Clinical analysis of HPV-positive oropharyngeal squamous cell cancer according to HPV genotype

Objective.: Oropharyngeal squamous cell carcinoma (OPSCC) has undergone a major epidemiologic transition, with high-risk human papillomavirus (HPV) emerging as the dominant etiologic factor. Although HPV-16 accounts for most HPV-positive OPSCC worldwide, a substantial minority of tumors harbor non-HPV- 16 genotypes, the clinical and prognostic significance of which remains uncertain, particularly in Asian populations. This study aimed to investigate HPV genotype distribution and survival outcomes in a singleinstitution cohort of HPV DNA-positive OPSCC regardless of p16 and to assess the prognostic significance of HPV genotype. Methods.: We retrospectively reviewed patients treated with curative intent for HPV-positive OPSCC at Seoul National University Bundang Hospital between 2003 and 2023. HPV status was determined using p16 immunohistochemistry and HPV DNA genotyping. Patients were classified as having HPV-16 or non-HPV-16 genotype. Overall survival (OS) and disease-free survival (DFS) were analyzed using Kaplan-Meier method and compared using the log-rank test. Results.: Of 254 eligible patients, 174 with HPV DNA-positive tumors and available HPV genotyping results were included in the final analysis. HPV-16 accounted for 74.7% of tumors, while non-HPV-16 genotypes comprised 25.3%, most commonly HPV-33, HPV-35, HPV-58, and HPV-18. A marked male predominance was observed across all genotypes. The clinical stage distribution did not differ significantly between the HPV-16 and non-HPV-16 groups overall; however, HPV-33-positive tumors showed higher nodal stage compared with HPV-16. OS and DFS were similar between the HPV-16 and pooled non-HPV-16 groups. In genotype-specific analyses, DFS did not differ significantly across groups, whereas HPV-35 was associated with poorer OS compared with HPV-16. Conclusion.: In this cohort, non-HPV-16 genotypes accounted for approximately one-quarter of HPV-positive OPSCC cases and demonstrated clinicopathologic heterogeneity with selected genotype-specific prognostic differences. Given the substantial proportion of non-HPV-16 genotypes and the marked male predominance observed in our cohort, our findings may have implications for future HPV prevention strategies.