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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.

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slide1

Lymphoma

Zhong Hua

Hematological Dept. Renji Hospital

lymphoma malignant lymphoma
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
Categories according to histopathology
  • Hodgkin Disease (HD)
  • Non-Hodgkin Lymphoma (NHL)
incidence
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
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
pathological classification rye
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
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
NHL Classification
  • Rappaport classification
  • Working Formulation(1982)
  • Kiel classification
  • REAL classification
  • WHO 2000
nci working formulation
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
Immunophenotype
  • B-cell Lymphoma: CD20+,CD79α+
  • T-cell Lymphoma: TDT+, CD3+,CD5+
who 2000 nhl b cell neoplasms
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
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
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
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 manifestations17
Clinical Manifestations

Related to the pathological changes

  • Night sweating
  • Weight loss(10% in 6m)
  • Splenomegaly
  • Hepatomegaly
clinical manifestations18
Clinical Manifestations
  • NHL
    • Enlargement of cervical lymphnodes
    • Enlargement of supraclavicular lymphnodes
    • Involve the oropharyngeal lymphoid tissue

(Waldeyer ring)

    • Fever, weight loss, night sweating
clinical manifestations20
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 manifestations21
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
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 findings23
Laboratory Findings
  • Immunological test:
    • HD: deficiency of cellular immunity;
    • NHL: M-protein(+)

Coombs’ test(+)

hypoglobulinemia

  • Other findings:
    • ESR ↑
    • AKP ↑
    • LDH ↑
laboratory findings24
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 findings25
Laboratory Findings
  • Molecular Biology changes in NHL
    • bcl-2
    • TCR
    • IgH
laboratory findings26
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
Diagnosis
  • Biopsy----Pathological Diagnosis
  • Histopathological classification
  • Immunomarkers

eg: NHL, diffused large cell, B cell

differential diagnosis
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 diagnosis35
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
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
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 197138
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 197139
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
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
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
Treatment

Principles

  • Pathological classification
  • Clinical Staging
  • Peripheral blood ,bone marrow
  • Function of important organs
  • General condition of patient
treatment44
Treatment

Methods

  • Surgery
  • Radiation
  • Chemotherapy
  • Biotherapy
  • PBSCT
treatment of hd
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 hd46
Treatment of HD
  • Radiation

dosage: involved field---- 40-44Gy

uninvolved field(prophylactic)

30-35Gy

treatment of hd48
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
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
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 nhl51
Treatment of NHL
  • Intermediate and High Grade Group

Combined Chemotherapy

Radiation if needed

treatment of nhl52
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 nhl53
Treatment of NHL
  • Other protocols
    • COP
    • m-BACOB
    • COP-BLAM
    • ESHAP: relapse lymphoma
treatment of nhl54
Treatment of NHL
  • Surgery
    • Localized focus (IA)
    • Single lymph node involvement
    • Single GI tract focus

Post-operation chemotherapy

treatment of nhl55
Treatment of NHL
  • Biotherapy:

Interferon : 3-5 million unit/d

partial response

improvement of 5-year DFS

treatment of nhl56
Treatment of NHL
  • Biotherapy:
  • Interferon:glucoprotein
    • Interferon : leukocytic Interferon
    • Interferon β: fibroblastic Interferon
    • Interferon υ: Lymphocytic Interferon
treatment of nhl57
Treatment of NHL
  • Biotherapy:
  • The mechanisms of Interferon
    • Anti-virus
    • Killing tumor cells
    • induced teminal differentiation of tumor cells
    • Activation other cytokines
treatment of nhl58
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 nhl59
Treatment of NHL

Biotherapy: Interferon

  • dosage
    • 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 nhl60
Treatment of NHL
  • Biotherapy:

Antibody----CD20

(Rituximab)

NEW!

treatment of nhl61
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
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

slide63

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
Mechanisms of action of monoclonal antibodies

NK, MoPMN

Antibody-dependent

cellular cytotoxicity

Synergy

CR3

FcgR

Complement-dependent

cytotoxicity

IL-10

iC3b

Proliferation

block

C1q

STAT3

Classical

pathway

CD55

bcl-2

CD59

Apoptosis

treatment of nhl65
Treatment of NHL

Peripheral Blood Stem Cell Transplantation

(PBSCT)

HD stage Ⅲ,Ⅳ

NHL stage Ⅲ,Ⅳ

international prognostic index ipi nhl
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
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
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
Conclusion
  • Pathological classification: HD or NHL
  • Clinical Manifestations: HD or NHL
  • Diagnosis;
  • Clinical staging; Ann Arbor
  • Treatment: HD and NHL