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