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Of note, the <jats:italic>CLDN18<\/jats:italic> gene encodes for 2 isoforms, claudin-18.1 (CLDN18.1) and 18.2 (CLD18.2). Recent evidence has shown CLDN18.2 can be expressed in a relatively high rate of cases of pancreatic ductal adenocarcinoma (PDAC). Based on these findings, preclinical research has been conducted, and clinical trials are currently underway testing anti-CLDN18.2 targeted regimens for patients affected by locally advanced unresectable and metastatic PDAC. Notably, the therapeutic strategies with specific antibodies are directed against CLDN18.2, while the antibody for IHC recognizes both isoforms, CLDN18.1 and CLDN18.2. Since CLDN18.1 is not expressed in the stomach or in the pancreas, IHC for CLDN18 in these sites can be considered specific for the isoform CLD18.2. At this time, no specific practical testing or interpretation guidelines have been proposed in this setting. However, there are several preanalytical and analytical variables and key potential pancreas-specific pitfalls, such as the frequently diffuse and strong CLDN18.2 expression in PDAC precursors, which will likely interfere with adequate CLDN18 staining and interpretation. To overcome these issues and steer the standardization of CLDN18 evaluation within the PDAC framework, this manuscript provides practical guidance on CLDN18 testing and scoring. The adoption of a standardized approach will help align all the efforts, both in research and clinical trial settings to optimally guide the most appropriate patients for anti-CLDN18.2 targeted therapies in PDAC.\n<\/jats:p>","DOI":"10.1007\/s00428-025-04222-2","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:58:55Z","timestamp":1755737935000},"page":"487-499","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Claudin-18.2 immunohistochemical evaluation in pancreatic cancer specimens: review and recommendations for routine testing and scoring"],"prefix":"10.1007","volume":"487","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4901-4908","authenticated-orcid":false,"given":"Claudio","family":"Luchini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina A.","family":"Matkowskyj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Kuwata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teri A.","family":"Longacre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Schirmacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Takamatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef","family":"R\u00fcschoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Fassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"issue":"4","key":"4222_CR1","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1056\/NEJMoa1903387","volume":"381","author":"T Golan","year":"2019","unstructured":"Golan T, Hammel P, Reni M et al (2019) Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. 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(consulting and speaker bureau). K.A.M. is advisory boards and consultant for Amgen, Astellas (also steering committee for CLDN18.2), Daiichi Sankyo, Inc., Elephas, and Merck. T.K. reports honoraria for consulting from Agilent, Amgen, Astellas (also steering committee for CLDN18.2), Bristle Myers Squibb, Myriad, Daiichi Sankyo, MSD, Guardant, GxD, and Roche Diagnostics; advisory role from Astellas, Daiichi Sankyo, and MSD. T.A.L. reports honoraria from Astellas (steering committee for CLDN18.2); P.S. reports honoraria (for advisory boards and presentations) from BMS, AstraZeneca, Falk, Eisai, Leica, Incyte, Roche, Astellas (including steering committee for CLDN18.2), and Novartis and research contracts from Incyte, Falk, Novartis, Leica, BMS, AstraZeneca, Chugai, and Illumina; M.T. reports honoraria from Daiichi Sankyo; advisory role from Astellas (also steering committee for CLDN18.2). J.R. is cofounder of Targos Molecular Pathology GmbH, now part of Discovery Life Sciences, to which speaker honoraria and personal funds for an advisor role from Astellas (also steering committee for CLDN18.2), AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo Inc, GSK plc, Merck Sharp & Dohme, Merck KGaA, and QuIP (Qualit\u00e4tssicherungs-Initiative Pathologie) are reimbursed. M.F. reports research funding (to their institution) from Roche, Thermofisher, and Diaceutics; personal honoraria as an invited speaker from Roche, Astellas, AstraZeneca, Lilly, Incyte, Bristol-Myers Squibb, Sanofi, Agilent, Merck Serono, Pierre Fabre, GSK, Novartis, and Amgen; and participation in advisory boards for Amgen, Astellas (also steering committee for CLDN18.2), Roche, Pfizer, Merck Serono, GSK, Novartis, and Janssen.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}}]}}