Head and neck cancer (HNC) is the sixth most common cancer, causing almost half a million deaths worldwide every year. The two subtypes of HNC are distinctly associated with smoking/drinking and/or human papillomavirus (HPV) infection. While the incidence of non-viral HNC is decreasing, HPV-positive HNC incidence has dramatically increased in the last few decades. Accumulating evidence from numerous studies shows molecular and clinical differences in mutations, gene expression regulation, treatment responses, and patient survival rates between HPV-positive and HPV-negative HNC. Here, we discuss the current status of HNC research and clinical approaches and suggest unanswered questions and future directions.

Head and neck squamous cell carcinoma (HNSCC) is a unique malignancy associated with two distinct risk factors: exposure to typical carcinogens and infection of human papillomavirus (HPV). HPV encodes the potent oncoproteins E6 and E7, which bypass many important oncogenic processes and result in cancer development. In contrast, HPV-negative HNSCC is developed through multiple mutations in diverse oncogenic driver genes. While the risk factors associated with HPV-positive and HPV-negative HNSCCs are discrete, HNSCC patients still show highly complex molecular signatures, immune infiltrations, and treatment responses even within the same anatomical subtypes. Here, we summarize the current understanding of biological mechanisms, treatment approaches, and clinical outcomes in comparison between HPV-positive and -negative HNSCCs.