Prognostic impact of p16 and HPV discordance in cancer of unknown primary: a systematic review and meta-analysis

Discordance between human papillomavirus (HPV) and its surrogate marker, p16INK4a (p16), raises concerns about the reliability of p16 as a sole prognostic marker. To investigate the impact of HPV, p16, and discordant HPV/p16 status on survival in squamous cell carcinoma of unknown primary in the head and neck (SCCUPHN). PubMed and EMBASE were searched for relevant studies that used a strict definition of SCCUPHN and reported survival outcomes stratified by HPV/p16 status. A meta-analysis assessed the prevalence and overall survival (OS). Twelve studies (<i>n</i> = 864) were included. The pooled prevalence rates were: 23% HPV+/p16+ SCCUPHN (95% CI: 14-33%); 50% HPV-/p16- (95% CI: 32–67%); 13% HPV-/p16+ (95% CI: 6–19%); and 6% HPV+/p16- (95% CI: 1–10%). OS hazard ratios were: 0.37 (95% CI: 0.17-0.78) for p16+ vs. p16-, 0.35 (95% CI: 0.19-0.64) for HPV+ vs. HPV-, and 0.24 (95% CI: 0.12–0.50) for HPV+/p16+ vs. HPV-/p16-. Only one study (<i>n</i> = 103) compared survival in the four HPV/p16 subgroups individually. HPV and p16 are individual positive prognostic markers in SCCUPHN. Although significant discordance exists, the current literature does not provide sufficient evidence to support risk stratifying SCCUPHN patients into four distinct HPV/p16 subgroups.