Pseudoendocrine differentiation in colorectal adenoarcinoma associated with EPCAM-mutated Lynch syndrome.

Abstract

Abstract: Lynch syndrome (LS) is an autosomal dominant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair genes or, less commonly, EPCAM deletions. LS-associated colorectal carcinomas often present at a young age and may show unusual histomorphological patterns, posing diagnostic challenges. We report a rare case of a 29-year-old female with EPCAM-mutated LS presenting as colonic adenocarcinoma with neuroendocrine-like rosette formation. The tumor initially mimicked mixed adenoneuroendocrine carcinoma (MANEC) due to biphasic histology and the presence of multiple rosettes. However, immunohistochemistry demonstrated negativity for synaptophysin and chromogranin, excluding true neuroendocrine differentiation with diffuse Pan CK and focal CDX2, CK20 positivity along with loss of MSH2 and MSH6. Further molecular analyses confirmed EPCAM exon 5-9 deletion. The tumor was ultimately classified as an MMR-deficient adenocarcinoma with pseudoendocrine morphology. This case broadens the histomorphological spectrum of LS-associated colorectal carcinomas and introduces the concept of a possible pseudoendocrine carcinoma arising in an epithelial malignancy. Recognition of this pattern is crucial to prevent misdiagnosis as MANEC, to guide appropriate management, facilitate familial screening, and highlight that not every rosette signifies neuroendocrine differentiation; some may represent LS in disguise.