Diffusion volume (DV) measurement in endometrial and cervical cancer: A new MRI parameter in the evaluation of the tumor grading and the risk classification

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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

Diffusion

volume

(DV)

measurement

in

endometrial

and

cervical

cancer:

A

new

MRI

parameter

in

the

evaluation

of

the

tumor

grading

and

the

risk

classiﬁcation

Pier

Paolo

Mainenti

a,∗

_,

_Laura

_Micol

_Pizzuti

a

_,

_Sabrina

_Segreto

b

_,

_Marco

_Comerci

a

_,

Simona

De

Fronzo

b

_,

_Federica

_Romano

b

_,

_Vincenzina

_Crisci

b

_,

_Michele

_Smaldone

b

_,

Ettore

Laccetti

b

_,

_Giovanni

_Storto

c

_,

_Bruno

_Alfano

a

_,

_Simone

_Maurea

b

_,

_Marco

_Salvatore

d

_,

Leonardo

Pace

e

a_IBB_CNR,_Napoli,_Italy

b_Dipartimento_di_Scienze_Biomediche_Avanzate,_Sezione_di_Radiologia,_Università_di_Napoli_“Federico_II”,_Napoli,_Italy c_IRCCS_CROB,_Rionero_in_Vulture,_Italy

d_IRCCS_SDN,_Napoli,_Italy

e_Dipartimento_di_Medicina_e_Chirurgia,_Università_degli_Studi_di_Salerno,_Salerno,_Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received9March2015

Receivedinrevisedform7September2015 Accepted25October2015 Keyword: MRI DWI ADCmaps Diffusionvolume Cervical Endometrial Cancer

a

b

s

t

r

a

c

t

Purpose:AnewMRIparameterrepresentativeofactivetumorburdenisproposed:diffusionvolume (DV),definedasthesumofallthevoxelswithinatumorwithapparentdiffusioncoefficient(ADC)values withinaspecificrange.Theaimsofthestudywere:(a)tocalculateDVonADCmapsinpatientswith cervical/endometrialcancer;(b)tocorrelateDVwithhistologicalgrade(G)andriskclassification;(c)to evaluateintra/inter-observeragreementofDVcalculation.

Materialsandmethods:Fifty-threepatientswithendometrial(n=28)andcervical(n=25)cancers under-wentpelvicMRIwithDWIsequences.Bothendometrialandcervicaltumorswereclassiﬁedonthebasis ofG(G1/G2/G3)andFIGOstaging(low/medium/high-risk).

Asemi-automatedsegmentationprocedurewasusedtocalculatetheDV.AfreehandclosedROI out-linedthewholevisibletumoronthemostrepresentativesliceofADCmapsdeﬁnedastheslicewiththe maximumdiameterofthesolidneoplasticcomponent.Successively,twothresholdsweregeneratedon thebasisofthemeanandstandarddeviation(SD)oftheADCvalues:lowerthreshold(LT=“meanminus threeSD”)andhigherthreshold(HT=“meanplusoneSD”).TheclosedROIwasexpandedin3D,including allthecontiguousvoxelswithADCvaluesintherangeLT-HT×10–3mm2_/s.

AKruskal–WallistestwasusedtoassessthedifferencesinDVamongGandriskgroups.

Intra-/inter-observervariabilityforDVmeasurementwasanalyzedaccordingtothemethodofBland andAltmanandtheintraclass-correlation–coefﬁcient(ICC).

Results:DVvaluesweresignificantlydifferentamongGandriskgroupsinbothendometrial(p<0.05)and cervicalcancers(p≤0.01).Forendometrialcancer,DVofG1(mean±sd:2.81±3.21cc)neoplasmswere significantlylowerthanG2(9.44±9.58cc)andG3(11.96±8.0cc)ones;moreover,DVoflowriskcancers (5.23±8.0cc)weresignificantlylowerthanmedium(7.28±4.3cc)andhighrisk(14.7±9.9cc)ones. Forcervicalcancer,DVofG1(0.31±0.13cc)neoplasmswassignificantlylowerthanG3(40.68±45.65 cc)ones;moreover,DVoflowriskneoplasms(6.98±8.08cc)wassignificantlylowerthanmedium (21.7±17.13cc)andhighrisk(62.9±51.12cc)onesandDVofmediumriskneoplasmswassignificantly lowerthanhighriskones.

Theintra-/inter-observervariabilityforDVmeasurementshowedanexcellentcorrelationforboth cancers(ICC≥0.86).

Conclusions:DVisanaccurateindexfortheassessmentofGandriskclassiﬁcationofcervical/endometrial cancerswithlowintra-/inter-observervariability.

∗ Correspondingauthorat:CorsoVittorioEmanuele,67080122Napoli,Italy.Fax:+390817616013. E-mailaddress:pierpamainenti@hotmail.com(P.P.Mainenti).

http://dx.doi.org/10.1016/j.ejrad.2015.10.014

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1. Introduction

Thetreatmentandprognosisofcarcinomaoftheuterinecervix

and endometrium are determined by the histological subtype,

grade(G)andFIGOstaging.MRIplaysacriticalroleinthe

preop-erativestagingofthesetumorsprovidingdiagnosticinformation

regardingtumorsize,depthofinvasion,inﬁltrationofcontiguous

organsandlymphnodeinvolvement;evaluationofthese

parame-terscontributeschieﬂyfortreatmentplanning[1–3].

DiffusionweightedMRimaging(DWI)isafunctionaltechnique

thatlooksattheBrownianmotionofwaterintissues.In

biologi-caltissues,theBrownianmotionisrestrictedbyinteractionswith

cellmembranes and macromoleculesona microscopiclevel as

wellasit is modiﬁed byanyarchitectural tissue changes [4,5].

IncreasedtissuecellularityobservedintumorsrestrictsBrownian

motion,whichcanbequantiﬁedbycalculationoftheapparent

dif-fusioncoefﬁcient(ADC).Inparticular,ADChasbeenshowntobe

inverselycorrelatedwithtumorcellularityandithasbeen

clini-callyappliedtodistinguishbenignfrommalignanttumors,toassess

tumorgrade,todelineatetumorextent,aswellastoevaluatetumor

treatmentresponse[5–17].

PreviousstudiesregardingtheapplicationsofDWIin

gyneco-logicdiseasesdemonstratedthatcervicalcancershavesigniﬁcantly

lowerADCvaluescomparedtonormalcervicaltissue[6–9].

Simi-larﬁndingshavebeenfoundinendometrialcancers,whichshow

lowerADC values than normal endometriumor benign lesions

[10–17].Ontheotherhand,thereisnoconsensusaboutthe

corre-lationofADCvalueswiththeGofthecervicalortheendometrial

tumors: some authors did not ﬁnd any signiﬁcant correlation

[11,12,14,18],whileothersfoundsigniﬁcantresultsonlyin

differ-entiatingG1fromG3lesionsinendometrialcancers[13].Moreover,

nosigniﬁcantdifferencewasobservedamongADCvaluesof

cer-vicalcancerwhentumorsweresubgroupedonthebasisofFIGO

staging[19].Therefore,thepotentialroleofADCvaluesinthe

eval-uationofGandFIGOstagingofthecervicalandendometrialcancer

isstillunclear.

Signiﬁcantdifferences arereportedin thetechniqueusedto

acquireandtoanalyzeDWI:heterogeneityofacquisition

param-eters (different b-values and acquisition planes), different ROI

placementmethods(singleROI,multipleROIs,manualROIs)and

different ADC values analysis (minimum ADC=ADCmin, mean

ADC=ADCmean,ADCmin/ADCmean=ADCratio)[6,7,10–15].Thus,

lackofacurrentstandardizedDWIprotocolmayhavecontributed

tothelargevarietyofresultsintherelationshipsbetweenADC

valuesandGandFIGOstaging[11–15,18,19].

Methods of ADC maps analysis different from conventional

ROIbasedmeasurementsand abletorepresentthewholesolid

viablecomponentoftheneoplasmmightovercometheabove

mis-matchingresults.Anewstrategy toanalyzetheADCmapsmay

besuggested by PET/CT: a positive correlationbetween tumor

FDGuptakeandthedegreeofcellularityhasbeendemonstrated

[20–22];asaconsequenceofthispositivecorrelation,themetabolic

tumorvolume(MTV),deﬁnedasthevolumeoftumortissueswith

FDGuptakehigherthanadeterminatethreshold,hasbeenshown

toestimatetheactivetumorburden[23].Inthesameway,a

param-etersimilartoMTVmaybecomputedonADCmaps.Becauseofthe

inversecorrelationbetweenADCandtumorcellularity,thevolume

oftissueshowingADCvaluesbelowadeterminatethresholdmay

berepresentativeoftheactivetumorburdenofaneoplasm.Thus,

adiffusionvolume(DV)maybedeﬁnedasthesumofallthevoxels

withinatumorwithADCvaluesbelowadeterminatethresholdand

mayrepresenttheactivetumorburden.Sofar,nostudiesdealing

withDVincancerhavebeenpublished.

Therefore,thepurposesofthepresentstudywere(1)todevelop

amethodtocalculatetheDVonADCmapsinpatientswithcervical

and endometrial cancers; (2) to evaluate the intra- and

inter-observeragreementoftheDVcalculation;(3)tocorrelatetheDV

aswellasthecommonlyusedADCvalueswiththehistological

tumorgradeandtheriskclassiﬁcationandtocomparedirectlythe

performanceoftheseparameters.

2. Materialsandmethods

2.1. Populationselection

Thisretrospectivestudyenrolledallpatientswithendometrial

orcervicalcancerwhounderwentpelvicMRIwithDWIsequences

atourinstitutionbetweenNovember2010andSeptember2012.

The inclusion criterion was histologically proven cervical or

endometrialcancer.Theexclusioncriterionwasprevious

preop-erativechemo-and/orradio-therapybeforeMRIexamination.

Thestudywasapprovedbylocalresearchethicscommittee.

BeforeMRIscan,allpatientsgavetheirinformedconsentto

per-formexaminationaswellasthepermissionfortheuseoftheir

anonymiseddataforresearchpurposes.Thisprocedurerepresents

astandardprotocolinourinstitution.

Theclinicalpresentation,thehistologicaltype,theGandthe

stagingforeachpatientwereobtainedfromtheclinicalrecordsof

thehospital.Thestagingwasdeterminedaccordingtothe

guide-linesoftheInternationalFederationofGynecologyandObstetrics

(FIGO).

Accordingto Gand FIGO staging, endometrial cancerswere

stratiﬁed in three classes of risk determining the management

strategyandprognosis(Table1):lowrisk(stageIAwithG1orG2),

mediumrisk (stageIA withG3or stageIBwithanyGorstage

II)and highrisk (stageIIIor IV)[24,25].Similarly,accordingto

FIGOstaging,cervicalcancerswerestratiﬁedinthree classesof

riskdeterminingthemanagementstrategyandprognosis(Table1):

lowrisk(earlystagedisease:stageIAorIB1orIIA1),mediumrisk

(earlystagebulkydisease:stageIB2orIIA2)andhighrisk(locally

advanceddisease:stageIIBorIIIorIV)[25,26].Thedeﬁnition“bulky

disease”identiﬁesearlystage(IBandIIA)neoplasmswithgreatest

diameter>4cm.Anincreasedriskofnodalinvolvementis

associ-atedtotheselesions[25,26].

2.2. MRItechnique

Images were acquired using a 3T MR scanner (Magnetom

TrioSiemens,Erlangen,Germany)equippedwithamultichannel

phasedarraycoil.Forallsequences,theﬁeldofview(FOV)and

thenumberofsliceswereoptimizedforeach individualpatient

tocovertheanatomyofinterest.Axialandcoronalplaneswere

acquiredperpendicularandparalleltothelongaxisoftheuterine

bodyforendometrialcancerandofcervixforcervicalcancer.

All patients underwent the following MRI unenhanced and

contrast-enhancedprotocol:

-T1-weightedturbospin-echo(TSE)intheaxial-obliqueplane(TR

828ms;TE10ms;slicethickness4mm;matrixsize256×256;

averages3;ﬂipangle140◦;acquisitiontime2.26min);

-T2-weightedTSEinthesagittalplane(TR4500ms;TE102ms;

slicethickness4mm;matrixsize256×256;averages3;

acquisi-tiontime2.26min);

-T2-weightedTSE in theaxial-oblique planewithandwithout

fat suppression(TR 5000ms; TE 94ms; slice thickness 4mm;

matrixsize 256×256;ﬂipangle140◦,averages2;acquisition

time2min);

-T2-weightedTSEinthecoronal-obliqueplane(TR6000ms;TE

106ms;slicethickness4mm;matrixsize256×256;averages2;

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Table1

Treatmentandprognosisofendometrialandcervicalcancerstratiﬁedforclassofrisk.

Endometrialadenocarcinoma Lowrisk Mediumrisk Highrisk

Treatment Totalhysterectomywithbilateral

salpingo-oophorectomy

Radicalhysterectomywithbilateral

salpingo-oophorectomyandpelvic

lymphadenectomy

Para-aorticlymphadenectomymaybe

considered RTisindicated

CTmaybeconsidered

Maximalsurgicaldebulkinginpatientswithagood

performancestatusassociatedtoCT/RT(stageIII) Anteriorandposteriorpelvicexenterationassociated toCT/RT(stageIVa)

PalliativesurgeryassociatedtoCT/RT(stageIVb)

Prognosis Fiveyearssurvivalrate:

>95%

Fiveyearssurvivalrate: 80–90%

Fiveyearssurvivalrate: StageIII:55–65%

StageIV:25–35%

Cervicalcarcinoma Lowrisk Mediumrisk Highrisk

Treatment StageIA

• Conizationortrachelectomy(if

fertilityistobepreserved) • Totalorradicalhysterectomy(if

fertilityisnottobepreserved)

• PLNDifLVSI

StageIB1andIIA1

• RadicalhysterectomyandPLND

• RTmaybeconsidered

RadicalhysterectomyandPLND

associatedtoRTandCT

CombinationofRT/CT

Prognosis Fiveyearssurvivalrate:

StageIA:>90%

StageIB1andIIA1:70–85%

Fiveyearssurvivalrate: 65–75%

Fiveyearssurvivalrate: StageIIB:55–65% StageIII:25–40% StageIV:<15%

-T1-weighted volume interpolated breath hold examination

(VIBE) (TR 3.30ms; TE 1.17ms; slice thickness 2mm; matrix

size256×256;averages1;ﬂipangle13◦;acquisitiontime20s

for each phase) before and after bolus injection of

gadopen-tetate dimeglumine (Magnevist; Berlex Laboratories; dose:

0.2mmol/kg; injection bya powerinjector; rateof injection:

3ml/secfollowedby20mlofnormalsalineﬂush)at30,60,120s

inthesagittalplaneandat180sintheaxial-obliqueplane;

BeforecontrastenhancedT1-VIBEsequences,DWIwasobtained

using a single-shot-echo-planar imaging sequence under free

breathingwithchemicalshiftselectivefat-suppressiontechnique

(SPAIR)andparallelimagingtechnique(GRAPPA-2).Thefollowing

parameterswereusedintheaxial-obliqueplanes(TR5700ms,TE

69ms,slicethickness4mm;matrixsize128×128;averages5;

b-value0,500and1000s/mm2,acquisitiontime3.07min)andinthe

sagittalplanes(TR5000ms,TE70ms,slicethickness4mm;matrix

size128_×128;averages5;b-value0,500and1000s/mm2,

acqui-sition time 3.10min). Followingtheacquisition ofb=0 images,

motion-probinggradientsinthreeorthogonalorientationswere

sequentiallyappliedforeachbvalue.ADCmapwascomputedfrom

theb=0imagesandthediffusion-weightedimagesreconstructed

forb=500and1000s/mm2.Thestandardsoftwareontheimaging

console(SyngoVE36A,Siemens,Erlangen,Germany)wasusedfor

ADCmapcalculation.

2.3. ADCmapsanalysis

Five differentradiologists(eachone withatleast 4years of

experienceinfemalepelvisMRimaging)wereaskedtoanalyse

theimages:threeofthemappliedadifferentROImethodto

calcu-latetheconventionalADCvalues(S.S.,L.P.,M.S.)andtwoofthem

(E.L.,S.D.)deﬁnedtheDV.Thechoicetoselectﬁveradiologistswas

dictatedbythenecessitytopreventthattheapplicationofeach

methodofanalysismightbeinﬂuencedbytheothers.Inorderto

performinter-andintra-observeranalysisofDV,tworadiologists

wereinvolvedandoneofthemwasaskedtorepeattheprocedure

onemonthlater(S.D.).

AllMRIsequencesperformedwereavailabletothereadersatthe

timeofADCmapsanalysis.Eachreaderwasaskedtoidentifythe

tumor,todeﬁneitscontoursandtorecognizethecystic/necrotic

portionsofthelesion.Eachreaderusedtheunenhanced,

contrast-enhancedandDWIimagestodeﬁnethesolidpartofthetumor

anditscontours.Thecystic/necroticportionsweredeﬁnedasareas

withﬂuid-likehyperintensesignalonT2imagesandDWIimages

obtainedatb0valueandwithoutenhancementonT1VIBElesions.

Eachsequencecouldbeinspectedindividuallyaswellas

compara-tivelywiththeothers;moreover,MRIfused-imageswereobtained

ifnecessary. TheROIs placementwas madeusingvisual

corre-lationof theADCmapswithinformation onthecorresponding

unenhanced,contrast-enhancedandDWIimages.Thereaderswere

blindedtoeachother’sresults,clinicalpatientdataandpathology

reports.

2.3.1. ADCvalues

ThreedifferentradiologistsanalyzedtheADCmapsapplying

eachoneamethod.ThemethodA(S.S.)consistedinplacinga

sin-gularROI,aslargeaspossible,withinthetumoronADCmaps,in

theslicecontainingthelargestsolidtumorarea.ThemethodB(L.P.)

consistedindrawingﬁvecircularROIs,wherepossible,

approxi-matelyof5mm2_,_within_the_tumor_on_ADC_maps,_in_each_slice_in

whichthetumorwasdetectable.ThemethodC(M.S.)consistedin

outliningoneROIwhichincludedthewholeneoplasticareaonADC

maps,ineachsliceinwhichthetumorwasdetectable.

For eachpatienttheADCvalues werecalculatedbothin the

axial-obliqueandthesagittalplanes.

TheROIswerealwaysplacedinthesolidcomponentsofthe

tumors,avoidingcystic/necroticareas.

TheADCvalueswereobtainedintermsofADC×10–3mm2_/s

(millimeterssquared/second).

ADCmin, ADCmean and ADCratio were calculated for each

method.

When using the method A, ADCmin and ADCmean were

extractedinthesingularROI.ForthemethodB,ADCminwasthe

minimumvalueofADCobtainedamongallthecircularplacedROIs,

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Fig.1.a,b,candd.Calculationofdiffusionvolume(DV)inapatientwithendometrialcancer.ThemostrepresentativesliceoftheneoplasmwasselectedonADCmaps(a). Thesolidlesionwasoutlinedmanuallywithaline;meanandstandarddeviation(SD)oftheADCvalueswerecalculatedontheresultingfreehandROI;twothresholdswere

successivelygenerated:lowerthreshold(LT)deﬁnedas“meanvalueminusthreeSD”andhigherthreshold(HT)deﬁnedas“meanvalueplusoneSD”(b).Theclosedsurface

wasdeﬁnedonthebasisofLTandHT(c).Successively,theclosedsurfacewasexpandedin3DincludingallthecontiguousvoxelswithADCvaluesintherangeLT–HT,as

aresulttheDVexpressedinccwasobtained(d).Inﬁgured,thedarkpartofthevolumerepresentstheleftsideofthetumorrespecttotherepresentativeslice,whilethe greenpartindicatestherightside.

extractedbyeachROI.InthemethodC,ADCminwasconsidered

astheminimumvalueofthetotalsliceswithinthetumor,while

ADCmeanwascalculatedastheaverageofmeanADCvaluesineach

slice.

2.3.2. Diffusionvolume(DV)

Asemi-automatedsegmentationprocedurewritteninMatlab

(TheMatworks)wasusedforimageanalysis.Thegoalofthe

seg-mentationprocedurewastoselectthesolidcellularpartsofthe

neoplasmandtoexcludethecystic/necrotic/inﬂammatoryones.

Theradiologistselectedthemostrepresentativeslice,deﬁnedas

theslicewiththemaximumdiameterofthesolidcomponentofthe

tumor,andsuccessivelyoutlinedmanuallythewholevisiblesolid

neoplasticcomponentwitha line.Meanandstandarddeviation

(SD)oftheADCvalueswerecalculatedontheresultingfreehand

ROI.Twothresholdsweresuccessivelygenerated:lowerthreshold

(LT)deﬁnedas“meanvalueminusthreeSD”andhigher

thresh-old(HT)deﬁnedas“meanvalueplusoneSD”.Theclosedsurface

representedbythefreehandROIwasexpandedin3D,including,

iteratively,allthecontiguousvoxelswithADCvaluesintherange

LT-HT.Attheendofprocess,theoperatorcheckedtheﬁnal3DROI

toverifythatnovoxeloutsidethecontoursofthesolid

neoplas-ticcomponentwasincluded,eventuallydeletedthemisclassiﬁed

voxelsandeditedtheﬁnal3D-ROI(Fig.1).

Asstatedabove,thecystic/necroticportionswereeliminatedon

thebasisofthevisualcomparisonofADCmapswithT2-weighted

andcontrast-enhancedimages,howeverweestimatedthatamore

restrictivequantitativelyapproachontheADCmapspreventedthe

erroneousinclusionofcomponentsdifferentfromsolidportions

ofthetumor.Theasymmetricrangeswitchedtowardthelower

ADCvalueswassuggestedbytheinversecorrelationbetweenADC

and tumorcellularity(the lower ADCcorrespondtothehigher

cellulardensityvoxels)aswellasthelowervaluesofADCfor

malig-nantcervicalandendometrialtumorrespecttonormaltissuesor

benignlesions.Asaresult,theHTrepresentedafurtherstrategy

toexcludeinﬂammatorychangesaccompanyingthetumoraswell

ascystic/necroticcomponentsnotidentiﬁedbyvisualcomparison

withunenhancedandcontrast-enhancedMRimagesandto

pre-venttheerroneousinclusionofcontiguousnormaltissues.TheLT

wasintendedtoexcludethenoisyvoxels.

Thewholeprocedurewasperformedforboththesagittaland

theaxialimagesbytworadiologistsforinter-observervariability

(E.L.andS.D.).Oneofthetwoobserversrepeatedtheprocedure

onemonthlatertoevaluateintra-observervariabilityoftheresults

(S.D.).

Onlytheprimarytumorswereincludedintheanalysis,andthus

pelviclymphnodeswerenotconsideredforDVanalysis.

2.4. MorphologicalvolumecalculatedonT2images

Anotherradiologist(F.R.)withatleast4yearsofexperiencein

femalepelvisMRimagingoutlinedthewholevisibletumorwith

aclosedlineineachsliceinwhichthetumorwasdetectable.The

closedlineincludedonlythesolidportionsofthetumors,avoiding

ﬂuid/necrotic portions.The T2 volume wasautomatically

com-putedonthebasisofeachslicearea,theslicethicknessandthe

inter-slicegap.

The procedurewas executed for both the sagittal and axial

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Fig.2.a,b,candd.MeanandstandarddeviationofDVvalues(expressedincc)ofendometrialcancersontheyaxis(aandc:axialDV;bandd:sagittalDV)accordingto grading(aandb)andriskgroupclassiﬁcation(candd)reportedonthexaxis.

TheT2volumewasconsideredequaltozerointhosepatientsin

whomthelesionwasnotdeﬁnedonT2imagesanditsidentiﬁcation

couldbeobtainedthankstotheothersetsofimages.

2.5. Statisticalanalysis

Kruskal–Wallistestwithpost-hocanalysiswasusedtoassess

thestatisticaldifferences inmeasuredparameters among

grad-inggroups as wellas among risk groups a nonparametric.A p

value<0.05wasconsideredsigniﬁcant.

Intra-and inter-observervariabilityfor tumorvolume

mea-surementswasanalyzed accordingtothemethodofBlandand

Altmanandbycalculatingintraclasscorrelationcoefﬁcient(ICC)

(0.00–0.2poor,0.21–04fair,0.41–0.6moderate,0.61–0.80good

and0.81–1.00excellentcorrelation)withcorresponding95%

con-ﬁdenceinterval(CI).Inthesameway,thedifferencebetweenaxial

andsagittalmeasurementswasevaluated.

Receiveroperatorcharacteristic(ROC)curveanalysiswas

per-formedtoevaluatetheimpactofthedifferentparametersonboth

Gandriskclassiﬁcation.ROCcurveswereﬁttedforeach

param-eterandtask, and theareaunderthecurve(AUC)wasusedas

performanceindex.The95%conﬁdenceintervalfortheareawas

usedtotestthehypothesisthatthetheoreticalareawas0.5.Ifthe

conﬁdenceintervaldidnotincludethe0.5value,thentherewas

evidencethatthetesthadanabilitytodistinguishbetweenthetwo

groups.Apvalue<0.05wasconsideredsigniﬁcant.Themethodof

Delongwasusedinordertocomparingtheareasundercorrelated

receiveroperatingcharacteristiccurves.

MedCalcStatisticalSoftwareversion13.1.2wasusedfor

sta-tisticalanalysis(MedCalcSoftwarebvba,Ostend,Belgium;http://

www.medcalc.org;2014).

3. Results

3.1. Patients

Thestudy groupconsistedof53 patients, 28 with

histologi-callyprovenendometrialcancer(agerange,31–85years;meanage

58±117years)and25withhistologicallyprovencervicalcancer

(agerange,22–73years;meanage47±121years).

Thirty-twopatientswerepostmenopausal(21with

endome-trialcancer,11withcervicalcancer).

TwoclinicalscenarioswereobservedbeforeMRI:(1)patients

with highly suspicious lesions at transvaginal ultrasonography

examination (n28);(2) patientswithpositive hysteroscopyfor

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Table2

Clinicalpresentation,histologicaltype,grade,FIGOstagingandclassesofriskofendometrialandcervicalcarcinoma.

Endometrialadenocarcinoma n◦ Cervicalcarcinoma n◦

Clinicalpresentation Metrorrhagia 9 Metrorrhagia 9

Menometrorrhagia 2 Menometrorrhagia 2

Vaginalbleeding 12 Vaginalbleeding 7

Asymptomatic 5 Asymptomatic 7

Histologicaltype Endometrioid 26 Squamous 25

Sarcomatoid 1

Squamous 1

Grade Grade1 8 Grade1 2

Grade2 13 Grade2 3

Grade3* ₇ _Grade₃ ₂₀

FIGOstaging IA 14 IA2 2

IB 11 IB1 7 IIIA 1 IB2 1 IIIC1 2 IIA1 2 IIA2 2 IIB 5 IIIB 4 IVA 1 IVB 1

Classesofrisk Lowrisk 13 Lowrisk 11

Mediumrisk 8 Mediumrisk 3

Highrisk 7 Highrisk 11

* _The_sarcomatoid_and_squamous_{adenocarcinomas}_were_taken_to_represent_the_equivalent_of_grade₃_endometrioid_{adenocarcinomas}_because_they_are_considered_to_be

aggressivehistologicalsubtypesandareassociatedwithaworseprognosisthanendometrioidadenocarcinoma.

Table3

Mean,standarddeviation(sd)andrangeofDVandT2volumeforendometrialandcervicalcancer.DVandT2volumeareexpressedincubiccentimeter.

Endometrialcancer Cervicalcancer

Axial Sagittal Axial Sagittal

Diffusionvolume(DV) Mean±sd 9.74±8.99 10.26±9.21 33.33±36.37 32.82±34.23 Range 0.45–33.66 0.39–35.81 0.20–205.33 0.19–181.67 T2volume Mean±sd 12.4±11.5 12.6±11.5 36.86±35.6 35.69±34.82 Range 0–36.45 0–36.8 0–215 0–198

No therapy (surgery, chemo-radiotherapy) was performed

beforeMRIstudy.

Theclinicalpresentation,thehistologicaltype,theG,theFIGO

stagingandtheriskclassiﬁcationclassesaresummarizedinTable2.

3.2. Images

Theprimarytumorwasdeﬁnedatleastinonesetofimagesinall

28patientswithendometrialcancerand25patientswithcervical

cancers.

3.2.1. Endometrialcancer

MeanvaluesandrangevaluesofDV,ADCmin,ADCmeanand

ADCratiofor eachROI protocoland T2volumearedisplayed in

Tables3and4.

BothaxialandsagittalDVvaluesweresigniﬁcantly(p=0.012;

p=0,021respectively)differentamongGgradegroups;in

particu-lar,post-hocanalysisrevealedasigniﬁcantdifferenceofG1vsG2

andG3(Fig.2aandFig.2b).Similarly,bothaxialandsagittalDV

valuesweresigniﬁcantly(p=0.014;p=0.02respectively)different

amongriskgroups;inparticular,post-hocanalysisrevealeda

sig-niﬁcantdifferenceofthelowriskversusthemediumandthehigh

risk(Fig.2candFig.2d).Moreover,theDVmeasuresobtainedon

axialandsagittalplanesshowedanexcellentcorrelation(Fig.3).

Noneoftheothervariables(ADCmin,ADCmean,ADCratio)using

anyof themethodA, Band C showedsigniﬁcant differenceat

Kruskal–Wallisanalysis.

Both axial and sagittal T2 volumes were not signiﬁcant at

Kruskal–WallisanalysisamongG-gradegroupsandriskgroups.

Fig. 3. Inter-planes reproducibility for diffusion volume (DV) measurements (expressedincc)performedinaxialandsagittalplanesfortheendometrial can-cer.Bland–AltmanplotsoftheaverageofaxialandsagittalDV(xaxis)againstthe differencebetweenaxialDVandsagittalDV(yaxis).Thecontinuouslinerepresents themeanabsolutedifferenceinDVbetweenthetwoplanes;thedashedlines rep-resentthe95%conﬁdenceintervalsofthemeandifferences.TheICCwasexcellent (ICC:0.94;95%CI:0.93–0.99).

3.2.2. Cervicalcancer

Mean values, standard deviation and range of DV, ADCmin,

ADCmeanandADCratioforeachROIprotocolandT2volumeare

(7)

Fig.4.a,b,candd.MeanandstandarddeviationofDVvalues(expressedincc)ofcervicalcancersontheyaxis(aandc:axialDV;bandd:sagittalDV)accordingtograding (aandb)andriskgroupclassiﬁcation(candd)reportedonthexaxis.

Fig.5.Inter-planesreproducibilityfordiffusionvolume(DV)measurements per-formedinaxialandsagittalplanesforcervicalcancer.Bland–Altmanplotsofthe averageofaxialandsagittalDV(xaxis)againstthedifferencebetweenaxialDVand sagittalDV(yaxis).Thecontinuouslinerepresentsthemeanabsolutedifferencein DVbetweenthetwoplanes;thedashedlinesrepresentthe95%conﬁdenceintervals ofthemeandifferences.TheICCwasexcellent(ICC:0.97;95%CI:0.95–0.99).

BothaxialandsagittalDVvalues weresigniﬁcantly(p=0.01)

differentamongGgradegroups;inparticular,post-hocanalysis

revealedasigniﬁcantdifferencebetweenG1andG3(Fig.4aand

b).Similarly,bothaxialandsagittalDVvaluesweresigniﬁcantly

(p<0.001)differentamongalltheriskgroups(Fig.4candd).

More-over,theDVmeasuresobtainedonbothaxialandsagittalplanes

showedanexcellentcorrelation(Fig.5).

Relatively to the method A, the axial ADCmean

(G1: 1.17×10–3mm2_/s; _G2: _0.84_×_10–3_mm2_/s; _G3:

0.75×10–3mm2_/s)_and_the_axial_ADCmin_(G1_0.96_×_10–3_mm2_/s;

G2:0.75×10–3mm2_/s;_G3:_0.56_×_10–3_mm2_/s)_were_{signiﬁcantly}

(p<0.05)differentamongGgradegroups;inparticular,post-hoc

analysisrevealedasigniﬁcantdifferenceofG1vsG3.Noneofthe

variables ofmethodA wasable todiscriminateamongtherisk

groups.

Relativelyto themethod B, theaxial ADCmean (earlystage

1.04×10–3mm2_/s;_early_stage_bulky_disease:_0.90_×_10–3_mm2_/s;

locallyadvanceddisease:0.79×10–3mm2_/s)_was_{signiﬁcantly}

dif-ferent (p=0.01) among the risk groups; in particular, post-hoc

analysisrevealedasigniﬁcantdifferenceoftheearlystagevsthe

earlystagebulkydiseaseandthelocallyadvanceddisease.None

ofthevariablesofmethodBwasabletodiscriminateamongtheG

(8)

Table4

Mean,standarddeviation(sd)andrangeofADCmean,ADCmin,ADCratioofeachmethodforendometrialandcervicalcancer.ADCminandADCmeanareexpressedin 10−3mm2_/s.

Endometrialcancer Cervicalcancer

Axial Sagittal Axial Sagittal

MethodA ADCmean Mean±sd 0.86±0.17 0.87±0.16 0.88±0.16 0.89±0.20 Range 0.58–1.30 0.55–1.20 0.57–1.37 0.56–1.53 ADCmin Mean±sd 0.68±0.16 0.67±0.13 0.73±0.15 0.47±0.17 Range 0.37–1.10 0.42–0.91 0.37–1.08 0.44–1.25 ADCratio Mean±sd 0.79±0.06 0.77±0.07 0.83±0.06 0.83±0.04 Range 0.56–0.89 0.6–0,99 0.66–0.98 0.77–0,90 MethodB ADCmean Mean±sd 0.93±0.16 0.95±0.17 0.94±0.15 0.97±0.20 Range 0.70–1.3 0.74–1.46 0.69–1.33 0.66–1.33 ADCmin Mean±sd 0.63±0.15 0.61±0.16 0.70±0.16 0.70±0.17 Range 0.37–1.09 0.42–1.21 0.39–1.06 0.44–1.00 ADCratio Mean±sd 0.68±0.10 0.65±0.10 0.73±0.07 0.72±0.08 Range 0.53–0.84 0.57–0.79 0.56–0.80 0.66–0.76 MethodC ADCmean Mean±sd 0.95±0.18 0.96±0.18 0.98±0.11 1.00±0.12 Range 0.68–1.52 0.68–1.49 0.73–1.14 0.72–1.10 ADCmin Mean±sd 0.66±0.20 0.66±0.19 0.66±0.13 0.67±0.13 Range 0.37–1.26 0.40–1.27 0.39–0.86 0.44–0.88 ADCratio Mean±sd 0.68±0.11 0.68±0.10 0.67±0.08 0.67±0.07 Range 0.42–0.83 0.42–0.86 0.52–0.84 0.53–0.79

Relativelytothe C method, noneof the variables (ADCmin,

ADCmean,ADCratio)wassigniﬁcantdifferentatKruskal–Wallis

analysis.

Kruskal–Wallisanalysisdidnotshowanysigniﬁcantdifference

amongGgradeforbothaxialandsagittalT2volumes.Onthe

con-trary,bothaxialandsagittalT2volumesweresigniﬁcantly(p=0.01)

differentamongtheriskgroups;inparticular,post-hocanalysis

differentiatedsigniﬁcantlythelocallyadvanceddiseasefromthe

earlystageandtheearlystagebulkydiseaseonaxialimagesand

thelocallyadvanceddiseasefromtheearlystageonsagittalimages.

3.2.3. Intra-andinter-observervariabilityofdiffusionvolume.

Theintra-observervariabilityandtheinter-observervariability

wereexcellent(ICC>0.81)relativelytobothendometrial(Fig.6)

andcervicalcancer(Fig.7).

3.2.4. ROCanalysis

Inordertoevaluateandcomparetheclinicalimpact,ifany,of

thedifferentparametersevaluated,ROCanalysiswasperformed

forbothGandriskclassiﬁcation.Actually,patientswithG1andG2

cancersweregrouped,aswellas,patientswithlowandmedium

classofrisk.

Inendometrialcancergroup,theROC-AUCforDVwas

statisti-callysigniﬁcantforbothGandriskclassiﬁcation(Tables5and6),

onthecontrarytheROC-AUCsforalltheotherparameterswere

notsigniﬁcant.

Incervicalcancergroup,onlytheROC-AUCfortheDVwas

statis-ticallysigniﬁcantforbothGandriskclassiﬁcation(Tables7and8).

TheROC-AUCsforalltheotherparameterswerenotsigniﬁcantfor

theriskclassiﬁcation.OnthecontrarytheROC-AUCsforADCratio

(methodAandC)andT2volumewerestatisticallysigniﬁcantforG.

Althoughnosigniﬁcantdifferencewasobservedwhencompared

theROC-AUCsforDV,T2volumeandADCratio,ROC-AUCforDV

showedahighervaluethantheothers.

4. Discussion

Quantitative imaging characterization using advanced

tech-niquesiscurrentlyanongoingtopicinoncology.Theresultsofthis

studysuggestthatDVshowslowintra-/inter-observervariability

andcorrelateswithbothgradingandriskclassiﬁcationofcervical

andendometrialcancers.TheDVvaluesweresigniﬁcantlydifferent

amongGandriskgroupsinbothendometrialandcervicalcancers.

Moreover,theDVperformsbetterthanmorecommonlyusedADC

values,asshownbytheROCanalysis.

Thepotentialroleof ADCvalues inthepreoperative

evalua-tionofGandriskclassiﬁcationofcervicalandendometrialcancer

iscontroversial[7,10,12–14].Theheterogeneousreportedresults

maybeinpartexplainedbyseveraldifferentissues:theADCmin

valuereﬂectsthefunctionalactivityofonlyasmallsampleofthe

totalongoingneoplasticprocess;theADCmeancalculationmaybe

inﬂuencedbytheROIpositioningandsize;theADCratiodepends

ontheaccuracyofbothADCminandADCmeanvalues.Therefore,

thesecontroversialresultssuggestthenecessitytoﬁndan

alter-nativemethodtoanalyzetheADCmaps.Inthepresentstudy,the

DVovercomesthelimitofeachADCvalueandeachmethodofADC

measurementintheassessmentofgradingandriskclassiﬁcationof

bothcervicalandendometrialcancers.TheDVselectstheportions

ofthetumorwithhighcellulardensities,whichrepresenttheactive

tumorburdenand indicatetheaggressivenessof theneoplasm.

Thisobservationiscorroboratedbythefollowingpreviousﬁndings

aboutPET/CTandPET/MRI:(a)theMTVrepresentsmoreaccurately

thanthemaximumstandardizeduptakevalue(SUVmax)theactive

(9)

Fig.6. a,b,c,dIntra-(aandb)andinter-(candd)observersreproducibilityfordiffusionvolume(DV)measurements(expressedincc)inaxial(aandc)andsagittalplanes (bandd)forendometrialcancer.Fortheintra-observerreproducibility,thesameoperatorcalculatedtwicetheDVinbothaxialandsagittalplanes:axial1DV,axial2DV, sagittal1DVandsagittal2DVofthesameoperatorwereobtained.Fortheinter-observersreproducibility,asecondoperatorcalculatedtheDVinbothaxialandsagittal planes:axial2DVandsagittal2DVofthesecondoperatorwereobtained.Bland–AltmanplotsoftheaverageoftheaxialDV(xaxis)againstthedifferencebetweenaxial DV(yaxis)ofthetwomeasurementsperformedbythesameoperator(a)andbythetwooperators(c);thecontinuouslinerepresentsthemeanabsolutedifferenceinDV betweenthetwomeasures;thedashedlinesrepresentthe95%conﬁdenceintervalsofthemeandifferences.Bland–Altmanplotsoftheintra-observerreproducibility(b) andinter-observerreproducibility(d)forsagittalplane.

Table5

ROC-AUCsrelativetoGclassiﬁcationofendometrialcancer.

AUC SE 95%C.I. pValue

ADCmean(methodA) 0.609 0.124 0.407–0.786 0.3788 ADCmean(methodB) 0.636 0.127 0.434–0.808 0.2824 ADCmean(methodC) 0.575 0.131 0.375–0.758 0.5688 ADCmin(methodA) 0.599 0.121 0.398–0.778 0.4163 ADCmin(methodB) 0.653 0.124 0.451–0.822 0.2158 ADCmin(methodC) 0.650 0.132 0.447–0.819 0.2554 ADCratio(methodA) 0.541 0.108 0.343–0.729 0.7050 ADCratio(methodB) 0.531 0.138 0.334–0.720 0.8245 ADCratio(methodC) 0.619 0.134 0.417–0.795 0.3730 T2volume 0.683 0.127 0.468–0.852 0.1521 DV 0.762 0.106 0.564–0.901 0.0137*

AUC:Areaunderthecurve;SE:Standarderror;C.I.:Conﬁdenceinterval.

*_A_p_value_<_0.05_was_considered_{signiﬁcant.}

metabolicactivityonFDG-PETalsohavemorerestricteddiffusion

onDWI,indicatinggreatercelldensity[30–31].

Since both endometrial and cervical cancers show ADC

val-uessigniﬁcantlylowerthannormalendometrial/cervicaltissueor

benignlesions[6,7,10–15]aswellastheviablesolidneoplastic

tis-suerespecttotumornecrosis[32],wesetanasymmetricwindow

aroundtheADCmeanshiftedtowardsthelowestvaluestomake

(10)

Fig.7.a,b,c,dIntra-(aandb)andinter-(candd)observersreproducibilityforthediffusionvolume(DV)measurementsexpressedinccinaxial(aandc)andsagittalplanes (bandd)forthecervicalcancer.Fortheintra-observerreproducibility,thesameoperatorcalculatedtwicetheDVinbothaxialandsagittalplanes:axial1DV,axial2DV, sagittal1DVandsagittal2DVofthesameoperatorwereobtained.Fortheinter-observersreproducibility,asecondoperatorcalculatedtheDVinbothaxialandsagittal planes:axial2DVandsagittal2DVofthesecondoperatorwereobtained.Bland–AltmanplotsoftheaverageoftheaxialDV(xaxis)againstthedifferencebetweenaxial DV(yaxis)ofthetwomeasurementsperformedbythesameoperator(a)andbythetwooperators(c);thecontinuouslinerepresentsthemeanabsolutedifferenceinDV betweenthetwomeasures;thedashedlinesrepresentthe95%conﬁdenceintervalsofthemeandifferences.Bland–Altmanplotsoftheintra-observerreproducibility(b) andinter-observerreproducibility(d)forsagittalplane.

Table6

ROC-AUCsrelativetoriskclassiﬁcationofendometrialcancer.

ADCmean(methodA) 0.541 0.120 0.343–0.729 0.7342 ADCmean(methodB) 0.602 0.123 0.401–0.781 0.4051 ADCmean(methodC) 0.558 0.131 0.359–0.74 0.6589 ADCmin(methodA) 0.514 0.118 0.319–0.706 0.9085 ADCmin(methodB) 0.626 0.121 0.424–0.800 0.2968 ADCmin(methodC) 0.622 0.129 0.421–0.797 0.3413 ADCratio(methodA) 0.650 0.103 0.447–0.819 0.1445 ADCratio(methodB) 0.639 0.118 0.437–0.811 0.2358 ADCratio(methodC) 0.585 0.130 0.385–0.767 0.5129 T2volume 0.714 0.128 0.500–0.875 0.0929 DV 0.816 0.105 0.625–0.936 0.0025*

* _A_p_value_<_0.05_was_considered_{signiﬁcant.}

burden.Asstatedinmaterialandmethodssection,thenecessity

toﬁxtheHT(“meanvalueplusoneSD”)wasintendedtoexclude

theinactiveregionsofthetumorsuchasinﬂammatory changes

accompanyingthetumoraswellasthecystic/necroticcomponents

notidentiﬁedbyvisualcomparisonwithunenhancedand

contrast-enhancedMRimagesandtopreventtheerroneousinclusionof

contiguousnormaltissues,whiletheLT(“meanvalueminusthree

(11)

Table7

ROC-AUCsrelativetoGclassiﬁcationofcervicalcancer.

ADCmean(methodA) 0.595 0.188 0.382–0.785 0.6126 ADCmean(methodB) 0.680 0.163 0.465–0.851 0.2706 ADCmean(methodC) 0.620 0.166 0.406–0.805 0.4692 ADCmin(methodA) 0.520 0.200 0.313–0.722 0.9205 ADCmin(methodB) 0.575 0.159 0.363–0.768 0.6381 ADCmin(methodC) 0.675 0.132 0.460–0.847 0.1833 ADCratio(methodA) 0.850 0.111 0.651–0.960 0.0015* ADCratio(methodB) 0.520 0.159 0.313–0.722 0.8996 ADCratio(methodC) 0.850 0.111 0.651–0.960 0.0016* T2volume 0.825 0.0865 0.605–0.952 0.0002* DV 0.895 0.0728 0.707–0.981 <0.0001*

Table8

ROC-AUCsrelativetoriskclassiﬁcationofcervicalcancer.

ADCmean(methodA) 0.610 0.117 0.397–0.797 0.3464 ADCmean(methodB) 0.685 0.108 0.470–0.854 0.0868 ADCmean(methodC) 0.513 0.119 0.307–0.716 0.9134 ADCmin(methodA) 0.503 0.120 0.298–0.707 0.9784 ADCmin(methodB) 0.558 0.121 0.348–0.755 0.6292 ADCmin(methodC) 0.513 0.121 0.307–0.716 0.9147 ADCratio(methodA) 0.692 0.108 0.477–0.859 0.0749 ADCratio(methodB) 0.565 0.119 0.354–0.760 0.5864 ADCratio(methodC) 0.513 0.120 0.307–0.716 0.9136 T2volume 0.839 0.102 0.621–0.959 0.0929 DV 0.948 0.0403 0.779–0.997 <0.0001*

besubjecttonoiseorartifactscontamination.Relativetothislast

instance,verylow(nonbiologicallymeaningful)ADCvaluesmaybe

observedalsoinregionswithlowsignalinb0imagesinwhichthe

voxelsareaffectedbyrandomsignallossduetonoiseorartifacts.

Inthesevoxels,ADCvaluescanbeverylowconsideringthatthe

ADCcalculationisbasedontheratiobetweenthesignalmeasured

ontheb0andtheb1images.

Everymethodofsegmentationrequeststhechoiceofa

thresh-oldorarangeandthischoicemayrepresentasourceofbias.For

thisreasonthethresholdortherangehastobechosenonthebasis

ofreasonablecriteria.Moreover,everymethodof segmentation

maybeimproved.TheexampleofMTVisthatdifferentmethodsof

segmentationhavebeenproposedasﬁxed(absoluteSUVmax,

per-centageofSUVmax)orgradientthresholds[33–36].Thatmeans

thattheMTVis stilllargelyusedasbiologicalimaging

parame-ter,althoughthemethodtocalculateithaschangedinthecourse

oftime.Someobservationshavetobereportedonthethresholds

usedinourstudy:(1)testingthreedifferentcoupleofthresholds

(“ADCmeanminus3/plus1SD”;“ADCmeanminus2,5/plus1,5SD”;

“ADCmeanminus2/plus2SD”)in8patients,weobservedthatthe

range“ADCmeanminus3/plus1SD”recruitedfewvoxelslocated

outsidethesolidpartofthetumorinonlyapatient,withan

over-allbetterperformancethantheothersranges;settingtherange

“ADCmeanminus3/plus1SD”,themanuallyeditingofthe

auto-matedsegmentationdidnotrequestrobustcorrectionsinanyofthe

53patients;(2)therange“ADCmeanminus3/plus1SD”isbased

onreasonableandrestrictivethresholdsﬁxedtoincludehigh

cel-lulardensityvoxels;(3)therange“ADCmeanminus3/plus1SD”

offeredanexcellentcorrelation(ICC>0.81)betweenthe

measure-mentsobtainedontheaxialandthesagittalplanes,anexcellent

agreement(ICC>0.81)attheintra-andinter-observervariability,

asigniﬁcantdiscriminationofthegradingandtherisk

classiﬁca-tionofbothcervicalandendometrialcancers;(4)theDVappears

asavalidbiologicalimagingparameter.Ofcourse,themethodof

segmentationweproposeinthepresentstudymaybeimproved

andreﬁnedwithincreasingdatacollectionandanalysis.

ThevolumesexpressedbytheDVweredifferentfromthose

computedonT2imagesandcorrelated signiﬁcantlywiththeG

andtheriskclassiﬁcation.ThisﬁndingsuggeststhattheDVand

themorphologicalvolume representdifferentaspectsofa

neo-plasmandthattheformerisnotexclusivelydeﬁnedbytheguide

ofanatomicalimages.Apossibleexplanationofthisresultisthat

theinﬂammatorychangesaccompanyingtheneoplasticinﬁltration

givesanoverestimationoftumorsizeonT2 images.The

asym-metric window around theADCmeanused tocalculate theDV

mayallowexcludingalsotheinﬂammatoryperilesionalreaction.

AsimilardiscrepancywasobservedbetweenFDG-PETvolume(at

SUVmaxcut-offpercentageof40%)andT2-weightedvolumein

cer-vicalcancerwithPET/MRI[37].Ontheotherhand,thesameAuthors

reportednosigniﬁcantdifferencebetweenFDG-PET(atSUVmax

cut-offpercentageof35%and40%),T2-weightedandDWIvolumes

incervicalcancerwithPET/MRI[31].Themaindifferencewithour

studyis relatedtothemethodof tumoroutlining:theAuthors

selectedthewholegrossneoplasticvolume,whilewelookedonly

atthesolidparts.Theseresultsaswellasourssuggestthat,rather

thandemonstratingoverlapordiscrepancybetween

morphologi-calandfunctionalvolume,itiscrucialtoﬁndandemphasizewhich

morphologicalandfunctionalinformationmayberepresentative

ofthetumorbiologicalcharacteristics.

Recently,thequantitativehistogramanalysisofADCmapshas

beenproposedintheidentiﬁcationofadversehistological

char-acteristicsofstageIcervicalcarcinoma[18].Wedidnotconsider

usingthequantitativehistogramanalysisinourpopulationbecause

themethodlooksattheheterogeneityevaluatingthewhole

neo-plasm(solidcellular,inﬂammatory,cystic/necroticparts)rather

thantheactiveneoplasticburdenwhichrepresentsthegoalofour

(12)

val-ueswouldbeanywaypresentingettingDVfromthepercentilesor

theskeworthekurtosismeasurements.

ThevariationsinROIsizeandpositioninghavebeenshowedto

haveasigniﬁcanteffectontumorADCvaluesandinter-observer

variabilityinpatientswithrectalcancer[38].Moreover,itisnot

clearlydeﬁnedwhichADCvalue(ADCmin,ADCmean,ADCratio)

ismorerepresentativeoftumoraggressiveness[6,7,10–15].Asa

consequence,wechosetoanalyzetheADCmapswiththree

differ-entsetsofROIsaswellastotestthreedifferentvaluesofADCto

preventthatthelackofcorrelationwithclinicalparameterscould

beattributedtothemethodofanalysis.Inourseries,the

correla-tionofallthetestedADCvalueswithgradingandriskclassiﬁcation

resultedunsatisfyingforbothendometrialandcervicalcancer.On

thecontrary,theDVappearedtoberepresentativeofthe

aggres-sivenessofthetumor.

Inconclusion,theDVcorrelateswithgradingandrisk

classiﬁ-cationofbothcervicalandendometrialcancersaswellasitshows

lowintra-/inter-observervariability.Prospectivestudiesinlarger

populationshavetobedesignedtoconﬁrmourobservations.

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