Abstract
BACKGROUND/OBJECTIVES: The association between gastroesophageal reflux disease (GERD) and extraesophageal malignancies remains unclear. This study aimed to systematically evaluate the relationship between GERD and these cancers. METHODS: PubMed, Embase, Scopus, Cochrane Library, and Web of Science were searched for studies reporting risk estimates-risk ratios (RRs), odds ratios (ORs), hazard ratios (HRs), or standardized incidence ratios (SIRs)-of GERD and extraesophageal malignancies. Mendelian randomization (MR) studies with available risk estimates and 95% confidence intervals (CIs) were also included. Pooled estimates with 95% CIs were calculated using a random-effects model. RESULTS: As of 21 May 2025, a total of 37 studies were included in the analysis. GERD was significantly associated with an increased risk of several extraesophageal malignancies, including pharyngeal cancer (pooled RR = 2.04; 95% CI: 1.38-3.02), with a particularly high risk observed for hypopharyngeal cancer (RR = 2.95; 95% CI: 1.99-4.37; I(2) = 60.24%). Elevated risks were also identified for laryngeal cancer (RR = 2.23; 95% CI: 1.41-3.52) and lung cancer (RR = 1.20; 95% CI: 1.01-1.42). No significant association was found between GERD and colorectal cancer (RR = 1.19; 95% CI: 0.68-2.09), and findings regarding oral cancer were inconsistent across studies. Six MR studies confirmed a positive causal relationship between GERD and lung cancer, while one MR study suggested a potential causal association with oral cancer and another with pancreatic cancer. CONCLUSIONS: Our findings suggest that GERD may be a significant risk factor for pharyngeal, laryngeal and lung cancers. Appropriate evaluation and surveillance in patients with GERD may be warranted.