Riskfactorsforlymphnodemetastasisinovariancancer:implicationsforsystematiclymphadenectomyPurpose:ThepurposeofthisstudywastoassesstheriskfactorsrelatedwithlymphMethods:WeretrospectivereviewedpatientsdiagnosedwithovariancancerbetweenJanuary2004andJanuary2012.Demographicsandpathologicfindingscorrelationswithlymphnodemetastaseswereassessed.Results:Atotalof256patientsunderwentcompletesurgicalstaging,includinglymphadenectomywerethereforeyzed.Themeannumberoflymphnodesobtainedbylymphadenectomywas20.5(range:2-57),andnodalmetastaseswerefoundin84patients(32.8%).Themeannumberofpositivelymphnodeswas3(range:1-40)inpatientswithlymphnodemetastasis.Atunivariateysis,histologytype(serousvs.non-serous),grade(G1vs.G2-3),andlevelofCA-125atdiagnosis(≤740U/mLvs.>740U/mL)weresignificantriskfactorsforlymphnodemetastases.Atmultivariateysis,histologytype(oddsratio[OR]2.728,95%confidenceinterval[CI]1.072-6.945,P=0.035),grade(OR1.897,95%CI1.209-2.977,P=0.005),andlevelofCA-125atdiagnosis(OR3.858,95%CI2.143-6.947,P<0.001)maintainedastatisticallysignificantassociationwithlymphnodemetastases.Thenodalmetastasesratescorrespondingto0,1,2,and3riskfactorswere0,4.0%,29.9%,and61.8%,respectively(P<0.001).Thenodalmetastasesratesof0-1riskfactorweresignificantlylowerthanthoseof2-3riskfactors(3.7%vs.40.6%;P<0.001).Conclusion:Histologytype,grade,andlevelofCA125atdiagnosisareidentifiablefactorsthatcanhelpthesurgeondecidewhethertoperformcomprehensivesurgicalstagingwithsystematiclymphadenectomy.:Ovariancancer;Lymphnodemetastases;Lymphadenectomy;CA-125;HistologytypeOvariancancerisahighlyfatalgynecologiccancerandthefifthleadingcauseofcancermortalityinwomen,with21,980newcasesand14,270deathsoccurringintheUnitedStatesin2014(1).In,ovariancanceristhetenthcancerincidencerateof7.95per100,000womenduring2009(2).Mostpatientswithovariancancerhaveadvanceddiseaseatthetimeofdiagnosisowingtoasymptomaticnatureforearlystagetumors,resultinginapoorlong-timesurvival(3,4).手術(shù)治療仍是癌的最重要治療方式，但是關(guān)于lymphadenectomy的價(jià)值一直以來(lái)都存在著爭(zhēng)議。癌的淋狀態(tài)會(huì)影響患者的生存(5-7)，因此成為癌InternationalFederationofGynecologyandObstetrics（FIGO）分期的重要指標(biāo)之一，淋轉(zhuǎn)移的患者分期至少為III期(8-9)。Thusrecognizingtheimportanceoftheprognosticvalueoflymphnodemetastasis,thesystematiclymphadenectomywasincludedintheguidelinesinFIGOstagingsystemRandomizedstudiesshowedthatsystematiclymphadenectomydetectsnodalmetastasesin13.6%-30.3%ofpatientswithovariancancer(10,11).Itwasfoundthattumorinvolvementoflymphnodewas14.2%(range6.1–29.6%)ofpatientswithclinicalstagesI–IIovariancancer(12).但目前仍缺乏確切的指標(biāo)來(lái)預(yù)測(cè)癌患者nodemetastasesinFIGOstagesItoIIIovariancanceranddeterminetheinfluenceriskfactorsontheincidenceoflymphnodesmetastasesandevaluatetheroleofsystematiclymphadenectomy.PatientsandFromDecember2004toMarch2012,atotalof256patientswithprimaryovariancancerwhounderwentcytoreductivesurgeryattheSunYat-SenUniversityCancerCenter(SYSUCC)wereretrospectivelyyzed.Cytoreductivesurgerywasconsideredtohaveachievedoptimaldebulkingwhentheresidualdiseasewas<1cm.Patientswithsynchronousormetachronoustumors,borderlinetumorsandstage(stageIV)ovariancancerwereexcluded.Otherpatientswithmissingdatawerealsoexcluded.ThestudywasapprovedbytheethicscommitteeofSYSUCC.Allpatientsprovidedwrittenconsentforstorageoftheirinformationinthehospitaldatabase,andfortheresearchuseoftheinformation.ClinicopathologicalPreoperativeserumCA-125levelsweremeasuredwithinoneweekbeforestaginglaparotomyusingaradioimmunoassaykit.TheuppernormalvalueofserumCA-125levelswas35U/mL.Afterthediagnosisofovariancarcinoma,patientsunderwentsurgicalstagingincludingbilalsalo-oophorectomyandtotalabdominalhysterectomy;washingcytology;randommultipleperitonealbiopsies;omentectomy;andsystematicpelvicand/orpara-aorticlymphadenectomy.Clinicopathologicalfactorswereusedtoassesstheriskoflymphnodemetastases.Factorsexaminedincludedage,menopausalstatus,histologicaltype,histologicalgrade,andserumCA-125atdiagnosis.Thetumorswerestagedaccordingtothe2013FIGOstagingsystemandhistologicallydeinedaccordingtoWorldHealthOrganization(WHO)classification.StatisticalTheχ2andFisher’sexacttestswereusedtoyzethedifferencesbetweenqualitativedata.Theoptimumcut-offpointfortheCA-125wasdeterminedbyuseofthereceiveroperatingcharacteristic(ROC)curve.Theindependenteffectsofclinicalandpathologicalfactorsonlymphnodemetastasiswerethendeterminedbymultiplelogisticregressionysis,inwhichfactorsthatwerestatisticallysignificantinunivariateysiswereenteredintomultiplelogisticregressionysis.AP-value0.05wasconsideredsignificantinallyses.AlldatawereyzedtheSPSSstatisticalsoftwarepackage,version17.0(IBMCorporation,Armonk,NY,USA).256例。Table1summarizestheclinicopatholgiccharacteristicsofthe256patients。所有患者中位發(fā)病56歲（19-76歲，57.8%（148/256）的患者為絕期女性，81.3%（208/256）的患者為漿液癌，andbyFIGOcriteria30.0%(82/256)wereinstageI,25.8%(66/256)instageII,and42.2%(108/256)patientsinstageIII.Tumorgradewasgrade1in10.9%patients(28/256),grade2in49.2%patients(126/256),andgrade3in39.9%patients(102/256).Themeannumberoflymphnodesobtainedbylymphadenectomywas20.5(range:2-57),andnodalmetastaseswerefoundin84patients(32.8%).Themeannumberofpositivelymphnodeswas3(range:1-40)inpatientswithlymphnodemetastasis.ThemedianandmeanvalueofpreoperativeserumCA-125levelswere330.3U/mL,and1254.6U/mL(range:12-18277U/mL),respectively.Theoptimalcut-offpointsofCA-125wereyzedusingROCcurve.Theresultsshowedthat740U/mLwastheoptimalcut-offpointforlymphnodemetastasis(AreaUnderrocCurve=0.655,P<0.001).Therefore,theoptimalcutoffvalueof740wasvalidatedasariskfactorforysisoflymphnodemetastasistoevaluatetheroleofsystematiclymphadenectomy.Table1showstheriskfactorsforlymphnodemetastasesatunivariateysis.Histologytype(serousvs.non-serous),grade(G1vs.G2-3),andserumlevelofatdiagnosisCA-125(≤740U/mLvs.>740U/mL)weresignificantriskfactorsforlymphnodemetastases,whileageandmenopausalstatuswerenot.Serousadenocarcinomahadthehighestincidenceofnodemetastaseswhencomparedwithotherhistologictypes(37.5%vs.12.5%%,P=0.001).Nolymphnodemetastaseswerefoundinpatientswithwelldifferentiatedtumors.Astatisticallysignificantdifferenceintheincidenceoflymphnodemetastaseswasobservedamongpatientswithmoderay-andpoorlydifferentiatedtumorscomparedtothosewithwelldifferentiatedtumors(36.5%-37.3%vs.0%;P<0.001).PatientswithCA-125≤740U/mLatdiagnosisconferredariskoflymphnodemetastasessignificantlylowerthanCA-125>740U/mLatdiagnosis(22.4%vs.53.5%,P<0.001).Atmultivariateysis,histologytype(oddsratio[OR]2.728,95%interval[CI]1.072-6.945,P=0.035),grade(OR1.897,95%CI1.209-2.977,P=andserumlevelofCA-125atdiagnosis(OR3.858,95%CI2.143-6.947,P<0.001)maintainedastatisticallysignificantassociationwithlymphnodemetastases.Forthesethreeindependentriskfactorsweregrouped,thenodalmetastasesratescorrespondingto0,1,2and3riskfactorswere0,4.0%,29.9%and61.8%,respectivelylow-riskgroup,andpatientswith2-3riskfactorswereconsideredhigh-riskgroup.Thenodalmetastasesratesoflow-riskgroupweresignificantlylowerthanthoseofhigh-riskgroup(3.7%vs.40.6%;P<0.001).Thepredictiveperformanceofthemodelwasinvestigated.UsingtheROCcurvewasconstructed,andthecalculatedareaunderthecurvewas0.740(P<0.001).Accordingtothegroupsofriskfactors,48patientswerenon-serousovariancancerswith6patientswithnodalmetastases,all6patientswithG2-3stageand4patientswithserumlevelofCA-125atdiagnosis>740U/mL,withtheprobabilityoflymphnodemetastasiswas66.7%(4/6)inhigh-riskgroupofpatientswithnon-serousovariancancer.在本研究中我們探討了影響癌患者pelvicorpara-aorticnodesmetastases的，結(jié)果發(fā)現(xiàn)histologytype,gradeandlevelofCA-125atdiagnosis是影響淋轉(zhuǎn)移的獨(dú)立。癌的淋清掃價(jià)值一直以來(lái)都存在著爭(zhēng)議，1988年的FIGO發(fā)布的surgicalstagingschemeforovariancancerthatincludedpelvicandpara-aorticlymphnodesamplingorlymphadenectomy.However,thebenefitoflymphadenectomyinovariancancerpatientsisstillcontroversial.Thereareseriouspost-operativecomplicationsassociatedwithlymphadenectomy,suchaslymphedemainthelowerextremitiesandpelviclymphcystswith itantinfectionandthesecandevelopintochronicconditions(13-15).Meta分析的研究發(fā)現(xiàn)lymphadenectomycanovariancancerbutnotinearlystage(FIGOI-IIstage)epithelialovariancancerorpatientswithresidualtumor≤2cm(16).隨機(jī)對(duì)照試驗(yàn)的結(jié)果亦未發(fā)現(xiàn)lymphadenectomy具有生存獲益（10。淋清掃術(shù)發(fā)現(xiàn)5-10%的I-II期的患者有淋轉(zhuǎn)移，由此改變分期(17-19)。因此，我們認(rèn)為lymphadenectomyisessentialforaccuratestagingandhasaprognosticandpotentiallytherapeuticrole.Chanetal.reportedanincreaseinthepercentageofpatientswhounderwentsystematiclymphadenectomyduringsurgicalstagingforovariancancerinthelastdecadeusingSurveillance,EpidemiologyandEndResultsdata(20).結(jié)的狀態(tài)評(píng)估對(duì)于癌患者的分期具有重要的意義但亦不是所有患者均需行淋清掃術(shù)。Inarandomizedstudyshowedthatsystematiclymphadenectomydetectsnodalmetastasesin8/59(13.6%)womenwithnoevidenceofresidualtumorandin30/99(30.3%)womenwhohadanyresidualtumorattheendofprimary(10).Itwas22%inanotherrandomizedstudy(11).Inthepresentretrospectivestudy,32.8%werelymphnodemetastases.可見(jiàn)大部分的癌患者并無(wú)淋轉(zhuǎn)移。目前對(duì)于影響癌淋轉(zhuǎn)移的仍沒(méi)有明確的定義研究已發(fā)histologicalgrade,histology,bilalityofadnexaldisease,menopause,thepreoperativeserumCA-125levelandlymphnodeinvolvementonimagingstudies等的并不統(tǒng)一(17,19,21,22,23)我們的研究結(jié)果發(fā)現(xiàn)histologytype,grade,andlevelofCA125atdiagnosis是影響淋轉(zhuǎn)移的獨(dú)立。研究發(fā)現(xiàn)1/3-1/4的漿液的患者淋轉(zhuǎn)移到腹膜后間隙，而粘液很少淋轉(zhuǎn)移(23)。Ditto等和Powless等發(fā)現(xiàn)漿液的淋，移率為28%-30%內(nèi)膜樣出現(xiàn)淋轉(zhuǎn)移為10.5%，但粘液未發(fā)現(xiàn)淋轉(zhuǎn)移(19,23)。Takeshima等的研究發(fā)現(xiàn)漿液癌、透明細(xì)胞癌、子膜樣、粘液的淋轉(zhuǎn)移率分別為36.7%，16.9%，15.6%和7.7%12.5%的患者淋轉(zhuǎn)移，粘液患者的淋轉(zhuǎn)移率為20（4/20內(nèi)1.1%（2/18，10淋轉(zhuǎn)移多因素分析結(jié)果提示漿液癌為影響癌患者淋轉(zhuǎn)移的危險(xiǎn)因素。Powless等及Baann等均證實(shí)漿液癌為影響淋轉(zhuǎn)移的，因素，而其他研究并未發(fā)現(xiàn)病理類型為影響淋轉(zhuǎn)移的(19,21,22)。結(jié)合我們的研究，對(duì)于術(shù)中病理證實(shí)為漿液癌的患者，應(yīng)高度注意淋轉(zhuǎn)Kleppe等的研究中，grade1,grade2,andgrade3disease的淋轉(zhuǎn)移率分別為4.0%，16.5%，和20.0%(12)。Baann等的研究亦提示grade3期為影響淋轉(zhuǎn)移的獨(dú)立。但也有研究得出了的結(jié)果(19,22)。我們的研究認(rèn)為grade2-3是影響淋轉(zhuǎn)移的獨(dú)立，同時(shí)提示grade1的患者可能可以避免淋清掃。SerumCA-125levelisknownasaclinicalprognosticfactorforsurvivalandresponsetotreatmentinpatientswithepithelialovariancancer(25-27).多個(gè)研究發(fā)現(xiàn)CA-125可以作為預(yù)測(cè)淋轉(zhuǎn)移的(28-30).Nevertheless,therehavebeenfewstudiesonthepredictionofnodalmetastasisinovariancancerusingthepreoperativeserumCA-125level.Kim等發(fā)現(xiàn)preoperativeserumCA-125level(>535U/mL)isariskfactorforlymphnodemetastasisinpatientswithepithelialovariancancer(22).Sudolmus等則發(fā)現(xiàn)CA125是預(yù)測(cè)癌淋轉(zhuǎn)移的，thebestcut-offpointwas72U/mL(21).而Ditto等則未發(fā)現(xiàn)CA125并不是淋轉(zhuǎn)（19盡管cut-offpoint和前面的研究不同但均提示CA125在評(píng)估癌患者的淋巴我們?cè)诎l(fā)現(xiàn)發(fā)現(xiàn)含有0,1,2,and3riskfactors的淋轉(zhuǎn)移率分別為0,29.9%,and61.8%,respectively(P<0.001)。根據(jù)含有的個(gè)數(shù)進(jìn)一步分為low-riskgroup(0-1riskfactor)andhigh-riskgroup(2-3riskfactor),結(jié)果顯示高危組患者的淋轉(zhuǎn)移率顯著高于低危組的患者(40.6%vs.3.7%;P<0.001)，提示根據(jù)進(jìn)行分組來(lái)預(yù)測(cè)淋轉(zhuǎn)移是可行的但是仍需要的研究來(lái)加Therearesomelimitationsofthecurrentstudy.Frist，Thiswasasinglecenterretrospectivestudyandhenceissubjecttoinherentbiases,thusthefindingsmaynotbeapplicabletothegeneralpopulation.Nevertheless,thepredictorsinthisstudycouldbethepatientsenrolledinthepresentstudywasunderwentcytoreductivesurgerywhichachievedoptimaldebulkingwhentheresidualdiseasewas<1cm.Therefore,themetastaticpatientswithFIGOstageIVwereexcludedinthepresentstudy.histologytype,grade,andlevelofCA125diagnosis是影響淋轉(zhuǎn)移的獨(dú)立.Sincethetherapeuticefficacyofsystematiclymphadenectomytoimprovesurvivalremainscontroversial.Thedecisiontoperformcompletesurgicalstagingwithlymphnodedissectioncanbemadewiththehelpofseveralprognosticriskfactorsidentifiablebeforeand/orduringsurgery.SiegelR,MaJ,JemalA.Cancerstatistics,2014.CACancerJClin.2014;64(1):9-ChenW,ZhengR,ZhangS,ZhaoP,LiG,WuL,HeJ.Theincidencesandmortalitiesofmajorcancersin,2009.ChinJCancer.2013;32(3):106-12.JemalA,ThomasA,MurrayT,ThunM.Cancerstatistics,2002.CACancerJClin.cancer:theNationalOvarianCancerEarlyDetectionProgram(NOCEDP).CancerTreatRes.2002;107:3-28.BaannC,BruckerSY,KraemerB,RothmundR,StaeblerA,FendF,WallwienerD,GrischkeEM.Theprognosticrelevanceofnodemetastasesinoptimallycytoreducedadvancedovariancancer.JCancerResClinOncol.2015Mar5.[Epubaheadofprint]BaannC,BaannR,BruckerSY,StaeblerA,FendF,GrischkeEM,WallwienerD.RoleofPelvicandPara-aorticLymphNodeMetastasesinOptimallyCytoreducedAdvancedOvarianCancer.AnticancerRes.AtasevenB,GrimmC,HarterP,PraderS,TrautA,HeitzF,duBoisA.Prognosticvalueoflymphnoderatioinpatientswithadvancedepithelialovariancancer.GynecolOncol.2014;135(3):435-40.PratJ.Ovarian,fallopiantubeandperitonealcancerstaging:RationaleandexnationofnewFIGOstaging2013.BestPractResClinObstetGynaecol.2015.pii:S1521-6934(15)00053-X.ZeppernickF,Meinhold-HeerleinI.ThenewFIGOstagingsystemforovarian,fallopiantube,andprimaryperitonealcancer.ArchGynecolObstet.Dell'AnnaT,SignorelliM,Benedetti-PaniciP,MaggioniA,FossatiR,FruscioR,MilaniR,BoccioloneL,BudaA,MangioniC,ScambiaG,AngioliR,CampagnuttaE,Gra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