Progression model of pancreatic carcinogenesis. Pancreatic intraepithelial neoplasia (PanIN) is an established precursor lesion of infiltrating pancreatic ductal adenocarcinoma that involves the normal ductal epithelium of the pancreas. PanIN lesions develop from normal acinar cells in the pancreas, probably as the result of an activating KRAS mutation, leading to the formation of a PanIN-1 lesion characterized by a tall columnar epithelium lining the duct system but with little nuclear atypia. The development of inactivating mutations in CDKN2A coincides with the progression of a PanIN-1 to a PanIN-2 lesion, characterized by loss of polarity, pseudostratification, papillary formations, and nuclear atypia. Inactivating mutations of TP53 and SMAD4 are late events and most often detected in PanIN-3 stage lesions. PanIN-3 lesions are recognized by their complete lack of polarity, marked nuclear atypia, high nuclear/cytoplasmic ratio, and pseudopapillary formation. Mutations in additional genes may also occur during PanIN formation that are not illustrated in this example.