内科学教学课件：Hematologic Malignancies

HematologicMalignanciesLymphomaLymphoma(malignantLymphoma)Agroupofmalignanttumorsoriginatedfromlymphnodesorotherlymphatictissues(tonsil,spleen,bonemarrow…)MalignanttumorsofimmunesystemCategoriesaccordingtohistopathologyHodgkinLymphoma(HL)Non-HodgkinLymphoma(NHL)VirchowBillrothALLMMCLLLymphomasHematopoieticstemcellNeutrophilsEosinophilsBasophilsMonocytesPlateletsRedcellsMyeloidprogenitorMyeloproliferativedisordersAMLLymphoidprogenitorT-lymphocytesPlasmacellsB-lymphocytesnaïvegerminalcenterIncidence0.84~1.39/100,000population(lowerthanwesterncountriesandJapan)50%atage20~40(rangefrom3mto82yrs)Male:Female1.4~3.7:1NHL2/3~4/5HD1/3~1/5(morefrequentinwesterncountries)Etiology1.Geneticalterations

Inheritedpolymorphisms(HLA)，

Acquiredgeneticmutations:radiation2.InfectionEpstein-Barr(EB)virus:Burkittlymphoma;HightiterofAntiEBvirusantibodyinHDHTLV-I:AdultTcelllymphomaH.pyloriinfection:MALTlymphoma3.AntigenstimulationChemicalexposuresyoungpatientswithCrohn’sdisease4.Immunosuppression

AIDSrheumaticdiseases(SLE,Sjogren'ssyndrome)post-transplantationLymphomaclassification(2001WHO)B-cellneoplasmprecursormatureT-cell&NK-cellneoplasmprecursorMatureHodgkinlymphomaNon-HodgkinLymphomasHDClassificationRyeclassification(baseonReed-Sternbergcell

morphology)WHOclassification(baseonmorphology,immunologyandcytogenesis)Pathologicalclassification(WHO2001)Nodularlymphocyte-predominantHodgkinlymphoma(NLPHL):localized,goodprognosis;5%ClassicalHodgkinlymphoma;LymphocyterichclassicalHodgkinlymphoma:localized,goodprognosis;5%Nodularsclerosis:young,stageIorII,relativelyfavorableprognosis;55%Mixedcellular:tendencyofdissemination,relativelypoorprognosis;25%Lymphocytedepleted:old,stageIIIorIV,poorprognosis;5%NHLClassificationRappaportclassificationWorkingFormulation(1982)KielclassificationREALclassificationWHO2000ImmunophenotypeB-cellLymphoma:CD20+,CD79α+

T-cellLymphoma:TDT+,CD3+,CD5+WHO2000:NHLB-cellNeoplasmsPrecursorB-cellNeoplasms1.PrecursorB-lymphoblasticleukemia/lymphomaMatureB-cellNeoplasms2.B-cellchroniclymphocyticleukemia/smalllymphocyticlymphoma3.B-cellprolymphocyticleukemia4.Lymphoplasmacyticlymphoma5.SplenicmarginalzoneB-celllymphoma(±villouslymphocytes)6.Hairycellleukemia7.Plasmacellmyeloma/plasmacytoma8.ExtranodalmarginalzoneB-celllymphomaofMALTtype9.NodalmarginalzoneB-celllymphoma(±monocytoidBcells)10.Follicularlymphoma11.Mantle-celllymphoma12.DiffuselargeB-celllymphoma13.Primaryeffusionlymphoma14.Burkitt’slymphomaWHO2000:NHLT-cellNeoplasmsPrecursorT-cellNeoplasms1.PrecursorT-lymphoblasticleukemia/lymphomaMatureT-cellNeoplasms2.T-cellprolymphocyticleukemia3.T-cellgranularlymphocyticleukemia4.AggressiveNK-cellleukemia5.AdultT-cellleukemia/lymphoma(HTLV-1)6.ExtranodalNK/T-celllymphoma,nasaltype7.Enteropathy-typeT-celllymphoma8.Hepatosplenicgamma-deltaT-celllymphoma9.Subcutaneouspanniculitis-likeT-celllymphoma10.Mycosisfungoides/Sezarysyndrome11.Anaplasticlarge-celllymphoma,T/nullcell,primarycutaneoustype12.Anaplasticlarge-celllymphoma,T/nullcell,primarysystemictype13.PeripheralT-celllymphoma,nototherwisecharacterized14.AngioimmunoblasticT-celllymphomaRelativefrequenciesofdifferentlymphomasHodgkinlymphomaNHLDiffuselargeB-cellFollicularOtherNHL~85%ofNHLareB-lineageClinicalManifestations

RelatedtothepathologicalchangesPainlesslymphadenopathy:cervical,supraclavicular,axillary…Symptomsduetolymphadenopathy:cough,dyspnea,superiorvenacavasyndromeClinicalManifestationsLymphnodesenlargementEnlargementofcervicallymphnodesEnlargementofsupraclavicularlymphnodesInvolvetheoropharyngeallymphoidtissue(Waldeyerring)ClinicalManifestationsExtranodalinfiltration:morecommoninNHLGItractinfiltration:smallintestine(ileum),stomach,ectHepatomegaly,splenomegaly,pulmonaryinfiltration,pleuraleffusion,CNSBMinfiltrationSkininfiltrationPulmonaryinfiltration,pleuraleffusionKidneyinvolvementCNSinvolvementClinicalManifestations

Age PainlessLN Wayof ExtraNodal Enlargement Spreading InvolvementHD youngfirstsymptomadjacentoriginlesscommon

NHLoldersimilar,lesscommonjumpingmorecommon

ClinicalManifestationsFever:persistentorperiodic(Pel-Ebsteinfever),especiallyinHD RelatedtothepathologicalchangesNightsweatingWeightloss(10%in6m)Lymphnodesenlargementsplenomegaly,hepatomegaly…Pruritusofskin,especiallyinHDLaboratoryFindings

Diagnosisdependsonbiopsyoflymphnodesorotherinvolvedorgans:Collapseofnormallymphnodestructure;CellheterogeneityPeripheralblood:slightanemia,usuallynochangesinWBCandPlateletcountBM:non-specificchangesHD:R-ScellinsmearandbiopsyNHL:increasedlymphocyteLaboratoryFindingsChromosomechangesinNHL:t(14;18):Follicularlymphomat(8;14):Burkitt’slymphomat(11;14):Mantle-celllymphomat(2;5):Ki-1+(CD30+)Anaplasticlarge-celllymphoma3q27:DiffuselargeB-celllymphomaLaboratoryFindingsImmunologicaltest:HD:deficiencyofcellularimmunity;NHL:M-protein(+)Coombs’test(+)hypoglobulinemiaOtherfindings:ESR↑AKP↑LDH↑LaboratoryFindingsMolecularBiologychangesinNHLbcl-2TCRIgHLaboratoryFindingsRadiographicfeaturesUltrasoundX-rayfilmComputerizedtomography(CT)ChestAbdomen,PelvisWhole-bodypositronemissiontomography(PET)MRI

Ultrasound

ultrasonicpunctureadvantage：realtimedisplay,accurate,noX-rayinjury,convenient,cheapdisadvantage：tissuelimitedInvolvement,prognosisandtherapeuticeffectevaluationadvantage：convenient,cheapdisadvantage：individualerror，standarddisparity

X-rayfilm（CT/MRI）CTscanbemostcommonlyusedadvantage：standarddisadvantage：opaquemedium,lowsensitivityMRIscandisadvantage：opaquemedium,highsensitivity,cheapdisadvantage：standarddisparityWhole-bodypositronemissiontomography

(PET)CASE2004-9-14女性30岁胃NHL术后弥漫大B细胞型下纵隔、后腹膜淋巴结SUVavg=10.5～20.0CASER-CHOP6次2006-5-9复查全身FDG代谢未见异常DiagnosisBiopsy----PathologicalDiagnosisHistopathologicalclassificationImmunomarkerseg:NHL,diffusedlargecell,BcellPrognosisinlymphomadiagnosisPathologictype（GCB，ABC）IPICytogeneticschromosomesabnormalMolecularbiologygeneabnormal

microRNAexpressionabnormal

InternationalPrognosticIndex(IPI)Patientsofallages RiskFactors

Age >60years PS 2-4 LDHlevel

Elevated Extranodalinvolvement

>1site Stage(AnnArbor)

III-IV

Patients60years(age-adjusted)

PS 2-4 LDH

Elevated Stage

III-IVShipp.NEnglJMed.1993;329:987.DifferentialDiagnosis

Lymphnodesenlargement Specific:TBInfection Non-specific:bacteria,virus,fungiMaligancies:hematological;solidtumorConnectivetissuediseases

DifferentialDiagnosisFeverInfection(bacteria,virus,TB,ect)ConnectivetissuediseaseMalignanttumorsMalignaciesinrelatedorgans

Gastrointestinaltumors,livercancer,ect

StageIStageIIStageIIIStageIVStagingoflymphomaA:absenceofBsymptoms B:fever,nightsweats,weightlossClinicalStaging---Subtype

GroupAWithoutgeneralsymptomsGroupBWithgeneralsymptomsunexplainedfever,>38C,lastingover3daysnightsweatingweightloss,>10%ofbodyweightwithin6months

StagingProceduresSymptomsandsignsX-rayfilm(chest,ect)andUltrasoundCT---chestandabdomenLaboratorystudyBMsmearandbiopsyStaginglaparotomyTreatment

PrinciplesPathologicalclassificationClinicalStagingPeripheralblood,bonemarrowFunctionofimportantorgansGeneralconditionofpatientTreatment

MethodsSurgeryRadiationChemotherapyBiotherapyPBSCTTreatmentofHDStageIA、IIAExtendedradiation(mantleformorinvertedYform)StageIB、IIB、IIIA、IIIB、IVCombinedchemotherapy+localizedradiationTreatmentofHDRadiation

dosage:involvedfield----40-44Gyuninvolvedfield(prophylactic)30-35Gy

TreatmentofHDChemotherapy:MOPPProtocolNitrogenMustard4mg/m2vday1,8VCR 1.4mg/m2vday1,8Procarbazine 70mg/m2p.o.day1-14Prednisone 40mg/m2p.o.day1-14Procarbazine:甲基苄肼TreatmentofHDChemotherapy:ABVDProtocolAdriamycin25mg/m2vday1,15Bleomycin 10mg/m2vday1,15VCR 1.4mg/m2vday1,15Dacarbazine375mg/m2vday1,15Dacarbazine：氮酰咪胺PrognosisintreatmentofHDTreatmentofNHLTreatmentstrategyaccordingtoIPIRiskStrata

InternationalPrognosticIndex(IPI)Patientsofallages RiskFactors

Age >60years PS 2-4 LDHlevel

Elevated Extranodalinvolvement

>1site Stage(AnnArbor)

III-IV

Patients60years(age-adjusted)

PS 2-4 LDH

Elevated Stage

III-IVShipp.NEnglJMed.1993;329:987.IPIRiskStrata Allages Low(L) 0-1 Low-intermediate(LI) 2 High-intermediate(HI) 3 High(H) 4-5 Age-adjusted L 0 LI1 HI 2 H 3RiskFactorsRiskGroupShipp.Blood.1994;83:1165.TreatmentofNHLLowGradeGroupFrequentlyfollowup,postponechemotherapySingledrug:CB1348(Leukeran)2mgb.i.d~t.i.dcyclophosphamide:100mg/dDiseaseprogressing----combinedchemotherapyFludarabinPentostatineCD20(Rituximab)

TreatmentofNHLIntermediateandHighGradeGroupCombinedChemotherapyRadiationifneeded

TreatmentofNHLChemotherapy:CHOPProtocolCTX 750mg/m2 v.day1ADR 50mg/m2 v.day1VCR 1.4mg/m2 v.day1Prednisone 100mg/m2 p.o.day1-5Durationofcycle14-21daysor21--28daysOR80-90%;CR50-60%;Curative<40%TreatmentofNHLOtherprotocols COP m-BACOB COP-BLAMESHAP:relapselymphoma

TreatmentofNHLSurgeryLocalizedfocus(IA)SinglelymphnodeinvolvementSingleGItractfocusPost-operationchemotherapyTreatmentofNHLBiotherapy:Interferon:3-5millionunit/d

partialresponse

improvementof5-yearDFS

TreatmentofNHLBiotherapy:Interferondosage500万U/m2，muscleorhypodemic，t.I.w300万U/m2，muscleorhypodemic,q.dCourseOneyearEfficiencyPrimarypatients，OR75％ExtendDFS

TreatmentofNHLBiotherapy:

Interferon：glucoproteinInterferon:leukocyticInterferonInterferonβ：fibroblasticInterferonInterferonυ：LymphocyticInterferon

TreatmentofNHLBiotherapy:ThemechanismsofInterferonAnti-virusKillingtumorcellsinducedteminaldifferentiationoftumorcellsActivationothercytokines

TreatmentofNHLBiotherapy:ApplicationofInterferon：Earlyandlowgradelymphoma，OR40~60％TcelllymphomaCombinedwithotherchemotherapyMaintainedtreatmentTreatmentofNHLBiotherapy:

Antibody----CD20 (Rituximab)

NEW!

TreatmentofNHLBiotherapy:－－AntibodyRituximabspecificbindingwithB-cellantigenCD20Cleaningtumorcellshemopoieticstemcell,progenitorcell,plasmacellandothernormaltissuearenotexpressCD20Safetyandefficiencymonoclonalantibody

Rituximab:MechanismsofAction

ClinicalapplicationofRituximabCombinedwithCHOPtreatmentofNHL

week12345678910111213141516171819202122Rituximab375mg/m2CHOPcoursesMaintained1/2MX4timesTreatmentofNHLPeripheralBloodStemCellTransplantation(PBSCT)

HDstageⅢ,ⅣNHLstag