Comparison of 68Ga-Dotatate PET/CT and 18F-FDOPA PET/CT for the diagnosis of pancreatic neuroendocrine tumors in a MEN1 patient

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Comparison of 68Ga-Dotatate PET/CT and

18F-FDOPA PET/CT for the diagnosis of pancreatic neuroendocrine tumors in a MEN1 patient

Marine Jullien, Thibault Reichert, Pascal D’anella, Frederic Castinetti, Anne Barlier, Thierry Brue, David Taieb, Thomas Cuny

To cite this version:

Marine Jullien, Thibault Reichert, Pascal D’anella, Frederic Castinetti, Anne Barlier, et al.. Com-

parison of 68Ga-Dotatate PET/CT and 18F-FDOPA PET/CT for the diagnosis of pancreatic neu-

roendocrine tumors in a MEN1 patient. Annales d’Endocrinologie, Elsevier Masson, 2020, 81 (1),

pp.39-43. �10.1016/j.ando.2019.11.001�. �hal-03121982�

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ScienceDirect

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Original article

Comparison of 68Ga-Dotatate PET/CT and 18F-FDOPA PET/CT for the diagnosis of pancreatic neuroendocrine tumors in a MEN1 patient

Comparaison du (68)Ga-DOTATATE TEP/TDM et du (18)F-FDOPA TEP/TDM pour le diagnostic des tumeurs neuroendocrines pancréatiques chez une patiente atteinte de NEM1

Marine Jullien

^a

, Thibault Reichert

^b

, Pascal D’Anella

^c

, Frédéric Castinetti

^a

, Anne Barlier

^d

, Thierry Brue

^a

, David Taieb

^b

, Thomas Cuny

^a,^∗

aInsermU1251,serviced’endocrinologie,MarseilleMedicalGenetics,HôpitaldelaConception,Aix-MarseilleUniversité,AP–HM,Marseille,France

bServicedemédecinenucléaire,hôpitaldelaTimone,Aix-MarseilleUniversité,AP–HM,Marseille,France

cServiced’endocrinologie,centrehospitalierd’Avignon,Avignon,France

dInsermU1251,laboratoiredebiologiemoléculaire,MarseilleMedicalGenetics,HôpitaldelaConception,Aix-MarseilleUniversité,AP–HM,Marseille, France

a r t i c l e i n f o

Keywords:

18F-FDOPAPET/CT 68Ga-DotatatePET/CT MEN1

Neuroendocrine Pancreas

a b s t r a c t

Context.–Pancreaticneuroendocrinetumors(PNETs)occurinmorethan80%ofpatientswithmultiple endocrineneoplasiatype1(MEN1)syndrome,withpredominanceofsmall(<1cm)non-functioning tumors,followedbygastrinomasandinsulinomas.Duetotheirsmallsize,thediagnosticperformanceof conventionalMRIandCTimagingishighlyvariable,witharealriskoffalse-negatives.Functionalimaging on111In-DTPA-OctreotideSPECTsomatostatinreceptorscintigraphy(Octreoscan^®)isthemodalityof choice,butshowsonly80%sensitivity.Alternatively,18F-fluorodihydroxyphenylalanine(FDOPA)and, morerecently,68Ga-DotatatePET/CTimagingarevaluableoptionsincaseofnegativeOctreoscan^®. Casereport.–A55old-yearwomandiagnosedwithMEN1syndrome,presentedwithmultipleasymp- tomaticbutprogressivePNETsrevealedonultrasoundendoscopy.Octreoscan^®wasnegative,aswas 18F-FDOPAPET/CT,whereas68Ga-DotatatePET/CTdetectedallPNETsfoundonendoscopy.

Conclusion.–WeherereportthefirstcaseofaMEN1patientwhosuccessfullyunderwenta68Ga- DotatatePET/CTfordetectionandfollow-upofPNETs,whilebothOctreoscan^®and18F-FDOPAPET/CT werenegative.

Motsclés:

(18)F-FDOPATEP/TDM 68(Ga)-DOTATATETEP/TDM NEM1

Neuroendocrine Pancréas

ré s um é

Contexte.–Lestumeursneuroendocrinespancréatiques(TNEPs)surviennentchez80%despatients atteintsdenéoplasieendocrinienne multipledetype1(NEM1),avecuneprédominance depetites tumeurs (<1cm), non fonctionnelles, suivies par les gastrinomes et les insulinomes. Du fait de leurpetitetaille,laperformancediagnostiquedel’imagerieconventionnelle(IRMetTDM)estvari- able,pouvantconduireàd’authentiquessituationsdefaux-négatifs.Le111In-DTPA-OctreotideSPECT (Octréoscan^®) (scintigraphie desrécepteursdela somatostatine)constitue l’imageriefonctionnelle de préférence, mais avec une sensibilité de seulement 80 %. En parallèle, le développement de l’imageriepartomographieparémissiondepositonscoupléeauscanner(TEP/TDM)utilisantla18F- fluorodihydroxyphenylalanine((18)F-FDOPA)ouplusrécemmentle68(Ga)-DOTATATEsontdesoptions intéressantes,encasd’Octréoscan^®négatif.

Casclinique.–Unepatienteâgéede55ans,suiviepouruneNEM1,futadmiseenraisondeTNEPsmultiples nonsymptomatiquesetprogressivesobjectivéesenécho-endoscopie.L’Octréoscan^®étaitnoncontributif, demêmequela(18)F-FDOPATEP/TDM,alorsquele68(Ga)-DOTATATETEP/TDMidentifiaitl’ensemble desTNEPsdétectéesenendoscopie.

∗ Correspondingauthor.

E-mailaddress:thomas.cuny@ap-hm.fr(T.Cuny).

https://doi.org/10.1016/j.ando.2019.11.001

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40 M.Jullienetal./Annalesd’Endocrinologie81(2020)39–43

Conclusion.–Nousrapportonsle1^ercasdepatientNEM1pourlequelleslésionsdeTNEPssontdétectées (etserontultérieurementsuivies)àl’aidedu68(Ga)-DOTATATETEP/TDM,alorsquel’Octréoscan^®ainsi quela(18)F-FDOPATEP/TDMétaientnoncontributifs.

1. Introduction

Multipleendocrineneoplasia type1(MEN1)isanautosomal dominantdisorder characterizedbythe occurrence ofparathy- roid,anteriorpituitaryandpancreaticneuroendocrineneoplasms (PNENs)[1].It is genetically related tomutationsin the MEN1 gene,causinganautomosaldominantinheritancewithmorethan 1500mutationscurrentlydescribed.Molecularalterationsaffect- ingtheMEN1signalingpathwayhavebeenidentifiedinfamilial aswellasinsporadicPNENs[2].Furthermore,thelatteroccurin morethan80%ofMEN1patients,withanoverrepresentationof small(i.e.<1cm insize)andmultiplenon-functioningtumours followed by gastrinomas and insulinomas [3].The diagnosis of PNENsrelies onboth conventional imaging suchas CT scan or pancreaticMRIandnuclearmedicineimagingmodalities,headed byIn-pentetreotidesingle-photonemissioncomputedtomogra- phy(CT)(octreoscan).However,intheparticularsettingofMEN1, octreoscanfailstoimage35to50%ofPNENs<1cmindiameter[4].

AssuchtheworkconductedbyMorgatetal.isofimportanceasit showedinaseriesof19patientswithMEN1,respectivesensitivi- tiesof20%foroctreoscanand76%for(68)Ga-DOTA-TOCPET/CTfor thedetectionofduodenopancreaticNENs[5].(68)Ga-DOTAtracers usedthePETtechniqueandhavehighaffinityforthesomatostatin receptorsubtype2(SSTR2),whichishighlyexpressedinneuroen- docrineneoplasms[6].BesidesSSTR2-derivedimagingmodalities, F-FDOPAPET/CTalsoemergedasreliableimagingtechniqueforthe detectionofNENs,especiallyincasesofpancreaticinsulinomas (after carbidopapremedication)[7] or smallintestine neuroen- docrineneoplasms(SiNENs)[8].Itsperformanceforthediagnosis of(other)PNENs inthesetting ofMEN1 syndromeiscurrently unknown.

We here report the first case of a MEN1 patient who suc- cessfullyunderwenta68(Ga)-DOTATATEPET/CTforthedetection ofsmallmultiplePNENsafterboth negative18F-FDOPAPET/CT (withcarbidopapremedication)and111In-DTPA-OctreotideSPECT (OctreoScan).

2. Casereport

In 2018, a 55 year-old woman was referred to ourdepart- mentforthefollowupofaMEN1syndromediagnosedin1999.

Herdiagnosiswasmadeinacontextofgeneticscreeningbecause hersisterwastheindexcaseandexceptionally,shebelongedto a family of 11 siblings(Fig.1) and carried theMEN1 mutation Exon9,c.1192delc;p.(Gln398Argfs*47).Inherpasthistory,shehas beentreatedforaprimaryhyperparathyroïdism(subtotalparathy- roidectomy)secondarytomultiglandulardiseaseattheageof45

Fig.1.Familytreeoftheprobandandhersiblings.

andisalsoregularlyfollowedupforanon-secreting3mm-right sidedpituitarymicroadenoma.Sheunderwentseveralabdominal CT-scanwhichfoundtwohypervascularlesionsof8mmeach,at theposteriorfaceofboththepancreaticbodyandthetail,respectively.Anechoendoscopywassubsequentlyperformedandfurther identifiedtwomorelesionsinthepancreasbetweenthebodyand thetail:intotal,therewere4lesionswhosemaximaldiametersize were10,12,14and15mm,respectively.Anultrasound-guidedfine needleaspirationwasperformedonthelargerlesionandthehis- tologywasconsistentwithaPNENgrade1(Ki67<2%,nomitose).A completehormonalassessmentwasstrictlynegativewhichmeant thatthosePNENlesionswerenon-secreting.Importantly,therewas noargumentforthepossibilityofan(occult)insulinoma.Ascom- paredtothepreviousechoendoscopy,thesizeofthe15-mmlesion increased,thereasonwhywesoughtforanotherandless inva- siveimaging modalityinthefollow-upofthis patient.Wethus performedanoctreoscan(132MBqOctreotideindium111)which wasnegativeforallthelesionspreviouslydescribed(Fig.2).We, thus,referredthepatienttothenuclearmedicinefortherealization ofa(18)F-FDOPAPET/CTwithcarbidopapremedication(Timone, GEDiscovery710PremedicationwithCarbidopa(200mg).Activ- ité:179MBq–4.53mCi,).However,thelesionsdidnotuptakeat alltheradiotracerandtheexamwasconsideredasnoncontribu- tive(Fig.2).Eventually,amultidisciplinarydecisionsuggestedto perform68(Ga)-DOTATATEPET/CT(hôpitaldelaTimone,PETCT Discovery710;PDL236mGy.cm,CTDI2,3mGy).Allofthe4lesions showedanuptakeoftheradiotracerwithrespectivemaximumSUV of28.4(lesion1),7.2(lesion2),7.4(lesion3)and14.6(lesion4), respectively(Fig.3B).Therewasnohypermetabolicadenopathy orfurtherlesions.Thepatientiscurrentlytreatedbysomatostatin analogsmonthly.

3. Discussion

Thediagnosis of digestiveneuroendocrine neoplasms inthe context of MEN1 remains a real challenge in clinical practice, in more than one way. First, PNENs represent one of the main cause of death in patients with MEN1, a majority of thesebeingattributable togastrinomas, responsiblefor gas- tricacidhypersecretion,multipleduodenalulcersandeventually life-threateninggastrointestinalhaemorrhage[9].Second,MEN1- relatedPNENsare,unliketheirsporadiccounterparts,usuallysmall (i.e.,<1cm),multiple,andoccuronabackgroundofdiffusepancre- aticmicroadenomatosis[3].Basedonthosecharacteristics,classic imaging procedures suchas C Tscan, MRI or Octreoscan^® can befaulted in terms of sensitivity aswell as in terms of speci- ficity,thelatterbeingrelatedtothefactthatdifferentphenotypes

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M.Jullienetal./Annalesd’Endocrinologie81(2020)39–43

Fig.2. A.MIP(MaximalIntensityProjections)picturesof(18)F-FDOPAand(68)Ga-DOTATATEofthepatient.B.Octreoscan^®ofthepatientwhichwasnoncontributivefor thedetectionofthepancreaticneuroendocrinelesions.

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42 M.Jullienetal./Annalesd’Endocrinologie81(2020)39–43

Fig.3. (18)F-FDOPA[A]and(68)Ga-DOTATATE[B].PET/CTimagesoftheMEN1patientwithPNENsidentifiedbyechoendoscopy.(68)Ga-DOTATATE[B]detectedthedifferent lesions(arrows1to4)inthepancreaswhile(18)F-FDOPAwasnegative.

Table1

Affinityprofiles(IC50)forhumansomatostatinreceptors(SSTR)ofaseriesofsomatostatinanalogs.

Peptides SSTR1 SSTR2 SSTR3 SSTR4 SSTR5

Somatostatin28 5.2±0.3 2.7±0.3 7.7±0.9 5.6±0.4 4.0±0.3

Octreotide >1,000 2.0±0.7 187±55 >1,000 22.6±6

Lanreotide >1,000 1.8±3.4 771±229 >1,000 53±12

In-DTPA-octreotide(pentetreotide) >1,000 22±3.6 182±13 >1,000 237±52

Ga-DOTATOC >1,000 2.5±0.5 613±140 >1,000 73±21

Ga-DOTATATE >1,000 0.2±0.04 >1,000 300±140 377±18

AllvaluesareIC50±SEMinnM.Adaptedfrom[18].

of PNENscan coexist in a MEN1patient (insulinoma and non- secretingtumorsforinstance).Inthecaseofinsulinoma,itiswell establishedthatthedensityofSSTR2islowerascomparedtoother typesofPNENs,whichcould,coupledtothesmallsizeofthelesion, beasourceoffalse-negativeduringOctreoscan^®.Today,echoendo- scopicultrasoundremainsthe“gold-standard”tobothaccurately localizelesionsequivocal ofPNENs andperform histopatholog- icalanalysis,asillustrated inourclinicalcase [1].However,its invasiveprocedureaswellasitsexclusivefocusofthepancreas gland,considerably limit its usefor appreciatingthe extension ofthedisease(e.g.livermetastasis)andfortheperiodicfollow- upofthepatient.Duetoitslowsensitivity,octreoscanhasbeen recentlychallengedbyothernuclearimagingmodalities,suchas SSTR2-PET/CTusingGallium-68(Table1).Therearecurrentlythree studieswhichassessedthediagnosisvalueof(68)Ga-DOTATATE or-DOTATOCPET/CTforthediagnosisofPNENsinMEN1patients [10–12].InthestudybyMorgatetal.(N=19),patientswithMEN1) thesensitivityof(68)Ga-DOTATOCPET/CTwas76%ascomparedto 20%withoctreoscan,respectively(P<0.0001).Moreover,(68)Ga- DOTATOCPET/CTdetectedlesionsofsmallersizethanoctreoscan (10.7±7.6and15.2±5.9mm,respectively,P<0.03)[10].Likewise, theresultsobservedbyLastoriaetal.(N=18MEN1patients)and Sadowskietal.(N=26MEN1patients),alsoconfirmedahighersen- sitivityof(68)Ga-DOTATATEPET/CTascomparedtoconventional imaging (including octreoscan) for thedetection of both PNEN lesionsinaMEN1patientsaswellasthediagnosisoflivermetasta- sis[11,12].BesidesSSTR2-relatedimaging,(18)F-FDOPAPET/CTis nowroutinelyusedinmanyreferalcenterstoconfirmtheneuroen- docrinenatureofpancreaticlesions.Acarbidopapremedication iscommonlyproposedtooptimizethesensitivityofthisimaging procedureinthedetectionofinsulinomas[7],aswellasincaseof non-secretingPNENs[13].Inthelatterstudy,itssensivitywaseven betterwhencomparedtoOctreoscan^®.Apreliminarystudysug- gestedabetterdiagnosisperformanceof(68)Ga-DOTANOC over (18)F-FDOPAfor thedetectionof digestiveNENs[14],however, therespectiveperformanceoftheseimagingmodalitiesintheset- tingofMEN1remainsunstudied.Overall,ithastoberecalledthat significanttechnicaldifferencesexistbetweenallthose imaging

modalities.Eventhoughthesamesomatostatinreceptorsubtype (i.e.SSTR2)istargetedby(68)Ga-DOTATATEandIn-pentetreotide, thespatialresolution of SPECT/CTisclearly lowerthat theone obtainedwithTEP/CT.Therefore,smalllesionsPNENarelikelyless detectedbyOctreoscan^®,independentlyofthedensityofmembra- nousSSTR2.Concerning(18)F-FDOPAPET/CT,adiffuseuptakefrom thepancreasusuallyoccursandconstitutesanobviouslimitation forthedetectionofsmallneuroendocrinelesionsofthepancreas.

Inthatrespect,carbidopapremedicationisnecessarytoimprove thesensitivityoftheexamfortheanalysisofthepancreas.

Our clinical case illustrates that (18)F-FDOPA PET/CT can lead to false negative resultsin a MEN1 patient and therefore shouldpromptclinicianstoprefer(68)Ga-DOTATATEPET/CT.As others [15], we think based on this observation, that (68)Ga- DOTATATE PET/CT should be now systematically performed at the initial diagnosis and in the follow-up of a patient with a MEN1syndrome.Anotherinterestingaspectofthisstatementis that(68)Ga-DOTATATEPET/CT,whenpositive,couldpavetheway foratheranosticapproachinMEN1patientswithPRRT(peptide radionuclidereceptortherapy)using¹⁷⁷Lu-DOTATATE[16].Thelat- terrecentlyshowedtobeavaluabletherapeuticoptioninpatients with SiNENs [17], although its efficacy in PNENs, especially in MEN1,remainstobestudied.

Ethicalapproval

This article does not contain any studies with animals and humanparticipantsperformedbyanyoftheauthors.

Informedconsent

Informedconsentwasobtainedfromallindividualparticipants includedinthestudy.

Funding

Thisstudywasnotfunded.

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M.Jullienetal./Annalesd’Endocrinologie81(2020)39–43

Disclosureofinterest

Theauthorsdeclarethattheyhavenocompetinginterest.

References

[1]Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 2012;97:2990–3011, http://dx.doi.org/10.1210/jc.2012-1230.

[2]Scarpa A.Thelandscapeofmolecularalterationsinpancreaticandsmall intestinalneuroendocrinetumours.AnnEndocrinol(Paris)2019;80:153–8, http://dx.doi.org/10.1016/j.ando.2019.04.010.

[3]Yates CJ, Newey PJ, Thakker RV. Challenges and controversiesin man- agement of pancreatic neuroendocrine tumours in patients with MEN1.

Lancet Diabetes Endocrinol 2015;3:895–905, http://dx.doi.org/10.1016/

S2213-8587(15)00043-1.

[4]ItoT,JensenRT.Imaginginmultipleendocrineneoplasiatype1:recentstudies showenhancedsensitivitiesbutincreasedcontroversies.IntJEndocrOncol 2016;3:53–66,http://dx.doi.org/10.2217/ije.15.29.

[5]Vélayoudom-Céphise FL, Morgat C, Schwartz P, Nunes ML, Guyot M, Schulz J, et al. Étude comparative de la TEP au68GaDOTATOC et de la tomoscintigraphie à l’111In-DTPA-octréotide pour le dépistagedes tumeurs neuroendocrinesduodénopancréatiques des patients por- teursd’une NEM1: étude pilote. Ann Endocrinol (Paris) 2015;76:322–3, http://dx.doi.org/10.1016/j.ando.2015.07.927.

[6]O’TooleD,SaveanuA,CouvelardA,GunzG,EnjalbertA,JaquetP,etal.The analysisofquantitativeexpressionofsomatostatinanddopaminereceptors ingastro-entero-pancreatictumoursopensnewtherapeuticstrategies.EurJ Endocrinol2006;155:849–57,http://dx.doi.org/10.1530/eje.1.02307.

[7]Leroy-FreschiniB, AmodruV,AddeoP,SebagF, VixM,BrunaudL, etal.

Early18F-FDOPAPET/CTimagingaftercarbidopapremedicationasavaluable diagnosticoptioninpatientswithinsulinoma.EurJNuclMedMolImaging 2019;46:686–95,http://dx.doi.org/10.1007/s00259-018-4245-3.

[8]SanthanamP,TaïebD.Roleof¹⁸F-FDOPAPET/CTimaginginendocrinology.

ClinEndocrinol(Oxf)2014;81:789–98,http://dx.doi.org/10.1111/cen.12566.

[9]GoudetP,MuratA,BinquetC,Cardot-BautersC,CostaA,RuszniewskiP,etal.

RiskfactorsandcausesofdeathinMEN1Disease.AGTE(Grouped’Étude desTumeursEndocrines) cohortstudyamong 758patients.WorldJSurg 2010;34:249–55,http://dx.doi.org/10.1007/s00268-009-0290-1.

[10]MorgatC,Vélayoudom-CéphiseF-L,SchwartzP,GuyotM,GayeD,VimontD, etal.Evaluationof68Ga-DOTA-TOCPET/CTforthedetectionofduodenopan- creaticneuroendocrinetumorsinpatientswithMEN1.EurJNuclMedMol Imaging2016;43:1258–66,http://dx.doi.org/10.1007/s00259-016-3319-3.

[11]SadowskiSM,MilloC,Cottle-DelisleC,MerkelR,YangLA,HerscovitchP, etal. Resultsof 68Gallium-DOTATATEPET/CT Scanningin Patientswith Multiple Endocrine Neoplasia Type 1. J AmColl Surg2015;221:509–17, http://dx.doi.org/10.1016/j.jamcollsurg.2015.04.005.

[12]Lastoria S, Marciello F, Faggiano A, Aloj L, Caracò C, Aurilio M, et al. Role of 68Ga-DOTATATE PET/CT in patients with multiple endocrine neoplasia type 1 (MEN1). Endocrine 2016;52:488–94, http://dx.doi.org/10.1007/s12020-015-0702-y.

[13]HelaliM,AddeoP,HeimburgerC,DetourJ,GoichotB,Bachellier P,etal.

Carbidopa-assisted18F-fluorodihydroxyphenylalaninePET/CTforthelocaliza- tionandstagingofnon-functioningneuroendocrinepancreatictumors.Ann NuclMed2016;30:659–68,http://dx.doi.org/10.1007/s12149-016-1110-y.

[14]AmbrosiniV,TomassettiP,CastellucciP,CampanaD,MontiniG,RubelloD,etal.

Comparisonbetween68Ga-DOTA-NOCand18F-DOPAPETforthedetectionof gastro-entero-pancreaticandlungneuro-endocrinetumours.EurJNuclMed MolImaging2008;35:1431–8,http://dx.doi.org/10.1007/s00259-008-0769-2.

[15]Marx SJ. Recent Topics Around Multiple Endocrine Neoplasia Type 1. J Clin Endocrinol Metab 2018;103:1296–301, http://dx.doi.org/

10.1210/jc.2017-02340.

[16]Vija L, Dierickx L, Courbon F. Receptor radionuclide targeting for neu- roendocrinetumors(NET)diagnosticandtherapy.AnnEndocrinol(Paris) 2019;80:166–71,http://dx.doi.org/10.1016/j.ando.2019.04.005.

[17]StrosbergJK.renningE¹⁷⁷Lu-DotatateforMidgutNeuroendocrineTumors.N EnglJMed2017;376:1390–2,http://dx.doi.org/10.1056/NEJMc1701616.

[18]Cuny T, Saveanu A, Taïeb D, Barlier A. Targeting somatostatin recep- tors in gastroenteropancreatic neuroendocrine tumours (GEPNETs):

which radiotracers for which tumours? Med Nucl 2010;34:310–7, http://dx.doi.org/10.1016/j.mednuc.2010.02.003.