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NCCNClinicalPracticeGuidelinesinOncologyNCCNGuidelines®)MalignantPeritonealMesotheliomaVersionDecemberVersion1.2022,12/22/21©2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon3/14/20227:05:54AM.Forpersonaluseonly.Notapprovedfordistribution.CopyrightotheliomaDavidS.Ettinger,MD/Chair†JohnsHopkinsDouglasE.Wood,MD/ViceChair¶CenterSeattleCancerCareAllianceJamesStevenson,MD/Lead†seComprehensiveCancerCenterDaraL.Aisner,MD,PhD≠UniversityofColoradoCancerCenterWallaceAkerley,MD†HuntsmanCancerInstituteJessicaR.Bauman,MD‡†FoxChaseCancerCenterAnkitBharat,MD¶enterDeboraS.Bruno,MD,MS†seComprehensiveCancerCenterJoeY.Chang,MD,PhD§TheUniversityofTexasLucianR.Chirieac,MD≠Dana-Farber/BrighamandWomen’sCancerCenterThomasA.D’Amico,MD¶DukeCancerInstituteMalcolmDeCamp,MD¶UniversityofWisconsinCarboneCancerCenterNHughesPhDesPanelDisclosuresThomasJ.Dilling,MD,MS§MoffittCancerCenterJonathanDowell,MD†veCancerCenterScottGettinger,MD†ÞYaleCancerCenter/SmilowCancerHospitalTravisE.Grotz,MD¶MatthewA.Gubens,MD,MS†UCSFHelenDillerFamilyveCancerCenterAparnaHegde,MD†O'NealComprehensiveCancerCenteratUABRudyP.Lackner,MD¶Fred&PamelaBuffettCancerCenterMichaelLanuti,MD¶lHospitalCancerCenterJulesLin,MD¶UniversityofMichiganRogelCancerCenterBillyW.Loo,Jr.,MD,PhD§StanfordCancerInstituteChristineM.Lovly,MD,PhD†Vanderbilt-IngramCancerCenterRenatoG.Martins,MD,MPH†CenterSeattleCancerCareAllianceErminiaMassarelli,MD,PhD†CityofHopeNationalMedicalCenterDanielMorgensztern,MD†SitemanCancerCenteratBarnes-JewishHospitalandWashingtonUniversitySchoolofMedicineGregoryA.Otterson,MD†CancerCenter-JamesCancerHospitaltuteJoseM.Pacheco,MD†UniversityofColoradoCancerCenterSandipP.Patel,MD‡†ÞMooresCancerCenterGregoryJ.Riely,MD,PhD†ÞJonathanRiess,MD‡UCDavisComprehensiveCancerCenterStevenE.Schild,MD§resaAShapiroMDPhDAditiP.Singh,MD†AbramsonCancerCenterattheUniversityofPennsylvaniaTaweeTanvetyanon,MD,MPH†MoffittCancerCenterJaneYanagawa,MD¶UCLAJonssonComprehensiveCancerCenterStephenC.Yang,MD¶JohnsHopkinsEdwinYau,MD,PhD†RoswellParkComprehensiveCancerCenterThomasNg,MD¶TheUniversityofTennesseeHealthSciencevocacyysMPEMtypesMPEMthelioidHistologyMPEMtmentBiphasicSarcomatoidHistologyorBicavitaryDiseaseMPEMsMPEMtypesMPEMthelioidHistologyMPEMtmentBiphasicSarcomatoidHistologyorBicavitaryDiseaseMPEMenignMulticysticorWellDifferentiatedPapillaryPeMMPEMceAfterPriorCRSHIPECMPEMPathologicReviewMPEMAlesofSurgeryMPEMBystemicTherapyMPEMCSupportiveCareMPEMDotheliomadexlievesthatthebestmanagementforanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.FindanNCCNMemberInstitution:/home/member-institutions.ofEvidenceanddationsotherwisedNCategoriesofEvidenceandConsensus.NCCNCategoriesofPreference:Allrecommendationsareconsideredappropriate.SeeNCCNCategoriesofPreferenceTheNCCNGuidelinesareastatementofevidenceandconsensusoftheauthorsregardingtheirviewsofcurrentlyacceptedapproachestotreatmentAnyclinicianseekingtoapplyorconsulttheNCCNGuidelinesisexpectedtouseindependentmedicaljudgmentinthecontextofindividualstancestodetermineanypatientscareortreatmentTheNationalComprehensiveCancerNetworkNCCNmakesnorepresentationsorwarrantiesofanykindregardingtheircontentuseorapplicationanddisclaimsanyresponsibilityfortheirapplicationoruseinanywayTheNCCNationalComprehensiveCancerNetworkAllrightsreservedTheNCCNGuidelinesandtheillustrationshereinmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.©2021.Version1.2022,12/22/21©2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon3/14/20227:05:54AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.otheliomadexINITIALEVALUATIONSuspicionforperitonealmesothelioma•recurrentascitesand/orperitonealthickening/masses•CTwithcontrastofchest/abdomen/pelvis•Midlinelaparoscopywithnodule/massbiopsies•Image-guidedcorebiopsyifconirmedidisciplinarymwithrienceeritonealtheliomammendedologictypesMPEMsiderserumCAsoluablemesothelinrelatedpeptideSMRPNote:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version1.2022,12/22/21©2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.MPEM-1PrintedbyMinTangon3/14/20227:05:54AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.otheliomadexPATHOLOGICDIAGNOSISPATHOLOGICSUBTYPESPeritonealmesotheliomabaMPeM PET/CTscanlioidBiphasic/sarcomatoidhistologyoraticaticBenignmulticysticorwell-differentiatedpapillaryPeMAsymptomaticandnoninvasiveimaryMimaryMimaryMimaryMbSeePrinciplesofPathologicReview(MPEM-A).cSeePrinciplesofSurgery(MPEM-B).Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version1.2022,12/22/21©2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.MPEM-2tivesurgerynttherapycfPrintedbyMinTangon3/14/20227:05:54AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.tivesurgerynttherapycfotheliomadexDISEASEFEATURESPRETREATMENTEVALUATIONTREATMENTUnicavitary,blepletetionleMedicallyinoperableand/orcompletecytoreductionnotachievableaturesd(includingaturesdPSPSAdjuvantsystemictherapyifsurgical/featuresdandnofeaturesdandno(CRS)(CRS)+hyperthermicmotherapyHIPECceSurveillancehSeeMPEM-4ImagingSurveillancehSeeMPEM-4therapyftherapyfpletetionlebSeePrinciplesofPathologicReview(MPEM-A).cSeePrinciplesofSurgery(MPEM-B).dPerioperativesystemictherapyshouldbeconsideredforhigh-riskfeaturessuchas:Ki-67>9%,nodalmetastasis,hightumorburden(PeritonealCancerIndex[PCI]>17),completenessofcytoreduction(CC)score>1,biphasicdisease,orbicavitarydisease.Patientswithfavorableprognosticprofile(ie,completecytoreduction,epithelioidsubtype,nolymphnodeinvolvement,Ki-67≤9%,PCI≤17)couldbefollowedinsurveillanceasthebenefitofadjuvanttherapyisunknown.eAdjuvantintraperitoneal(IP)chemotherapymaybeconsideredforpatientsthatdonotreceiveHIPEC.fSPrinciplesofSystemicTherapy(MPEMee-C).gSeePrinciplesofSupportiveCare(MPEM-D).hRecommendedsurveillance:CTchest/abdomen/pelvisevery3–6mox5ythenyearlyuntil10y.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version1.2022,12/22/21©2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.MPEM-3PrintedbyMinTangon3/14/20227:05:54AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.otheliomadexDISEASEFEATURESPRETREATMENTEVALUATIONTREATMENTBiphasic/vitaryvitarydiseasebcterterCciSystemictherapyfaregbSeePrinciplesofPathologicReview(MPEM-A).cSeePrinciplesofSurgery(MPEM-B)regardingoperabilityaftersystemictherapyinselectedpatients.fSPrinciplesofSystemicTherapy(MPEMee-C).gSeePrinciplesofSupportiveCare(MPEM-D).iRepeatCRS+HIPECcanbeconsideredinpatientswhoare>12mofrompriorCRSandareotherwiseconsideredtohaveoperabledisease.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.MPEM-4Version1.2022,12/22/21©2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon3/14/20227:05:54AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.otheliomadexDISEASEFEATURESPRETREATMENTEVALUATIONTREATMENTBenignmulticysticorillaryPeMillaryPeMbSymptomatic/recurrentorMicroinvasiveAsymptomaticandnoninvasivencehonwithonwithgingsurveillancehsymptomatic/gingsurveillancehEMbSeePrinciplesofPathologicReview(MPEM-A).cSeePrinciplesofSurgery(MPEM-B).hRecommendedsurveillance:CTchest/abdomen/pelvisevery3–6mox5ythenyearlyuntil10y.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.MPEM-5Version1.2022,12/22/21©2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon3/14/20227:05:54AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.otheliomadexPRINCIPLESOFPATHOLOGICREVIEWPathologicEvaluation•Malignantmesotheliomaoriginatesfromthecellsintheserosalliningthatsurroundsthebodycavities.Ofallmesotheliomas,~85%arisefromthepleura,~15%arisefromtheperitoneum,andtheremainder(<1%)originatesfromthepericardiumorthetunicavaginalis.1•IntheUnitedStates,diffusemalignantpleuralmesotheliomaaffects~3,000patientseachyear,withanannualincidenceof~1in100,000.2,3•Thepurposeofthepathologicevaluationofmalignantmesotheliomaisbasedonthepathologicassessmentoftumortissue,whichcanbeobtainedfromcorebiopsysampling,pleurectomy,orothermoreextensiveresectionssuchasextrapleuralpneumonectomy.Givenitsrarityandoverlappingmicroscopicfeatureswithotherconditions,thehistologicdiagnosisofdiffusemalignantmesotheliomacanbechallenging.•Toestablishapathologicdiagnosisofmesothelioma,diagnostictoolsthatareusedclinicallyincludehistologicassessment,immunohistochemistry(IHC),cytogenetics,andmoleculartechniques(suchastargetednext-generationsequencing[NGS],fluorescenceinsituhybridization[FISH],andsingle-nucleotidepolymorphismarrays).Despitethemultiplediagnostictoolkits,thediagnosisreliesprimarilyonproperhistologicassessmentandimmunohistochemistry.•TheneweditionoftheWorldHealthOrganization(WHO)ClassificationofThoracicTumorsbytheInternationalAgencyforResearchonCancer(IARC)introducedthefollowingchangesfromtheprevious2015edition:pNewentity:MesotheliomainSitupNewterminology:DiffusePleuralMesothelioma(insteadofDiffuseMalignantPleuralMesothelioma)pNewterminology:LocalizedPleuralMesothelioma(insteadofLocalizedMalignantPleuralMesothelioma)pNewterminology:Well-differentiatedpapillarymesothelialtumor(WDPMT,insteadofWell-differentiatedpapillarymesothelioma)pGenetictumorsyndromesinvolvingthethorax:BAP1tumorpredispositionsyndromeisahereditarycancersyndromecausedbyheterozygousgermlinepathogenicvariantsintheBAP1(BRCA1associatedprotein1)gene.•Thedescriptionsbelowrefertodiffusemesothelioma,whichwillbenamedmesotheliomaforthepurposeofsimplicity.assification•Mesotheliomaisclassifiedintothreehistologictypes:epithelioid,biphasic(mixed),andsarcomatoid,whichhavesignificantprognosticvalue.1•Thedeterminationofhistologictypesisbasedonthecytologicfeaturesofthetumor:pEpithelioidmesotheliomaischaracterizedbyepithelioid-to-roundcells.pSarcomatoidmesotheliomaischaracterizedbyspindledcellswithtaperednuclei.pBiphasicmesotheliomacontainsbothepithelioidandsarcomatoidcomponentsinvariousproportions,witheachcomprisingatleast10%ofthetumor.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version1.2022,12/22/21©2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.MPEM-AOF8PrintedbyMinTangon3/14/20227:05:54AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.otheliomadexPRINCIPLESOFPATHOLOGICREVIEWMesotheliomaClassification(continued)•Withineachhistologictype,mesotheliomacanbedividedintoseveralsubtypesandpatternsbasedonitscytologic,architectural,andbackgroundstromalfeatures.4pOtherrarevariantsofepithelioidmesotheliomaincludeclear-cell,signetring-cell,rhabdoid,deciduoid,andsmall-cell.5-7Tumorcellsarearrangedindiversearchitecturalpatternsthatincludetubulopapillary,trabecular,solid,acinar,micropapillary,oradenomatoid.pInsarcomatoidmesothelioma,subtypesdescribedincludeconventional/spindlecell,desmoplastic8,9andlymphohistiocytoid.10-12Asubsetofsarcomatoidmesotheliomaexhibitsheterologousdifferentiationwithosteosarcomatous,chondrosarcomatous,and/orrhabdomyosarcomatouselements.9pTheassignmentofhistologictypecanbechallenging,giventheinter-tumoralandintra-tumoralmorphologicheterogeneity.Appropriatetypeclassificationofmesotheliomaisnonethelessimportant,giventheprognosticsignificanceofdifferenthistologictypes.pStudiescomparingtheconcordancebetweenhistologictypeininitialbiopsieswithsubsequentresectionshaveshownthattheaccuracyoftypingincreaseswithahighernumberofbiopsies.13Whilesarcomatoidhistologyinbiopsiesishighlypredictiveofsarcomatoidhistologyinresections,epithelioidhistologyinbiopsiesisnotentirelyspecificandischangedtobiphasicorsarcomatoidtypesinresectionsinupto20%ofpatients.13HistologicCriteriaforMesothelioma•Inmesothelioma,thegoalsofhistologicassessmentaretoconfirmthepathologicdiagnosisandtodeterminethehistologictype,whichallowsforprognosticationandtreatmentplanning.Forthediagnosisofmesothelioma,oneneedstoestablisheachofthethreeconditionsbelow:pThelesionisdiffuseandnotsolitary.Correlationwithclinicalandradiologicfindingsisneededtoconfirmthatthedistributionofthetumorisdiffuseratherthansolitary.Whilealmostall(>99%)mesotheliomasarediffuse,rarecasesoflocalizedpleuralmesotheliomahavebeendescribed,whicharesolitary,haveadifferentpathogenesis,andharborarelativelylessaggressiveclinicalcourse.14-17pThelesionalcellsaremesothelial.Giventhemorphologicoverlapbetweenmesotheliomaanddiversemimicssuchascarcinomas,IHCcanbeusedtoconfirmthepresenceofmesothelialdifferentiationinthetumorcells.Othertoolssuchascytogeneticsandmolecularanalysismayalsobehelpfulinsomeinstances(seenextpage).pThelesionalcellsaremalignant.Histologicassessmentisintegraltoestablishthatthemesothelialcellsaremalignant.Morphologicfeaturesthatdistinguishmesotheliomafromreactiveconditionsinclude:1)invasionintoadjacenttissue,suchasadiposeorfibroustissue,andskeletalmuscle;2)full-thicknessserosalinvolvement;and3)formationofexpansilenodules(consideredasatypeoffibroustissueinvasion).Thepresenceoftissueinvasionisconsideredtobethemostreliablecriterionindistinguishingmesotheliomafromreactivemesothelialproliferations.18,19Ontheotherhand,“worrisome”featuressuchasnecrosis,cytologicatypia,andmitosesshouldbeinterpretedwithcaution,sinceeachcanbepresentinreactivepleuritisanddonotnecessarilyindicatemalignancy.•Interpretationcanbedifficultwhenthereislimiteddiagnostictissue,tangentialsectioning,artifactsfromhistologicprocessing,and/orentrapmentofadjacentstructuresmimickinginvasion.18,20Foramesothelialproliferationthatissuspiciousfor,butnotdefinitiveformalignancy,onemayreportthefindingsas“atypicalmesothelialproliferation”andrecommendre-biopsyand/orclosefollow-up.•Inthedistinctionbetweenmesotheliomaandbenign,reactivemesothelialproliferations,theroleofancillarystudieshadbeenlimiteduntilrecently,whenBAP1orMTAPIHCandCDKN2AcopynumberassessmentbyFISHmayaidthedistinctioninsomeinstances(seenextNote:Allrecommendationsarecategory2Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.MPEM-AVersion1.2022,12/22/21©2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.2OF8PrintedbyMinTangon3/14/20227:05:54AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.otheliomadexPRINCIPLESOFPATHOLOGICREVIEWImmunohistochemistryMarkerstoconfirmmesothelialdifferentiation•IHCisintegraltothepathologicdiagnosisofmesotheliomainclinicalpractice.•Usefulimmunohistochemicalmarkersinclude:1)positivemarkerstoconfirmmesothelialdifferentiation,suchasWT1,calretinin,andD2-40;and2)negativemarkerstoexcludemimics,suchaspolyclonalCEA,TTF-1,andclaudin-4.22-24Oneofthecaveatsisthatnoindividualimmunohistochemicalmarkerisentirelysensitiveandspecific.Therefore,itisrecommendedthatapanelincludingatleasttwomesothelialmarkers(calretinin,WT1,D2-40)andtwocarcinomamarkers(claudin4,TTF-1,polyclonalCEA)shouldbeusedtoestablishthediagnosis.25•Broad-spectrumkeratins(AE1/AE3,pancytokeratin,MNF116)arenotspecificandareexpressedinbothmesotheliomaandcarcinomas.•Sarcomatoidmesotheliomaoftenshowsfocaltoabsentexpressionformostmesothelialmarkers,withthemostsensitivemarkerbeingD2-40/podoplanin.26•Recently,GATA3hasbeenexploredasapotentialdiagnosticmarkerforsarcomatoidmesotheliomassinceGATA3isexpressedinonly~10%–20%ofsarcomatoidcarcinoma27andstronglyexpressedinallsarcomatoid/desmoplasticmesotheliomas.28Markerstoconfirmamesothelialmalignantproliferation•Althoughthedistinctionbetweenmesotheliomaandreactivemesothelialproliferationsprimarilyreliesonhistologicassessment,thiscanbechallenginginsomecases.•Atpresent,onlyBRCA-1relatedprotein-1(BAP1)andmethylthioadenosinephosphorylase(MTAP)IHC,andcyclin-dependentkinaseinhibitor2A(p16)FISHhavesufficientpublicationsandreproducibilityofresultstobeconsideredasestablishedmarkers.21pBAP1IHCisaspecific,(thoughnotsensitive)markertodistinguishmesotheliomafromreactivemesothelialproliferations.pBAP1isatumorsuppressorimplicatedinthepathogenesisofmesothelioma,uvealmelanoma,cholangiocarcinoma,andclear-cellrenalcellcarcinoma.29Recurrentsomaticand/orgermlinemutationsinBAP1arepresentinmesothelioma.AsasurrogateforBAP1genomicstatus,BAP1IHCisusedasadiagnosticmarkerformesothelioma,whereasreactiveproliferationshaveintactBAP1nuclearstaining.AberrantBAP1proteinexpression,definedascompletelossofnuclearBAP1stainingispresentin~50%–70%ofmesotheliomaepithelioidtype30-36butinlessthan20%insarcomatoidtype.37pMTAPIHChasbeenusedasadiagnosticmarkerformesothelioma.38MTAPislocatednearCDKN2Aonthechromosomalregion9p21.LossofcytoplasmicMTAPstainingisconsideredasurrogateforchromosomal9plossasdeterminedbyconcurrentCDKN2AFISHtesting38andhasbeenreportedin~40%–60%ofmesotheliomabutrarelyinreactiveproliferations.34-36pAlthoughMTAPaloneisnotsensitive,combineduseofBAP1andMTAPIHCmayimprovethesensitivityandspecificity.34-36Since~10%–20%oflungadenocarcinomahaveMTAPloss,35MTAPIHCisnotusefulfordistinctionbetweenmesotheliomaandlungcarcinoma.•AdditionalIHCmarkerssuchas5-hydroxymethylcytosine(5-HMC),enhancerofzestehomolog2(EZH2),cyclinD1,andprogrammeddeathligand-1(PD-L1),andNF2byFISHareallpotentiallyusefultodistinguishmesotheliomafromreactivemesothelialproliferations,butneedfurtherstudysincetheirutilityinclinicalpracticeremainsunclear.21Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version1.2022,12/22/21©2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.MPEM-A3OF8PrintedbyMinTangon3/14/20227:05:54AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright©2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.otheliomadexPRINCIPLESOFPATHOLOGICREVIEWMarkersaspotentialprognosticandpredictivemarkers•RecentstudiesexploredimmunohistochemicaltargetsaspotentialprognosticandpredictivemarkerspPatientswithpleuralmesothelioma,epithelioidtype,withlossofBAP1byIHCandretainedp16expressionbyIHChaveprolongedsurvivalinbothunivariateandmultivariateanalyses.39pMesotheliomapatientswithgermlineBAP1mutationshaveaprolongedsurvival.40,41pALKrearrangementsbyIHCfoundinrarepatientswithperitonealmesothelioma42-45haveshowndramaticresponsewithALKinhibitortherapies.46,47•PD-L1(CD274),anegativeregulatorofimmunecheckpoint,representsatargetinimmunotherapy,withPD-L1IHCevaluatedasapredictivebiomarkerindiversetumortypes.48•TheutilityofPD-L1IHCasapredictivemarkertoimmunecheckpointinhibitorsandtheoptimalassessmentcriteriainmesotheliomaremainunclear.CytogeneticFeatures•Mostmesotheliomasarecharacterizedbycomplexnumericalandstructuralkaryotypicalterations.49•Althoughnospecificchromosomalabnormalitiesarepathognomonicformesothelioma,lossofchromosomalregion9pincludingCDKN2A
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