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%淋巴瘤的發(fā)生2015-9-15高倉(cāng)健羅京李開(kāi)復(fù)IncidenceMale: 1.39/100,000；Female: 0.84/100,000NHL increasing over timeHD stable during the years在常見(jiàn)腫瘤中分別占第9(男性),第10(女性)發(fā)達(dá)國(guó)家：12-15/10萬(wàn)；中國(guó)：1.6-2.1/10萬(wàn)淋巴瘤在歐美國(guó)家占惡性腫瘤死亡的第6位，我國(guó)位于第10位。每年發(fā)病

3、率平均增加4,增長(zhǎng)最迅速的惡性腫瘤Thomas Hodgkin (1798-1866)新發(fā)病例數(shù)估計(jì)死亡數(shù)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, 包膜下竇正常的淋巴結(jié)直徑約1mm,淋巴竇是確定淋巴結(jié)最可靠的結(jié)構(gòu)T區(qū)：副皮質(zhì)區(qū)+濾泡間區(qū); B區(qū)：淋巴濾泡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、巴環(huán)）Bone Marrow全身癥狀：發(fā)熱、盜汗及體重減低（皮膚瘙癢）；淋巴結(jié)腫大； 組織器官侵潤(rùn)特點(diǎn)臨床起病：?jiǎn)蝹€(gè)或多個(gè)淋巴結(jié)或結(jié)外組織和器官病變發(fā)生部位：身體各處 早期表現(xiàn)：無(wú)痛性進(jìn)行性淋巴結(jié)腫大。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（周期性發(fā)熱 ）: 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重組基因）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).正電子發(fā)射體層成像 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. 淋巴結(jié)腫大：感染（病毒、細(xì)菌）、免疫（結(jié)締組織病、壞死性淋巴結(jié)炎）、腫瘤性疾?。[瘤轉(zhuǎn)移、

14、白血病等）With other causes of fever: SBE, connective tissue disease, chronic or acute infectious disease. 以發(fā)熱為主要表現(xiàn)的淋巴瘤：TB、敗血癥、結(jié)締組織病、壞死性淋巴結(jié)炎、惡性組織細(xì)胞病等。淋巴瘤的診斷過(guò)程病史：發(fā)熱、盜汗及體重減低；淋巴結(jié)腫大；組織器官侵潤(rùn)實(shí)驗(yàn)室: 血液ESR, LDH, 2MG poor prognosis； IgH and TCR gene rearrangement； Bone marrow aspirate and biopsy；影像學(xué)檢查: X-ray，超聲檢查、CT

15、，MRI及PET-CT病理學(xué)：形態(tài)學(xué)：分型免疫學(xué)檢查：Monoclonal antibodyB/T cell NHL,遺傳學(xué)檢查：t(14;18) Follicular ；t(11;14) Mantle cell lymphoma；t(8;14) Burkitt lymphoma分子生物學(xué)：基因芯片、基因突變，F(xiàn)ISH, PCR定量Diagnosis: 淋巴瘤的診斷實(shí)施 臨床高度懷疑，病史，查體，實(shí)驗(yàn)室檢查 細(xì)針穿刺進(jìn)展為活檢針穿刺，但更傾向于切除活檢（組織學(xué)） 有經(jīng)驗(yàn)的病理學(xué)專(zhuān)家 WHO分類(lèi)、分型（2008年更新） 緊急處理 出血和感染 器官阻塞 腫瘤快速進(jìn)展臨床分期檢查及診斷1 2 3 4

16、病史體格檢查一般狀況B癥狀實(shí)驗(yàn)室檢查查血查骨髓查腦脊液影像學(xué)及其他X線(xiàn)CT超聲PET鎵67心電圖內(nèi)窺鏡等病理學(xué)形態(tài)學(xué)免疫學(xué)檢查遺傳學(xué)檢查分子生物學(xué) 基因芯片基因突變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初級(jí)濾泡次級(jí)濾泡初級(jí)濾泡和次級(jí)濾泡B區(qū): CD20T區(qū): CD3副皮質(zhì)區(qū)濾泡間區(qū)組織切

20、片染色形態(tài)學(xué)CD3和PAX5免疫組化染色CD20CD3多拷貝體原位雜交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細(xì)

21、胞譜系是疾病定義的出發(fā)點(diǎn)B、T或 NK 細(xì)胞每種疾病都是具有臨床和實(shí)驗(yàn)室特征的獨(dú)立實(shí)體形態(tài)學(xué)、免疫表型、遺傳學(xué)特征、臨床表現(xiàn)與病程疾病累及部位常常是重要的生物學(xué)特征性標(biāo)志臨床特征的應(yīng)用是一個(gè)新的方面；診斷的依據(jù)2009年9月更新分類(lèi)WHO病理分類(lèi)原則WHO淋巴組織腫瘤分類(lèi)(2008)B 淋巴母細(xì)胞白血病/淋巴瘤B 淋巴母細(xì)胞白血病/淋巴瘤，NOS B 淋巴母細(xì)胞白血病/淋巴瘤，具有重現(xiàn)性細(xì)胞遺傳學(xué)異常B 淋巴母細(xì)胞白血病/淋巴瘤，具有t(9;22)(q34;q11.2); BCR-ABL1 B 淋巴母細(xì)胞白血病/淋巴瘤，具有t(v;11q23); MLL 重排 B淋巴母細(xì)胞白血病/淋巴瘤，具有

22、t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1) B 淋巴母細(xì)胞白血病/淋巴瘤，具有超二倍體 B 淋巴母細(xì)胞白血病/淋巴瘤，具有亞二倍體(亞二倍體ALL) B 淋巴母細(xì)胞白血病/淋巴瘤，具有t(5;14)(q31;q32); IL3-IGH B 淋巴母細(xì)胞白血病/淋巴瘤，具有t(1;19)(q23;p13.3); E2A-PBX1; (TCF3-PBX1) T淋巴母細(xì)胞白血病/淋巴瘤慢性淋巴細(xì)胞白血病/小淋巴細(xì)胞淋巴瘤 前B細(xì)胞白血病 脾邊緣區(qū)淋巴瘤 毛細(xì)胞白血病 脾淋巴瘤/白血病，未分類(lèi)* 脾彌漫紅髓的小B細(xì)胞淋巴瘤 毛細(xì)胞白血病-變異型 淋巴漿細(xì)胞淋巴瘤華氏

23、巨球蛋白血癥 重鏈病Alpha重鏈病Gamma重鏈病 Mu重鏈病 漿細(xì)胞瘤骨的孤立性漿細(xì)胞瘤 髓外漿細(xì)胞瘤 粘膜相關(guān)淋巴組織結(jié)外邊緣區(qū)淋巴瘤 (MALT淋巴瘤) 結(jié)內(nèi)邊緣區(qū)淋巴瘤 兒童結(jié)內(nèi)邊緣區(qū)淋巴瘤 濾泡性淋巴瘤 兒童濾泡性淋巴瘤 原發(fā)于皮膚的濾泡中心淋巴瘤套細(xì)胞淋巴瘤 彌漫大B細(xì)胞淋巴瘤 (DLBCL)，NOS 富含T/組織細(xì)胞的大B細(xì)胞淋巴瘤 原發(fā)于中樞神經(jīng)系統(tǒng)的DLBCL 原發(fā)于皮膚的DLBCL，腿型 老年性EB病毒陽(yáng)性的DLBCL 與慢性炎癥相關(guān)的DLBCL 淋巴樣肉芽腫病 原發(fā)于縱隔（胸腺）的大B細(xì)胞淋巴瘤血管內(nèi)大B細(xì)胞淋巴瘤 ALK陽(yáng)性的大B細(xì)胞淋巴瘤 漿母細(xì)胞性淋巴瘤 HHV8

24、相關(guān)的大B細(xì)胞淋巴瘤 多 中心Castleman 病 原發(fā)性滲出性淋巴瘤 伯基特淋巴瘤B細(xì)胞淋巴瘤，不能分類(lèi)型,，具有介于彌漫大B細(xì)胞淋巴瘤與伯基特淋巴瘤之間的特征 B細(xì)胞淋巴瘤，不能分類(lèi)型，具有介于彌漫大B細(xì)胞淋巴瘤與典型霍奇金病之間的特征前T細(xì)胞白血病 大顆粒T淋巴細(xì)胞白血病 NK細(xì)胞性慢性淋巴細(xì)胞增殖性疾病 侵襲性NK細(xì)胞白血病 兒童系統(tǒng)性EB病毒陽(yáng)性的T細(xì)胞淋巴增殖性疾病 類(lèi)水痘樣淋巴瘤 成人T細(xì)胞白血病/淋巴瘤 結(jié)外NK/T細(xì)胞淋巴瘤，鼻型 腸道病相關(guān)性T細(xì)胞淋巴瘤 肝脾T細(xì)胞淋巴瘤 皮下脂膜炎樣T細(xì)胞淋巴瘤 蕈樣真菌病 Szary 綜合征原發(fā)于皮膚的CD30陽(yáng)性的T細(xì)胞增殖性疾病

25、淋巴瘤樣丘疹病 原發(fā)于皮膚的間變性大細(xì)胞淋巴瘤原發(fā)于皮膚的 T細(xì)胞淋巴瘤 原發(fā)于皮膚的CD8陽(yáng)性侵襲性嗜表皮的細(xì)胞毒性T細(xì)胞淋巴瘤 原發(fā)于皮膚的CD4陽(yáng)性小/中間T細(xì)胞淋巴瘤 外周T細(xì)胞淋巴瘤，NOS 血管免疫母細(xì)胞性T細(xì)胞淋巴瘤 間變性大細(xì)胞性淋巴瘤，ALK陽(yáng)性間變性大細(xì)胞性淋巴瘤，ALK陰性霍奇金淋巴瘤結(jié)節(jié)淋巴細(xì)胞為主型霍奇金淋巴瘤 典型霍奇金淋巴瘤結(jié)節(jié)硬化型典型霍奇金淋巴瘤 富含淋巴細(xì)胞的典型霍奇金淋巴瘤 混合細(xì)胞性典型霍奇金淋巴瘤 淋巴細(xì)胞消減型典型霍奇金淋巴瘤 移植后淋巴細(xì)胞增殖性疾病 (PTLD)早期損傷漿細(xì)胞增生 感染性單核細(xì)胞增多樣PTLD 多形性 PTLD 單一形態(tài)的 PTL

26、D (B- 及T/NK-細(xì)胞型) #典型霍奇金淋巴瘤型PTLD # 前體細(xì)胞侵襲性B細(xì)胞成熟T/NK細(xì)胞HL和PTLD惰性B細(xì)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將HL分為：結(jié)節(jié)性淋巴細(xì)胞為主型（NLPHL），和經(jīng)典型（CHL）。 病例形態(tài)、免疫表型、分子生物學(xué)、臨床表現(xiàn)和生物行為均有

29、差異。CHL分為：淋巴細(xì)胞為主型（LRHL），結(jié)節(jié)硬化型（NSHL）， 混合細(xì)胞型（MCHL），淋巴細(xì)胞消減型（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將HNL分為：B細(xì)胞、T細(xì)胞和NK T細(xì)胞，以及灰區(qū)NHL。歐美NHL病理分型中國(guó)NHL病理分型Click to edit Master title styleClick to edit Master subtitle style結(jié)外發(fā)病多分期較晚多我國(guó)淋巴瘤的特點(diǎn)HL少濾泡淋巴瘤少發(fā)病少好治的少年輕的少NHL多彌漫型多總數(shù)多難治的多男的多總數(shù)多難治的多男的多T細(xì)胞淋巴瘤占20-30%，遠(yuǎn)多于歐美國(guó)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、療原則） 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-(自體），Allo-（異基因） 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單抗） 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新抗體為基礎(chǔ)的治療: 新的靶標(biāo)靶標(biāo)單克隆抗體CD20Ofatumumab, IMMU-106, Ocrelizumab, GA101, AME-133v, PRO 131921CD22Epratuzumab（依帕珠單抗） CD25Daclizumab（達(dá)珠單抗，anti-Tac） CD30SGN-30 和 MDXO60 CD40SGN-40 和 HCD122 CD52Alemtuzumab（阿侖單抗） CD80Galiximab新靶標(biāo)：小分子靶向藥物Blood, 2011 Feb; 117(5): 1453-62HSCTIndications: First-line: Very aggressive, CR