Mutational spectrum of intraepithelial neoplasia in pancreatic heterotopia

Abstract

Heterotopic pancreatic parenchyma recapitulates the normal pancreas in extra-pancreatic locations and on rare occasions can even give rise to pancreatic adenocarcinoma. The genetic signatures of pancreatic adenocarcinoma and its precursor lesions are well characterized. We explored the genetic alterations in precursor lesions (intraductal papillary mucinous neoplasms [IPMN], pancreatic intraepithelial neoplasia [PanIN]) in patients with pancreatic heterotopias but without concomitant pancreatic ductal adenocarcinomas. This allowed us to determine whether the stereotypical dysplasia—infiltrating carcinoma sequence also occurs in these extra-pancreatic foci. Seven cases of heterotopic pancreas with ductal precursor lesions were identified. These included two IPMNs with focal high grade dysplasia and five PanINs with low to moderate grade dysplasia (PanIN grades 1–2). Neoplastic epithelium was micro-dissected and genomic DNA was extracted. Sequencing of commonly mutated hotspots (KRAS, TP53, CDKN2A, SMAD4, BRAF, and GNAS) in pancreatic ductal adenocarcinoma and its precursor lesions was performed. Both IPMNs were found to have KRAS codon 12 mutations. The identification of KRAS mutations suggests a genetic pathway shared with IPMN of the pancreas. No mutations were identified in our heterotopic PanINs. One of the possible mechanisms for the development of dysplasia in these lesions is field effect. At the time of these resections there was no clinical or pathologic evidence of a prior or concomitant pancreatic lesion. However, a clinically undetectable lesion is theoretically possible. Therefore, while a field effect cannot be excluded, there was no evidence for it in this study.

Diversity of Precursor Lesions For Pancreatic Cancer: The Genetics and Biology of Intraductal Papillary Mucinous Neoplasm

“…At the microscopic level, there is a “gray area” presented by intermediate sized lesions (between 5 and 10 mm) for which pathologists have recently proposed the term “incipient IPMN”. 26 , 27 , 28 Overall, the considerable overlap between PanINs and early IPMNs is one of the key issues of debate at present in the clinical community. For example, it remains unclear whether lesions fated to become IPMN arise de novo or whether IPMN arise from early PanIN lesions, or whether both scenarios exist.…”

Targeting reactive oxygen species in development and progression of pancreatic cancer

“…Most cases of PDA develop from precursor lesions known as pancreatic intraepithelial neoplasia (PanIN) [17]. Besides PanIN, other precursor lesions that are present in the pancreas include mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs) [18].…”

Nesidioblastosis Associated with Pancreatic Heterotopia as a Differential Diagnosis of Hypoglycemia: A Literature Review and Case Report

“…The cause is unknown, although migration failure is believed to occur with fragments of pancreatic tissue dispersed throughout the gastrointestinal tract during embryogenesis, developing into an isolated topography of the main pancreatic gland [ 26 ]. This tissue, although ectopic, has the same risk of topic pancreas to development of benign and malign lesion, with reports of pancreatic adenocarcinoma and intraepithelial neoplasm [ 27 ].…”