【内科PPT课件】-淋巴瘤

1、淋巴瘤（ Lymphoma ）Outline for Lymphoma Definition Incidence Etiology Clinical Manifestation Diagnosis Differential Diagnosis Treatment PrognosisLymphomaDefinition: Lymphomas are a group of malignant tumors originating from lymph nodes or other lymphatic tissues.Lymphoma may occur in any tissue or organ

2、 around the body.Two categories: Hodgkins lymphoma (HL) 15%non-Hodgikins lymphoma (NHL) 80-90%淋巴瘤的发生2015-9-15高仓健罗京李开复IncidenceMale: 1.39/100,000；Female: 0.84/100,000NHL increasing over timeHD stable during the years在常见肿瘤中分别占第9(男性),第10(女性)发达国家：12-15/10万；中国：1.6-2.1/10万淋巴瘤在欧美国家占恶性肿瘤死亡的第6位，我国位于第10位。每年发病

3、率平均增加4,增长最迅速的恶性肿瘤Thomas Hodgkin (1798-1866)新发病例数估计死亡数EtiologyNo clear risk factors & unknown cause Infectious Agents: EB virus: Burkitt lymphoma , HL HTLV-I: T cell leukemia /lymphoma Human herpes virus-6; -8: primary body cavity lymphoma Measles virus（MV） Helicobacter pylori (Hp): MALT Immune Dysfu

4、nction: Autoimmune disorders, Congenital or acquired immunodeficiency, etc. Genetic Lesions: HLOthers: Environmental factors, Occupational exposure, x-rayPathological FeaturesCharacteristics of typical pathological changes in lymph glands of lymphomaDestruction of normal follicular structure by a gr

5、eat number of abnormal lymphocytes or histiocytes;Infiltration of tissues surrounding the capsule by the tumor cells;Damage of capsule and the subcapsular sinuses.subcapsular sinuses, 包膜下窦正常的淋巴结直径约1mm,淋巴窦是确定淋巴结最可靠的结构T区：副皮质区+滤泡间区; B区：淋巴滤泡Clinical Manifestations1. Systemic manifestations: fever, weigh

6、t loss, night sweet, pruritusseverity: asymptomatic to extremely illtime course: evolution over weeks, months, or years2. Regional lymph node presentations Firm rubbery lymph nodes without pain.Cervical, supraclavicular, axillary lymphadenopathy may be the initial complaint without pain.3. Infiltrat

7、ionThoracic cavity: mediastina, lung, trachea, esophagus, heart, etc，Abdomen: stomach, gut, spleen, liver, bladder, etc.CNS: compression of spinal cord, high intracranial pressure, etc Bone: pain, pathological fractureSkin: mass, ulcer, pruritus, subcutaneous nodule, etc.Waldeyers tonsillar ring（咽部淋

8、巴环）Bone Marrow全身症状：发热、盗汗及体重减低（皮肤瘙痒）；淋巴结肿大； 组织器官侵润特点临床起病：单个或多个淋巴结或结外组织和器官病变发生部位：身体各处 早期表现：无痛性进行性淋巴结肿大。Enlarged lymph nodes-painlessDistant spread Extranodal sites involved are commonHigh fever AggressiveEnlarged lymph nodes-painlessContiguous spreadExtranodal sites relatively uncommon except in advan

9、ced disease “B” symptoms: pruritusPel-Ebstein fever（周期性发热 ）: 1/6 casesHL ManifestationsNHL ManifestationsLaboratory FindingsComplete blood cell countNormocytic normochromic anemiaLeucocytosis, lymphocytosisLeukoerythroblastic picture - BM infiltrationESR, High serum LDH, 2-microglubin：poor prognosis

10、 IgH and TCR gene rearrangement：PCRBone marrow aspirate and biopsyNormal, or late involvement.Trephine biopsy- diffuse or follicular infiltrationImmunological:Monoclonal antibodyB/T cell NHL,Karyotypic/Genetic:t(14;18) Follicular lymphoma（Bcl-2）t(11;14) mantle cell lymphoma（bcl-1/JH重组基因）t(8;14) Burk

11、itt lymphoma（myc）Imaging StudiesX-ray: Chest Ultrasound StudyCT scan: thorax, abdomen, skull, neckMRI: thorax, abdomen PET-CT: PET-CT in LymphomaPositron emission tomography CT scan showing persisting areas of active disease in the mediastinum and cervical region (arrows).正电子发射体层成像 PET-CTPET-CTDiagn

12、osisThe diagnosis is usually established by biopsy，the histopathological classification * Need enough tissue to assess cells & architectureImprint of the biopsy of lymph node, smear from aspirated material, imprint of the skin lesion could aid to make the diagnosisStaging ProceduresSymptoms and Sign

13、sChest X-ray filmCT scan: chest and abdomenBM examinationBlood biochemistry studyBiopsy: lymph nodes and other organsDifferential DiagnosisWith other causes of lymph nodes enlargement such as tuberculosis, septicemia, collagen disease, cancer metastasis. 淋巴结肿大：感染（病毒、细菌）、免疫（结缔组织病、坏死性淋巴结炎）、肿瘤性疾病（肿瘤转移、

14、白血病等）With other causes of fever: SBE, connective tissue disease, chronic or acute infectious disease. 以发热为主要表现的淋巴瘤：TB、败血症、结缔组织病、坏死性淋巴结炎、恶性组织细胞病等。淋巴瘤的诊断过程病史：发热、盗汗及体重减低；淋巴结肿大；组织器官侵润实验室: 血液ESR, LDH, 2MG poor prognosis； IgH and TCR gene rearrangement； Bone marrow aspirate and biopsy；影像学检查: X-ray，超声检查、CT

15、，MRI及PET-CT病理学：形态学：分型免疫学检查：Monoclonal antibodyB/T cell NHL,遗传学检查：t(14;18) Follicular ；t(11;14) Mantle cell lymphoma；t(8;14) Burkitt lymphoma分子生物学：基因芯片、基因突变，FISH, PCR定量Diagnosis: 淋巴瘤的诊断实施 临床高度怀疑，病史，查体，实验室检查 细针穿刺进展为活检针穿刺，但更倾向于切除活检（组织学） 有经验的病理学专家 WHO分类、分型（2008年更新） 紧急处理 出血和感染 器官阻塞 肿瘤快速进展临床分期检查及诊断1 2 3 4

16、病史体格检查一般状况B症状实验室检查查血查骨髓查脑脊液影像学及其他X线CT超声PET镓67心电图内窥镜等病理学形态学免疫学检查遗传学检查分子生物学 基因芯片基因突变FISHPCR定量Clinical Staging (Ann Arbor Classification, 1971)StageDefinitionIInvolvement of single lymph node region (I) or of a single extralymphatic organ or site (IE)IIInvolvement of two or more lymph node regions on t

17、he same side of diaphragm (II) or localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (IIE)IIIInvolvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by involvement of the spleen (

18、IIIS) or by localized involvement of an extralymphatic organ or site (IIIE) or both (IIISE)Clinical Staging (Ann Arbor Classification, 1971)StageDefinitionIVDiffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymphnode involvementThe absenc

19、e or presence of fever, night sweats and /or unexplained loss of 10% or more body weight in the 6 months preceding diagnosis are to be denoted in all cases by the suffix letters A or B, respectively.Staging of LymphomaMorphology ML-Gross Reed-Sternberg cell初级滤泡次级滤泡初级滤泡和次级滤泡B区: CD20T区: CD3副皮质区滤泡间区组织切

20、片染色形态学CD3和PAX5免疫组化染色CD20CD3多拷贝体原位杂交EBERClassificationsHL: The characteristic finding is the presence of Reed-Sternberg cells in the tumor structureNHL: include over 20 discrete entities with characteristic morphologic, immunophenotypic, genetic, and clinical features：85% of NHL are B-cell lymphomas细

21、胞谱系是疾病定义的出发点B、T或 NK 细胞每种疾病都是具有临床和实验室特征的独立实体形态学、免疫表型、遗传学特征、临床表现与病程疾病累及部位常常是重要的生物学特征性标志临床特征的应用是一个新的方面；诊断的依据2009年9月更新分类WHO病理分类原则WHO淋巴组织肿瘤分类(2008)B 淋巴母细胞白血病/淋巴瘤B 淋巴母细胞白血病/淋巴瘤，NOS B 淋巴母细胞白血病/淋巴瘤，具有重现性细胞遗传学异常B 淋巴母细胞白血病/淋巴瘤，具有t(9;22)(q34;q11.2); BCR-ABL1 B 淋巴母细胞白血病/淋巴瘤，具有t(v;11q23); MLL 重排 B淋巴母细胞白血病/淋巴瘤，具有

22、t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1) B 淋巴母细胞白血病/淋巴瘤，具有超二倍体 B 淋巴母细胞白血病/淋巴瘤，具有亚二倍体(亚二倍体ALL) B 淋巴母细胞白血病/淋巴瘤，具有t(5;14)(q31;q32); IL3-IGH B 淋巴母细胞白血病/淋巴瘤，具有t(1;19)(q23;p13.3); E2A-PBX1; (TCF3-PBX1) T淋巴母细胞白血病/淋巴瘤慢性淋巴细胞白血病/小淋巴细胞淋巴瘤 前B细胞白血病 脾边缘区淋巴瘤 毛细胞白血病 脾淋巴瘤/白血病，未分类* 脾弥漫红髓的小B细胞淋巴瘤 毛细胞白血病-变异型 淋巴浆细胞淋巴瘤华氏

23、巨球蛋白血症 重链病Alpha重链病Gamma重链病 Mu重链病 浆细胞瘤骨的孤立性浆细胞瘤 髓外浆细胞瘤 粘膜相关淋巴组织结外边缘区淋巴瘤 (MALT淋巴瘤) 结内边缘区淋巴瘤 儿童结内边缘区淋巴瘤 滤泡性淋巴瘤 儿童滤泡性淋巴瘤 原发于皮肤的滤泡中心淋巴瘤套细胞淋巴瘤 弥漫大B细胞淋巴瘤 (DLBCL)，NOS 富含T/组织细胞的大B细胞淋巴瘤 原发于中枢神经系统的DLBCL 原发于皮肤的DLBCL，腿型 老年性EB病毒阳性的DLBCL 与慢性炎症相关的DLBCL 淋巴样肉芽肿病 原发于纵隔（胸腺）的大B细胞淋巴瘤血管内大B细胞淋巴瘤 ALK阳性的大B细胞淋巴瘤 浆母细胞性淋巴瘤 HHV8

24、相关的大B细胞淋巴瘤 多 中心Castleman 病 原发性渗出性淋巴瘤 伯基特淋巴瘤B细胞淋巴瘤，不能分类型,，具有介于弥漫大B细胞淋巴瘤与伯基特淋巴瘤之间的特征 B细胞淋巴瘤，不能分类型，具有介于弥漫大B细胞淋巴瘤与典型霍奇金病之间的特征前T细胞白血病 大颗粒T淋巴细胞白血病 NK细胞性慢性淋巴细胞增殖性疾病 侵袭性NK细胞白血病 儿童系统性EB病毒阳性的T细胞淋巴增殖性疾病 类水痘样淋巴瘤 成人T细胞白血病/淋巴瘤 结外NK/T细胞淋巴瘤，鼻型 肠道病相关性T细胞淋巴瘤 肝脾T细胞淋巴瘤 皮下脂膜炎样T细胞淋巴瘤 蕈样真菌病 Szary 综合征原发于皮肤的CD30阳性的T细胞增殖性疾病

25、淋巴瘤样丘疹病 原发于皮肤的间变性大细胞淋巴瘤原发于皮肤的 T细胞淋巴瘤 原发于皮肤的CD8阳性侵袭性嗜表皮的细胞毒性T细胞淋巴瘤 原发于皮肤的CD4阳性小/中间T细胞淋巴瘤 外周T细胞淋巴瘤，NOS 血管免疫母细胞性T细胞淋巴瘤 间变性大细胞性淋巴瘤，ALK阳性间变性大细胞性淋巴瘤，ALK阴性霍奇金淋巴瘤结节淋巴细胞为主型霍奇金淋巴瘤 典型霍奇金淋巴瘤结节硬化型典型霍奇金淋巴瘤 富含淋巴细胞的典型霍奇金淋巴瘤 混合细胞性典型霍奇金淋巴瘤 淋巴细胞消减型典型霍奇金淋巴瘤 移植后淋巴细胞增殖性疾病 (PTLD)早期损伤浆细胞增生 感染性单核细胞增多样PTLD 多形性 PTLD 单一形态的 PTL

26、D (B- 及T/NK-细胞型) #典型霍奇金淋巴瘤型PTLD # 前体细胞侵袭性B细胞成熟T/NK细胞HL和PTLD惰性B细胞HL, Rye conference, 1965FormsRS cellsPathologicalClinical featuresLymphocyte richRareNodular infiltration predominantly with mature lymphocytesLocalized, good prognosis Nodular sclerosisAlways present lacunar typeInterlacing bands of co

27、llagen dividing the cellular infiltrate into islandsOccurs in young persons, stage I or II at the time of diagnosis, prognosis relatively favorableMixed cellularityManyFibrosis with localized necrosis, infiltration of neutrophils, eosinophils and plasma cells, lymphocytes and histiocytes Tendency to

28、 disseminate, prognosis relatively poorLymphocytedepletionVariable in numberPredominantly infiltration of hitiocytes, disseminated fibrosis and necrosis Occurs in old age stage III or IV at the time of diagnosis, prognosis usually poorWHO将HL分为：结节性淋巴细胞为主型（NLPHL），和经典型（CHL）。 病例形态、免疫表型、分子生物学、临床表现和生物行为均有

29、差异。CHL分为：淋巴细胞为主型（LRHL），结节硬化型（NSHL）， 混合细胞型（MCHL），淋巴细胞消减型（LDHL）NHL, NCI working Formulation (1982)GradesPathologyImmunophenotypeLow GradeSmall lymphocytic (SLL)Follicular, small cleaved cell (FSCL)Follicular, mixed small cleaved and large cell (FMC)B cell, rarely T cellB cellB cellIntermediate GradeFo

30、llicular, large cell (FLCL)Diffuse, small cleaved cell (DSCL)Diffuse, mixed small cleaved and large cell (DML)Diffuse, large cell (cleaved and non-cleaved) (DLCL)B cellB cell, occasionally TB cell, T cellB cell, T cellHigh GradeLarge cell immunoblastic (IBL)Lymphoblastic (convoluted and non-convolut

31、ed)(LL)Small non-cleaved cell (Burkitt and non-Burkitt)(SNCL)B cell, T cellThymic T cellB cellWHO将HNL分为：B细胞、T细胞和NK T细胞，以及灰区NHL。欧美NHL病理分型中国NHL病理分型Click to edit Master title styleClick to edit Master subtitle style结外发病多分期较晚多我国淋巴瘤的特点HL少滤泡淋巴瘤少发病少好治的少年轻的少NHL多弥漫型多总数多难治的多男的多总数多难治的多男的多T细胞淋巴瘤占20-30%，远多于欧美国家T

32、reatmentCategorySurvival of untreated patientsCurabilityTo treat or not to treatNHLIndolentYearsGenerally not curableGenerally defer Watch&WaitRx/asymptomaticAggressiveMonthsCurable in someTreatVery aggressiveWeeksCurable in someTreatHLAll typesVariable months to yearsCurable in mostTreatTreatment（治

33、疗原则） Chemotherapy: HL- ABVD, MOPP，- NHL- CHOP, CHOPE, DICE, ESHAP，- Radiotherapy Surgery Immunotherapy: Interferon-，CIK，NK，CarT Target therapy: B Rituxan (Anti CD20), Anti CD30，- HSCT：Auto-(自体），Allo-（异基因） Control of symptoms and complications OthersTreatment Approach for HLStageChoice of TreatmentIA

34、, IIAChemotherapy （ABVD） + IrradiationIB, IIB, IIIA, IIIB，IVCombined chemotherapy + Local radiotherapyMOPP or ABVD; ICE; DHAP;ESHAP Complications of treatmentInfertilityMOPP ABVD; males femalesSecondary malignancyskin, AML, lung, MDS, NHL, thyroid, breast.Cardiac diseaseDisease, Drugs, The effective

35、ness of radiotherapy for NHL is much lower than HL, Combination chemotherapy is the mainstay of curative treatment in NHL. Local radiotherapy may be needed.Immune comprehensive treatment。Treatment Approach for NHLIndolent Lymphomas “Watch & Wait” B-R，R-COP, R-CVP, R-FND R：Rituxan（CD20单抗） Single alky

36、lating agents Fludarabine /R Lenalidomide /R Radioimmunotherapy Aggressive lymphomasStandard chemotherapy regimens used in NHLCHOP or R-CHOP: CHOP most common and effective chemotherapeutic regimen. (repeat every three weeks) C-cyclophosphamide 750mg/m2 iv d1 H-doxorubicin (Adriamycin) 50-70mg/m2 iv

37、 d1 O-vincristine (Oncovin) 1.4mg/m2 iv d1 P-prednisone 100mg po d1-5CHOP-EBACOPMACOP-BESHAPDICEGEHyperCVAD Monoclonal AntibodiesRituximab (Rituxan): approved for indolent CD20 positive B-NHLs, but has activity in diffuse large B-cell lymphoma.Rituximab (Rituxan) can be used in combination with chem

38、otherapy.MechanismsComplement-mediated cytotoxicity Antibody-dependent cell-mediated cytotoxicityApoptosisPotential side effects Flu-like symptoms during infusionFeverTarget therapy新抗体为基础的治疗: 新的靶标靶标单克隆抗体CD20Ofatumumab, IMMU-106, Ocrelizumab, GA101, AME-133v, PRO 131921CD22Epratuzumab（依帕珠单抗） CD25Daclizumab（达珠单抗，anti-Tac） CD30SGN-30 和 MDXO60 CD40SGN-40 和 HCD122 CD52Alemtuzumab（阿仑单抗） CD80Galiximab新靶标：小分子靶向药物Blood, 2011 Feb; 117(5): 1453-62HSCTIndications: First-line: Very aggressive, CR