Prognostic heterogeneity of HPV-associated oropharyngeal cancer in a Taiwanese population

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) is increasing worldwide, with a well-established link to human papillomavirus (HPV). However, evidence on how lifestyle risk factors—particularly smoking, alcohol consumption, and betel-quid chewing—modify the prognostic impact of HPV-associated disease remains limited, especially in regions with high exposure burden such as Taiwan. Understanding the interplay between viral and lifestyle determinants is essential for accurate prognostication and treatment planning. METHODS: We conducted a retrospective cohort study of 5,671 OPSCC patients using data from the Taiwan Cancer Registry between 2018 and 2021. p16 status was used as a surrogate marker for HPV infection. Overall survival and cancer-specific survival were compared across p16 status, age, sex, tumor location, cancer stage, lifestyle risk factors and treatment pattern using Kaplan–Meier method and multiple Cox models. Treatment-stratified analyses were additionally performed to evaluate whether lifestyle risk factors modified prognosis within p16-positive disease. RESULTS: Overall, 23.2% of OPSCC cases were p16-positive, with substantially higher p16 positivity among females (52.5%) and in tonsillar subsites. p16-positive patients had significantly better 5-year overall survival (69.0%; 95% CI, 66.0%-71.8%) than p16-negative patients (37.9%; 36.1%-39.6%). However, among p16-positive individuals, the presence of multiple lifestyle risk factors markedly attenuated the survival advantage, reducing 5-year overall survival from 78.6% (74.0%-82.5%) in those without lifestyle exposures to 57.6% (52.6%-62.4%) in those with smoking plus other risks. These gradients persisted after multivariable adjustment and across treatment modalities. In contrast, lifestyle risk factors were not independently associated with survival in p16-negative OPSCC, where prognosis was primarily driven by tumor stage, subsite, and treatment. CONCLUSIONS: This nationwide study provides novel evidence that the prognostic benefit associated with p16 positivity is substantially attenuated by multiple lifestyle risk factors. These findings highlight the importance of integrating viral and behavioral determinants into prognostic assessment and treatment planning. They also underscore the need to pair HPV-associated prevention strategies with efforts to reduce tobacco, alcohol, and betel-quid use in regions with high burdens of these exposures.