Clinicopathological Characteristics and Molecular Analyses of Multifocal Intraductal Papillary Mucinous Neoplasms of the Pancreas

Abstract

Objective To examine the clinicopathologic features and clonal relationship of multifocal intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Background Intraductal papillary mucinous neoplasms are increasingly diagnosed cystic precursor lesions of pancreatic cancer. Intraductal papillary mucinous neoplasms can be multifocal and a potential cause of recurrence after partial pancreatectomy. Methods Thirty four patients with histologically documented multifocal IPMNs were collected and their clinicopathologic features catalogued. In addition, thirty multifocal IPMNs arising in 13 patients from 3 hospitals were subjected to laser microdissection followed by KRAS pyrosequencing and loss of heterozygosity (LOH) analysis on chromosomes 6q and 17p. Finally, we sought to assess the clonal relationships among multifocal IPMNs. Results We identified 34 patients with histologically documented multifocal IPMNs. Synchronous IPMNs were present in 29 patients (85%), whereas 5 (15%) developed clinically significant metachronous IPMNs. Six patients (18%) had a history of familial pancreatic cancer. A majority of multifocal IPMNs (86% synchronous, 100% metachronous) were composed of branch duct lesions, and typically demonstrated a gastric-foveolar subtype epithelium with low or intermediate grades of dysplasia. Three synchronous IPMNs (10%) had an associated invasive cancer. Molecular analysis of multiple IPMNs from 13 patients demonstrated nonoverlapping KRAS gene mutations in 8 patients (62%) and discordant LOH profiles in 7 patients (54%); independent genetic alterations were established in 9 of the 13 patients (69%). Conclusions The majority of multifocal IPMNs arise independently and exhibit a gastric-foveolar subtype, with low to intermediate dysplasia. These findings underscore the importance of life-long follow-up after resection for an IPMN.

Intraductal papillary mucinous neoplasms and mucinous cystadenomas: current status and recommendations

“…Moreover, the loss of expression of p16/CDKN2, CDKN1C and ppENK may also be observed in these lesions (39). Recently, several studies (40)(41)(42) have demonstrated the presence of GNAS (mainly in the intestinal subtype) and/or KRAS (pancreatobiliary subtype) mutations in up to 96% of IPMNs. GNAS mutations have become a promising diagnostic tool, as they seem to be selectively present in IPMNs and, consequently, absent in MCAs.…”

Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation

“…Prognostically, PanIN-derived PDA is an aggressive disease associated with an average survival of 6 mo after diagnosis, usually due to late diagnosis. In contrast, IPMN-derived PDA is more indolent, with a 5-year survival after surgical resection approaching 50% (Poultsides et al 2010;Mino-Kenudson et al 2011;Matthaei et al 2012). Thus, understanding the key differences in signals that regulate PanIN and IPMN formation is essential for prognostic and predictive biomarker development schemes that will in turn lead toward personalized therapy.…”

Pancreatic cancer from bench to bedside: molecular pathways and treatment options

“…Due to more frequent and better diagnostic imaging as well as physicians' awareness, IPMN lesions are increasingly identified in the pancreas, the ideal management of these patients is still an ongoing debate (62). It has been observed that pancreatic cancer that is associated with IPMNs has a much more favorable prognosis than pancreatic cancer that arises from PanINs (63)(64)(65). A possible explanation could be different genetic mutations during evolution of pancreatic cancer from its precursors.…”