Immunohistochemical and molecular features of sporadic and FAP-associated duodenal adenomas of the ampullary and nonampullary mucosa.
ABSTRACT The pathogenesis of duodenal adenomas is not well elucidated. Much of the literature pertains to ampullary adenomas and those associated with familial adenomatous polyposis (FAP). In this study, we evaluated the molecular features of a series of sporadic duodenal adenomas (n=22) that developed distal to the ampulla, and compared them with the features of sporadic ampullary adenomas (n=9) and FAP-related polyps (n=12). Using a combination of immunohistochemical studies [cytokeratins 7 and 20, E-cadherin, beta-catenin, p53, MLH-1, MSH-2, MSH-6, and O6-methylguanine methyltransferase (MGMT)], DNA sequencing [beta-catenin, adenomatous polyposis coli (APC), p53, KRAS, and BRAF], and a polymerase chain reaction-based microsatellite instability assay; we assessed each case for abnormalities in the Wnt signaling and mitogen-activated protein kinase pathways and DNA repair mechanisms. Wnt signaling pathway abnormalities occurred in sporadic, nonampullary (82%), and ampullary (77%) adenomas at comparable rates, usually reflecting nuclear beta-catenin immunostaining (64% and 44%, respectively), and APC rather than beta-catenin, mutations. KRAS mutations were infrequent in sporadic, nonampullary adenomas (18%), and FAP-related adenomas (9%); moderately frequent in ampullary adenomas (44%); and none of the cases harbored BRAF mutations. Only 4 (13%) sporadic adenomas showed nuclear p53 staining, but no p53 mutations were detected in exons 5 to 8. Loss of O-methylguanine methyltransferase immunostaining was identified in 1 sporadic, nonampullary adenoma, and none of the polyps in any group showed loss of MLH-1, MSH-2, or MSH-6 staining, or high-frequency microsatellite instability. We conclude that sporadic and FAP-related adenomas show similar molecular features, regardless of their anatomic location. Similar to colorectal adenomas, they harbor APC and KRAS mutations; but BRAF mutations, p53 alterations, and DNA mismatch repair abnormalities are rare.
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ABSTRACT: It has been speculated that intraductal dissemination, via the pancreatic duct, bile duct, or mammary duct, is a unique form of cancer cell spread. However, clinical evidence to confirm this form of dissemination has been lacking. Here we report a case of papillary adenocarcinoma of the ampulla of Vater in which retrograde dissemination to the pancreatic duct was strongly suggested. A 79-year-old woman underwent pancreatoduodenectomy for a 22 mm microinvasive papillary adenocarcinoma of the ampulla. Multiple carcinomas in situ were found in the pancreatic duct distant from the ampulla. Seven months later, she underwent a second operation for a recurrent papillary adenocarcinoma at the pancreato-jejunal anastomosis showing exophytic and expansive growth into the jejunal lumen that connected to an intraductal adenocarcinoma in the pancreatic body. None of these tumors showed invasive growth, or vascular or neural invasion, being separate from each other but sharing identical histological, immunohistochemical, and molecular features; papillary growth, a pancreatobiliary phenotype, the same pattern of genomic loss of heterozygosity, and no mutation of the KRAS, TP53, and GNAS genes. These results imply that this papillary adenocarcinoma of the ampulla of Vater had disseminated to the pancreatic duct in a retrograde manner and recurred in the remnant pancreas.Pathology International 01/2014; 64(1):39-44. DOI:10.1111/pin.12131 · 1.59 Impact Factor
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ABSTRACT: Gastric and duodenal adenomas exhibit a significant morphological and phenotypical diversity and are classified into intestinal-type, foveolar-type, and pyloric gland adenomas. We analyzed the mutations in GNAS, KRAS, BRAF, and CTNNB1 and the expressions of mismatch repair (MMR) proteins in 80 gastric and 32 duodenal adenomas with histologically distinct subtypes as well as in 71 gastric adenocarcinomas. Activating GNAS mutations were found in 22 of the 35 pyloric gland adenomas (PGAs) (63%) but in none of the foveolar-type or intestinal-type adenomas or in the adenocarcinomas. Fourteen PGAs (41%), 2 foveolar-type adenomas (9%), 5 intestinal-type adenomas (9%), and one adenocarcinoma (1%) had KRAS mutations. BRAF mutations were absent in all the adenomas and adenocarcinomas that were examined. CTNNB1 mutations were only found in 2 intestinal-type adenomas (4%). Notably, 13 of the 14 KRAS-mutated gastric and duodenal PGAs had concurrent GNAS mutations. The loss of the MMR proteins, which is indicative of microsatellite instability, was observed in 1 PGA (3%), 12 foveolar-type adenomas (52%), 1 intestinal-type adenoma (2%), and 5 adenocarcinomas (7%). These observations indicate that each histological subtype of gastric and duodenal adenomas has a distinct genetic background. In particular, the present study identified the frequent presence of activating GNAS mutations, which are often associated with KRAS mutations, as a characteristic genetic feature of PGAs of the stomach and duodenum. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.The Journal of Pathology 03/2013; 229(4). DOI:10.1002/path.4153 · 7.33 Impact Factor
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ABSTRACT: CpG island methylator phenotype (CIMP) has been found in multiple precancerous and cancerous lesions, including colorectal adenomas, colorectal cancers, and duodenal adenocarcinomas. There are no reports in the literature of a relationship between CIMP status and clinicopathologic features of sporadic duodenal adenomas. This study sought to elucidate the role of methylation in duodenal adenomas and correlate it with KRAS and BRAF mutations. CIMP+ (with more than 2 markers methylated) was seen in 33.3% of duodenal adenomas; 61% of these CIMP+ adenomas were CIMP-high (with more than 3 markers methylated). Furthermore, CIMP+ status significantly correlated with older age of patients, larger size and villous type of tumor, coexistent dysplasia and periampullary location. MLH1 methylation was seen in 11.1% of duodenal adenomas and was significantly associated with CIMP+ tumors, while p16 methylation was an infrequent event. KRAS mutations were frequent and seen in 26.3% of adenomas; however, no BRAF mutations were detected. Furthermore, CIMP-high status was associated with larger size and villous type of tumor and race (non-white). These results suggest that CIMP+ duodenal adenomas may have a higher risk for developing malignancy and may require more aggressive management and surveillance.Epigenetics: official journal of the DNA Methylation Society 02/2014; 9(5). DOI:10.4161/epi.28082 · 5.11 Impact Factor