Pancrea'cCys'cLesionsGuidelines:toadoptortoadapt?

FILIPEVILASBOASGastroenterologyDepartment,CentroHospitalardeSãoJoão,Porto

filipe.vboas.silva@gmail.com

Toadapt!

Pancrea4cCys4cLesionsGuidelines:

toadoptortoadapt?

Agenda

•  Importanceoftheproblem

•  Importanceoftrustworthyguidelines

•  Currentguidelines•  Maindifferencesbetweenguidelines:

–  Imagingmodali4es

–  Indica4onsforEUS-FNA– Cystfluidmarkers/newendoscopicmodali4es

–  Indica4onsforsurgery– Surveillance

MCNSCA

PC SB-IPMN

TheproblemofPancrea4cCys4cLesions

AbdominalMRIPreven4vemedicalcare(Germany)

(n=2803;1821men;meanage51years)

2.5%

De Jong et al. Clin Gastroenterol Hepatol 2010 Changetal.Medicine2016

AbdominalCTHealthscreenexam2003-2013(Seoul,Korea)

(n=21745;60%men;meanage58.7years)

2.1%

ClinicalImportance

MunigalaSetal,GastrointestEndosc.2016

Retrospec4velongitudinalcohortstudy

PancCystsCT/MRIN=755ptsVscontrolwithoutcystsN=520215FU1998-2007.

IncidencerateofPaCawas5.08and.32

per1000pa4ent-years

HRPaCainallpa4entswithcystswas

19.64(95%CI,12.12-31.82;P<.0001)

ClinicalImportance

•  Malignancyoccursvirtuallyonlyinmucinouscysts;

•  Most(~60%)incidentalPCLsareBD-IPMNs

•  IPMNcanprogressfromlowertohighergradesofdysplasiaand,ul4mately,PDAC;

•  IPMNsonsurveillance:112invasivecancersin3980pts(37caseseries)over14380person-yearsFU

–  2.8%overall,0.72%peryear

ShimizuYetal.Pancreas.2013

ScheimanJMetal.Gastroenterology.2015

Guidelines

“Eminence-based” “Evidence-based”

Development Singleindividual

smallgroupexpertsGroupprocess

Conflictsofinterest Strongrisk DisclosureofCOI

Point(s)ofview Riskofdomineering

personali4esCollec4veprocess

Cost Cheaper Expensive

Methods ??

Delphimethod

ModifiedDelphitechnique

Nominalgroup

NIHconsensusconference

NimishVetal.AmJGastroenterol2011

•  Developmentofreliableguidelines:

•  Keypriorityforhealthcareproviders•  Promotebestcareforpa4ents

Guidelines

European2018

ACG2018AGA2015

RevisedFukuoka2017

Italian2014

Toomany...Confusing…Howtochoosewhichtofollow?

Cys4clesionsGuidelines

Broadlyconcordant •  MD-IPMNs,mixed-IPMNsand

SPNs…à  SURGERY

•  MCN:nomalignancyifø<4cmandnomuralnodule

•  Enhancingsolidnodule/definitesolidnodule≥5mm/+cytology/MPD≥10mm

•  SCA:Noneedofresec4onorsurveillance(exceptsymptoma4c)

DiscordantinBD-IPMNs…•  EUSIndica4ons

•  Impactofcystsize

•  Thresholdforsurgery

•  Surveillanceintervalsandcessa4on

Reasonsforthecontroversy…

•  Dificulttodevelopguidelineswithoutunderstandingthenaturalhistoryofdisease;

•  Lowqualityofevidence;

•  Keylimita4onofmostofavailableguidelines:– Managementbasedonknowledgeofcysthistology

–  Focusedoncystcharacteris4csratherthanthepa4entandtheirul4mateprognosis

•  Alwaysconsidertheauthorsandthemethods

SeveralSurgeons,

Gastroenterologists,

Radiologists,

Pathologists

Europe

Considertheauthors…

4Gastroenterologists

NorthAmerica

7Surgeons

3Pathologists

2Oncologists

2Gastroenterologists

America/Asia/Europe

Considerthemethods…

AppraisalofGuidelines,ResearchandEvalua4oninEurope(AGREE)IIinstrument.

FalconiMetal.Pancreatology2015

Allguidelines:scoreslowerthantheminimumAGREE

standardizedscoreregardingRigorofDevelopment

Considerthemethods…

Guideline Consensusprocess

ICG-RevisedFukuoka2017 ConsensusSymposium

AGA2015 GRADEframework

European2018 GRADEframework

ACG2018 GRADEframework

Italian2014 Delphiprocedure;Oxfordcriteria

hqp://www.gradeworkinggroup.org/

GRADE:GradingofRecommenda4onsAssessment,DevelopmentandEvalua4on

Maintopics…

•  Ini4alassessment:Imagingmodali4es

•  Indica4onsforEUS-FNA•  Cystfluidmarkers/Newdiagnos4cmodali4es

•  Indica4onsforsurgery•  Surveillance:– How?–  Interval?– Forhowlong?

Imagingmodali4es

Guideline Imagingrecomenda'onICG(RevisedFukuoka2017)

Pancrea4cprotocolCTorMRCPforcysts>5mmsize

AGA2015 MRI

European2018 MRI-MRCPand/orCT

ACG2018 MRIorCT

Italian2014 MRI-MRCPand/orCT

Indica4onsforEUS-FNA

Guideline EUS-FNAICG(RevisedFukuoka2017) *Worrisomefeatures

AGA2015 **≥2high-riskfeaturesEuropean2018 Clinicalorradiologicalfeaturesofconcern;

HyperenhancementonCH-EUS

ACG2018 Cystsinwhichthediagnosisisunclear,andwherethe

resultsarelikelytoaltermanagement

Italian2014 “suspicious”morphologicalfeaturesoruncertain

radiologicdiagnosis

*Worrisomefeatures:pancrea44s,cyst≥3cm,enhancingmuralnodule<5mm,thickened/enhancingcystwalls,mainductsize

5-9mm,abruptchangeincaliberofpancrea4cductwithdistalpancrea4catrophy,lymphadenopathy,

increasedserumCA19-9,cystgrowthrate>5mm/2years

**AGAHigh-riskfeatures:dilatedMPD(≥5mm),≥3cmcystornon-enhancingsolidcomponent

EUS-FNA

•  Diagnosemainductinvolvement

•  Confirmasolidcomponent

•  Diagnosehigh-gradedysplasiaorcancer

•  Cyststhathaveclearindica'onforresec'onbasedonimaging/symptomsdonotneedEUS!

EUS-FNA

Retrospec4vecohortstudy

210ptswithPCLshadEUS2004-2015.

Therequirement≥2HRFwouldhave

decreasedthenumberofEUS

proceduresby91%,butreducedthesensi'vityforpancrea'cmalignancyto50%.

DivyanshooRetal.SurgEndosc.2018

CystFluidAnalysis/Newmodali4es

Guideline CEA Biochemistry Cytology Molecularanalysis

Comments

ICG(RevisedFukuoka2017) M amylase inves4ga4onal

KRAS/GNAS

Inves4ga4onal

EUS-FNAfor

citologyand

molecular

iss4ll

considered

inves'ga'onal

AGA2015 R R Inves4ga4onal

European2018 R Lipase RKRAS/GNAS

(condi4onal)

Brushcitologyandforcepsbiopsynot

recommended

ACG2018 R - RNotreadyfor

clinicalprac4ce

Brushcitology

andforceps

biopsynot

recommended

Italian2014 R amylase R -

CA19.9when

CEA

indeterminate

R:recommended;M:men4oned;-notmen4oned

CystFluidAnalysis

•  CEA:–  Level≥192ng/mLdis4nguishesmucinous,fromnon-mucinouscysts(Sens75%;Spec84%)

–  Inaccuratetopredictgrade!

•  Cytology:– Meta-analysis:42%Sens;99%Specdifferen4a4ngmucinousvsnon-mucinous

•  KRAS/GNAS/othermolecularmarkers–  Costlyandmaynotaddtostandardanalysis!

GillisAetal.HPB(Oxford)2015

NgamruengphongSetal.DigLiverDis.2013

BruggeWRetal.Gastroenterology2004

Vilas-BoasFetal.JClinGastroenterol.2018

•  Through-the-needleforcepsbiopsy(Moray-USEndoscopy)

•  ContrastEnhancedEndoscopicUltrasound

•  Cytologybrush(Echobrush®)

•  Needlewithsidefenestra4on(Procore–Cook)

•  CystoscopyandPancreatoscopy(Spyglass®)

•  ConfocalLASEREndomicroscopy(nCLE)

Surgery

Guideline Symptoms MPD Muralnodule

Posi'vecitology Size Comments

ICG(RevisedFukuoka2017)

+

jaundice≥10mm

+

5mmcut-off+ -*

HRS,

Considerlifeexpectancy,

comorbidi'esandloca'on

AGA2015 NA dilated + + -**and/or2

features

European2018

+

Jaundice,

acute

pancrea44s

≥10mm

(5-9.9mm

rela4ve

indica4on)

+

5mmcut-off+

≥4cm

(rela4ve

indica4o

n)

Growthrate≥5mm/year,new-

onsetDM

elevatedCA19.9

ACG2018

+

Jaundice,

acute

pancrea44s

≥5mm + +≥3cm

Growthrate≥3mm/year,new-

onsetDM

elevatedCA19.9

Italian2014 + ≥10mm + +

Familyhistory(≥2firstdegree

rea4ves*cystsizealoneisnotanappropriateparametertoindicatesurgeryBUTconsidersurgery>2cm,youngfitpts

**posi4vecitologyand/orbothsolidcomponentandMPDdila4on

IPMNs:Individualizeddecision...

Considerthepa'ent!!!

EuropeanGuidelines

Del-ChiaroMetal.Gut.2018

Preemp4vesurgeryCancersurgery

ConsiderIPMNnaturalhistory…

Retrospec4veMul4centricstudy

N=281elderyIPMNpts(BD159;MD122)(231WF;50HRS)Medianage:70yrs

MedianFU51months.

IPMNsWF:5-yearDSSis96%àconserva4ve

management!

IPMNsHRS:40%riskofIPMN-relateddeath.

reinforcingthatsurgicalresec4onshouldbe

offeredtofitpa4ents

CrippaSetal.Gut.2017

5-yearDSS:97%

5-yearDSS:60%

Pa4ent-orientedPCNManagement

Retrospec4vecohort(2005-2010)

N=1800ptswithPCNs;MedianFU=5.7yrs

Stra4fiedbasedonCharlsoncomorbidityindexandbaselinecystfeatures

402deaths–22%(43pancca;359non-pancrea'c)

Pa4ent-relatedfactors+cystfeaturesàhelp

guidePCNmanagement

KwokKetal.AmJGastroenterol.2017

IPMNs:importanceofgrowthrate...

KwongWetal.DigDisSci2015

Retrospec4veMul4centricstudy

N=284pts(BD-IPMNwithoutWForHRS)

FUmedian56months.

Growthrate≥5mm/year-->HR19.5(95%CI2.4-157.8)

Surveillance…mucinouscysts

Guideline Follow-upindica'ons Stopsurveillance

ICG(RevisedFukuoka2017)

<1cm–CT/MRin2-3years

1-2cm–CT/MRyearlyx2thenlengthenas

appropriate

*2-3cm–EUSin3-6monthsthenlengthenas

appropriate

*>3cm–MRI/EUSevery3-6monthsupto1year

Lifelong

(un4lnotfitforsurgery)

AGA2015 MRIa{eroneyearthenMRIevery2yearsStableappearanceaoer

fiveyears

European2018EUS/MRIandCA19-9a{ersixmonths

then

EUS/MRIandCA19-9yearly

Lifelong

(un4lnotfitforsurgery)

Intensifica'onaoer5yrs?

ACG2018 Cystsizeguidessurveillance

(similartoICG)

Whennotfitforsurgery,

assessu'lityinthose>75years

Italian2014 Cystsizeguidessurveillance

(similartoICG)Lifelong

*considersurgeryinyoungfitpa4entswithneedforprolongedsurveillance

Stopsurveillance?No!

CrippaSetal.AmJGastroenterol.2017

Retrospec4veMul4centricstudy

N=144pts(BD-IPMNwithoutWForHRS)withFU>5years(yearlyMRI/MRCP)

MedianFU84months.Rateofmalignancy2%;12yearDSS98.6%

New-onsetofWF/HRSin26pts(18%)aoermedianFU71and77.5months.Oneoutofsixpa4entsdevelopedWF/HRSbeyond5yearsofsurveillance.

Persistentsurveillanceisrequired.Indeed,closerfollow-upevalua'onsshouldbeconsideredaoer5yearsfromini'aldiagnosis.

Stopsurveillance?Maybe…

PergoliniIetal.Gastroenterology2017

Retrospec4veunicentricstudy

N=577ptsBD-IPMNundersurveillance

MedianFU82months.363ptssurveillance>5yrsOverall,45pa4ents(7.8%)developedpanc

malignancy,5ofthemaoer10yrsofFURiskofmalignancy,almost8%,lastedfor10years

ormore

Cyststhatremain1.5cmformorethan5yearsmightbeconsideredlow-risk

Whichguidelineshouldwefollow?

RevisedFukuoka AGA EuropeanThemostaggressive

towardsurgeryThemostconserva4ve

Themostaggressive

towardsurveillance

Leastlikelytomissa

malignancy

Higherpossibilityfor

missingamalignancyIndividualizeddecision

“Livewithunnecessarysurgery” “Livewithuncertainty” “Livewithexcessive

cost”

AdaptedfromTimothyB.Gardner,DDWClinicalSymposium2017

Take-Homemessages

•  Fullmul4disciplinarydiscussionupfront!!

•  Surgeryathigh-volumecenters!

•  Discusstheop4onswiththepa4ents

–  Alltheevidencerelatedtothemanagementofpancrea4ccystsisgradedasverylow

quality

–  Highrisks4gmatahavethehighestPPVformalignancy

•  Treatmentandsurveillancedecisions:

–  Decisiontoobservevsresecto{enremainsindividual

–  Considerlifeexpectancy,comorbidi4esandloca4on

–  Mostpa4entswilldiewiththecystratherthanfromit…

•  Strictadherencetoapar'cularguidelineisprobablynotthebestop'onàADAPT!!