ReviewRole of human papillomavirus in non-oropharyngeal head and neck cancers
Introduction
Head and neck cancer (HNC) mainly includes squamous-cell carcinomas occurring in the oral cavity, pharynx and larynx. After the exclusion of nasopharynx, HNCs are responsible for approximately 550,000 new cases and 300,000 deaths in the world each year [1]. About three quarters of HNCs occur in men, but substantial differences exist in the male-to-female ratio across countries. Similarly, there are vast geographical differences in the incidence of HNC [1], [2]. A large part of the variation in HNCs by gender and country can be explained by differences in tobacco smoking and chewing and alcohol consumption [3], [4], [5]. The role of chronic infection with high-risk human papillomavirus (HPV) types in the etiology of HNC has gradually emerged during the past two decades. Evidence is much stronger and more consistent for oropharyngeal cancer (OPC) than other HNCs [6], [7], [8].
An increase in incidence rates of OPC has been reported in the last two decades in men in several high-income countries despite decreasing rates of other tobacco-associated cancers including oral cancer [9]. In addition, the fraction of HPV-positive OPC also increased in the same period in the United States, and in Europe [9], [10] whereas no clear change was observed for other HNC [10]. These findings support the notion that the etiology of OPC and non-OPC HNC partly differ and that the contribution of HPV infection to the burden of HNC is increasing, at least in populations among whom tobacco smoking has diminished [9].
The distinction of the oropharynx from both the oral cavity and the rest of the pharynx is especially important for studies on the association between HPV and HNC but the classification of the anatomical site of origin in HNC can be challenging. Successive versions of the World Health Organization (WHO) International Classification of Diseases (ICD) and the corresponding ICD Oncology (ICD-O) [11] are widely used in epidemiological and clinical studies and cancer registries [2]. However, many HNCs are diagnosed at advanced stages, and synchronous multiple primary cancers are relatively common in the head and neck [11].
In the present article we review and discuss the current knowledge on the involvement of HPV infection in non-oropharyngeal HNC. Our article includes a summary of the early literature on the topic (Section ‘Early reports and case series’), and two new meta-analyses of studies published after 1999 on molecular HPV markers in HNC tissue biopsies (Section ‘Comparison of molecular HPV markers across major HNC sites’) and serological HPV markers in case-control studies (Section ‘Comparison of HPV serology across major HNC sites and controls’). Meta-analyses were restricted to studies in which HPV markers were similarly assessed in OPC and other HNC. OPC was used as reference category in studies based on molecular HPV markers in cancer biopsies whereas cancer-free controls were used in studies based on serological HPV markers. The complex relationship between the effect of HPV and tobacco smoking in major HNC sites is highlighted in section ‘Combined effect of HPV and tobacco in major HNC sites’. Finally the state of art and the remaining gaps in the understanding of the role of HPV in non-OPC HNC will be discussed in Section “Discussion and conclusions”.
Section snippets
Early reports and case series
HPV is one of the most powerful human carcinogens, and a dozen high-risk HPV types are the primary cause of cancer of the cervix and ano-genital tract [7], [8]. The implication of HPV in HNC causation was initially suggested by different lines of reasoning that largely relied on analogies between malignant and benign lesions of the ano-genital tract and of the head and neck [6].
Studies based on cancer registries showed geographic correlations between the incidence rates of HNC and cancer of the
Data retrieval and reporting
The NIH’s NCBI PubMed search engine was used to retrieve citations published between January 2000 and April 2013 using the MeSH terms “papillomaviridae” or “papillomavirus infections” or “dna, viral” in combination with “head and neck neoplasms” or “mouth neoplasms” or “oropharyngeal neoplasms” or “pharyngeal neoplasms” or “hypopharyngeal neoplasms” or “laryngeal neoplasms” or “nasopharyngeal neoplasms” or “paranasal sinuses neoplasms” or “nasal cavity neoplasms” or “salivary gland neoplasms”.
Data retrieval and reporting
Despite the lack of tumor site-specificity, serological HPV markers allow case-control comparisons by avoiding a reliance on tissue biopsies (which are not applicable to controls) or exfoliated oral cells from brushing or oral rinse (both of which may not be effective at accurately comparing the presence of HPV across different HNC sites) [17].
Data on detection of HPV16 E6 and HPV16 E7 antibodies in serum samples (referred to as seropositivity to HPV16 E6 and HPV16 E7) was extracted from
Data retrieval and reporting
We reviewed case-control studies that provided information on the interaction between HPV infection and non-viral risk factors, notably tobacco use. ORs for non-viral risk factors, including those for tobacco use, were seldom shown separately by HPV status for individual HNC sites. The issue of interaction had, therefore, to be addressed in different ways, e.g., using stratification by either HPV status or HNC site or comparing unadjusted and tobacco-adjusted HPV-associated ORs. Most of
Discussion and conclusions
In our review we have assessed the role of HPV infection in the onset of oropharyngeal and non-oropharyngeal HNCs by comparing the detection of molecular and serological HPV markers and the interaction between HPV and non-viral risk factors across anatomical sites. We showed that, regardless of the type of marker that had been used, there was a large and consistent difference in the strength and consistency of the association with HPV between OPC and non-OPC HNC. The difference was, however,
Role of funding source
This work was supported by the Institut National du Cancer (INCa), SPLIT project N°2011/196. Dr. Jean-Damien Combes was supported by a fellowship from the Association pour la Recherche sur le Cancer (ARC, N°20111204169). The funders had no role in the design of the study; the collection, analysis and interpretation of the data; the decision to submit for publication; or the writing of the manuscript. The views expressed in this publication are those of the authors and not necessarily those of
Conflict of Interest
None declared.
Acknowledgements
The authors would like to thank Drs. Alyce A. Chen and Gary Clifford for their comments and Mr. Jerome Vignat and Ms. Veronique Chabanis for technical assistance.
References (51)
- et al.
Population attributable risk of tobacco and alcohol for upper aerodigestive tract cancer
Oral Oncol
(2011) - et al.
Global burden of cancers attributable to infections in 2008: a review and synthetic analysis
Lancet Oncol
(2012) - et al.
Detection of EBV and HPV in nasopharyngeal carcinoma by in situ hybridization
Exp Mol Pathol
(2006) - et al.
Detection of human papilloma virus and p16 expression in high-grade adenoid cystic carcinoma of the head and neck
Mod Pathol
(2012) - et al.
Human papillomavirus, Epstein-Barr virus, human herpesvirus 8 and human cytomegalovirus involvement in salivary gland tumours
Oral Oncol
(1998) - et al.
A generic capture ELISA for recombinant proteins fused to glutathione S-transferase: validation for HPV serology
J Immunol Methods
(2001) - et al.
HPV-associated head and neck cancer: a virus-related cancer epidemic
Lancet Oncol
(2010) Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. [computer program]
(2010)- Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M, et al. Cancer Incidence in Five Continents, vol. IX. IARC...
- et al.
Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium
Cancer Epidemiol Biomarkers Prev
(2009)
Human papillomavirus and cancers of the upper aerodigestive tract: a review of epidemiological and experimental evidence
Cancer Epidemiol Biomarkers Prev
Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer-systematic review and meta-analysis of trends by time and region
Head Neck
Comparative epidemiological aspects of oro-genital cancers
Second primary cancers following anal and cervical carcinoma: evidence of shared etiologic factors
Am J Epidemiol
Papillomaviruses and cancer of the upper digestive and respiratory tracts
Curr Top Microbiol Immunol
HPV and cancer of the aerodigestive tract
Papillomavirus Rep
Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review
Cancer Epidemiol Biomarkers Prev
Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study
J Natl Cancer Inst
Low human papillomavirus prevalence in head and neck cancer: results from two large case-control studies in high-incidence regions
Int J Epidemiol
Evidence for a causal association between human papillomavirus and a subset of head and neck cancers
J Natl Cancer Inst
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