458 Background: Helicobacter pylori (Hp) is a recognized gastric carcinogen, but its role in esophageal cancer remains uncertain. Previous observational studies have suggested histology-specific effects, with a potential protective association in esophageal adenocarcinoma (EAC) and inconsistent findings in esophageal squamous cell carcinoma (ESCC). We performed a large pooled meta-analysis to clarify these associations. Methods: A systematic literature search was conducted across PubMed, EMBASE, and Google Scholar from inception through May 2025 to identify observational studies evaluating the association between Helicobacter pylori infection and esophageal cancer. Eligible studies were included. Data extraction was performed independently, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Pooled estimates were generated using the Mantel–Haenszel method with random-effects models in RevMan 5.4. Analyses were stratified by histology (EAC vs ESCC), with heterogeneity assessed using I² statistics. Results: A total of 43 observational studies were included, comprising 21 studies of esophageal adenocarcinoma (EAC) and 22 studies of esophageal squamous cell carcinoma (ESCC). When all studies were combined, Hp infection was associated with a significant reduction in overall esophageal cancer risk (pooled OR 0.69, 95% CI 0.64–0.75). In histology-specific analyses, Hp infection demonstrated a strong protective association with EAC (OR 0.60, 95% CI 0.50–0.71; I² = 32%). The forest plot for EAC showed that the majority of studies reported inverse associations, and large population-based datasets contributed heavily to the protective signal. In contrast, ESCC analysis yielded an OR of 0.84 (95% CI 0.64–1.09; I² = 79%), indicating no statistically significant association and substantial heterogeneity. The ESCC forest plot revealed inconsistent findings across geographic regions and study designs, with several series suggesting inverse associations while others reported null effects. Collectively, these results highlight a robust protective effect of Hp in EAC and a weaker, heterogeneous relationship in ESCC. Conclusions: Hp infection appears to play a histology-specific role in esophageal carcinogenesis. In this pooled analysis, Hp was strongly protective against adenocarcinoma but showed no significant association with squamous carcinoma. Further research is required to understand why these effects differ and how eradicating H. pylori might change esophageal cancer risk.
Shah et al. (2026) studied this question.