Immunohistochemical evaluation of K-ras, p53, and HER-2/neu expression in hyperplastic, dysplastic, and carcinomatous lesions of the pancreas: Evidence for multistep carcinogenesis

Apple, Sophia K.; Hecht, J. Randolph; Lewin, David; Jahromi, Soraya A; Grody, Wayne W.; Nieberg, Roberta K.

doi:10.1016/s0046-8177(99)90265-4

Cited by 115 publications

(57 citation statements)

References 26 publications

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“…Another marker that labeled about 60% of the cases was p53. [24][25][26] The expression of these markers was particularly helpful in cases in which the epithelium of the cystic structures was extremely flattened and therefore difficult to distinguish from the non-neoplastic epithelium of retention cysts. Cystic duct-like structures as an integral part of some pancreatic ductal adenocarcinomas were already described by Frantz 27 and have been mentioned in the more recent literature.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic ductal adenocarcinomas with cystic features: neither rare nor uniform

et al. 2005

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Cystic tumors of the pancreas are uncommon but important because of their diverse pathology and biology. Their wide spectrum also includes cystic variants of otherwise solid tumors, such as cystic endocrine tumors, cystic acinar cell carcinomas and ductal adenocarcinomas with cystic changes. In this study, we screened pancreatic ductal adenocarcinomas and their variants for macrocystic changes and determined the nature of the cysts (neoplastic vs non-neoplastic). Of 483 tumors 38 (8%) had cystic features. The largest group consisted of 24 pancreatic ductal adenocarcinomas showing a large-gland pattern with small cysts whose diameter varied between 0.5 and 1.8 cm. The epithelial lining of these cysts was generally positive for CEA (83%) and/or MUC1 (71%) and MUC5AC (74%). p53 was positive in 57% of the cases. The second group of cystic tumors (8/483) showed degenerative cystic cavities with diameters ranging between 1 and 6 cm. This group consisted of poorly differentiated pancreatic ductal adenocarcinomas, undifferentiated carcinomas with or without osteoclast-like giant cells and one adenosquamous carcinoma. In the third group of cystic tumors there were four pancreatic ductal adenocarcinomas containing tumor-related retention cysts. Their epithelial cells were positive for MUC5AC, but negative for CEA, MUC1 and p53. The fourth group consisted of two pancreatic ductal adenocarcinomas showing closely attached pseudocysts caused by tumor-associated pancreatitis. The results indicate that a considerable number of pancreatic ductal adenocarcinomas and their variants display cystic features and must therefore be considered in the differential diagnosis of cystic neoplasms of the pancreas. Moreover, not all of the cystic structures we observed were neoplastic in nature. They may also represent nonneoplastic changes, such as retention cysts and inflammatory pseudocysts.

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Section: Discussionmentioning

confidence: 99%

Pancreatic ductal adenocarcinomas with cystic features: neither rare nor uniform

et al. 2005

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“…The neoplastic nature of LG and HG PanIN is supported by the discovery of multiple genetic alterations within it, most notably K-ras mutation, overexpression of p53 protein, and loss of p16 protein expression (31)(32)(33)(34). K-ras abnormalities, most often mutations in Codon 12, have been demonstrated in neoplastic ductal epithelium isolated from patients with a history of pancreatic cancer as well as from those with no history of pancreatic neoplasia and from autopsy specimens (33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

“…K-ras abnormalities, most often mutations in Codon 12, have been demonstrated in neoplastic ductal epithelium isolated from patients with a history of pancreatic cancer as well as from those with no history of pancreatic neoplasia and from autopsy specimens (33)(34)(35)(36). Overexpression of p53 is found most commonly in invasive pancreatic carcinoma; however, it may also be overexpressed in PanIN, especially HG PanIN (34,(37)(38)(39). Apple and colleagues (34) demonstrated a relationship between p53 overexpression and increasing grades of epithelial atypia.…”

Section: Discussionmentioning

confidence: 99%

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Neoplasms of the Ampulla of Vater with Concurrent Pancreatic Intraductal Neoplasia: A Histological and Molecular Study

et al. 2001

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Adenoma and adenocarcinoma of the ampulla of Vater are uncommon neoplasms of the gastrointestinal tract that are found with increased frequency in familial adenomatous polyposis syndrome (1-3). Ampullary adenoma represents the precursor lesion to adenocarcinoma, and a coexistent adenoma can be identified frequently in patients with ampullary adenocarcinoma (1, 2). Because of their premalignant nature, ampullary adenomas are often resected either by polypectomy or, in the case of larger lesions, by pancreaticoduodenectomy (1,4,5). An association between adenomas of the ampullary region and pancreatic intraductal neoplasia has not been documented previously. Adenocarcinoma of the pancreas is often associated with pancreatic intraductal neoplasia (PanIN), which is thought to represent the precursor lesion for this cancer (6 -12). Several case reports documenting progression of high-grade (HG) PanIN to invasive pancreatic adenocarcinoma over time (17 mo to 29 y) support the role of PanIN as a precursor of carcinoma (10,13,14).The relationship between ampullary adenoma and PanIN has not been investigated previously, and only one analysis of the relationship between

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“…However, it remains to be clarified how these alterations are involved in the initiation and progression of this type of tumor. The lack of expression of c-erbB-2 (HER-2/neu) and of p53 emphasizes that the pathogenesis of solid pseudopapillary tumor differs from that of usual carcinoma of the pancreas (50,51,52). However, the role of cyclins and cyclin-dependent kinase inhibitors has not yet been fully investigated in pancreatic adenocarcinoma (53,54).…”

Section: Discussionmentioning

confidence: 99%

Deregulated Expression of Cell Cycle–Associated Proteins in Solid Pseudopapillary Tumor of the Pancreas

2001

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Solid pseudopapillary tumor of the pancreas was studied in a 20-year-old woman and a 54-year-old woman. In the younger patient, the tumor had metastasized to the liver 8 years after distal pancreatectomy. In both neoplasms, the distinct histologic pattern of solid, pseudopapillary, and degenerative cystic areas was present. Analysis by means of immunohistochemistry revealed a diffuse expression for vimentin, neuron-specific enolase, and a focal positivity for ␣1-antitrypsin, whereas epithelial markers were negative in the tumor of the older patient and only focally expressed in the tumor of the younger patient. Immunohistochemical analysis of cell cycle-associated proteins provided an overexpression of cyclin D1 and cyclin D3 in both tumors, although to varying degrees. In addition, the cyclin-dependent kinase inhibitors p21, and to a lesser extent p27, were up-regulated just as mdm2. There was no accumulation of p53 protein, and Ki67-positive cells were extremely scarce. Analysis of the liver metastases showed an immunoreactive profile similar to that of the primary tumor. The results show a deregulation of the cell cycle with overexpression of cell cycle-activating proteins D1 and D3 and a probably counterbalancing upregulation of the cyclin-dependent kinase inhibitors p21 and p27. The findings may explain the low pool of Ki67-reactive tumor cells and the generally good clinical outcome of these tumors. Whether a more profound dysbalance of the cell cycle regulation is responsible for the development of metastatic disease remains to be clarified.

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Immunohistochemical evaluation of K-ras, p53, and HER-2/neu expression in hyperplastic, dysplastic, and carcinomatous lesions of the pancreas: Evidence for multistep carcinogenesis

Cited by 115 publications

References 26 publications

Pancreatic ductal adenocarcinomas with cystic features: neither rare nor uniform

Pancreatic ductal adenocarcinomas with cystic features: neither rare nor uniform

Neoplasms of the Ampulla of Vater with Concurrent Pancreatic Intraductal Neoplasia: A Histological and Molecular Study

Deregulated Expression of Cell Cycle–Associated Proteins in Solid Pseudopapillary Tumor of the Pancreas

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