1 Squamous cell carcinoma in the oral cavity and cervix Prof. Bettina Borisch, FRCPath

Zürich-5-nov 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

Zürich-5-nov 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.

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

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

Zürich-5-nov Male and female cancers worldwide in 2002

Zürich-5-nov 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)‏

Zürich-5-nov 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

Zürich-5-nov 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

Zürich-5-nov 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

Zürich-5-nov Risk factors for cervical cancer M olecular - 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)‏

Zürich-5-nov Approximate lifeftime risks In percentage of the whole population Exposure to HPV75% Exposure to high risk HPV50% Persistent high grade CIN10% Invasive carcinoma1.3% Dying of cervical cancer0.4%

Zürich-5-nov 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

Zürich-5-nov 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

Zürich-5-nov Histology of CIN I HPV - ISHKi 67p16INK4 H&E

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Zürich-5-nov 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

Zürich-5-nov 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

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

Zürich-5-nov 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

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

Zürich-5-nov 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

Zürich-5-nov Phylogram of human papillomaviruses (HPVs) belonging to supergroup A. The sequence name is displayed at the end of each line. The values on the graph show the distances of evolution.

Zürich-5-nov 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

Zürich-5-nov 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

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

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

Zürich-5-nov 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

Zürich-5-nov 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?