组织细胞肿瘤2022.v1-NCCN（英文版）

NCCNClinicalPracticeGuidelinesinOncologyNCCNGuidelines®)HistiocyticNeoplasmsersionMayVersion1.2022,05/20/2022©2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon6/4/20227:40:08AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.dex*RonaldS.Go,MD/Chair‡MayoClinicCancerCenter*EricJacobsen,MD/Vice-Chair†Dana-Farber/BrighamandWomen'sCancerCenter|MassachusettsGeneralHospitalCancerCenterbertBaiocchiMDPhDeOhioStateUniversityComprehensivecerCenterJamesCancerHospitaldSoloveResearchInstituteMDrehensiveCancerCenterUniversitysSeidmanCancerCenterandendClinicChildrensHospitalnshensiveCancerCenterCampbellMDPhDdeChildrensResearchHospitalhScienceDonW.Coulter,MD€Fred&PamelaBuffettCancerCenterEliDiamond,MDYloanKetteringCancerCenterAronFlagg,MD€YaleCancerCenter/SmilowCancerHospitalesPanelDisclosuresrAaronMGoodman,MD‡xoMooresCancerCenterGauravGoyal,MD‡†O'NealComprehensiveCancerCenteratUABDitaGratzinger,MD,PhD≠StanfordCancerInstitutePaulCHendrieMDPhDCancerResearchCenterianceigmanMDPhDComprehensiveCancerCenterAbramsonCancerCenterheUniversityofPennsylvaniaReemKarmali,MD,MS‡RobertH.LurieComprehensiveCancerCenterofNorthwesternUniversityNicoleKarras,MD€CityofHopeNationalMedicalCenterDavidMorgan,MD‡Vanderbilt-IngramCancerCenterAnneC.Raldow,MD,MPH§UCLAJonssonComprehensiveCancerCenterAlexandraStefanovic,MD‡†stituteSrinivasK.Tantravahi,MBBS,MRCP‡HuntsmanCancerInstituteattheUniversityofUtahKellyWalkovich,MD€UniversityofMichiganRogelCancerCenteriasZambidisMDPhDeSidneyKimmelComprehensiverCenteratJohnsHopkinsLingZhang,MD≠‡MoffittCancerCenterlowPhDxBonemarrowtransplantation‡Hematology/Hematologyoncology†MedicaloncologyYNeurology/Neuro-oncology≠Pathology¥Patientadvocacy€Pediatriconcology§Radiotherapy/radiationoncology*DiscussionWritingCommitteeMemberVersion1.2022,05/20/2022©2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon6/4/20227:40:08AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.dexlievesthatthebestlievesthatthebestmanagementforanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.FindanNCCNMemberInstitution:/home/member-institutions.ofEvidenceanddationsotherwisedNCategoriesofEvidenceandConsensus.NCCNCategoriesofPreference:Allrecommendationsareconsideredappropriate.SeeNCCNCategoriesofPreference.SummaryoftheGuidelinesUpdatesLangerhansCellHistiocytosis:•Workup/Evaluation(LCH-1)•TissueBiopsyAnalysis(LCH-2)•UnifocalLCH(LCH-3)•MultisystemorMultifocalSingle-SystemLCHorUnifocalLCHInvolvingCriticalOrgans(LCH-4)•Follow-Up,Relapsed/RefractoryDisease(LCH-5)Disease•Workup/Evaluation(ECD-1)•TissueBiopsyAnalysis(ECD-2)•Presentation(ECD-3)sease•Workup/Evaluation(RDD-1)•TissueBiopsyAnalysis(RDD-2)•Unifocal/MultifocalDisease(RDD-3)TAherapyHISTBareHISTCTheNCCNGuidelinesareastatementofevidenceandconsensusoftheauthorsregardingtheirviewsofcurrentlyacceptedapproachestotreatmentAnyclinicianseekingtoapplyorconsulttheNCCNGuidelinesisexpectedtouseindependentmedicaljudgmentinthecontextofindividualstancestodetermineanypatientscareortreatmentTheNationalComprehensiveCancerNetworkNCCNmakesnorepresentationsorwarrantiesofanykindregardingtheircontentuseorapplicationanddisclaimsanyresponsibilityfortheirapplicationoruseinanywayTheNCCNationalComprehensiveCancerNetworkAllrightsreservedTheNCCNGuidelinesandtheillustrationshereinmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.©2022.Version1.2022,05/20/2022©2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.UPDATESVersion1.2022,05/20/2022©2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon6/4/20227:40:08AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.dexsionoftheNCCNGuidelinesforHistiocyticNeoplasmsfromVersionincludeRadiologicEvaluation•Whole-body"FDG"PET/CTincludingdistalextremities(vertextotoes)(AlsoforECD-1,RDD-1)LaboratoryEvaluation•ModifiedMAP2K1/"2"(AlsoforECD-1,RDD-1)•Footnote"f"isnew:SeePrinciplesofSupportiveCare(HIST-C)(AlsoforLCH-5,ECD-1,ECD-3,RDD-1,HIST-B)LCH-2•Column4,toppathway,modified:BRAFV600E(VE1)"strong"positive,equivalenttoBRAFmutation.•Column5,modifiedMolecular"testing"(AlsoforECD-2)•Column6,modifiedfirstandthirdbranchpoints:LCHwithoutmutation/"fusions"(AlsoforECD-2)LCH-3•Column2,thirdbranchpoint,modified:(ie,CNS,liver,spleen,heart)(AlsoforthebottompathwayandLCH-4)•Column3,isolatedboneinvolvement,modified:p"Watchandwait"wasrevisedas"observation"(Alsoforsecondandthirdbranchpoints,LCH-4,RDD-3)pAdded"bisphosphonate"•IsolatedskindiseasepPsoralenplus"UVA";andnarrowbandUVB•Footnote"m":Bonelesionsnotamenabletolocaltherapiesduetosizeandlocation,isnewcorrespondingbisphosphonate.LCH-4•Column2,bottompathwaymodified:SingleSystem-LungPulmonaryLCH•Footnote"n",modified:ForneurodegenerativeLCH,imagingchangesprecedeclinicalprogression"clinicalfindingsmaynotbeaccompaniedbyimagingchanges."Cognitivesymptomsshouldbecarefullymonitored,andearlytreatmentshouldbeconsidered.LCH-5•Modifiedheader:"Treatmentfor"Relapsed/RefractoryDiseaseECD-1•LaboratoryEvaluationpBullet9,2ndsub-bulletmodified:"CSF1R"•TreatmentpBullet1modified:Considerwatchandwait"observation"forpatientswithasymptomaticdiseaseandnoimpendingorgandysfuction"criticalorganinvolvement(eg,cardiovascular,CNS,liver)"UPDATESVersion1.2022,05/20/2022©2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon6/4/20227:40:08AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.dexsionoftheNCCNGuidelinesforHistiocyticNeoplasmsfromVersioninclude•Immunohistochemistryfirstbullet:"OCT2+"isnew.•Footnote"f"modifiedtoinclude,AnovelstudyshowedthatOCT2immunohistochemistrymightbehelpfulinselectcasestoconfirmasuspecteddiagnosisofRDD,togetherwithothercommondiagnosticmarkers.RavindranA,etal.AmJSurgPathol2021;45:35-44.HIST-A,5of5•Modified:*Moderatetostrongpositivityshouldcorrelatewithmolecularalteration;BRAFVE1,ALK,andphosphorylatedtyrosinereceptorkinase(pTRK)aremutuallyexclusive.HIST-B,1of6•Multisystemorpulmonary"single-systemlung"LCH:pMethotrexate+cytarabinemovedfromPreferredregimens,IrrespectiveofmutationtoOtherrecommendedregimens,Irrespectiveofmutation.(AlsoforCNSlesionsonHIST-B,2of6).pBinimetinibandselumetinibarenewunderOtherrecommendedregimens,MAPkinasepathwaymutation,ornotdetectablemutation,ortestingnotavailable.(AlsoforCNSlesionsonHIST-B,2of6).pAllogeneichematopoieticcelltransplantisanewoptionforhighlyselectpatientswithrelapsed/refractoryLCHthatismultisystem,single-systemlung,orwithCNSlesions.Thisisacategory2A,usefulincertaincircumstancesrecommendation,(alsoforHIST-B,2of6).◊Withthefollowingreferences:–IngramW,DesaiSR,GibbsJSR,etal.Reduced-intensityconditionedallogeneichaematopoietictransplantationinanadultwithLangerhans'cellhistiocytosisandthrombocytopeniawithabsentradii.BoneMarrowTransplant,2006;37:713-715.–XicoyB,RiberaJM,BatlleM,etal.[SustainedremissioninanadultpatientwithLangerhanscellhistiocytosisfollowingT-celldepletedallogeniccelltransplantation].MedClin(Barc),2006;127:716.•Bonediseaseonlyp"Bisphosphonate"wasaddedasaheadingforzoledronicacidandpamidronate.HIST-B,3of6terDisease•Thefollowingregimenswereaddedfor"Targetedtherapy"under"Usefulincertaincircumstances"pAlectinibforALKfusionpBrigatinibforALKfusionpCeritinibforALKfusionpLorlatinibforALKfusion◊Reference–KempsPG,PicarsicJ,DurhamBH,etal.ALK-positivehistiocytosis:anewclinicopathologicspectrumhighlightingneurologicinvolvementandresponsestoALKinhibition.Blood2022;139:256-280.HIST-B,4of6Rosai-DorfmanDisease•Modified:Thalidomide(forcutaneous"involvement"skindiseaseonly).•PrinciplesofSupportiveCareisanewpageintheguidelines.INTROVersion1.2022,05/20/2022©2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon6/4/20227:40:08AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.dexINTRODUCTIONTheseGuidelinesdescribetreatmentrecommendationsforadultswithhistiocyticneoplasms.Inscenarioswherethereislittleevidenceintheadultpopulation,recommendationsareextrapolatedfrompediatricstudies.nblurryvisiondecreasedhearingmassardiovasculardyspneaorthopneaMusculoskeletalbonepain,backpainmphadenopathyGastrointestinaldiarrheamelenaSkinerythematousnblurryvisiondecreasedhearingmassardiovasculardyspneaorthopneaMusculoskeletalbonepain,backpainmphadenopathyGastrointestinaldiarrheamelenaSkinerythematousrash,subcutaneousnodules,attentiontoearcanalsinfraorbitalregionperineum,axillae,inguinalregion,nthelasmaEndocrinepolydipsia/polyuria,decreasedlibidoNeurologicataxiadysarthriaseizures,cognitivedecline,disconjugategazecranialnervepalsies,dysarthria,ataxicortPsychiatricdepressionanxietyesSelectedPatientsBasedonSymptomsorOrganInvolvementMRIbrainmastoidpituitarywithcontrastsellaturcicahtheartcatheterizationmonaryfunctiontestsCTchestabdomenandpelviswithcontrastUSabdomenliverspleenEndoscopicretrogradecholangiopancreatographyERCP)uctsdilatedonCTUSrexxraytionspecialtyConsultationsasNeededDermatologypriortoinitiationofBRAForMEKinhibitortherapye,f•OphthalmologypriortoinitiationofMEKinhibitortherapye,f•Dental/Periodontal•Smokingcessationbliativemedicine•Spleen•OralmucosaungSreactiveproteinMorningurineandserumosmolalityumcortisolwithACTHFSHLHwithtestosteronemales)andestradiol(females)TSHandfreeT4ssuebiopsydseeLCHldtypeorequivocalcasesformutationsintheMAPKpathwayASKRASMAPKandPIKCABonemarrowaspiratebiopsyseeLCH-2)onaryologycrinology•Whole-bodyFDGPET/CTcincludingdistalextremities(vertextoHigh-resolutionCTofthechestforpulmonaryLCH•ProlactinandIGF-1•Trans-thoracicechocardiogramSeeTreatment(LCH-3)sisdexWORKUP/EVALUATIONaitesofInvolvementnen•Lymphnode•LiverConstitutionalfeversnightsweats,Constitutionalfeversnightsweats,fatigue,headache,myalgiasRadiologicEvaluationCompletebloodcountCBCwithdifferentialseeLCH2)ntsComprehensivemetabolicpanelincludingliverandkidneyntsaAdaptedwithpermissionfromGoyalG,etal.MayoClinProc2019;94:2054-2071.bProvideresourcesforsmokingcessation.SeeNCCNGuidelinesforSmokingCessation.cForpatientswithhigh-riskbonelesionsand/orsuspectedtohavemultisystemdisease.dSeePrinciplesofPathology(HIST-A).eSeeManagementofToxicitiesAssociatedwithTargetedTherapy(ME-K)intheNCCNGuidelinesforMelanoma:Cutaneous.fSeePrinciplesofSupportiveCare(HIST-C).Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.LCH-1Version1.2022,05/20/2022©2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.onuejiderbonemarrowbiopsytoruleoutcyticlymphohistiocytosisoridneoplasmgSeeNCCNGuidelinesforplasticSyndromesandNCCNGuidelinesfortiveNeoplasmsPrintedbyMinTangon6/4/20227:40:08AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022onuejiderbonemarrowbiopsytoruleoutcyticlymphohistiocytosisoridneoplasmgSeeNCCNGuidelinesforplasticSyndromesandNCCNGuidelinesfortiveNeoplasmssisdexTISSUEBIOPSYANALYSISFORLCHCBCabnormalityistryhaLangerinistryhaLangerinCD207)+,S100+,cyclinD1+,BRAFV600E(VE1)+/-cyteswithgroovednucleiosinophiliastrongpositive,equivalenttoBRAFmutationLCHwithoutionsiionsiLCHwithBRAFherMAPKhwayemutationsionsstudystudyincludingBRAFotherMAPKBRAFincludingBRAFotherMAPKaldSeePrinciplesofPathology(HIST-A).gForpatientswithsuspectedLCHorhistiocytosisandbiopsyisnotpossiblebecauseoflocationorriskfactors,mutationalanalysisoftheperipheralbloodisanoption.hAminimalpanelwouldincludeCD1a,S100,andLangerin;cyclinD1andBRAFV600E(VE1)immunohistochemistryisrecommended.iMoleculartestingforsomaticmutationsandfusionscanbeperformedinastepwisemannerorinparallel,dependingonclinicalneedandinstitutionalprotocols.Thefrequencyofsuspectedmolecularlesionsshoulddrivetheorderoftestingifastepwisealgorithmischosen.Allele-specificpolymerasechainreaction(PCR)forBRAFV600EmutationscanbethefirststepifBRAFV600E(VE1)immunohistochemistryisnotavailableorisequivocal.SomaticmutationNGSpaneltestingshouldcoverthecommonMAPKpathwaymutations.RNA-basedmolecularpanelincludingfusiontestingshouldcoverBRAF,ALK,andNTRK1rearrangements.IfthereisclinicalconcernforALKrearrangement,oriffusionpaneltestingisnotavailable,ALKimmunohistochemistryandfluorescenceinsituhybridization(FISH)studiesmaybeperformed.jFreshorparaffin-embeddedtissueisusedforNGSstudy;peripheralbloodmaybeinformativeinmultisystemdisease.TheNGSpanelshouldcoverthecommonMAPKpathwaymutations(BRAF,ARAF,NRAS,KRAS,MAP2K1/2,andPIK3CA).Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version1.2022,05/20/2022©2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.LCH-2icosteroidinjectionskRadiationtherapylowdosefor2sitesofdiseaselsUVAnarrowbandUVBdiseaseCHPrintedbyMinTangon6/4/20227:40:08AM.Forpersonaluseonly.icosteroidinjectionskRadiationtherapylowdosefor2sitesofdiseaselsUVAnarrowbandUVBdiseaseCHsisdexitedervationifasymptomaticemSeeHISTBIsolatedboneinvolvementvationrticosteroidtopicalrticosteroidtopicalorinjectionkvationlvationltherapywithoutinvolvementofiticalorgansieCNSMultisystemormultifocalsingle-systemLCHorUnifocalLCHinvolvingcriticalorgans(ie,CNS,liver,spleen)HkTriamcinoloneinjectionorequivalentcorticosteroid.lUseclinicaljudgmentfor3sites.mBonelesionsnotamenabletolocaltherapiesduetosizeandlocation.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.LCH-3Version1.2022,05/20/2022©2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.Singlesystem-PrintedbyMinTangon6/4/20227:40:08AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.Singlesystem-sisdexMultisystemorMultifocalsingle-systemLCHorUnifocalLCHalnsieCNSAsymptomaticnandnimpendingorgandysfunctionMultisystemand/orSystemicticingfunctionlvementntherapyseticingfunctiontherapytherapyresponse•Smokingcessationb•Observationnisone•Systemictherapy•LungtransplantforsevereorrefractorycasesbProvideresourcesforsmokingcessation.SeeNCCNGuidelinesforSmokingCessation.nForneurodegenerativeLCH,clinicalfindingsmaynotbeaccompaniedbyimagingchanges.Cognitivesymptomsshouldbecarefullymonitored,andearlytreatmentshouldbeconsidered.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.LCH-4Version1.2022,05/20/2022©2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon6/4/20227:40:08AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.sisdexImagingofinvolvedsitestoevaluatetreatmentresponse(PET/CT[preferred],CT,orMRI)•After2–3cyclesofsystemictherapyandatcompletion•Aftercompletionofsurgicalcurettage•Afterradiationtherapyance•H&Pandlabsasclinicallyindicated•Imaging:PET/CT(preferred),CT,orMRIpEvery3–6monthsforthefirst2yearspostcompletionoftreatmentp>2years:nomorethanannuallypForasymptomaticpatientswithasingle-sitebonelesion,imagingsurveillancecanpotentiallyendafteryear1,withcontinuedtrackingofsymptoms•PulmonaryfunctiontestingforpulmonaryLCH•Bonemarrowevaluationinthepresenceofcytopeniasorotherbloodcountabnormalities(toruleoutassociatedmyeloidneoplasm)•RegularskinexaminationandECGforpatientstreatedwithBRAFinhibitorse,f•Monitorevery1–2yearsforpituitaryhormoneabnormalitiesSEDSystemictherapy•Ifdurationofresponse>1year,considersameregimen;otherwiseusearegimennotusedforfirst-linepyMEKintheNCCNGuidelinesforMelanomaCutaneousfSeePrinciplesofSupportiveCare(HIST-C).Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.LCH-5Version1.2022,05/20/2022©2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.OphthalmologypriortoinitiationofMEKinhibitortherapyc,dPrintedbyMinTangon6/4/20227:40:08AM.Forpersonaluseonly.Notapprovedfordistribution.CopyrightOphthalmologypriortoinitiationofMEKinhibitortherapyc,ddexWORKUP/EVALUATIONaCommonSitesofInvolvement•LongbonesinmostcasespBilateralandsymmetricdiaphysealandmetaphysealosteosclerosiswithsubchondralsparing•Othersitesinclude:pOrbits:retro-orbitalmasswithexophthalmos;xanthelasmapCNS:pituitarygland,posteriorfossapLungs:interstitialchangespVascular:periaorticinfiltrate;pericardium,rightatriumpRetroperitoneal/perinephric("hairykidney");mesenteryMedicalHistoryandPhysicalExamination•Constitutional:fevers,nightsweats,fatigue•HEENT:doublevision,retro-orbitalpain,xanthelasma,exophthalmos•Cardiovascular:dyspnea,orthopnea,hypertension,irregularpulse,bradycardia,cardiomegaly,murmurs•Pulmonary:dyspnea,cough,diminishedaeration,rales•Neurologic:disconjugategaze,cranialnervepalsies,dysarthria,ataxicormagneticgait,sensoryormotorimpairment,hyperreflexia,ataxia,dysarthria,dysphagia,limbweakness,cognitivedecline•Musculoskeletal:bonepain•Dermatologic:xanthelasma,rash•Endocrine:polydipsia/polyuria,gynecomastia,decreasedlibido•Psychiatric:depression,anxiety,disinhibition,inappropriatelaughingorcrying,pseudobulbaraffectRadiologicEvaluation•Whole-bodyFDGPET/CTincludingdistalextremities(vertextotoes)•MRIbrainwithcontrast•CardiacMRISelectedPatientsBasedonSymptomsorOrganInvolvement•CTsinuseswithcontrast•CTchest,abdomen,andpelviswithcontrast•Trans-thoracicechocardiogramaAdaptedwithpermissionfromGoyalGetal.Blood2020;135:1929-1945.bSeePrinciplesofPathology(HIST-A).•MRIsellaturcica•Technetium-99mMDPbonescintigraphy•MRIorbitwithcontrast•MRItotalspinewithcontrast•Renalarteryultrasound•High-resolutionCTchest•Pulmonaryfunctiontests•TesticularultrasoundLaboratoryEvaluation•CBCwithdifferential(seeECD-2)•Comprehensivemetabolicpanelincludingliverandkidneyfunctionassessments•C-reactiveprotein•Morningurineandserumosmolality•MorningserumcortisolwithACTH•FSH/LHwithtestosterone(males)andestradiol(females)•TSHandfreeT4suebiopsybsuebiopsybseeECDpTargeted-capture,NGSinBRAFV600Ewild-typeorequivocalcasesformutationsintheMAPKpathwaysuchasARAF,NRAS,KRAS,MAP2K1/2,PIK3CA,CSF1RpGenefusionassay•Bonemarrowaspirate/biopsy(se