Somatic Mutations in PIK3CA and Activation of AKT in Intraductal Tubulopapillary Neoplasms of the Pancreas

Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan.
The American journal of surgical pathology (Impact Factor: 4.59). 09/2011; 35(12):1812-7. DOI: 10.1097/PAS.0b013e31822769a0
Source: PubMed

ABSTRACT Intraductal tubulopapillary neoplasm (ITPN) is a recently recognized rare variant of intraductal neoplasms of the pancreas. Molecular aberrations underlying the neoplasm remain unknown. We investigated somatic mutations in PIK3CA, PTEN, AKT1, KRAS, and BRAF. We also investigated aberrant expressions of phosphorylated AKT, phosphatase and tensin homolog (PTEN), tumor protein 53 (TP53), SMAD4, and CTNNB1 in 11 cases of ITPNs and compared these data with those of 50 cases of intraductal papillary mucinous neoplasm (IPMN), another distinct variant of pancreatic intraductal neoplasms. Mutations in PIK3CA were found in 3 of 11 ITPNs but not in IPMNs (P = 0.005; Fisher exact test). In contrast, mutations in KRAS were found in none of the ITPNs but were found in 26 of the 50 IPMNs (P = 0.001; Fisher exact test). PIK3CA mutations were associated with strong expression of phosphorylated AKT (P < 0.001; the Mann-Whitney U test). Moreover, the expression of phosphorylated AKT was apparent in most ITPNs but only in a few IPMNs (P < 0.001; the Mann-Whitney U test). Aberrant expressions of TP53, SMAD4, and CTNNB1 were not statistically different between these neoplasms. Mutations in PIK3CA and the expression of phosphorylated AKT were not associated with age, sex, tissue invasion, and patients' prognosis in ITPNs. These results indicate that activation of the phosphatidylinositol 3-kinase pathway may play a crucial role in ITPNs but not in IPMNs. In contrast, the mutation in KRAS seems to play a major role in IPMNs but not in ITPNs. The activated phosphatidylinositol 3-kinase pathway may be a potential target for molecular diagnosis and therapy of ITPNs.

  • Pathology 02/2015; 47(2):169-71. DOI:10.1097/PAT.0000000000000228 · 2.62 Impact Factor
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    ABSTRACT: There are three types of pancreatic neoplasms that predominantly have an intraductal growth pattern: the common, usually cystic, intraductal papillary mucinous neoplasms (IPMNs), the rare usually solid intraductal tubulopapillary neoplasms (ITPNs) and the rare intraductal tubular pyloric gland type adenoma. In addition to these three tumor types, pancreatic neoplasms with a usually solid growth pattern such as acinar cell carcinomas, neuroendocrine tumors and undifferentiated carcinomas, may present, though very rarely, as predominantly intraductally growing neoplasms. IPMNs can be subclassified into main duct and branch duct tumors, into low- and high-grade dysplasia groups, and into tumors with intestinal, pancreatobiliary, oncocytic or gastric cellular differentiation. The intestinal, pancreatobiliary and oncocytic type IPMNs occur predominantly in the main duct of the head of the pancreas and more commonly progress to invasive adenocarcinomas. The gastric type IPMNs are frequently multifocal, occur predominantly in the branch ducts of the uncinate process and have a low risk of progressing to invasive carcinoma. The prognosis for patients with an IPMN depends largely on the subtype and the presence and the stage of an invasive carcinoma. ITPNs are nodular tumors, often in the pancreatic head and composed of densely packed tubular glands. Molecular genetics reveal KRAS, GNAS and RNF43 as the most frequently mutated genes in IPMNs, while ITPNs show wild type KRAS. Recent progress in genetic sequencing of pancreatic neoplasms and the identification of specific genetic mutations, also holds promise for the future development of novel gene based diagnostic tests in intraductal neoplasms of the pancreas that might even been used in preoperative conditions.
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    ABSTRACT: The patient was a 61-year-old male who was referred to our hospital after dilatation of the main pancreatic duct was detected by screening ultrasonography. Computed tomography revealed a protruding lesion measuring 15 mm in diameter within the main pancreatic duct in the head of the pancreas, and magnetic resonance cholangiopancreatography revealed interruption of the duct at the tumor site. We performed pancreaticoduodenectomy under a suspected diagnosis of invasive ductal carcinoma. Gross examination of the resected specimen showed that the tumor invaginated into the main pancreatic duct, and no mucin was found. Histological examination revealed proliferation of high-grade dysplastic cells in a tubulopapillary growth pattern. Immunohistochemically, cytokeratin 7 expression was detected, but not trypsin expression. Based on these morphological features, we diagnosed the tumor as intraductal tubulopapillary neoplasm (ITPN). We report the case with bibliographic consideration, together with a review of intraductal neoplasms of the pancreas encountered at our institution.
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Mar 1, 2015