Elsevier

Oral Oncology

Volume 51, Issue 3, March 2015, Pages 229-236
Oral Oncology

Review
Do high-risk human papillomaviruses cause oral cavity squamous cell carcinoma?

https://doi.org/10.1016/j.oraloncology.2014.11.011Get rights and content

Summary

High-risk human papillomaviruses (HR-HPV) are an established etiologic factor for a growing number of oropharyngeal cancers. However, their potential role in other upper aerodigestive tract locations is still a matter of debate, particularly in the oral cavity. This is of paramount importance as in the future diagnosis, treatment and follow up in head and neck squamous cell carcinoma may vary according to HPV status. This article reviews the recent published data and highlights some of the pitfalls that have hampered the accurate assessment of HR-HPV oncological role outside the oropharynx. We demonstrate that, in contrast to the oropharynx, only a small fraction of cancers located in the oral cavity seem to be HPV-related even in young non-smoking non-drinking patients. We emphasize several relevant factors to consider in assumed HPV-induced oral cavity cancers and discuss the current theories that explain why HPV-induced cancers arise preferentially in the oropharynx.

Introduction

Oral squamous cell carcinomas are a major global health issue. These tumors represent a heterogeneous group affecting the oral cavity and oropharynx. Tobacco, alcohol and betel quid abuse are the traditional risk factors. Their annual estimated incidence is around 275,000 for oral cavity and 85,000 for oropharyngeal cancers [1], [2]. There is wide geographical variation in the incidence of these cancers and the highest rates of oral cavity squamous cell carcinoma (OCSCC) are found in the Indian subcontinent (i.e. India, Pakistan, Sri Lanka, Bangladesh, etc.). In these countries, OCSCC is the most common cancer in men and may contribute up to 25% of all new cancer cases [3]. In Western countries, as tobacco consumption drops, the incidence of OCSCCs and more generally of head and neck squamous cell carcinomas (HNSCC) is stabilizing or falling [4]. However, amongst these tumors those arising in the oropharynx are on the increase. This epidemiologic change has been attributed to high-risk human papillomavirus (HPV) and particularly to type 16, which is now recognized as a causative agent in a growing subset of oropharyngeal squamous cell carcinomas (OPSCCs) [5]. Indeed, numerous studies have demonstrated a two to three fold increase in the prevalence of HPV-driven OPSCC over the last three decades, especially in North America and Northern Europe [6], [7], [8]. The underlying reasons are still poorly understood and several hypotheses have been proposed: changes in sexual behavior [9], decreased rates of tonsillectomy performed in the pediatric population since the 70s [10] and progress in the diagnostic work up and HPV testing assays [11]. Considering current trends, it is estimated that high-risk HPV (HR-HPV) will become the dominant etiologic factor for OPSCC, in the coming decades, in most Western countries [6]. These tumors have distinct epidemiologic features and oncogenic mechanisms that differ from their HPV-negative counterparts [12], [13]. Additionally, their prognosis is much more favorable which has led the medical community to consider new treatment strategies. Indeed, it is possible that less intensive treatment regimens could achieve similar efficacy with less toxicity and improved quality of life [14]. In spite of considerable advances in the understanding of these tumors, numerous issues are still unresolved, particularly the potential role of HR-HPV in oral cavity carcinogenesis [15]. Many studies, using a variety of techniques, have demonstrated the presence of the HPV genome in OCSCCs. However, compared to the evidence of a link between HR-HPV and oropharyngeal cancers, the role of HR-HPV in oral cavity cancers remains uncertain. This issue is of paramount importance, as in the coming years, diagnosis, treatment and follow up in HNSCC may vary according to HPV status. This article reviews the published data on the potential role of HR-HPV in OCSCCs.

Section snippets

Oral cavity squamous cell carcinoma and HR-HPV infection

Many studies [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29] have identified a high proportion of OCSCC with detectable HPV DNA (Table 1). In a recent systematic review, summarizing 60 publications on 4195 patients with OCSCC, Isayeva et al. [30] found that 705 (16.8%) of these tumors contained HPV DNA especially the HPV16 genotype. The rates of HPV-positive cancers ranged from 0 to 94.7% in the studies that were analyzed and the weighted prevalence was 20.2%

Detection of viral transcripts in oral cavity squamous cell carcinoma

As the presence of HPV DNA alone is insufficient evidence for a causal association, some studies [42], [43], [44], [45], [46], [47], [48] have assessed the expression of E6/E7 oncogenes in OCSCC (Table 2). Compelling evidence of HPV E6/E7 mRNA expression in OCSCC has been reported, however few authors have performed comprehensive analyses of large series. Braakhuis et al. [42] have studied 143 oral cancers, including 106 OCSCC and 37 OPSCC for the presence of viral DNA and E6/E7 mRNA expression

Other biological markers to assess HR-HPV potential role in oral cavity carcinogenesis

As few authors have assessed the expression of the viral oncogenes in OCSCC, it may be helpful to analyze the results obtained with other biological markers that are related to HPV induced malignancies.

Oral cavity squamous cell carcinomas in patients without traditional risk factors, a role for HR-HPV?

Several recent publications have reported that an increasing number of non-smoking, non-drinking young patients are affected by oral tongue squamous cell carcinoma (OTSCC) [61], [62]. This suggests that non-traditional etiologies, such as HR-HPV may be responsible for this increase. A few studies have specifically addressed this issue (Table 3) but most of them indicate that HR-HPVs are not involved in the pathogenesis of these tumors [45], [53], [63], [64], [65], [66], [67]. Siebers et al. [63]

Relevant factors to consider in assumed HPV-induced oral cavity squamous cell carcinoma

As mentioned above, a limited number of OCSCCs, containing HR-HPV DNA, are transcriptionally active. E6/E7 mRNA expression is considered the gold standard for clinically relevant HPV infection and only this subset of OCSCC should be considered to be HPV-related. Although, the clinical and biological features associated with HPV-induced OPSCCs should apply to assumed HPV-induced OCSCCs, studies should specifically assess the following points.

HNSCC, induced by excessive tobacco and alcohol

Why do HPV-driven cancers of the head and neck develop preferentially in the tonsils?

Understanding why HPV-induced cancers of the upper aero-digestive tract arise preferentially in the tonsils is an important issue. In uterine cervical cancer, the archetypal HPV-induced malignancy, we also observe that it arises exclusively at a specific site – the squamocolumnar junction (SCJ). This site was traditionally viewed as an area of weakness where the virus infects the basal keratinocytes via defects in the epithelial covering [36]. However, the true reasons, why cervical neoplasms

Conclusion

Although HPV-DNA has been detected in a significant number of OCSCC, E6/E7 mRNA expression seems to be very limited, suggesting a potential oncologic role in only a small fraction of these tumors. p16 protein over expression is an inadequate biomarker of HPV transcriptional activity in the oral cavity and should not be used as a surrogate marker in this setting. A majority of non-smokers and non-drinkers are affected by HPV-related disease in OPSCC. Available data suggest that this is not the

Conflict of interest statement

No funding source, no financial disclosures from any authors.

Acknowledgement

The authors are grateful for the contribution of Cedric Verjat in producing the figures.

References (82)

  • E.M. O’Regan et al.

    P16(INK4A) genetic and epigenetic profiles differ in relation to age and site in head and neck squamous cell carcinomas

    Hum Pathol

    (2008)
  • J. Brägelmann et al.

    Oral cavity tumors in younger patients show a poor prognosis and do not contain viral RNA

    Oral Oncol

    (2013)
  • X.H. Liang et al.

    Prevalence and significance of human papillomavirus in oral tongue cancer: the Mayo Clinic experience

    J Oral Maxillofac Surg

    (2008)
  • H. Mirghani et al.

    Oropharyngeal cancers: relationship between epidermal growth factor receptor alterations and human papillomavirus status

    Eur J Cancer

    (2014)
  • C.H. Chung et al.

    p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma

    J Clin Oncol

    (2014)
  • J. Ferlay et al.

    GLOBOCAN 2002. Cancer incidence, mortality and prevalence worldwide. IARC cancer base (2002 estimates)

    (2004)
  • J. Ferlay et al.

    Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008

    Int J Cancer

    (2010)
  • E.M. Sturgis et al.

    Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers?

    Cancer

    (2007)
  • A.K. Chaturvedi et al.

    Human papillomavirus and rising oropharyngeal cancer incidence in the United States

    J Clin Oncol

    (2011)
  • E. Garnaes et al.

    A high and increasing HPV prevalence in tonsillar cancers in Eastern Denmark, 2000–2010: the largest registry-based study to date

    Int J Cancer

    (2014 Oct 4)
  • G. D’Souza et al.

    Oral sexual behaviors associated with prevalent oral human papillomavirus infection

    J Infect Dis

    (2009)
  • M. Frisch et al.

    Changing patterns of tonsillar squamous cell carcinoma in the United States

    Cancer Causes Control

    (2000)
  • J. Chenevert et al.

    Squamous cell carcinoma metastatic to neck from an unknown primary: the potential impact of modern pathologic evaluation on perceived incidence of human papillomavirus-positive oropharyngeal carcinoma prior to 1970

    Laryngoscope

    (2012)
  • S.J. Smeets et al.

    Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus

    Oncogene

    (2006)
  • A.C. Jung et al.

    Biological and clinical relevance of transcriptionally active human papillomavirus (HPV) infection in oro-pharynx squamous cell carcinoma

    Int J Cancer

    (2010)
  • H. Mirghani et al.

    Treatment de-escalation in HPV-positive oropharyngeal carcinoma: ongoing trials, critical issues and perspectives

    Int J Cancer

    (2014 Mar 13)
  • M.L. Gillison et al.

    Evidence for a causal association between human papillomavirus and a subset of head and neck cancers

    J Natl Cancer Inst

    (2000)
  • C.C. Ragin et al.

    11q13 amplification status and human papillomavirus in relation to p16 expression defines two distinct etiologies of head and neck tumours

    Br J Cancer

    (2006)
  • E.M. Smith et al.

    Complex etiology underlies risk and survival in head and neck cancer human papillomavirus, tobacco, and alcohol: a case for multifactor disease

    J Oncol

    (2012)
  • A. Sharma et al.

    Human papillomavirus-positive oral cavity and oropharyngeal cancer patients do not have better quality-of-life trajectories

    Otolaryngol Head Neck Surg

    (2012)
  • J.P. Klussmann et al.

    Prevalence, distribution, and viral load of human papillomavirus 16 DNA in tonsillar carcinomas

    Cancer

    (2001)
  • S.J. Smeets et al.

    A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen

    Int J Cancer

    (2007)
  • J. Laco et al.

    Biologic importance and prognostic significance of selected clinicopathological parameters in patients with oral and oropharyngeal squamous cell carcinoma, with emphasis on smoking, protein p16(INK4a) expression, and HPV status

    Neoplasma

    (2012)
  • K.B. Ribeiro et al.

    Low human papillomavirus prevalence in head and neck cancer: results from two large case-control studies in high-incidence regions

    Int J Epidemiol

    (2011)
  • Z. Deng et al.

    Viral load, physical status, and E6/E7 mRNA expression of human papillomavirus in head and neck squamous cell carcinoma

    Head Neck

    (2013)
  • A. Barwad et al.

    Human papilloma virus associated head and neck cancer: a PCR based study

    Diagn Cytopathol

    (2012)
  • E. Kaminagakura et al.

    High-risk human papillomavirus in oral squamous cell carcinoma of young patients

    Int J Cancer

    (2012)
  • T. Isayeva et al.

    Human papillomavirus in non-oropharyngeal head and neck cancers: a systematic literature review

    Head Neck Pathol

    (2012)
  • A.R. Kreimer et al.

    Human Papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review

    Cancer Epidemiol Biomarkers Prev

    (2005)
  • R. Herrero et al.

    Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study

    J Natl Cancer Inst

    (2003)
  • B. Klingenberg et al.

    P16 INK4A overexpression is frequently detected in tumour-free tonsil tissue without association with HPV

    Histopathology

    (2010)
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