The Alpha, Beta, Gammas of Oral Human Papillomavirus Infection and Head and Neck Cancer Risk

Alpha human papillomavirus (α-HPV) infection (overwhelmingly HPV-16) is an established cause of head and neck squamous cell carcinoma (HNSCC), predominantly oropharyngeal cancer (OPC).¹ Although this is a widely accepted causal association, a critical piece of evidence has been missing: a link between oral HPV infection and subsequent risk of HNSCC. In this issue of JAMA Oncology, Agalliu et al² report findings from a prospective investigation of oral HPV infection (ie, HPV DNA detection in oral samples) and HNSCC risk.² After analyzing 132 HNSCC cases and 396 controls nested within 2 prospective cohorts, the authors found that oral HPV-16 DNA detection was associated with a 22-fold increase in OPC risk. These data are remarkably consistent with risk estimates from numerous case-control studies.¹ However, the study by Agalliu et al contributes to the existing body of evidence by supporting a temporal association between HPV exposure and HNSCC. Previous nested case-control studies have observed serological measures of HPV exposure (eg, seropositivity to HPV-16 viral capsid or E6 and/or E7 oncoproteins) to increase risk of OPC.¹ By linking oral HPV detection directly to HNSCC risk, the Agalliu data have important implications for the use of oral HPV detection for OPC screening.¹