Clinical implications of the molecular characterization of intraductal papillary mucinous neoplasms of the pancreas

Abstract

Intraductal papillary mucinous neoplasm (IPMN) is a pre-malignant, mucin-producing epithelial lesion arising from pancreatic ducts. Observational reports define IPMN behavior as ranging from indolent, asymptomatic lesions to dysplasia that sometimes degenerate into pancreatic adenocarcinoma. The goal of IPMN management is riskreducing surgery for high-risk cysts and observation of the remainder. Discriminating high-from low-risk IPMN disease still relies on imaging and clinical cyst characteristics. Here, we review the accepted classification of IPMN including the most common histological subtypes, their clinical features, and currently-accepted high-risk phenotypes. We then deeply examine the known molecular landscape of IPMN, which has largely been derived from post-resection analysis. This includes those gene variants unique to IPMN, chiefly GNAS and RNF43, but also examines the overlap between IPMN and conventional pancreatic adenocarcinoma. Utilizing molecular markers in the clinical setting relies on endoscopically-obtained cyst fluid and presumes that it accurately represents the molecular characteristics of the cystic epithelium. We synthesize existing data on mutational analysis from IPMN cyst fluid and consider the benefits and proper role of current commercially-available cyst fluid molecular analysis kits. We conclude that carefully interpreted molecular analysis of resected IPMN tissue reveals insights into its biology and natural history while cyst fluid analysis offers prognostication and data to guide treatment decisions. However, knowledge gaps remain, especially in characterizing IPMN molecular heterogeneity, time to progression, and correlating cyst fluid genotype data with surveillance strategies. As such, substantial additional research is required before the promise of true molecular guidance of IPMN management can be realized.

Digital spatial profiling of intraductal papillary mucinous neoplasms: Toward a molecular framework for risk stratification

“…Mutations such as TP53, CDKN2A, SMAD4, and others may be predictors of HGD or invasive carcinoma when present, but their prevalence is relatively low, and the sensitivity is limited. Numerous studies have proposed possible mRNA, microRNA, and protein biomarkers for high-risk IPMN, but to date, none has been incorporated into clinical use because of prognostic inaccuracies (13)(14)(15)(16)(17)(18).…”

Digital Spatial Profiling of Intraductal Papillary Mucinous Neoplasms: Towards a Molecular Framework for Risk Stratification

“…Mutations such as TP53, CDKN2A, SMAD4, and others may be predictors of HGD or invasive carcinoma when present, but their prevalence is relatively low, and the sensitivity is limited. Numerous studies have proposed possible mRNA, microRNA, and protein biomarkers for high-risk IPMN, but to date none has been incorporated into clinical use due to prognostic inaccuracies (13)(14)(15)(16)(17)(18).…”

Telemedicine and intraductal papillary mucinous neoplasms: Analysis of a new follow-up strategy during COVID-19 outbreak

“…IPMNs are mucin-filled dilated ducts lined with neoplastic cells forming papillae with a diverse range of morphologies and varying grades of atypia 10 . Since described in 1996 by the World Health Organization, the understanding of its histopathologic features and the prevalence of associated invasive pancreatic adenocarcinoma has been the main objective of the different studies 11 . IPMNs have risk of malignant transformation, ranging from 19% to 30% in branch-duct IPMN (BD-IPMN) and as high as 40% to 60% in main-duct IPMN (MD-IPMN) 12 .…”