Claudin-18 expression in oesophagogastric adenocarcinomas: a tissue microarray study of 523 molecularly profiled cases

Abstract

Background: Claudin-18 (CLDN18) is a highly specific tight junction protein of the gastric mucosa. An isoform of CLDN18, the Claudin 18.2, has recently emerged as an innovative drug target for metastatic gastric cancer.

Methods: We investigated the immunohistochemical profile of CLDN18, p53, p16, E-cadherin, MSH2, MSH6, MLH1, PSM2, HER2, and PDL-1 in a large series of 523 primary gastric carcinomas (GCs; n = 408) and gastro-oesophageal carcinomas (GECs; n = 115) and 135 matched and synchronous nodal metastases. The status of HER2 and EBER by means of chromogenic in situ hybridisation (CISH) was also evaluated.

Results: High membranous CLDN18 expression was present in 150/510 (29.4%) primary cases and in 45/132 (34.1%) metastases. An abnormal expression (i.e. nuclear and/or cytoplasmic) was observed in 115 (22.5%) primary cases and in 33 (25.0%) metastases. A 38.8% of the cases showed significant CLDN18 intratumoural variability among the different tissue microarray cores obtained from the same tumour. Positive membrane CLDN18 expression was statistically associated with non-antral GCs (p = 0.016), Lauren diffuse type (p = 0.009), and with EBV-associated cancers (p < 0.001).

Conclusions: CLDN18 is frequently expressed in gastric and gastro-oesophageal cancers; further studies should investigate the prognostic significance of CLDN18 heterogeneity in order to implement its test into clinical practice.

Fig. 1

a CLDN18 expression in normal gastric glands. b High CDLN18 expression in a gastric cancer (the adenocarcinoma is covered by normal gastric glands, which show an intense CLD18 positivity). c Moderate CLDN18 expression in cancer glands. d Low CLDN18 expression. e A negative CDLN18 tumour near to positive CLDN18 normal gastric glands. f Low CLDN18 expression in signet-ring cell carcinoma surrounding a positive single normal gastric gland. g CDLN18 intratumour variability. h Moderate-to-strong nuclear and cytoplasmic CLDN18 positivity. (Original magnifications ×20; scale bar 100 µm)

Fig. 2

Distribution of CLDN18-positive primary cases: among gastro-oesophageal (GEC) and gastric (GC) carcinomas (a), according to location within the gastric mucosa (b), according to tumour histotypes (c) and according to tumour grading (d). e CLDN18 status assessed in matched primary and metastatic tumours (n = 128). f Graphic summary of clinicopathological and immunohistochemical/in situ hybridisation results observed in the present study. Cases are disposed in columns, clinicopathological and molecular features in rows; missing data are in black, positive data are in red (i.e. high-CLDN18 expression; HER2 overexpression or amplification; presence of alterations in the proteins of the DNA mismatch repair; EBER-positive staining; p53 aberrant cases; E-cadherin-negative cases; p16-negative cases). Lauren lighter lines: diffuse-type carcinomas; Ming lighter lines are cases with expansive growth pattern; tumour staging from yellow (stage I) to dark red (stage IV); tumour grading from light blue (grade 1) to dark blue (grade 3)