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

Table 1 Clinical and morphological criteria defining features in intraductal papillary mucinous neoplasm management guidelines

	Clinic			Serology	Cytology	Morphology
	Jaundice	Acute pancreatitis	New-onset diabetes	CA19-9 (≥ 37 U/mL)	HGD/MLG	MPD > 10 mm	MPD 5-9.9 mm	Mural module > 5 mm	Mural module < 5 mm	Solid component	Cyst size	Wall enlargement	Lymphadenopathy	Growth rate
International evidence-based Kyoto guidelines	HRS	WF	WF	WF	HRS	HRS	WF	HRS	WF	HRS	WF (≥ 30 mm)	WF	WF	WF (≥ 2.5 mm/year)
European evidence-based guidelines	AI	RI	RI	RI	AI	AI	RI	AI	RI	AI	RI (≥ 40 mm)	NA	NA	RI (≥ 5 mm/year
AGA	NA	NA	NA	NA	CF	HRF (size not specified)		NA	NA	HRF	HRF (≥ 30 mm)	NA	NA	NA
ACG	HRC	HRC	NA	HRC	HRC	HRC	HRC	HRC	HRC	HRC	HRC (≥ 30 mm)	NA	NA	HRC (≥ 3 mm/year)

CA19-9: Carcinoembryonic antigen 19-9; HGD: High-grade dysplasia; MLG: Moderate-grade dysplasia; MPD: Main pancreatic duct; AGA: American Gastroenterological Association; ACG: American College of Gastroenterology; HRS: High-risk stigmata; AI: Absolute indication; NA: Not available; HRC: High-risk characteristic; WF: Worrisome feature; RI: Relative indication; CF: Concerning features; HRF: High-risk feature.

Table 2 Real world clinical accuracy and key tradeoffs for different intraductal papillary mucinous neoplasm management guidelines

Guideline family	Sensitivity	Specificity	Key trade-offs	Ref.
Kyoto 2024 (IAP)	100%	20%	Pros: Almost no missed HGD/IC	[18]
			Cons: Very high overtreatment; many surgeries for low-grade IPMN; increases morbidity and costs
IAP/Fukuoka 2017 (≥ 1 WF or HRS)	90%-98%	16%-45%	Pros: Captures most HGD/IC; strong safety margin	[20]
			Cons: Over-calls risk; many unnecessary resections; psychological burden and repeated EUS/imaging for WF
European Evidence-Based 2018	94%-96%	24%	Pros: Good detection of high-risk disease; harmonized with European practice	[20]
			Cons: Low specificity → high surgical rates and overtreatment risk
AGA 2015	27%-62%	77%-91%	Pros: Few unnecessary surgeries; high specificity avoids morbidity and cost	[20]
			Cons: Substantial risk of missing HGD/IC (up to 45% may be missed in some cohorts); unsafe for high-risk IPMN
ACG 2018	Moderate-high (IAP-like)	Low-moderate	Pros: Good capture of advanced disease; cyst-type-specific guidance; clinically usable algorithms	[19]
			Cons: Still low specificity; many patients undergo EUS-FNA or resection unnecessarily
ACR 2017 (imaging-driven)	High (IAP-like)	Low-moderate	Pros: Easy to apply in imaging-first workflows; high sensitivity	[20]
			Cons: Overdetection leads to frequent EUS and surgeries; less nuanced than GI-society guidelines

IAP: International Association of Pancreatology; HGD/IC: High-grade dysplasia/invasive carcinoma; IPMN: Intraductal papillary mucinous neoplasm; HRS: High-risk stigmata; EUS: Endoscopic ultrasound; WF: Worrisome feature; AGA: American Gastroenterological Association; ACG: American College of Gastroenterology; FNA: Fine-needle aspiration; ACR: American College of Radiology; GI: Gastrointestinal.

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.