This document discusses the epidemiology and carcinogenesis of premalignant lesions of the cervix. It notes that cervical cancer is caused by HPV in almost 100% of cases. HPV infection goes through stages of acquisition, persistence of the virus, progression to precancerous lesions like CIN 1, 2, and 3, and potential invasion if not treated. Risk factors for acquisition and persistence include early sexual activity, multiple partners, and co-factors like smoking.

1. DR.MANINDER AHUJA
08/26/13DR.Maninder Ahuja VP FOGSI1
EPIDEMIOLOGY AND
CARCINOGENESIS OF
PREMALIGNANT LESIONS OF
CERVIX

2. DR.MANINDER AHUJA
Director AHUJA NURSING HOME & INFERTILITY
CENTRE
FARIDABAD
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DR.Maninder Ahuja VP FOGSI

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5. 08/26/13DR.Maninder Ahuja VP FOGSI5
EPIDEMIOLOGY AND
CARCINOGENESIS OF HPV

6. Global Burden of Cervical
Cancer
►500,000 women diagnosed per year
►270,000 deaths per year
>1 million new cases of cervical cancer each year,
2050
 Expected increase in cervical cancer by 2020 is 40%
1. Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004;
2. Parkin DM, et al. Eur J Cancer 2001; 37(Suppl 8):S4-S66. 08/26/136 DR.Maninder Ahuja VP FOGSI

7. 72,825
Deaths
Annually
Approx. 200 women die every day
Every 7 minutes a women dies
Approx. 8 women die every hour
Burden of Disease in
India
1. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers in India. Summary
Report 2010. [Accessed on 5th
July,2010]. Available at www. who. int/ hpvcentre
08/26/137 DR.Maninder Ahuja VP FOGSI

8. Key Statistics on
India
1. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers in India. Summary
Report 2010. [Accessed on 5th
July,2010]. Available at www. who. int/ hpvcentre
Incidence of Cervical Cancer has increased & Mortality has decreased
08/26/138 DR.Maninder Ahuja VP FOGSI

9. Incidence of cervical cancer
GLOBOCAN 2002 Cancer Incidence, Mortality andPrevalence India
• Cervical cancer ranks No. 1 among cancers in
Indian women followed by breast cancer
• Every year 134420 Indian women are diagnosed
with Cervical cancer and around 72,825 die from
the disease
• 1 out of 4 women who die due to Cervical Cancer in
the world is an Indian
08/26/139 DR.Maninder Ahuja VP FOGSI

10. Cervical cancer
prevalence in India
> 45 /
100,000 WHO 2009 08/26/1310 DR.Maninder Ahuja VP FOGSI

11. Cervical cancer contributes to over 2.7 million years
of life lost among women dying between the ages of
25 and 64 years worldwide, some 2.4 million of
which occur in the developing countries and only 0.3
million in the developed countries.
This difference is because of lack of
screening for premalignant lesions of Cervix
in developing countries
Magnitude of the problem
08/26/1311 DR.Maninder Ahuja VP FOGSI

12. FACT SHEET
08/26/13DR.Maninder Ahuja VP FOGSI12
Cervical cancer is caused by HPV in almost 100% of
cased proved by epidemiological studies and molecular
studied of cervical cancers
It is preventable by primary screening by vaccination
and secondary prevention by various screening
modalities and management stratgies.

13. 08/26/13DR.Maninder Ahuja VP FOGSI13
Comparison of prevalence of CX Cancer in LOW and HIGH income regions

14. HPV TYPES
Over 118 different HPV types have been identified.
About 40 of these are known to infect the cervical
epithelium
 12 are classified as carcinogens.
Genital HPV types have been classified into different
groups according to their
association with cervical cancer:
08/26/1314 DR.Maninder Ahuja VP FOGSI

15. Comparative high risk and low
risk types
established high-risk types, which are considered as known
human carcinogens (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58and
59).
HPV 16 and 18 account for about 70% of all cervical cancer
Probable high-risk types, which are considered as probably
carcinogenic (68)
• Possible high-risk types, which are considered as possible
carcinogenic (26, 30, 34, 53, 66, 67, 69, 70, 73, 82, 85 and 97)
• Low-risk types, which are considered as non-carcinogenic
and are found mainly in genital warts and the normal
epithelium (6 and 11)
08/26/1315 DR.Maninder Ahuja VP FOGSI

16. The most frequent types of HPV
08/26/13der Ahuja VP FOGSI

17. NATURAL HISTORY OF HPV
AND CERVICAL CANCER
08/26/1317 DR.Maninder Ahuja VP FOGSI

18. FOUR STEPS IN CERVICAL
CANCER
Infection
Persistence
Progression
Invasion
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19. Fact sheet
HPV is one of the most commonnly sexually transmitted
infections
Almost all of the women are infected with HPV at some
time in their life after being sexually active
Most of infections are cleared within two years
08/26/1319 DR.Maninder Ahuja VP FOGSI

20. Risk factors for acquistion of
HPV Infection
Early age of sexual activity
More number of male partners
More partners of husband or male partner
Homo sexuals or MSM (male having sex with
male ORWSW- women having sex with
women)
08/26/1320 DR.Maninder Ahuja VP FOGSI

21. TRANSMISSION OF INFECTION
Sexual act
Anal sex
 skin to skin contact
Mother to child
Use of same undergarments
Sometimes by oral sex
08/26/1321 DR.Maninder Ahuja VP FOGSI

22. Clearance
60 % clears within one year
80% clears within two years
Most HPV infections are asymptomatic
08/26/1322 DR.Maninder Ahuja VP FOGSI

23. Spectrum of Changes in Cervical Squamous
Epithelium Caused by HPV Infection1
NormalNormal
CervixCervix
HPV Infection /HPV Infection /
CIN* 1CIN* 1
CIN 2 / CIN 3 /CIN 2 / CIN 3 /
Cervical CancerCervical Cancer
*CIN = cervical intraepithelial neoplasia
1. Adapted from Goodman A, Wilbur DC. N Engl J Med. 2003;349:1555–1564. Copyright © 2003 Massachusetts Medical Society. All rights reserved. Adapted with permission.08/26/1323 DR.Maninder Ahuja VP FOGSI

24. HPV LIFE CYCLE IN CERVIX
HPV Particles reach the basal layer through a break in the .viral genome is maintained in the
basal layer and as basal cell differentiate, viral life cycle goes through amplification, assembly
and virus realease,and concomitant expression of early genes to late genes including L1 and
L2 which assemble into virus capsids.
08/26/1324 DR.Maninder Ahuja VP FOGSI

25. HPV GENES
 HPV genes are designated as E or L according to their expression in
the early or late differentiation stages of the epithelium:
 E1, E2, E5, E6, and E7 are expressed early in the differentiation,
 E4 is expressed throughout,
 and L1 and L2 are expressed during the final stages of
differentiation. E6 and E7 are the primary HPV oncoproteins.
 At some still undefined point during progression to precancerous
lesions, E6 and E7 expression is deregulated by either genetic or
epigenetic changes, leading to their over-expression in the full-
thickness epithelial lesion.
 These proteins have numerous cellular targets, with p53 and
 retinoblastoma tumour suppression protein (pRB) being the most
important. E6 inhibition of p53 blocks apoptosis, whereas E7
inhibition of pRB abrogates cell-cycle arrest.
08/26/1325 DR.Maninder Ahuja VP FOGSI

26. PERSISTENCE
< 5 YEARS
08/26/1326 DR.Maninder Ahuja VP FOGSI

27. PERSISTENCE and PROGRESSION
Persistence is defined as detection of the same HPV type two
or more times, within a given time interval between
Persistence of high-risk HPV types is necessary for the
development, maintenance and progression of precancerous
lesions.
Only a small fraction of infections will persist and the lag time
between infection
 Appearance of the first microscopic evidence of
precancerous lesions can be surprisingly short, often within 5
years.
Long-term persistence is not strictly correlated with
carcinogenicity of HPV types, since some non-carcinogenic
types show long persistence as well (e.g., HPV 61).
08/26/1327 DR.Maninder Ahuja VP FOGSI

28. RISK FACTORS FOR INFECTION
PERSISTENCE and PROGRESSION TO
CANCER
• Environmental or Host cofactors:including
long-term use of hormonal contraceptives,
tobacco smoking, high parity,
genetic,HIV,Chalemydia ,HSV ,Poor nutrition
• Viral cofactors, such as infection with specific
HPV types, coinfection with other HPV types,
HPV variants, viral load, and viral integration
08/26/1328 DR.Maninder Ahuja VP FOGSI

29. OTHER CO FACTORS
 Women who are younger at first full-term pregnancy
are at increased risk of developing cervical cancer later
in life compared to women who become pregnant at
older ages.
 There is some support for the hypothesis that
antioxidant nutrients may play a protective role in
cervical carcinogenesis.
Women with diets low in fruits and vegetables may be at
increased risk for cervical cancer.
Overweight has been associated with an increased risk
of adenocarcinoma of the cervix.
08/26/1329 DR.Maninder Ahuja VP FOGSI

30. VIRAL COFACTORS
Even further, variants of HPV types can also modify
cancer risk. For example, an elevated risk of cervical
cancer associated with some variants of HPV 16 (non-
European variants) has been suggested.
The total risk of precancerous lesions for a woman
infected with several HPV types coinfection) maybe
increased compared with women infected with only one
of those same HPV types.

Although not fully proved, HPV viral load (particularly
for HPV 16) may be a marker for establishing persistent
HPV infection and increase the risk of progression
08/26/1330 DR.Maninder Ahuja VP FOGSI

31. HOST COFACTORS
Immunological factors.
Individuals with immunosuppression caused by HIV
infection,
treatment for an autoimmune disease or
organ transplantation are at increased risk of HPV-
associated anogenital cancers.
This association appears to be stronger for women with
a low CD4T-lymphocyte count.
08/26/1331 DR.Maninder Ahuja VP FOGSI

32. 08/26/1332 DR.Maninder Ahuja VP FOGSI

33. 08/26/1333 DR.Maninder Ahuja VP FOGSI

34. CIN I
 CIN 1 is a histopathological
diagnosis of HPV infection,
and should not be considered
as a precancerous lesion. CIN
1 has a lower risk of
progression to cervical cancer
than cytological lesions
grouped as LSIL.
 Persistent CIN over 2/3 yrs
should be followed up
08/26/1334 DR.Maninder Ahuja VP FOGSI

35. CIN II
CIN 2 is heterogeneous. It is
sometimes produced by
non-carcinogenic HPV
types,
Regression potential of 40%
over an approximately 2-
year period.
Thus, CIN 2 represents an
equivocal precancerous
lesion, but it is treated in
some regions to provide a
safety margin against
cervical cancer risk.
08/26/1335 DR.Maninder Ahuja VP FOGSI

36. CIN 3
CIN 3 is the true
precursor of
precancerous lesions,
and will progress to
cancer if untreated at a
rate of around 30% over
20 years.
When high-grade CIN
(CIN 2 or worse) is
diagnosed, treatment is
mandatory. Overall
treatments are more than
90% effective.
08/26/1336 DR.Maninder Ahuja VP FOGSI

37. 08/26/13DR.Maninder Ahuja VP FOGSI37
Other cancers associated with HPV

38. 08/26/1338 DR.Maninder Ahuja VP FOGSI