Impact of Smoking on Outcomes in HPV-Positive Oropharyngeal Squamous Cell Carcinoma in a Chinese Cohort Under AJCC 8th Edition Staging

<b>Objectives</b>: Human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinoma (OPSCC) represent biologically distinct subtypes. However, the role of tobacco exposure in the pathogenesis of each remains incompletely understood. This study aimed to evaluate the prognostic implications of smoking in patients with HPV-positive OPSCC, with stratification based on the eighth edition of the American Joint Committee on Cancer (AJCC-8) staging system. <b>Methods</b>: We retrospectively analyzed all OPSCC cases managed at our institution between January 2011 and January 2024. Smoking history was dichotomized into <10 and ≥10 pack-years. Survival outcomes-including overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS)-were calculated using the Kaplan-Meier method. Log-rank testing and multivariable Cox proportional hazards modeling were used to assess prognostic factors and identify risk groups. An interaction analysis was also conducted to determine whether smoking alters the survival benefit conferred by HPV positivity. <b>Results</b>: Of the 329 patients included, 181 (55%) had a history of smoking, while 148 (45%) had never smoked. Among all patients, 211 (64.1%) were HPV-positive. HPV-positive cases exhibited superior 3- and 5-year OS, DSS, and PFS compared with HPV-negative tumors (<i>p</i> < 0.001). Within the HPV-positive cohort, never-smokers had the most favorable survival outcomes. Notably, interaction modeling demonstrated that the survival benefit of HPV positivity was markedly diminished among smokers, with hazard ratios approaching unity. <b>Conclusions</b>: Tobacco use negates the survival advantage typically associated with HPV-positive OPSCC. These findings highlight the critical need to account for smoking history in treatment planning and when considering eligibility for de-intensification strategies in HPV-related diseases.