outside regular surveillance Contrast imaging techniques to diagnose hepatocellular carcinoma incirrhotics Annals of Hepatology

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ContentslistsavailableatScienceDirect

Annals of Hepatology

j o ur na l ho me p ag e:w w w . e l s e v i e r . e s / a n n a l s o f h e p a t o l o g y

Original article

Contrast imaging techniques to diagnose hepatocellular carcinoma in cirrhotics outside regular surveillance

Massimo Iavarone

^a,∗

, Mauro Viganò

^b

, Nicole Piazza

^a

, Vincenzo Occhipinti

^b

,

Angelo Sangiovanni

^a

, Marco Maggioni

^c

, Gioacchino D’Ambrosio

^d

, Laura V. Forzenigo

^e

, Fabio Motta

^f

, Pietro Lampertico

^a

, Maria-Grazia Rumi

^b

, Massimo Colombo

^g

aC.R.C.“A.M.&A.MigliavaccaCenterforLiverDisease”andDivisionofGastroenterologyandHepatology,UniversityofMilanandFondazioneIRCCSCa’

GrandaMaggioreHospital,Milan,Italy

bHepatologyUnit,OspedaleSanGiuseppe,UniversitàdiMilano,Milan,Italy

cDepartmentofPathology,FondazioneIRCCSCa’Granda,Milan,Italy

dDepartmentofPathology,OspedaleMultimedica,Milan,Italy

eRadiologyUnit,FondazioneIRCCSCa’Granda,Milan,Italy

fRadiologyUnit,OspedaleSanGiuseppe,Milan,Italy

gCenterforTranslationalHepatologyResearch,ClinicalandResearchCenterHumanitasHospital,Rozzano,Italy

a r t i c l e i n f o

Articlehistory:

Received14March2018 Accepted28September2018 Availableonline17April2019

Keywords:

Intra-hepaticcholangiocarcinoma Contrast-enhancedCT-scan Magneticresonance Fineneedleliverbiopsy Abdominalultrasound

a b s t r a c t

Introductionandaim:TheAmericanAssociationfortheStudyoftheLiver(AASLD)recommendscontrast computerizedtomography(CT-scan)andmagneticresonance(MRI)todiagnosehepatocellularcarci- noma(HCC)arisingincirrhoticpatientsundersemiannualsurveillancewithabdominalultrasound(US).

AUSguidedﬁneneedlebiopsy(FNB)servesthesamepurposeinradiologicallyundiagnosedtumors andincidentallydetectednodulesincirrhoticsoutsidesurveillance.Inthispopulation,weevaluatedthe performanceofradiologicaldiagnosisofHCCaccordingto2010AASLDrecommendations.

Materialsandmethods:AllcirrhoticpatientswithalivernoduleincidentallydetectedbyUSwereprospec- tivelyinvestigatedwithasequentialapplicationofCT-scan/MRIexaminationandaFNB.

Results:Between2011and2015,94patients(meanage67years)hadalivernodule(total120)detected byUSinthecontextofhistologicallyconﬁrmedcirrhosis.Meannodulesdiameterwas40(10–160)mm, 87(73%)<5cm.Athistology,84(70%)noduleswereHCC,8(7%)intrahepaticcholangiocarcinoma,6(5%) metastases,2(2%)neuroendocrinetumorsand20(16%)benignlesions.Hyperenhancementinarterial phasefollowedbywash-outinvenousphasesonatleastoneradiologicaltechniquewasdemonstrated in62nodules(61HCC,1highgradedysplasticnodule),withaspeciﬁcityof97%(IC95%:85–100%), sensitivity73%(IC95%:62–81%)anddiagnosticaccuracy80%,being64%for≥5cmHCC.SensitivityofAFP

>200ng/mLwas12%(IC95%:6–23%).

Conclusion:Asinglecontrastimagingtechniqueshowingatypicalcontrastpatternconﬁdentlyidenti- ﬁesHCCalsoincirrhoticpatientswithanincidentallivernodule,therebyreducingtheneedforFNB examinations.

1. Introduction

Thedetectionthroughasemiannualsurveillanceprogramwith abdominalultrasound (US)of a smallhepatocellular carcinoma (HCC)incirrhoticpatientsisassociatedwithmeasurableclinical

∗ Correspondingauthorat:C.R.C.“A.M.&A.MigliavaccaCenterforLiverDisease”, DivisionofGastroenterologyandHepatology,UniversityofMilan,FondazioneIRCCS Ca’GrandaMaggioreHospital,ViaF.Sforza28,20122Milan,Italy.

E-mailaddress:[email protected](M.Iavarone).

beneﬁts,includingimprovedsurvival[1–4].Onthecontrary,the limitedaccessworldwidetoascreeningprogramforanearlydiag- nosiscanrestraintheaccesstocurativetreatmentsinpopulations atrisk(i.e.patientswithnon-alcoholicfattyliverdisease(NAFLD) andalcoholicliverdisease)[5–8].Adherencetosurveillancewith UShasimportantdiagnosticimplicationstoo,sincetheradiologi- caldiagnosisofHCCwithasinglepositivetechnique(i.e.computed tomography–CT-scanormagneticresonanceimaging–MRI)has notbeenextensivelyvalidatedinnodulesdetectedoutsideregu- larsurveillance[3,4].Infact,theseradiologicalcriteriawerebuilt onprospectively collecteddatabasesofpatientswitha de-novo

https://doi.org/10.1016/j.aohep.2018.09.002

creativecommons.org/licenses/by-nc-nd/4.0/).

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livernoduledetectedduringsurveillance[9–11],whilethesame algorithmwasnevervalidatedinthemanagementoflivernodules incidentallydetectedinpatientsoutsideofanysurveillancepro- gram.Indeed,theonlytwostudiestestingthediagnosticaccuracy ofcontrastimagingincirrhoticswithanincidentalHCC,omitted toprovideseparateﬁguresof sensitivityand speciﬁcityof con- trastimagingforincidentaltumorsalone[12,13].Forinstance,the dimensionalincreaseofnodulesinsurveillanceorthechangeinthe appearanceofpre-existingnodulestoeitherultrasoundorTC/MRI are suspect criteria that cannot beapplied to non-surveillance patients.Inaddition,therearebenignlesions,relativelyfrequentin thehealthyliver,theoreticallyrareinthecirrhoticliver,presenting asimilarcontrast-enhancedpattern.Finally,theAmericanCollege ofGastroenterologyintheirguidelineforthemanagementoffocal liverlesionsappliedthenon-invasivecriteriaonthebasisofexpert opinionandtheirdiagnosticalgorithmneedsvalidationforpatients withriskforHCCoutsidesurveillanceprograms[14].

Ina cohortof prospectivelyrecruited cirrhoticpatientswith anincidentallydetectedlivernoduleoutsideofanysurveillance program, we investigated sensitivity, speciﬁcity and diagnostic accuracyoftherecallpolicyforHCCbasedonsequentialapplica- tionofcontrastCT-scan,MRIandecho-guidedﬁneneedlebiopsy (FNB)asrecommendedbythe2010AmericanAssociationforthe StudyoftheLiver(AASLD)guidelines.

2. Patientsandmethods

Thisprospectivestudystartedin January2011andincluded patientswithcompensatedcirrhosisoutsidesurveillanceprograms withUSwhowereincidentallyfoundtohavealivernoduledur- ingclinicalexaminationwithabdominalUS andweretherefore referredtothelivercentersatPoliclinicHospitalorSanGiuseppe Hospital,Universityof Milan(Fig.1).Allpatientsreferredfrom othercentersforalivernodule,underwentanewUSinourCen- terstobeconfirmedafterthefirstvisitandthereaftertheprotocol started.Thestudyprotocolisconformingtotheethicalguidelines ofthe1975DeclarationofHelsinkiandit wasapprovedbythe InstitutionalReviewBoardoftheHospital.Aftergivinganinformed consentinthepresenceofanindependentwitness,patientswere assessedfollowingthecollectionofadetailedmedicalhistory,a physicalexamination,completebloodcountandbiochemicaltests, includingserumalpha-fetoprotein(AFP),andmarkersforviralhep- atitisandautoimmunity,todefinetheunderlyingliverdiseaseif previouslyunknown,andfinallyenrolled.

Cirrhosiswasdiagnosedbyhistologyoronclinicalgroundsby usingabdominalUSfeaturesofblunted,nodularliveredgeaccom- panied by splenomegaly (>13cm) and <100×10³/␮L platelets, esophagealvarices.ExcludedwerepatientsunderUS-surveillance, patientswithapreviouslydiagnosedHCCandpatientswithdecom- pensatedliverdisease,i.e.Child–PughC.Patients–withrecently diagnosedcirrhosisinwhomalivernodulewasdetectedduring theirﬁrstUS–wereconsideredrecruitableintothestudy,since theywerenotconsideredunder-surveillanceprogram.

2.1. Studydesign

AbdominalCTscanwascarriedoutwithin1monthfromthefirst USdetectionorconfirmation(forpatientsreferredfromothercen- ters)ofalivernodule.IfCTscanshowedatypicalvascularpattern in≥1cmnodules,patientsunderwentFNBdirectlytoconfirmthe diagnosisofHCC;otherwiseMRIwasperformedaftertheCTscan.

Inallpatients,aUS-guidedFNBwascarriedoutforthedeﬁnitive diagnosiswithin2monthsfromtheinitialdetection(Fig.1).We arbitrarilyintroducedCT-scanasﬁrstimagingtechniqueforcost effectivenessreasons[9,15].

2.2. Characterizationofthelivernodules

The diagnostic reference was histology through a FNB per- formedwithinthenoduleandthesurroundingliverparenchyma.

AllvisiblenodulesbyabdominalUSunderwenthistologicalchar- acterization. The procedure was repeated in all patients with unsolvedhistologicaldiagnosis,i.e.patientsshowingsimilarhis- tologicalfeatureswithinandoutsidethelivernodule.Allpatients withnoduleslackinghistologicalfeaturesofmalignancy,repeated USat3months’intervalsandanabdominalCT/MRIat6months’

intervalstoassesschangesinsizeandinthevascularpatternofthe noduleatimaging.Allnoduleseitherenlargingorshowingchanges inthevascularpattern,underwentarepeatedFNBexamination.

TheclinicalimpactofthediagnosisofHCCusingserumAFPlevel

>200ng/mLinpatientswitha>2cmnodule,accordingtothe2005 AASLDrecommendationswasevaluatedaswell[16].

2.3. Deﬁnitionofvascularpatternofthenodules

Arterial hypervascularization was deﬁned as an increased contrastenhancementofthenodule(hyperdensityonCT,hyper- intensity on MRI), taking place during the arterial phase of examination,ascomparedtothesurroundingliverparenchyma (wash-in).Portal/venouscontrastwash-outwasahypoenhanced patternofthenodule(hypodensityonCT,hypointensityonMRI) withrespect tothesurroundingliver parenchyma takingplace duringtheportal/venousandlateequilibriumphases.Thetypical radiologicalpatternofHCCwasthehyperenhancementduringthe arterialphasefollowedbycontrastwash-outofthenoduleduring portal/venousandlateequilibriumphases[17].

Weconsideredtypicalonlythosenoduleswithacompleteand homogeneoushyperenhancementinthearterialphase,otherwise weconsideredtheincompleteenhancementasinhomogeneous.CT andMRIimageswereblindlyread,ﬁrstlyindependentlyandina fewcasesjointlywheneveradiscordantresultwasobtainedbytwo experiencedradiologists(LVFandFM).Patientswithadiscrepant resultwerere-evaluatedinadedicatedreadingsessionbythetwo radiologists–unawareoftheliverbiopsyresults–toreachashared ﬁnalradiologicaldescription.

Theradiologicalpatternhasbeenalsoevaluatedforallnodules accordingtoLi-RADSv2017guidelines[18].

2.4. CT-scanandMRI

CT-scanwasperformedwitha 64detectorMDCT(Deﬁnition Siemens,Erlangen,Germany).Inallpatients,weusedabolustrack- ingtechniquetodeterminetheoptimaldelaytimetostartarterial acquisition.

MRIwasperformedwitha1.5-Tsystem(Avanto,SiemensMed- icalSystems,Erlangen,Germany)usingasix-channelphased-array bodycoilforsignaldetectionandgadolinium(GadobenateDimeg- lutamine0.5mmol/L,Multihance,Bracco,Milan,Italy)ascontrast medium.Allpatientsunderwentmultiphasiccontrast-enhanced dynamic3-dimensionalMRIofthewholeliverwithfatsuppres- sion.Inallpatientsweusedbolustrackingtechniquetooptimize thedelaytimetoacquirearterialphase.

Boththetechniqueswereperformedin accordancewiththe technicalindicationsoftheAmericanCollegeofGastroenterology guidelinesandaspreviouslypublishedbyourgroup[9,14].

2.5. Liverhistology

TheFNBprocedurewasperformedusinga21-gaugetrenchant needleformicrohistology(Biomol,HSHospitalService,Italy)to examine both intra-and extra-noduleliver parenchyma tissue:

the comparativeevaluation of the noduleand the surrounding

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Fig.1.Studyﬂow-chart.

parenchyma has been shown to increase the diagnostic accu- racyofhistology.Inthestudytheevaluationofthesurrounding liverparenchyma wouldalsoconfirm thediagnosisof cirrhosis ifdeemednecessary. Thediagnosiswasmade accordingtothe InternationalWorkingPartycriteria[19].Formalinfixedparaffin embeddedliversectionswereexaminedseparatelyandthenjointly bytwo experienced liverpathologists(MM and GD)who were unawareoftheresultofradiologicalexaminations.

2.6. Liverdisease

Patientswereclassiﬁedaccordingtothefollowingcategories forthecauseofcirrhosis:(1)hepatitisBvirus(HBV)infection– patientswithapositiveserumtestforhepatitisBsurfaceantigen only;(2)hepatitisCvirus(HCV)infection–patientspositiveonly forboththeantibodytohepatitisCvirusandHCV-RNA;(3)alco- holabuse–adailyintake>60gofethanolinwomenor>80gin men,formorethanl0years,only;(4)NAFLD–accordingtothe AASLDpracticeguidelines[20];(5)multiplecauses–thiscategory includedpatientswithacombinationoftheabovefactors.

2.7. Statisticalanalysis

Thebaseline characteristicsof thepatientsare expressedas medianandrangeorcountandproportion.Comparisonofpatients withaHCCandpatientswithnon-HCCnoduleswasdonebythe Student’sttestortheMann–Whitneytestforcontinuousvariables andFisher’sexacttestforcategoricalvariables.Aconventionalp

value<0.05 wasconsideredstatisticallysigniﬁcant.Calculations weredonewithStata10.0 statisticalpackage (Stata1944–2007, CollegeStation,TX,USA).

3. Results

Ninety-fourpatientswithaChild–PughAorBcirrhosisandan incidentallydetectedlivernodule,wereincluded.Theindications toUSexamination,whichleadtotheidentiﬁcationofalivernodule, were:abnormalliverenzymesorﬁrstdetectionofHCV-Ab/HBsAg positivityin30(32%),abdominalpainin16(17%),weightlossor anemiain5(5%),apreviousnon-HCCcancerin10(11%),occasional abdominalUSin18(19%)andotherreasonsin15(16%).

3.1. Diagnosisoflivernodule

Atotalof120noduleswereidentifiedbyabdominalUSandcon- firmedbyCT-scan/MRIexaminations(Table1).Livernodulesize rangedfrom10 to160mm(mean40mm),with87(73%) nod- ulesbeingsmallerthan50mm.AnFNBwassuccessfullycarried out in all patients. Four out of 120nodules showedhistologi- calfeaturessimilarwithinandoutsidethenoduleatfirstbiopsy (correspondingtoa totalof3%false-negative resultsatthefirst biopsy)underwentasecondFNBtoreachthefinaldiagnosis.At histology,84(70%)noduleswereHCCin70patients,8(7%)intrahepaticcholangiocarcinoma(iCC),6(5%)metastasesofeithercolon orlungcancerorlymphomaand2(2%)neuroendocrinetumors.

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Table1

Demographyofpatientswithcompensatedcirrhosiswithalivernoduledetectedbyabdominalultrasoundoutsidesurveillance.

Allpatients HCC NonHCC pvalue

Patients,no. 94 70 24

Nodules,no. 120 84 36

Males,no.(%) 73(78) 58(83) 15(63) 0.05

Age,yrs^a 70(44–85) 67(44–83) 73(48–85) 0.24

Riskfactors,no.(%)

HBV 8(9) 8(11) 0 0.1

HCV 28(30) 23(33) 5(21) 0.3

Alcohol 22(23) 18(26) 4(17) 0.4

NAFLD 16(17) 8(11) 8(33) 0.02

Mixed 20(21) 13(19) 7(29) 0.4

Diabetes,no.(%) 30(32) 24(34) 6(25) 0.46

Child–PughclassA,no.(%) 87(93) 64(91) 23(96) 1.0

AFP,ng/mL^a 9(1–60,000) 11(1–60,000) 4(1–101) 0.24

AFP>200ng/mL,no.(%) 8(9) 8(11) 0 0.10

Nodulesize,mm^a 40(10–160) 40(10–160) 30(10–100) 0.4

10–20mm,no.(%) 29(24) 15(18) 14(39) 0.02

21–49mm,no.(%) 58(48) 46(55) 12(33) 0.05

≥50mm,no.(%) 33(28) 23(27) 10(28) 1.0

Nodulesnumber

Single,no.(%) 60(64) 52(74) 8(33) 0.0005

2–3,no.(%) 20(21) 10(14) 10(42) 0.008

Multiple,no.(%) 13(14) 7(10) 6(25) 0.09

HBV,hepatitisBvirus;HCV,hepatitisCvirus;NAFLD,non-alcoholicfattyliverdisease;AFP,alpha-fetoprotein.

aMedian(range).

Table2

Finaldiagnosisof120livernodulesdetectedoutsideregularsurveillancestratiﬁedbysize.

Nodulesize No. HCC iCC MTX NET HGDN LGDN MRN Other^a

10–20mm 29 15(52%) 2(7%) 0 0 2(7%) 4(14%) 2(7%) 4(14%)

21–49mm 58 46(79%) 1(2%) 3(5%) 2(3%) 1(2%) 1(2%) 3(5%) 1(2%)

≥50mm 33 23(70%) 5(15%) 3(9%) 0 0 0 0 2(6%)

Total 120 84(70%) 8(7%) 6(5%) 2(2%) 3(2%) 5(4%) 5(4%) 7(6%)

HCC,hepatocellularcarcinoma;iCC,intrahepaticcholangiocarcinoma;MTX,metastasis;NET,neuroendocrinetumor;HGDN,highgradedysplasticnodule;LGDN,lowgrade dysplasticnodule;MRN,macroregenerativenodule.

a5steatoticnodules,2granulomas.

Accordingto safety concerns, noseeding has beenreported in ourcohort,amongthesenoduleswithafinaldiagnosisofmalig- nancy.Theremaining20noduleswerenon-malignantlesions:3 (2%)highgradedysplasticnodules(HGDN),5(4%)lowgradedysplasticnodules,5(4%)macroregenerativenodules,5(4%)steatotic lesionsandtwo(2%)granulomas(Table2).One-hundredandsev- enteen(98%)nodulesyieldedconcordantreadings,whereasinthe 3noduleswithdiscordantresults,afinalunivocalinterpretation wasreachedbydiscussionbetweenthetwopathologists(2with afinaldiagnosisofHCCand1withafinaldiagnosisofiCC).HCC andnon-HCCnoduleswereequallydistributedintermsofpatient age,size,Child–PughandAFPlevels.Theetiologiesofliverdisease wereequallydistributedbetweenpatientswithHCCandnon-HCC nodules,yetNAFLDwasamorefrequentdiagnosisamongnon-HCC nodules(Table1).Amongnon-HCCnodulesnon-malignantlesions contributed12outof14≤2cmnodules,whileiCCandmetastases werefoundin8/10≥5cmnodulesand4/6>3cmnodulesatpre- sentation.AlltheeightpatientswithanAFP>200ng/mLhadHCC;

ofthemsixhadatleastanodule>2cmaccomplishingboththecri- teriafortheAFP-basedHCCdiagnosisaccordingtothe2005AASLD recommendations:theratesofsensitivity,speciﬁcity,positiveand negativepredictivevaluesandaccuracyofAFPforthediagnosisof HCCwere12%(IC95%6–23%),100%(IC95%75–100%),100%,22%

and29%,respectively.

Amongthe70patientswithadiagnosisofHCC,39werestaged BCLC0/A,16BCLCBand15inanadvancedstage.Amongthe6iCC, onlyonewasclassifiedT1N0M0whileonewasclassifiedT2N0M0 accordingtotheTNMclassification;theotherfourtumorswere alreadymetastaticintheirfirstpresentation.

3.2. Radiologicalinvestigations

ContrastCTand/orMRIconﬁrmedallnodulesdetectedbyUS.

ByCT-scan,thetypicalcontrastenhancementpatternforHCCwas detectedin50(42%)nodules.Twelve(10%)noduleslackingatypical vascularpatternforHCCatCT-scanweresubsequentlyclassiﬁed asHCCbyMRI.AUS-guidedFNBwasdeemednecessarytoobtain adiagnosisintheremaining58(48%)noduleslackingthetypical featuresforHCCatbothradiologicaltechniques.One-hundredand eight(90%)nodulesyieldedconcordantreadings,whereasinthe 12noduleswithdiscordantresults,aﬁnalunivocalinterpretation wasreachedbydiscussionbetweenthetworadiologists(2outof 62wash-inandwash-outpatternand4withoutthetypicalpattern forHCC).

AccordingtoAASLD,sequentiallyapplyingthetworadiological techniques,atypicalcontrastenhancementpatternforHCCwas shownin62nodules(61HCC,1HGDN)withaspeciﬁcityof97%

(IC95%85–100%),andasensitivityof73%(IC95%62–81%)anda diagnosticaccuracyof80%(Table3),withoutanydifferencewith respecttoriskfactors.WhenconsideringonlyCT-scan(ﬁrstradio- logicalmethodusedinallnodulesfordiagnosis)thespeciﬁcitywas 100%(IC95%91.4–100%),andsensitivity56.8%(IC95%45.8–67.3%) andadiagnosticaccuracyof70.5%.

HCC ≥5cm in sizeless frequently showedthecharacteristic radiologicalfeaturescomparedtobothsmall(1–2cm)and2–5cm HCC,showingadiagnosticsensitivityaslowas48%(IC95%29–67%, Table3).Table4showsthedifferentradiologicalpatternsofatypi- cal≥5cmHCCwhereasFig.2showsafrequentlydetectedpattern ofinhomogeneoushyperenhancementfollowedbywash-outina

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Table3

Sensitivityandspeciﬁcityofthetypicalvascularpattern(washin+washout)ofasingleradiologicaltechniqueforthediagnosisofHCCin94patientswith>1cmnodules, stratiﬁedbynodulesize.

Nodulesize PrevalenceofHCC Sensitivity(IC95) Speciﬁcity(IC95) PPV NPV Accuracy

10–20mm 15(52%) 0.733(0.476–0.895) 0.928(0.665–0.999) 0.917 0.762 0.828

21–49mm 46(79%) 0.847(0.715–0.927) 1.0 (0.718–1.0) 1.0 0.635 0.879

≥50mm 23(70%) 0.478(0.292–0.670) 1.0 (0.679–1.0) 1.0 0.451 0.636

Overall 84(70%) 0.726(0.622–0.811) 0.972(0.846–0.999) 0.984 0.603 0.800

HCC,hepatocellularcarcinoma;IC,intervalofconﬁdence;PPT,positivepredictivevalue;NPV,negativepredictivevalue.

Table4

AtypicalfeaturesofMRI/CT-scanimagingandserumAFPlevelsin12HCC≥5cm.

Size(mm) Arterialphase Portalvenousphase Delayedphase AFPvalue(ng/mL)

60 Inhomogeneoushyperenhancement Nowash-out Nowash-out 29

78 Inhomogeneoushyperenhancement Inhomogeneouswash-out Inhomogeneouswash-out 16

50 Hyperenhancement Nowash-out Nowash-out 7

90 Inhomogeneoushyperenhancement Inhomogeneouswash-out Inhomogeneouswash-out 60,000

100 Inhomogeneoushyperenhancement Inhomogeneouswash-out Inhomogeneouswash-out 549

55 Inhomogeneoushyperenhancement Wash-out Wash-out 7

68 Nohyperenhancement Wash-out Wash-out 2593

80 Inhomogeneoushyperenhancement Nowash-out Nowash-out 15

68 Nohyperenhancement Wash-out Wash-out 17

55 Hyperenhancement Nowash-out Nowash-out 29

AFP,alpha-fetoprotein.

Fig.2.AtypicalCT-scanresultsinaHCCnodule51mminsize.Nothomogeneouscontrastuptakeduringthearterial,portal-venousanddelayedphase.

5.5cmHCC.Thesensitivityincreasedto77%(IC95%69–86%)con- sidering typical contrastenhancement pattern for HCC also an inhomogeneoushyperenhancementfollowedbywash-out,with- outanychangeinspeciﬁcity,withadiagnosticaccuracyincreased to83%.Thisapproachfurtherdecreasedtheneedforhistological characterizationto45%ofallUS-detectednodules.

The 16 non-HCC malignant nodules showed heterogeneous arterialpatternsonCT-scan/MRI,withoutevidenceofwash-out inportal/venousanddelayedphases(Table5).Accordingtothe Li-RADScriteria,the120noduleswerecategorizedasLR-2in8, asLR-3in35,asLR-4in9,asLR-4/LR-5in17andasLR-5in51 (SupplementaryTable1).

3.3. AdditionalnodulesmissedbyUS

CT-scan and MRI wereable todetect 45 additional nodules thatwereinitiallymissedbyabdominal-USin14(15%)patients.

Therewere8(57%) synchronousHCC,3(21%)iCC,1metastatic coloncancer,1neuroendocrinetumorand1multiplegranulomas.

Thirty-seven(82%)were≥1cmnodules,allwiththesameradiolog- icalpatterncomparedtothehistologicallycharacterizednodules.

However,thesenoduleswerenotcountedforthesensitivityand speciﬁcityanalyses.HCCwassinglein52(74%)patients,including 36(69%)<5cmtumorsinsize,andmultiplein18(17%),including 3(17%)patientswith≤3nodules≤3cminsize.

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Table5

MRI/CT-scanfeaturesandserumAFPlevelsof16non-HCCmalignantnodules.

Size(mm) Arterialphase Portalvenousphase Delayedphase AFPvalue(ng/mL) Riskfactor Diagnosis 100 “Ring-like”hyperenhancement “Ring-like”hyperenhancement “Ring-like”hyperenhancement 8 NAFLD ColonMTX

90 Inhomogeneoushyperenhancement Nowash-out Nowash-out 2 HCV ColonMTX

25 Nowash-in “Ring-like”hyperenhancement “Ring-like”hyperenhancement 8 Multiple LungMTX

30 Hyperenhancement Hyperenhancement Hyperenhancement 1 Multiple NHLa

55 Hyperenhancement Hyperenhancement Hyperenhancement 24 HCV ColonMTX

25 “Ring-like”hyperenhancement “Ring-like”hyperenhancement “Ring-like”hyperenhancement – – ColonMTX 55 “Ring-like”hyperenhancement “Ring-like”hyperenhancement “Ring-like”hyperenhancement 4 Multiple iCC

50 “Ring-like”hyperenhancement Nowash-out Nowash-out 2 Multiple iCC

55 “Ring-like”hyperenhancement “Ring-like”hyperenhancement “Ring-like”hyperenhancement 2 NAFLD iCC

60 “Ring-like”hyperenhancement Inhomogeneouswash-in Inhomogeneouswash-in 3 NAFLD iCC

20 “Ring-like”hyperenhancement Nowash-out Nowash-out 13 HCV iCC

98 Nowash-in “Ring-like”hyperenhancement “Ring-like”hyperenhancement 3 Alcohol iCC

35 “Ring-like”hyperenhancement Inhomogeneouswash-in Inhomogeneouswash-in – – iCC

55 Nowash-in “Ring-like”hyperenhancement “Ring-like”hyperenhancement – – iCC

30 Hyperenhancement Hyperenhancement Hyperenhancement 6 NAFLD NET

25 Hyperenhancement Hyperenhancement Hyperenhancement – – NET

MTX,metastasis;iCC,intrahepaticcholangiocarcinoma;NET,neuroendocrinetumor;AFP,alpha-fetoprotein;HCV,hepatitisCvirus;NAFLD,non-alcoholicfattyliverdisease;

NHL,nonHodgkinlymphoma.

4. Discussion

Thisstudysuggeststhatthe2010AASLDrecallalgorithmfor thediagnosisofHCCincirrhoticpatientsundersurveillancesuc- cessfullyappliesalsotothediagnosisofaHCCnoduleincidentally detectedincirrhoticpatientswho hadnever beensubjectedto abdominal ultrasound previously. Thus we proved a diagnostic hypothesisonwhichtheguidelinesleftfreedomofinterpretation andtheclinicalpracticewasnotuniform.Theratesofincidentally detectedlivernodulesinthisstudyweresimilartothoseprevi- ouslyreportedinothergeographicalareas[14],thusconﬁrming thatHCCistheprevalent(70%)livernodulefoundincirrhoticsinde- pendentlyontheindicationsofUSexamination[9,10,21,22].Atthe sametime,therelativelyhigherratesofiCCandsecondarytumors inourcohortcomparedtopreviousreports[9–11,13,23],probably reﬂecttheenrollmentofpatientswithreasonsforUSexamination otherthanliver-relateddiseases,likeabdominalpain,anemia,or unexplainedweightloss,togetherwithaprevioushistoryofnon- HCCtumors,morefrequentlyrelatedtoiCCormetastaticcancers.

Ourﬁndingthat non-invasiveradiologicalalgorithm of2010 AASLDrecommendationsledtoaconclusivediagnosisofHCCin halfofpatientswithanincidentallydetectedtumor,isclinically meaningful,especiallyconsideringtheincreasingincidenceofHCC ingroupswheresurveillanceisseldomundertakenorlesseffec- tive(i.e.inpatientswithNAFLDoralcoholicliverdisease)[5,6,24].

Whileourobservationsﬁllagapofliversocietiesrecommenda- tionsrestrictingtheuseofnon-invasivecriteriaforHCCdiagnosisto patientsundersurveillanceonly[9–11],atthesametimetheycom- prisewiththeAGArecommendationsthatendorsenon-invasive criteriaforthediagnosisofHCCinpatientswithriskfactorsfor livercancer,independentlyontheuptakeofsurveillance[14].In ourstudy,thediagnosisofHCCbytheAASLDalgorithmbasedona singlecontrastimagingtechniquewasasaccurateasthatreported inpatientsunderUS surveillance,thusconﬁdentlyreducingthe needforFNBproceduresby52%.Inourstudy,infact,only58nod- ules(eventuallydecreasedto54ifinhomogeneoushyperenhancing nodules followed by wash out are considered) required a FNB examination,comparedto120nodulesinthescenariowherethe AASLDcriteriaareexclusivelyappliedtocirrhoticpatientsunder surveillance.Asamatteroffact,theapplicationofouralgorithm wouldresultinatrivialrate(1%,apatientwithHGDN)offalsepos- itivediagnosis–aspreviouslyreported–[10,13]whereHGDNisa premalignantlesionconsideredbyseveralspecialistsworthtobe treatedwithlocalablation,aswell[25].Itisworthtooutlinethat inpreviousstudiestheratesofmisdiagnosisofHGDNwithCTand MRIscanwerehigherthaninourcohort,reachingapproximately

10%[13],therebyfuelingthediscussiononthecosteffectiveness ofovertreatingbenignliverlesionsthathoweverhaveamalig- nantpotential.Importantly,inanalogywithsurveillancestudies, weconfirmedthatthediagnosisof HCCbasedon“wash-inand wash-out”patternofthecontrastatCTandMRIcouldconfidently separateHCCfromiCCnodulesandsecondarytumorsoftheliver [26,27].Moreover,ourdata confirmedpreviousstudiesfor iCC, showingthe“ring-likehyperenhancement”inarterialphasewith- outwash-out,asafrequentvascularpatternforthesetumorsalsoin cirrhoticlivers[26,27].Theevaluationofthe120nodulesaccording totheLi-RADScriteriaturnedtobefeasibleandreliableparticularly inthosenoduleswithareferencediagnosisofHCCbyhistology:71 (85%)HCCnoduleswerecategorizedasprobablyordefinitelyHCC accordingtotheLi-RADScriteriawithonly3(14%)benignnodules wronglyattributedtothiscategory[18].

Thediagnosticaccuracyofradiologywassuboptimal(64%)ina fewpatientswithanodulelargerthan5cmcomparedtopatients withsmallerlesions.Suchadiscrepancymaybetheconsequenceof thestringentcriteriaweadopted,havingconsidered“non-typical”

those nodules with an inhomogeneouscontrast up-take in the arterialphase. LargeHCCnodulesmayshowaninhomogeneous wash-induringthearterialphaseofaCTorMRIinconsequenceof immaturevascularizationofrapidproliferatingtumorcellsfavor- ingspontaneoustumorcell necrosis[28].Thus, a lessstringent approachwouldhaveleadustoobtainaradiologicaldiagnosisof HCCinthreemoreHCCnoduleslargerthan5cm,furtherreducing theneedforhistologyinnodulescharacterizedbyinhomogeneous contrastup-takeinthearterialphasewithwash-outduringthe portal-venousphases.Incontrastwiththevastmajority(82%)of 1–2cmnodulesthataredetectedfollowingsurveillance[9,10],only 22(23%)patientsofourcohorthadsimilarsmallnoduleswhereas 72(77%)hadlargerthan2cmtumorsincluding30(32%)witha noduleequalorlargerthan5cm.SerumAFPhadnoaddeddiagnos- ticvalueeveninthesettingofpatientswithlargerHCCnodules, inparticularthose≥5cm,acombinationofAFP≥200ng/mLand wash-outresultedinasensitivityof8%andadiagnosticaccuracy of34%.FurtheroutliningthegreaterdiagnosticaccuracyofCTand MRIwithrespecttoUS,15%ofourpatientshadadditionalHCCnod- ulesdetectedbycontrastimagingthathadescapeddetectionwith US.

TheprevalenceofHCCnoduleswaslower(52%)amongnodules

≤2cmcomparedtotheothersizecategorieswithahigherdiag- nosticaccuracy(88%)andahigherNPV(76%)ofthetypicalHCC patternbyimagingtechniques,suggestingalowerriskoffalseneg- ativeresults.However,consideringtheriskofdelaythediagnosis ofsmallandcurableHCCandevenofiCC,wesuggestanaggressive

(7)

diagnosticpolicywithhistologicalcharacterizationafternegative CT-scanandMRI.

Asexpected,therateofpatientswithasinglenodulelargerthan 5cminsizeorwithmorethan3noduleslargerthan3cminsize [29],washigherthantheprevalence(1%)ofde-novoHCCincir- rhoticpatientsunderUS-surveillance[23].Allinall,ourﬁndings lendindirectsupporttosurveillanceasaneffectiveapproachto enhanceaccessofcirrhoticpatientstocurativetreatmentofHCC [1,2],only17(14%)ofourpatientsreceivedcurativetreatments, comparedto25%ofhistoricalseriesofpatientswithaHCCdetected duringsurveillancebetween1987and2001[30].

Werecognizethatourstudyhassomelimitations.Inparticular, wehaveconductedthestudyintwotertiarylevelcenterswitha highqualityequipmentandinterpretedbyradiologistsdedicated toliverdiseasesassessment:probablyamulticenterstudyinvolv- inglessspecializedcentersisneededtoconﬁrmthedatawehave obtainedintermsofspeciﬁcityandsensitivity.

Inconclusion,theaccuracyof the2010AASLDalgorithm for thediagnosisofHCCwithasinglecontrastimagingwasvalidated incirrhoticpatientswitha>1cmnoduledetectedoutsideanyUS surveillance,leadingtoasigniﬁcantsavingofFNBprocedures.

Abbreviations

HCC hepatocellularcarcinoma NAFLD non-alcoholicfattyliverdisease US abdominalultrasound

CT computedtomography MRI magneticresonanceimaging FNB ﬁneneedlebiopsy

AASLD AmericanAssociationfortheStudyoftheLiver AFP alpha-fetoprotein

HBV hepatitisBvirus HCV hepatitisCvirus

iCC intra-hepaticcholangiocarcinoma HGDN highgradedysplasticnodules LGDN lowgradedysplasticnodules Funding

None.

Conﬂictofinterest

Nonerelevanttothemanuscript.

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,atdoi:10.1016/j.aohep.2018.09.002.

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