2008年恶性淋巴瘤WHO分类解读复旦大学附属肿瘤医院朱雄增Presentation Title 220世纪70年代恶性淋巴瘤的分类RappaportKielLukes-CollinsBNLIDorfmanWHO六种分类提出者依据不同理论和术语对淋巴瘤分型和命名，产生很大混乱和争论，难以解释临床试验的结果，也无法进行国际交流Presentation Title3NCI组织6个中心12位病理学家对1100例淋巴瘤进行研究，结果显示6个分类自身重复性好，但没有一个分类明显优于其它分类1982年，NCI制订了能提供临床使用，又能与上述分类之间相互转换的NHL工作程式（WF）Presentation Title4Presentation Title 5上世纪90年代前淋巴瘤分类存在的问题用单一原则定义所有疾病—Rappaport：细胞大小，生长方式—Kiel、Lukes-Collins：正常相应细胞—WF：预后组（生存情况）依据一个或一小组专家的工作提出分类病理医师仅依据形态学特点分类，没有考虑与临床的相关性Presentation Title61994年，国际淋巴瘤研究小组（ILSG）提出淋巴组织肿瘤的欧美修改分类（REAL）2001年，世界卫生组织（WHO）提出造血淋巴组织肿瘤分类REAL/WHO分类原则定义淋巴瘤的不同类型应能被病理医师识别，且与临床相关定义每一独立疾病依据一组特点（形态学、免疫表型、遗传学和临床）目前对大多数淋巴瘤的病因尚不清楚，每一特点的相对重要性不同，即没有“金标准”尽可能按假定相应正常细胞和分化阶段分类，按临床和形态学相似性归类Presentation Title72008年恶性淋巴瘤WHO分类美国（SH）和欧洲（EAHP）血液病理学会SH和EAHP推选8位主编—髓细胞系：J. Vardiman(US), J. Thiele(DE)—淋巴细胞系：S. Swerdlow, E, Jaffe, N. L. Harris (US),E. campo(ES), Pileri(IT), H. Stein (DE)—75位作者：美，加，欧，亚，澳WHO临床顾问委员会—髓细胞和急性白血病：Chicago, 2007. 2.—淋巴组织：Airlie House VA, 2007.3.共识会议Lyon, 2007. 9出版2008.9Presentation Title8Presentation Title 9WHO 2008：重要议题髓细胞肿瘤—新遗传学资料—新分类淋巴组织肿瘤—ALL/LBL的遗传学分类—小的克隆性淋巴细胞群—某些疾病共识指南—新的疾病/亚型/变型/分级交界性（灰区）肿瘤分类前体细胞肿瘤分类新变动母细胞性浆细胞样树突细胞肿瘤—以前称为“母细胞NK细胞淋巴瘤/白血病”细胞系不明确的急性白血病—急性未分化白血病（AUL）—混合性表型急性白血病（MPAL）T-淋巴母细胞性淋巴瘤/白血病（T-ALL）B-淋巴母细胞性白血病/淋巴瘤（B-ALL）—遗传学亚型Presentation Title10Presentation Title 11CD4CD56Presentation Title12B-ALL/LBL遗传学分型t(9；22)（q34；q11.2）；BCR/ABLt(v；11q23)；MLL重排t(12；21)（p13；q22）；TEL/AML1(ETV6-RUNX1)高二倍体低二倍体（低二倍体ALL）t(5；14)（q31；q32）；（IL3-IGH）t(1；19)（q23；P13.3）；（E2A-PBX1；TCF3/PBX1）Presentation Title 13小的克隆群—？早期/前体病变新技术已能在健康人群的血液、骨髓和淋巴结中检测到小的克隆性淋巴细胞群—免疫表型（IgL限性，CD5,CD10,BCL2）—遗传学（IGH-r，BCL2-r）可能并不表明存在进展为恶性肿瘤的危险性类似于30年前对MGUS的认识这方面内容在骨髓瘤，CLL和FL中有讨论共识指南（一）CLL—在缺乏组织累及时，周围血具有CLL表型的单克隆淋巴细胞必须≥5ｘ109/L—其它：单克隆B淋巴细胞增多症（MBL）Waldenstrom巨球蛋白血症—LPL患者的骨髓中存在任何形式的异常蛋白Presentation Title14共识指南（二）浆细胞骨髓瘤—症状性还是无症状性，终末器官损伤（CRAB）—国际分期系统（白蛋白，β2微球蛋白）—TC分组（易位-cyclinD基因）—细胞遗传学分组（预后良好、预后不良）皮肤淋巴瘤：EORTC分类Presentation Title15浆细胞骨髓瘤症状性浆细胞骨髓瘤—血清或尿中M蛋白—骨髓克隆性浆细胞或浆细胞瘤—相关器官或组织损害（高血钙、肾功能不全、贫血、骨病变）无症状（闷燃型）骨髓瘤—血清M蛋白＞30g/L和/或—骨髓中克隆性浆细胞≥10％—无相关器官或组织损害或无骨髓瘤相关症状Presentation Title16骨髓瘤国际分期系统标准Ⅰ：血清？微球蛋白＜3.5mg/L血清白蛋白＞3.5g/LⅡ：介于Ⅰ和Ⅲ之间Ⅲ：血清？微球蛋白＞5.5mg/L中位生存期62个月44个月29个月Presentation Title17Presentation Title 18骨髓瘤中易位和cyclinD1基因预后良好组：6p21、11q13、D1、非高倍体（？）预后不良组：D1+D2（？）、4p16、16q23、t20q11预后未确定组：D2Presentation Title 19骨髓瘤中细胞遗传学预后分组预后不良—间期分析：-13或非整倍体—FISH：t（4；14）、t（14；16）或t（14；20）—FISH：-17p13—低二倍体预后良好—无上述不良预后的异常改变—高二倍体—FISH：t（1；14）或t（6；14）Presentation Title 20滤泡性淋巴瘤（FL）分级弥漫性区域亚型/变型—胃肠道FL—儿童FL—滤泡间肿瘤（原位FL）原发性皮肤滤泡中心淋巴瘤FL分级（CAC意见）肿瘤学家希望分级简化或废除分级考虑FL1-3A不再分级，作为一个独立疾病考虑FL3B为DLBCL“滤泡性”变型Presentation Title21Presentation Title 22Follicular Lymphoma:Clinical impact of gradingGrades 1&2: equal survival, not affected by adriamycin Grade 3: improved OS and FFS with adriamycinGrade 3A and 3B: no difference (not shown)Presentation Title 23FL分级（病理医师的意见）没有足够资料确保：—将FL3B与其它FL分开或与DLBCL归在一起—废除分级FL1和FL2之间没有差别—将FL1和2称为FL1FL3A变为FL2FL3B变为FL3—但这将与对按2001年WHO分级存活而且还需治疗的病人产生混淆Presentation Title 24FL分级（最后决定——作微小改动）依据中心母细胞数/比例估计—FL1-2＝CB少（“低级别”）—FL3＝CB多（＞15/hpf）FL3A —仍存在CCFL3B —CB成片弥漫性区域—符合FL3标准，仍需与DLBCL分开—不再用“FL3伴弥漫性区域”Presentation Title 25FL分级FL with DLBCL•Diffuse area = No follicles–(CD23/CD21+)•If diffuse area meets criteria forFL3A/B, a separate diagnosis ofDLBCL is made.–Diffuse large B-cell lymphoma (25%)–Follicular lymphoma, Grade 3A (75%)Presentation Title26Presentation Title 27胃肠道FL•Small intestine–Duodenum: 85%•Morphology,immunophenotype, genetics similar to nodal FL–Bcl2+ CD10+ Bcl6+, often IgA+•Clinically indolent, localized –Asymptomatic (incidental);abdominal pain–Most localized (Stage I/II)–Curable with resection, often no treatment–Systemic recurrence unusual •?Arise from follicularcomponent of MALT儿童FL•Localized cervical or otherperipheral lymph node;adolescent or young adult;male predominance•Large follicles, resemblingPTGC, follicle lysis;effacement of nodalarchitecture•Clonality demonstrated byimmunophenotype,molecular genetic analysis•FL:–CD10+ Bcl6+ CD43+ Bcl2-•MZL:–CD10-Bcl6-(residual GCpresent) Bcl2 +/-cIg+/-•DDX–Reactive LN–FL vs MZL•Often cured wth minimaltherapy; no dissemination•Are these really malignant?Presentation Title28“原位”FL•Architecturally normal－appearinglymph node or other lymphoidtissue–One or more follicles withBcl2+clonal B cells–Usually an incidental findingon Bcl2 staining.•Clinical–Minority with overt FLelsewhere (earlier,concurrent, later)–Most no FL•Nodal equivalent of smallclones of BCL2R cells inblood of normal subjects–2nd “hit”required for FL•Evaluate for FL; don’t treat!Presentation Title29Presentation Title 30PCFCL•Morphology–Often diffuse or follicular and diffuse–CB and large CC (may be called DLBCL)»CB numerous, but not sheets •Immunophenotype–CD20+, Bcl6+ CD10-/+ Bcl2-/+•Genetics–BCL2 usually germline •Clinical–Head and neck, trunk;–Indolent, localized; no nodal spread–Prognosis independent of gradePresentation Title31成熟B细胞肿瘤分类新变动DLBCL—新类别—结外原发部位—病毒相关（EBV、HHV8）交界性肿瘤—BL和DLBCL —PMBL和NSCHL弥漫性大B细胞淋巴瘤（DLBCL）DLBCL,NOS—GCB/ABC，形态学变型—富于T细胞/组织细胞LBCL—原发性CNS DLBCL—原发性皮肤DLBCL（“腿型”）—老年人EBV+DLBCLDLBCL,伴有慢性炎症淋巴瘤样肉芽肿病原发性纵隔（胸腺）LBCL血管内LBCLALK+DLBCL浆母细胞性淋巴瘤原发性渗出性淋巴瘤LBCL,起自HHV8相关多中心性Castleman病Presentation Title32Presentation Title33DLBCL 的预后亚群DNA 微阵列分析能用于化疗后预测生存率Rosenwald A et al. N Engl J Med . 2002;346:1937-1947.Activated B-cell–likeType 3Germinal-center B-cell–like Overall survival (years)P r o b a b i l i t y02468101.00.50.0HighLevel of gene expression LowGerminal-center B-cell–likeType 3Activated B-cell–likeG e n e sPresentation Title34-+-Germinal CenterCD10+ orBCL6+ and MUM1-Non-Germinal CenterCD10-and MUM1+orCD10-and BCL6-IHC确定DLBCL细胞起源CD10BCL6MUM1++ or -+ or --+ or -+--+ or -34%76%ABC GCB 5 Year OS (Pre-R)Presentation Title 35B细胞淋巴瘤，不能分类，具有DLBCL和BL之间中间性特点许多病例，尤其在成人，不能明确归入BL或DLBCL 这些病例生物学和临床上不同于BL和DLBCL，不宜归入其中一类这不是一个独立病种，需进一步明确BL/DLBCL•Lymphomas withmorphological and geneticfeatures of both DLBCL andBL, but that for biological andclinical reasons should not beincluded in these categories•Morphology:–Intermediate between BL andDLBCL (medium-sized cells,large cells)•Immunophenotype:–C/w BL (CD10+ Bcl6+ Ki67high) but may be Bcl2+•Genetics:–MYC, BCL2, both (doublehit), complex karyotypes•Clinical:–May occur in pts w/hx FL–Aggressive, short survival(especially double hit cases)Presentation Title 36Presentation Title37PMBL/NSCHLSavage et al, Rosenwald et al, 2003PMBL and CHL cell lines share gene expression profile•NSCHL and PMBL are 2 common young adult mediastinal lymphomas•Share immunophenotypic and genetic features–Ig-, loss of B-cell receptor signaling –Activation of cytokine JAK-STAT pathway–TNF family members expressed »CD30, TRAF1–Constitutive NF-kappa B activation »cREL nuclear localization–Aberrant activation of tyrosine kinases and activation of the PI3K/ATK pathway •Borderline cases are increasingly recognized “Grey-zone lymphoma ”PMBL/NSCHL•Definition–A B lineage lymphoma with overlappingclinical, morphological and/orimmunophenotypic features betweenclassical Hodgkin lymphoma (CHL) anddiffuse large B-cell lymphoma (DLBCL),especially primary mediastinal largeB-cell lymphoma (PMBL).•Morphology:–Large cells, lacunar, R-S like, in sheets;variable sclerosis, fibrous bands,inflammatory backgroud–CD45+ CD30+ Pax5+ CD20+/-CD79a+/-CD15+/-CD10-Bcl6 /+•Clinical:–Young men (20-40), mediastinal–Aggressive, often fatal–?Treat as CHL or DLBCLPresentation Title38成熟T细胞肿瘤新变动EBV相关T细胞克隆性淋巴组织增生（儿童，亚洲）—儿童系统性EBV＋T细胞淋巴组织增生性疾病（伴有慢性活动性EBV感染）—痘疮样-水痘病样淋巴瘤皮肤T细胞淋巴瘤的新类型（EORTC）—原发性皮肤侵袭性親表皮性CD8＋细胞毒性T细胞淋巴瘤—原发性皮肤rδT细胞淋巴瘤—原发性皮肤小/中CD4+T细胞淋巴瘤ALCL,ALK+和ALCK，ALK-—ALK＋＝一种明确的临床病理独立病种—ALK－＝组织学与ALK＋相同；临床上可能不同于PTCL－NOSPresentation Title39Presentation Title40EBERPresentation Title41CD3CD8Presentation Title 42Presentation Title 43CD3Presentation Title 44Anaplastic Large-CellLymphoma,ALK+•Morphology: sinusoidal, largecells, eccentric, kidney-shapednuclei, abundant cytoplasm witheosinophilic paranuclear region–Small cell, histiocyte-richvariants•Immunophenotype:–T-cell Ag+/-CD30+ ALK+–EMA+ CD25+ CGP+•Genetics:–t(2;5) and variants•Clinical: children and youngadults, M>>F, nodal orextranodal; aggressive butcurablePresentation Title 45Anaplastic Large-cell Lymphoma,ALK-•Morphology:–Large cells with abundantcytoplasm, focal cohesive growth,round to horseshoe-shaped nuclei,sometimes pleomorphic;cytoplasmic paranuclear hof insome cells (“hallmark cells ”) –ie,identical to ALK+ ALCL•Immunophenotype:–CD30+ strong, all cells, membraneand Golgi pattern; no B-cellantigens (Pax5-), ALK-•Clinical:–Adult (med 60y); prognosisintermediate between ALK+ andPTCL-NOSFailure-free SurvivalALCL ALK+vs.ALCL ALK -Presentation Title46Failure-free SurvivalALK neg ALCL vs PTCL-U Presentation Title47小结（一）病理学家和肿瘤学家达成国际间共识—一致的术语和标准化的诊断标准有利于临床试验和提高可重复性—当今血液病理学会联合委员会加上肿瘤学家的参与，能够继续》增加或删除疾病》融入新资料：遗传学、基因表达、蛋白Presentation Title48小结（二）疾病定义的多参数方法—结合形态学、免疫表型、遗传学和临床特点—临床上实用，而且生物学上适用的分类能够融入新的资料强调“真正的”疾病有利于研究发病机理、预后、靶向治疗现在已认识了60多种独立病种Presentation Title49存在问题小B细胞肿瘤特性需进一步明确—FL病理特点（分级）危险性分层的实用方法—儿童FL和MZL：是真正恶性肿瘤？—新的类型DLBCL再分类/危险性分层灰区：进一步澄清ALK-ALCL：是“真正”独立病种？与HL的区别融入GEP的新资料—分类和预后判断上用于免疫表型的一组抗体—在首次诊断和分类上微阵列的作用Presentation Title50。