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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
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.
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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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significantadvanceneededisthedevelopmentofanaccurate,personalizedinterpretationofthe
individualdiseasestatus.
Thismaybeaccomplishedbythedevelopmentofanalgorithmicintegrationof
informationobtainedfromsynthesisoftheclinical,histopathological,imagingandmolecular
informationavailablefromtheneoplasmofeachsubject.
DISCLOSURE
LBisaconsultantforAAAandIpsen,KHisaconsultantforSofieBiosciences.Noother
potentialconflictofinterestrelevanttothisarticlewasreported.
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38. SrirajaskanthanR,KayaniI,QuigleyAM,SohJ,CaplinME,BomanjiJ.Theroleof68Ga‐DOTATATEPETinpatientswithneuroendocrinetumorsandnegativeorequivocalfindingson111In‐DTPA‐octreotidescintigraphy.JNuclMed.2010;51:875‐882.39. SkouraE,MichopoulouS,MohmaduveshM,etal.TheImpactof68Ga‐DOTATATEPET/CTImagingonManagementofPatientswithNeuroendocrineTumors:ExperiencefromaNationalReferralCenterintheUnitedKingdom.JNuclMed.2016;57:34‐40.40. DeppenSA,BlumeJ,BobbeyAJ,etal.68Ga‐DOTATATEComparedwith111In‐DTPA‐OctreotideandConventionalImagingforPulmonaryandGastroenteropancreaticNeuroendocrineTumors:ASystematicReviewandMeta‐Analysis.JNuclMed.2016;57:872‐878.41. AmbrosiniV,CampanaD,TomassettiP,FantiS.(6)(8)Ga‐labelledpeptidesfordiagnosisofgastroenteropancreaticNET.EurJNuclMedMolImaging.2012;39Suppl1:S52‐60.42. SadowskiSM,NeychevV,MilloC,etal.ProspectiveStudyof68Ga‐DOTATATEPositronEmissionTomography/ComputedTomographyforDetectingGastro‐Entero‐PancreaticNeuroendocrineTumorsandUnknownPrimarySites.JClinOncol.2016;34:588‐596.43. PutzerD,GabrielM,HenningerB,etal.Bonemetastasesinpatientswithneuroendocrinetumor:68Ga‐DOTA‐Tyr3‐octreotidePETincomparisontoCTandbonescintigraphy.JNuclMed.2009;50:1214‐1221.44. AmbrosiniV,NanniC,ZompatoriM,etal.(68)Ga‐DOTA‐NOCPET/CTincomparisonwithCTforthedetectionofbonemetastasisinpatientswithneuroendocrinetumours.EurJNuclMedMolImaging.2010;37:722‐727.45. HaugA,AuernhammerCJ,WanglerB,etal.Intraindividualcomparisonof68Ga‐DOTA‐TATEand18F‐DOPAPETinpatientswithwell‐differentiatedmetastaticneuroendocrinetumours.EurJNuclMedMolImaging.2009;36:765‐770.46. KayaniI,ConryBG,GrovesAM,etal.Acomparisonof68Ga‐DOTATATEand18F‐FDGPET/CTinpulmonaryneuroendocrinetumors.JNuclMed.2009;50:1927‐1932.47. FendlerWP,BarrioM,SpickC,etal.68Ga‐DOTATATEPET/CTInterobserverAgreementforNeuroendocrineTumorAssessment:ResultsofaProspectiveStudyon50Patients.JNuclMed.2017;58:307‐311.48. CampanaD,AmbrosiniV,PezzilliR,etal.Standardizeduptakevaluesof(68)Ga‐DOTANOCPET:apromisingprognostictoolinneuroendocrinetumors.JNuclMed.2010;51:353‐359.49. PartelliS,RinzivilloM,MauriziA,etal.TheroleofcombinedGa‐DOTANOCand(18)FDGPET/CTinthemanagementofpatientswithpancreaticneuroendocrinetumors.Neuroendocrinology.2014;100:293‐299.
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50. KunduP,LataS,SharmaP,SinghH,MalhotraA,BalC.Prospectiveevaluationof(68)Ga‐DOTANOCPET‐CTindifferentiatedthyroidcancerpatientswithraisedthyroglobulinandnegative(131)I‐wholebodyscan:comparisonwith(18)F‐FDGPET‐CT.EurJNuclMedMolImaging.2014;41:1354‐1362.51. BahriH,LaurenceL,EdelineJ,etal.Highprognosticvalueof18F‐FDGPETformetastaticgastroenteropancreaticneuroendocrinetumors:along‐termevaluation.JNuclMed.2014;55:1786‐1790.52. NilicaB,WaitzD,StevanovicV,etal.Directcomparisonof(68)Ga‐DOTA‐TOCand(18)F‐FDGPET/CTinthefollow‐upofpatientswithneuroendocrinetumourtreatedwiththefirstfullpeptidereceptorradionuclidetherapycycle.EurJNuclMedMolImaging.2016;43:1585‐1592.53. PanagiotidisE,AlshammariA,MichopoulouS,etal.ComparisonoftheImpactof68Ga‐DOTATATEand18F‐FDGPET/CTonClinicalManagementinPatientswithNeuroendocrineTumors.JNuclMed.2017;58:91‐96.54. ObergK,KrenningE,SundinA,etal.ADelphicconsensusassessment:imagingandbiomarkersingastroenteropancreaticneuroendocrinetumordiseasemanagement.EndocrConnect.2016;5:174‐187.55. BinderupT,KniggeU,LoftA,FederspielB,KjaerA.18F‐fluorodeoxyglucosepositronemissiontomographypredictssurvivalofpatientswithneuroendocrinetumors.ClinCancerRes.2010;16:978‐985.56. OksuzMO,WinterL,PfannenbergC,etal.Peptidereceptorradionuclidetherapyofneuroendocrinetumorswith(90)Y‐DOTATOC:istreatmentresponsepredictablebypre‐therapeuticuptakeof(68)Ga‐DOTATOC?DiagnIntervImaging.2014;95:289‐300.57. KratochwilC,StefanovaM,MavriopoulouE,etal.SUVof[68Ga]DOTATOC‐PET/CTPredictsResponseProbabilityofPRRTinNeuroendocrineTumors.MolImagingBiol.2015;17:313‐318.58. JensenEH,KvolsL,McLoughlinJM,etal.Biomarkerspredictoutcomesfollowingcytoreductivesurgeryforhepaticmetastasesfromfunctionalcarcinoidtumors.AnnSurgOncol.2007;14:780‐785.59. ObergK,ModlinIM,DeHerderW,etal.Consensusonbiomarkersforneuroendocrinetumourdisease.LancetOncol.2015;16:e435‐446.60. PavelM,JannH,PrasadV,DrozdovI,ModlinIM,KiddM.NETBloodTranscriptAnalysisDefinestheCrossingoftheClinicalRubicon:WhenStableDiseaseBecomesProgressive.Neuroendocrinology.2017;104:170‐182.61. ModlinIM,DrozdovI,KiddM.Theidentificationofgutneuroendocrinetumordiseasebymultiplesynchronoustranscriptanalysisinblood.PLoSOne.2013;8:e63364.
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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
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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
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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
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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
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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
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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
Ga-DOTATATE NEN IMAGING: INTERPRETATION,68CURRENT CONCEPTS IN
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