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.
2. DR.MANINDER AHUJA
Director AHUJA NURSING HOME & INFERTILITY
CENTRE
FARIDABAD
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DR.Maninder Ahuja VP FOGSI
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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
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.
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)
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17. NATURAL HISTORY OF HPV
AND CERVICAL CANCER
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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
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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
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
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
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
Global incidence The incidence of cervical cancer varies widely around the world, with the highest incidence in developing countries. Incidence rates exceeding > 30 cases per 100 , 000 population occur in Latin America and Sub-Saharan Africa with lower incidences observed in Western Europe, North America and Japan. The incidence rates for each country are available from the International Agency for Research on Cancer (IARC) database. The main reason for these variations in incidence is the availability of screening programmes in developed countries but not in poorer developing countries. Screening can detect the early signs of cervical cancer, allowing for prompt treatment to prevent the development of invasive and potentially fatal cervical cancer. It is important to understand that these figures are not necessarily accurate everywhere. They are sourced from World Health Organization and IARC data , which varies in quality depending on country. Data from Finland, for example, will be perfect because they have good records systems and all cancers are routinely reported. In India, by contrast, very few centres report into data sources and, in some areas of Africa, incidence figures are an estimate only because of the lack of availability of cancer registries or other reporting mechanisms . Likewise, t he incidence in China is reported to be low but this may be because of under-reporting . Reference Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004 .
MSM – Male having sex with male WSW – WOMEN HAVING SEX WITH WOMEN
Key Point Integration of HPV into the DNA of the infected host cell is commonly associated with high-risk oncogenic HPV types 1 and is linked to the activity of E6 and E7 proteins. 2 Background HPV infects its host by penetrating through mucosal tears in the basal membrane. 3 In benign HPV-associated skin lesions, the HPV virus maintains its genome as episomes at low copy numbers (10–200 copies/cell) in the basal cells of the epithelium separate from the host cell DNA. To maintain its viral DNA as an episome, viral E1 and E2 proteins are expressed. Failure to express E1 leads to the integration of the HPV genome into the host cell chromosome. 3 Integration of HPV into the DNA of the infected host cell is commonly associated with high-risk oncogenic HPV types 1 and is c onsidered an important step in tumor progression. 2 In malignant HPV-associated skin lesions, HPV DNA integration into the host cell’s chromosome regularly occurs through a break in the viral genome around the E1/E2 region . Integration-mediated disruption of E2 may trigger uncontrolled expression of E6 and E7, resulting in cellular transformation. 2 The E6 protein associates with the tumor suppressor protein p53 and promotes proteolytic destruction of the protein. This leads to malignant transformation and loss of regulated cell growth. The E7 protein associates with the retinoblastoma protein (pRB), which inactivates the cell cycle restriction function of this protein. 2 References 1. Gallo G, Bibbo M, Bagella L, et al. Study of viral integration of HPV-16 in young patients with LSIL. J Clin Pathol . 2003;56:532 –53 6. 2. Syrj änen KJ, Syrj änen SM. Molecular biology of papillomaviruses. In: Papillomavirus Infections in Human Pathology . Chichester, United Kingdom: John Wiley & Sons, Inc.; 2000: 11–51. 3. Doorbar J. The papillomavirus life cycle. J Clin Virol . 2005;32(suppl):S7–S15. 3/Doorbar/p. S9/col 1/¶2; col 2/¶1 1/Gallo/p. 534/col 1 /¶1 2/Syrjanen/p. 32/col 2/¶2; p 33/col 1/¶2 2/Syrjanen/p. 12/Table 2.1; p. 18/col 2/¶2,3; p. 39/col 1/¶2,3; col 2/¶4; p. 40/col 1/¶1; col 2/¶3 1/Gallo/p. 534/col 1 /¶1 2/Syrjanen/p. 32/col 2/¶2; p 33/col 1/¶2 3/Doorbar/p. S8/col 2/¶3 1/Goodman/p. 1559/Figure 2
There is no single moment in time that is recognized as a cut-off point between transience and persistence.
HPV infection is a necessary factor in the development of almost all cervical cancer. However, most women infected with HPV do not develop cervical cancer, indicating that certain other risk factors play a role. These other risk factors may help to predict which women exposed to HPV are more likely to develop cervical cancer. • Although the risk factors for infection persistence and progression to cancer have not been disentangled, we have some evidence of potential cofactors. These can be grouped into three categories:
The current available evidence for an association between diet, nutritional status and cervical HPV carcinogenesis is not yet convincing,
However, full evaluation often depends on technical issues of the HPV assay used in the different studies.
Host cofactors related to progression are still unclear, but probably the most important are the immunological factors.
Heterogeneity in biology (and definition) still exists in precancerous lesions. To discuss which lesions do not represent precancerous ones is important for diagnostic specificity. Diagnosis of CIN 1 incorporates the errors of placement, processing, and interpretation of colposcopically-guided biopsy, although such a diagnosis is poorly reproduced even when made on the basis of large tissue specimens. Most CIN 1 is associated with HPV infection and has a high rate of spontaneous regression. Among cytologically normal HPV DNA-positive women, the risk of LSIL is between 25-40% after 1-3 years of follow-up. The vast majority will return to normality in 4 years. Women with a persistent diagnosis of CIN 1 may progress to CIN 2/3 at a rate of 15% over 2 years. Persistent CIN 1 needs to be followed up as some of these cases may harbour hidden CIN 2/3.