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Multi-detectorspiralCTstudyoftherelationshipsbetweenpulmonaryground-glassnodulesandbloodvesselsEurRadiol(2013)23:32713277Multi-detectorspiralCTstu1AbstractObjective:Toinvestigatetherelationshipsbetweenpulmo-naryground-glassnodules(GGN)andbloodvesselsandtheirdiagnosticvaluesindifferentiatingGGNs.Conclusion:DifferentGGNshavedifferentrelationshipswithvessels.UnderstandingandrecognisingcharacteristicGGN-vesselrelationshipsmayhelpidentifywhichGGNsaremorelikelytobemalignant.AbstractObjective:Toinvesti2KeyPointsMulti-detectorCToffersnewinformationaboutground-glassnodules.Differenttypesofground-glassnoduleshavedifferentrelationshipswithvessels.Thismayhelpidentifywhichground-glassnodulesarelikelytobemalignant.KeyPointsMulti-detectorCTo3IntroductionWiththeextensiveacceptanceoflow-dosemulti-detectorspiralCTinlungcancerscreening,thenumberofdetectedGGNsorfocalground-glassopacities(fGGOs)hasdramaticallyincreased.GGNscanresultfromneoplasms,suchaspulmonaryadenocarcinoma,orbenigndiseases,suchasfocalfibrosis,inflammationoralveolarhaemorrhage.IntroductionWiththeextens4Inaddition,pre-invasiveabnormalities,includingatypicaladenomatoushyperplasia(AAH)andadenocarcinomainsitu(AIS).IthasbeenreportedthattheproportionofmalignancyinGGNsishigherthaninsolidpulmonarynodules(SPNs)andthemajorityofmalignantGGNsareadenocarcinoma.Duetoimagingresemblance,however,itisextremelychallengingtodifferentiatemalignantGGNsfromtheaforementionedbenigncounterparts.Inaddition,pre-invasiveabno5AccuratedifferentialdiagnosisofGGNswillassistphysicianstomaketreatmentdecisionsandimprovetreatmentoutcomesandprognosis.SeveralinvestigatorshavesuggestedthatanalysisofrelationshipsbetweenSPNsandsurroundingvesselscanhelppredictthelikelihoodofmalignancyinsuchnodules.TherelationshipbetweenGGNsandbloodvesselsremainsunknown.WhetherthisrelationshipcanbeutilisedtofacilitatethediagnosisofmalignantGGNsisaworthyofinvestigation.Accuratedifferentialdiag6MaterialsandmethodsPatientsTheimagingdataofpatientswithpulmonaryGGNsreceivingthin-sectionmulti-detectorCTexaminationatourhospitalinJanuary2011throughNovember2012wereretrospectivelyreviewed.Alllesionsweresolitaryandmostofthem(104/108)surgicallyresectedwithin2weeksafterCTscanning.Materialsandmethods7InclusioncriteriaTheGGNsizewaslessthan3cminthelargestdimension.ground-glassopacity(GGO)comprisedmorethan50%oftheareaofthelesiononCT.-Anareaofover50%GGOwassetasthecutoffvaluetoexcludesolid/semi-solidlesions.-AlthoughsolidnodulesfrequentlyhadGGOcomponentsaroundtheirmargin,probablyrepresentingsurroundingoedemaormerelypooraerationofthesurroundinglungtissuesduetocompressionorretractionbynodules,thesenoduleshadalreadybeenwellinvestigatedusingCTandthereforewerenotthestudyobjects8Ultimately,108patientswereenrolledintothisstudy,including38malesand70femaleswithmeanageof58.1812.89years(range,22to79years).43patientswereasymptomatic,28hadrespiratorysymptoms,and37hadlungcancerriskfactors,suchassmokingandfamilyhistory.Ultimately,108p9Accordingtopathologicalfindings,GGNsweredividedintothreegroups:(1)Benigndiseasegroup(10cases),includingfournodulesdiagnosedwithacombinationofclinicalsymptomsandimagingpresentations(nodulesdisappearedorgraduallyreducedinsizeonmultiplefollow-upCTimaging)andsixnodulesconfirmedbypathologicalexamination(1caseofsclerosinghaemangiomaand5casesofchronicinflammation).(2)Preinvasivediseasegroup(24cases),including7AAHsand17AISs.Accordingtopathological10(3)theinvasiveadenocarcinomagroup(74cases),confirmedpathologically,therewere39non-mucinousminimallyinvasiveadenocarcinomas(MIA)and35invasiveadenocarcinomas(IAC;specifically,13lepidicpredominantadenocarcinomas;19acinus-predominantadenocarcinomas;2papillary-predominantadenocarcinomasand1solidpredominantwithmucin粘蛋白production).(3)theinvasiveadenocarcin11CTimaginganalysisprotocolparameters:0.625-mmsectionwidthwitha0.625-mmreconstructioninterval,pitchof0.984,120kVand250mA.Allimageswerereviewedwithahigh-resolution,2,0481,560pixel,standardlungwindow(ww,1,500HU;wl,-500HU)andmediastinalwindow(ww,350HU;wl,50HU)GGNscanbefurthersubdividedintomixedground-glassnodules(mGGNs)andpureground-glassnodules(pGGNs).ThepercentageoftheGGOcomponentwascalculatedasfollows:(DGGO-D)/DGGO100,whereDGGOisthelargestdiameteroftheentirelesionandDisthelargestdiameterofthesolidcomponentwithinthelesion.CTimaginganalysisprotocolpa12BloodvesselanalysiswasperformedintermsofvascularmorphologyandvascularrelationshipswithGGNlesions.thediameterofpulmonaryvesselsgraduallydecreasesfromthehilumtowardtheperiphery.Ifthediameterofthevascularsegmentwithinlesionswaslargerthantheproximalsegmentorlesionvesselswereapparentlywiderthanothervesselsatthesamebranchlevel,thevesselwasdeemedasabnormalvascularbroadening.Thevesselswereconsideredtobedistortedorrigidiftravelingastrayfromtheexpectednormalcourse.Bloodvesselanalysiswasper13Multiplesupplyingvessels,withdifferentoriginatingsources,convergingtowardalesion,wereprobablyindicativeofanincreasedbloodcirculationwithin.Tofurtherclarifyaffiliationsofsupplyingvessels,wetracedvascularcoursesslice-wisebackwardtomajorvesselsinthehilum.TherelationshipsbetweentheGGNsandsupplyingbloodvesselswereanalysedinaxialimages,MPRimagesCPRimages.Multiplesupplyingvessels,wi14theGGN-vesselrelationshipswerecategorizedintofourtypesaccordingtoimagingfeatures:typeI(pass-by),vesselspassedbyGGNswithoutdetectablesupplyingbranchestolesions.typeItheGGN-vesselrelationsh15typeII(pass-through),vesselspassedthroughthelesionswithoutobviousmorphologicalchangesintravelingpathorsize.typeII(pass-through),16typeIII(distorted/dilated),vesselswithinlesionsweretortuousorrigidwithoutanincreaseinamounttypeIII(distorted/dilat17typeIV(complicated),morecomplicatedvasculatureotherthandescribedintheaforementionedtypeswithinGGNs,forinstance,coexistenceofirregularvasculardilationandvascularconvergencefrommultiplesupplyingvessels.typeIV(complicated),morec18PathologicalanalysisThepathologicaldiagnosisandcategorisationofAAH,AIS,MIAandIACweremadebasedonthenewpulmonaryadenocarcinomaclassification,2011edition.GGNswereresectedbyvideo-assistedthoracoscopyorthoracotomysurgery.Allhistologicalpreparationsandanalyseswereperformedbytwoseniorpathologists.Inthecaseofdisagreements,aconsensuswasreachedaftermutualdiscussionand/orconsultationwithathirdpathologist.PathologicalanalysisThepath19StatisticalanalysisSPSS16.0forWindows,SPSS,Chicago,IllIndependentttestwasusedtocomparedifferentpathologicalgroups(benigndiseases,preinvasivediseasesandinvasiveadenocarcinoma)ofGGN.CorrelationsbetweenpathologicalfindingsofGGNsandGGN-vesselrelationshipswereexaminedusingSpearmansranktest.GGN-vesselrelationshipsbetweenMIAandIACdiseaseswerecomparedusingPearsonschi-squaredtest.Whentherewasanexpectedvalue1orapretestprobabilityclosetothetestlevel,Fishersexacttestwasusedinstead.StatisticalresultswereconsideredsignificantwhenthePvaluewaslessthan0.05.StatisticalanalysisSPSS16.020ResultsSize variation of GGN lesionsTheaverageGGNsizeinthebenigngroup,preinvasivegroupandadenocarcinomasgroupwas8.12.5mm,9.35.6mmand14.86.0mm,respectively.Nosignificantdifferencesexistedbetweenthepreinvasivegroupandthebenigngroup(t=0.64,p=0.53).However,thereweresignificantdifferencesbetweenbenignandpreinvasivegroupsandtheinvasiveadenocarcinomagroup(t=6.31,p=0.00;t=3.98,p=0.00).ResultsSizevariationofGGN21 Correlations between GGN-vessel relationships and pathological findingsOf108GGNs,typeI,II,IIIandIVGGNvessellrelationshipswereobservedin9,58,21and20cases,respectively.thetypeIIGGN-vesselrelationshipwasthedominantrelationshipineachpathologicalgroup,seenin9benign(90.0%),16preinvasive(66.7%)and33invasive(44.6%)GGNcases.CorrelationsbetweenGGN-22comparedwiththelowincidenceoftypeIIIandIVrelationshipsinbenignandpreinvasivegroupsthecombinedincidenceoftypeIII(25.7%)andIV(25.7%)relationshipsintheinvasiveadenocarcinomagroupreached51.3%.comparedwiththelowincidenc23MIA couldpresentfourtypes,withtypeIIasthemajortype(48.7%).ThecombinationoftypeIIandIVcomprised about80%oftheMIAsubgroup;forIAC,typeIIandIII hadthesameproportionof40%,hencethecombinationof 80%.StatisticalstudiesshowednodifferenceintypeIIbuta significantdifferencewasfoundintypeIIIandIVbetween MIAandIAClesions(p=0.02).MIAcouldpresentfourtypes24Thevessel(s)travelingthroughGGNcouldbeartery(ies)(categoryA),vein(s)(categoryB),orartery(ies)andvein(s)(categoryC).TherewerenosignificantdifferencesandcorrelationsbetweenvascularcategoriesandGGNgroups(p=0.50and0.96,respectively).Thevessel(s)travelingthroug25AfurtherexaminationofthecorrelationbetweenvascularcategoriesandGGNswithtypeIIIandIVrelationshipsdidnotgenerateanysignificantresults(p=0.70).Afurtherexaminationofthec26DiscussionSolitarypulmonarynodules(SPNs)arecommonfindingsinCTexaminationsandcanbedividedintotwogroupsbasedondensityvariation:solidnodulesandGGNs.In2011,theInternationalAssociationfortheStudyofLungCancer,the AmericanThoracicSocietyandtheEuropeanRespiratorySocietyproposedanewclassificationforlungadenocarcinomas.Inthenewclassificationsystem,thetermbronchioloalveolarcarcinoma(BAC)isnolongerused.TheformerBACconceptapplicabletomultiplecategoriesinthenewclassificationsystem,suchasAIS,MIAandthemucinoussubtypeofadenocarcinoma.BothAISandAAHlesionsareclassifiedaspreinvasiveadenocarcinomaunderthenewclassificationsystemDiscussionSolitarypulmonary27EarlystagelungcancersoftenpresentasGGNsinCTimages;thus,itisimportanttobefamiliarwiththecharacteristicsofGGNswithmalignantpotential,astimelysurgicalresectionwillimprovepatientsurvivalandqualityoflife,andforpatientswithbenignGGNs,unnecessarysurgicalprocedurescanbeavoided.Earlystagelungcancersoften28Clinicaldatahaveshownthatnodulesizeisanindependentpredictivefactorofmalignancy,withsizeincreasingthelikelihoodofmalignancyincreasing,consistentwithourresultsthatthemeansizesofGGNsinbenign,preinvasiveandadenocarcinomagroupswere8.1mm,9.3mmand14.7mm.Clinicalexperiencehasdemonstratedthatsomecommonimagingfeaturesofmalignantnodules,suchaspleuralindentation,spiculationandlobulation,areseldomseeninveryearlystagemalignantGGNs.Clinicaldatahaveshownthat29Thisdemandsfurtherinvestigationofthisparticularabnormalimagingfindingtominimisemisdiagnosis.InthemanagementofGGNsinourpatients,clinicalguidelinesfromtheFleischnerSocietyandNationalComprehensiveCancerNetwork(NCCN)werereferenced.Eachindividualcasewasdiscussedbyamultidisciplinaryteam,includingdiagnosticradiologists,thoracicsurgeonsandpathologists,togenerateconsequentmanagementstrategies.Allpatientsreceivedadequatefollow-upobservationwith/withoutsupportiveorantiinflammatorytreatment,whichexplainedthefactthatfourGGNsdisappearedpriortothenextscheduledCTexamination.Thisdemandsfurtherinvestiga30Exceptforthesefourcaseswithoutbiopsy,nodularlesionsintheremaining104patientsweresurgicallyremovedbecauseofthecontinuousincreaseinsizeand/ormassonfollow-upimagingstudies.ConsideringthedramaticallyincreasingincidenceoflungcancerinChina,patientsandphysiciansareveryalerttoitandthetreatmentmightbemoreaggressivethaninWesterncountries.Exceptforthesefourcaseswi31Tumourbiologystudieshaverevealedthatvasculatureremodellingorneoangiogenesisisoneoftheinitiatingeventsoccurringintheearlystageoftumourdevelopment.Therefore,analysisofGGNsandrelatedbloodsupplyingvesselscouldprovideinformationonGGNdifferentiation.SmallbloodvesselsandtherelationshipsbetweenvesselsandlesionscanbereadilyrevealedandevaluatedinCTimagesacquiredwithmodernmulti-detectorscanners,especiallywhenimagingdataarepost-processedusingadvancedcomputertechniques,includingMPRandCPR.ManystudieshavedemonstratedthatrelationshipsbetweenSPNsandvessels,especiallythevascularconvergencesign(VCS),arevaluableforestimationofthemalignancypotentialofSPNsTumourbiologystudieshavere32SomestudiesindicatedthatdiseaseprogressionfromAAH,AIS,MIAtoIACisacomplicated,polygene-involveddynamicprocess.MIAorIACmaygraduallydevelopfromAAHandAIS.InterstitialfibrehyperplasiawithinlesionsisthemaincontributingfactortotypeIIIandIVvascularmorphologicalchanges.theformationmechanismofVCS,leadingtotheconclusionthatthecourseofadjacentvesselsissubjecttolesions,especiallywhendiseasesinfiltratethebronchiovascularbundleandinterlobularseptaSomestudiesindicatedthatdi33Asaresult,involvedvesselsmightappeardistorted,rigidorconcentratedtowardsthelesion.Thus,itisreasonabletopostulate假设thatthevascularconvergencesigncommonlyseeninSPNs.Actually,thetypeIVGGN-vesselrelationshipresemblesVCStosomedegree.Theinvasiveadenocarcinomagroupiscomposedoftwosubgroups,MIAandIAC.SubgroupanalysisshowedMIAandIAChaddifferentpatternsofGGN-vesselrelationships.Asaresult,involvedvessels34TypeIIIvascularmorphologicalchangeswereobservedmoreoftenintheIACthanMIAsubgroup,indicatingthatwithincreasingmalignancy,fibrehyperplasiastimulatedbymalignanttissuesmaybecomemoresevere,andsubsequentlyimpactsonvasculaturebecomeaggravated.Furthermore，tumourmetabolismisfasterthaninnormaltissues;therefore,thebloodsupplydemandedbytumoursismuchhigherthaninnormaltissues.Thesemechanismsindirectlyleadtovesselproliferationandirregularluminaldilation.TypeIIIvascularmorphologica35Somestudieshaveshownthatendogenousand/orextrinsictumorangiogenesisandneovascularisationcouldbethedrivingfactorsofvascularabnormalitiesobservedinmalignantearlystage.AsaCTimagingsign,VCSdescribesarelationshipbetweenSPNsandvessels,oneormultiplevesselsconcentratingtowardsandpassingthroughlesionsorbeingtruncatedattheedgeoflesions.Somestudieshaveshownthate36Involvedvesselsmayappeartortuous,rigidorirregularlywideningandlinktopulmonaryarteriesorpulmonaryveins.Inthisstudy,theGGN-vesselrelationshipswerecategorizedintofourtypes.StatisticalanalysisindicatedthatwhentherelationshipwastypeIIIorIV,especiallytypeIV,itwashighlylikelythatGGNsweremalignantinvasiveadenocarcinoma,withMIAmorethanIAC.Incontrast,themajorityofbenignandpreinvasivecaseswasseenintypeIortypeIIGGN-vesselrelationships.Involvedvesselsmayappearto37Amajordrawbackofthisstudyisthelimitednumberofcases,especiallyinthebenigngroup,whichmaycompromisethediagnosticpower.Hence,aprospectiveclinicaltrialwithmoreGGNcasesiswarrantedtofurtherevaluateandvalidatethediagnosticvalueoffindingsinthisstudy.Additionally,thisstudycouldbestrengthenediftheanalysiswereconductedwithacombinationofvesseltypesandotherGGNfeatures,suchassizeandmass.Massmeasurementscanreflectlesiongrowthearlierwithlessvariabilitythandiametermeasurements.Amajordrawbackofthisstud38Inconclusion,thisstudydemonstratesthatdifferentGGNsmighthavedifferentrelationshipswithvesselsduetovariationindevelopmentalbiologyandbehaviour.UnderstandingandrecognizingGGN-vesselrelationshipsinCTimagingandthestrongcorrelationbetweeninvasiveadenocarcinomaandtypeIIIandIVrelationshipsmayhelpidentifywhichGGNsaremorelikelytobemalignant.Inconclusion,thisstudydem39
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