Cytoplasmic MSH2 immunoreactivity in a patient with Lynch syndrome with an EPCAM–MSH2 fusion

Aims Immunohistochemistry for mismatch repair (MMR) proteins is being increasingly used to examine the MMR status in tumors. The present study reports the case of a colon cancer patient with Lynch syndrome, who exhibited unusual cytoplasmic MMR protein localization. Methods and Results Histologically, the colon cancer was diagnosed as medullary carcinoma associated with prominent tumor infiltrating lymphocytes and a Crohn's-like reaction. Immunohistochemistry revealed cytoplasmic and nuclear expression of MSH2 in non-neoplastic cells and exclusively cytoplasmic expression in tumor cells. MSH6 expression was nuclear in non-neoplastic cells but was lost in tumor cells. Nuclear expression of MLH1 and PMS2 was retained in both non-neoplastic and tumor cells. The tumor was microsatellite instability-high, which is indicative of defective MMR function. A subsequent germline mutation analysis identified a genomic deletion spanning the 3′ region of EPCAM and the 5′ region of MSH2, resulting in an inframe fusion of EPCAM and MSH2. Conclusions The unusual cytoplasmic immunoreactivity of MSH2 was considered attributable to the non-functional EPCAM-MSH2 fusion product. The present case illustrates that not only loss of expression, but also abnormal localization of MMR proteins, is indicative of the defective MMR system. This article is protected by copyright. All rights reserved.