The molecular pathology of precursor lesions of pancreatic cancer

It has become evident over the past decade that pancreatic ductal adenocarcinoma (PDAC) does not originate de novo, but rather, through a multistep progression that involves histologically defined precursor lesions. Three major subtypes of precursor lesions of PDAC have been identified to date, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN). PanINs constitute by far the most common precursor lesion, and are, by definition, microscopic in nature, while IPMNs and MCNs occur less frequently and are macroscopic (e.g., radiographically detectable) precursor lesions. In addition to the development of consensus histopathological criteria for the identification and classification of PDAC precursors, there has also been considerable progress made in characterizing the genetic alterations underlying these lesions. Elucidating the molecular pathology of precursor lesions has enabled a better understanding of the pathogenesis of early pancreatic neoplasia, and provided a seedbed for developing tools for early detection and chemoprevention of PDAC. The histopathology, molecular genetics as well as clinical implications and possible directions for future research of PanINs, IPMNs, and MCNs will be discussed in this chapter.