Claudin 18 is not a biomarker for breast mucinous tumor

BACKGROUND: Breast mucinous cystadenocarcinoma (BMCA) is an exceptionally rare malignancy that may resemble mucinous neoplasms of the pancreas, ovary, lung and colorectum. Claudin 18 (CLDN18), particularly its gastric-associated isoform CLDN18.2, is an emerging therapeutic target; however, CLDN18 immunoreactivity has not been systematically evaluated in BMCA. We investigated whether CLDN18 could distinguish BMCA from breast mucinous carcinoma (BMC) and selected extramammary mucinous mimics. METHODS: Immunohistochemical (IHC) analysis for CLDN18, CK7 and CK20 was performed on 42 mucinous neoplasms comprising BMCA (n=3), BMC (n=9), pulmonary invasive mucinous adenocarcinoma (n=8), colorectal mucinous adenocarcinoma (n=10), ovarian mucinous tumors (n=6) and pancreatic mucinous cystic neoplasms (n=6). Staining intensity and percentage of positive cells were independently evaluated by two pathologists. Previously published TRPS1, organ-lineage marker and molecular findings from the same three BMCA cases were incorporated for diagnostic correlation. RESULTS: All three BMCA and all nine BMC cases were CK7-positive, CK20-negative and lacked membranous CLDN18 staining. Mammary lineage and differentiation of the three BMCA cases were supported by previously shown TRPS1 nuclear expression. CLDN18 staining was detected in 5/6 pancreatic, 5/6 ovarian and 6/8 pulmonary mucinous tumors, while seven of ten colorectal cases were negative, two were focally positive and one was diffusely positive. CLDN18 thus provided information beyond CK7/CK20, particularly in pancreatic, ovarian and pulmonary mucinous tumors, but not in mammary mucinous tumors including BMCA. CONCLUSION: In this limited cohort of three BMCA, CLDN18 did not distinguish BMCA from BMC. TRPS1 provided positive support for mammary lineage, whereas CLDN18 negativity offered supplementary exclusionary evidence against selected extramammary mucinous tumors. CLDN18 should therefore be interpreted with morphology, clinical findings, CK7/CK20 and established lineage markers. Larger multicenter studies are warranted to validate its adjunctive diagnostic role in mucin-rich breast lesions.