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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

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

carcinoma of the uterine cervix and oral squamous cell carcinoma what do they have in common
Zürich-5-nov-2008Carcinoma 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
carcinoma of the uterine cervix and oral squamous cell carcinoma what do they have in common3
Zürich-5-nov-2008Carcinoma 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.
slide4
Zürich-5-nov-2008Estimated numbers of incidence and mortality of cancers in women worldwide in 2002(Data shown in thousands)‏
carcinoma of the uterine cervix and oral squamous cell carcinoma what do they have in common7
Zürich-5-nov-2008Carcinoma 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)‏
human papillomavirus hpv
Zürich-5-nov-2008Human 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
two viral oncogenic proteins
Zürich-5-nov-2008Two 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
molecular evidence linking hpv to cancer in general and to cervical cancer in particular
Zürich-5-nov-2008Molecular 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
risk factors for cervical cancer m olecular epidemiologic data
Zürich-5-nov-2008Risk 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)‏
approximate lifeftime risks
Zürich-5-nov-2008Approximate 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%
human papillomavirus hpv13
Zürich-5-nov-2008Human 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
fate of epithelial hpv infection
Zürich-5-nov-2008Fate 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
histology of cin i
Zürich-5-nov-2008Histology of CIN I

H&E

HPV - ISH

Ki 67

p16INK4

link cervical cancer hpv well established
Zürich-5-nov-2008Link 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
viral replication in oral epithelia
Zürich-5-nov-2008Viral 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
slide19
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

detection of hpv in ohnscc hpv prevalence in ohnscc
Zürich-5-nov-2008Detection 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
hpv phylogeny and oral cancer
Zürich-5-nov-2008HPV 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
slide23
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.

modes of transmission
Zürich-5-nov-2008Modes 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
natural history of hpv infection in the oral hn region
Zürich-5-nov-2008Natural 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
slide26
Zürich-5-nov-2008

Kaplan – Meier curves of 114 cases of oral or laryngeal carcinomas

HPV as an prognostic factor in oral / HNSCC?

hpv16 in oral squamous cell carcinoma clinical correlates and 5 year survival
Zürich-5-nov-2008HPV16 in oral squamous cell carcinoma:Clinical correlates and 5-year survival

Sugiyama et al. 2007, Br J Oral Maxillofacial Surg

clinicopathological correlates
Zürich-5-nov-2008Clinicopathological 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
open questions
Zürich-5-nov-2008Open 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?