Simultaneous PET/MR head-neck cancer imaging: Preliminary clinical experience and multiparametric evaluation

ContentslistsavailableatScienceDirect

European

Journal

of

Radiology

jo u r n al ho me p a g e : w w w . e l s e v i e r . c o m / l o c a t e / e j r a d

Simultaneous

PET/MR

head–neck

cancer

imaging:

Preliminary

clinical

experience

and

multiparametric

evaluation

M.

Covello

_,

_C.

_Cavaliere

_,

_M.

_Aiello

_,

_M.S.

_Cianelli

_,

_M.

_Mesolella

_,

_B.

_Iorio

_,

_A.

_Rossi

_,

E.

Nicolai

a_{IRCCSSDN,ViaE.Gianturco,111-113–80143,Naples,Italy}

b_{DepartmentofOtorhinolaryngoiatry,FedericoIIUniversity,Naples,Italy}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received17March2014

Receivedinrevisedform26March2015 Accepted11April2015 Keywords: Hybridimaging PET/MR SUV DCE DWI

Headandneckcancer

a

b

s

t

r

a

c

t

Purpose:ToevaluatetheroleofsimultaneoushybridPET/MRimagingandtocorrelatemetabolicPETdata withmorpho-functionalparametersderivedbyMRIinpatientswithhead–neckcancer.

Methods:Forty-fourpatients,withhistologicallyconfirmedheadand neckmalignancy(22primary tumorsand22follow-up)werestudied.Patientsinitiallyreceivedaclinicalexamandendoscopywith directbiopsy.NextpatientsunderwentwholebodyPET/CTfollowedbyPET/MRofthehead/neckregion. PETandMRIstudieswereseparatelyevaluatedbytwoblindedgroups(bothincludedoneradiologist andonenuclearphysician)inordertodefinethepresenceorabsenceoflesions/recurrences.Regionsof interest(ROIs)analysiswasconductedontheprimarylesionatthelevelofmaximumsizeonmetabolic (SUVandMTV),diffusion(ADC)andperfusion(Ktrans_,V

e,kepandiAUC)parameters.

Results:PET/MRexaminationsweresuccessfullyperformedonall44patients.Agreementbetweenthe twoblindedgroupswasfoundinanatomicallocationoflesionsbyPET/MR(Primarytumors:Cohen’s kappa0.93;Follow-up:Cohen’skappa0.89).TherewasasignificantcorrelationbetweenCT-SUV meas-uresandMR(e.g.,CT-SUVVOIvs.MR-SUVVOI:=0.97,p<0.001fortheentiresample).Therewas alsosignificantpositivecorrelationsbetweentheROIarea,SUVmeasures,andthemetabolicparameters (SUVandMTV)obtainedduringbothPET/CTandPET/MR.Asignificantnegativecorrelationwasobserved betweenADCandKtrans_{valuesintheprimarytumors.Inaddition,asignificantnegativecorrelationexisted}

betweenMRSUVandADCinrecurrenttumors.

Conclusion:OurstudydemonstratesthefeasibilityofPET/MRimagingforprimarytumorsandrecurrent tumorsevaluationsofhead/neckmalignantlesions.WhenassessingHNC,PET/MRallowssimultaneous collectionofmultiparametricmetabolicandfunctionaldata.Thistechniquethereforeallowsforamore completecharacterizationofmalignantlesions.

©2015ElsevierIrelandLtd.Allrightsreserved.

1. Introduction

Headandneckcancers(HNC)accountforapproximately4–5%

ofallmalignantdisease.Ofthese,headandnecksquamouscell

car-cinoma(HNSCC)comprisesthevastmajority(90%)[1].Diagnosis

ofheadandneckcanceristypicallyachievedbyacombinationof

physicalexaminationandeithernasopharyngoscopyand/or

laryn-goscopywithdirectbiopsies.However,thefirstmanifestationof

the diseasecommonly involvesthe cervical lymph nodes, also

thepresenceofdistantmetastasesanddifferentprimariesmust

beconsidered.Followingdiagnosis,accuratestagingiscriticalfor

∗ Correspondingauthor.fax:+39081668841. E-mailaddress:echoplanare@gmail.com(M.Covello).

selectionoftheappropriatetreatmentstrategy.Forearly-stage

dis-ease,surgeryorradiotherapyarethemostcommontreatments,

withasuccessrateofabout80%[2].Postoperativeradiotherapyis

typicallyrecommendedwhentheriskforlocoregionalrecurrence

exceeds20%[3].Forpatientswhosediseaseisnotcontrolledwith

definitiveradiotherapy,salvagesurgeryisrecommended[3].For

regionallyadvancedHNSCC,concurrentchemo-radiotherapyhas

beenwidely used[4].Currently, positronemission tomography

(PET)andmagneticresonance(MR)arewell-establishedimaging

techniquesforthestaging[5]andfollow-upofHNC.MRtechniques,

suchasdiffusionweightedimaging(DWI)anddynamiccontrast

enhancement (DCE), along with fluorodeoxyglucose (FDG)-PET

are thebasilar imaging techniques usedto assess angiogenesis

andmetabolisminHNSCC.Developmentofnoninvasiveimaging

biomarkersmightassistinplanningoptimaltreatmentstrategies,

http://dx.doi.org/10.1016/j.ejrad.2015.04.010

whichmayleadtoa morefavorabletherapeuticoutcome [6,7].

Therecentcommercialintroductionof hybridPET/MRscanners

offernewpossibilitiesforoncologicimaging,combiningthewide

rangeofphysiologicalinformation(glucosemetabolism,cell

prolif-eration,hypoxia,cellreceptorexpression)achievablebydifferent

PETtracerswiththehighspatialandcontrastresolutionofMRI.

Moreover, advanced MRI techniques (DWI, DCE and MR

spec-troscopy)yieldfunctionalinformationthatmaycomplementthe

findingsof PET imaging. Todate, severalPET/MRI studies have

shownpromisingresultsforclinicaloncologicapplications[8,9].

ThebestapplicationsforPET/MRIimagingexistforHNC.Duetothe

complexanatomyofthisregionthesuperbsoft-tissuecontrast

res-olutionofMRIisextremelyuseful.Forthisreason,PET/MRIseems

tobehighlyaccurateintheevaluationofprimaryextension

(T-staging).However,ithasnosignificantbenefitwithlymphnodes

involvement(N-staging)andlimitedimprovementformetastasis

detection(M-staging)whencomparedtoPET/CTexamination[10].

Therefore,theaims ofthestudy weretoevaluatefeasibility

ofsimultaneoushybridPET/MRimaginginpatientswithHNC.In

addition,metabolicdataobtainedfromPETandmorphologicand

functionaldata(DWI,DCE)obtainedbyMRIonprimarytumors

and recurrentlesionswere correlated.In this context, thenew

technologyofsimultaneousPET/MRscanningcanbesuitablefor

acomprehensivemultiparametricassessment.Wepresentour

ini-tialclinicalexperiencewithsimultaneousPET/MRimaginginthe

evaluationofpatientsaffectedbyHNC.

2. Materialsandmethods

2.1. PatientpopulationandImagingprotocol

InaccordancewiththeinstitutionalreviewboardandEthical

Committee,44consecutivepatients(meanage57±12;23males

and9females)withhistologicallyconfirmedheadandneck

malig-nancy(22primarytumorsand22recurrenttumors)werestudied

betweenMarch,2012toJune,2013.Exclusioncriteriaconsisted

of>150mg/dLbloodglucose,pregnancy,andstandard

contraindi-cationforMRI.Forprimarytumors,notherapyhasbeenstarted

atthetimeofMRimaging.Forrecurrentlesions,imagingsession

hasbeenperformed6–8weeksaftertheendoftreatment

(includ-ing12patientstreatedwithsurgery,4withradiotherapy,andthe

remainingwithacombination ofsurgeryand radiotherapy).All

patientsunderwent aonedaysingle-injectionimaging protocol

includingPET/CTandsubsequentPET/MR.

Briefly,patientswerefastedforatleast6hbeforescanning,

fol-lowedbybloodglucoseassessmentpriortoFDGinjection.Adoseof

406±40MBqof[18F]-FDGwasinjectedbasedonthepatient’sbody

weight.Followinganuptakeperiod(81±15min),patients

under-wentaPET/CTscan.AftercompletionofthePET/CTscan,patients

thenreceivedaheadandneckPET/MRexamination.

2.2. PET/CTacquisition

PET/CTacquisitionwasperformedonaGeminiTF(Philips

Med-icalSystems,Best,TheNetherlands)tomographdesignedwitha

multi-ringLYSOblockdetectorssystemandanominalaxial

reso-lutionnearthecenteroffieldofviewof4.8mm(FWHM)withan

absolutesensitivityof6.6kcps/MBq,aspreviouslyreported[11].

Accordingtoourroutineprotocolforoncologicalstudies,PET

data was acquired in sinogram mode for 15min with

ama-trix size of 144×144. PET data were reconstructed using the

LOR-TF-RAMLAalgorithm,therefore datawaspostfilteredwith

a three-dimensional isotropic gaussian of 4mm at FWHM.

CT-basedattenuationmaps werecreatedwitha low doseCTscan

(120kV,80mA)usingcommonlyemployedbi-linearscaling.The

acquisitiontimewas3minperbedposition(BP),with5\6BPs(each

21cm)coveringthetrunkofthepatientsstartingfromthepelvis

andmoveduptowardthehead.Followingwholebodyacquisition

anadditionalBPwasacquiredfocusingonthehead/neckregion.

Theresultwasatotalacquisitiontimeofapproximately18mins

perpatientforPET/CT.

Thepatientswerepositionedsupinewiththeirarmsbrought

togetherabovetheheadfortotalbodyacquisitionandwiththeir

armsrestingatthesidesforhead/neckacquisition.

2.3. PET/MRAcquisition

PET/MRwasperformedontheBiographmMR(Siemens

Health-care,Erlangen,Germany).Thissystemconsistsofa3TMRIscanner

featuring high-performance gradient systems (45mT/m) and a

slewrateof200T/m/s.ThePET/MRsystemisequippedwithTotal

ImagingMatrixcoiltechnology(SiemensHealthcare),coveringthe

entirebodywithmultipleintegratedradiofrequencysurfacecoils.

Thecoils,patienttable,andcableshavebeenredesignedforPET/MR

inordertominimizetheirattenuationandtoallowunimpairedPET

acquisitionwiththecoilsinplace.AfullyfunctionalPETsystem

equippedwiththeavalanchephotodiodetechnologyisembedded

intothemagneticresonancegantry.

ThePETscannerhasaspatialresolutionof4.1mm(FWHM)at

1cmandof5.0mm(FWHM)at10cmfromthetransverseFOVand

asensitivityof11.72kcps/MBqatthecenteroftheFOV.

Onaverage,thePET/MRscanstartedabout20minafterthestart

ofthePET/CTacquisition.Bedpositionwasestablishedinorderto

getfullcoverageofthehead/neckregion.Aftercorrectpositioning

wasestablished,thecombinedPET/MRacquisitionwasperformed.

First,acoronal2-pointDixon3-dimensionalvolumetric

inter-polatedbreath-holdT1-weightedMRIsequencewasacquiredand

used for the generation of attenuationmaps and for anatomic

allocation of the PET results. The software of theMRI scanner

automaticallygenerates4differentimages:T1-weightedin-phase,

T1-weighted out-of-phase, water-only, and fat-only.

Simulta-neouslywiththestartoftheDixonMRIsequence,PETacquisition

began toensure correct temporal and regional correspondence

betweenMRIandPETdata.ThePETacquisitiontimewas4minand

consideringsimultaneousMRacquisitionthetotalPET/MR

exami-nationlastedabout30min.

2.4. PETdatareconstruction

PETdataobtainedonthePET/CTand PET/MRscannerswere

processed withcomparable reconstructionand correction

algo-rithms. For both modalities, emission data were corrected for

randoms, dead time, scatter, and attenuation. A 3-dimensional

attenuation-weightedordered-subsetsexpectationmaximization

iterativereconstructionalgorithm(AWOSEM3D)wasappliedwith

3iterationsand21 subsets,gaussiansmoothing of4mminfull

widthathalfmaximum,andazoomof1.Attenuationmapswere

obtainedfromtheCT databybilineartransformation,as

imple-mentedinthepost-processingsoftwareofthePET/CTscannerand

wereusedforattenuationcorrectionofthePET/CTdata.

2.5. MRI-basedattenuationcorrection

PETattenuationcorrection(AC)isacriticalissueforintegrated

PET/MRIscanners.Contrarily toX-rayCT, which inherently

pro-videsapatient-specificmeasurementoftheelectrondensity,MRI

signalisonlyrelatedtoprotondensity.Therefore,MRIis

intrinsi-callyunabletomeasureattenuationfactorsduetoelectrondensity.

Proposedsolutionsaresubstantiallybasedonthecombinationof

custom-tailoredMRIacquisitionswithimageprocessing,pattern

Inthiswork,clinicallyapprovedACisperformedbymeansofthe

attenuationmapsgeneratedonthebasisofthe2-pointDixonMRI

sequencesobtainedforeveryBP.Thisapproachhasrecentlybeen

demonstratedtoprovideresultscomparabletothoseof

conven-tionalattenuationcorrectionbylowdoseCT[12].Theprocedure

hasbeenimplementedinthepost-processingsoftwareofthe

scan-nerandoperatesautomatically.TheDixonfat-andwater-weighted

imageswereused tocreate anattenuationmap with4distinct

tissue-classes:background,lungs,fat,andsofttissue.Attenuation

ofthePETsignalcausedbyinstrumentation,suchasthepatient

bedandthefixedMRIcoils,isautomaticallyintegratedintothe

attenuationmaps[13].

It is worth noting that suchAC approach ignores the

pres-enceofbonystructures,thereforelimitingquantitativeaccuracyin

anatomicaldistrictscontaining(orcloseto)bones[14].Toaddress

thisissue,morerefinedACtechniquesarecurrentlyunder

investi-gationandclinicalvalidation[15].

2.6. MRacquisition

TheMRIprotocolwasperformedwithadedicated16channel

headandneckcoilincluding:coronalSTIR,axialFSET2-weighted,

axial FSET1-weighted,axial diffusion-weightedimaging (DWI),

andasingle-shotechoplanar2DSPAIR.Inthissequencethreeb

valueswereapplied:0,500and800s/mm2_.

Perfusionstudiesweredynamicallyacquiredimmediatelyafter

intravenousadministrationofparamagneticcontrast(Magnevist®_,

Bayer-Schering,Berlin,Germany)with50measurementsofvolume

InterpolatedGREprecededbytwopre-contrastmeasurementsof

thesamesequenceatavariableflipangle(2◦ and15◦).The

con-trastagentadministration(0.2ml/kgbodyweight)wasdonewith

aflow-rateof3.5ml/s,followedbysalineflush,usingapower

injec-tor.

Inaddition,afterdynamicacquisitions,avolumeInterpolated

GREisotropicathighresolutionandaT1-weightedturbospinecho

withfatsuppressionwereacquired.

Table1 shows technicaldetails of theabove-mentionedMR sequences.

InordertoobtaingoodMRIimagequality,allpatientswere

care-fullyinstructedtorefrainfromvigorousswallowingorbreathing

duringimageacquisitionespeciallyduringtheacquisitionofDWI

sequences.Smallbreaksweremadebetweenindividualsequences

toallowpatientstoclearthethroatofmucoussecretions,cough,

orswallow.

2.7. Dataprocessingandmultiparametricanalysis

PETdataobtainedsimultaneouslywithCTandMRexamination

wereprocessed withcomparable reconstruction and correction

algorithms.Forbothmodalities,emissiondatawerecorrectedfor

randoms,deadtime,scatter,andattenuation.

Tumortissuewasidentifiedasanyvoxelinthe3Ddatasetwith

countsgreaterthana fixedthresholdfractionofthepeak

activ-ityinthetumor.Thethresholdlevelfortumorcharacterization

wasselectedasa StandardizedUptake Value(SUV)equal toor

higher than 3.5 [16]. The SUVs were calculated automatically

by the software (Syngo.via, Siemens Medical Systems) using

the body weight method: SUV=[decay corrected tissue

activ-ity (kBq/ml)]/[injected18F-FDG doseper body weight(kBq/g)].

ThemaximumSUV(SUVmax)andmeanSUV(SUVmean)ofthe

tumortissuewerederivedautomaticallybythesoftwareusinga

voxel-of-interest(VOI)methodoftissuedelineationforboththe

acquisitions.Moreover,basedonSUVvalues,avolumetric

charac-terizationoflesionburdenwasmadeassuggestedinaprevious

study[17]consideringametabolictumorvolume(MTV)witha

thresholdof40%ofthemaximumsignalintensity(MTV40).

Twogroupsofoneseniorradiologistexperiencedinheadand

neckimaging(8and10yearsexperience)andonenuclearmedicine

specialist(9and7yearsexperience)wereblindedtothePET/CT

findings and consensuallyreviewed tumor findings on PET/MR

imagesinconsensus.Primarytumorsizeandinfiltrationof

neigh-boringstructureswereassessed(Fig.1A).Acomparisonbetween

PET/CTandPET/MRfindingshasnotbeenperformedconsidering

thatCTexaminationwaswithoutcontrastagentinjectionandthis

couldbiastheanalysisbyunderestimatingCTdiagnosticaccuracy

(Fig.1B).

Subsequently,theDCE-MRimagesweretransferredfor

post-processing to a workstation running commercially available

softwarefortissueperfusionestimation(Tissue4D,Siemens

Med-icalSystems).Aftermotioncorrectionandregistrationofthe

pre-and post-contrast acquisitions, T1 mapping was automatically

performed and a freehand region-of-interest (ROI)was plotted

aroundthetumorincludingtheneighboringvessels(carotid

arter-ies,jugularvein). Thepharmacokineticmodeling wasbased on

atwo-compartmentmodelthatallowsforthecalculationofthe

following:transferconstantbetweenvascular,extravascular,and

extracellularspace(EES)(Ktrans_{);thevolumeofEES(}

_v

e);the

con-stantbetweenEESandbloodplasma(kep);theinitialareaunder

theconcentrationcurve(iAUC)[18].Ktrans_{isaparameterrelated}

tovesselpermeabilityandtissuebloodflow.TheleakagespaceVe

isamarkerofcelldensity,thekepisatransferconstantfromthe

extracellular/extravascularspacetoplasma,and iAUC isrelated

tothebloodvolumeinthetissueofinterest[18].Arterial input

function(AIF)wasrelated togadolinium doseinjectedand was

modeledbyabi-exponentialfunctionusinganintermediatemode

providedbythesoftware.For thesubsequenttumorROI

analy-sis,PET/MRdatasets(PETacquisition,axialT1post-contrastand

axialT2sequences,axialADCmap,andsingleperfusionmapsfor

Ktrans_,

_v

e,kep andiAUC)wereevaluatedintoaunified

measure-mentsframeworkcustomizedintotheSyngo.viasoftwareplatform

(SiemensMedicalSolutions)allowingavisualcomparisonofthe

multiparametric data.Post-contrast T1-weightedas wellas

T2-weightedimageswereutilizedtodrivethetumoroutlineinmajor

diameterlesionslice,whichavoidsnecroticareasandlarge

feed-ingvessels.Therefore,ROIareavalue,referredasthetumorsize

inthemajordiameterlesionslicewasextractedforeachpatient.

Formultiparametriccomparisons,theROIoutlinewasdrawnwith

thesamepositionandextentoneachmaptoautomaticallyextract

maximum and mean values for each parameter (SUVmax and

SUVmeanforthePET; ADCmaxandADCmeanforthediffusion;

Ktrans_,k

ep,

v

maps)(Fig.1A).

Table1

SummaryofMRacquisitionprotocolandsequences.

Sequencename Orientation Repetitiontime(ms) Echotime(ms) Flipangle(◦) Voxelsize(mm3_{) Acquisitiontime(min:s)}

STIR Coronal 5000 84 125 1.1×0.8×3.5 2:02

FSET2-w Axial 5000 117 90 0.7×0.7×3.0 3:10

FSET1-w Axial 590 9.9 150 0.9×0.6×3.0 4:32

DWI Axial 13,800 70 2.8×2.8×4.0 2:11

VolumeInterpolatedGRE Axial 5.37 1.78 15 1.7×1.2×3.6 0:10

VolumeInterpolatedGREISO Axial 4.93 2.29 9 1×1×1 4:41

Fig.1.InA,ROIplacementformultiparametricanalysisina70y.o.malewithHNSCClesioninprimarystaging.ROI(inred)wasmanuallyoutlinedonpost-contrast T1-weighted(T1+C)andT2-weighted(T2)imagesinmajordiameterlesionslice,andfollowingdrawnwithsamepositionandextentoneachmap.InB,acoronalviewofthe samepatientfrombothPET/MRandPET/CTacquisitions.

Moreover, standardized ROIs (1cm2_{) were placed in the}

paraspinalmuscleofeach patientin order toobtainSUV,ADC, andDCE-MRIestimatesinthenormaltissueandprovidesignificant differencescomparedwiththetumortissue.

2.8. Statisticalanalysis

Multiparametricdata wereexportedand analyzedusingthe Sigmaplotv10.0programwithSigma-Statintegrationv3.2(SPSS,

Erkrath,Germany).Ap-valueoflessthan0.05wasconsidered sta-tisticallysignificant.Thevaluesarepresentedasmean±standard deviation(SD).

TheKolmogorov–Smirnovtestwasfirstusedtoexamineifthe datawasnormallydistributed.Cohen’skappawasusedto eval-uateagreementforprimarytumordetectioninPET/MRbetween thetwogroupsofobservers,withoutaccountingforlymphnodes involvementandputativedistantmetastases.Anydifferencesin theparametersestimationsbetweenthenormalandtumortissue andbetweentheprimarytumorsandrecurrentlesionswere deter-minedwitha t-studenttest. Spearman’scorrelationcoefficients werecalculatedtocompareMRIandCTbasedSUVvaluesandto comparemetabolicdiffusionandperfusionparameters.A correla-tioncoefficientof≤0.35wasconsideredlow,0.36–0.67moderate, 0.68–0.90high,and≥0.90tobeexcellentcorrelations[19].

3. Results

3.1. Feasibilityandinterobserveragreement

AllPET/CTandPET/MRstudieswereacquiredsuccessfullyand

weresuitableforfurtherevaluation.

Satisfactoryagreementbetweenthetwoobservergroupswas

foundinanatomicallocationoflesionsbyPET/MR(T-staging)with

nosignificantdifferencesbetweenthetwoclinicallydefinedgroups

(Primarytumors:97%,Cohen’skappa0.93;Recurrenttumors:93%,

Cohen’skappa0.89).

3.2. Multiparametriccomparisonintheoverallsampleand

subgroupsdefinition

ThesummarystatisticsfortheFDG-metabolism,diffusion,and

perfusion measurements in the healthy muscle tissue and the

tumorsaredemonstratedinTable2.

Representativecasesofmultiparametrichead–neckimagingare

showninFigs.2and3.

Whengroupingallpatientstogether(n=44)therewasa

signifi-cantpositivecorrelationsbetweentheROIarea,theSUVmeasures,

and the SUV estimations. Conversely, there was a significant

negativecorrelationbetweenMRSUVROI,andADCMean.There

wasalsoasignificantnegativecorrelationbetweenADCMeanand

Ktrans_{Mean(Table3).}

Inparticular,thereweretwosubgroupsidentifiedforpatients

inprimaryorrecurrenttumors.Primarytumors(n=22)included

11laryngeal,3oral,1sinonasal,2oropharingeal,3parotid,and2

rhinopharingealcancers.

Recurrenttumors(n=22)included14casesoflaryngeal,3oral,

2sinonasal,1parotid,and2rhinopharingealcancers.Inparticular,

11patientsreceivedonlysurgicaltreatment,4radiotherapy,and7

bothchemo-andradiotherapy.

3.3. Multiparametriccomparisoninprimarytumors

Asforasprimarytumorsthecorrelationanalysisdemonstrated

asignificantcorrelationbetweentheROIarea,theSUVmeasures,

andtheSUVestimations.

Conversely,therewasasignificantnegativecorrelationbetween

ADCMeanandKtrans_{Mean(Fig.2;Table3).}

3.4. Multiparametriccomparisoninrecurrenttumors

Asforasrecurrenttumors,theSpearman’scoefficientanalysis

amongthedifferentparametersinthetumorsitesdemonstrateda

significantcorrelationbetweentheROIareaandtheMRSUVROI.

However,thecorrelationwasnotsignificantwithCTSUVVOIorMR

SUVVOI(p=0.35and.23,respectively),whichwasdemonstratedin

primarytumors.Asignificantcorrelationwasalsofoundbetween

theSUVmeasures,MRSUVVOI,andMRSUVROI.Finally,a

signifi-cantnegativecorrelationwasfoundbetweenMRSUVROIandADC

mean(Fig.3;Table3).

No significant differences were detected between the two

groupsformetabolic,diffusionandperfusionparameters.SUV

esti-mationandallperfusionparameters(Ktrans_,k

ep,

v

tumorsweresignificantlyhighercomparedtonormalmuscletissue

inboththegroups(Primarytumors:p<0.001;Recurrenttumors

p<0.001)(Figs.1and2,Table2).Conversely,theADCmeanvalue

intumorswassignificantlylowercomparedtonormalparaspinal

Table2

Summaryofmetabolic,diffusionandperfusionparametersinboththegroups.

Parameter Overallsample Primarytumors Recurrenttumors Muscle

Mean SD Mean SD Mean SD Mean SD

AGE 60.94 2.23 62.52 12.35 59.36 12.93

AREA–Tumorsize (cm2₎ 2.73 0.37 2.99 4.90 2.47 1.73 1 0 CTSUVMean 5.77 1.76 4.53 4.53 7.01 5.75 0.715** _0.065 CTMTV (cm3₎ 14.42 1.62 15.56 19.48 13.27 14.24 MRSUVMean 7.78 2.39 6.09 5.05 9.47 8.91 0.721** _0.077 MRMTV (cm3₎ 11.92 1.58 13.03 16.59 10.81 11.78 SUVMean2D 20.36 1.35 19.40 24.10 21.32 17.66 0.724** _0.079 ADCMean (␮m2_/s) 1193.26 0.14 1193.14 481.68 1193.4 187.09 1483.58* _108.2

Ktrans_Mean(min−1₎

(×1000) 268.09 13.60 277.71 167.29 258.48 150.82 51.18* _10.36 kepMEAN (min−1_)(×100) 83.99 5.98 88.22 62.30 79.76 31.73 51.59* _14.36 iAUCMean (mMmin)(×50) 901.54 17.73 914.08 472.24 889.01 539.96 166.21* _30.27 veMean (×1000) 326.35 25.84 308.08 124.99 344.62 133.11 103.52* _22.03

Abbreviations:CT:computedtomography;SUV:standardizeduptakevalue;MR:magneticresonance;MTV:metabolictumorvolume;ADC:apparentdiffusioncoefficient; Ktrans_{:transferconstantbetweenvascularandEES;kep:constantbetweenEESandbloodplasma;iAUC:initialareaundertheconcentrationcurvein60s;ve:thevolumeof}

EESperunitofvolumeoftissue.

*_p≤0.05; **_p≤0.01.

Fig.2.Multiparametricevaluationofmorphological(T1,andT1+C),metabolic(PET)andfunctional(DWI,ADC,iAUC,ve,kep,andKtrans)ina57y.omalewithrightvocalcord

HNSCCandanteriorcommissureinfiltrationinprimarystaging.Theincreaseofthicknessandenhancementofthetumorsiteinthemorphologicalacquisitions,theincrease ofFDG-uptake,andthereduceddiffusivityinADCwithanincreaseofperfusionparametersweredetected.

Fig.3. Multiparametricevaluationofmorphological(T1,andT1+C),metabolic(PET)andfunctional(DWI,ADC,iAUC,ve,kep,andKtrans)ina69y.o.malerecurrencyafter

surgeryforaHNSCCofthelarynx.Theincreaseofthicknessandenhancementofthetumorsiteinthemorphologicalacquisitions,theincreaseofFDG-uptake,andthe reduceddiffusivityinADCwithanincreaseofperfusionparametersweredetected.

Table3

Significantcorrelationsinmultiparametricanalysis.

Parameters Spearman’s

coefficient

Significance(p value) Overallsample

ROIareavs.CTSUVVOI 0.66 <0.001

ROIareavs.MRSUVVOI 0.61 <0.001

ROIareavs.MRSUVROI 0.61 <0.001

CTSUVVOIvs.MRSUVVOI 0.97 <0.001

CTSUVVOIvs.MRSUVROI 0.88 <0.001

MRSUVVOIvs.MRSUVROI 0.91 <0.001

CTMTVvs.MRMTV 0.94 <0.001

MRSUVROIvs.ADCMean −0.36 0.04

ADCMeanvs.Ktrans_{Mean −0.5 <0.001}

Primarytumors

ROIareavs.CTSUVVOI 0.51 0.04

ROIareavs.MRSUVVOI 0.45 0.04

ROIareavs.MRSUVROI 0.53 0.01

CTSUVVOIvs.MRSUVVOI 0.95 <0.001

CTSUVVOIvs.MRSUVROI 0.81 <0.001

MRSUVVOIvs.MRSUVROI 0.83 <0.001

CTMTVvs.MRMTV 0.93 <0.001

ADCMeanvs.Ktrans_{Mean −0.42 0.04}

Recurrenttumors

ROIareavs.MRSUVROI 0.61 0.04

MRSUVVOIvs.MRSUVROI 0.99 0.01

MRSUVROIvs.ADCmean −0.72 0.01

Abbreviations:ROIarea:tumorsizein2Dmajorlesionsize;Abbreviations:CT: computedtomography;SUV:standardizeduptakevalue;MTV:metabolictumor volume;ADC:apparentdiffusioncoefficient;Ktrans_{:transferconstantbetween} vas-cularandEES.

muscle(Primarytumors:p<0.001;Recurrenttumors:p<0.001) (Table2).

4. Discussion

ThisstudydemonstratedthefeasibilityofPET/MRexamination

fortheevaluationoftheT-stadiuminpatientswithheadandneck

cancerduringstagingorfollow-up.ThisstudyalsofoundPET/MR

examinationtohaveahighinter-observeragreementforlesion

detectionandsignificantrelationshipsamongseveralmetabolic,

diffusion,andperfusionparametersintheprimarytumor.

InthepastthreedecadesPEThasdemonstrateditsvaluein

pro-vidingnon-invasiveinformationoftissueatthemolecularlevel.

The valueof PET lies in itshigh sensitivity tracking of in vivo

biomarkers, however it lacks precise anatomical information,

whichhasbeenovercomewiththeintroductionofthePET/CT

scan-ners.18F-labeledfluorodeoxyglucosepositronemission

tomogra-phy([18F]FDGPET)iscommonlyusedinHNSCCfortumorstaging,

monitoringoftreatmentresponses,detectionofrecurrences,and

radiotherapyplanning[5].AlthoughPET/CTiscurrentlythegold

standardforoncologicalimaging,severallimitationsexist,which

include:substantialamountsofionizingradiationfromrepeated

PET/CTscansduringdiagnosticandfollow-upexaminations;the

anatomicalcontributionofCTislimitedinsofttissuesandareas

withcomplexanatomy(i.e.theheadandneck&pelvisregion).

Theseissuescanbeovercomewithrecentlylaunchedfully

inte-gratedhybridPET/MRscanners,whichcanperformsimultaneous

acquisitionofPETandMRI.BycombininganatomicalMRI,DW-MRI,

DCE-MRIandPETimagingtoobtainconcertedinformationabout

cellularity,perfusionandbiologicalactivityofthetumor(i.e.byuse

ofFDG,FLTorCholine),wehypothesizethatthesensitivityandthe

specificityinoncologystagingcanbeimproved.However,currently

nospecificclinicalindicationforPET/MRhasbeenestablished.

PET/CTand PET/MRstudieswereacquiredin all44 patients

without side effects and were suitable for further evaluation.

Althoughseveralstudieshavedemonstratedthefeasibilityofthis

new powerful tool in oncological imaging, the head and neck

regionincludescomplexanatomywithmanydifferenttissuesin

asmallregionandisoftenaffectedbyinvoluntarymotionartifacts

duringimagingacquisition.Theabilitytoperformsimultaneous

acquisition decreases the acquisition time bypassing putative

co-registrationproblems,especiallyforhigh-temporalresolution

phenomenalikeperfusion.

Indeed,softwarefusionofPETandMRIdataischallenginginthe

neckandthesimultaneousacquisitionoftheMRIandPETdata

pro-videsimprovedcoregistration.ThefeasibilityofPET/MRinthehead

andneckregionhasalsobeenreportedbyothergroups,

demon-stratingagoodMRimagequalitywithoutimpairmentofthePET

signal[20,21].

ThehighcontrastresolutionofMRIcomparedtoCTcreateda

morefinedifferentiationofheadandnecktissues,whichprovideda

correctstagingandfollow-upofHNSCC,mainlyforTstadium

char-acterization[10].Arecentarticlethatexaminedthirtypatientswith

HNCcanceratprimarytumorsfoundahigherdiagnosticaccuracy

forTevaluationsfromretrospectivelyfusedPET/MRcomparedto

PET/CTandacomparableaccuracyforN-staging[22].Ourcurrent

studyalsosupportsthispreviousreportbydemonstratingexcellent

agreementbetweenthetwoobservergroupsfortheanatomic

allo-cationoflesionsbyPET/MR(T-staging).Thishasalsobeenfound

inotherstudies,examiningdifferenttypesofcancer(lymphnodes

anddistantmetastases)revealinginter-readeragreementbetween

observersofabout0.5[23]and0.7[24].

Asfor the correlationanalysis, there wasa significant

posi-tiverelationshipbetweentheROIarea(tumorsizeinthemajor

axiallesion diameter)and theSUV.Thiscorrelationshowsthat

biggerlesionshavehighermetabolicactivity,althoughthe

pres-enceofnecroticintralesionalregionscanbiasSUVestimation.In

this study, we limit this bias performinga manual tumor

out-linein majordiameterlesion slice, avoiding necrotic areasand

largefeedingvessels.Althoughtherearecontroversialresultswith

respecttothecorrelationbetweenthelesionsizeandSUV

measure-ment[25,26]thedifferencesfoundbetweenprimaryandrecurrent

tumors couldbealsodue totheeffect of differenttherapies on

lesionhomogeneity.Fruehwald-Pallamaretal.[26] reportedno

significantdifferences in ADCvalues andSUVmax betweenthe

variousTstagesin31patients.Thepossibleinclusionof

inflamma-tion,fibrosisand/ornecrosiswithintheROIlesionareameasured

alongthemajoraxisisalikelyconsequenceofsurgery,

radiothe-rapy,chemotherapyordifferentcombinedtherapeuticapproaches

duringthefollow-up.Forthesereasons,inordertoreduceeffects

related to treatments, 6–8 weeks from the end of treatment

passedbeforetheimagingstudyofrecurrentlesions.Alsoprevious

reportsandthecurrentstudyhavefoundcomparableestimatesof

metabolicparameters(SUVandMTV)betweenPET/CTandPET/MR

mainly in primary tumors and theoverall sample. In a recent

report[23],averyhighcorrelationbetweentheSUVvaluein

18F-FDG-PET/MRand18F-FDG-PET/CTimaginghasbeendetectedfor

primarytumors,lymphnode,anddistantmetastasesin14patients.

Otherauthors[12,24]foundnostatisticallysignificantdifferencein

diagnosticcapabilitybetweenPET/CTandPET/MRin17patients.

AlthoughMRI-basedACisstillunderdebate[14],2-pointDixon

approachforMRIattenuationhasrecentlyprovidedresults

com-parable tothose of conventional attenuationcorrectionby low

doseCT[12].HighcorrelationbetweenSUVestimatedbyPET/CT

andPET/MRresultingfromthisstudysupportstheseconclusions,

accordingtoapreviouswork[14].Inthecurrentstudywhen

exam-iningmetabolic(SUV),diffusion(ADC)andperfusionparameters

(Ktrans_,k

ep,iAUC,

v

corre-lationbetweenMRSUVROIandADCMeaninrecurrenttumorsand

theoverallsample.Althoughthecelldensity(estimatedbyADC)

andglucosemetabolism(estimatedbySUV)ofatumoraredifferent

physiologicalparameters,onerecentreporthasshownapositive

[26,28]haveobservednosignificantcorrelationbetweenthesetwo

parameterswithMRIandPET/CT.Thenegativecorrelationresulting

fromthisstudyshowsthathighercellularityofthelesions,

reflect-ingonalowADC,parallelswithanincreasedglucoseuptakeand

cellularmetabolism.Controversialresults[26–28],instead,canbe

duetotumorinhomogeneityandcontextualnecroticareas,where

thefreediffusionofwaterprotonsresultsinnoADCrestriction[26].

Inaddition,therewasasignificantnegativecorrelationbetween

ADCMean and Ktrans _{Mean in primary tumors and the overall}

sample. Although few studies have investigated the

relation-ship among these parameters, the resultsappear controversial

[26–28].AninversecorrelationbetweenADCandKtrans_hasalso

beendetectedfor othertumors(i.e.brain)[27],whichsuggests

anintricaterelationshipbetweenvascularpermeability andthe

tumormicroenvironment.Inthis context, twotumoral features

mayexplainthenegativecorrelationbetweentheseparameters.

Fromoneside,tumorproliferationincreasescelldensityandADC

restrictionwhile,fromtheotherhand,neoangiogenesisincreases

immature tumoral vessels and, thereby, vascular permeability

expressedbyKtrans_.

Finally,perfusionparameterssuchasKtrans_havebeen

demon-stratedtobepotentiallypredictiveofpatientresponsetotherapy,

howevercontroversialresultscanbedebated[29].Anydifferences

maybeattributedtotheappliedpharmacokineticmodelling(e.g.

(extended)Toftsmodelormoreelaboratedmodelslikethe

shutter-speedone)[18].Inanycase,Ktransseemstobesuitabletomonitor

therapy(relative)changesintumorsthoughthecorrectnessofthe

absolutevaluesmaybenotalwaysclaimed[30].

5. Conclusions

OurstudydemonstratesthefeasibilityofPET/MRimaging in

theT-stadiumevaluationofHNClesionsduringstagingor

follow-up.Thisintroducesamorecompletecharacterizationofmetabolic,

diffusion,andperfusioncharacteristicsofprimarylesions.

The strength and the originality of this study exists in the

involvementofmultiparametricMRI,whichincludebothdiffusion

andperfusionevaluationsthatarecollectedsimultaneouslyduring

PET/MRacquisition.

Although further improvements should be performed to

increasethevalueofhybridacquisitionofPET/MR(improved

atten-uationcorrectionalgorithmfor bone segmentation,and surface

dedicatedcoilsforheadandneckregion),webelievethis

analy-sismayplayacrucialroleinprognosisandtreatmentofpatients

whenconsideringthepredictivevalueoftheseparameters[29].

Conflictofinterest

Allauthorshavenoconflictsofinterestandnodisclosuresof

financialinteresttoreport.

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