Recent studies have clearly described the current epidemic of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) in North America and beyond [3, 4]. Using tumors from patients from three American population based cancer registries in the Surveillance, Epidemiology and End Results (SEER) program, Chaturvedi et al  conclusively demonstrated that HPV-positive OPSCC has increased markedly (225%) over the last three decades. Improved survival for patients with HPV-positive OPSCC was reported and our results agree with this finding. Patients tend to be younger, non-smokers, and non-drinkers with low rates of comorbid illness [3, 5, 6]. The observed high cure rates in this high functioning cohort of younger patients has led to an increased emphasis on post-treatment quality of life, as treatment side effects will potentially need to be endured for decades. Consequently, several studies have been initiated with the goal of the long-term sequelae of therapy for patients with HPV-positive OPSCC, such as the substitution of cetuximab for cisplatin in RTOG-1016.
However, a fraction of these patients still relapse and succumb to disease following conventional therapy. Ang et al  demonstrated that 21.2% of patients with HPV-positive tumors relapsed within 3 years, with 13.6% of these cases due to locoregional recurrence, and 8.7% due to the development of distant metastases. The biological reasons for this difference in treatment effectiveness are poorly understood. A partial explanation may be the specific HPV type implicated. In cervical cancer, HPV types 18 and 58 are associated with a poorer prognosis, while HPV-31 portends improved survival compared with HPV-16 [11–13]. To date only one study has demonstrated investigated a differential response or clinical presentation by HPV type in head and neck cancer. Rautava et al., retrospectively analyzed 106 patients with tumors from multiple head and neck sites including 31 oropharyngeal patients . HPV genotyping was performed with a Luminex based Multimetrix® genotyping kit. In contrast with most studies, they found a very high rate of infection in non-oropharyngeal sites including the oral cavity (76%) and larynx (40%), as well as very high rate of co-infection (44%) and the presence of low-risk subtypes 6 and 11 (20%) [2, 15]. HPV was not found to be predictive of survival and there was no difference in outcome based on HPV type .
Although limited conclusions can be drawn given the small numbers of HPV types other than HPV-16 in our cohort, our data suggests that HPV-16 cancers may present more frequently with lymph node metastases and may have a poorer outcome compared with non-16 high-risk HPV types. Given the low frequency of HPV-positive OPSCC presentations that are not due to HPV-16, a very large multi-institutional series with HPV genotyping would need to be assembled in order to answer this question definitively.
A tremendous step forward in the battle against the multiple cancers caused by HPV is the implementation of HPV vaccination programs worldwide. The quadrivalent HPV vaccine is highly effective in preventing benign and precancerous lesion lesions due to HPV types 6, 11, 16 and 18 including cervical and anal dysplasia [16, 17]. Due to the significant lag time between infection and the development of malignancy, it will take decades to determine if these vaccines are effective in preventing anogenital and head and neck cancers. Indeed, most individuals develop HPV infection in their teens and twenties , however the average age of diagnosis of HPV-positive patients in our study was 58 years (range, 43–86). Due to this significant time gap as well as low rates of use of this vaccine in both males and females, the burden of HPV-related cancers will be an important clinical problem for the foreseeable future.
HPV-positive cancers are fundamentally distinct from traditional tobacco and alcohol related cancers . Viral oncogenes E6 and E7 cause the degradation of wild-type p53 and pRb, respectively, while p16 is overexpressed. This is in contrast to frequent mutations of p53 and loss of p16 seen in conventional head and neck cancer . The differences between HPV-positive and conventional head and neck cancers was further highlighted in two landmark papers by Stransky and Agrawal that reported large-scale whole exome sequencing of head and neck cancers [19, 20]. These studies revealed approximately a two to four-fold increase in number of mutations in HPV-negative compared with HPV-positive cancers and confirmed the differences in p53 and p16 outlined above. Despite these differences, there were significant overlaps in the mutational profiles of the two cancer types, including mutations in the NOTCH receptors (NOTCH1-3), HRAS, and PIK3CA that were seen in both HPV-positive and negative disease. Potentially, high-throughput technologies including expression microarrays, RNA-seq, and exome sequencing of large cohorts of HPV-positive OPSCC can identify biomarkers of local, regional and distant relapse as well as biological differences between cancers due to different HPV types. Patients at high-risk of failure could undergo treatment intensification with the goal of increasing survival, while low-risk patients could have their treatment de-intensified in order to optimize post-treatment quality of life. This would be a significant step towards customized care for patients with HPV-positive HNSCC.