HPV prevalence in esophageal cancer: an updated systematic review and meta-analysis

Objectives: Esophageal cancer (EC) is a significant global health concern. Human papillomavirus (HPV) has been proposed as a potential etiological factor, though its role, especially in esophageal adenocarcinoma (EAC), remains controversial. This study aims to systematically review and update the meta-analysis of HPV prevalence in both esophageal squamous cell carcinoma (ESCC) and EAC, and to assess the association between HPV infection and EC risk. Methods: A comprehensive literature search of PubMed, Scopus, and Web of Science was performed to identify studies published between January 1, 2000, and November 28, 2025 that reported HPV prevalence in EC, with a specific focus on both ESCC and EAC. Data on HPV genotypes, detection methods, and study characteristics were extracted and analyzed using random-effects models. Prevalence estimates were calculated for various detection methods, and meta-regression was used to identify sources of heterogeneity. Results: A total of 151 studies, including 18,913 EC cases, were analyzed. HPV prevalence in EC varied by detection method, with polymerase chain reaction (PCR)-based studies showing an overall prevalence of 31% (95% CI: 25%-36%). Regionally, East Asia exhibited the highest prevalence (44%, 95% CI: 35%-53%). HPV prevalence was consistently higher in ESCC (29%, 95% CI: 23%-36%) compared to EAC (16%, 95% CI: 5%-30%). HPV-16 was the most prevalent genotype, showing a stronger association with ESCC than EAC. Meta-regression identified geographic region as a significant predictor of HPV prevalence. A pooled odds ratio (OR) of 2.92 (95% CI: 2.19-3.90) indicates a strong association between HPV infection and increased EC risk. Conclusions: HPV infection-particularly HPV-16-is epidemiologically associated with esophageal cancer, with higher detection rates observed in ESCC. However, current evidence is insufficient to establish HPV as a definitive causal driver of EC, especially for EAC, due to the predominance of observational designs and limited mechanistic confirmation.