The role of human papillomavirus in p16‐positive oral cancers
The oral cavity is the most common non‐oropharyngeal HNSCC site where HPV is implicated.4 Nevertheless, the role of HPV in oral cancer is controversial, with reported prevalence of HPV ranging from 0% to 90%.2 Some studies may have mixed oral cavity and base of tongue tumours, leading to falsely higher rates of HPV in oral cancer. At present, the prevalence and role of HPV in non‐oropharyngeal sites remains unclear and a causal relationship has not been established. Immunohistochemical (IHC) staining for p16 is used as a surrogate marker for HPV infection in oropharyngeal SCC, with HPV‐positive tumours overexpressing p16.8
HPV oncogenes E6 and E7 are required for tumour initiation and immortalization.9 They are highly associated with carcinogenetic activity and are responsible for inhibition of the tumour suppressors p53 and retinoblastoma protein (pRb).10 Moreover, E7‐driven inactivation of pRb in high‐risk (HR) HPVs has been shown to lead to p16 overexpression.3 This interferes with cell cycle control and promotes genetic instability and cancer progression.11
In a previous study,14 we performed retrospective immunohistochemical (IHC) staining to determine the expression of several proteins in 129 formalin‐fixed paraffin‐embedded (FFPE) specimens from a well‐defined cohort of consecutive oral squamous cell carcinoma (OSCC) patients. We found 23 (18%) of these patients displayed p16 overexpression, which was significantly increased in non‐smokers and non‐drinkers who were less than 70 years old. This result warranted further investigation given the association between p16 overexpression and HPV in HNSCC. We hypothesize that if p16 could be used as a surrogate marker for HPV in OSCC, it may further indicate prognosis.
Our first aim for this study was to determine whether p16 IHC‐positive OSCCs actually harbour HPV. Secondly, we aimed to identify either HPV E6 or E7 mRNA in these tumours as a marker of transcriptionally active virus that may be responsible for oncogenesis in these patients. Finally, we aimed to assess the utility of p16 as a surrogate marker for HPV infection in OSCC.