Lymphoma Zhong Hua Hematological 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 0.84~1.39 /100,000 population (lower than western countries and Japan) 50% at age 20~40 (range from 3m to 82 yrs) Male : Female 1.4~3.7:1 NHL 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 HD HTLV-I: Adult T cell lymphoma H.pylori infection: MALT lymphoma Immunity of host:AIDS, post-transplantation

Classification of lymphoma

Reed-Sternberg cell

Pathological classification(Rye) HD---Reed-Sternberg cell (Hodgkin’s cell) Lymphocyte predominant---localized , good prognosis. Nodular sclerosis---relatively favorable prognosis Mixed cellular---tendency of dissemination, relatively poor prognosis Lymphocyte depleted---poor prognosis

Pathological classification(WHO 2000) HD---Reed-Sternberg cell (Hodgkin’s 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 classification REAL classification WHO 2000

NCI Working Formulation Low Grade Small Lymphocytic Follicular, small cleaved cell Follicular, mixed small cleaved and large cell Intermediate 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+,CD79α+ T-cell Lymphoma: TDT+, CD3+,CD5+

WHO 2000: NHL B-cell Neoplasms Precursor B-cell Neoplasms 1. Precursor B-lymphoblastic leukemia/lymphoma Mature 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.Burkitt’s lymphoma

WHO 2000: NHL T-cell Neoplasms Precursor T-cell Neoplasms 1. Precursor T-lymphoblastic leukemia/lymphoma Mature 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 infection Follicular 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 lymphoma Burkitt lymphoma: CD20+, CD22+, CD5-, t(8,14) Angio-immunoblastic T-cell lymphoma Cutaneous T-cell Lymphoma: mycosis fungoides/Sezary syndrome, CD3+, CD4+, CD8 - Peripheral T –cell lymphoma Adult T-cell lymphoma Anaplastic large cell lymphoma:RS cell,CD30 +, t(2,5)

Clinical Manifestations Related to the pathological changes Painless lymphadenopathy: cervical, supraclavicular, axillary Symptoms due to lymphadenopathy---cough , dyspnea, superior vena cava syndrome Fever : persistent or periodic (Pel-Ebstein fever), especially in HD

Clinical Manifestations Related to the pathological changes Night sweating Weight loss(10% in 6m) Splenomegaly Hepatomegaly

Clinical Manifestations NHL Enlargement of cervical lymphnodes Enlargement of supraclavicular lymphnodes Involve the oropharyngeal lymphoid tissue (Waldeyer ring) Fever, weight loss, night sweating

Clinical Manifestations Extra nodal infiltration: more common in NHL GI tract infiltration: small intestine( ileum), stomach, ect Hepatomegaly, splenomegaly, pulmonary infiltration,pleural effusion,CNS BM infiltration Skin infiltration Pulmonary infiltration, pleural effusion Kidney involvement CNS involvement

Clinical Manifestations Age Painless LN Way of Extra Nodal Enlargement Spreading Involvement HD young first symptom origin less common adjacent NHL more similar, jumping more common older less common

Laboratory Findings Diagnosis depends on biopsy of lymph nodes or other involved organs Peripheral blood: slight anemia , usually no changes in WBC and Platelet count BM: non-specific changes HD: R-S cell in smear and biopsy NHL: increased lymphocyte

Laboratory Findings Immunological test: Other findings: HD: deficiency of cellular immunity; NHL: M-protein(+) Coombs’ test(+) hypoglobulinemia Other findings: ESR ↑ AKP ↑ LDH ↑

Laboratory Findings Chromosome changes in NHL: t(14;18): Follicular lymphoma t(8;14): Burkitt’s 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 features Ultrasound Chest-x-ray film: the mediastinal lymphonodes Computerized tomography(CT) Chest Abdomen, Pelvis Gallium-67 scintigraphy Whole-body positron emission tomography(PET)

Diagnosis Biopsy----Pathological Diagnosis Histopathological classification Immunomarkers 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 tumors Malignacies 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(ⅠE)

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(ⅡE)

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 A Without general symptoms Group B With general symptoms unexplained fever , >38C, lasting over 3 days night sweating weight loss, >10% of body weight within 6 months

Staging Procedures Symptoms and signs X-ray film (chest, ect) and Ultrasound CT---chest and abdomen Laboratory study BM smear and biopsy Staging laparotomy

Treatment Principles Pathological classification Clinical Staging Peripheral blood ,bone marrow Function of important organs General condition of patient

Treatment Methods Surgery Radiation Chemotherapy Biotherapy PBSCT

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 Protocol Nitrogen Mustard 4mg/m2 v day 1 , 8 VCR 1.4mg/m2 v day 1,8 Procarbazine 70mg/m2 p.o. day1 -14 Prednisone 40mg/m2 p.o. day1 - 14

Treatment----HD Chemotherapy: ABVD Protocol Adriamycin 25mg/m2 v day 1, 15 Bleomycin 10mg/m2 v day 1, 15 VCR 1.4mg/m2 v day 1, 15 Dacarbazine 375mg/m2 v day 1, 15

Treatment of NHL Low Grade Group Frequently follow up, postpone chemotherapy Single drug :CB1348 (Leukeran) 2mg b.i.d ~t.i.d cyclophosphamide: 100mg/d Disease progressing ----combined chemotherapy Fludarabin Pentostatine CD20(Rituximab)

Treatment of NHL Intermediate and High Grade Group Combined Chemotherapy Radiation if needed

Treatment of NHL Chemotherapy: CHOP Protocol CTX 750mg/m2 v. day 1 ADR 50mg/m2 v. day 1 VCR 1.4mg/m2 v. day 1 Prednisone 100mg/m2 p.o. day 1-5 Duration of cycle 14 - 21 days or 21 --28 days OR 80-90%; CR 50-60%; Curative <40%

Treatment of NHL Other protocols COP m-BACOB COP-BLAM ESHAP: relapse lymphoma

Treatment of NHL Surgery Post-operation chemotherapy Localized focus (IA) Single lymph node involvement Single GI tract focus Post-operation chemotherapy

Treatment of NHL Biotherapy: Interferon : 3-5 million unit/d partial response improvement of 5-year DFS

Treatment of NHL Biotherapy: Interferon：glucoprotein Interferon : leukocytic Interferon Interferon β： fibroblastic Interferon Interferon υ： Lymphocytic Interferon

Treatment of NHL Biotherapy: The mechanisms of Interferon Anti-virus Killing tumor cells induced teminal differentiation of tumor cells Activation other cytokines

Treatment of NHL Biotherapy: Application of Interferon ： Early and low grade lymphoma，OR 40~60％ T cell lymphoma Combined with other chemotherapy Maintained treatment

Treatment of NHL Biotherapy: Interferon dosage Course Efficiency 5MU/m2，muscle or hypodemic ，t.I.w 3MU/m2， muscle or hypodemic , q.d Course One year Efficiency Primary patients， OR75％ Intermediate grade，OR10～15％ Extend DFS

Treatment of NHL Biotherapy: Antibody----CD20 (Rituximab) NEW!

Treatment of NHL Biotherapy: －－ Antibody Rituximab specific binding with B-cell antigen CD20 Cleaning tumor cells hemopoietic stem cell, progenitor cell, plasma cell and other normal tissue are not express CD20 Safety and efficiency monoclonal antibody

Clinical application of Rituximab Combined with CHOP treatment of NHL Maintained 3 M X4 times Rituximab 375mg/m2 week 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 CHOP courses

Rituximab Mechanisms of Action NHL allg.01 additional effects: induction of apoptosis restoration of chemosensitivity in resistant cells Ritux allg.01

Mechanisms of action of monoclonal antibodies NK, Mo PMN Antibody-dependent cellular cytotoxicity Synergy CR3 FcgR Complement-dependent cytotoxicity IL-10 Proliferation block – iC3b C1q STAT3 Classical pathway CD55 bcl-2 CD59 Apoptosis

Treatment of NHL Peripheral Blood Stem Cell Transplantation (PBSCT) HD stage Ⅲ,Ⅳ NHL stage Ⅲ,Ⅳ

International prognostic index IPI (NHL) Age: <60 vs >60 years Tumor stage: Stage Ⅰor Ⅱ vs Stage Ⅲ or Ⅳ(advanced) Performance status: 0 or 1 vs 2 Serum LDH: < normal vs > normal Extranodal sites: <1 vs > 1

IPI: Definition of Risk Group 0 or 1 Low risk 2 Low-intermediate risk 3 High-intermediate risk 4 High risk

International prognostic index IPI (HD) Relative Risk Male: 1.35 Age: ≥45-year 1.28 Stage: Ⅳ 1.39 Albumin: <40g/L 1.49 Hb: <105g/L 1.35 WBC: ≥15x109/L 1.41 Lymphocytes: <600/ul 1.38

Conclusion Pathological classification: HD or NHL Clinical Manifestations: HD or NHL Diagnosis; Clinical staging; Ann Arbor Treatment: HD and NHL