We read with great interest the recent study examining temporal trends in human papillomavirus (HPV)–related oropharyngeal squamous cell carcinoma (OPSCC) in Chinese populations 1. By analysing a large cohort from two major cancer centres over more than a decade, the authors provide important insights into the evolving epidemiology of HPV-associated OPSCC in China. Their findings—particularly the rising proportion of p16-positive tumours and the reported regional and demographic heterogeneity—represent a valuable contribution to understanding the potential transition of HPV-related OPSCC from a traditionally Western-dominant disease to a more globally relevant oncological challenge. Nevertheless, several aspects of the study merit further consideration. First, the use of p16 immunohistochemistry as the sole surrogate marker of HPV-driven OPSCC may introduce a degree of etiologic misclassification when interpreting epidemiological trends 2. Although p16 overexpression is widely accepted in clinical practice as a surrogate for transcriptionally active HPV infection, accumulating evidence suggests that a subset of p16-positive tumours may be HPV-negative when assessed using molecular assays such as HPV DNA detection or E6/E7 mRNA analysis 3. This distinction becomes particularly relevant in population-based trend analyses, where modest misclassification may amplify apparent temporal increases in HPV-associated disease. Providing complementary molecular confirmation in a subset of cases, or discussing the potential magnitude of p16-based misclassification, would strengthen the interpretation of the reported upward trend. Second, the observed temporal increase in HPV-related OPSCC might partly reflect evolving diagnostic and testing practices rather than a purely biological shift in disease incidence. The implementation of the AJCC eighth edition staging system has substantially increased awareness and routine testing for p16 in OPSCC 4. Consequently, the proportion of cases undergoing HPV testing may have increased over time, potentially inflating the apparent rise in HPV-positive disease 5. Clarifying annual testing coverage, or presenting the proportion of tested versus untested OPSCC cases across study periods, would help readers better contextualise the reported epidemiological trend. Third, the intriguing regional and urban–rural differences observed in HPV-positive OPSCC warrant a more nuanced exploration of potential confounding factors. Geographic variation in smoking prevalence, alcohol consumption, healthcare access, sexual behaviour patterns and diagnostic referral pathways may all contribute to the observed disparities 6. Multivariable analyses adjusting for these variables—or at least a more detailed discussion of their potential influence—would help distinguish true epidemiological heterogeneity from differences in case ascertainment or population structure. Finally, the study highlights an important public-health implication: the potential emergence of HPV-associated OPSCC as a growing cancer burden in China. As HPV vaccination programs expand globally, understanding regional epidemiologic trajectories will become increasingly important for guiding vaccination policy and cancer prevention strategies 7. Future studies integrating nationwide cancer registry data, molecular HPV testing and behavioural risk-factor information would provide a more comprehensive picture of HPV-related OPSCC epidemiology in China and other rapidly transitioning populations 8. In summary, this study provides timely and valuable data on the changing landscape of HPV-related OPSCC in China. Addressing the issues of HPV ascertainment, testing practices and potential confounding in geographic comparisons would further strengthen the interpretation of these findings and enhance their relevance for both epidemiological research and cancer prevention policy. We congratulate the authors on their important contribution and hope that these considerations may help to further refine the interpretation and future direction of this line of research. Hongshuai Liu: conceptualization; investigation; writing – original draft. Taotao Zhang: investigation; writing – original draft. Linrong Wu: investigation; writing – review and editing. Zhisen Shen: conceptualization; investigation; writing – review and editing; supervision. The authors declare no conflicts of interest.
Liu et al. (Tue,) studied this question.