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Epidemiology and carcinogenesis  of premalignant lesions of cervix
 

Epidemiology and carcinogenesis of premalignant lesions of cervix

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Cervicall cancer is number one cancer in India and mortality is every seven minute one woman is dyign of cervical cancer. And we still have to make a desicsion that these women's lives are worth ...

Cervicall cancer is number one cancer in India and mortality is every seven minute one woman is dyign of cervical cancer. And we still have to make a desicsion that these women's lives are worth saving by doing simple screening tests like VIA. Cytology by PAP Or LBC and HPV DNA ,

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  • 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.
  • RRR –recurrent respiratory polyposis GWS – Genital warts RRP- recurrent respiratory polyposis

Epidemiology and carcinogenesis  of premalignant lesions of cervix Epidemiology and carcinogenesis of premalignant lesions of cervix Presentation Transcript

  • DR.MANINDER AHUJA 08/26/13DR.Maninder Ahuja VP FOGSI1 EPIDEMIOLOGY AND CARCINOGENESIS OF PREMALIGNANT LESIONS OF CERVIX
  • DR.MANINDER AHUJA Director AHUJA NURSING HOME & INFERTILITY CENTRE FARIDABAD • VICE PRESINDET FOGSI • PRESIDENT ELECT INDIAN MENOPAUSE SOCIETY • DEPUTY SECRETARY GENERAL SAFOMS • BOOK “STEP BY STEP MANAGEMENT OF MENOPAUSE” • THREE CHAPTERS IN JEFFCAOTE BOOK OF GYNAECOLOGY UPDATED IN 2008 • CHAPTERS IN “ 3RD EDITION OF FOGSI’S Priciples& Practice Of Obstetrics &Gynaecology for Post Graduates” • Three Chapters in “Operative Obst.&Gynaecology”editors dr.Randhir Puri&Dr.Narendra Malhotra • Editor of Manual on “ Prevention of Cervical Cancer” • DVD ON “PRESCRIPTION OF EXERCISE FROM ADOLESCENT TO MENOPAUSE” • Dvd on “EXERCISE IN PREGNANCY” • EDUCATIONAL CD ON MENOPAUSE • PRESIDENT FARIDABAD OBST&GYNAE SOCIETY • CHAPTER SECRETARY INDIAN MENOPAUSE SOCIETY (FARIDABAD) • CHAIRPERSON PUBLIC AWARENESS COMMITTEE OF IMS • CHAIRPERSON GERIATRIC GYNAECOLOGICAL COMMITTEE 08/26/132 DR.Maninder Ahuja VP FOGSI
  • 08/26/13DR.Maninder Ahuja VP FOGSI3 DVDs ON EXERCISE
  • Mid life New Beginnings North Zone Yuva FOGSI 2 0 1 3 22nd Nov to 24th Nov Venue- Hotel Radisson Amritsar 08/26/134 DR.Maninder Ahuja VP FOGSI YOU ARE INVITED TO NORTH ZONE YUVA FOGSI BROCHURE ON FOGSI WEB SITE
  • 08/26/13DR.Maninder Ahuja VP FOGSI5 EPIDEMIOLOGY AND CARCINOGENESIS OF HPV
  • 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
  • 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
  • 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
  • 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
  • Cervical cancer prevalence in India > 45 / 100,000 WHO 2009 08/26/1310 DR.Maninder Ahuja VP FOGSI
  • 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
  • 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.
  • 08/26/13DR.Maninder Ahuja VP FOGSI13 Comparison of prevalence of CX Cancer in LOW and HIGH income regions
  • 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
  • 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
  • The most frequent types of HPV 08/26/13der Ahuja VP FOGSI
  • NATURAL HISTORY OF HPV AND CERVICAL CANCER 08/26/1317 DR.Maninder Ahuja VP FOGSI
  • FOUR STEPS IN CERVICAL CANCER Infection Persistence Progression Invasion 08/26/1318 DR.Maninder Ahuja VP FOGSI
  • 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
  • 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
  • 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
  • Clearance 60 % clears within one year 80% clears within two years Most HPV infections are asymptomatic 08/26/1322 DR.Maninder Ahuja VP FOGSI
  • 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
  • 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
  • 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
  • PERSISTENCE < 5 YEARS 08/26/1326 DR.Maninder Ahuja VP FOGSI
  • 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
  • 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
  • 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
  • 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
  • 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
  • 08/26/1332 DR.Maninder Ahuja VP FOGSI
  • 08/26/1333 DR.Maninder Ahuja VP FOGSI
  • 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
  • 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
  • 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
  • 08/26/13DR.Maninder Ahuja VP FOGSI37 Other cancers associated with HPV
  • 08/26/1338 DR.Maninder Ahuja VP FOGSI