Presumed Intraductal Papillary Mucinous Neoplasms in Individuals at High Risk for Pancreatic Cancer

IMPORTANCE Pancreaticcysticlesionsarecommonduringsurveillanceofindividualsathereditary riskforpancreaticcancer,butwhethertheirincidenceandprogressiondifferacrossgeneticrisk groupsremainsuncertain. OBJECTIVE Tocomparetheincidence,morphologiccharacteristics,andprogressionofpresumed intraductalpapillarymucinousneoplasms(IPMNs)inindividualsathighriskofPCacrosshereditary riskgroups. DESIGN, SETTING, AND PARTICIPANTS Thismulticentercohortstudywasconductedfrom January2016toDecember2025at25centersparticipatingintheItalianRegistryofFamiliesatRisk ofPancreaticCancer.Participantswereindividualsundergoingpancreaticsurveillancewithmagnetic resonanceimagingwithcholangiopancreatographyand/orendoscopicultrasonography. EXPOSURE Familialpancreaticcancerwithoutpathogenicgermlinevariantsvspathogenicgermline variant(PGV)carrierstatus,furthergroupedinto3predefinedcategories:PGV1(Peutz-Jeghers syndromeorCDKN2A sequencevariantcarriers),PGV2(BRCA2 orATM variantcarriers),andPGV3 (Lynchsyndrome–associatedgenesorBRCA1 orPALB2 variantcarriers). MAIN OUTCOMES AND MEASURES CumulativeincidenceofpresumedIPMNs,longitudinal changesinindexcystdiameterandmainpancreaticductdiameter,andprogressiontoworrisome featuresorhigh-riskstigmata.MultivariableCoxproportionalhazardsregressionwasusedto estimatehazardratios(HRs)forincidentIPMNs,adjustedforhereditaryrisk,age,sex,bodymass index,tobaccosmokingstatus,anddiabetes. Key Points Question Dotheincidenceandshort- termprogressionofpresumed intraductalpapillarymucinous neoplasms(IPMNs)differacross individualsgroupedbyhereditary pancreaticcancer(PC)riskfactorswho areundergoingsurveillance? Findings Inthiscohortstudyof1688 individualsathighriskofPCundergoing pancreaticsurveillance,cumulative incidenceofnewpresumedIPMNs,cyst growthtrajectories,andprogressionto worrisomefeaturesorhigh-riskstigmata didnotdiffersignificantlyacross hereditaryriskgroups. Meaning Thesefindingssuggestthat surveillanceofpresumedpancreatic cysticprecursorlesionsmaybeguided primarilybyimagingphenotypeand intervalchangeratherthangermline subgroupalone. RESULTS Among1688high-riskindividuals(medianage,56years[IQR,50-64years];1055women [62.5%]),496(29.4%)hadapresumedIPMN.Medianfollow-upfromenrollmentwas17months (IQR,0-36months).Atotalof1298participants(76.9%)didnothaveapresumedpancreaticcystat baseline,and124(9.6%)oftheseparticipantsdevelopedanincidentlesionduringfollow-up.Inthe complete-casemultivariableanalysisof1245participantsand123events,PGV1(adjustedHR[AHR], 1.82;95%CI,0.97-3.43),PGV2(AHR,0.81;95%CI,0.45-1.45),andPGV3(AHR,0.70;95%CI,0.34- 1.44)werenotassociatedwithincidentcystdevelopmentcomparedwithFPC,whereasolderage wasassociatedwithhigherincidence(AHRperyear,1.04;95%CI,1.02-1.05).Longitudinal trajectoriesofcystgrowth(time × groupinteraction:χ2 = 14.4;df = 15;P = .49)andmainpancreatic ductdiameter(time × groupinteraction:χ2 = 4.35;df = 15;P > .99)didnotdiffersignificantlyacross