Intraductal neoplasms of the pancreas: Current concepts and controversies regarding definitions, evolving classifications, diagnostic challenges and clinical significance.

Intraductal neoplasms of the pancreas encompass a spectrum of epithelial proliferations within the pancreatic ductal system and are broadly classified into flat-type and mass-forming lesions. Flat-type neoplasms, such as pancreatic intraepithelial neoplasia (PanIN), consist of microscopic epithelial changes, whereas mass-forming intraductal neoplasms-including intraductal papillary mucinous neoplasm (IPMN), intraductal oncocytic papillary neoplasm (IOPN), and intraductal tubulopapillary neoplasm (ITPN)-produce clinically or radiologically detectable ductal dilatation or cystic masses. Both categories represent important precursors to invasive pancreatic carcinoma, and accurate classification, grading, and distinction between pseudo-invasion and true invasion remain critical for patient management and prognostication. Gastric-type IPMNs, most often arising in branch ducts, tend to exhibit indolent behavior. Intestinal-type IPMNs, typically involving the main duct and characterized by MUC2 and CDX2 expression, carry a higher risk of progression to invasive colloid carcinoma, which generally has a more favorable outcome. Pancreatobiliary-type IPMNs frequently involve the main duct, express MUC1 and MUC5AC, and more commonly progress to tubular invasive carcinoma resembling pancreatic ductal adenocarcinoma. IOPN and ITPN constitute distinct mass-forming intraductal neoplasms. IOPN typically presents as a large cystic lesion with complex papillary architecture and demonstrates recurrent PRKACA or PRKACB fusions. ITPN is defined by its predominantly tubular growth pattern, mucin-poor phenotype, and absence of MUC5AC expression. Both entities are associated with favorable outcomes following complete resection. Recognition of these intraductal neoplasms is essential, as they must be distinguished from other cystic pancreatic lesions such as mucinous cystic neoplasm (MCN), which is defined by its characteristic ovarian-type stroma.