Pancreatic Intraepithelial Neoplasia in Association With Intraductal Papillary Mucinous Neoplasms of the Pancreas

Abstract

The development of pancreatic cancer (PC) several years after curative resection for noninvasive intraductal papillary mucinous neoplasm (IPMN) and the presence of PC distant from IPMN suggest that PC may develop independently of the IPMN. Here, we identified pancreatic intraepithelial neoplasia (PanIN) lesions, the putative precursors of PC, in the ducts of pancreata resected for IPMN and assessed the frequency of molecular aberrations common to PanIN and PC, within these lesions. The protein expression of p53, p21(WAF1/CIP1), cyclin D1, p16(INK4A) and DPC4/Smad4 were examined by immunohistochemistry in 267 PanIN lesions from a cohort of 23 patients with IPMN. Overexpression of p21(WAF1/CIP1) was present in PanIN-1A and -1B lesions and increased in frequency in PanIN-2 and PanIN-3. Overexpression of p53 and cyclin D1, and loss of p16(INK4A) expression were detected in PanIN-2 and PanIN-3 lesions. Loss of DPC4/Smad4 expression occurred only in the PanIN-3 lesions. PanIN lesions that were more dysplastic than the coincident IPMN were identified in 5 of 12 patients, and 2 of these contained a greater number of aberrations in protein expression than the IPMN. PanIN lesions seen in association with IPMN demonstrate molecular and histologic changes identical to PanIN lesions found in association with PC and, in some cases, are more advanced than the associated IPMN. These data suggest that PanIN lesions found in the ducts of a pancreas with IPMN may be relevant to the development of PC either coincident with IPMN or in the remnant pancreas after curative resection of IPMN.

Incidence of Synchronous and Metachronous Pancreatic Carcinoma in 168 Patients with Branch Duct Intraductal Papillary Mucinous Neoplasm

“…However, the pancreatic intraepithelial neoplasia (PanIN) lesions may play a crucial role in the pathogenesis of PC development occurring in the pancreas with BD-IPMN. PanIN lesions, especially PanIN-2 and -3, are widely believed to represent the putative precursors of PC [19,20,21]. PanIN lesions are reported to be found extensively in the ducts of resected pancreas harboring IPMN [19,22,23].…”

Significance of DNA methyltransferase-1 and histone deacetylase-1 in pancreatic cancer

“…Currently, there are no ideal markers that provide sufficient sensitivity and specificity in the clinic, making it difficult for early diag-nosis. Recently, pathologists raised the concepts that pancreatic intraepithelial neoplasias (PanINs) and intraductal papillary mucinous neoplasms (IPMNs) are precancerous lesions for pancreatic ductal adenocarcinoma (PDAC), providing new targets for studies on the initiation of pancreatic cancer (1)(2)(3). Several studies have focused on the molecular biology and histopathological changes associated with PanINs and IPMNs, and demonstrated their importance in the progression of pancreatic cancer (4)(5)(6)(7)(8).…”

p16, p21, and p53 proteins play an important role in development of pancreatic intraepithelial neoplastic

“…The authors showed a loss of this protein expression in 30% of the flat-lesions in pancreatic ducts without significant atypia (currently PanIN 1A), 27% of papillary lesions without significant atypia (now PanIN 1B), 55% of papillary lesions without atypia (now PanIN 2) and 71% of carcinoma in situ (now PanIN 3). In Biankin's study [20], the expression of p16 protein was present in 71% of normal pancreatic ducts, 74% of PanIN 1A, 76% of PanIN 1B, 61% of PanIN 2, 29% of PanIN 3, and only in 17% of invasive cancer cases. Based on the findings described in this study and the research carried out by Wilentz et al [19], Maitra et al [18], and Biankin et al [20], it can be concluded that inactivation of p16INK4a gene resulting in loss of p16 expression is common and can be regarded as an early indicator occurring in the development of pancreatic cancer.…”

“…In Biankin's study [20], the expression of p16 protein was present in 71% of normal pancreatic ducts, 74% of PanIN 1A, 76% of PanIN 1B, 61% of PanIN 2, 29% of PanIN 3, and only in 17% of invasive cancer cases. Based on the findings described in this study and the research carried out by Wilentz et al [19], Maitra et al [18], and Biankin et al [20], it can be concluded that inactivation of p16INK4a gene resulting in loss of p16 expression is common and can be regarded as an early indicator occurring in the development of pancreatic cancer. In addition, Maitra [18] stated that loss of p16 expression increased with increasing dysplasia in pancreatic ducts and preceded inactivation of p53 and DPC4.…”