淋巴组织肿瘤

1、淋巴瘤Lymphoma基础医学院病理学系同济医院病理研究所敖启林,DrJohnK.C.CHAN陈国璋,4thEditionPublished20/9/2008,第一节概述一、定义“来源于”成熟淋巴细胞及其前体细胞（淋巴母细胞）的恶性肿瘤，分为非霍奇金/白血病和霍奇金淋巴瘤两大类。二、分类（一）非霍奇金淋巴瘤(NHL)：包括B，T和NK细胞（70%）1、前体细胞：B/T/NK前体细胞（淋巴母细胞）淋巴瘤（2%）2、成熟细胞：成熟细胞淋巴瘤（68%）B细胞（54%）T细胞（12%）NK/T或NK细胞（2%）,(二)霍奇金淋巴瘤(HL):特殊类型成熟B细胞淋巴瘤(30%)结节性淋巴细胞为主型（1.5

2、%）经典型(28.5%)(缺陷性B细胞)结节硬化型淋巴细胞丰富型混合细胞型淋巴细胞消减型,第二节淋巴结的免疫结构（immunoarchitecture）一、概念：通过免疫组织化学染色显示淋巴结的结构特征。包括肿瘤性或非肿瘤性细胞的成分（淋巴细胞,辅助性非淋巴细胞,淋巴窦,血管,网状纤维等）、数量、分布方式等特征。通过对比，掌握正常和异常免疫结构，对淋巴结病变进行诊断和鉴别诊断。高质量的组织学切片和合理的免疫标记物的选择是识别免疫结构的关键。,二、淋巴结的正常免疫结构（一）淋巴结结构:皮质,髓质,窦,被膜和纤维小梁,（二）B淋巴细胞分布：1.主要在浅皮质区的初级和次级滤泡，髓索和副皮质区也含一定

3、量B细胞;2.B细胞分化过程中的形态和免疫学特征成为非霍奇金B细胞淋巴瘤分类的基础。,PrepreBcell,PreBcell,ImmatureBcell,MatureBcell,ActivatedBcell,Plasmacell,Precursorcells;antigennon-responsive,VirginBcells;antigenresponsive,Germinalcenterantigenencountered,TdT,CD20,CD22,CD19,PAX5,CD79a,CD10,Bcl-6,CD138,CytoplasmicCD22,Immunoarchitectureof

4、normallymphnode,Bcells(CD20+,CD10+,BCL-6+),Tcells(CD3+);onlysmallnumbersofCD20+cells,1、初级滤泡：处女型B细胞和成熟小淋巴细胞；,CD20,2、次级滤泡：由生发中心、套区和边缘区构成。,Organizationofsecondarylymphoidfollicle,Marginalzonecells(IgM),Mantlezonecells(IgM+D),Folliclecentercells(IgM,IgG,IgAorIgE,notIgD),:约2:1，当:8-10:1或:3:1提示轻链限制表达,次级滤泡生

5、发中心、套区和边缘区免疫标记：（1）生发中心(GerminalCenter,GC)：1）中心细胞和中心母细胞：CD10+,BCL-6+,Bcl-2-,2）滤泡树突细胞(Folliculardendriticcells,FDC):CD21+,CD23+,CD35+3）T细胞：CD4+,CD10+,CXCL13/PD-1+,少量CD57+4）可染体巨噬细胞：CD68+,lysozyme+,CD11c+（2）套区:处女型B细胞和记忆细胞,表达IgM,IgD（3）边缘区：无特殊标记，绝大多数次级滤泡难以鉴别，腹腔淋巴结易识别。,CD20,CD79a,CD21,CD10,Bcl-6,反应性滤泡增生的特点

6、对T细胞依赖性抗原的反应滤泡增多，大小、形态不等，可弥漫分布，主要位于皮质区，无背靠背现象。典型生发中心具有极性(Polarity):明区和暗区，套区明显，扁桃体组织更易识别；星天现象，中心细胞和中心母细胞混杂，免疫染色：生发中心细胞BCL-2-，ki-67指数较高。滤泡间区一般无B细胞弥漫阳性，B细胞CD43和CD5阴性。,Darkzone,Lightzone,BCL-2,Ki67,Marginalzonecells,CD20,（三）T淋巴细胞分布：副皮质区(paracortex),T淋巴细胞为主(CD4CD8):主为小淋巴细胞，偶尔出现大细胞(可以是活化的B细胞);含有高内皮静脉(High

7、endothelialvenules,HEV):血液淋巴细胞入淋巴结的通道;含有指状树突细胞(interdigitatingdendriticcells,IDC):S100+的专职抗原递呈细胞；,Prothymocyte,Subcapsularthymocyte,Corticalthymocyte,Medullarythymocyte,PeripheralTcell,Precursorcells,MatureTcells,Cytoplasmic,Surface,CD4,CD8,CD1,CD4,CD8,CD3,CD2,CD7,TdT,IDC,CD3,副皮质区增生,常见病因:病毒感染,接种疫苗，药

8、物，自身免疫疾病,皮病性淋巴结炎，肿瘤转移等形态特征：副皮质扩大，可形成结节；HEV增生；混合小淋巴细胞和转化淋巴细胞，浆细胞，树突细胞，嗜酸性粒细胞等；免疫染色：主为T细胞，或T/B细胞混合,一般无B细胞为主弥漫分布。,Immunoblast,Infectiousmononucleosis,CD20,CD3,LargecellscomprisemixtureofBandTcells-Reactiveprocess,CD30+cellsarescatteredandstainingisweakormoderate,whichindicatestheheterogeneityofthelarge

9、cellpopulation.,CD30stainingisdiffuselystrongpositive,whichindicatesthemonocloneentity.,Kappa,Lambda,LargeBcellsarepolytypic,T细胞为主时支持良性的依据（谨慎！）：（1）结构不同程度保留：淋巴窦和皮质淋巴滤泡；（2）大细胞群体分布不规则或呈地图样，不形成膨胀性团块；（3）无浸润现象：上皮,脂肪,血管,神经,纤维间质中单行排列；（4）细胞无明显异型：BLeukemia(ALL):BTUntreated:rapidlyfatalAggressivetherapy:goodsu

10、rvivalCannotpredictlineagefrommorphologyDefiningmarker:TdT+，CD99,CD20,CD79a,B-LBL,T-LBL,滤泡性淋巴瘤FOLLICULARLYMPHOMA,UsuallyinvolvinglymphnodesHigh-stagediseaseatpresentationPathology:RecapitulatestheorganizationandcytologyofthenormalgerminalcentersKeyimmunophenotype:Bmarker+,CD10+,Bcl6+,Bcl2+Follicular

11、lymphomainvolvingsomeextranodalsites(suchasskin,duodenum,testis)showdistinctiveclinicalandbiologicfeaturesGenetics:Iggenerearrangement;t(14;18)(q32;q21)bcl-2generearrangement(duetoBCL2/IGHtranslocation),Follicularlymphomavsreactivefollicularhyperplasia,MajorcriterionCloselypackedfolliclesthroughout,

12、withscantyinterfolliculartissues,1majorcriterionor3minorcriteria.Butconfirmbyancillarytestsifuncertain,滤泡性淋巴瘤主要诊断标准示意图,Majorcriterionfulfilledin80%ofcasesoffollicularlymphoma,Justgoontohighmagnificationtoconfirmfolliclecentercellmorphology,Centrocytesoftenhavetriangularshapednuclei,滤泡性淋巴瘤的次要诊断标准,Int

13、heremaining20%ofcases(non-crowdedfollicles),acombinationofminorcriteria(3)havetobeconsidered,andsupplementedbyancillarystudiesasrequired,MinorcriteriaNotingible-bodymacrophagesCellularmonotony:centrocytepredominanceNocellularpolarisationAbsentorincompletemantlesFolliclesinperinodaltissuesDysplasticf

14、ollicularcentercells,e.g.signetringcells,frequentcytoplasmicglobulesAtypicalcellsininterfolliculartissuesInvasionofwallsofbloodvessels,FollicularlymphomavsRFH:ancillarytechniques,Immunostainingforbcl-2MostusefulimmunostainNormal:BothTandBcellspositiveexceptfolliclecentercellsLookforpositivestainingo

15、fcellsinfolliclecenters:positivestainingsupportsdiagnosisoflymphoma,Reactivefollicles,Follicularlymphoma(Bcl-2immunostaining),Commonmisconceptionsinhematopathology,Negativebcl-2stainrulesoutfollicularlymphomaThetruth:Itdoesnot.20-25%offollicularlymphomacasesarenegative.Pursuewithotherteststoconfirmo

16、rrefuteadiagnosisoffollicularlymphoma,Bcl-2staininginfollicularlymphoma,Bcl-2,LookforevidenceinterfollicularinvasionDenselypackedCD20+orCD79+B-cellsbetweenfolliclesisindicativeofinterfollicularinvasionPresenceofasignificantnumberofCD10+lymphoidcells(notneutrophils,whicharealsoCD10+)betweenfolliclesa

17、lsoindicatesinterfollicularinvasionLookforvascularinvasionManyCD10+cellsinthewallsofperinodalbloodvessels,CD20,CD10,LookformonoclonalityorlowproliferationindexImmunostainforIgtolookforlightchainrestrictionDemonstratedbyKi67,alowKi67indexfavorsdiagnosisoffollicularlymphomaoverRFH(meanindex15.6%vs64.9

18、%);ahighKi67indexisinconclusiveMolecularanalysisIggenerearrangementbySouthernblotorPCR(NotethatPCRmayhavefalsenegativeresults)DetectionofBCL2generearrangementbySouthernblot,PCRorFISH,Kappa,Lambda,FL1:Ki67,RFH:Ki67,FL3:Ki67,套细胞淋巴瘤Mantlecelllymphoma:morphology,Diffuse,vaguelynodular,ormantlezonepatter

19、nBroadcytologicspectrumClassictype:smalllymphoidcellswithirregulartoroundnucleiBlastoidvariant(lymphoblasts,butTdT-)PleomorphicvariantOftenwithsolitaryepithelioidhistiocytesInterspersednakednuclei(folliculardendriticcells)Genetics:Iggenerearrangementt(11,14)(q13;q32),GrowthpatternofMCL,Roundnuclei,M

20、antlecelllymphoma:biologicmarkers,Bmarker+,CD5+,CD10-,CD23-,IgM+,IgD+Keydefiningfeature:CyclinD1+duetot(11;14)(q13;q32)orcryptictranslocation,CyclinD1,粘膜相关淋巴组织Mucosa-AssociatedLymphoidTissue(MALT),SpecializedsecondarylymphoidcompartmentsofmucosaltissuesNatural,e.g.,Waldeyersring,smallintestine,lungA

21、cquiredinautoimmunedisease/inflammatione.g.,thyroid,salivarygland,lacrimalgland,stomachSimilarorganizationaslymphnode:B-cellfollicles,T-cellzonesLymphoidcellsacquirehomingproperties,LOWGRADEBCELLMALTLYMPHOMA(extranodalmarginalzoneB-celllymphoma),Usuallylocalizedatpresentation(66-79%)Recurrenceatothe

22、rMALTsites(“homing”)Manycanbetreatedbylocoregionaltherapyoreradicationofantigen-stimulationsourceCompleteremissionrate=72%5-yearoverallsurvival=74%(Gastric:90%),HistologicfeaturesoflowgradeMALTlymphoma,Small/medium-sizedcells(lymphocytes,centrocyte-like,monocytoidBcells)Patterns:diffuse,interfollicu

23、lar,marginalzoneLymphoepitheliallesionsPlasmacellsarecommonReactivelymphoidfollicles+/-colonization,LowgradeMALTlymphoma:Immunophenotype,Aneoplasmofpost-germinalcenterBcellsPanB+,CD10-,CD5-,CyclinD1-,CD23-Keyfeatures:siteofinvolvementlymphoepitheliallesionexclusionofotherlowgradeB-celllymphomas,Afte

24、rHelicobactereradicationtherapy,弥漫性大B细胞淋巴瘤DIFFUSELARGEBCELLLYMPHOMA（DLBCL）,CommonestnodalB-celllymphomaAheterogeneousentityFinalcommonpathwayforhighgradetransformationoflowgradeB-celllymphomas,Centroblastic/Immunoblastic,Multilobated,Pleomorphic,BURKITTLYMPHOMA,Threedifferentforms:Endemic(Equatorial

25、Africa;strongassociationwithEBV90%;commonlyaffectingjaws,gonads,kidneys)Sporadic(EBVassociationonly15%;commonlyinvolvingterminalileumandWaldeyersring)AIDS-related(EBVassociation30%;commonlyinvolvinglymphonodeandbonemarrow)AfricancasescanalsobeAIDS-related!,Burkittlymphoma,t(8;14)(q24;q32)orvariants,

26、withtranslocationbetweenc-mycandIggeneMostlyadiseaseofyoungpatientsHighlyaggressive,butpotentiallycurablebychemotherapy,Burkittlymphoma:Immunogenetics,ProbablycorrespondstoIgM+blastsingerminalcenterPan-B+,CD10+,Bcl-6+,Bcl-2-Keyfeatures:C-MYCtranslocationmedium-sizedcellshighKi67index：100%germinalcen

27、tercellphenotype,CD20,CD10,Ki67,外周T和NK细胞淋巴瘤PERIPHERALTANDNKCELLLYMPHOMAS,Uncommon;80%),ExtranodalNK/Tcelllymphoma:Pathology,Necrosis(apoptosis)commonAngioinvasioncommon(notinvariablyseen)Broadcytologicspectrum:small,medium-sizedorlargecells,ormixedMayhavemanyadmixedinflammatorycells,Small,Medium-siz

28、ed,Large,Broadcytologicspectrum,ExtranodalNK/Tcelllymphoma:immunophenotype,CD2+.sCD3-,cCD3e+,CD56+Cytotoxicgranulesperforin,granzymeB,TIA-1positiveCD4,CD5,CD7,CD8:usuallynegativeKeyfeatures:CD56+,EBER+IfCD56-,requiresEBER+andcytotoxicgranules+fordiagnosis,SurfaceCD3,CytoplasmicCD3,CD56,Frozentissue,

29、Paraffinsection,PERIPHERALTCELLLYMPHOMAUNSPECIFIED外周T细胞淋巴瘤，非特殊型,AwastebasketcategoryVariableclinicalmanifestationsUsuallyhighstagedisease(nodal/extranodal)MayhaveeosinophiliaAggressive;relapsecommonTheextranodalcasesoftenexpressacytotoxiccellphenotype,PeripheralT-celllymphoma:Morphologiccluesforreco

30、gnition,PredominantparacorticalinvolvementProminenthighendothelialvenulesSpectrumofcellssizesandshapesIrregularnuclearcontoursClearcellsManyadmixedepithelioidhistiocytesandeosinophils,ButimmunostainingessentialforconfirmingTlineage,ANAPLASTICLARGECELLLYMPHOMA,primarysystemicform间变性大细胞淋巴瘤，原发系统性,Tends

31、tooccurinchildrenandyoungadultsNodalorextranodalpresentation(whichmayincludeskin,softtissue,bone,G.I.tract)Immunophenotype:CD30+;EMAusually+T-lineagemarkers+/-(Tornullcell)AproportionofcasesexpressALKduetotranslocationinvolvingALKgene,Hallmarkcells,ALKtranslocation(orexpression)hashelpedtodefineahom

32、ogeneoussubgroupofALCLThiscanbeeasilydetectedbyimmunostainingforALK-permittingre-definitionofthemorphologicspectrumofALCL:ClassicaltypeMonomorphicSmallcellLymphohistiocyticHypocellular,CD30,OverallsurvivalPrimarysystemicformofALCL,0,5,10,Years,ALCL,ALK+*,100%,50%,ALCL,ALK-,霍奇金淋巴瘤HODGKINLYMPHOMA,Lymp

33、hocytepredominance,Mixedcellularity,Nodularsclerosis,Lymphocytedepletion,NodularlymphocytepredominantHodgkinlymphoma(N-LPHL),RYECLASSIFICATION,WHOCLASSIFICATION,5,10,Years,Overallsurvival,N-LPHLdefinedbyimmunohistochemistry,cHLdefinedbyimmunohistochemistry,p=0.0071,Alymphomacharacterizedby:presenceo

34、fReed-Sternbergcellsandtheirvariantsconfirmedbymmunohistochemistryinanappropriatereactivecellularenvironment,Reed-Sternbergcellsandvariants,DiagnosticReed-SternbergcellsMononuclearHodgkincellLacunarcellL&HcellPleomorphicReed-SternbergcellKi67+100%,NoneedtofinddiagnosticReed-SternbergcellsinrenderingadiagnosisofHodgkinlymphoma.Itsokayifcellsarelargeenough,withprominentnucleoliandcompatibleimmunophenotype.,Reed-Sternbergcellsandvariants,Smalllymphocytes,Nuclearsizeofmostneoplasticcellsus