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

Table 3 Clinical performance and key limitations of biomarkers relevant for intraductal papillary mucinous neoplasm risk stratification

Biomarker	Study design/cohort	Source	Endpoint definition	Sensitivity, %	Specificity, %	Key limitations	Ref.
NGS mutation panel (KRAS/GNAS + progressors)	Retrospective	Cyst fluid	Mucinous cyst advanced neoplasia	85	96	Retrospective design; complex NGS workflow; variant interpretation burden	[54]
NGS mutation panel (IPMN-specific)	Prospective	Cyst fluid	Mucinous cyst advanced neoplasia	84	92	Requires NGS infrastructure; not included in later meta-analysis	[54]
TP53 + PI3K pathway mutations	Retrospective	Cyst fluid	IPMN with advanced neoplasia	88	95	Limited cohort size; mutation prevalence dependent	[55]
Das-1 mAb	Retrospective	Tissue	High risk and malignant IPMN	85	95	Early cohort; limited external validation	[58]
Das-1 mAb	Retrospective	Cyst fluid	High risk and malignant IPMN	89	100	Small sample size	[58]
Das-1 mAb	Retrospective	Cyst fluid	High risk and malignant PCL	88	99	Included MCNs as well as IPMNs	[59]
Das-1 mAb (EV-based)	Case-control	Serum EVs	LGD vs HGD/invasive IPMN	82	40	Markedly reduced specificity in blood	[60]
Das-1 mAb (EV-based, HGD only)	Case-control	Serum EVs	LGD vs HGD IPMN only	100	30	Poor specificity; limited clinical utility	[60]
IL-1β	Retrospective	Cyst fluid	Low risk vs high risk lesions	79	95	Potential confounding by inflammation	[65]
IL-1β	Larger retrospective cohort	Cyst fluid	Low/moderate IMPN vs HGD/invasive IPMN	64.3	83.8	Lower sensitivity at higher cutoff	[66]
IL-1β + CA19-9	Retrospective	Cyst fluid + serum	Low/moderate IMPN vs HGD/invasive IPMN	27.5	100	Sensitivity too low for screening	[66]
PGE2	Retrospective	Cyst fluid	LGD vs HGD/invasive IPMN	63	79	Weak stand-alone performance	[69]
PGE2 + CEA	Retrospective	Cyst fluid	LGD vs HGD/invasive IPMN	78	100	Requires multi-marker testing	[69]
PGE2	Larger cohort	Cyst fluid	Low/moderate IMPN vs HGD/invasive IPMN	60.0	78.7	Modest predictive value	[66]
PGE2 + IL-1β	Retrospective	Cyst fluid	Low/moderate IMPN vs HGD/invasive IPMN	42.9	89.0	Limited incremental benefit	[66]
MUC5AC (EV-based)	Case-control	Serum EVs	LGD vs HGD/invasive IPMN	45	100	Single study; low sensitivity	[60]
MUC5AC (EV-based, HGD only)	Case-control	Serum EVs	LGD vs HGD/invasive IPMN	9	100	Extremely poor sensitivity	[60]

NGS: Next generation sequencing; IPMN: Intraductal papillary mucinous neoplasm; PI3K: Phosphoinositide 3-kinase; mAb: Monoclonal antibody; PCL: Plasma cell leukemia; MCN: Mucinous cystic neoplasm; EV: Extracellular vesicles; LGD: Low-grade dysplasia; HGD: High-grade dysplasia; IL: Interleukin; CA19-9: Carcinoembryonic antigen 19-9; PGE₂: Prostaglandin E2; CEA: Carcinoembryonic antigen; MUC5AC: Mucin 5AC.