The expression of the tight junction protein and therapeutical target Claudin 18.2 is heterogeneously distributed within esophageal and gastric adenocarcinoma.

Claudin 18.2 (CLDN18.2) is a therapeutically relevant biomarker in esophageal (EAC) -and gastric adenocarcinoma (GAC). Little is known about its heterogeneity within the primary tumor and corresponding metastases and how many biopsies are needed to determine the true CLDN18.2 status of a tumor. CLDN18.2 was assessed in 1,283 patients (822 EAC, 461 GAC), using the antibody clone 43-14 A. Eight virtual endoscopic biopsies were taken from digitized whole tumor blocks. 204 of 822 EAC (24.8%) and 132 of 461 GAC (28,6%) were positive for CLDN18.2. In GAC, CLDN18.2 expression showed a trend towards less invasive growth (p = 0.02) and less common lymph node metastasis (p = 0.07) and was more often observed within the EBV-associated subtype (p = 0.01). When comparing the expression in one biopsy with the whole tissue section, the sensitivity for CLDN18.2 was low (58.8%). The sensitivity increased to a maximum of 76.5% with 6 and 8 biopsies (positive likelihood ratio = 17.8). Discordant expression between primary tumor and corresponding local lymph node metastasis was observed in 18.5%. This study highlights that CLDN18.2 is a heterogeneously expressed biomarker, within the tumor tissue as well as in primary tumor and corresponding lymph node metastasis. In case of CLN18.2-negative results the representativity of the biopsies must be critically assessed and a re-biopsy might be recommendable.