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Squamous cell carcinoma in

the oral cavity and cervix
Prof. Bettina Borisch, FRCPath

Institut de mdecine sociale et prventive
Dpartement de pathologie et immunologie
Hpitaux universitaires de Genve
Universit de Genve
bettina.borisch@medecine.unige.ch
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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
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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.
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Estimated numbers of incidence and mortality of
cancers in women worldwide in 2002
(Data shown in thousands)
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Estimated numbers of incidence and mortality of
cancers in men worldwide in 2002
(Data shown in thousands)
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Male and female cancers worldwide in 2002
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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)

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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
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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
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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

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Risk factors for cervical cancer
Molecular - 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)
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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%
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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
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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

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Histology of CIN I
HPV - ISH Ki 67 p16INK4 H&E
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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
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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
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Oral/HN Squamous cell carcinoma
Well differentiated
Moderately diff
Poorly differentiated
Basaloid SCC Verrucous carcinoma
Other variants:
Spindle
Papilllary
Adenosquamous
acantholytic
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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

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Correlation presence of HPV and
histological features
Szentirmay et al. 2005
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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
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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.
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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

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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

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Kaplan Meier curves of 114 cases of oral or laryngeal carcinomas
HPV as an prognostic factor in oral / HNSCC?
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HPV16 in oral squamous cell carcinoma:
Clinical correlates and 5-year survival
Sugiyama et al. 2007, Br J Oral Maxillofacial Surg
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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
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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?