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Squamous cell carcinoma in the oral cavity and cervix

Prof. Bettina Borisch, FRCPath Institut de médecine sociale et préventive Département de pathologie et immunologie Hôpitaux universitaires de Genève Université de Genève bettina.borisch@medecine.unige.ch. Squamous cell carcinoma in the oral cavity and cervix.

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Squamous cell carcinoma in the oral cavity and cervix

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  1. Prof. Bettina Borisch, FRCPath Institut de médecine sociale et préventive Département de pathologie et immunologie Hôpitaux universitaires de Genève Université de Genève bettina.borisch@medecine.unige.ch Squamous cell carcinoma in the oral cavity and cervix Zürich-5-nov-2008

  2. Zürich-5-nov-2008 Carcinoma of the uterine cervix and oral squamous cell carcinoma? What do they have in common? • Carcinoma of the uterine cervix is the second most common female malignancy in the world • Oral squamous cell carcinoma is a major cause of cancer morbidity and mortality worldwide

  3. Zürich-5-nov-2008 Carcinoma of the uterine cervix and oral squamous cell carcinoma? What do they have in common ? • Cervical cancer is a world wide disease but early detection has reduced the mortality in affluent countries. • Oral cancer has the highest incidence in developing countries, especially among tobacco and alcohol users and betel quid chewers.

  4. Zürich-5-nov-2008 Estimated numbers of incidence and mortality of cancers in women worldwide in 2002(Data shown in thousands)‏

  5. Zürich-5-nov-2008 Estimated numbers of incidence and mortality of cancers in men worldwide in 2002(Data shown in thousands)‏

  6. Zürich-5-nov-2008 Male and female cancers worldwide in 2002

  7. Zürich-5-nov-2008 Carcinoma of the uterine cervix and oral squamous cell carcinoma? What do they have in common ? • They both derive from epithelia that are similar , upper aero digestive tract mucosa and that of ectocervix and vagina • non keratinizing squamous epithelia • Epithelia that undergo stepwise maturation from immature basal layer cells to surface keratinocytes • Strong association of cervical and oral cancer with human papillomavirus (HPV)‏

  8. Zürich-5-nov-2008 Human papillomavirus (HPV)‏ • HPVs are epitheliotropic DNA viruses present in the skin and mucosa • More than 70 types have been described • Mucosal and genital HPVs are divided into low risk (HPVs 6,11,42,43,44) and high risk (HPVs 16,18,31,33,35,45,51,52,56)‏ • High risk HPV infection contributes to carcinogenesis and tumor progression through two viral oncogenes: E6 and E7

  9. Zürich-5-nov-2008 Two viral oncogenic proteins • E6 and E7 oncogenes encode proteins of about 151 and 98 amino acids, respectively • E6 forms a complex with p53, loss of p53 leads to deregulation of the cell cycle • E6 prevents senescence by upregulation of telomerase • E7 forms complexes with RB family proteins, negative regulators of cell growth, releases E2F, that induces cell cycle progression via host genes (upregulation of Cyclin E and p16INK4)‏ • E6 and 7 are critical in extending the life span of epithelial cells – a necessary component of tumour development

  10. Zürich-5-nov-2008 Molecular evidence linking HPV to cancer in general and to cervical cancer in particular • HPV-DNA is detected by hybridisation techniques in over 95% of cervical cancers • Specific HPV types are associated with cervical cancer (high risk) versus condylomata (low risk)‏ • Viral genes disrupt cell cycle (E6 and E7)‏ • However, the evidence does not implicate HPV as the only factor

  11. Zürich-5-nov-2008 Risk factors for cervical cancerMolecular - epidemiologic data • Early age at first intercourse • Multiple sexual partners • Increased parity • A male partner with multiple partners • The presence of cancer-associated HPV • Persistent detection of high-risk HPV • Exposure to oral contraceptives and nicotine • Genital infections (chlamydia)‏

  12. Zürich-5-nov-2008 Approximate lifeftime risks In percentage of the whole population • Exposure to HPV 75% • Exposure to high risk HPV 50% • Persistent high grade CIN 10% • Invasive carcinoma 1.3% • Dying of cervical cancer 0.4%

  13. Zürich-5-nov-2008 Human papillomavirus (HPV)‏ • HPV is an obligatory intranuclear organism that must infect mitotically active cells in order to establish infection in the epithelium • Infection has to access the basal cells of multilayered epithelium in 3 different ways: • Mucosal injury, metaplastic epithelium or squamo-columnar junction

  14. Zürich-5-nov-2008 Fate of epithelial HPV-infection Mitotically active cell reached by HPV: • 1) latent infection, viral replication is connected with the cell cycle, cells appear morphologically intact • 2) latent infection may convert into replicative infection, in terminally differentiated cells the complete virion assembles • 3) The majority of initial infections become virus-free spontaneously

  15. Zürich-5-nov-2008 Histology of CIN I H&E HPV - ISH Ki 67 p16INK4

  16. Zürich-5-nov-2008

  17. Zürich-5-nov-2008 Link cervical cancer – HPV well established • What is the evidence linking HPV infection with cancers of the oral cavity including head and neck? • Oral/Head and neck squamous cell carcinoma (O/HNSCC) is a locally aggressive disease. Some areas traditionally report a high incidence (France, South India, Eastern Europe, Japan). Tobacco and alcohol are well established risk factors

  18. Zürich-5-nov-2008 Viral replication in oral epithelia • Koilocytes, atypia, akanthosis, epithelial thickening • Basal layers of squamous cell epithelium of the oral cavity or oropharynx • At the reserve cell layer in the respiratory epithelium • In the larynx, metaplastic alteration, multilayered squamous cell epithelium, papillomas and finally carcinomas develop

  19. Zürich-5-nov-2008 Moderately diff Well differentiated Poorly differentiated Oral/HN Squamous cell carcinoma Basaloid SCC Verrucous carcinoma Other variants: Spindle Papilllary Adenosquamous acantholytic

  20. Zürich-5-nov-2008 Detection of HPV in OHNSCC / HPV-prevalence in OHNSCC • The results vary and depend on the detection method used (usually HPV general primer sets)‏ • Initial studies in the 80ies • The reported overall frequency of HPV DNA in OHNSCC varies from 14-61%, (46.5%)‏ • Multiple infections are relatively common (22-48%)‏ • Close association between infection and a subset of OHNSCC with basaloid / verrucous histological features

  21. Zürich-5-nov-2008 Correlation presence of HPV and histological features Szentirmay et al. 2005

  22. Zürich-5-nov-2008 HPV phylogeny and oral cancer • All « genital or mucosal » types of HPV belong to supergroup A • Within supergroup A eleven subgroups have been defined on the basis of genetical and biological similarities • Groupe A2 are mainly in skin warts, A 6,7 and 9 in genital high grade dysplasia and carcinoma • A 6,7,9,10, and 11 are the most frequently occuring types in the head and neck region

  23. Zürich-5-nov-2008 Phylogram of human papillomaviruses (HPVs) belongingto supergroup A. The sequence name is displayed at the end of eachline. The values on the graph show the distances of evolution.

  24. Zürich-5-nov-2008 Modes of transmission • It is generally accepted that transmission of genital infections is associated with sexual contacts • What about the head and neck region ? • Perinatal transmission to neonates at birth has been described • Some HPV types in newborns have not been found in their mothers • Oral-genital or oral-anal sex • Multiple pathways for HPV transmission

  25. Zürich-5-nov-2008 Natural history of HPV infection in the oral / HN region • The general presence of HPV in normal oral mucosa has not been defined yet • Sampling of healthy cells is not standardized (basal cell layer)‏ • 1-60% positivity, (probably 10%)‏ • HPV may colonize healthy mucosa, which later leads to malignant transformation

  26. Zürich-5-nov-2008 Kaplan – Meier curves of 114 cases of oral or laryngeal carcinomas HPV as an prognostic factor in oral / HNSCC?

  27. Zürich-5-nov-2008 HPV16 in oral squamous cell carcinoma:Clinical correlates and 5-year survival Sugiyama et al. 2007, Br J Oral Maxillofacial Surg

  28. Zürich-5-nov-2008 Clinicopathological correlates • Patient with HPV+ oral cancers are young, non-drinkers, non-smokers, female • Prognostic significance of HPV is still under debate • Recent data suggest that NFkB family proteins such as p65 in HPV infected oral cancer may be linked to improved differentiation and better prognosis of the disease when treated • Molecular biology: frequent LOH 3p and 9p21, inactivation of p16 gene, LOH at 17p with mutation of the p53 associated with progression

  29. Zürich-5-nov-2008 Open questions : • Why HPV is found in virtually all cervical cancers, but only a subset of oral carcinoma has yet to be explained • HPV is rarely found in premalignant oral lesions, and may therefore not be necessary for the progression of oral mucosa to malignancy • HPV detection for patient management on the oral setting? • Simple screening test such as exfoliative cytology in oral mucosa lesions - feasable ? • More insights into pathogentic factor interplay • Vaccin for HNSCC?

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