The Dual Roles of Esophageal Submucosal Glands: Protection and Pathogenesis in Benign and Malignant Disease: A Scoping Review

Background: Esophageal submucosal glands (SMGs) contribute to mucosal defense through bicarbonate, mucin, and reparative-factor secretion. Chronic reflux may impair these functions and remodel the glandular compartment, potentially linking SMG injury to reflux esophagitis, Barrett’s esophagus (BE), and esophageal adenocarcinoma (EAC). Objective: To map the human, animal, and in vitro literature on the physiological and pathological roles of esophageal SMGs and to identify evidence gaps relevant to reflux injury, BE, EAC, and endoscopic therapy. Methods: This scoping review was reported in accordance with PRISMA-ScR. Embase, Web of Science, PubMed, and Google Scholar were searched from inception to 15 January 2025. Two reviewers independently screened records against prespecified eligibility criteria. The protocol was not registered. Results: The review included 97 full-text publications and 7 conference abstracts. The full-text set comprised 89 original studies and 8 reviews; review articles were used for context and citation tracing rather than counted as independent primary evidence. The mapped literature supports secretory and reparative functions of SMGs and documents injury-associated remodeling, including loss of mucinous acini and expansion of atrophic, oncocytic, or duct-like phenotypes. Marker expression, spatial continuity, and clonal observations are compatible with glandular participation in repair and Barrett-associated biology, but do not establish a unique cell of origin and lineage relationships remain unresolved. Conclusions: Esophageal SMGs occupy a plausible interface between mucosal protection and pathological plasticity. The most consequential gaps are the lack of longitudinal human evidence, source-resolved lineage information, standardized reporting of glandular phenotypes, and human models that reproduce reflux exposure and the stromal niche.