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 genetical ly inactivated in over half of infiltrating ductal adenocarcinomas of the p ancreas. Immunohistochemical labeling for the DPC4 gene product using a mon oclonal antibody has recently been shown to be an extremely sensitive and s pecific marker for DPC4 gene alterations in pancreatic adenocarcinomas. Muc inous 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 MCN s has not been examined. The immunohistochemical expression of Dpc4 protein was therefore examined in 36 mucinous cystic neoplasms using this previous ly characterized monoclonal antibody. The 36 mucinous cystic neoplasms stud ied 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 neopla stic epithelium. In striking contrast, only one (14%) of seven infiltrating carcinomas expressed Dpc4 in the neoplastic epithelium (p = 0.0001), The a djacent stroma retained expression of this protein in all 36 cases. In inva sive MCNs with loss of Dpc4 expression, areas of carcinoma in situ were ide ntified in the same paraffin sections, and these areas of carcinoma in situ retained expression of Dpc4. The frequent loss of Dpc4 expression in invas ive MCNs indicates that genetic inactivation of Dpc4 occurs late in the neo plastic progression of these tumors and suggests a relationship to the deve lopment of invasion.