ReviewDo high-risk human papillomaviruses cause oral cavity squamous cell carcinoma?
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)
Global epidemiology of oral and oropharyngeal cancer
Oral Oncol
(2009)- et al.
WHO international agency for research on cancer monograph working group. A review of human carcinogens − Part B: Biological agents
Lancet Oncol
(2009) - et al.
Incidence of human papillomavirus in oropharyngeal squamous cell carcinomas: now and 50 years ago
Hum Pathol
(2012) - et al.
Role of human papillomavirus in non-oropharyngeal head and neck cancers
Oral Oncol
(2014) - et al.
Human papillomavirus genotype distribution in oropharynx and oral cavitycancer in France – the EDiTH VI study
J Clin Virol
(2011) - et al.
HPV genotypes and their prognostic significance in head and neck squamous cell carcinomas
J Clin Virol
(2012) - et al.
Early squamous cell carcinoma of the oral tongue:comparing margins obtained from the glossectomy specimen to margins from the tumor bed
Oral Oncol
(2013) - et al.
HPV in oral squamous cell carcinoma vs. head and neck squamous cell carcinoma biopsies: a meta-analysis (1988–2007)
Ann Oncol
(2008) - et al.
Human papillomavirus (HPV) status of non-tobacco related squamous cell carcinomas of the lateral tongue
Oral Oncol
(2014) - et al.
Low etiologic fraction for high-risk human papillomavirus in oral cavity squamous cell carcinomas
Oral Oncol
(2013)