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Hpv and cancer of the oral cavity
a
b
Christian U. Hübbers & Baki Akgül
a
Jean-Uhrmacher-Institute for Otorhinolaryngological Research, University of Cologne, Geibelstr. 29, 50931 Cologne, Germany;
b
Institute of Virology, University of Cologne, Fürst-Pückler-Str. 56, 50935 Cologne, Germany
Accepted author version posted online: 05 Feb 2015.
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HPV AND CANCER OF THE ORAL CAVITY
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Christian U. Hübbers1 and Baki Akgül2
1
Jean-Uhrmacher-Institute for Otorhinolaryngological Research, University of Cologne, Geibelstr. 29, 50931 Cologne,
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2
Institute of Virology, University of Cologne, Fürst-Pückler-Str. 56, 50935 Cologne, Germany
Corresponding author: Dr. Baki Akgül, baki.akguel@uk-koeln.de
Key words
Abbreviations
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Human papillomavirus, Head and neck cancer, oral squamous cell cancer,
(human papillomavirus)
HNSCC
(head and neck squamous cell carcinoma)
OPSCC
(oropharyngeal squamous cell carcinoma)
OSCC
(oral squamous cell carcinoma)
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Abstract
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HPV
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Germany;
Increased awareness of human papillomavirus (HPV) as an etiological cause of head and neck squamous cell carcinoma
has increased the interest in analysis of distinct oral sub-sites. It is currently under debate, whether HPV plays a role in
the development of squamous cell carcinoma of the oral cavity (OSCC). The weakness in most published studies is the
1
lack of performing different HPV detection tests combined with analysis for biological activity of the virus. In addition,
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different sub-sites of the oral cavity had been combined to a single entity, which retrospectively leads to a highly
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heterogeneous basis of data. In this review we mainly discuss the unclear role of HPV in OSCC development.
2
HPV positivity in head and neck cancers
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Squamous cell carcinoma of the head and neck (HNSCC) is an anatomically heterogeneous group of neoplasms arising
from the mucosal surface of the oral cavity, oropharynx, hypopharynx, larynx and nasopharynx. Each year approximately
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epidemiological work suggests considerable differences between HNSCC related to tumour sub-site. Unfortunately, a
shortcoming in many publications is the fact that a simplified grouping of cancers of different head and neck regions as a
single entity is retrospectively leading to a highly heterogeneous basis of data. Therefore, important distinctions between
2, 3
. Over the last decade it has become
M
anatomic sub-sites and their natural histories have not been attributed in detail
clear that human papillomaviruses (HPV) not only cause genital and anal cancers, but are also an etiological cause for a
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subset of HNSCC. There are solid indications that incidence and prevalence of HPV-associated HNSCC are increasing
which are particularly discussed to be correlated with a decline in smoking habits
increased incidence of HPV infections in HNSCC of approximately 50%
6, 7
4, 5
. Recent publications showed an
with HPV16 being the most prevalent type in
ep
at least 90% of this cancer 8. Whereas the majority of HPV-driven cancers of the head and neck are oropharyngeal
squamous cell carcinoma (OPSCC) comprising the tonsils and base of the tongue
9, 10
, it is currently in debate whether
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263,000 cases of oral cavity cancer and 135,000 cases of pharyngeal cancer are diagnosed worldwide 1. Recent
HPV may also have a role in other HNSCC sub-sites.
Oncogenic function of HPV
HPV is a small DNA virus with a specific tropism for squamous epithelia. To date, 202 different HPV types have been
3
isolated (International HPV Reference Center; (http://ki.se/en/labmed/international-hpv-reference-center) and HPV types
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infecting the mucosa are further classified into high- and low-risk groups based on the relative malignant potential of the
lesions they cause. Whereas low-risk HPVs, such as HPV6 and HPV11, cause benign warts, high-risk HPVs, such as
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11, 12
. In a
persistent infection the viral E2 protein is tightly controlling the expression of the main viral oncoproteins E6 and E7.
These proteins are the key drivers of tumourigenesis by inactivating two of the most important tumour suppressors, pRb
and p53
13
. In premalignant and malignant lesions, E2 function gets abrogated, which subsequently leads to higher
14
. The inhibition of the tumour suppressor proteins p53 and pRb alters cell cycle
M
expression levels of E6 and E7
pathways regulating cellular proliferation, apoptosis, as well as genetic instability, which can lead to the formation of
15
. The binding of high-risk HPV E7 protein with pRb results in the release of the transcription factor E2F
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epithelial lesions
from the pRb-E2F protein complex and the promotion of cell cycle progression and also leads to the release of the
p16INK4A gene from its transcriptional inhibition. As a consequence, p16INK4A protein is expressed at a high level and is
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thus considered as a reliable surrogate marker for high-risk HPV infection 16.
HPV infection of the oral cavity
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HPV16 and HPV18, cause premalignant squamous intraepithelial neoplasias that can progress to cancer
While HPV is an important cause of OPSCC, it is currently unclear whether HPV may also have a role in other head and
neck cancer sub-sites, including oral squamous cell carcinoma (OSCC). A specific role of HPV in the development of
OSCC was hypothesized in 1983 and since then is still debated
17-19
. The generally accepted risk factors for cancers of
4
the oral cavity (including tumours of the tongue, floor of the mouth, gingiva, gum, palate, lip mucosa and other sides of the
20
21
, betel quid chewing
and alcoholic beverage drinking
22
. The healthy adult population
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mouth) are tobacco smoking
shows a prevalence for any HPV type of 2-8% in the oral cavity, with HPV16 being the most commonly identified type
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.
25-27, 29
. Furthermore, high-risk
sexual behaviour including oral-genital sex has been found to be associated with transmission of HPV infections between
oral and genital sites
26, 30, 31
. Immunodeficiency (e.g. HIV infection) and smoking seem to increase the risk for oral HPV
infection, i.e. make infections more likely to persist
31
32
. Initial studies suggest that most oral HPV infections are likely to be
. Thus, persistence of the virus might be the critical factor for the development of HPV-related
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cleared within a year
diseases.
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Subclinical and premalignant oral HPV infection
In other parts of the body, such as the genital tract, HPV infects exclusively the basal cells of the epithelium, where the
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virus can remain latent. There is evidence that HPV also infects gingival tissue
33, 34
. The periodontal pocket is the only
location of the gingival mucosa where basal cells are exposed to the environment. The periodontal pocket enlarges during
progression of periodontitis as a result of chronic inflammatory processes
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Notably, the prevalence of HPV seems to be significantly higher in men than in women
23-28
35
. In the presence of chronic inflammation,
increased basal cell proliferation leads to higher viral load in saliva as well as higher risk of HPV transmission
36
. In a
recent hospital-based case-control study with histologically confirmed HNSCC cases, periodontitis was associated with
more than 4-fold increased odds of HNSCC. The strength of association was greatest in the oral cavity, followed by
5
oropharynx and larynx
35, 37
. This led to the hypothesis that chronic inflammation and continuous epithelial proliferation in
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the junctional gingiva could favour the replication of HPV and might be an important reservoir for HPV in the oral mucosa.
In (potentially) premalignant oral lesions an increased HPV DNA positivity of 20-64% was described
5, 19, 24, 38-41
. A recent
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indicating biologically active viral infection, revealed 17.5% positivity for high-risk HPVs in oral epithelial dysplasias (for
discussion of p16INK4A immunohistochemistry see below) 42.
Does HPV play a causal role in OSCC development?
established
M
In contrast to the clear picture in OPSCC, where the prognostic relevance of biologically active HPV infection is
18, 43, 44
, no such clear association can be found for OSCC. Contradictory studies exist, which are either in
45, 46
, or of worse outcome
47-49
, as well as
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favour of a better survival probability for HPV-positive OSCC patients
supporting no effect on patient survival 24, 50, 51. A number of publications analysing larger cohorts underline that HPV DNA
and especially HPV16 is present in 10-25% of tumours of the oral cavity, which is higher than in the healthy control
19, 24, 50, 52
ep
population but smaller than in OPSCC
. In OSCC, HPV16 is followed less frequently by HPV18 (including
occasional co-infections with HPV16). Types HPV31, HPV33 and other high-risk types are rarely found
24, 52
. However, in
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report by McCord et al. (2013) combining in situ hybridization and immunohistochemical staining against p16INK4A,
this respect it should be noted that several studies only tested for selected types namely HPV16 and HPV18 or used more
general detection methods not determining the exact type. Beside the general term ‘oral cavity’ used in several studies, it
is difficult to estimate the specific prevalence of HPV DNA for the individual sub-sites. Comprehensive studies testing
6
larger numbers of patients (>80) and describing anatomic sub-sites as well as HPV DNA frequency per site indicate that
19, 24, 31, 50, 52-55
(Table 1). Frequencies are varying between studies, but floor of
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HPV can be found in any of the sub-sites
mouth (9-42%) and the tongue (8-25%) seem to be predominantly infected by HPV. Whereas HPV DNA is present in a
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etiologically HPV-driven
18, 56, 57
. OPSCC are in part truly HPV associated since active high-risk HPV-infection goes along
with E6/E7 expression leading to deregulation of especially p53 / pRb and p16INK4A overexpression
14, 58-60
. Beside the fact
that HPV DNA can be detected in a subset of OSCC, a series of recent reports presented clear data showing a
50
. Studies analysing expression of E6/E7 in HPV DNA positive
M
discrepancy in HPV DNA positivity and oncogene activity
OSCC could detect expression of viral oncogenes in only 6-7% of cases
50, 52, 61
supporting the assumption that HPV is
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not biologically active in the majority of OSCC. In addition, most HPV-positive OSCC are negative for p16INK4A
overexpression and enhanced p16INK4A levels can also be found in HPV-negative tumours. Moreover, there are
HPV/p16INK4A positive tumours, in which viral oncogene expression could not be determined 50. Apparently, p16INK4A levels
ep
might not contribute to decipher active HPV status and other mechanisms controlling p16 INK4A expression in this tumour
entity might exist including mutations, deletion or methylation of CDKN2A (gene coding for p16INK4A). Results from the
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reasonable subgroup of OSCC, it has been shown that not all of HPV DNA positive tumours can be regarded as
cervix uteri show that HPV-driven malignant transformation occurs at a distinct cell population of junctional cells
harbouring a unique gene-expression profile that differs from squamous and columnar cells. It is tempting to speculate
that similar gene expression profiles also exist at other sites where transition of squamous epithelium into glandular or
7
reticular epithelium occurs (e.g. the oropharynx) and that these conditions influence HPV oncogene expression and rarely
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promote malignant transformation.
Conclusion:
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entity with many unresolved issues. The lack of a clear molecular evidence raises the question if HPV DNA-positive
OSCC are HPV-driven, since the presence of HPV-DNA does not mean the presence of a biologically active HPV per se.
In spite of the fact that OSCC is the most common type of oral cancer representing approximately 90% of malignant
M
tumours in this site, also other tumour entities exist in the oral cavity. Among the non-SCC are adenocarcinoma, adenoid
cystic carcinoma from major or minor salivary gland, Kaposi Sarcoma, lymphoma, malignant melanoma and metastatic
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cancers from other head and neck sites 62, 63. As discussed for nasopharyngeal carcinomas, a distinct subset of truly HPVdriven OSCC might have arisen from the oropharynx 24. Further prospective studies focusing on larger collections of welldefined anatomical regions and tumour entities are needed to decipher risk factors for oral cancers. This should include
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exact typing of HPV, detection of viral activity by means of E6/E7 and cellular p16INK4A expression analyses combined with
patient survival data. Consequently, these results will provide the basis for the design of future clinical trials.
Funding
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Several studies showed that HPV DNA is present in a considerable number of OSCC but still represents a distinct clinical
The authors would like to thank the Jean-Uhrmacher Foundation for financial support of CUH.
8
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Syrjänen 2011
Review
1885
Isayeva et al., 2012
Review
4195
Durray et al., 2012
Research
article
162
Duncan et al., 2013
Research
article
81
HPV detection methods
rip
t
OSCC subsites and
sitespecific
HPVpositivity
Overall HPV DNA positivity
Concordanc
e between
HPV DNA
positivity
and other
methods
$
Cancers of other sites
tested
WP = 20.2%; 95% CI 16.0% 25.2%
$
larynx, sinonasal tract,
nasopharynx
44%
No
No
8.6%
Yes
No
OR = 3.98; 95% CI: 2.62 - 6.02
Lip mucosa
(66.7%)
Palate
(33.3%)
Floor of
mouth
(24.0%)
Tongue
(23.2%)
Retromolar
trigone
(16.7%)
Cheek
(14.3%)
Gums
(14.3%)
Jawbone
(0%)
Buccal
mucosa
(25.0%)
Floor of
the mouth
(9.1%)
Tongue
(8.3%)
Gingiva
(7.7%)
Hard
palate (0%)
Lip mucosa
(0%)
an
us
c
No. of
OSCC
GP5+ / GP6+ PCR, type specific
INK4A
E6/E7 PCR, P16
/ p53 / EGFR
IHC, ISH
No
M
Article type
te
d
Reference
PCR, p16
INK4A
IHC
ep
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Table 1:Studies analysing cohorts > 80 OSCC patients by use of independend HPV detection methods.
17
Research
article
275
89
n.d.
5.9%; 95% CI 3.6 - 8.2
No
No
rip
t
Reuschenbach et al.,
2013
SPF10 PCR, TaqMan qRT-PCR, ISH
INK4A
p16
IHC
an
us
c
104
Floor of
mouth
(37.5%)
Tongue
(25.0%)
Alveolar
process
(16.7%)
Hard
palate
(12.5%)
Gingiva
(4.2%)
Lip mucosa
(4.2%)
Buccal
mucosa
(0%)
Retromolar
trigone
(0%)
Vestibule
of mouth
(0%)
Floor of
mouth
(42.0%)
Tongue
(23.2%)
Mandibula
r alveole
(18.8%)
Lip mucosa
(7.2%)
Buccal
mucosa
(5.8%)
Maxillar
alveole
(2.9%)
n.d.
M
409
PCR-EIA, ISH
INK4A
p16
IHC
25.1%
No
No
9.6%
No
Oropharynx, Nasopharynx
14.6%
No
Hypopharynx, Larynx
ep
te
d
Research
article
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Lingen et al., 2013
Walline et al., 2013
Chung et al., 2014
Research
article
Research
article
PCR Mass-array, ISH, p16
IHC
INK4A
p16
IHC, ISH
INK4A
18
Floor of
mouth
(n.d.)
Buccal
mucosa
(n.d.)
Alveolar
process
(n.d.)
Oral
tongue
(n.d.)
Retromolar
trigone
(n.d.)
p16
INK4A
IHC, ISH, HPV16-E6 Qpcr
4%
No
Oropharynx, Larynx,
Hypopharynx
rip
t
102
an
us
c
Research
article
ep
te
d
M
WP = weighted prevalence, OR = odds ratio; CI = confidence interval
ISH = in situ hybridization, IHC = Immunohistochemistry, EIA= enzyme linked immuno
assay
EGFR: epidermal growth factor receptor
n.d. = not described
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Upile et al., 2014
19