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More than 90% of tumors of the pancreas are ductal adenocarcinomas, derived from the exocrine pancreatic ducts. The remaining cases are comprised of a whole variety of histologic subtypes such as inraductal papillary mucinous neoplasms, mucinous cystic neoplasms, solid pseudopapillary tumor of the pancreas, acinar cell carcinoma, and pancreatic endocrine tumors. Amongst the putative epidemiologic risk factors for pancreatic adenocarcinoma, two that have been validated by large case control studies are chronic pancreatitis and long standing diabetes mellitus. A small percent of cases fall under the rubric of familial pancreatic adenocarcinomas, although the implicated genetic locus is still unknown. As previously stated, stage (based on lymph node status and residual tumor post-resection) and tumor size remain the most important prognostic determinants for this otherwise uniformly dismal disease, but histologic grade has been shown to play some role as well.
There is no doubt that pancreatic adenocarcinoma is a genetic disease and the evolution of this tumor requires the progressive accumulation of molecular abnormalities in native pancreatic ducts. Several tumor suppressor genes have been implicated in tumorigenesis, the most frequent of which is the cell cycle inhibitor p16, located on chromosome 9p21. Approximately 80% of pancreatic adenocarcinomas demonstrate loss of p16 function by mutations, homozygous deletions or hypermethylation. Another relatively "pancreas specific" recessive oncogene gene is DPC4 ("deleted in pancreatic adenocarcinoma 4"), which is located on chromosome 18q, and inactivated in approximately 50% of pancreatic tumors, usually by mutations or allelic deletions. p53, the most commonly mutated tumor suppressor gene in human cancers, is inactivated in 50-70% of pancreatic tumors. A small, but significant minority of patients with pancreatic adenocarcinoma harbor germline or somatic mutations of the BRCA2 gene, which is more commonly associated with breast and ovarian cancers. In addition to inactivating mutations of tumor suppressor genes, activating mutations of the K-ras oncogene have been detected in 80-100% of pancreatic cancers, and almost always involve codon 12. Similarly, the Her-2/neu oncogene is amplified in greater than 50% of pancreatic cancers, while a quarter demonstrate cyclin D1 overexpression. The existence of preneoplastic duct lesions that precede pancreatic adenocarcinoma has been known for a long time, but it is only recently that a uniform system of nomenclature has been adopted for these changes, under the rubric of Pancreatic Intraepithelial Neoplasiia or PanIN. Many of the genetic abnormalities (K-ras mutations, Her-2/neu amplification, p16, p53 and Dpc4 inactivation) seen in pancreatic adenocarcinomas are shared by PanIN lesions, but the timing of these changes are different. For example, K-ras mutations are an early event seen even in mildly abnormal duct epithelium, while loss of Dpc4 expression occurs late in the multistep model of carcinogenesis. The presence of these genetic changes in precursor lesions brings hope that they can be used for the early diagnosis and treatment of pancreatic cancer.
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