Abstract
Globally, the incidence of head and neck squamous cell carcinoma (HNSCC) has increased over recent decades and is projected to continue to rise, largely driven by increases in oropharyngeal squamous cell carcinoma (OPSCC), which is linked to HPV infection. HPV infection is also involved in the development of other cancers (anogenital and cervical), and almost 100% of cervical cancer patients are positive for HPV. OPSCC is the most common HPV-associated cancer in men and has exceeded the incidence of cervical cancer cases in women in the USA. Our knowledge of the carcinogenesis process from HPV infection to OPSCC development has been primarily extrapolated from cervical cancer models. While the cooperation of tobacco smoking and HPV infection is documented in cervical cancer, mechanistic studies to address this interaction in management and control of HNSCC are scarce and are also extrapolated from cervical cancer models. The molecular heterogeneity of HNSCC constitutes a tremendous challenge, and despite advances in several fronts in the management and control of HNSCC, short- and long-term treatment-associated morbidities remain substantial. In addition to deaths directly caused by this disease, survivors of this cancer have the second-highest rate of suicide compared with other cancers survivors. Given the existing gaps in our knowledge and the current clinical challenges, future studies including a number of new conceptual and methodological elements discussed in this review can lead to the discovery of biomarkers for early detection of the disease and novel strategies that will advance our knowledge to intercept and prevent HNSCC.