Transcript Lymphoms (maliganant Lymphomas)

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;
1.
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%
2.
3.
4.
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
Lymphoma: CD20+,CD79α+
 T-cell Lymphoma: TDT+, CD3+,CD5+
 B-cell
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
1.

2.
3.
4.
5.
6.
7.
8.

9.
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
HD
Age
Painless LN
Enlargement
Way of
Spreading
Extra Nodal
Involvement
young
first symptom
origin
adjacent
less common
similar,
less common
jumping
more common
NHL more
older
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:
– 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
 Histopathological
Diagnosis
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
Procarbazine
70mg/m2 p.o. day1 -14
Prednisone
40mg/m2 p.o. day1 - 14
day 1,8
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
– 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
– 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)
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
Rituximab
375mg/m2
Maintained 3 M
X4 times
week
1
2
3
4
5
6
7
8
9
10 11 12
CHOP courses
13 14 15 16 17 18 19
20 21 22
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
IL-10
Proliferation
block
iC3b
–
Complement-dependent
cytotoxicity
C1q
STAT3
bcl-2
CD55
CD59
Apoptosis
Classical
pathway
Treatment of NHL
Peripheral Blood Stem Cell Transplantation
(PBSCT)
HD
stage Ⅲ,Ⅳ
NHL
stage Ⅲ,Ⅳ
International prognostic index IPI (NHL)





Age:
Tumor stage:
<60 vs >60 years
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
2
3
4
Low risk
Low-intermediate risk
High-intermediate risk
High risk
International prognostic index IPI (HD)







Male:
Age: ≥45-year
Stage: Ⅳ
Albumin: <40g/L
Hb: <105g/L
WBC: ≥15x109/L
Lymphocytes: <600/ul
Relative Risk
1.35
1.28
1.39
1.49
1.35
1.41
1.38
Conclusion
Pathological classification: HD or NHL
 Clinical Manifestations: HD or NHL
 Diagnosis;
 Clinical staging; Ann Arbor
 Treatment: HD and NHL
