CLDN18.2 expression in gastroesophageal adenocarcinoma: prevalence, heterogeneity, and prognostic implications in Spanish patients

Claudin 18 isoform 2 (CLDN18.2) has emerged as a novel therapeutical target for HER2-negative, locally advanced, or metastatic gastroesophageal adenocarcinoma. However, reported prevalence rates vary widely (24-47%), underscoring the need for accurate population-specific data. This study investigates the CLDN18.2 prevalence in Spanish patients with gastroesophageal adenocarcinoma and explores its correlation with other biomarkers and clinicopathological factors. We retrospectively analyzed endoscopic biopsy samples from gastroesophageal adenocarcinoma patients across three Spanish institutions. CLDN18.2 expression was evaluated by immunohistochemistry using the Ventana CLDN18 (43-14A) assay and PS2+ scoring, with cases showing membranous 2+ or 3+ staining in ≥ 75% of tumor cells classified as positive. Clinicopathological and biomarker data were retrieved from medical records. CLDN18.2 was positive in 33% (89/270) of cases. Although histological type was not correlated with CLDN18.2 status, cases with poorly cohesive morphology exhibited heterogeneous staining, with a predominance of moderately and strongly stained cells. A weak to moderate inverse correlation was identified between signet ring cell content and CLDN18.2 staining (r = -0.29, p = 0.028). No significant differences were observed in clinical outcome. However, among patients with advanced-stage disease, CLDN18.2-positive intestinal tumors were associated with worse progression-free survival (HR 2.58, 95% CI 1.18-5.63; p = 0.029). These findings confirm a 33% prevalence of CLDN18.2 expression in the Spanish population, aligning with reports from other Western European cohorts. The significant heterogeneity in poorly cohesive cases and an inverse correlation with signet ring cell content pose diagnostic challenges for pathologists. Moreover, the association between CLDN18.2 positivity and worse progression-free survival in intestinal adenocarcinoma supports a potential role in tumor progression and metastasis, warranting further research.