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. 2025 Mar;86(4):640-646.
doi: 10.1111/his.15407. Epub 2024 Dec 27.

Expression of claudin-18.2 in cholangiocarcinoma: a comprehensive immunohistochemical analysis from a German tertiary centre

Maximilian N Kinzler  1 , Steffen Gretser  2 , Falko Schulze  2 , Katrin Bankov  2   3 , Nada Abedin  1 , Wolf O Bechstein  4 , Fabian Finkelmeier  1   5 , Stefan Zeuzem  1 , Henning Reis  2 , Peter J Wild  2   5   6 , Dirk Walter  1
Affiliations

Expression of claudin-18.2 in cholangiocarcinoma: a comprehensive immunohistochemical analysis from a German tertiary centre

Maximilian N Kinzler et al. Histopathology. 2025 Mar.

Abstract

Aims: Anti-claudin-18.2 (CLDN18.2) therapy was recently approved for the treatment of gastric or gastro-oesophageal junction adenocarcinoma. The aim of the present study was to investigate the expression of CLDN18.2 in cholangiocarcinoma (CCA) to determine whether there is a subgroup of patients who might also benefit from anti-CLDN18.2 therapy.

Methods and results: A tissue microarray (TMA) cohort of all CCA patients who underwent surgical resection with curative intent between August 2005 and December 2021 at University Hospital Frankfurt were immunohistochemically evaluated using the VENTANA® CLDN18 (43-14A) antibody. Tumour positivity for CLDN18.2 was determined as follows: ≥ 75% of tumour cells with moderate-to-strong CLDN18 membranous staining. In total, 160 patients with surgically resected CCA were suitable for immunohistochemistry (IHC) analysis. Of the patients, 13.1% (n = 21) showed moderate to strong membranous staining of VENTANA® CLDN18 antibody, while 86.9% (n = 139) were negative. Subtype analysis revealed strong differences in CLDN18 expression. Positive staining of CLDN18 could be observed in 26.5% (n = nine of 34) and 7.4% (n = seven of 95) of the perihilar (pCCA) and intrahepatic (iCCA) subgroup, respectively. CCA patients with CLDN18 expression had a more frequently intraoperative finding of distant metastasis (P = 0.002), lymph node metastasis (P = 0.008) and positive perineural invasion (Pn1) status (P = 0.022).

Conclusions: The present study suggests that a subset of patients with CCA exhibited a marked expression of CLDN18.2. These findings underline the need to perform a clinical study evaluating the efficacy of anti-CLDN18.2 therapy in patients suffering from CCA.

Keywords: CLDN18; biomarker; cholangiocarcinoma; surgical oncology; tight junctions.

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Conflict of interest statement

F.F. received travel support from Ipsen, Abbvie, Astrazeneca and speaker/advisory fees from AbbVie, MSD, Ipsen, Astrazeneca, Roche, BMS; S.Z. received consultancy and/or speaker's bureau, Abbvie, BioMarin, Boehringer Ingelheim, Gilead, GSK, Ipsen, Madrigal, MSD/Merck, NovoNordisk, SoBi and Theratechnologies; H.R., advisory board of Bristol‐Myers Squibb and Roche, received honoraria from Roche, Bristol‐Myers Squibb, Janssen‐Cilag, Novartis, Astra Zeneca, MCI, CHOP GmbH, Sanofi, Boehringer‐Ingelheim, GlaxoSmithKline, Merck and Diaceutics, received travel support from Philips, Roche and Bristol‐Myers Squibb and received grants from Bristol‐Myers Squibb; P.J.W. received consulting fees and honoraria for lectures by Bayer, Janssen‐Cilag, Novartis, Roche, MSD, Astellas Pharma, Bristol‐Myers Squibb, Thermo Fisher Scientific, Molecular Health, Guardant Health, Sophia Genetics, Qiagen, Eli Lilly, Myriad, Hedera Dx and Astra Zeneca; research support was provided by Astra Zeneca. The authors declare that there is no relationship relevant to the manuscripts’ subject. All other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Representative images of claudin‐18.2 (CLDN18) expression in cholangiocarcinoma (CCA). Representative immunohistochemistry of negative (A), low (B), moderate (C) and strong (D) expression of VENTANA® CLDN18 staining in tissue microarray (TMA) cores of CCA patients. Scale bars: 200 μm for overview and 50 μm for inlay. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 2
Figure 2
Distribution of claudin‐18.2 (CLDN18) expression among cholangiocarcinoma (CCA) subtypes. dCCA, distal cholangiocarcinoma; iCCA, intrahepatic cholangiocarcinoma; LD‐iCCA, large duct‐type intrahepatic cholangiocarcinoma; pCCA perihilar cholangiocarcinoma; SD‐iCCA, small duct‐type intrahepatic cholangiocarcinoma.
See this image and copyright information in PMC

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