Dpc4 protein in mucinous cystic neoplasms of the pancreas: Frequent loss of expression in invasive carcinomas suggests a role in genetic progression

DPC4 (MADH4, SMAD4) is a nuclear transcription factor shown to be genetically inactivated in over half of infiltrating ductal adenocarcinomas of the pancreas. Immunohistochemical labeling for the DPC4 gene product using a monoclonal antibody has recently been shown to be an extremely sensitive and specific marker for DPC4 gene alterations in pancreatic adenocarcinomas. Mucinous cystic neoplasms (MCNs) are a biologically less aggressive subtype of pancreatic neoplasm that may show benign, borderline, or overtly malignant features. However, the role of DPC4 inactivation in the development of MCNs has not been examined. The immunohistochemical expression of Dpc4 protein was therefore examined in 36 mucinous cystic neoplasms using this previously characterized monoclonal antibody. The 36 mucinous cystic neoplasms studied included 23 adenomas, 1 tumor with borderline potential, 5 tumors with carcinoma in situ, and 7 invasive carcinomas. Twenty-nine (100%) of the 29 noninvasive mucinous cystic neoplasms strongly expressed Dpc4 in the neoplastic epithelium. In striking contrast, only one (14%) of seven infiltrating carcinomas expressed Dpc4 in the neoplastic epithelium (p = 0.0001). The adjacent stroma retained expression of this protein in all 36 cases. In invasive MCNs with loss of Dpc4 expression, areas of carcinoma in situ were identified in the same paraffin sections, and these areas of carcinoma in situ retained expression of Dpc4. The frequent loss of Dpc4 expression in invasive MCNs indicates that genetic inactivation of Dpc4 occurs late in the neoplastic progression of these tumors and suggests a relationship to the development of invasion.