Complete Loss of EPCAM Immunoexpression Identifies EPCAM Deletion Carriers in MSH2-Negative Colorectal Neoplasia

SIMPLE SUMMARY: Colorectal carcinomas from patients with Lynch syndrome (LS) due to EPCAM deletions show loss of MSH2 expression. The aim of our study was to evaluate the usefulness of EPCAM expression in identifying carriers of EPCAM deletion among patients with MSH2-negative lesions. MSH2 and EPCAM immunohistochemistry was performed in a large series of lesions (190) composed of malignant and benign neoplasms as well as precursor lesions of different organs from 71 patients with suspected LS due to MSH2 alterations. Germ-line analysis confirmed LS in 68 patients due to MSH2 mutations (53) and EPCAM deletions (15). Among colorectal lesions with lack of MSH2 expression, only 17 were EPCAM-negative and belonged to patients with EPCAM deletions. We confirm that loss of EPCAM expression identifies EPCAM deletion carriers with 100% specificity and we recommend adding EPCAM IHC to the algorithm of MSH2-negative colorectal neoplasia. ABSTRACT: The use of epithelial cell adhesion molecule (EPCAM) immunohistochemistry (IHC) is not included in the colorectal cancer (CRC) screening algorithm to detect Lynch syndrome (LS) patients. The aim of the present study was to demonstrate that EPCAM IHC is a useful tool to guide the LS germ-line analysis when a loss of MSH2 expression was present. We retrospectively studied MSH2 and EPCAM IHC in a large series of 190 lesions composed of malignant neoplasms (102), precursor lesions of gastrointestinal (71) and extra-gastrointestinal origin (9), and benign neoplasms (8) from different organs of 71 patients suspicious of being LS due to MSH2 alterations. LS was confirmed in 68 patients, 53 with MSH2 mutations and 15 with EPCAM 3′-end deletions. Tissue microarrays were constructed with human normal tissues and their malignant counterparts to assist in the evaluation of EPCAM staining. Among 154 MSH2-negative lesions, 17 were EPCAM-negative, including 10 CRC and 7 colorectal polyps, and 5 of them showed only isolated negative glands. All lesions showing a lack of EPCAM expression belonged to patients with EPCAM 3′-end deletions. EPCAM IHC is a useful screening tool, with 100% specificity to identify LS patients due to EPCAM 3′-end deletions in MSH2-negative CRC and MSH2-negative colorectal polyps.