Stains & CD markers
Claudin 18.2
Copyright: 2024-2025, PathologyOutlines.com, Inc.
PubMed Search: Claudin 18.2
Claudin 18.2
Authors: Trevor Toussieng, D.O., Rondell P. Graham, M.B.B.S., Aatur D. Singhi, M.D., Ph.D., Kevin Waters, M.D., Ph.D.
Editorial Board Members: Christian M. Schürch, M.D., Ph.D., Wei Chen, M.D., Ph.D.
Last author update: 13 May 2025
Last staff update: 13 May 2025
Copyright: 2024-2025, PathologyOutlines.com, Inc.
PubMed Search: Claudin 18.2
Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Clinical features | Interpretation | Uses by pathologists | Prognostic factors | Microscopic (histologic) images | Positive staining - normal | Positive staining - disease | Negative staining | Molecular / cytogenetics description | Sample pathology report | Additional references | Practice question #1 | Practice answer #1Cite this page: Toussieng T, Graham RP, Singhi AD, Waters K. Claudin 18.2. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsclaudin182.html. Accessed September 11th, 2025.
Definition / general
- Claudin 18 is part of the claudin multigene family of tight cell junction proteins in epithelial cells of lung (claudin 18.1 isoform) and stomach (claudin 18.2 isoform) tissue
- Claudin 18.2 is a targetable antigen in treating gastric / gastroesophageal junction (GEJ) adenocarcinomas and is under investigation for additional uses
Essential features
- Claudin 18 is a tight junction protein expressed in lung (claudin 18.1) and stomach (claudin 18.2) tissue
- Claudin 18.2 expression is maintained in a portion of gastric / gastroesophageal junction adenocarcinomas and aberrantly expressed in a portion of pancreatic adenocarcinomas
- Claudin 18 positivity is defined as moderate to strong membranous staining (intensity 2 - 3+) in at least 75% of neoplastic cells evaluated across a section containing at least 50 tumor cells
- Claudin 18 immunohistochemistry (IHC) is a companion diagnostic for treatment of gastric / gastroesophageal junction tumors with anti-claudin 18.2 therapy
Terminology
- Claudin 18.2, CLDN18.2
Pathophysiology
- CLDN18 gene is on chromosome 3q22 and contains 6 exons and 5 introns, with 2 different splice variants that get translated as 2 isoforms (CLDN18.1 and CLDN18.2) (Gene 2011;481:83)
- CLDN18 is a downstream target gene of the T / EBP / NKX2.1 homeodomain transcription factor and is specifically expressed in epithelial cells of the lung and stomach (Mol Cell Biol 2001;21:7380)
- Isoform 2 of claudin 18 (claudin 18.2) is a highly selective gastrocyte lineage marker (Clin Cancer Res 2008;14:7624)
- Claudin 18.2 downregulation in gastric adenocarcinoma shows lower invasion depth and more frequent lymphovascular invasion (Sci Rep 2023;13:20047)
Clinical features
- Claudin 18 expression in Barrett esophagus may contribute to greater acid resistance (Am J Physiol Gastrointest Liver Physiol 2007;293:G1106)
Interpretation
- Membranous staining: inclusive of circumferential (complete and partial), basolateral / lateral and microluminal membranous staining
- Positivity is assessed based on both the staining intensity (strong [3+], moderate [2+], weak [1+] and none [0]) and the percentage of tumor cells staining (0 - 100%)
- As a biomarker for gastric / gastroesophageal junction adenocarcinomas, claudin 18 is considered positive when ≥ 75% of tumor cells show moderate to strong (2 - 3+) membranous staining
- Percentage of tumor cells that meet the criteria for positivity is determined by a ratio: the numerator includes all tumor cells in a section with 2 - 3+ intensity membranous staining; the denominator includes all tumor cells in a section (minimum of 50 viable cells)
- Claudin 18 can be assessed in gastric / gastroesophageal junction adenocarcinomas on either biopsy or resection material from either the primary site or a metastasis
- Claudin 18 was positive in ~35 - 40% locally advanced HER2 negative gastric / gastroesophageal junction adenocarcinomas assessed across two phase III clinical trials (SPOTLIGHT and GLOW) (Lancet 2023;401:1655, Nat Med 2023;29:2133)
Uses by pathologists
- Claudin 18 IHC (clone 43-14A) is a Food and Drug Administration (FDA) approved companion diagnostic for targeted treatment of gastric / gastroesophageal junction tumors with zolbetuximab
- Zolbetuximab is under a phase II study (NCT03816163) for targeted treatment of metastatic pancreatic adenocarcinoma tumors with positive claudin 18 IHC
- Positivity in this trial is defined as moderate to strong (2 - 3+) membranous staining in ≥ 75% of viable tumor cells
- Identifying metastasis of adenocarcinoma as either gastric or pancreaticobiliary in origin (Am J Surg Pathol 2020;44:1643, Sci Rep 2024;14:17648)
- Claudin 18 positivity is sensitive and specific for gastric origin in neuroendocrine tumors (Arch Pathol Lab Med 2022;147:559)
- Several anti-CLDN18.2 antibody drug conjugates (ADC) are being developed with different CLDN18 IHC cutoff values (Lancet Oncol 2025;26:227, Cancer Network: Anti-CLDN18.2 ADC Receives FDA Fast Track Designation in Advanced PDAC [Accessed 13 May 2025)
Prognostic factors
- Expression of claudin 18.2 in gastric cancer does not significantly affect progression free or overall survival (Sci Rep 2024;14:17648, Sci Rep 2023;13:20047)
- Gastric cancers that are positive for claudin 18.2 expression are reported to more frequently metastasize to the peritoneum than distant lymph nodes or the liver (Sci Rep 2024;14:17648)
- Anti-claudin 18.2 therapy (zolbetuximab) with chemotherapy prolongs overall survival in HER2 negative, locally advanced, unresectable or metastatic gastric / gastroesophageal junction adenocarcinoma (SPOTLIGHT and GLOW trials) (Lancet 2023;401:1655, Nat Med 2023;29:2133)
- Claudin 18.2 expression was not associated with expression of other biomarkers commonly used in gastric / gastroesophageal junction adenocarcinomas, such as MMR, HER2 and PDL1 (J Pers Med 2021;11:1095, ESMO Open 2024;9:102232)
Microscopic (histologic) images
Contributed by Trevor Toussieng, D.O.
Normal oxyntic mucosa
Intestinal metaplasia, stomach
Autoimmune metaplastic atrophic gastritis
Oxyntic mucosa, low grade dysplasia
Barrett esophagus
Barrett esophagus, high grade dysplasia
Gastroesophageal junction adenocarcinoma
Gastric adenocarcinoma, intestinal type
Gastroesophageal junction adenocarcinoma, poorly differentiated
Metastatic gastric adenocarcinoma
Well differentiated gastric neuroendocrine tumor
Metastatic gastric NET
Poorly differentiated pancreatic ductal adenocarcinoma
Benign lung
Positive staining - normal
- CLDN18.2
- Positive in gastric epithelial cells (Clin Cancer Res 2008;14:7624)
- Positive in duodenal Paneth cells (J Pathol 2006;208:633)
Positive staining - disease
- CLDN18.2
- Gastric adenocarcinoma (68 - 77%; any staining) (Arch Pathol Lab Med 2022;147:559, Clin Cancer Res 2008;14:7624, Am J Surg Pathol 2020;44:1643)
- Intestinal type (70%), diffuse type (60%) (Arch Pathol Lab Med 2022;147:559)
- Distal esophagus / gastroesophageal junction adenocarcinoma (75 - 78%; any staining) (Arch Pathol Lab Med 2022;147:559, Clin Cancer Res 2008;14:7624)
- Gastric well differentiated neuroendocrine tumors (80%; any staining) (Arch Pathol Lab Med 2022;147:559)
- Dysplasia, low or high grade, stomach (61%; any staining) (Arch Pathol Lab Med 2022;147:559)
- Dysplasia, low or high grade, distal esophagus / gastroesophageal junction (78%; any staining) (Arch Pathol Lab Med 2022;147:559)
- Nondysplastic intestinal metaplasia of stomach (variable; lower prevalence of expression in complete intestinal metaplasia and in the setting of autoimmune metaplastic atrophic gastritis) (Arch Pathol Lab Med 2022;147:559)
- Nondysplastic intestinal metaplasia of distal esophagus / gastroesophageal junction (93%; any staining) (Arch Pathol Lab Med 2022;147:559)
- Pancreatic adenocarcinoma (68 - 80%) (Am J Surg Pathol 2020;44:1643, Clin Cancer Res 2008;14:7624)
- Gastric adenocarcinoma (68 - 77%; any staining) (Arch Pathol Lab Med 2022;147:559, Clin Cancer Res 2008;14:7624, Am J Surg Pathol 2020;44:1643)
Negative staining
- Nongastric well differentiated neuroendocrine tumors (< 1%) (Arch Pathol Lab Med 2022;147:559)
- Esophageal squamous cell carcinoma (Clin Cancer Res 2008;14:7624)
- Pancreatic neuroendocrine carcinoma (Clin Cancer Res 2008;14:7624)
- Ovarian mucinous carcinoma (24%) (Clin Cancer Res 2008;14:7624)
- Ovarian serous carcinoma (Clin Cancer Res 2008;14:7624)
- Colorectal cancer metastasis to ovary (21%) (Clin Cancer Res 2008;14:7624)
Molecular / cytogenetics description
- Claudin 18 expression is maintained in a portion of gastric / gastroesophageal junction adenocarcinomas; positive staining is not due to a mutation or amplification that could be identified through DNA based molecular techniques
Sample pathology report
- Gastroesophageal junction, biopsy:
- Poorly differentiated adenocarcinoma (see comment)
- Comment: Positive, moderate to strong (2 - 3+) membranous claudin 18 immunohistochemical staining in ~85% of tumor cells.
Additional references
Practice question #1
Which of the following is true regarding claudin 18 immunohistochemistry?
- Claudin 18 is positive in benign pancreatic glands
- Claudin 18 stains in a nuclear pattern
- Loss of claudin 18 in gastric adenocarcinoma is associated with a better prognosis
- Loss of claudin 18 in gastric adenocarcinoma is associated with a worse prognosis
- Positivity is defined as moderate to strong (2 - 3+) membranous staining in ≥ 75% of viable tumor cells
Practice answer #1
E. Positivity is defined as moderate to strong (2 - 3+) membranous staining in ≥ 75% of viable tumor cells. Claudin 18 IHC shows a membranous staining pattern with both intensity and quantity of viable tumor cells reported.
Answer A is incorrect because claudin 18 is negative in benign pancreatic glands but may be aberrantly expressed in pancreatic adenocarcinoma.
Answer B is incorrect because it is a membranous stain.
Answers C and D are incorrect because positivity or negativity of claudin 18 in gastric adenocarcinoma does not affect progression free or overall survival.
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Reference: Claudin 18.2
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Reference: Claudin 18.2
