CURRENT CONCEPTS IN 68Ga DOTATATE NEN IMAGING...

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CURRENTCONCEPTSIN68Ga‐DOTATATENENIMAGING:INTERPRETATION,

BIODISTRIBUTION,DOSIMETRYANDMOLECULARSTRATEGIES.

LisaBodei1,ValentinaAmbrosini2,KenHerrmann3,4andIrvinModlin5

1MolecularImagingandTherapyService,DepartmentofRadiology,MemorialSloanKettering

CancerCenter,NewYork,USA;

2NuclearMedicine,DepartmentofExperimentalDiagnosticandSpecializedMedicine,University

ofBolognaandS.Orsola‐MalpighiHospital,Bologna,Italy;

3DepartmentofMolecularandMedicalPharmacology,DavidGeffenSchoolofMedicineatUCLA,

USA

4KlinikfürNuklearmedizin,UniversitätsklinikumEssen,Essen,Germany;

5YaleUniversitySchoolofMedicine,DepartmentofSurgery,NewHaven,USA.

CorrespondingAuthor:

LisaBodei,MD,PhD

MolecularImagingandTherapyService

DepartmentofRadiology

MemorialSloanKetteringCancerCenter

1275YorkAvenue,Box77,NewYork,NY10065

T:212.639.5387F:212.717.5282

E:[email protected]

Runningtitle:CurrentConceptsin68Ga‐DOTATATEPET/CT

Wordcount:6702

Journal of Nuclear Medicine, published on August 17, 2017 as doi:10.2967/jnumed.116.186361by on January 10, 2020. For personal use only. jnm.snmjournals.org Downloaded from

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ABSTRACT

68Ga‐DOTATATEPET/CTprovidesinformationofthelocation(s)ofsomatostatinreceptor

expressingtumors.Integratingthisimagingdataeffectivelyinpatientcarerequirestheclinical

history,thehistopathologyandbiomarkerinformationaswellasgrade,stageandpriorimaging.

Previoustherapiesandtechnicalaspectsofthestudyshouldbeconsidered,giventheirabilityto

altertheinterpretationoftheimages.Thisincludesphysiologicbiodistributionoftheradiotracer,

aswellasconditionsthatengenderfalsepositiveresults.

ThisCMEdocumentprovidesaguidetotheperformanceandinterpretationof68Ga‐DOTATATE

PET/CTanddescribesitsroleinthediagnosticalgorithmofneuroendocrineneoplasms(NEN)

andisoverallutilityintheirmanagement.

by on January 10, 2020. For personal use only. jnm.snmjournals.org Downloaded from


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INTRODUCTION

Neuroendocrineneoplasmsexhibitvariablesymptomatology,suchastumormasseffectsorthe

biologicalconsequencesofthebioactiveaminesecretion,frequentlydelayingdiagnosis.Some

patientspresentwithsymptomsrelatedtoinappropriatepeptideoraminehypersecretion,but

themajorityofthesetumorsarenonfunctioning.Nonfunctioningtumorsareusuallydiscovered

whentheyarelarge,andhavemetastasizedtotheliver.Thus,eventhoughthelesionsaremostly

well‐differentiatedandslow‐growing,withaminorityofaggressiveforms,theoutcomemaybe

poorduetodiagnosticdelay(1).

SomatostatinreceptorimagingoffersanopportunitytoidentifyreceptorexpressingNENs(2)(3).

Radiolabeledsomatostatinanalogs(SSA)wereintroducedinthe1980sforimagingof

NENs(4,5)(Figure1).

CLINICALSCENARIOOFNENs

NENsarerelativelyraretumorsoriginatingfromubiquitousneuroendocrinecells

distributedthroughoutthebody.Thesecellssynthesize,store,andsecretevariouscirculating

hormonesandneurotransmitters(Table1)(6).

NENsconstitute0.66%ofallmalignanciesintheUnitedStates,accordingtotheSurveillance,

Epidemiology,andEndResults(knownasSEER)database,containing48.195NENs(1970‐2006),

withanincidenceincreasingatarateof3‐10%peryear(7).Thisincrementisrelatedtothe

introductionofmoresensitivediagnostictools,andtoanincreasedawarenessbycliniciansand

pathologists(1,8).TheprevalenceofNENsissubstantialgiventheoftenindolentnatureofthe

diseaseprocess.Themajority(66%)ariseinthethegastro‐entero‐pancreaticarea,while25%



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occurinthelung(7).Therecognitionthattheprevalenceasagastrointestinalcancerisonly

exceededbythatofcoloncancerhasincreasedfocusontheproblem(1).

LessfrequentformsofNENsincludepheochromocytoma,paraganglioma,medullary

thyroidcarcinoma,andneuroblastoma.Pheochromocytomaandparagangliomasderivefrom

sympatheticchromaffintissueintheadrenalmedullaandfromtheextra‐adrenalparaganglial

systemofthethoraxandabdomen(9).Thefrequentmalignantpropensityofthesetumors

reflectsthegeneticbackground.Over50%oftumorsareduetogeneticalterations(10).

Pheochromocytomaexhibitsanoverallincidenceof0.8cases/100,000/yearover30yearsinthe

whitepopulation,accordingtotheRochesterEpidemiologyProject(11).

CLASSIFICATION

Since1963,manyNENclassificationshavebeenadopted,basedontheembryologicorigin

ofthetumor(foregut,midgut,hindgut),degreeofdifferentiation,andsiteoforigin(12)Theterm

“carcinoid”hasbeenabandonedforgastro‐entero‐pancreaticNENs.Theprognosticassessment

ofgastroenteropancreaticNENshasimprovedsignificantlysincetheintroductionofthe

EuropeanNeuroendocrineTumorSociety(knownasENETS)andWorldHealthOrganization

(WHO)2010stagingandgradingsystems.TheWorldHealthOrganization2010classification

scoresgastro‐entero‐pancreaticNENsintoG1,G2andG3,basedonthemorphologyandKi‐67

scoringindex1andMANEC(mixedadenoneuroendocrinecarcinoma)(13).AlthoughmostNENs

arewelldifferentiated(G1,G2),around5.6‐8%areG3(Ki‐67>20%)(14).Recentevidence

highlightstheneedtofurtherstratifypatientsintheG3groupbasedontheirdifferentclinical

behaviorandresponsetotreatmentintowell‐differentiatedNETG3(Ki‐6720‐50%)andpoorly‐

differentiatedNECG3(Ki‐67>50%).

1Gastro‐entero‐pancreaticneuroendocrinetumorG1:Ki‐67<2%;neuroendocrinetumorG2:Ki‐67=3‐20%;neuroendocrinecarcinomaG3:Ki‐67>20%



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CurrentclassificationofbronchopulmonaryNENsincludestypicalandatypicalcarcinoid,

largecellsneuroendocrinecarcinoma,small‐cellcarcinomaanddiffuseidiopathicpulmonary

neuroendocrinecellshyperplasia(thelatterconsideredapre‐invasiveform).Anewclassification

oflungneuroendocrinetumorshasbeenproposedbytheWorldHealthOrganization(15)and

wasendorsedbyEuropeanNeuroendocrineTumorSociety.Similarlytogastro‐entero‐pancreatic

NENs,thisthree‐tiergradingsystemiscenteredonKi‐67index,withspecificallygeneratedcut‐

offs2.

Thetumorgrading,histopathologytype,primarysiteandstagingreflectonthepotential

metastaticspreadand,therefore,impactonthetumorburdenandthesubsequentchoiceof

therapeuticoptions(Table2).Thesecharacteristics,togetherwithpriortreatmenthistoryare

fundamentalwhenreadinga68Ga‐DOTATATEscan.

68Ga‐DOTATATEPET/CT

Indications

68Ga‐DOTATATE(68Ga‐DOTA‐Tyr3‐Thr8‐octreotide)isaradiolabeledsomatostatin

analogueindicatedforusewithpositronemissiontomography(PET/CT)forlocalizationof

somatostatinreceptor(SSR)positiveNENsinadultandpediatricpatients(16).

SSRimagingisusedforstagingandrestagingandtoselectpatientsfortherapywith“cold”or

radiolabeled(PRRT)somatostatinanalogs(17,18).TherationaleofSSRimagingisthetumorcell

receptor‐mediatedinternalizationofthereceptor‐radio‐analogcomplexanditsretentioninthe

cytoplasm.

2BronchopulmonaryneuroendocrineneoplasmG1:Ki‐67<4%,nonecrosis;G2:Ki‐67=4‐25%andnecrosisin<10high‐powerfields(HPF);G3:Ki‐67>25%andnecrosisin>10HPF.



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ThreeSSAPeptidesandChoiceofDOTATATE

111In‐pentetreotideorOctreoScan®wasthefirstapprovedradiopharmaceuticalforNEN

imaging.Overthepast15years,thistracerdemonstratedtheutilityofsomatostatinreceptor

imaging.ThedevelopmentofGallium‐68‐labeledagents,suitableforusewithPET/CThas

markedlyenhancedlesiondetection(duetoimprovedresolution)andquantitationwiththe

68Ga‐labeledoctreotidederivatives(68Ga‐SSA‐PET/CT),DOTATOC(DOTA‐Tyr3‐octreotide),

DOTANOC(DOTA‐Nal3‐octreotide),andDOTATATE(18‐20).Theseanalogsretainanoctreotide‐

likeaffinityprofileand,inparticular,highaffinityforSSTR2(e.g.0.2±0.04nMforSSTR2with

68Ga‐DOTATATE,muchgreaterthan22±3.6nMof111In‐pentetreotide(21)).OnlyDOTANOC

exhibitssubstantialaffinityforSSTR3(22).Despitethesedifferencesinreceptoraffinity,aclear

superiorityofonecompoundovertheothershasnotbeendemonstrated.Acomparisonof68Ga‐

DOTATOCversus68Ga‐DOTATATEPET/CTinthesamepatients,yieldedcomparablediagnostic

accuracy,despitepotentialadvantagesfor68Ga‐DOTATOCinthenumberofdetectedlesionsand

thehigherSUVmax(23).However,arecentcomparisonof68Ga‐DOTATATEand68Ga‐DOTANOC

PET/CTinthesameNENpatients,showedhigherSUVmaxvaluesfor68Ga‐DOTATATEonalesion

basis,andcomparablediagnosticaccuracyonapatientbasis(24).Theinconclusiveresultson

thisissuereportedintheliteraturepossiblyreflecttheparticularreceptorconfigurationofthe

individualtumorsandthelackofinternationallyrecognizedcriteriaforSSRPETinterpretation.

BasedonthedemonstratedsuperiorityofDOTATATEPET/CTimagingcomparedto111In‐

octreotide,theUSFoodandDrugAdministrationhasapproved68Ga‐DOTATATEforlocalization

ofsomatostatinreceptorpositiveNETsinadultandpediatricpatients.

Technique



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ThepotentialbenefitsofwithdrawalofSSAtreatment,oratleastofscanningpatientsat

theendofthecoverageperiodoftheanalog,isstillunderdebateandnointernationalconsensus

hasbeenreached.Ifdiscontinuationisclinicallyfeasibleandperformed,short‐actinganalogs

shouldbestoppedforatleast48hrs,whilelong‐actingformulationsshouldbediscontinuedfor

4‐6weeks(16).RecentdatainvestigatingtheimpactofSSAon68Ga‐DOTATATEPET/CTinthe

samepatientsstudiedonandofftreatmentintwoconsecutivedays,donotsupporttheneedfor

discontinuation.Theauthorsreportedreduceduptakeatphysiologicsiteswithunchangedtumor

uptake,inthepatientsundertreatment,resultinginhigherimagecontrast(25).Sincenormal

organandtumoruptaketendstoincreasethelongerthePETscanoccursaftersomatostatin

analogueadministration(26)andsincerigorousdataontimingisunavailable,manycentersscan

patientsattheendoftheSSAtreatmentcycle,ifpossible(e.g.priortothesubsequentSSA

injection),otherwisemaintainingthesametimeintervalfromtheSSAinjectionasintheprevious

scan.

AccordingtotherecentEuropeanAssociationofNuclearMedicineguidelinesandtheUS

FoodandDrugAdministrationapprovedlabel,therecommendedactivitytoobtaingoodimage

qualityis2MBq/kgofbodyweight(0.054mCi/kg)upto200MBq(5.4mCi)administeredas

intravenousbolusinjection.

68Ga‐DOTATATEcanbeeithersuppliedalreadylabeledorasakittobereconstitutedaccording

tothemanufacturer's(AdvancedAcceleratorApplications)instructions

(http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208547s000lbl.pdf).

Beforeinjection,theradioactivityshouldbeverifiedwithadosecalibrator.Injected

radioactivityshouldbewithin±10%oftherecommendeddosage.



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Patientsshouldbeencouragedtodrinkasufficientamountofwaterbeforeadministration

(e.g.1liter,iftolerated,withorwithoutoralcontrast),followingtraceradministration,to

increaseimagequalityintheabdomen,andtovoidfrequently.

ThePET/CTacquisitiontypicallybegins45‐60minutesaftertheintravenous

administrationoftheradiopeptide,fromtopoftheskulltomidthighs,preferablyina3Dmode.

Foradetaileddescriptionofthescanningprotocolandimagereconstruction,refertothe

EuropeanAssociationofNuclearMedicineprocedureguidelinesfor68Ga‐DOTA‐peptides(16,27).

Theuseofintravenouscontrastmediamayfurtherenhancethedetection.However,instandard

usage,unenhancedPET/CTisconsideredsufficient.

Biodistribution

Theclearanceof68Ga‐DOTATATEfromthebloodisrapid.DynamicPETstudies

demonstratedthatarterialactivityeliminationisbi‐exponentialwithnoradioactivemetabolites

detectedinserumandurineinthefirst4hrs.Radioactivityintheblooddecreasestolessthan

5.3%ofthepeaklevelwithin45minofthedynamicscanningandto2.2%at195minafter

injection.After50min,theaccumulationinallorgansplateausandmaximaltumoractivity

accumulationisreachedat70±20minpost‐injection(28).Excretionoccursalmostexclusivelyvia

thekidneys.

PhysiologicaluptakeishighinSSTR2‐richorganssuchaspituitarygland,spleen,adrenals,

liver,pelvi‐calycealsystemofthekidneysandurinarybladder.Loweruptakemay

physiologicallybeobservedinthethyroid,pancreatichead,stomach,smallandlargebowel,and

prostate(Figure2)(29).



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SUVhasbeendemonstratedtocorrelatewithreceptordensityuptovaluesof

approximately25,correspondingtothesteady‐stateKivaluesof0.2mL/cm3/min,afterwhich

therelationshipisnotlinear,andthismayleadtounderestimationofreceptorexpression(28).

Dosimetry

Estimatedabsorbeddosesperinjectedactivityfororgansandtissuesfollowthe

biodistribution,peakingat1,2,and3hpost‐injectioninthespleen,followedbykidneysandliver

(Table3).Thehighestabsorbeddosesareobservedinthespleenandurinarybladderwall,

followedbykidney,adrenals,andliver.Thereportedtotaleffectivedosewas0.021±0.003

mSv/MBq(30).

Theeffectiveradiationdoseresultingfromtheadministrationof185MBq(5mCi)toan

adultweighing75kg,isabout4.8mSv(31).Forthisactivity,thetypicalradiationdosetothe

criticalorgans,whicharetheurinarybladderwall,thespleen,andthekidneys,areabout0.125,

0.282,and0.0921mSv/MBq,respectively(31).Sincethespleenhasthehighestphysiological

uptake,higheruptakeanddosetonormalortumortissuesmayoccurinpatientswith

splenectomy,asdemonstratedfor68Ga‐DOTATOC(32).Theeffectivedosederivingfromthelow‐

doseCTcomponentisgenerallyintherangeof9 mSvfor80mAlow‐doseCT,whilefor10mA

ultra‐lowdoseCTitiscloserto1mSv.

Interpretation

Assessmentofimagesshouldbeguidedbyclinicalinformation.Asageneralrule,besides

areasofphysiologicuptake,clearlyoutlinedfociofuptakeshouldberegardedaspositiveforSSR

expressionandthusconsideredtopotentiallyrepresentneuroendocrineneoplasm(Figure3,



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SupplementalFigure1).68Ga‐DOTATATEhascertainlimitationswhichhavetobetakeninto

accounttoadequatelyinterpretthecorrespondingscans.Therearealternativeconditionsthat

mayexhibitincreasedSSRexpressionandhence,representpotentialsourcesoffalsepositives

(Figure4,5,SupplementalFigure2).Thesemainlyincludeareasofinflammationorinfection

containingactivatedlymphocytesandmacrophages,suchasradiationpneumonitis,gastritis,

sequelaeofrecentsurgeries,reactivelymphadenopathyandgranulomatouslesions.Forexample,

thethyroidgenerallyexhibitslow‐gradeuptake(SUVmax1.4‐7.7,SUVmean3.0(29)).More

intensediffuseuptakecouldrepresentthyroiditis(duetotheSSR‐positivediffuselymphocyte

infiltration),whilefocaluptakecouldrepresentnodulardisease(33).Anareathatrequires

carefulconsiderationistheheadofthepancreas,particularlytheuncinateprocess,whichmay

exhibitavariablephysiologicuptake,focalordiffuse,of68Ga‐DOTATATE,relatedtothegreat

concentrationofpancreaticpolypeptidecells(16).Thisrepresentsapotentialsourceof

misinterpretation,sincethepancreasandtheduodenumarefrequentsitesofNENs.Therehave

beenattemptsatdefiningaSUVmaxthresholdtodistinguishbenignfrommalignantpancreatic

uptakeofDOTA‐SSApeptides(34,35).However,giventhelargeoverlapbetween

benign/physiologicandmalignantuptakeandthelargeinter‐scannermeasurementvariance,the

mereuptakeshouldnotbeusedtodiagnosepancreaticNENswithoutthedemonstrationofa

clearlesionatthecompanionCToratcorrelativediagnosticcross‐sectionalimaging(36).Other

commonnonNEN‐relatedsourcesofuptakeincludeaccessoryspleens/splenules,whichcouldbe

erroneouslyinterpretedaslymphnodes.Ifsufficientlylarge,considerationoflesionattenuation

andarterial‐phasecontrastbehaviormaybeofassistance(Figure6).

Prolongedtherapywith“cold”SSAmayreducethebackgroundphysiologicuptaketothe

spleenandliver.



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Falsenegativesaremostcommonlyrelatedtolesionsize(spatialresolutionisaround5.5‐

7mmwithpotentialadditionaldetrimentaleffectsduetopartialvolumeeffect,Figure7),recent

analogtherapy(althoughthisissueisdebated),alterationofreceptorexpressionbyrecent

chemotherapyortrulyreceptor‐negativedisease(e.g.benigninsulinomas,highgradeNENs).In

caseofhigh‐gradetumors,correlationwithFDGPET/CTmaybeuseful.Highphysiological

uptakeaspreviouslydescribedinorganssuchasspleen,liver,adrenals,pituitarygland,inthe

pelvi‐calycealsystemofthekidneysandurinarybladder,andtoalesserdegreeinthethyroid,

pancreatichead,stomach,smallandlargebowel,andprostatecanmaskiso‐intenseorsmall

pathologicalSSTR2expression.

ClinicalValue

68Ga‐DOTA‐peptidesPET/CTisthegoldstandardfunctionalimagingmodalitytostudy

welldifferentiatedNENsinEuropeandisincludedinEuropeanguidelines(16).Inthepast

decade,manyreportsdemonstratedthesuperiorityofSSRPET/CT(withDOTATATE,DOTATOC

orDOTANOC)oversinglephotonscintigraphy(includingSPECT/CT),morphologicalimaging

(CT/MR)orPET/CTwithotherradiopharmaceuticals(16,19,20,37‐41).Inarecentprospective

trialincluding131patientswithgastroenteropancreaticNENsandunknownprimaryNENs,68Ga‐

DOTATATEshowedahigherdetectionrate(95.2%)comparedto111In‐pentetreotideSPECT/CT

(30.9%)andCTorMRI(45.6%)(42).

Thelargestsinglestudyspecificallyaddressing68Ga‐DOTATATEdiagnosticaccuracyin

NENs(39)wasretrospectiveandincluded728patientsand1,258PET/CTscans.68Ga‐

DOTATATEPET/CTshowedhighsensitivity(>94%)andspecificity(>92%)forNENlesion

localization,withthehighestaccuracyforprimarymidguttumors.Theresultsreportedby



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Skouraetal.areinlinewiththeonesreportedinmuchsmallerpreviousstudiesusingPET/CT

witheitherDOTATOCorDOTANOC(16,20,43‐46).Overall,somatostatinreceptorPET/CT

showedahighaccuracy(≥96%)forthedetectionofwell‐differentiatedNENsateitherthe

primaryorthemetastaticsites(mostlylymphnodes,liver,bone,lung)(20,39,44).

CurrentguidelinesindicatethehighdiagnosticaccuracyofsomatostatinreceptorPET/CT

fordetectingdiseaseextension(atbothstagingandrestaging),identificationoftheunknown

primarysiteandselectionofcandidatesforPRRT(16).

TheroleofPET/CTfortheassessmentoftumorresponsetotreatmentisstillunder

debatesinceareductionofuptakecanindicateareductionoftumorvolume(andofreceptor

number)butcannotexcludethepresenceofundifferentiatedclonesthatmaybeSSR‐negative.

ConsideringthefactthatSSRPET/CTpositivitypredictsthelocalizationof“cold”and

radiolabeledSSA‐basedtreatmentoptions,itisevidentthattheclinicalimpactof68Ga‐

DOTATATEreliesnotmerelyinabetterdiagnosticaccuracybutalsoimpactstherapeutic

managementwithcoldSSAorPRRT.

Arecentlypublishedsystematicreview(47)(includingdatafrom1,561patients)reported

anoverallchangeinmanagementin44%(range:16‐71%)after68Ga‐SSA‐PET/CT(witheither

DOTATOC,DOTATATEorDOTANOC).Abouthalfofthesecaseswereprovidedbyasinglestudy

employing68Ga‐DOTATATE(728/1561,47%)(39).Skouraetal.reportedthatthetreatmentplan

waschangedin40.9%(515/1278)ofthe68Ga‐DOTATATEPET/CTbecauseofnew,unexpected

findings.InmostcasesthenewtreatmentcomprisedchemotherapyorPRRT(70.3%,362/515)

whilelessfrequentoptionsincludesurgery(afterdetection/confirmationofNENprimarysite,

10.1%,52/515)andsecond‐linechemotherapy(13.8%,71/515).Lesscommonmanagement

changesincludedongoingtreatmentdiscontinuation(2/515),rejectionofPRRT(2/515),and



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selectionoflivertransplantcandidatesbyexcludingextrahepaticdisease(2/515).Previous

reportsinsmallerpatientpopulationreportedsimilarfindings(42).

68Ga‐SSA‐PET/CThasalsobeendemonstratedtoproviderelevantprognosticinformation:

sincetheintensityofuptakeisanindirectmeasureoftumordifferentiation,higheruptake

correlatedwithabetterprognosis(48).

Theroleof68Ga‐SSA‐PET/CTintheG3NENsisdebated.Bydefinition,G3includespoorly

differentiatedtumors,however,especiallyinthesubgroupwithKi‐6720‐50%,theclinical

behaviorismoresimilartoG2tumors.Inthissetting,acomplementaryrolewithFDGcan

thereforebeenvisioned.Viceversa,68Ga‐SSA‐PET/CTincasespresentinghigherKi67>50%,even

ifpositive,willlikelynotimpactmanagement.

TheaddedvalueofFDGinthewell‐differentiatedNENs(G1andG2)isstillunderdebate

andnointernationalconsensushasbeenreached(49‐53).

Accordingtocurrentevidence,theroleofFDGisnotroutinelyrecommendedinG1NENs

(whereitcouldbeconsideredonlyinselectedcaseswhenaspecificclinicalindication/suspicion

ispresent),whileitmayhaveaclinicalroleinG2NENs,especiallyforhigherKi‐67values,based

onclinicalindications(e.g.patientswithCTprogressionorwithSRPET/CTnegativelesions).

Recently,itwasinfactshownthat18FDG‐PET/CTshouldbeonlyusedinselectedcasesforKi‐

67<12%(53)asheretheclinicalmanagementuniquelyrelieson68Ga‐DOTATATE.

CurrentEuropeanNeuroendocrineTumorSocietyguidelines(2016)indicateapotential

roleforFDGonlyfortheG3group,whensurgeryisindicated.Severalstudies,mostly

retrospective,investigatedtheroleofcombinationof68Ga‐SSA‐PET/CTandFDG‐PET/CTinNENs.

However,theywerehamperedbysmallpatientpopulationandbytheheterogeneityofthetumor

primarysite(awell‐knownfactoraffectingFDGpositivity).Inarecentmultinational,



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multidisciplinaryDelphiconsensusmeetingofNENexperts(n=33)(54),18FDG‐PET/CTwas

consideredvaluablefordifferentiatinghigh‐fromlow‐gradetumors,andforitsprognostic

implications.Noconsensus,however,wasreachedregardingcombining18FDG‐and68Ga‐SSA‐

PET/CTortheirtiminginadiagnosticsetting.

Acombinedimagingmodalitytoachieveacompletebiologicalcharacterizationdefininga

moreaggressivebehaviorisappealing.Infact,themeredetectionofahighernumberoflesions

oreventhedetectionofFDG‐positivityisnotnecessarilyassociatedtoadifferentmanagementin

allcasesandnuclearmedicine/oncologydepartments.However,thereisinternationalconsensus

onthefactthatFDGpositivitycorrelateswithaworseprognosis(55),but,thetreatment

strategiestobeimplementedinFDGpositivecasesarenotstandardized.Therationalefor

employingFDGreliesonitsabilitytoidentifythepresenceofaggressivediseasefocithatmay

turnintoabetterstratificationofpatientsatmajorriskforprogression.Theclinicalscenarioof

double‐tracerimagingfindingsrangesfrompurelySSR‐positive/FDG‐negativecasestoFDG‐

positive/SSR‐negativecases,withaveryheterogeneousintermediategrouppresentingvarious

patternsofuptakeinthesamepatientwithbothtracersinthesameorindifferentlesionsover

time(52).Themostimportantlessonderivingfromthesestudiesisthedemonstrationofthe

heterogeneousnatureofNENs.

SSRimagingisusedtoselectpatientsforPRRT.Whilethecriteriaarewell‐definedand

validatedforOctreoScan,withthe4‐pointKrenningscale,basedontherelativetumoruptake

comparedtotheoneofnormalorgans(liver,kidneysandspleen,wheregrade1:uptake<liver

(liverexcluded),grade2:uptake=liver,grade3:uptake>liver,andgrade4:>>kidneysand

spleen)(4),thereisnoconsensusonwhatshouldbeconsideredsufficientuptakeat68Ga‐SSA‐

PET/CT.SomeauthorshavereportedSUVmaxthresholdsforPRRTenrollment,basedon



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retrospectiveanalysese.g.SUVmaxof17.9and16.4arereportedfor68Ga‐DOTATOC(56,57).

However,thisapproachishamperedbythelimitedreproducibilityofSUVmaxvaluesacross

differentscanners.Morefrequentlyinclinicalpractice,theKrenningscaleisadaptedtothe

volumetric68Ga‐SSA‐PET/CTimage,andlesionuptakegreaterthantheliverisconsidered

suitableforPRRT.

IntegrationwithintheDiagnosticAlgorithmofNENs

Biomarkersareaviableadjuncttoimageinterpretation.ThesecretoryactivityofNENsis

quantifiableandfacilitatestheirdetection.PreviouslychromograninA(CgA)wasconsidered

usefulbutrigorousassessmentoverthelastdecadehasledtodecreasedenthusiasminitsusage,

duetonormallevelsin~30‐40%ofNENs,andfalselyelevatedlevelsinpatientswithrenal

failure,cardiacdiseaseorPPItherapy(58).Moreover,alterationsincirculatingCgAlevelsare

oftennon‐concordantwithimagingandprospectivestudieshavenotconfirmedaroleforCgAin

predictingordefiningprogression(54).Tobetterreflect,besidesthemeresecretoryactivity,the

complexbiologicalactivitiesofanevolvingneoplasm(cellproliferation,growthfactorsignaling,

etc),thatconstitutethe“hallmarksofcancer”,andprovidemorerelevantinformationontumor

behavior,newapproacheshavebeenintroduced,includingwholegenomicsequencing,

circulatingmiRNAandtumortranscripts(59).EvaluationofcirculatingmRNA(transcript

analysis)hasprovidedinformationondiseasestatusthatisofsubstantialclinicalutilityin

clinicalmanagementofNENs(60,61).ThisstrategyutilizessimultaneousPCR‐basedanalysesof

multipleNETgenesmeasurableinthebloodandalgorhythmictransformationintoa

mathematicalindexofdiseaseactivity(59,62).NENgenebloodlevelscorrelatedwith68Ga‐DOTA‐

SSAPET/CTimagingandcoulddefinediseasestatus(63).



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CurrentimagingstrategiesandbiomarkersinNENmanagementaddressedatarecent

DelphiconsensusmeetingofNENexperts(54),indicatedagreementontheuseofCTorMRIin

conjunctionwithfunctionalimaging.Duetoitssynergisticvalue68Ga‐DOTATATEisoftenusedin

additiontomorphologicalimagingmodalitiessuchasCTandMRI.PET/CTscannersarewidely

availableandthecorrespondingCT,ifperformedwithdiagnosticqualityandcontrastmedia,

mayimprovethediagnosticaccuracyparticularlyinorganswithhighphysiologic68Ga‐

DOTATATEuptakeandinthelung.EspeciallygastroenteropancreaticNENsarewellsuitedfor

dedicatedPET/MRIasMRIaddsimportantinformationtothedetectionofabdominallesions,

particularlyintheliver(SupplementalFigure3)(64,65)whereasCTremainssuperiorforthe

detectionandcharacterizationoflunglesions.Asdiscussed,18FDGdetectsdedifferentiated

lesionsexpressingnoorfewSSTR2(53).Acommonindicationfor18FDG‐PET/CTis

morphologicallygrowinglesionswithadiscordant68Ga‐DOTATATEfinding.

Theseobservationsareworthyoffurtherclinicalstudytoprovideevidencethatthe

interfaceofimagingandcirculatingmolecularindicesoftumorevolutionislikelytoenhance

dynamicassessmentoftumorstatus.

68Ga‐DOTA‐peptidesPET/CThassignificantlyadvancedtheapproachtoNENs.Its

widespreadimplementationisbaseduponitsprovenclinicalutilityandfacilitationofclinical

management.Overallitrepresentsthegoldstandardfunctionalimagingmodalityforthe

assessmentofwell‐differentiatedNENsinconjunctionwithanatomicimaging(CT/MR).An

unmetneedistheevaluationoftheclinicalimpactofthedualapproach18F‐FDG‐and68Ga‐SSA‐

PET/CTinthedecision‐makingalgorithm,giventhenumerousindicationsfromliteratureofthe

prognosticimpactofFDGavidityintermsofoverallandtreatment‐specificsurvival.Afurther



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17

significantadvanceneededisthedevelopmentofanaccurate,personalizedinterpretationofthe

individualdiseasestatus.

Thismaybeaccomplishedbythedevelopmentofanalgorithmicintegrationof

informationobtainedfromsynthesisoftheclinical,histopathological,imagingandmolecular

informationavailablefromtheneoplasmofeachsubject.

DISCLOSURE

LBisaconsultantforAAAandIpsen,KHisaconsultantforSofieBiosciences.Noother

potentialconflictofinterestrelevanttothisarticlewasreported.



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62. ModlinIM,DrozdovI,AlaimoD,etal.AmultianalytePCRbloodtestoutperformssingleanalyteELISAs(chromograninA,pancreastatin,neurokininA)forneuroendocrinetumordetection.EndocrRelatCancer.2014;21:615‐628.63. BodeiL,KiddM,ModlinIM,etal.Genetranscriptanalysisbloodvaluescorrelatewith(6)(8)Ga‐DOTA‐somatostatinanalog(SSA)PET/CTimaginginneuroendocrinetumorsandcandefinediseasestatus.EurJNuclMedMolImaging.2015;42:1341‐1352.64. HopeTA,PampaloniMH,NakakuraE,etal.Simultaneous(68)Ga‐DOTA‐TOCPET/MRIwithgadoxetatedisodiuminpatientswithneuroendocrinetumor.AbdomImaging.2015;40:1432‐1440.65. BeiderwellenKJ,PoeppelTD,Hartung‐KnemeyerV,etal.Simultaneous68Ga‐DOTATOCPET/MRIinpatientswithgastroenteropancreaticneuroendocrinetumors:initialresults.InvestRadiol.2013;48:273‐279.66. HerrmannK,CzerninJ,WolinEM,etal.Impactof68Ga‐DOTATATEPET/CTonthemanagementofneuroendocrinetumors:thereferringphysician'sperspective.JNuclMed.2015;56:70‐75.



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FIGURELEGENDS

Figure1.Optimalstrategyfor68Ga‐DOTATATEPET/CTevaluation



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Figure2.Normalbio‐distributionof68Ga‐DOTATATE(A).Physiologicintenseuptakeisnotedinthepituitary,liver,spleen,kidneys,adrenals,anduncinateprocessofthepancreas(B,solidarrow,dashedcircle)Variabledegreeofuptakeinthethyroid,intestine,andurinarybladder.



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Figure3.Upstagingofapatientwithhistoryofsmall‐intestineNENanda6.5‐cmlesionwithintherightproximalfemurwithbenignappearanceatpriorMR.Unexpectedsoft‐tissueandbonemetastasesweredetected(arrows,B).Theintendedtreatmentwasconvertedfromsurgeryandoctreotidetosurgery,octreotide,plusselectiveradiotherapyofbonemetastases(adaptedfrom(66).



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Figure4.PatientwithilealNET(singlearrow)presentedadditionalfocaluptake(twoarrows)inthepelvis[axialviewsofPET(A),fusedPET/CT(B)andCT(C)].FusedPET/CTimagesclarifiedthisfindingasphysiologicuptakeintherightureter.



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Figure5.Increased68Ga‐DOTATATEprostataticuptake.AxialprojectionsofPET[(A),fusedPET/CT(B)andCT(C)].ThepatienthadknownBPHandthecorrespondinguptakeisthereforenon‐tumorspecific.



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Figure6.Patientwithrepeatedflushingunderwent68Ga‐DOTATATEPET/CT[axialfusedPET/CT(A)andCT(B)images].Focaluptake(arrow)inthepancreatictailwascharacterizedbasedonclinicaldataandMRI,indicatingthepresenceofasplenuleabuttingthetailofpancreas(reprintedfrom(47)).



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Figure7.60yofemalepreviouslyundergoneilealNETresection,currentlyonSSAwithassociatedcholelithiasisscheduledforsurgery(solidarrow,C).Priortosurgery,68Ga‐DOTATATEPET/CT(A,B,simplehepaticcyst,dashedarrow,C)andCgA(bluecircles,D)werenegative.However,circulatingneuroendocrinetranscriptslevels(redcircles,D)werepositive.Positivetranscriptlevelsareindicativeofthepresenceofprimary,residualormetastaticNET.Atcholecystectomy,therewasnoevidenceofhepaticmetastases.Randomintra‐operativehepaticneedlebiopsy,however,demonstratedthepresenceofneuroendocrinetumormetastases.



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Table1.GastrointestinalandPancreaticNeuroendocrineCellTypesandSecretoryProducts

Cell type Localization Products Delta (D) Entire GI tract Somatostatin

Enterochromaffin (EC) Entire GI tract Serotonin/substance P/guanylin/melatonin

Enterochromaffin-like (ECL)

Gastric fundus Histamine

Gastrin (G) Gastric antrum & duodenum Gastrin Ghrelin (Gr) Entire GI tract Ghrelin

I Duodenum CCK K Duodenum/jejunum GIP L Small intestine GLP-1, PYY, NPY

Motilin (M) Duodenum Motilin Neurotensin (N) Small intestine Neurotensin

Secretin (S) Duodenum Secretin Vasoactive intestinal peptide

(VIP) Entire GI tract VIP

X Stomach: fundus and antrum Amylin Beta Pancreas Insulin

Alpha Pancreas Glucagon Delta Pancreas Somatostatin

Pancreatic Polypeptide (PP) Pancreas PP CCK=cholecystokinin;GIP=gastricinhibitorypeptide;GLP‐1=glucagon‐likepeptide1;PYY=polypeptideYY(tyrosine,tyrosine);NPY=neuropeptideY(tyrosine);PP=pancreaticpolypeptide.



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Table2.CharacterizationandClinicalPresentationofgastro‐entero‐pancreaticandbroncho‐pulmonaryNENs

Site ClinicalpresentationGastrointestinal Gastric ‐TypeI:atrophicgastritis‐gastrindependent

‐TypeII(MEN1):Menindependent‐gastrinrelated(ZES)‐TypeIII:gastrinindependent;clinicallyaggressive

Duodenal Variousphenotypes:gastrinoma,so‐called“carcinoid,”somatostatinoma

Jejunal “carcinoid”—classicsymptoms(flushing,diarrhea);clinicallyaggressive

Ileal “carcinoid”—classicsymptoms(flushing,diarrhea);clinicallyaggressive.TypicalCTappearanceofcontrastenhancingspiculatedmass,sometimescontainingcalcifications,surroundedbylinesofdesmoplasticreactions.

Appendiceal ‐“Carcinoid”:usuallypresentasappendicitisorincidentalfindingatlaparotomy/laparoscopyandgenerallyradicallycuredaftersurgicalexcision;‐Gobletcellcarcinoid(mucinouscarcinoid):clinicallyaggressive.

Colonic Carcinoidsymptomsarerare,presentationsimilartoadenocarcinoma

Rectal Localmanifestations—pain,bleedingHepatic >95%aremetastasesfromgastro‐entero‐pancreaticNENprimary.

TypicalCTappearanceofhypodensemasses,withrichenhancementduringthearterialphase,revertingtohypodenseduringtheportalphase.AtMR(mostsensitivetechnique)lesionsenhanceaftergadolinium,arterialphaseandfastspin‐echoT2‐weightedsequencesarethebestsequences

Pancreatic Gastrinoma(Zollinger‐EllisonSyndrome)

Pepticulcerationandsecretorydiarrhea;60‐90%malignantbehavior

Insulinoma Hypoglycemia;generallysmallandsomatostatinreceptor(SSR)negative;5–15%malignantandgenerallySSR‐positive

Glucagonoma Skinrash(migratingnecrolyticerythema),weightloss,diabetes;60%malignant

VIPoma Secretorydiarrhea(Verner‐Morrisonsyndrome);80%malignantSomatostatinoma Diabetes,gallstones;oftenacomponentofageneticsyndrome;60%

malignantGRFoma Acromegaly;30%malignantACTHoma PresentasCushingsyndrome;aggressivebehavior;>90%malignantP‐NENcausingcarcinoidsyndrome

Diarrhea,flushing;68–88%malignant



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P‐NENcausinghypercalcemia

Symptomsofhypercalcemia;80–90%malignant

Nonfunctioning Localmasseffects;60–90%malignant.Bronchopulmonary Typicalcarcinoid Frequentlycentral,withcough,wheezing,hemoptysisandsignsof

bronchialobstruction;functionalwhenmetastatic(carcinoid,Cushing,acromegalyorSyndromeofInappropriateAntidiureticHormoneSecretion,SIADH);relativelyindolentbiologicalbehavior.MaybepartofMEN1

Atypicalcarcinoid Frequentlyperipheralandasymptomatic;maypresentwithcoughingandwheezingorfunctionalsyndrome;fromindolenttoaggressive.MaybepartofMEN1.

LargeCellNeuroendocrineCarcinoma

Aggressivelymetastaticandrapidlyprogressing.

SmallCellLungCancer

Aggressivelymetastaticandrapidlyprogressing.

ThymicNETs Frequentlylarge,50%functional,usuallyACTH‐inducedCushingsyndrome.MaybepartofMEN1.Frequentlymetastatic.

Chromaffin Pheochromocytoma/Paraganglioma

80‐85%arisefromadrenalmedulla,15‐20%extra‐adrenal.Themajorityassociatedwithcatecholaminehypersecretion(mostfrequently,hypertension,tachycardia,headache,pallor,sweatingandanxiety),withafrequentparoxysmalcomponent



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Table3.AbsorbedDosesof68Ga‐DOTATATEinSelectedOrgans.

AnatomicalLocation Absorbeddose(mGy/MBq±SD)(30)

Absorbeddose(mGy/MBq±SD)(31)

Kidney 0.093±0.016 0.092±0.028Liver 0.050±0.015 0.045±0.015Gallbladderwall 0.016±0.002 0.015±0.001Spleen 0.109±0.058 0.028±0.121Adrenals 0.086±0.052 0.015±0.001Lungs 0.006±0.001 0.012±0.0004Urinarybladderwall 0.098±0.048 0.125±0.062Redmarrow 0.015±0.003 0.010±0.0004Totalbody 0.014±0.002 0.013±0.0003Effectivedose(mSv/MBq) 0.021±0.003 0.026±0.003



Supplemental Figure 1. Patient with lymph node metastasis from resected ileal NET underwent 68Ga-DOTATATE PET/CT

for restaging (coronal PET, fused PET/CT and PET (A), axial PET, fused PET/CT and CT (C)). An additional bone

metastasis in the right femur was detected resulting in management change (external-beam radiation).

A

B



Supplemental Figure 2. A female with a NET underwent a 68Ga-DOTATATE PET/CT to rule out recurrence. The only

suspicious finding is evident in the sagittal projections {PET (A), fused PET/CT (B) and CT (CT)} exhibiting a clearly

intense 68Ga-DOTATATE uptake in the pelvis. Corresponding morphologic information provided by patient history and CT

confirmed the presence of a tampon (“hot tampon”); non attenuation corrected images also exhibited increased uptake.

A B C



Supplemental Figure 3. Follow-up imaging of a G2 neuroendocrine tumor of the ileocecal valve, status post ileocolic and mesenteric node

resection. MRI (C, axial DWI B500 sequence, solid arrow) shows restricted diffusion in subcentimeter foci scattered throughout the liver

suspicious for metastases, probably below PET resolution for 68Ga-DOTATATE, which is negative a these sites (B) and only demonstrates a

larger lesion in segment 6 (A, solid arrow). 68Ga-DOTATATE, however, demonstrates uptake in borderline enlarged mesenteric nodes (D, E,

dashed arrow and circle) adjacent to the surgical clips, peritoneal implants and left breast nodule (A, dotted arrow and arrowhead), which are

then characterized as suspicious for recurrence.

A

B C

D E



Supplemental Figure 4. Patient affected by an atypical bronchial carcinoid, stage IIIa, status post resection and adjuvant

chemotherapy, presenting now with evidence of right hilar node recurrence (A, B, dashed arrow) to guide a possible loco-

regional approach. 68Ga-DOTATATE PET/CT revealed the presence of an additional focus of tracer avidity in the left

sacrum (C, solid arrow) without CT correlate, however, suspicious for metastasis. A subsequent biopsy confirmed the

metastatic etiology. The patient was scheduled for systemic therapy.

B C

A B C



Doi: 10.2967/jnumed.116.186361Published online: August 17, 2017.J Nucl Med. Lisa Bodei, Valentina Ambrosini, Ken Herrmann and Irvin Modlin, 0 BIODISTRIBUTION, DOSIMETRY AND MOLECULAR STRATEGIES

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