Characteristics and pathways for the development of intraductal papillary mucinous neoplasms of the pancreas

Abstract

Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are categorized into four distinct types: gastric, intestinal, pancreatobiliary, and oncocytic types. Each is associated with specific clinicopathological features. The aim of this study was to uncover the molecular mechanisms underlying the development of these types of IPMNs. We obtained 103 specimens with lesions of various types, including 49 gastric, 26 intestinal, 22 pancreatobiliary, and 6 oncocytic lesions, from 43 IPMNs, including 36 with multiple types. Comparative analysis was performed by targeted sequencing of 37 genes in the different lesion types within each pancreas. Gastric-type low-grade lesions were observed in all 36 tumors with multiple types, with 245 mutations identified across all samples. The average number of mutations was significantly different between different lesion grades and types including 1.88 for low-grade lesions, 2.77 for high-grade lesions, and 2.38 for invasive lesions. By type, there were 1.96 for gastric-type, 2.92 for intestinal-type, 2.73 for pancreatobiliary-type, and 2.17 for oncocytic-type lesions. Tracing the mutations between lesions containing multiple types in the same pancreas suggested three developmental pathways, denoted as "progressive", "divergent", and "independent". These findings suggest that gastric-type low-grade lesions have a risk of progression into high-grade lesions of other types. Therefore, patients with low-grade gastric-type IPMNs should be under constant surveillance.