Expression of CD133 in Neuroendocrine Neoplasms of the Digestive Tract: A Detailed Immunohistochemical Analysis

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are potentially malignant with variable biologic behavior that originates from neuroendocrine cells of digestive tract. Recently, the existence of cancer stem cells (CSC) was demonstrated in tumors of gastrointestinal tract. CD133 is a transmembrane glycoprotein that serves as a CSC marker in various malignancies. However, the expression of CD133 in neuroendocrine neoplasms (NEN) of digestive tract has not been studied. We evaluated tissue expression of CD133 by immunohistochemistry in 90 NENs of digestive tract with their matched non-neoplastic mucosa including stomach (n = 15), small intestine (n = 7), appendix (n = 3), colon (n = 8), rectum (n = 41), pancreas (n = 2), gallbladder (n = 4) and liver (n = 10). Tumors were divided according to 2010 WHO classification. CD133 was expressed in 30.3% (17/56) of well-differentiated neuroendocrine tumors (NET), 26.1% (6/23) of poorly-differentiated neuroendocrine carcinomas (NEC) and 63.6% (7/11) of mixed adenoneuroendocrine carcinoma (MANECs). MANEC refers to existence of both adenocarcinoma and NEC together, each one comprising at least 30% of the tumor. CD133 was expressed in cytoplasm, luminal-side of cell membrane, or both and the staining pattern correlated with tumor growth pattern. CD133 expression was not significantly correlated with tumor grade, site, expression of neuroendocrine markers (chromogranin-A and synaptophysin) and patients’ survival. Thus, CD133 expression may lack prognostic significance in GEP-NETs. Importantly, CD133 was not detectable in non-neoplastic neuroendocrine cells of digestive system including pancreatic islets. In conclusion, CD133 is expressed in poorly-differentiated NECs and well-differentiated NETs of the digestive tract.