesions

Pap Smear Classes Old WHO System CIN System Bethesda System
Class I Normal Normal NILM
Class II Atypia Atypia ASC-US/ASC-H
Class III Mild Dysplasia CIN 1 LSIL
Class III Moderate Dysplasia CIN 2 HSIL
Class III Severe Dysplasia CIN 3 HSIL
Class IV Carcinoma in Situ CIN 3 HSIL

True precursors of cervical cancer: true precancerous lesion

 CIN 3 (from the squamous cells)

 Adenocarcinoma in-situ (AIS) – from the glandular/columnar cells of the endocervix

HPV 16, 18 and 45 DNA positivity by cervical disease grade (Chart)

HPV 33, 58, 31, 52, and 35 DNA positivity by cervical disease grade (Chart)

HPV 39, 59, 51, 56 and 68 DNA positivity by cervical disease grade (Chart)

Natural History of Dysplasia

Attribute Mild Moderate CIS

Number of studies 17 12 21
Number of patients 4505 2247 767
Regress 57% 43% 32%
Persist 32% 35% 56%
Progression to CIN 3 11% 22%
Progression to invasive cancer 1% 5% 12%

Toronto Natural History Study: Percentage of Progression

Dysplastic State (by cytology) 2 year 5 year 10 year

Mild to moderate or worse 11.1% 20.4% 28.8%
Mild to Severe or worse 2.1% 5.5% 9.9%
Moderate to Severe or worse 16.3% 25.1% 32.0%
Severe to Cancer 12.1% 16.8% 20.7%

Natural History of Dysplasia

 > 80% of CIN 1 regress by 1 – 2 years

 About 5 – 10% of CIN 1 progress to CIN 3 within 5 years
 > 60% of CIN 2 regress within 3 years
 About 15 – 20% of CIN 2 progress to CIN 3
 < 5% of CIN 1 progress to invasive cancer
 < 10% of CIN 2 progress to invasive cancer
 About 50% of CIN 3 progress to invasive cancer; progression takes 5 – 30 years
 Progression from CIN 1 – CIN 3 is comparatively rapid (< 6 years) but progression from CIN 3
to cancer is a slow process

Factors influencing progression of CIN

 Type of HPV infection: high risk with HPV 16 and 18

 Immune Status: High risk following immunosuppression
 Aneuploidy
 Cytological abnormality: CIN 3
 Age
Management of Low Grade PAP smears

Objectives of Cervical Cancer Screening

 To prevent invasive cervical cancer

o Detect and treat CIN 2/3, AIS (cancer precursor)
 The effectiveness is evaluated by reduction in
o Cancer incidence
o Cancer mortality rate’

 Pap smear is just a screening test for cernical nepplasia not a diagnostic test
 The risk of underlying lesions depends on the severity of cytological abnormality
 Cervical lesions are often of various severities including cellular appearances on the slide
(atypical squamous cells  carcinoma in situ)
 Approximate likelihood of regression
o CIN 1 – 57%
o CIN 2 – 43%
o CIN 3 – 32%
 Screening Tests Available
o Cytology – Conventional and Liquid Base
o HPV tests
o Visual Inspection with Acetic Acid/Lugol’s Iodine (VIA/VILI)

WHO Papanicolaou Bethesda CIN

Normal Class I Negative for Normal
Intraepithelial lesion
or malignancy
Atypical Class II Reactive Cellular No significant cellular
Changes changes
ASC-US Squamous Atypia
HPV Changes
Mild Dysplasia Class III LSIL CIN I/HPV Infection
Moderate Dysplasia Class III HSIL CIN II
Severe Dysplasia/CIS Class IV HSIL CIN III
SCCA/Adeno CA Class V SCCA/Adeno CA SCCA/Adeno CA

Management Options

 Repeat screening at regular intervals: for low risk

 Increased surveillance
o Shorter screening interval: for intermediate risk
 Colposcopy: for high risk
 Treatment: for extremely high risk