1. Lymphoma
Zhong Hua
Hematological Dept. Renji Hospital

2. 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

3. Categories according to histopathology
Hodgkin Disease (HD)
Non-Hodgkin Lymphoma (NHL)

4. 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)

5. 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

6. Classification of lymphoma

7. Reed-Sternberg cell

8. 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

9. 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%

10. NHL Classification Rappaport classification Working Formulation(1982)
Kiel classification
REAL classification
WHO 2000

11. 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)

12. Immunophenotype B-cell Lymphoma: CD20+,CD79α+
T-cell Lymphoma: TDT+, CD3+,CD5+

13. 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

14. 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

15. 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)

16. 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

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

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

20. 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

21. 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

22. 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

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

24. 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

25. Laboratory Findings
Molecular Biology changes in NHL
bcl-2
TCR
IgH

26. 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)

33. Diagnosis Biopsy----Pathological Diagnosis
Histopathological classification
Immunomarkers
eg: NHL, diffused large cell, B cell

34. Differential Diagnosis
Lymph nodes enlargement
Specific: TB
Infection
Non-specific: bacteria, virus, fungi, ect
Maligancies: hematological (leukemia,ect); solid tumor metastasis
Connective tissue diseases

35. Differential Diagnosis
Fever
Infection ( bacteria , virus, TB, ect )
Connective tissue disease
Malignant tumors
Malignacies in related organs
Gastrointestinal tumors, liver cancer, ect

36. Clinical Staging (Ann Arbor 1966)
Stage I
Involvement of a single lymph node region or of a single extranodal organ or site(ⅠE)

37. 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)

38. 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).

39. Clinical Staging (Ann Arbor 1971)
Stage IV:
Diffused or disseminated involvement of one or more extranodal organs, with or without associated lymph node enlargement.

41. 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

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

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

44. Treatment
Methods
Surgery
Radiation
Chemotherapy
Biotherapy
PBSCT

45. Treatment of HD Stage IA 、IIA
Extended radiation(mantle form or inverted Y form)
Stage IB、IIB、IIIA、IIIB、IV
Combined chemotherapy+localized radiation

46. Treatment of HD Radiation dosage: involved field---- 40-44Gy
uninvolved field(prophylactic)
30-35Gy

48. Treatment of HD Chemotherapy: MOPP Protocol
Nitrogen Mustard 4mg/m2 v day 1 , 8
VCR mg/m2 v day 1,8
Procarbazine mg/m2 p.o. day1 -14
Prednisone mg/m2 p.o. day1 - 14

49. Treatment----HD Chemotherapy: ABVD Protocol
Adriamycin mg/m2 v day 1, 15
Bleomycin mg/m2 v day 1, 15
VCR mg/m2 v day 1, 15
Dacarbazine mg/m2 v day 1, 15

50. 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)

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

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

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

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

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

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

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

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

59. 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

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

61. 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

62. Clinical application of Rituximab
Combined with CHOP treatment of NHL
Maintained 3 M X4 times
Rituximab 375mg/m2
week
CHOP courses

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

64. 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

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

66. 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

67. IPI: Definition of Risk Group
0 or Low risk
Low-intermediate risk
High-intermediate risk
High risk

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

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