"Simple Mucinous Cysts" associated with pancreatic ductal adenocarcinoma: clinicopathologic and radiologic characterization of an enigmatic cyst and additional evidence for its possible pre-cancerous nature.

Simple mucinous cyst (SMC), previously also termed mucinous non-neoplastic cyst, is now recognized as a separate category in the WHO Classification of Pancreatic Tumours. Recent studies have increasingly identified malignancy-associated molecular alterations, high-grade dysplasia (HGD), and even cases of PDAC arising in SMC. We aimed to define the radiologic and pathologic characteristics of this rare entity and to investigate its association with PDAC by analyzing findings from 920 consecutive cases.SMCs were identified in 15 of 920 PDACs (1.6%); together with 7 additional unpublished SMCs, a total of 22 cases were analyzed. Radiologically, SMCs were typically solitary, unilocular, well-circumscribed, round-to-oval cysts with thin, often enhancing walls. They lacked features of IPMNs such as main duct communication (commonly showing a visible separation from the main duct) and cyst-by-cyst architecture. A distinctive feature was their frequent protrusion into the peripancreatic fat. Histologically, SMCs showed a paucicellular fibrous wall lined by mucinous epithelium, often with epithelial denudation. All cases exhibited cytologic atypia. Among the 7 non-PDAC SMCs, four harbored HGD, with a mean cyst size of 2.4 cm. PDAC-associated SMCs were all adjacent to the carcinoma, lacked mural nodules, and had a mean cyst size of 2.7 cm; HGD was identified in 2 of 15.This study further characterizes the pathologic and radiologic phenotype classified as SMC in the 2026 WHO classification and identifies features that aid its distinction from conventional IPMNs, MCNs, secondary cysts, and other mimics. The occurrence of SMCs in 1.6% of PDAC resections, their spatial proximity to PDAC, the presence of HGD, and previously reported cancer-related molecular alterations provide additional evidence that SMC is likely a pre-cancerous lesion, closely related to yet distinct from other pancreatic precursors. Further studies, including clonality analyses, are needed to determine whether associated PDACs develop through sequential progression from SMC, through a branch-off pathway, or independently in the same patient. Until the natural history and molecular relationships of SMC are clarified, management within the broader framework used for mucinous pancreatic cysts appears prudent.