‘UNMIXING’ Mixed-Type Intraductal Papillary Mucinous Neoplasms–Rethinking Malignancy Risk Beyond Radiological Appearance

OBJECTIVE: To determine the rate of malignancy in radiologically classified mixed-type intraductal papillary mucinous neoplasms (IPMNs) undergoing surgical resection compared to main-duct (MD) and branch-duct (BD) IPMNs. BACKGROUND: Mixed-IPMNs are widely perceived as high-risk lesions; however, limited and heterogeneous data available on this category raise uncertainty regarding their true risk profile. METHODS: Retrospective analysis of 836 consecutive resected IPMNs (2000-2025) from a prospectively maintained single-institution database. IPMNs were classified and compared based on preoperative imaging. Malignancy was defined as high-grade dysplasia or invasive carcinoma. RESULTS: Of 773 patients who met inclusion criteria, 305 (39.4%) had a radiologically defined mixed-IPMN, 135 (17.5%) MD-IPMN, and 333 (43.1%) BD-IPMN. Malignancy was observed in 46.5% of mixed-IPMNs (142/305), 79.2% MD-IPMNs (107/135), and 33.9% BD-IPMNs (113/333). The rate of invasive carcinoma was 19.0% (58/305) in mixed-IPMNs and 45.9% (62/135) in MD-IPMNs ( P <0.001). In the absence of high-risk stigmata, the malignancy rate of mixed-IPMNs decreased to 24.7% (46/186), and did not differ from that of BD-IPMNs (51/252, 20.2%; P =0.263). Moreover, when main pancreatic duct (MPD) dilatation was the single worrisome feature, the malignancy rate was 6.3%, with risk increasing significantly only in the presence of multiple worrisome features or when MPD dilatation reached 7-8 mm. Furthermore, in one-third of radiologically defined mixed-IPMNs (103/305), final pathology revealed no MPD involvement. CONCLUSIONS: Mixed-IPMNs are highly heterogeneous and have a lower malignancy rate than previously reported in resected cohorts. In the absence of high-risk stigmata, most lesions are benign, highlighting limitations of current risk stratification and selection for surgery.