Elsevier

Oral Oncology

Volume 50, Issue 5, May 2014, Pages 370-379
Oral Oncology

Review
Role of human papillomavirus in non-oropharyngeal head and neck cancers

https://doi.org/10.1016/j.oraloncology.2013.11.004Get rights and content

Summary

Accurate estimates of the fraction of head and neck cancer (HNC) attributable to human papillomavirus (HPV) infection are essential to predict the effectiveness of interventions based on vaccination against HPV or HPV-testing. In addition, if supported by currently on-going clinical trials, attribution of a HNC to HPV may allow better and less toxic treatments. Here we focused on studies in which the prevalence of molecular and serological HPV markers was similarly assessed in oropharyngeal and non-oropharyngeal HNC. Large data on HPV DNA detection by PCR and p16 expression in HNC biopsies suggests that the probability of a cancer of the oral cavity, larynx, and hypopharynx being attributable to HPV is at least 5-fold lower than that for oropharyngeal cancer. Seropositivity for HPV16 E6 or E7 shows larger differences across sites, but findings vary between studies. Because HPV DNA and p16 detection lack specificity, and E6 and E7 antibody detection lacks sensitivity, these tests are not totally satisfactory. Limited data on in situ hybridization or HPV E6/E7 mRNA, mainly from the United States, suggests that HPV-attributable HNC is rare in the oral cavity (∼3%), larynx (∼7%), and hypopharynx (∼0%). Data on HPV in other rarer HNCs are extremely limited and essentially negative. Available data do not allow the establishment of the way HPV infection and tobacco may interact in non-oropharyngeal HNC. The exclusion of oropharynx as a site of tumor origin and the identification of robust fingerprints of HPV-driven carcinogenesis are the priorities to improve the estimate of HPV-attributable non-oropharyngeal HNC.

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.

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