Bridging the intraductal papillary mucinous neoplasm risk stratification gap: A critical review of current and emerging biomarkers

Intraductal papillary mucinous neoplasms (IPMNs) are the most common cystic precursor to pancreatic ductal adenocarcinoma. However, current clinical guidelines do not sufficiently distinguish indolent lesions from high-grade dysplasia or invasive carcinoma. The existing risk stratification frameworks are either sensitivity-focused (e.g. , International Association of Pancreatology, European, American College of Gastroenterology) or specificity-oriented (e.g. , American Gastroenterological Association). They must balance the risk of missed cancer against substantial overtreatment. Therefore, numerous diagnostic and prognostic biomarkers have been investigated, including cyst fluid carcinoembryonic antigen, cytology, next-generation sequencing panels, cytokines such as interleukin 1β and prostaglandin E2, glycoproteins such as carbohydrate antigen 19-9 and mucin 5AC, and cell-surface markers such as Das-1. Although several markers were promising in early studies, their performance has been limited by small cohorts, surgically-enriched populations, inconsistent histopathologic endpoints, frequent pooling of high-grade dysplasia and invasive carcinoma, and heterogeneous sample platforms. Few biomarkers have undergone rigorous multicenter validation or cost-effectiveness assessment, and many require technically complex workflows that limit widespread adoption. This critical review summarizes the current evidence and delineates the methodological, biological, and translational barriers that impede accurate IPMN risk stratification. We also identify key pitfalls in the biomarker literature and outline the priorities necessary to bridge the gap between early proof-of-concept studies and clinical integration into IPMN management.