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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

Christian U. Hübbers1 and Baki Akgül2

t
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1
Jean-Uhrmacher-Institute for Otorhinolaryngological Research, University of Cologne, Geibelstr. 29, 50931 Cologne,

Germany;

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2
Institute of Virology, University of Cologne, Fürst-Pückler-Str. 56, 50935 Cologne, Germany

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Corresponding author: Dr. Baki Akgül, baki.akguel@uk-koeln.de

Key words

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Human papillomavirus, Head and neck cancer, oral squamous cell cancer,

M
Abbreviations

HPV (human papillomavirus)

HNSCC d
(head and neck squamous cell carcinoma)
te
OPSCC (oropharyngeal squamous cell carcinoma)
ep

OSCC (oral squamous cell carcinoma)

Abstract
c

Increased awareness of human papillomavirus (HPV) as an etiological cause of head and neck squamous cell carcinoma
Ac

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,

different sub-sites of the oral cavity had been combined to a single entity, which retrospectively leads to a highly

t
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heterogeneous basis of data. In this review we mainly discuss the unclear role of HPV in OSCC development.

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an
M
d
te
c ep
Ac

2
 HPV positivity in head and neck cancers

Squamous cell carcinoma of the head and neck (HNSCC) is an anatomically heterogeneous group of neoplasms arising

t
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from the mucosal surface of the oral cavity, oropharynx, hypopharynx, larynx and nasopharynx. Each year approximately

263,000 cases of oral cavity cancer and 135,000 cases of pharyngeal cancer are diagnosed worldwide 1. Recent

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epidemiological work suggests considerable differences between HNSCC related to tumour sub-site. Unfortunately, a

us
shortcoming in many publications is the fact that a simplified grouping of cancers of different head and neck regions as a

an
single entity is retrospectively leading to a highly heterogeneous basis of data. Therefore, important distinctions between
2, 3
anatomic sub-sites and their natural histories have not been attributed in detail . Over the last decade it has become

M
clear that human papillomaviruses (HPV) not only cause genital and anal cancers, but are also an etiological cause for a

subset of HNSCC. There are solid indications that incidence and prevalence of HPV-associated HNSCC are increasing

d
which are particularly discussed to be correlated with a decline in smoking habits 4, 5
. Recent publications showed an
te
6, 7
increased incidence of HPV infections in HNSCC of approximately 50% with HPV16 being the most prevalent type in

at least 90% of this cancer 8. Whereas the majority of HPV-driven cancers of the head and neck are oropharyngeal
ep

9, 10
squamous cell carcinoma (OPSCC) comprising the tonsils and base of the tongue , it is currently in debate whether
c

HPV may also have a role in other HNSCC sub-sites.

Ac

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

infecting the mucosa are further classified into high- and low-risk groups based on the relative malignant potential of the

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lesions they cause. Whereas low-risk HPVs, such as HPV6 and HPV11, cause benign warts, high-risk HPVs, such as
11, 12
HPV16 and HPV18, cause premalignant squamous intraepithelial neoplasias that can progress to cancer . In a

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persistent infection the viral E2 protein is tightly controlling the expression of the main viral oncoproteins E6 and E7.

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These proteins are the key drivers of tumourigenesis by inactivating two of the most important tumour suppressors, pRb
13

an
and p53 . In premalignant and malignant lesions, E2 function gets abrogated, which subsequently leads to higher
14
expression levels of E6 and E7 . The inhibition of the tumour suppressor proteins p53 and pRb alters cell cycle

M
pathways regulating cellular proliferation, apoptosis, as well as genetic instability, which can lead to the formation of
15
epithelial lesions . The binding of high-risk HPV E7 protein with pRb results in the release of the transcription factor E2F

d
from the pRb-E2F protein complex and the promotion of cell cycle progression and also leads to the release of the
te
p16INK4A gene from its transcriptional inhibition. As a consequence, p16INK4A protein is expressed at a high level and is

thus considered as a reliable surrogate marker for high-risk HPV infection 16.
ep

HPV infection of the oral cavity

c

While HPV is an important cause of OPSCC, it is currently unclear whether HPV may also have a role in other head and
Ac

neck cancer sub-sites, including oral squamous cell carcinoma (OSCC). A specific role of HPV in the development of
17-19
OSCC was hypothesized in 1983 and since then is still debated . 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 22
mouth) are tobacco smoking , betel quid chewing and alcoholic beverage drinking . The healthy adult population

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23-28
shows a prevalence for any HPV type of 2-8% in the oral cavity, with HPV16 being the most commonly identified type .
25-27, 29
Notably, the prevalence of HPV seems to be significantly higher in men than in women . Furthermore, high-risk

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sexual behaviour including oral-genital sex has been found to be associated with transmission of HPV infections between

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26, 30, 31
oral and genital sites . Immunodeficiency (e.g. HIV infection) and smoking seem to increase the risk for oral HPV
32

an
infection, i.e. make infections more likely to persist . Initial studies suggest that most oral HPV infections are likely to be
31
cleared within a year . Thus, persistence of the virus might be the critical factor for the development of HPV-related

M
diseases.

Subclinical and premalignant oral HPV infection

d
In other parts of the body, such as the genital tract, HPV infects exclusively the basal cells of the epithelium, where the
te
33, 34
virus can remain latent. There is evidence that HPV also infects gingival tissue . The periodontal pocket is the only
ep

location of the gingival mucosa where basal cells are exposed to the environment. The periodontal pocket enlarges during
35
progression of periodontitis as a result of chronic inflammatory processes . In the presence of chronic inflammation,
c

36
increased basal cell proliferation leads to higher viral load in saliva as well as higher risk of HPV transmission . In a
Ac

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
 35, 37
oropharynx and larynx . This led to the hypothesis that chronic inflammation and continuous epithelial proliferation in

the junctional gingiva could favour the replication of HPV and might be an important reservoir for HPV in the oral mucosa.

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5, 19, 24, 38-41
In (potentially) premalignant oral lesions an increased HPV DNA positivity of 20-64% was described . A recent

report by McCord et al. (2013) combining in situ hybridization and immunohistochemical staining against p16INK4A,

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indicating biologically active viral infection, revealed 17.5% positivity for high-risk HPVs in oral epithelial dysplasias (for

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discussion of p16INK4A immunohistochemistry see below) 42.

Does HPV play a causal role in OSCC development?

an
In contrast to the clear picture in OPSCC, where the prognostic relevance of biologically active HPV infection is

M
18, 43, 44
established , no such clear association can be found for OSCC. Contradictory studies exist, which are either in
45, 46 47-49
favour of a better survival probability for HPV-positive OSCC patients , or of worse outcome , as well as

d
supporting no effect on patient survival 24, 50, 51. A number of publications analysing larger cohorts underline that HPV DNA
te
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
24, 52
occasional co-infections with HPV16). Types HPV31, HPV33 and other high-risk types are rarely found . However, in
c

this respect it should be noted that several studies only tested for selected types namely HPV16 and HPV18 or used more
Ac

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
HPV can be found in any of the sub-sites (Table 1). Frequencies are varying between studies, but floor of

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mouth (9-42%) and the tongue (8-25%) seem to be predominantly infected by HPV. Whereas HPV DNA is present in a

reasonable subgroup of OSCC, it has been shown that not all of HPV DNA positive tumours can be regarded as

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18, 56, 57
etiologically HPV-driven . OPSCC are in part truly HPV associated since active high-risk HPV-infection goes along

us
with E6/E7 expression leading to deregulation of especially p53 / pRb and p16INK4A overexpression 14, 58-60
. Beside the fact

an
that HPV DNA can be detected in a subset of OSCC, a series of recent reports presented clear data showing a
50
discrepancy in HPV DNA positivity and oncogene activity . Studies analysing expression of E6/E7 in HPV DNA positive

M
50, 52, 61
OSCC could detect expression of viral oncogenes in only 6-7% of cases supporting the assumption that HPV is

not biologically active in the majority of OSCC. In addition, most HPV-positive OSCC are negative for p16INK4A

d
overexpression and enhanced p16INK4A levels can also be found in HPV-negative tumours. Moreover, there are
te
HPV/p16INK4A positive tumours, in which viral oncogene expression could not be determined 50. Apparently, p16INK4A levels

might not contribute to decipher active HPV status and other mechanisms controlling p16 INK4A expression in this tumour
ep

entity might exist including mutations, deletion or methylation of CDKN2A (gene coding for p16INK4A). Results from the
c

cervix uteri show that HPV-driven malignant transformation occurs at a distinct cell population of junctional cells
Ac

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

promote malignant transformation.

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Conclusion:

Several studies showed that HPV DNA is present in a considerable number of OSCC but still represents a distinct clinical

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entity with many unresolved issues. The lack of a clear molecular evidence raises the question if HPV DNA-positive

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OSCC are HPV-driven, since the presence of HPV-DNA does not mean the presence of a biologically active HPV per se.

an
In spite of the fact that OSCC is the most common type of oral cancer representing approximately 90% of malignant

tumours in this site, also other tumour entities exist in the oral cavity. Among the non-SCC are adenocarcinoma, adenoid

M
cystic carcinoma from major or minor salivary gland, Kaposi Sarcoma, lymphoma, malignant melanoma and metastatic

cancers from other head and neck sites 62, 63. As discussed for nasopharyngeal carcinomas, a distinct subset of truly HPV-

d
driven OSCC might have arisen from the oropharynx 24. Further prospective studies focusing on larger collections of well-
te
defined anatomical regions and tumour entities are needed to decipher risk factors for oral cancers. This should include

exact typing of HPV, detection of viral activity by means of E6/E7 and cellular p16INK4A expression analyses combined with
ep

patient survival data. Consequently, these results will provide the basis for the design of future clinical trials.
c

Funding
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The authors would like to thank the Jean-Uhrmacher Foundation for financial support of CUH.

8
 References

1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008:

t
rip
GLOBOCAN 2008. Int J Cancer 2010; 127:2893-917.

2. Rautava J, Syrjanen S. Human papillomavirus infections in the oral mucosa. Journal of the American Dental

c
Downloaded by [New York University] at 06:28 19 February 2015

Association 2011; 142:905-14.

us
3. Hashibe M, Sturgis EM. Epidemiology of oral-cavity and oropharyngeal carcinomas: controlling a tobacco epidemic

an
while a human papillomavirus epidemic emerges. Otolaryngologic clinics of North America 2013; 46:507-20.

4. Kim L, King T, Agulnik M. Head and neck cancer: changing epidemiology and public health implications. Oncology

M
2010; 24:915-9, 24.

5. Jayaprakash V, Reid M, Hatton E, Merzianu M, Rigual N, Marshall J, et al. Human papillomavirus types 16 and 18

d
in epithelial dysplasia of oral cavity and oropharynx: a meta-analysis, 1985-2010. Oral oncology 2011; 47:1048-54.
te
6. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -
ep

unrelated oral squamous cell carcinomas in the United States. Journal of clinical oncology : official journal of the American

Society of Clinical Oncology 2008; 26:612-9.

c

7. Majchrzak E, Szybiak B, Wegner A, Pienkowski P, Pazdrowski J, Luczewski L, et al. Oral cavity and oropharyngeal
Ac

squamous cell carcinoma in young adults: a review of the literature. Radiology and oncology 2014; 48:1-10.

8. Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell

9
 carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005; 14:467-75.

9. D'Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, et al. Case-control study of human

t
rip
papillomavirus and oropharyngeal cancer. N Engl J Med 2007; 356:1944-56.

10. Nasman A, Attner P, Hammarstedt L, Du J, Eriksson M, Giraud G, et al. Incidence of human papillomavirus (HPV)

c
Downloaded by [New York University] at 06:28 19 February 2015

positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 2009; 125:362-6.

us
11. zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002;

an
2:342-50.

12. Doorbar J, Quint W, Banks L, Bravo IG, Stoler M, Broker TR, et al. The biology and life-cycle of human

M
papillomaviruses. Vaccine 2012; 30 Suppl 5:F55-70.

13. Moody CA, Laimins LA. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer 2010;

10:550-60. d
te
14. Rampias T, Sasaki C, Weinberger P, Psyrri A. E6 and e7 gene silencing and transformed phenotype of human
ep

papillomavirus 16-positive oropharyngeal cancer cells. J Natl Cancer Inst 2009; 101:412-23.

15. Akgül B, Cooke JC, Storey A. HPV-associated skin disease. J Pathol 2006; 208:165-75.
c

16. von Knebel Doeberitz M. New molecular tools for efficient screening of cervical cancer. Dis Markers 2001; 17:123-8.
Ac

17. Syrjänen K, Syrjänen S, Lamberg M, Pyrhonen S, Nuutinen J. Morphological and immunohistochemical evidence

suggesting human papillomavirus (HPV) involvement in oral squamous cell carcinogenesis. International journal of oral

10
 surgery 1983; 12:418-24.

18. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, et al. Human papillomavirus and survival of

t
rip
patients with oropharyngeal cancer. N Engl J Med 2010; 363:24-35.

19. Syrjänen S, Lodi G, von Bultzingslowen I, Aliko A, Arduino P, Campisi G, et al. Human papillomaviruses in oral

c
Downloaded by [New York University] at 06:28 19 February 2015

carcinoma and oral potentially malignant disorders: a systematic review. Oral diseases 2011; 17 Suppl 1:58-72.

us
20. IARC. Tobacco Smoke and Involuntary Smoking. Lyon, 2004.

an
21. IARC. Smokeless Tobacco Products. Lyon, 2007.

22. IARC. Alcohol Drinking. Lyon, 1988.

M
23. Kreimer AR, Villa A, Nyitray AG, Abrahamsen M, Papenfuss M, Smith D, et al. The epidemiology of oral HPV

infection among a multinational sample of healthy men. Cancer Epidemiol Biomarkers Prev 2011; 20:172-82.

24. d
Isayeva T, Li Y, Maswahu D, Brandwein-Gensler M. Human papillomavirus in non-oropharyngeal head and neck
te
cancers: a systematic literature review. Head and neck pathology 2012; 6 Suppl 1:S104-20.
ep

25. Gillison ML, Broutian T, Pickard RK, Tong ZY, Xiao W, Kahle L, et al. Prevalence of oral HPV infection in the

United States, 2009-2010. JAMA : the journal of the American Medical Association 2012; 307:693-703.
c

26. Pickard RK, Xiao W, Broutian TR, He X, Gillison ML. The prevalence and incidence of oral human papillomavirus
Ac

infection among young men and women, aged 18-30 years. Sexually transmitted diseases 2012; 39:559-66.

27. Bui TC, Markham CM, Ross MW, Mullen PD. Examining the association between oral health and oral HPV

11
 infection. Cancer prevention research 2013; 6:917-24.

28. Lang Kuhs KA, Gonzalez P, Struijk L, Castro F, Hildesheim A, van Doorn LJ, et al. Prevalence of and risk factors

t
rip
for oral human papillomavirus among young women in Costa Rica. The Journal of infectious diseases 2013; 208:1643-52.

29. Kero K, Rautava J, Syrjanen K, Grenman S, Syrjanen S. Oral mucosa as a reservoir of human papillomavirus:

c
Downloaded by [New York University] at 06:28 19 February 2015

point prevalence, genotype distribution, and incident infections among males in a 7-year prospective study. European

us
urology 2012; 62:1063-70.

an
30. D'Souza G, Agrawal Y, Halpern J, Bodison S, Gillison ML. Oral sexual behaviors associated with prevalent oral

human papillomavirus infection. The Journal of infectious diseases 2009; 199:1263-9.

M
31. Chung CH, Bagheri A, D'Souza G. Epidemiology of oral human papillomavirus infection. Oral oncology 2014;

50:364-9.

32. d
Beachler DC, D'Souza G. Oral human papillomavirus infection and head and neck cancers in HIV-infected
te
individuals. Current opinion in oncology 2013; 25:503-10.
ep

33. Madinier I, Doglio A, Cagnon L, Lefebvre JC, Monteil RA. Southern blot detection of human papillomaviruses

(HPVs) DNA sequences in gingival tissues. Journal of periodontology 1992; 63:667-73.

c

34. Hormia M, Willberg J, Ruokonen H, Syrjanen S. Marginal periodontium as a potential reservoir of human
Ac

papillomavirus in oral mucosa. Journal of periodontology 2005; 76:358-63.

35. Tezal M. Interaction between Chronic Inflammation and Oral HPV Infection in the Etiology of Head and Neck

12
 Cancers. International journal of otolaryngology 2012; 2012:575242.

36. Stubenrauch F, Laimins LA. Human papillomavirus life cycle: active and latent phases. Seminars in cancer biology

t
rip
1999; 9:379-86.

37. Tezal M, Sullivan MA, Hyland A, Marshall JR, Stoler D, Reid ME, et al. Chronic periodontitis and the incidence of

c
Downloaded by [New York University] at 06:28 19 February 2015

head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 2009; 18:2406-12.

us
38. Hafed L, Farag H, Shaker O, El-Rouby D. Is human papilloma virus associated with salivary gland neoplasms? An

an
in situ-hybridization study. Archives of oral biology 2012; 57:1194-9.

39. Kristoffersen AK, Enersen M, Kverndokk E, Sunde PT, Landin M, Solheim T, et al. Human papillomavirus subtypes

M
in oral lesions compared to healthy oral mucosa. J Clin Virol 2012; 53:364-6.

40. Mattila R, Rautava J, Syrjanen S. Human papillomavirus in oral atrophic lichen planus lesions. Oral oncology 2012;

48:980-4. d
te
41. Mravak-Stipetic M, Sabol I, Kranjcic J, Knezevic M, Grce M. Human papillomavirus in the lesions of the oral
ep

mucosa according to topography. PloS one 2013; 8:e69736.

42. McCord C, Xu J, Xu W, Qiu X, McComb RJ, Perez-Ordonez B, et al. Association of high-risk human papillomavirus
c

infection with oral epithelial dysplasia. Oral surgery, oral medicine, oral pathology and oral radiology 2013; 115:541-9.
Ac

43. Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L, et al. Evidence for a causal association

between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000; 92:709-20.

13
 44. Marur S, D'Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer

epidemic. The Lancet Oncology 2010; 11:781-9.

t
rip
45. Schwartz SR, Yueh B, McDougall JK, Daling JR, Schwartz SM. Human papillomavirus infection and survival in oral

squamous cell cancer: a population-based study. Otolaryngol Head Neck Surg 2001; 125:1-9.

c
Downloaded by [New York University] at 06:28 19 February 2015

46. Elango KJ, Suresh A, Erode EM, Subhadradevi L, Ravindran HK, Iyer SK, et al. Role of human papilloma virus in

us
oral tongue squamous cell carcinoma. Asian Pacific journal of cancer prevention : APJCP 2011; 12:889-96.

an
47. Kozomara R, Jovic N, Magic Z, Brankovic-Magic M, Minic V. p53 mutations and human papillomavirus infection in

oral squamous cell carcinomas: correlation with overall survival. Journal of cranio-maxillo-facial surgery : official

M
publication of the European Association for Cranio-Maxillo-Facial Surgery 2005; 33:342-8.

48. Duray A, Descamps G, Decaestecker C, Remmelink M, Sirtaine N, Lechien J, et al. Human papillomavirus DNA

d
strongly correlates with a poorer prognosis in oral cavity carcinoma. The Laryngoscope 2012; 122:1558-65.
te
49. Lee LA, Huang CG, Liao CT, Lee LY, Hsueh C, Chen TC, et al. Human papillomavirus-16 infection in advanced
ep

oral cavity cancer patients is related to an increased risk of distant metastases and poor survival. PloS one 2012;

7:e40767.
c

50. Reuschenbach M, Kansy K, Garbe K, Vinokurova S, Flechtenmacher C, Toth C, et al. Lack of evidence of human
Ac

papillomavirus-induced squamous cell carcinomas of the oral cavity in southern Germany. Oral oncology 2013; 49:937-42.

51. Annertz K, Rosenquist K, Andersson G, Jacobsson H, Hansson BG, Wennerberg J. High-risk HPV and survival in

14
 patients with oral and oropharyngeal squamous cell carcinoma - 5-year follow up of a population-based study. Acta oto-

laryngologica 2014; 134:843-51.

t
rip
52. Lingen MW, Xiao W, Schmitt A, Jiang B, Pickard R, Kreinbrink P, et al. Low etiologic fraction for high-risk human

papillomavirus in oral cavity squamous cell carcinomas. Oral oncology 2013; 49:1-8.

c
Downloaded by [New York University] at 06:28 19 February 2015

53. Duncan LD, Winkler M, Carlson ER, Heidel RE, Kang E, Webb D. p16 immunohistochemistry can be used to detect

us
human papillomavirus in oral cavity squamous cell carcinoma. Journal of oral and maxillofacial surgery : official journal of

an
the American Association of Oral and Maxillofacial Surgeons 2013; 71:1367-75.

54. Walline HM, Komarck C, McHugh JB, Byrd SA, Spector ME, Hauff SJ, et al. High-risk human papillomavirus

M
detection in oropharyngeal, nasopharyngeal, and oral cavity cancers: comparison of multiple methods. JAMA

otolaryngology-- head & neck surgery 2013; 139:1320-7.

55. d
Upile NS, Shaw RJ, Jones TM, Goodyear P, Liloglou T, Risk JM, et al. Squamous cell carcinoma of the head and
te
neck outside the oropharynx is rarely human papillomavirus related. The Laryngoscope 2014.
ep

56. van Houten VM, Snijders PJ, van den Brekel MW, Kummer JA, Meijer CJ, van Leeuwen B, et al. Biological

evidence that human papillomaviruses are etiologically involved in a subgroup of head and neck squamous cell
c

carcinomas. Int J Cancer 2001; 93:232-5.

Ac

57. Wiest T, Schwarz E, Enders C, Flechtenmacher C, Bosch FX. Involvement of intact HPV16 E6/E7 gene expression

in head and neck cancers with unaltered p53 status and perturbed pRb cell cycle control. Oncogene 2002; 21:1510-7.

15
 58. Hoffmann M, Tribius S, Quabius ES, Henry H, Pfannenschmidt S, Burkhardt C, et al. HPV DNA, E6*I-mRNA

expression and p16INK4A immunohistochemistry in head and neck cancer - how valid is p16INK4A as surrogate marker?

t
rip
Cancer Lett 2012; 323:88-96.

59. Olthof NC, Straetmans JM, Snoeck R, Ramaekers FC, Kremer B, Speel EJ. Next-generation treatment strategies

c
Downloaded by [New York University] at 06:28 19 February 2015

for human papillomavirus-related head and neck squamous cell carcinoma: where do we go? Rev Med Virol 2012; 22:88-

us
105.

an
60. Olthof NC, Speel EJ, Kolligs J, Haesevoets A, Henfling M, Ramaekers FC, et al. Comprehensive analysis of

HPV16 integration in OSCC reveals no significant impact of physical status on viral oncogene and virally disrupted human

M
gene expression. PloS one 2014; 9:e88718.

61. Kouvousi M, Xesfyngi D, Tsimplaki E, Argyri E, Ioannidou G, Ploxorou M, et al. Prevalence of human

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papillomavirus in 45 greek patients with oral cancer. Journal of oncology 2013; 2013:756510.
te
62. Daley T, Darling M. Nonsquamous cell malignant tumours of the oral cavity: an overview. Journal 2003; 69:577-82.
ep

63. Shiiba M, Unozawa M, Higo M, Kouzu Y, Kasamatsu A, Sakamoto Y, et al. Controlling distant metastasis and

surgical treatment are crucial for improving clinical outcome in uncommon head and neck malignancies, such as non-
c

squamous cell carcinoma. Molecular and clinical oncology 2014; 2:609-17.

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 Table 1:Studies analysing cohorts > 80 OSCC patients by use of independend HPV detection methods.

t
Reference Article type No. of OSCC sub- HPV detection methods Overall HPV DNA positivity Concordanc Cancers of other sites
OSCC sites and e between tested

rip
site- HPV DNA
specific positivity
HPV- and other
positivity methods
Syrjänen 2011 Review 1885 OR = 3.98; 95% CI: 2.62 - 6.02 $ No

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Isayeva et al., 2012 Review 4195 WP = 20.2%; 95% CI 16.0% - $ larynx, sinonasal tract,
25.2% nasopharynx

us
Durray et al., 2012 Research 162 Lip mucosa GP5+ / GP6+ PCR, type specific 44% No No
INK4A
article (66.7%) E6/E7 PCR, P16 / p53 / EGFR
Palate IHC, ISH

an
(33.3%)
Floor of
mouth
(24.0%)
Tongue
(23.2%)

M
Retromolar
trigone
(16.7%)
Cheek
(14.3%)
d Gums
(14.3%)
te
Jawbone
(0%)
INK4A
Duncan et al., 2013 Research 81 Buccal PCR, p16 IHC 8.6% Yes No
article mucosa
ep

(25.0%)
Floor of
the mouth
(9.1%)
Tongue
(8.3%)
c

Gingiva
(7.7%)
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Hard
palate (0%)
Lip mucosa
(0%)

17
 Lingen et al., 2013 Research 409 Floor of SPF10 PCR, TaqMan qRT-PCR, ISH 5.9%; 95% CI 3.6 - 8.2 No No
INK4A
article mouth p16 IHC
(37.5%)
Tongue

t
(25.0%)

rip
Alveolar
process
(16.7%)
Hard
palate

c
(12.5%)
Downloaded by [New York University] at 06:28 19 February 2015

Gingiva

us
(4.2%)
Lip mucosa
(4.2%)
Buccal
mucosa

an
(0%)
Retromolar
trigone
(0%)
Vestibule
of mouth

M
(0%)
Reuschenbach et al., Research 275 Floor of PCR-EIA, ISH 25.1% No No
INK4A
2013 article mouth p16 IHC
(42.0%)
Tongue

d (23.2%)
Mandibula
te
r alveole
(18.8%)
Lip mucosa
(7.2%)
ep

Buccal
mucosa
(5.8%)
Maxillar
alveole
(2.9%)
c

INK4A
Walline et al., 2013 Research 104 n.d. PCR Mass-array, ISH, p16 9.6% No Oropharynx, Nasopharynx
article IHC
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INK4A
Chung et al., 2014 Research 89 n.d. p16 IHC, ISH 14.6% No Hypopharynx, Larynx
article

18
 INK4A
Upile et al., 2014 Research 102 Floor of p16 IHC, ISH, HPV16-E6 Qpcr 4% No Oropharynx, Larynx,
article mouth Hypopharynx
(n.d.)
Buccal

t
mucosa

rip
(n.d.)
Alveolar
process
(n.d.)
Oral

c
tongue
Downloaded by [New York University] at 06:28 19 February 2015

(n.d.)

us
Retromolar
trigone
(n.d.)

an
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

M
n.d. = not described

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te
c ep
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