Barrett’s esophagus (BE) has been recognized as a precursor to esophageal adenocarcinoma (EAC). BE lesions are frequently treated by Endoscopic Submucosal Dissection (ESD) to allow for adequate staging and as a first step in the treatment of BE lesions. Lesions at the gastroesophageal junction (GEJ) present clinical challenges due to their diverse morphology and varying malignant potential. Our objective was to distinguish the clinicopathologic features of GEJ lesions from non-GEJ lesions for effective risk stratification and treatment planning.

We retrospectively analyzed 108 patients with target lesions originating from Barrett’s esophagus (87 located in the GEJ region and 21 in the non-GEJ region) who underwent ESD. We assessed their clinicopathological features and clinical outcomes. Lesions were classified according to the Siewert classification, differentiating those with a maximal mucosal base ranging from −5 cm to +2 cm from those situated more than +5 cm above the GEJ. Chi-square tests were employed to assess the associations between lesion location and histology, submucosal invasion depth and morphology, as classified by the Paris classification.

GEJ lesions displayed a significantly different distribution of histological grades compared to non-GEJ lesions (p < 0.001), with high-grade dysplasia and adenocarcinoma more present at the GEJ. The depth of neoplastic submucosal invasion also varied significantly by location, with GEJ lesions showing higher rates of both superficial and deep submucosal cancer infiltration (pT1a, pT1b) (p < 0.001). Also morphological patterns differed substantially between groups (p = 0.023), with pejorative morphologies, particularly IIb and IIc components according to Paris classification, more commonly seen in GEJ lesions, while non-GEJ lesions exhibited a more varied distribution (Is-IIa according to Paris classification). Both groups showed no significant differences in ESD outcomes regarding procedural complications.

Our analysis revealed that GEJ lesions have a distinctly more aggressive profile than non-GEJ lesions. Our preliminary data showed that GEJ lesions have a greater prevalence of pejorative morphologies, higher histological severity and deeper invasion. The significantly increased rates of high-grade dysplasia and adenocarcinoma at the GEJ strongly suggest that this region represents a biologically distinct and more vulnerable microenvironment, where neoplastic progression may accelerate or manifest at a more advanced stage. This heightened aggressiveness aligns with the unique exposure of the junctional zone to mixed gastric and esophageal refluxate, chronic inflammation, and aberrant metaplastic remodeling. Overall, these findings underscore the intrinsic worrisome nature of GEJ lesions and highlight the importance of rigorous, multimodal assessment in managing junctional lesions.