Insights into the Pathogenesis of Pancreatic Cystic Neoplasms

Abstract

With the current epidemic of diagnosed pancreatic cystic neoplasms on the rise, a substantial amount of work has been done to unravel their biology, thus leading to implications on clinical decision making. Recent genetic profiling of resected human specimens has identified alterations in signaling pathways involving KRAS and GNAS signaling as early events in the pathogenesis of intraductal pancreatic mucinous neoplasms. Progressively, mutations in genes such as TP53, SMAD4, RNF43, and others are thought to characterize invasive and advanced lesions. The role of inflammation in fueling the growth and transformation of these cysts has also begun to be studied with greater interest. A number of promising clinical studies have attempted to integrate these genetic insights into classifying these cysts and treating patients. We have reviewed existing literature on similar lines besides commenting on some useful animal models that recapitulate molecular and phenotypic progression of these cysts.

Keywords: GNAS; Intraductal pancreatic mucinous neoplasm; KRAS; Mucinous cystic neoplasm; Pancreatic cystic neoplasms; RNF43; Serous cystadenoma.

Figure 1

Figure 1A. Mutational pathogenesis of IPMN. IPMNs are believed to arise from pancreatic ductal cells which acquire a mutation in either KRAS or GNAS in most cases. Intestinal IPMNs tend to have a higher frequency of GNAS mutations compared to pancreatobiliary IPMNs which give rise to colloid and tubular forms of invasive cancer respectively. The progression from a low grade lesion to an invasive phenotype occurs through accumulation of mutations in RNF43, P16/INK4A, SMAD4 and TP53. Figure 1B. Mutational pathogenesis of MCN and SCN. Most Mucinous cystic adenomas harbor early KRAS mutation and malignant lesions accumulate abnormalities in TP53 and SMAD4. Serous cystadenomas result from an abnormalities (either LOH or allelic deletion) in VHL gene.