Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity

Abstract

Medullary carcinomas of the pancreas are a recently described, histologically distinct subset of poorly differentiated adenocarcinomas that may have a unique pathogenesis and clinical course. To further evaluate these neoplasms, we studied genetic, pathological, and clinical features of 13 newly identified medullary carcinomas of the pancreas. Nine (69%) of these had wild-type K-ras genes, and one had microsatellite instability (MSI). This MSI medullary carcinoma, along with three previously reported MSI medullary carcinomas, were examined immunohistochemically for Mlh1 and Msh2 expression, and all four expressed Msh2 but did not express Mlh1. In contrast, all of the medullary carcinomas without MSI expressed both Msh2 and Mlh1. Remarkably, the MSI medullary carcinoma of the pancreas in the present series arose in a patient with a synchronous but histologically distinct cecal carcinoma that also had MSI and did not express Mlh1. The synchronous occurrence of two MSI carcinomas suggests an inherited basis for the development of these carcinomas. Indeed, the medullary phenotype, irrespective of MSI, was highly associated with a family history of cancer in first-degree relatives (P < 0.001). Finally, one medullary carcinoma with lymphoepithelioma-like features contained Epstein-Barr virus-encoded RNA-1 by in situ hybridization. Therefore, because of medullary carcinoma's special genetic, immunohistochemical, and clinical features, recognition of the medullary variant of pancreatic adenocarcinoma is important. Only by classifying medullary carcinoma as special subset of adenocarcinoma can we hope to further elucidate its unique pathogenesis.

Figure 1.

Histology of medullary carcinoma of the pancreas. The tumor has a syncytial growth pattern of the cells.

Figure 2.

Histology of a medullary carcinoma of the pancreas with lymphoepithelioma-like features. A: The neoplasm has the characteristics of medullary carcinoma with the additional finding of an intense intratumoral lymphocytic infiltrate. B: In situ hybridization for Epstein-Barr virus-encoded RNA-1 is positive in the nuclei of the neoplastic cells.

Figure 3.

K-ras sequencing of codon 12 of a medullary carcinoma (A) and a poorly differentiated conventional adenocarcinoma (B). The medullary carcinoma has a wild-type K-ras gene, but the conventional adenocarcinoma has a GGT (gly) to GAT (asp) mutation.

Figure 4.

BAT 25 and BAT 26 PCR products for two medullary carcinomas, a conventional adenocarcinoma, and normal pancreas. For both the BAT 25 and BAT 26 PCR products: lane 1, pancreatic medullary carcinoma with a microsatellite shift; lane 2, normal pancreas from the same patient; lane 3, a different pancreatic medullary carcinoma without a shift; and lane 4, a conventional ductal adenocarcinoma without a shift. The shifting medullary carcinoma and the normal pancreas are both from the patient with synchronous pancreatic and colonic carcinomas.

Figure 5.

Immunohistochemistry for DNA repair-gene products in medullary carcinomas of the pancreas. A: This medullary carcinoma has intact nuclear labeling for the MSH2 gene product. B: Another medullary carcinoma has no expression of Mlh1. Note that the nuclei of stromal cells do express Mlh1.

Figure 6.

Histology of the Mlh1-deficient pancreatic (A) and colonic (B) carcinomas from the patient presumed to have HNPCC. Both carcinomas had MSI, and both had wild-type K-ras genes. Note that the histological patterns of the two cases are different: the pancreas has the medullary phenotype, whereas the colon cancer is gland-forming.