Clinical Profile and Survival of Oropharyngeal Squamous-Cell Carcinoma in a Region of Northern Spain with a Low HPV-Attributable Fraction: A Retrospective Cohort Study

Background/Objectives: p16 immunohistochemistry is the standard surrogate for HPV causation in oropharyngeal squamous-cell carcinoma (OPSCC), but p16/HPV discordance is more frequent where the HPV-attributable fraction is low. We assessed the p16-positive fraction, p16/HPV-DNA discordance, and survival of OPSCC in northern Spain. Methods: Retrospective cohort of 152 consecutive OPSCC (2019–2024). HPV-DNA PCR was performed selectively in p16-positive tumours; selection was assessed with a quantitative bias analysis. Overall survival (OS) was analysed with Kaplan–Meier and Cox regression. Results: Fifty-seven tumours (37.5%) were p16-positive; these patients were younger, drank less often, and more often had tonsil/base-of-tongue primaries. HPV-DNA was negative in six of twenty-eight tested p16-positive tumours (discordance 21.4%; 95% CI 10.2–39.5). Testing favoured never-drinkers, and sensitivity analyses for selective testing gave estimates of 16–36%. Two-year OS was 86.3% for p16-positive and 53.9% for p16-negative disease. p16 negativity was associated with death after adjustment for stage, alcohol, and age (HR 3.00; 95% CI 1.44–6.26), but the association was attenuated in curatively treated patients (HR 2.30; 95% CI 0.99–5.33). Conclusions: In this region, about one in three OPSCC is p16-positive and one in five tested p16-positive tumours lacks HPV-DNA. Systematic dual p16/HPV testing is advisable before p16 status guides staging or de-escalation.