Claudin 18.2 Expression in Gastric Adenocarcinoma: Diagnostic Reproducibility and Clinicopathologic Associations in A...

Background: Claudin 18.2 (CLDN18.2) has become a clinically relevant therapeutic target in gastric adenocarcinoma (GC), with zolbetuximab now approved for use in CLDN18.2-positive, HER2-negative advanced disease. The aim of this study was to evaluate the prevalence, intratumoral reproducibility, and clinicopathologic associations of CLDN18.2 expression in a Western cohort of resected GC. Methods: CLDN18.2 expression was evaluated by immunohistochemistry in 204 resected GCs arranged in tissue microarrays containing duplicate tumor cores corresponding to the tumor center and invasive front. Correlations between paired cores, clinicopathologic parameters, additional biomarkers (E-cadherin, HER2, p53, mismatch repair (MMR)), and clinical outcomes were analyzed. Results: Using the clinical cutoff, 29.9% of cases were CLDN18.2-positive. Inter-core reproducibility was excellent (93.8% concordance, κ = 0.871), indicating minimal intratumoral heterogeneity. CLDN18.2 positivity was consistently associated with male sex, an infiltrative invasive front and absence of necrosis (p < 0.05) and occurred more frequently in MMR-proficient tumors (p = 0.041 at the 50% cutoff). CLDN18.2-positive cases showed higher rates of strong diffuse membranous E-cadherin staining (p < 0.001). At the clinical cutoff, CLDN18.2-positive patients were younger (p = 0.049). No associations were found with HER2, p53, recurrence, or cancer-specific survival. However, tumors with extreme expression (Z-score ≥ 250; 14.4%) showed increased Borrmann type IV GC, lymphovascular invasion and cancer-related mortality (p = 0.038), with strengthened significance in stage III tumors (disease-specific survival, p = 0.026). Conclusions: CLDN18.2 shows excellent intratumoral reproducibility and a stable biological profile in GC, supporting its diagnostic reliability in biopsies and value as a predictive biomarker. A subset with extreme expression demonstrated aggressive features, suggesting a potential "claudin-driven" phenotype requiring further study.