P16 as a Prognostic Biomarker for Nonoropharyngeal Squamous Cell Cancers: Avatar or Mirage?

The etiologic implication and prognostic roles of p16-positive tumor status are well established for squamous cell cancers (SCCs) of the oropharynx (1) but remain controversial for nonoropharyngeal SCCs (non-OPCs) of the head and neck. In the oropharynx, human papillomavirus (HPV)–driven carcinogenesis leads to p16 overexpression, which renders p16 a logical surrogate for HPV tumor detection (2–4). However, non-OPCs do not have an analogous molecular profile. The overall prevalence of HPV- or p16-positive non-OPCs appears to be low (5–7). Furthermore, the proportion of p16-positive non-OPCs exceeds that for HPV-positive individuals (8–11), with only the former showing a survival benefit in limited studies (12). Therefore, consensus guidelines do not support testing of non-OPCs for HPV or p16 as their prognostic implications have not yet been established (13). In this issue of the Journal, Bryant et al. challenge this dogma by suggesting that p16 may still have prognostic value (14).

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