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1沐风书苑iDr John K.C.CHAN陈国璋2沐风书苑i4th EditionPublished 20/9/20083沐风书苑i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%） 4沐风书苑i(二)霍奇金淋巴

2、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5沐风书苑i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。6沐风书苑i二、淋巴结的正常免疫结构（一）淋巴结结构:

3、皮质,髓质,窦,被膜和纤维小梁7沐风书苑i（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。8沐风书苑i9沐风书苑i10沐风书苑iPre pre B cellPre B cellImmature B cellMature B cellActivated B cellPlasma cellPrecursor cells; antigen non-responsiveVirgin B cells; antigen responsiveGerminal center & post G

4、C cells; antigen encounteredTdTCD20, CD22CD19, PAX5CD79aCD10Bcl-6CD138Cytoplasmic CD2211沐风书苑iImmunoarchitecture of normal lymph nodeB cells (CD20+,CD10+,BCL-6+)T cells (CD3+); only small numbers of CD20+ cells12沐风书苑i13沐风书苑i 1、初级滤泡：处女型B细胞和成熟小淋巴细胞； 14沐风书苑iCD202、次级滤泡：由生发中心、套区和边缘区构成。15沐风书苑iOrganization

5、of secondary lymphoid follicle Marginal zone cells (IgM)Mantle zone cells (IgM+D)Follicle center cells (IgM, IgG, IgA or IgE, not IgD):约2:1，当:8-10:1或:3:1提示轻链限制表达16沐风书苑i次级滤泡生发中心、套区和边缘区免疫标记：（1）生发中心(Germinal Center, GC)： 1）中心细胞和中心母细胞：CD10+,BCL-6+,Bcl-2-, 2）滤泡树突细胞(Follicular dendritic cells, FDC) : CD21

6、+,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。17沐风书苑iCD2018沐风书苑iCD79a19沐风书苑i20沐风书苑i21沐风书苑i22沐风书苑iCD2123沐风书苑iCD10Bcl-624沐风书苑i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(Pol

7、arity):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。25沐风书苑i26沐风书苑i27沐风书苑iDark zoneLight zone28沐风书苑i BCL-2 Ki6729沐风书苑iMarginal zone cells30沐风书苑iCD2031沐风书苑i（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 endothel

8、ial venules,HEV): 血液淋巴细胞入淋巴结的通道;含有指状树突细胞(interdigitating dendritic cells,IDC): S100+ 的专职抗原递呈细胞；32沐风书苑i33沐风书苑i34沐风书苑iProthymocyteSubcapsular thymocyteCortical thymocyteMedullary thymocytePeripheral T cellPrecursor cellsMature T cellsCytoplasmicSurfaceCD4CD8CD1CD4, CD8CD3CD2CD7TdT35沐风书苑i36沐风书苑iIDC37沐风

9、书苑iCD338沐风书苑i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。39沐风书苑i40沐风书苑i41沐风书苑iImmunoblastInfectious mononucleosis42沐风书苑iCD20CD3 Large cells comprise mixture of B and T cells-Reactive process43沐风书苑iCD30+ cell

10、s are scattered and staining is weak or moderate, which indicates the heterogeneity of the large cell population.CD30 staining is diffusely strong positive, which indicates the monoclone entity. 44沐风书苑iKappaLambdaLarge B cells are polytypic45沐风书苑iT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

11、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): B TUntreated: rapidly fatalAggressive therapy: good survivalCannot predict lineage from morphologyDefining marker: TdT+，CD9978沐风书苑i79沐风书苑i80沐风书苑iCD20CD79aB-LBL81沐风书苑iT-LBL82沐风书苑i滤泡性淋巴瘤FOLLICULAR LYMPHOMAUsually involving ly

12、mph nodesHigh-stage disease at presentationPathology: Recapitulates the organization and cytology of the normal germinal centersKey immunophenotype: B marker+, CD10+, Bcl6+, Bcl2+ Follicular lymphoma involving some extranodal sites (such as skin, duodenum, testis) show distinctive clinical and biolo

13、gic featuresGenetics:Ig gene rearrangement; t(14;18)(q32;q21) bcl-2 gene rearrangement (due to BCL2/IGH translocation)83沐风书苑iFollicular lymphoma vsreactive follicular hyperplasiaMajor criterionClosely packed follicles throughout, with scanty interfollicular tissues1 major criterion or 3 minor criter

14、ia.But confirm by ancillary tests if uncertain84沐风书苑i滤泡性淋巴瘤主要诊断标准示意图 Major criterion fulfilled in 80% of cases of follicular lymphomaJust go on to high magnification to confirm follicle center cell morphology85沐风书苑i86沐风书苑i87沐风书苑iCentrocytes oftenhave triangularshaped nuclei88沐风书苑i滤泡性淋巴瘤的次要诊断标准In the

15、 remaining 20% of cases (non-crowded follicles), a combination of minor criteria (3) have to be considered, and supplemented by ancillary studies as required89沐风书苑iMinor criteria No tingible-body macrophagesCellular monotony: centrocyte predominanceNo cellular polarisationAbsent or incomplete mantle

16、sFollicles in perinodal tissuesDysplastic follicular center cells, e.g. signet ring cells, frequent cytoplasmic globulesAtypical cells in interfollicular tissuesInvasion of walls of blood vessels90沐风书苑i91沐风书苑i92沐风书苑i93沐风书苑i94沐风书苑iFollicular lymphoma vs RFH: ancillary techniquesImmunostaining for bcl

17、-2Most useful immunostainNormal: Both T and B cells positive except follicle center cellsLook for positive staining of cells in follicle centers: positive staining supports diagnosis of lymphoma95沐风书苑iReactive follicles96沐风书苑iFollicular lymphoma (Bcl-2 immunostaining) 97沐风书苑iCommon misconceptions in

18、 hematopathologyNegative bcl-2 stain rules out follicular lymphomaThe truth: It does not. 20-25% offollicular lymphoma cases are negative.Pursue with other tests to confirmor refute a diagnosis offollicular lymphoma98沐风书苑iBcl-2 staining infollicular lymphomaGrade(Cytologic composition)Bcl-2 immunore

19、activityI (predominantly small cells)100%II (mixed small and large cells)85%III (predominantly large cells)75%99沐风书苑i100沐风书苑iBcl-2101沐风书苑iLook for evidence interfollicular invasionDensely packed CD20+ or CD79+ B-cells between follicles is indicative of interfollicular invasionPresence of a significa

20、nt number of CD10+ lymphoid cells (not neutrophils, which are also CD10+) between follicles also indicates interfollicular invasion Look for vascular invasion Many CD10+ cells in the walls of perinodal blood vessels102沐风书苑iCD20103沐风书苑iCD10104沐风书苑i105沐风书苑iLook for monoclonality or low proliferation i

21、ndexImmunostain for Ig to look for light chain restrictionDemonstrated by Ki67, a low Ki67 index favors diagnosis of follicular lymphoma over RFH (mean index 15.6% vs 64.9%); a high Ki67 index is inconclusiveMolecular analysisIg gene rearrangement by Southern blot or PCR (Note that PCR may have fals

22、e negative results)Detection of BCL2 gene rearrangement by Southern blot, PCR or FISH106沐风书苑iKappaLambda107沐风书苑iFL1: Ki67RFH: Ki67108沐风书苑iFL3: Ki67109沐风书苑i套细胞淋巴瘤Mantle cell lymphoma: morphologyDiffuse, vaguely nodular, or mantle zone patternBroad cytologic spectrumClassic type: small lymphoid cells

23、with irregular to round nucleiBlastoid variant ( lymphoblasts, but TdT-)Pleomorphic variantOften with solitary epithelioid histiocytesInterspersed naked nuclei (follicular dendritic cells)Genetics: Ig gene rearrangement t(11,14) (q13;q32) 110沐风书苑i Growth pattern of MCL111沐风书苑i112沐风书苑i113沐风书苑i114沐风书苑

24、iRound nuclei115沐风书苑iMantle cell lymphoma: biologic markersB marker+, CD5+, CD10-, CD23-, IgM+, IgD+Key defining feature: Cyclin D1+ due to t(11;14) (q13;q32) or cryptic translocation116沐风书苑iCyclin D1117沐风书苑i 粘膜相关淋巴组织 Mucosa-Associated Lymphoid Tissue(MALT)Specialized secondary lymphoid compartments

25、 of mucosal tissuesNatural, e.g., Waldeyers ring, small intestine, lungAcquired in autoimmune disease/inflammation e.g., thyroid, salivary gland, lacrimal gland, stomachSimilar organization as lymph node: B-cell follicles, T-cell zonesLymphoid cells acquire homing properties118沐风书苑i119沐风书苑iLOW GRADE

26、 B CELL MALT LYMPHOMA (extranodal marginal zone B-cell lymphoma)Usually localized at presentation (66-79%) Recurrence at other MALT sites (“homing”)Many can be treated by locoregional therapy or eradication of antigen-stimulation sourceComplete remission rate = 72%5-year overall survival = 74% (Gast

27、ric: 90%)120沐风书苑iHistologic features of low grade MALT lymphomaSmall/medium-sized cells (lymphocytes, centrocyte-like, monocytoid B cells)Patterns: diffuse, interfollicular, marginal zoneLymphoepithelial lesionsPlasma cells are commonReactive lymphoid follicles +/- colonization121沐风书苑i122沐风书苑i123沐风书

28、苑i124沐风书苑iLow grade MALT lymphoma: ImmunophenotypeA neoplasm of post-germinal center B cellsPan B+, CD10-, CD5-, Cyclin D1-, CD23 -Key features: site of involvementlymphoepithelial lesionexclusion of other low grade B-cell lymphomas125沐风书苑iAfter Helicobacter eradication therapy126沐风书苑i弥漫性大B细胞淋巴瘤DIFF

29、USE LARGE B CELL LYMPHOMA（DLBCL）Commonest nodal B-cell lymphomaA heterogeneous entityFinal common pathway for high grade transformation of low grade B-cell lymphomas127沐风书苑iCentroblastic/Immunoblastic128沐风书苑i129沐风书苑iMultilobatedPleomorphic130沐风书苑iBURKITT LYMPHOMAThree different forms:Endemic (Equato

30、rial Africa; strong association with EBV 90%; commonly affecting jaws, gonads, kidneys)Sporadic (EBV association only 15%; commonly involving terminal ileum and Waldeyers ring)AIDS-related (EBV association 30%; commonly involving lymphonode and bone marrow)African cases can also be AIDS-related!131沐

31、风书苑iBurkitt lymphomat(8;14) (q24;q32) or variants, with translocation between c-myc and Ig geneMostly a disease of young patientsHighly aggressive, but potentially curable by chemotherapy132沐风书苑i133沐风书苑i134沐风书苑iBurkitt lymphoma: ImmunogeneticsProbably corresponds to IgM+ blasts in germinal centerPan

32、-B+, CD10+, Bcl-6+, Bcl-2-Key features:C-MYC translocation medium-sized cellshigh Ki67 index：100%germinal center cell phenotype135沐风书苑iCD20CD10136沐风书苑iKi67137沐风书苑i外周T和NK细胞淋巴瘤PERIPHERAL T AND NK CELL LYMPHOMASUncommon; 80%)149沐风书苑iExtranodal NK/T cell lymphoma: PathologyNecrosis (apoptosis) common An

33、gioinvasion common (not invariably seen)Broad cytologic spectrum: small, medium-sized or large cells, or mixedMay have many admixed inflammatory cells150沐风书苑i151沐风书苑i152沐风书苑iSmallMedium-sizedLargeBroad cytologic spectrum153沐风书苑iExtranodal NK/T cell lymphoma:immunophenotypeCD2+. sCD3-, cCD3e+, CD56+

34、Cytotoxic granules perforin, granzyme B, TIA-1 positiveCD4, CD5, CD7, CD8: usually negativeKey features: CD56+, EBER+If CD56-, requires EBER+ and cytotoxic granules+ for diagnosis154沐风书苑iSurface CD3Cytoplasmic CD3CD56Frozen tissueParaffin section155沐风书苑iPERIPHERAL T CELL LYMPHOMA UNSPECIFIED外周T细胞淋巴瘤

35、，非特殊型A wastebasket categoryVariable clinical manifestationsUsually high stage disease (nodal/extranodal)May have eosinophiliaAggressive; relapse commonThe extranodal cases often express a cytotoxic cell phenotype156沐风书苑iPeripheral T-cell lymphoma:Morphologic clues for recognitionPredominant paracort

36、ical involvementProminent high endothelial venulesSpectrum of cells sizes and shapesIrregular nuclear contoursClear cellsMany admixed epithelioid histiocytes and eosinophilsBut immunostaining essential for confirming T lineage157沐风书苑i158沐风书苑i159沐风书苑iANAPLASTIC LARGE CELL LYMPHOMA, primary systemic f

37、orm间变性大细胞淋巴瘤，原发系统性Tends to occur in children and young adultsNodal or extranodal presentation (which may include skin, soft tissue, bone, G.I. tract)Immunophenotype:CD30+; EMA usually +T-lineage markers +/- (T or null cell)A proportion of cases express ALK due to translocation involving ALK gene160沐

38、风书苑iHallmark cells161沐风书苑iALK translocation (or expression) has helped to define a homogeneous subgroup of ALCLThis can be easily detected by immunostaining for ALK - permitting re-definition of the morphologic spectrum of ALCL:Classical typeMonomorphicSmall cellLymphohistiocyticHypocellular162沐风书苑i

39、163沐风书苑iCD30164沐风书苑i Overall survivalPrimary systemic form of ALCL0510YearsALCL, ALK+*100%50%ALCL, ALK-165沐风书苑i 霍奇金淋巴瘤 HODGKIN LYMPHOMA166沐风书苑iLymphocyte predominanceMixed cellularityNodular sclerosisLymphocyte depletionNodular lymphocyte predominant Hodgkin lymphoma (N-LPHL)Classical Hodgkin lympho

40、ma(cHL)Lymphocyte-richMixed cellularityNodular sclerosisLymphocyte depletionRYE CLASSIFICATIONWHO CLASSIFICATION167沐风书苑i510YearsOverall survivalN-LPHL defined by immunohistochemistrycHL defined by immunohistochemistryp = 0.0071168沐风书苑iA lymphoma characterized by:presence of Reed-Sternberg cells and

41、their variants confirmed by mmunohistochemistryin an appropriate reactive cellular environment 169沐风书苑iReed-Sternberg cells and variantsDiagnostic Reed-Sternberg cellsMononuclear Hodgkin cellLacunar cellL&H cellPleomorphic Reed-Sternberg cellKi67+100%No need to find diagnostic Reed-Sternberg cellsin rendering a diagnosis of Hodgkin lymphoma.Its okay if cells are large enough, with prominentnucleoli and compatible immunophenotype.170沐风书苑iReed-Sternberg cells and variantsSmall lymphocytesNuclear size of most neoplastic cells usually exceeds 3 ti