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,Lymphoma,Zhong HuaHematological Dept. Renji Hospital,Lymphoma (malignant Lymphoma),A group of malignant tumors originated from lymph nodes or other lymphatic tissues(tonsil, spleen, bone marrow , ect)Malignant tumors of immune system,Categories according to histopathology,Hodgkin Disease (HD) Non-Hodgkin Lymphoma (NHL),Incidence,0.841.39 /100,000 population (lower than western countries and Japan)50% at age 2040 (range from 3m to 82 yrs)Male : Female 1.43.7:1NHL 90%HD 10% (more frequent in western countries),Etiology,Unclear: virus? H.pylori? Immune system deficient? Epstein-Barr(EB) virus: Burkitt lymphoma; High titer of Anti EB virus antibody in HDHTLV-I: Adult T cell lymphomaH.pylori infection: MALT lymphoma Immunity of host:AIDS, post-transplantation,Classification of lymphoma,Reed-Sternberg cell,Pathological classification(Rye),HD-Reed-Sternberg cell (Hodgkins cell)Lymphocyte predominant-localized , good prognosis.Nodular sclerosis-relatively favorable prognosisMixed cellular-tendency of dissemination, relatively poor prognosis Lymphocyte depleted-poor prognosis,Pathological classification(WHO 2000),HD-Reed-Sternberg cell (Hodgkins cell)Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL):localized , good prognosis; 5%Classical Hodgkin lymphoma;Lymphocyte rich classical Hodgkin lymphoma: localized , good prognosis; 5%Nodular sclerosis: young,stage I or II , relatively favorable prognosis; 55%Mixed cellular:tendency of dissemination, relatively poor prognosis; 25%Lymphocyte depleted: old, stage III or IV,poor prognosis; 5%,NHL Classification,Rappaport classification Working Formulation(1982)Kiel classificationREAL classificationWHO 2000,NCI Working Formulation,Low Grade Small Lymphocytic Follicular, small cleaved cell Follicular, mixed small cleaved and large cellIntermediate Grade Follicular, large cell Diffuse, small cleaved cell Diffuse, mixed small cleaved and large cell Diffuse, large cell(cleaved and non-cleaved)High Grade Large cell immunoblastic Lymphoblastic Small non-cleaved cell(Burkitt or non-Burkitt),Immunophenotype,B-cell Lymphoma: CD20+,CD79+ T-cell Lymphoma: TDT+, CD3+,CD5+,WHO 2000: NHL B-cell Neoplasms,Precursor B-cell Neoplasms 1. Precursor B-lymphoblastic leukemia/lymphomaMature B-cell Neoplasms 2.B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma 3.B-cell prolymphocytic leukemia 4.Lymphoplasmacytic lymphoma 5.Splenic marginal zone B-cell lymphoma (villous lymphocytes) 6.Hairy cell leukemia 7.Plasma cell myeloma/plasmacytoma 8.Extranodal marginal zone B-cell lymphoma of MALT type 9.Nodal marginal zone B-cell lymphoma (monocytoid B cells) 10. Follicular lymphoma 11.Mantle-cell lymphoma 12.Diffuse large B-cell lymphoma 13.Primary effusion lymphoma 14.Burkitts lymphoma,WHO 2000: NHL T-cell Neoplasms,Precursor T-cell Neoplasms 1. Precursor T-lymphoblastic leukemia/lymphomaMature T-cell Neoplasms 2.T-cell prolymphocytic leukemia 3.T-cell granular lymphocytic leukemia 4.Aggressive NK-cell leukemia 5.Adult T-cell leukemia/lymphoma (HTLV-1) 6.Extranodal NK/T-cell lymphoma, nasal type 7.Enteropathy-type T-cell lymphoma 8.Hepatosplenic gamma-delta T-cell lymphoma 9.Subcutaneous panniculitis-like T-cell lymphoma 10. Mycosis fungoides/Sezary syndrome 11.Anaplastic large-cell lymphoma, T/null cell, primary cutaneous type 12. Anaplastic large-cell lymphoma, T/null cell, primary systemic type 13.Peripheral T-cell lymphoma, not otherwise characterized 14.Angioimmunoblastic T-cell lymphoma,Common Kinds of NHL in WHO 2001,Marginal Zone Lymphoma:CD5+,BCL-2+,indolent lymphoma MALT Lymphoma: t(11,18), H.pylori infectionFollicular lymphoma: CD5+,BCL-2+ , t(14,18)Diffusse large B cell lymphoma: BCL-2+ , t(3,14) Mantle cell Lymphoma: CD5+, t(11,14) ,BCL-2+, invasive lymphomaBurkitt lymphoma: CD20+, CD22+, CD5-, t(8,14) Angio-immunoblastic T-cell lymphomaCutaneous T-cell Lymphoma: mycosis fungoides/Sezary syndrome, CD3+, CD4+, CD8 - Peripheral T cell lymphoma Adult T-cell lymphomaAnaplastic large cell lymphoma:RS cell,CD30 +, t(2,5),Clinical Manifestations,Related to the pathological changesPainless lymphadenopathy: cervical, supraclavicular, axillarySymptoms due to lymphadenopathy-cough , dyspnea, superior vena cava syndromeFever : persistent or periodic (Pel-Ebstein fever), especially in HD,Clinical Manifestations,Related to the pathological changesNight sweatingWeight loss(10% in 6m)SplenomegalyHepatomegaly,Clinical Manifestations,NHLEnlargement of cervical lymphnodes Enlargement of supraclavicular lymphnodesInvolve the oropharyngeal lymphoid tissue (Waldeyer ring)Fever, weight loss, night sweating,Clinical Manifestations,Extra nodal infiltration: more common in NHLGI tract infiltration: small intestine( ileum), stomach, ectHepatomegaly, splenomegaly, pulmonary infiltration,pleural effusion,CNSBM infiltrationSkin infiltrationPulmonary infiltration, pleural effusionKidney involvementCNS involvement,Clinical Manifestations,Age Painless LN Way of Extra Nodal Enlargement Spreading InvolvementHDyoung first symptom origin less common adjacentNHL more similar, jumping more commonolder less common,Laboratory Findings,Diagnosis depends on biopsy of lymph nodes or other involved organsPeripheral blood: slight anemia , usually no changes in WBC and Platelet countBM: non-specific changesHD: R-S cell in smear and biopsyNHL: increased lymphocyte,Laboratory Findings,Immunological test: HD: deficiency of cellular immunity; NHL: M-protein(+) Coombs test(+) hypoglobulinemiaOther findings: ESR AKP LDH ,Laboratory Findings,Chromosome changes in NHL: t(14;18): Follicular lymphoma t(8;14): Burkitts lymphoma t(11;14): Mantle-cell lymphoma t(2;5): Ki-1+(CD30 +) Anaplastic large- cell lymphoma 3q27: Diffuse large B-cell lymphoma,Laboratory Findings,Molecular Biology changes in NHL bcl-2 TCR IgH,Laboratory Findings,Radiographic featuresUltrasoundChest-x-ray film: the mediastinal lymphonodesComputerized tomography(CT)ChestAbdomen, PelvisGallium-67 scintigraphyWhole-body positron emission tomography(PET),Diagnosis,Biopsy-Pathological DiagnosisHistopathological classificationImmunomarkers eg: NHL, diffused large cell, B cell,Differential Diagnosis,Lymph nodes enlargement Specific: TB Infection Non-specific: bacteria, virus, fungi, ect Maligancies: hematological (leukemia,ect); solid tumor metastasis Connective tissue diseases,Differential Diagnosis,Fever Infection ( bacteria , virus, TB, ect ) Connective tissue disease Malignant tumorsMalignacies in related organs Gastrointestinal tumors, liver cancer, ect,Clinical Staging (Ann Arbor 1966),Stage I Involvement of a single lymph node region or of a single extranodal organ or site(E),Clinical Staging (Ann Arbor 1971),Stage II: two or more lymph node regions on the same side of the diaphragm localized extranodal organ and one or more lymph node regions on the same side of the diaphragm(E),Clinical Staging (Ann Arbor 1971),Stage III lymph node regions on both sides of the diaphragm or with localized extranodal organ (III E) or spleen (IIIs)or both (III ES).,Clinical Staging (Ann Arbor 1971),Stage IV: Diffused or disseminated involvement of one or more extranodal organs, with or without associated lymph node enlargement.,Clinical Staging-Subtype,Group AWithout general symptoms Group BWith general symptomsunexplained fever , 38C, lasting over 3 daysnight sweating weight loss, 10% of body weight within 6 months,Staging Procedures,Symptoms and signs X-ray film (chest, ect) and UltrasoundCT-chest and abdomenLaboratory studyBM smear and biopsyStaging laparotomy,Treatment,Principles Pathological classificationClinical StagingPeripheral blood ,bone marrowFunction of important organs General condition of patient,Treatment,MethodsSurgeryRadiationChemotherapyBiotherapyPBSCT,Treatment of HD,Stage IA 、IIA Extended radiation(mantle form or inverted Y form) Stage IB、IIB、IIIA、IIIB、IV Combined chemotherapy+localized radiation,Treatment of HD,Radiation dosage: involved field- 40-44Gy uninvolved field(prophylactic) 30-35Gy,Treatment of HD,Chemotherapy: MOPP ProtocolNitrogen Mustard 4mg/m2 v day 1 , 8VCR 1.4mg/m2 v day 1,8Procarbazine 70mg/m2 p.o. day1 -14Prednisone 40mg/m2 p.o. day1 - 14,Treatment-HD,Chemotherapy: ABVD ProtocolAdriamycin 25mg/m2 v day 1, 15Bleomycin 10mg/m2 v day 1, 15VCR 1.4mg/m2 v day 1, 15Dacarbazine 375mg/m2 v day 1, 15,Treatment of NHL,Low Grade GroupFrequently follow up, postpone chemotherapySingle drug :CB1348 (Leukeran) 2mg b.i.d t.i.d cyclophosphamide: 100mg/dDisease progressing -combined chemotherapyFludarabinPentostatineCD20(Rituximab),Treatment of NHL,Intermediate and High Grade Group Combined Chemotherapy Radiation if needed,Treatment of NHL,Chemotherapy: CHOP ProtocolCTX 750mg/m2v. day 1ADR 50mg/m2v. day 1VCR 1.4mg/m2v. day 1Prednisone 100mg/m2p.o. day 1-5Duration of cycle 14 - 21 days or 21 -28 daysOR 80-90%; CR 50-60%; Curative 40%,Treatment of NHL,Other protocolsCOPm-BACOBCOP-BLAM ESHAP: relapse lymphoma,Treatment of NHL,SurgeryLocalized focus (IA)Single lymph node involvementSingle GI tract focusPost-operation chemotherapy,Treatment of NHL,Biotherapy: Interferon : 3-5 million unit/d partial response improvement of 5-year DFS,Treatment of NHL,Biotherapy: Interferon：glucoproteinInterferon : leukocytic Interferon Interferon ： fibroblastic InterferonInterferon ： Lymphocytic Interferon,Treatment of NHL,Biotherapy:The mechanisms of InterferonAnti-virusKilling tumor cellsinduced teminal differentiation of tumor cells Activation other cytokines,Treatment of NHL,Biotherapy:Application of Interferon ：Early and low grade lymphoma，OR 4060T cell lymphomaCombined with other chemotherapyMaintained treatment,Treatment of NHL,Biotherapy: Interferondosage5MU/m2，muscle or hypodemic ，t.I.w3MU/m2， muscle or hypodemic , q.dCourseOne yearEfficiencyPrimary patients， OR75Intermediate grade，OR1015Extend DFS,Treatment of NHL,Biotherapy: Antibody-CD20 (Rituximab),NEW!,Treatment of NHL,Biotherapy: AntibodyRituximab specific binding with B-cell antigen CD20Cleaning tumor cells hemopoietic stem cell, progenitor cell, plasma cell and other normal tissue are not express CD20Safety and efficiency monoclonal antibody,Clinical application of Rituximab,Combined with CHOP treatment of NHL,week,1 2 3 4 5 6 7 8 9 10 11 12 13 14