1、 淋巴瘤 Lymphoma 淋巴瘤Dr John K.C.CHAN陳國璋Dr John K.C.CHAN4th EditionPublished 20/9/20084th Edition第一節 概述一、定義 “來源于”成熟淋巴細胞及其前體細胞（淋巴母細胞）的惡性腫瘤，分為非霍奇金/白血病和霍奇金淋巴瘤兩大類。二、分類（一）非霍奇金淋巴瘤(NHL)：包括B，T和NK細胞（70%） 1、前體細胞： B/T/NK前體細胞（淋巴母細胞）淋巴瘤（2%） 2、成熟細胞：成熟細胞淋巴瘤（68%） B細胞（54%） T細胞（12%） NK/T或NK細胞（2%） 第一節 概述(二)霍奇金淋巴瘤(HL):特殊類型

2、成熟B細胞淋巴瘤(30%) 結節性淋巴細胞為主型（1.5%） 經典型(28.5%) (缺陷性B細胞) 結節硬化型 淋巴細胞豐富型 混合細胞型 淋巴細胞消減型(二)霍奇金淋巴瘤(HL):特殊類型成熟B細胞淋巴瘤(30%第二節 淋巴結的免疫結構 （immunoarchitecture）一、概念：通過免疫組織化學染色顯示淋巴結的結構特征。包括腫瘤性或非腫瘤性細胞的成分（淋巴細胞,輔助性非淋巴細胞,淋巴竇,血管,網狀纖維等）、數量、分布方式等特征。通過對比，掌握正常和異常免疫結構，對淋巴結病變進行診斷和鑒別診斷。高質量的組織學切片和合理的免疫標記物的選擇是識別免疫結構的關鍵。第二節 淋巴結的免疫結構

3、（immunoarc二、淋巴結的正常免疫結構（一）淋巴結結構:皮質,髓質,竇,被膜和纖維小梁二、淋巴結的正常免疫結構（二）B淋巴細胞分布： 1.主要在淺皮質區的初級和次級濾泡，髓索和副皮質區也含一定量B細胞; 2.B細胞分化過程中的形態和免疫學特征成為非霍奇金B細胞淋巴瘤分類的基礎。（二）B淋巴細胞分布：淋巴組織腫瘤-課件淋巴組織腫瘤-課件Pre pre B cellPre B cellImmature B cellMature B cellActivated B cellPlasma cellPrecursor cells; antigen non-responsiveVirgin B ce

4、lls; antigen responsiveGerminal center & post GC cells; antigen encounteredTdTCD20, CD22CD19, PAX5CD79aCD10Bcl-6CD138Cytoplasmic CD22Pre pre B cellPre B cellImmatuImmunoarchitecture of normal lymph nodeB cells (CD20+,CD10+,BCL-6+)T cells (CD3+); only small numbers of CD20+ cellsImmunoarchitecture of

5、 normal l淋巴組織腫瘤-課件 1、初級濾泡：處女型B細胞和成熟小淋巴細胞； 淋巴組織腫瘤-課件CD202、次級濾泡：由生發中心、套區和邊緣區構成。CD202、次級濾泡：由生發中心、套區和邊緣區構成。Organization of secondary lymphoid follicle Marginal zone cells (IgM)Mantle zone cells (IgM+D)Follicle center cells (IgM, IgG, IgA or IgE, not IgD):約2:1，當:8-10:1或:3:1提示輕鏈限制表達Organization of seconda

6、ry lym次級濾泡生發中心、套區和邊緣區免疫標記：（1）生發中心(Germinal Center, GC)： 1）中心細胞和中心母細胞：CD10+,BCL-6+,Bcl-2-, 2）濾泡樹突細胞(Follicular dendritic cells, FDC) : CD21+,CD23+, CD35+ 3）T細胞：CD4+, CD10+, CXCL13/PD-1+,少量CD57+ 4）可染體巨噬細胞：CD68+,lysozyme+,CD11c+（2）套區:處女型B細胞和記憶細胞,表達IgM, IgD （3）邊緣區：無特殊標記，絕大多數次級濾泡難以鑒別，腹腔 淋巴結易識別。次級濾泡生發中心、套

7、區和邊緣區免疫標記：CD20CD20CD79aCD79a淋巴組織腫瘤-課件淋巴組織腫瘤-課件淋巴組織腫瘤-課件CD21CD21CD10Bcl-6CD10Bcl-6反應性濾泡增生的特點對T細胞依賴性抗原的反應濾泡增多，大小、形態不等，可彌漫分布，主要位于皮質區，無背靠背現象。典型生發中心具有極性(Polarity):明區和暗區，套區明顯，扁桃體組織更易識別；星天現象，中心細胞和中心母細胞混雜，免疫染色：生發中心細胞BCL-2-，ki-67指數較高。濾泡間區一般無B細胞彌漫陽性，B細胞CD43和CD5陰性。反應性濾泡增生的特點淋巴組織腫瘤-課件淋巴組織腫瘤-課件Dark zoneLight zon

8、eDark zoneLight zone BCL-2 Ki67 BCL-2 Ki67Marginal zone cellsMarginal zone cellsCD20CD20（三）T淋巴細胞分布：副皮質區(paracortex)T淋巴細胞為主 (CD4CD8): 主為小淋巴細胞，偶爾出現大細胞 (可以是活化的B細胞);含有高內皮靜脈 (High endothelial venules,HEV): 血液淋巴細胞入淋巴結的通道;含有指狀樹突細胞(interdigitating dendritic cells,IDC): S100+ 的專職抗原遞呈細胞；（三）T淋巴細胞分布：副皮質區(paraco

9、rtex)T淋巴淋巴組織腫瘤-課件淋巴組織腫瘤-課件ProthymocyteSubcapsular thymocyteCortical thymocyteMedullary thymocytePeripheral T cellPrecursor cellsMature T cellsCytoplasmicSurfaceCD4CD8CD1CD4, CD8CD3CD2CD7TdTProthymocyteSubcapsular thymoc淋巴組織腫瘤-課件IDCIDCCD3CD3副皮質區增生常見病因: 病毒感染, 接種疫苗，藥物，自身免疫疾病, 皮病性淋巴結炎，腫瘤轉移等形態特征：副皮質擴大，可形

10、成結節； HEV增生； 混合小淋巴細胞和轉化淋巴細胞，漿細胞，樹突細胞，嗜酸性粒細胞等；免疫染色：主為T細胞，或T/B細胞混合,一般無B細胞為主彌漫分布。副皮質區增生常見病因: 病毒感染, 接種疫苗，藥物，自身免疫淋巴組織腫瘤-課件淋巴組織腫瘤-課件ImmunoblastInfectious mononucleosisImmunoblastInfectious mononuclCD20CD3 Large cells comprise mixture of B and T cells-Reactive processCD20CD3 Large cells comprisCD30+ cells a

11、re 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. CD30+ cells are scattered and KappaLambdaLarge B cells are polytypicKappaLambdaLarge B cells are pT細胞為主時支持良性

12、的依據（謹慎！）：（1）結構不同程度保留：淋巴竇和皮質淋巴濾泡；（2）大細胞群體分布不規則或呈地圖樣，不形成膨脹性團塊；（3）無浸潤現象：上皮,脂肪,血管,神經,纖維間質中單行排列；（4）細胞無明顯異型： BLeukemia (ALL): B TUntreated: rapidly fatalAggressive therapy: good survivalCannot predict lineage from morphologyDefining marker: TdT+，CD99 淋巴母細胞淋巴瘤Rapidly growing淋巴組織腫瘤-課件淋巴組織腫瘤-課件CD20CD79aB-LBL

13、CD20CD79aB-LBLT-LBLT-LBL濾泡性淋巴瘤FOLLICULAR LYMPHOMAUsually involving lymph 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

14、 (such as skin, duodenum, testis) show distinctive clinical and biologic featuresGenetics:Ig gene rearrangement; t(14;18)(q32;q21) bcl-2 gene rearrangement (due to BCL2/IGH translocation)濾泡性淋巴瘤FOLLICULAR LYMPHOMAUsuaFollicular lymphoma vsreactive follicular hyperplasiaMajor criterionClosely packed f

15、ollicles throughout, with scanty interfollicular tissues1 major criterion or 3 minor criteria.But confirm by ancillary tests if uncertainFollicular lymphoma vsreactiv濾泡性淋巴瘤主要診斷標準示意圖 Major criterion fulfilled in 80% of cases of follicular lymphomaJust go on to high magnification to confirm follicle c

16、enter cell morphology濾泡性淋巴瘤主要診斷標準示意圖 Major criterio淋巴組織腫瘤-課件淋巴組織腫瘤-課件Centrocytes oftenhave triangularshaped nucleiCentrocytes often濾泡性淋巴瘤的次要診斷標準In the remaining 20% of cases (non-crowded follicles), a combination of minor criteria (3) have to be considered, and supplemented by ancillary studies as r

17、equired濾泡性淋巴瘤的次要診斷標準In the remaining Minor criteria No tingible-body macrophagesCellular monotony: centrocyte predominanceNo cellular polarisationAbsent or incomplete mantlesFollicles in perinodal tissuesDysplastic follicular center cells, e.g. signet ring cells, frequent cytoplasmic globulesAtypica

18、l cells in interfollicular tissuesInvasion of walls of blood vesselsMinor criteria 淋巴組織腫瘤-課件淋巴組織腫瘤-課件淋巴組織腫瘤-課件淋巴組織腫瘤-課件Follicular lymphoma vs RFH: ancillary techniquesImmunostaining for bcl-2Most useful immunostainNormal: Both T and B cells positive except follicle center cellsLook for positive stai

19、ning of cells in follicle centers: positive staining supports diagnosis of lymphomaFollicular lymphoma vs RFH: anReactive folliclesReactive folliclesFollicular lymphoma (Bcl-2 immunostaining) Follicular lymphoma (Bcl-2 immCommon misconceptions in hematopathologyNegative bcl-2 stain rules out follicu

20、lar lymphomaThe truth: It does not. 20-25% offollicular lymphoma cases are negative.Pursue with other tests to confirmor refute a diagnosis offollicular lymphomaCommon misconceptions in hematBcl-2 staining infollicular lymphomaBcl-2 staining infollicular l淋巴組織腫瘤-課件Bcl-2Bcl-2Look for evidence interfo

21、llicular invasionDensely packed CD20+ or CD79+ B-cells between follicles is indicative of interfollicular invasionPresence of a significant number of CD10+ lymphoid cells (not neutrophils, which are also CD10+) between follicles also indicates interfollicular invasion Look for vascular invasion Many

22、 CD10+ cells in the walls of perinodal blood vesselsLook for evidence interfollicuCD20CD20CD10CD10淋巴組織腫瘤-課件Look for monoclonality or low proliferation indexImmunostain for Ig to look for light chain restrictionDemonstrated by Ki67, a low Ki67 index favors diagnosis of follicular lymphoma over RFH (m

23、ean 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 false negative results)Detection of BCL2 gene rearrangement by Southern blot, PCR or FISHLook for monoclonality or low KappaLambdaKappaLambdaFL1: Ki67RF

24、H: Ki67FL1: Ki67RFH: Ki67FL3: Ki67FL3: Ki67套細胞淋巴瘤Mantle cell lymphoma: morphologyDiffuse, vaguely nodular, or mantle zone patternBroad cytologic spectrumClassic type: small lymphoid cells with irregular to round nucleiBlastoid variant ( lymphoblasts, but TdT-)Pleomorphic variantOften with solitary e

25、pithelioid histiocytesInterspersed naked nuclei (follicular dendritic cells)Genetics: Ig gene rearrangement t(11,14) (q13;q32) 套細胞淋巴瘤Mantle cell lymphoma: m Growth pattern of MCL Growth pattern of MCL淋巴組織腫瘤-課件淋巴組織腫瘤-課件淋巴組織腫瘤-課件Round nucleiRound nucleiMantle cell lymphoma: biologic markersB marker+,

26、CD5+, CD10-, CD23-, IgM+, IgD+Key defining feature: Cyclin D1+ due to t(11;14) (q13;q32) or cryptic translocationMantle cell lymphoma: biologiCyclin D1Cyclin D1 粘膜相關淋巴組織 Mucosa-Associated Lymphoid Tissue(MALT)Specialized secondary lymphoid compartments of mucosal tissuesNatural, e.g., Waldeyers ring

27、, 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 properties 粘膜相關淋巴組織 淋巴組織腫瘤-課件LOW GRADE B CELL MALT LYMPHOMA (extranodal marginal zo

28、ne 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% (Gastric: 90%)LOW GRADE B CELL MALT LYMPHOMAHistol

29、ogic 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 +/- colonizationHistologic features of low gra淋巴組織腫瘤-課件淋巴組織腫瘤

30、-課件淋巴組織腫瘤-課件Low 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 lymphomasLow grade MALT lymphoma: ImmunAfter Helicobacter eradication thera

31、pyAfter Helicobacter eradication彌漫性大B細胞淋巴瘤DIFFUSE LARGE B CELL LYMPHOMA（DLBCL）Commonest nodal B-cell lymphomaA heterogeneous entityFinal common pathway for high grade transformation of low grade B-cell lymphomas彌漫性大B細胞淋巴瘤DIFFUSE LARGE B CELCentroblastic/ImmunoblasticCentroblastic/Immunoblastic淋巴組織腫瘤

32、-課件MultilobatedPleomorphicMultilobatedPleomorphicBURKITT LYMPHOMAThree different forms:Endemic (Equatorial 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 asso

33、ciation 30%; commonly involving lymphonode and bone marrow)African cases can also be AIDS-related!BURKITT LYMPHOMAThree differenBurkitt 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 c

34、hemotherapyBurkitt lymphomat(8;14) (q24;q淋巴組織腫瘤-課件淋巴組織腫瘤-課件Burkitt lymphoma: ImmunogeneticsProbably corresponds to IgM+ blasts in germinal centerPan-B+, CD10+, Bcl-6+, Bcl-2-Key features:C-MYC translocation medium-sized cellshigh Ki67 index：100%germinal center cell phenotypeBurkitt lymphoma: Immunog

35、enetiCD20CD10CD20CD10Ki67Ki67外周T和NK細胞淋巴瘤PERIPHERAL T AND NK CELL LYMPHOMASUncommon; 80%)Extranodal NK/T cell lymphomaNExtranodal NK/T cell lymphoma: PathologyNecrosis (apoptosis) common Angioinvasion common (not invariably seen)Broad cytologic spectrum: small, medium-sized or large cells, or mixedMa

36、y have many admixed inflammatory cellsExtranodal NK/T cell lymphoma:淋巴組織腫瘤-課件淋巴組織腫瘤-課件SmallMedium-sizedLargeBroad cytologic spectrumSmallMedium-sizedLargeBroad cyExtranodal NK/T cell lymphoma:immunophenotypeCD2+. sCD3-, cCD3e+, CD56+ Cytotoxic granules perforin, granzyme B, TIA-1 positiveCD4, CD5, C

37、D7, CD8: usually negativeKey features: CD56+, EBER+If CD56-, requires EBER+ and cytotoxic granules+ for diagnosisExtranodal NK/T cell lymphoma:Surface CD3Cytoplasmic CD3CD56Frozen tissueParaffin sectionSurface CD3Cytoplasmic CD3CD5PERIPHERAL T CELL LYMPHOMA UNSPECIFIED外周T細胞淋巴瘤，非特殊型A wastebasket cate

38、goryVariable clinical manifestationsUsually high stage disease (nodal/extranodal)May have eosinophiliaAggressive; relapse commonThe extranodal cases often express a cytotoxic cell phenotypePERIPHERAL T CELL LYMPHOMA UNSPeripheral T-cell lymphoma:Morphologic clues for recognitionPredominant paracorti

39、cal involvementProminent high endothelial venulesSpectrum of cells sizes and shapesIrregular nuclear contoursClear cellsMany admixed epithelioid histiocytes and eosinophilsBut immunostaining essential for confirming T lineagePeripheral T-cell lymphoma:Mo淋巴組織腫瘤-課件淋巴組織腫瘤-課件ANAPLASTIC LARGE CELL LYMPHO

40、MA, primary systemic form間變性大細胞淋巴瘤，原發系統性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

41、involving ALK geneANAPLASTIC LARGE CELL LYMPHOMAHallmark cellsHallmark cellsALK 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 typeMonomorp

42、hicSmall cellLymphohistiocyticHypocellularALK translocation (or expressi淋巴組織腫瘤-課件CD30CD30 Overall survivalPrimary systemic form of ALCL0510YearsALCL, ALK+*100%50%ALCL, ALK- Overall survivalPrimary syst 霍奇金淋巴瘤 HODGKIN LYMPHOMA 霍奇金淋巴瘤 HODGKIN LYLymphocyte predominanceMixed cellularityNodular sclerosis

43、Lymphocyte depletionNodular lymphocyte predominant Hodgkin lymphoma (N-LPHL)Classical Hodgkin lymphoma(cHL)Lymphocyte-richMixed cellularityNodular sclerosisLymphocyte depletionRYE CLASSIFICATIONWHO CLASSIFICATIONLymphocyte predominanceMixed c510YearsOverall survivalN-LPHL defined by immunohistochemi

44、strycHL defined by immunohistochemistryp = 0.0071510YearsOverall survivalN-LPHLA lymphoma characterized by:presence of Reed-Sternberg cells and their variants confirmed by mmunohistochemistryin an appropriate reactive cellular environment A lymphoma characterized by:Reed-Sternberg cells and variants

45、Diagnostic 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.Reed-Sternberg cells and variaReed-Sternberg cells and variantsSmall lymphocytesNuclear size of most neoplastic cells usually exceeds 3 times that of small lymphocyt