淋巴组织肿瘤.ppt

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 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 Immunoarchitectureofnormallymphnode 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 CD4 CD8 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 Highendothelialvenules 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 whichindicatestheheterogeneityofthelargecellpopulation 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 2 5倍小淋巴细胞 常无透明胞质 核形态较规则 圆形或椭圆形 轻度扭曲或折叠 5 免疫染色 常为CD4 为主 少为CD8 为主 AIDS 骨髓移植等 一般无CD4 CD8 或CD4 CD8 表型 PanT 无缺失 少见ALK TdT CD56 Tcellreceptor等表达 斑驳状 Autoimmunelymphoproliferativesyndrome ALPS 斑驳状 Reactivelargelymphoidcell immunoblast Smalllymphocytes Nuclearsizeusuallydoesnotexceed2 5timesthatofsmalllymphocyte Nucleususuallyroundorovoid anddoesnotshowirregularfoldings 四 髓索 medullarycord 富含浆细胞可以清晰或不清晰反应性B细胞的扩张延伸 如反应性淋巴滤泡增生 浆细胞型Castlemandisease 五 淋巴窦 sinus 输入淋巴管 被膜下窦 间窦 髓窦 输出淋巴管 被覆窦内皮 D2 40 含组织细胞和淋巴样细胞 腹腔内淋巴结窦常扩张 较明显 深处窦的存在常提示良性病变 六 纤维结缔组织网Connectivetissueframework 纤维被膜 延伸至结内的梁索 可见梁索周窦 正常时可能不清晰 反应性病变常清晰 常有淋巴结周围炎 第三节淋巴瘤分类WHOClassification2008非霍奇金淋巴瘤non Hodgkinlymphomas霍奇金淋巴瘤Hodgkinlymphomas 非霍奇金淋巴瘤分类WHOClassificationofnon Hodgkinlymphomas 2001 Precursorlymphoblasticlymphoma leukemia BorTcelltype MatureB cellneoplasmsMatureT cellandNK celllymphomas 成熟B细胞肿瘤MatureB cellneoplasms WHO B cellCLL SLLB cellprolymphocyticleukemiaLymphoplasmacyticlymphomaMantlecelllymphomaFollicularlymphomaExtranodalmarginalzoneB celllymphomaofMALTtype NodalmarginalzoneB celllymphomaSplenicmarginalzoneBcelllymphomaHairycellleukemiaDiffuselargeB celllymphoma includingmediastinallargeB celllymphoma BurkittlymphomaPlasmacytoma myeloma 成熟T细胞或NK细胞肿瘤MatureT cell NK cellneoplasms WHO T cellprolymphocyticleukemiaT celllargegranularlymphocyticleukemiaAggressiveNKcellleukemiaExtranodalNK Tcelllymphoma nasal typeMycosisfungoides SezarysyndromeAngioimmunoblasticTcelllymphoma PeripheralT celllymphoma unspecifiedAdultT cellleukemia lymphomaAnaplasticlargecelllymphoma Tornullcell primarysystemictypePrimarycutaneousanaplasticlargecelllymphomaSubcutaneouspanniculitis likeT celllymphomaEnteropathy typeT celllymphomaHepatosplenicT celllymphoma 非霍奇金淋巴瘤临床生物学行为分类 Indolentlymphoma Good Aggressivelymphoma Bad Highlyaggressivelymphoma Ugly Unusuallocalizedindolentlymphoma 惰性淋巴瘤Indolentlymphomas smallcelllymphoma FollicularlymphomaB cellCLL smalllymphocyticlymphomaLymphoplasmacyticlymphomaSplenicandnodalmarginalzonelymphoma 惰性淋巴瘤临床特征 UsuallyolderadultsSlow growing occasionallywaxingandwaningUsuallyhighstage III IV atpresentation blood marrowinvolvementcommonTakesmanyyearstokillpatientifuntreatedLowproliferativefraction oftenincurable Despitetreatment diseasecontrol repeatedrelapseistheruleTreatmentdoesnotaltertheeventualoutcome thusobservationwithouttreatmentisanoption Survivalcurveofindolentlymphomas Survival 100 0 Years 0 10 侵袭性淋巴瘤Aggressivelymphomas largecelllymphoma DiffuselargeB celllymphomaMantlecelllymphoma AllperipheralTcelllymphomas includingALCL NKcelllymphomasexcept Mycosisfungoides PrimarycutaneousanaplasticlargecelllymphomaT cellLGLleukemia 侵袭性淋巴瘤临床特征 Anyage usuallyadultsRapid growingmassEvenlydistributedoverthestages blood marrowinvolvementuncommon badprognosis notsobadifmarrowinvolvedbyfollicularlymphoma Untreated willkillin1 2yearsHighproliferativefraction potentiallycurablewithchemotherapy radiotherapy80 CR 2 3norelapse Survivalcurveofaggressivelymphomas Survival 100 0 Years 0 10 Treated Untreated Comparisonofsurvivalcurves Survival 100 0 Years 0 10 AggressiveNHL IndolentNHL Paradoxicallybetteroutcomeinthelongrun 高度侵袭性淋巴瘤Highlyaggressivelymphomas Medium sizedcelllymphoma LymphoblasticlymphomaBurkittlymphoma Highlyaggressivelymphomas Children youngadultsVeryrapidlygrowing oncologicemergencyOftenhighstage marrowinvolvementcommon CNSinvolvementmayoccurUntreated willkillinweekstomonthsVeryhighproliferativefraction highlyresponsivetotreatment Standardchemotherapy nogood veryaggressivechemotherapy manycured Survivalcurveofhighlyaggressivelymphomas Survival 100 0 Years 0 10 Treated Untreated 局限性惰性淋巴瘤Localizedindolentlymphomas ExtranodalmarginalzoneB celllymphomaofmucosa associatedlymphoidtissue MALT typePrimarycutaneousanaplasticlargecelllymphoma Localizedindolentlymphomas IndolenttumorCanoccurinanyageOftenlocalizedatpresentationManypatientscanapparentlybecured thereisasuggestionofplateauinsurvivalcurve althoughlaterelapsesarepossibleCanundergoregressionspontaneousforprimarycutaneousALCLwithanti HelicobactertherapyforgastricextranodalMZL 各型淋巴瘤的临床病理特征 淋巴母细胞淋巴瘤 RapidlygrowingtumorLymphoma T BLeukemia ALL B TUntreated rapidlyfatalAggressivetherapy goodsurvivalCannotpredictlineagefrommorphologyDefiningmarker TdT CD99 CD20 CD79a B LBL T LBL 滤泡性淋巴瘤FOLLICULARLYMPHOMA UsuallyinvolvinglymphnodesHigh stagediseaseatpresentationPathology RecapitulatestheorganizationandcytologyofthenormalgerminalcentersKeyimmunophenotype Bmarker CD10 Bcl6 Bcl2 Follicularlymphomainvolvingsomeextranodalsites suchasskin duodenum testis showdistinctiveclinicalandbiologicfeaturesGenetics Iggenerearrangement t 14 18 q32 q21 bcl 2generearrangement duetoBCL2 IGHtranslocation Follicularlymphomavsreactivefollicularhyperplasia MajorcriterionCloselypackedfolliclesthroughout withscantyinterfolliculartissues 1majorcriterionor 3minorcriteria 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 Intheremaining20 ofcases non crowdedfollicles acombinationofminorcriteria 3 havetobeconsidered andsupplementedbyancillarystudiesasrequired MinorcriteriaNotingible bodymacrophagesCellularmonotony centrocytepredominanceNocellularpolarisationAbsentorincompletemantlesFolliclesinperinodaltissuesDysplasticfollicularcentercells e g signetringcells frequentcytoplasmicglobulesAtypicalcellsininterfolliculartissuesInvasionofwallsofbloodvessels 2020 3 17 95 可编辑 FollicularlymphomavsRFH ancillarytechniques Immunostainingforbcl 2MostusefulimmunostainNormal BothTandBcellspositiveexceptfolliclecentercellsLookforpositivestainingofcellsinfolliclecenters positivestainingsupportsdiagnosisoflymphoma Reactivefollicles Follicularlymphoma Bcl 2immunostaining Commonmisconceptionsinhematopathology Negativebcl 2stainrulesoutfollicularlymphoma Thetruth Itdoesnot 20 25 offollicularlymphomacasesarenegative Pursuewithotherteststoconfirmorrefuteadiagnosisoffollicularlymphoma Bcl 2staininginfollicularlymphoma Bcl 2 LookforevidenceinterfollicularinvasionDenselypackedCD20 orCD79 B cellsbetweenfolliclesisindicativeofinterfollicularinvasionPresenceofasignificantnumberofCD10 lymphoidcells notneutrophils whicharealsoCD10 betweenfolliclesalsoindicatesinterfollicularinvasionLookforvascularinvasionManyCD10 cellsinthewallsofperinodalbloodvessels CD20 CD10 LookformonoclonalityorlowproliferationindexImmunostainforIgtolookforlightchainrestrictionDemonstratedbyKi67 alowKi67indexfavorsdiagnosisoffollicularlymphomaoverRFH meanindex15 6 vs64 9 ahighKi67indexisinconclusiveMolecularanalysisIggenerearrangementbySouthernblotorPCR NotethatPCRmayhavefalsenegativeresults DetectionofBCL2generearrangementbySouthernblot PCRorFISH Kappa Lambda FL1 Ki67 RFH Ki67 FL3 Ki67 套细胞淋巴瘤Mantlecelllymphoma morphology Diffuse vaguelynodular ormantlezonepatternBroadcytologicspectrumClassictype smalllymphoidcellswithirregulartoroundnucleiBlastoidvariant lymphoblasts butTdT PleomorphicvariantOftenwithsolitaryepithelioidhistiocytesInterspersed nakednuclei folliculardendriticcells Genetics Iggenerearrangementt 11 14 q13 q32 GrowthpatternofMCL Roundnuclei Mantlecelllymphoma 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 Waldeyer sring smallintestine lungAcquiredinautoimmunedisease inflammatione g thyroid salivarygland lacrimalgland stomachSimilarorganizationaslymphnode B cellfollicles T cellzonesLymphoidcellsacquirehomingproperties LOWGRADEBCELLMALTLYMPHOMA extranodalmarginalzoneB celllymphoma Usuallylocalizedatpresentation 66 79 RecurrenceatotherMALTsites homing Manycanbetreatedbylocoregionaltherapyoreradicationofantigen stimulationsourceCompleteremissionrate 72 5 yearoverallsurvival 74 Gastric 90 HistologicfeaturesoflowgradeMALTlymphoma Small medium sizedcells lymphocytes centrocyte like monocytoidBcells Patterns diffuse interfollicular marginalzoneLymphoepitheliallesionsPlasmacellsarecommonReactivelymphoidfollicles colonization LowgradeMALTlymphoma Immunophenotype Aneoplasmofpost germinalcenterBcellsPanB CD10 CD5 CyclinD1 CD23 Keyfeatures siteofinvolvementlymphoepitheliallesionexclusionofotherlowgradeB celllymphomas AfterHelicobactereradicationtherapy 弥漫性大B细胞淋巴瘤DIFFUSELARGEBCELLLYMPHOMA DLBCL CommonestnodalB celllymphomaAheterogeneousentityFinalcommonpathwayforhighgradetransformationoflowgradeB celllymphomas Centroblastic Immunoblastic Multilobated Pleomorphic BURKITTLYMPHOMA Threedifferentforms Endemic EquatorialAfrica strongassociationwithEBV 90 commonlyaffectingjaws gonads kidneys Sporadic EBVassociationonly 15 commonlyinvolvingterminalileumandWaldeyer sring AIDS related EBVassociation 30 commonlyinvolvinglymphonodeandbonemarrow AfricancasescanalsobeAIDS related Burkittlymphoma t 8 14 q24 q32 orvariants withtranslocationbetweenc mycandIggeneMostlyadiseaseofyoungpatientsHighlyaggressive butpotentiallycurablebychemotherapy Burkittlymphoma Immunogenetics ProbablycorrespondstoIgM blastsingerminalcenterPan B CD10 Bcl 6 Bcl 2 Keyfeatures C MYCtranslocationmedium sizedcellshighKi67index 100 germinalcentercellphenotype CD20 CD10 Ki67 外周T和NK细胞淋巴瘤PERIPHERALTANDNKCELLLYMPHOMAS Uncommon 10 ofallnon Hodgkin slymphomasinCaucasians but15 20 inChineseLessfavorableoutcomecomparedwithaggressiveBcelllymphomas TandNKcelllymphomas Entitieswithdifferentoutcome FavorableprognosisPrimarycutaneousanaplasticlargecelllymphoma spontaneousregression Anaplasticlargecelllymphoma T nullcellMycosisfungoidesT cellLGLleukemia HighlyaggressiveAdultT cellleukemia lymphomaNKcellleukemiaExtranodalNK TcelllymphomaHepatosplenicTcelllymphoma PeripheralTcelllymphoma外周T细胞淋巴瘤 PredominantlynodalAngioimmunoblasticT celllymphomaAnaplasticlargecelllymphoma T null cellPeripheralT celllymphoma unspecified ANGIOIMMUNOBLASTICT CELLLYMPHOMA血管免疫母细胞性T细胞淋巴瘤 CommonesttypeofnodalTcelllymphomaFever skinrash systemicsymptomsGeneralizedlymphnodesIncreasedserumIg polyclonal CoombspositivehemolyticanemiaAlthoughsomerespondtosteroid prognosisisunfavorable succumbingtoinfectioncomplications AneoplasmoffollicularcenterThelpercellsPanT usuallyCD4 butalsomanyCD8 cells CD10 CXCL13 PD 1Keyfeatures ArborizingvenulesLymphoidcellsoftenwithroundnuclei clearcellscommonirregularmeshworksoffolliculardendriticcellaroundvenulesCD10 CXCL13 TcellsoutsidefollicleIsolatedEBV cells mostlyBcells CD3 CD21 CXCL13 EXTRANODALNK TCELLLYMPHOMA结外NK T细胞淋巴瘤 Mass formingneoplasmofputativeNKcelllineage cCD3 sCD3 CD56 germlineTCRgenes Designated NK Tcell becausewhilemostcasesappeartobeofNKlineage somemaybecytotoxicTcellneoplasms MoreprevalentamongOrientals MexicansandSouthAmericansthanWesternpopulationsMostlyaffectingadultsMostlyinvolvingextranodalsites ExtranodalNK Tcelllymphoma NASALNK TCELLLYMPHOMAInvolvingupperaerodigestivetractNasalobstruction masslesion ormidfacialdestructivediseaseUsuallystageIBehaviorvariablebutgenerallyaggressive EXTRANASALNK TCELLLYMPHOMAInvolvingvariousextranasalsites esp skin testis G I tract softtissue UsuallystageIII IVHighlyaggressive withmostdyingwithin1 2years 80 ExtranodalNK Tcelllymphoma Pathology Necrosis apoptosis commonAngioinvasioncommon notinvariablyseen Broadcytologicspectrum small medium sizedorlargecells ormixedMayhavemanyadmixedinflammatorycells Small Medium sized 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 Paraffinsection PERIPHERALTCELLLYMPHOMAUNSPECIFIED外周T细胞淋巴瘤 非特殊型 AwastebasketcategoryVariableclinicalmanifestationsUsuallyhighstagedisease nodal extranodal MayhaveeosinophiliaAggressive relapsecommonTheextranodalcasesoftenexpressacytotoxiccellphenotype PeripheralT celllymphoma Morphologiccluesforrecognition PredominantparacorticalinvolvementProminenthighendothelialvenulesSpectrumofcellssizesandshapesIrregularnuclearcontoursClearcellsManyadmixedepithelioidhistiocytesandeosinophils ButimmunostainingessentialforconfirmingTlineage ANAPLASTICLARGECELLLYMPHOMA primarysystemicform间变性大细胞淋巴瘤 原发系统性 TendstooccurinchildrenandyoungadultsNodalorextranodalpresentation whichmayincludeskin softtissue bone G I tract Immunophenotype CD30 EMAusually T lineagemarkers Tornullcell AproportionofcasesexpressALKduetotranslocationinvolvingALKgene Hallmarkcells ALKtranslocation orexpression hashelpedtodefineahomogeneoussubgroupofALCLThiscanbeeasilydetectedbyimmunostainingforALK permittingre definitionofthemorphologicspectrumofALCL ClassicaltypeMonomorphicSmallcellLymphohistiocyticHypocellular CD30 OverallsurvivalPrimarysystemicformofALCL 0 5 10 Years ALCL ALK 100 50 ALCL ALK 霍奇金淋巴瘤HODGKINLYMPHOMA Lymphocytepredominance Mixedcellularity Nodularsclerosis Lymphocytedepletion NodularlymphocytepredominantHodgkinlymphoma N LPHL RYECLASSIFICATION WHOCLASSIFICATION 5 10 Years Overallsurvival N LPHLdefinedbyim