In recent decades, it has become clear that most oropharyngeal squamous cell carcinomas (OPSCCs) are associated with human papillomavirus (HPV), with a distinct biology and favorable prognosis vs head and neck squamous cell carcinomas (HNSCCs) that originate in other anatomic subsites. The reasons for the superior survival outcomes and treatment responses seen in HPV-related OPSCC are not entirely well understood. However, it is known that viral oncoproteins within tumor cells can serve as a source of antigenic stimulation for immune cells w ithin the tumor microenvironment. Radiation and chemotherapy release these viral antigens from dying tumor cells, effectively turning the tumor into an in situ vaccine. These concepts are supported by the superior responses of HPV-related OPSCC to radiation, chemotherapy, and immune checkpoint inhibitors. However, the role of HPV in the prognosis of HNSCC outside the oropharynx is less clear. Fewer oral, laryngeal, and hypopharyngeal tumors are positive for HPV, although tumors at these sites are not routinely tested. Adding to the mystery, studies investigating whether these nonoropharyngeal, HPV-positive tumors are associated with improved prognosis vs their HPV-negative counterparts have shown mixed results. Tumors from other anatomic subsites of the head and neck often contain transcriptionally active virus and a nonkeratinizing, endophytic growth pattern similar to HPV-positive OPSCC, suggesting that the oncogenesis of these tumors is driven by the virus. However, collectively, these studies suggest that the association between HPV status and prognosis is not nearly as strong outside the oropharynx. In the case of cervical cancer, the effects of HPV on prognosis are also controversial, but this has been challenging to investigate because most cervical cancer cases are associated with HPV.
