Human Papillomavirus Testing in Head and Neck Squamous Cell Carcinoma in 2020: Where Are We Now and Where Are We Going?

High risk human papillomavirus (HPV) has transformed head and neck oncology in the past several decades. Now that we have recognized that HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is a unique cancer type with distinct clinicopathologic features and favorable prognosis, it has become essential to test patients in routine practice. We have progressed greatly in our knowledge of this disease and gone, over the past two to three decades, from doing testing in highly variable amounts and methods to, now, with the help of national and international guidelines and patient staging requirements, to a situation where almost all patients with OPSCC are getting accurate classification through at least p16 immunohistochemistry. However, we are still struggling with how to accurately test specimens from cervical lymph nodes, and, in particular, on fine needle aspiration. In addition, many patients with non-oropharyngeal SCC are getting clinically unnecessary p16 and/or HPV-specific testing. The trends suggest progressive improvement in practices, but many practical questions still remain. On the horizon are myriad non-tissue-based tests, such as HPV serology and plasma DNA, DNA-based testing of fine needle aspirate fluid, computerized analysis of digitized pathology and radiology images, and machine learning from clinical and pathologic features, that may render pathologists largely obsolete for establishing HPV status for our patients' tumors. This review takes a brief look back in time to where we have been, then characterizes current practices in 2020 and lingering questions, and, finally, looks ahead into the possible future of HPV testing in patients with head and neck SCC.