Prognostic relevance of cutavirus DNA in human papillomavirus DNA-negative oropharyngeal squamous cell carcinoma: a retrospective cohort study

Abstract Background Human papillomavirus (HPV) status is the strongest prognostic determinant in oropharyngeal squamous cell carcinoma (OPSCC). As HPV-positive and HPV-negative OPSCC represent distinct disease entities, the prevalence and prognostic relevance of other viral infections may differ between these subgroups. This study aimed to determine the prevalence of tumor-associated viruses in OPSCC according to HPV DNA status and evaluate their association with clinical outcomes, with particular emphasis on HPV DNA-negative disease. Methods Tumor specimens from 106 Japanese patients with OPSCC were analyzed for the presence of HPV, cutavirus (CuV), Epstein–Barr virus (EBV), human cytomegalovirus (HCMV), and Merkel cell polyomavirus (MCPyV) using real-time polymerase chain reaction. Viral prevalence and loads were assessed according to HPV DNA status, and associations between viral detection and clinicopathological characteristics were evaluated. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier methods and Cox proportional hazards regression models. Results In the overall cohort, HPV, CuV, EBV, HCMV, and MCPyV DNA was detected in 47 (44%), 23 (22%), 21 (20%), 6 (6%), and 1 (1%) cases, respectively. Among HPV DNA-negative OPSCC cases ( n = 59), CuV, EBV, HCMV, and MCPyV DNA was detected in 14 (24%), 8 (14%), 3 (5%), and 1 (2%) cases, respectively. Viral loads did not differ significantly according to HPV DNA status. Within the HPV DNA-negative subgroup, CuV DNA positivity was significantly associated with shorter PFS (log-rank P < 0.001), whereas no significant association was observed with OS. Univariable Cox regression analysis identified CuV DNA positivity as the only viral factor significantly associated with PFS in HPV DNA-negative OPSCC (hazard ratio, 3.14; 95% confidence interval, 1.55–6.35; P = 0.001). CuV DNA positivity remained significantly associated with shorter PFS after adjustment for clinicopathological factors, whereas EBV, HCMV, and MCPyV DNA positivity was not significantly associated with clinical outcomes. Conclusions CuV DNA positivity was associated with shorter PFS in HPV DNA-negative OPSCC. CuV DNA positivity may have prognostic relevance in HPV DNA-negative OPSCC, although its biological significance and causal relevance remain unclear. Larger studies are warranted to validate these findings and further clarify the significance of CuV DNA detection in OPSCC.