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癌症診療準則與核心測量 -淋巴瘤
彰化基督教醫院 內科部血液腫瘤科
張正雄
Agenda
• Lymphocyte differentiation
• Classification of lymphomas
• Disease definitions and symptoms
• Tests that identify specific lymphoid histologies
• Staging
• Cancer registry
• Treatment and prognosis
• Summary
Lymphocyte differentiation
3
Regenerative Medicine, 2006.4
Image A provided courtesy of Stefano A. Pileri, MD Image B: Copyright © 2005 Massachusetts Medical Society. All rights reserved. Chiorazzi N, et al. N Engl J Med. 2005;352:804-815.
B Antigen-Induced B-Cell Maturation
Immature/transitionalB cell
Marginal-zoneB cell Follicular
B cell
T-cell-independentantigen T-cell-dependent
antigen
Outsidegerminal center
Notobligatory
Insidegerminal center
Obligatory
V-gene mutation
Plasma cell Memory cell Plasma cell Memory cell
With or without V-gene mutations V-gene mutations
B-cell Differentiation
B‐cell Differentiation
6
T‐cell Differentiation
7
Major Types of B‐Cell Lymphoma
B-CLL
Mantlecell NHL
B-ALLsubtypes Myeloma
B-CLL
Large B lymphoma
Burkitt
Follicularcenter cells
Smallcleaved
ImmunoblasticIndolent
Aggressive or “high grade”Indolent or“low grade”
Lymphoplasmacytic NHL
Marginal zone NHL
Classification of lymphomas
9
Historical Classification Systems for Non‐Hodgkin Lymphoma
• Working Formulation • Low grade
∙ A. Small lymphocytic, consistent with chronic lymphocytic leukemia ∙ B. Follicular, predominantly small‐cleaved cell ∙ C. Follicular, mixed small‐cleaved, and large cell
• Intermediate grade∙ D. Follicular, predominantly large cell ∙ E. Diffuse, small‐cleaved cell ∙ F. Diffuse mixed, small and large cell ∙ G. Diffuse, large cell, cleaved, or noncleaved cell
• High grade∙ H. Immunoblastic, large cell ∙ I. Lymphoblastic, convoluted, or nonconvoluted cell ∙ J. Small noncleaved‐cell, Burkitt, or non‐Burkitt
• Rappaport Classification
∙Diffuse lymphocytic, well‐differentiated
∙Nodular lymphocytic, poorly differentiated
∙Nodular mixed, lymphocytic, and histiocytic
∙Nodular histiocytic ∙Diffuse lymphocytic, poorly differentiated∙Diffuse mixed, lymphocytic, and histiocytic∙Diffuse histiocytic
∙Diffuse histiocytic ∙Diffuse lymphoblastic ∙Diffuse undifferentiated Burkitt or non‐
Burkitt
Classification of Tumors
2008 –WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, 4th edition, October 2008
11
2008 WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues
Basic principle: Classification for all neoplasms based on:
• Morphology and biologic features
• Genetic• Immunophenotype
• Clinical features
12
2008 WHO Classification ‐ Lymphoid
• Precursor Lymphoid Neoplasms• Mature B‐Cell Neoplasms
• Mature T‐Cell and NK‐Cell Neoplasms
• Hodgkin Lymphoma
• Histiocytic and Dendritic Cell Neoplasms
• Post‐Transplant Lymphoproliferative Disorders
13
Precursor Lymphoid Neoplasms
14
Table B7: Precursor Lymphoid Neoplasms
WHO Preferred Term ICD-O-3
B lymphoblastic leukemia/lymphoma No Code
B lymphoblastic leukemia/lymphoma with hyperdiploidy 9815/3
B lymphoblastic leukemia/lymphoma with hypodiploidy (hypodiploid ALL) 9816/3
B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities No Code
B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); E2A-PBX1 (TCF3-PBX1) 9818/3
B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1) 9814/3
B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32); IL3-IGH 9817/3
B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2); BCR-ABL1 9812/3
B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged 9813/3
B lymphoblastic leukemia/lymphoma, NOS 9811/3
T lymphoblastic leukemia/lymphoma 9837/3
Mature B‐Cell Neoplasms – part I
15
Table B8: Mature B-Cell Neoplasms
WHO Preferred Term ICD-O-3
ALK positive large B-cell lymphoma 9737/3
B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma
9596/3
B-cell prolymphocytic leukemia 9833/3
Burkitt lymphoma 9687/3
Chronic lymphocytic leukemia/small lymphocytic lymphoma 9823/3
Diffuse large B-cell lymphoma (DLBCL), NOS 9680/3
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
9699/3
Extraosseous plasmacytoma 9734/3
Follicular lymphoma 9690/3
Hairy cell leukemia 9940/3
Heavy chain disease 9762/3
Intravascular large B-cell lymphoma 9712/3
Mature B‐Cell Neoplasms – part II
16
WHO Preferred Term ICD-O-3
Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease
9738/3
Lymphomatoid granulomatosis 9766/1
Lymphoplasmacytic lymphoma 9671/3
Mantle cell lymphoma 9673/3
Plasma cell myeloma 9732/3
Plasmablastic lymphoma 9735/3
Primary cutaneous follicle centre lymphoma 9597/3
Primary effusion lymphoma 9678/3
Primary mediastinal (thymic) large B-cell lymphoma 9679/3
Solitary plasmacytoma of bone 9731/3
Splenic B-cell lymphoma/leukemia, unclassifiable 9591/3
Splenic marginal zone lymphoma 9689/3
T-cell/histiocyte rich large B-cell lymphoma 9688/3
Mature T‐Cell and NK‐Cell Neoplasms
17
Table B9: Mature T-Cell and NK-Cell NeoplasmWHO Preferred Term ICD-O-3
Adult T-cell leukemia/lymphoma 9827/3
Aggressive NK-cell leukemia 9948/3
Anaplastic large cell lymphoma, ALK positive 9714/3
Angioimmunoblastic T-cell lymphoma 9705/3
Chronic lymphoproliferative disorder of NK-cells 9831/3
Enteropathy-associated T-cell lymphoma 9717/3
Extranodal NK/T cell lymphoma, nasal type 9719/3
Hepatosplenic T-cell lymphoma 9716/3
Hydroa vacciniforme-like lymphoma 9725/3
Lymphoimatoid papulosis 9718/3
Mycosis fungoides 9700/3
Peripheral T-cell lymphoma, NOS 9702/3
Primary cutaneous anaplastic large cell lymphoma 9718/3
Primary cutaneous CD30 positive T-cell lymphoproliferative disorders No Code
Primary cutaneous CD4 positive small/medium cell T-cell lymphoma 9709/3
Primary cutaneous gamma-delta T-cell lymphoma 9726/3
Sezary syndrome 9701/3
Subcutaneous panniculitis-like T-cell lymphoma 9708/3
Systemic EBV positive T-cell lymphoproliferative disease of childhood 9724/3
T-cell prolymphocytic leukemia 9834/3
Hodgkin Lymphoma
18
Table B10: Hodgkin Lymphoma
WHO Preferred Term ICD-O-3
Classical Hodgkin lymphoma 9650/3
Lymphocyte-depleted classical Hodgkin lymphoma 9653/3
Lymphocyte-rich classical Hodgkin lymphoma 9651/3
Mixed cellularity classical Hodgkin lymphoma 9652/3
Nodular lymphocyte predominant Hodgkin lymphoma 9659/3
Nodular sclerosis classical Hodgkin lymphoma 9663/3
Histiocytic Cell and Dendritic Cell Neoplasms
19
Table B11: Histiocytic and Dendritic Cell Neoplasm
WHO Preferred Term ICD-O-3
Disseminated juvenile xsanthogranuloma No Code
Fibroblastic reticular cell tumor 9759/3
Follicular dendritic cell sarcoma 9758/3
Histiocytic sarcoma 9755/3
Indeterminate dendritic cell tumor 9757/3
Langerhans cell histiocytosis 9751/3
Langerhans cell sarcoma 9756/3
Histiocytic Cell Neoplasms
20
Table 14.01 True histiocytic malignancy, a vanishing diagnosis.
Original diagnosis Currently considered
Histiocytic lymphoma, nodular and diffuse Diffuse large B‐cell lymphomaFollicular lymphoma, grade 3Peripheral T‐cell lymphomaHistiocyte‐rich variants of B‐cell, T‐cell, and Hodgkin lymphomaAnaplastic large cell lymphoma
Histiocytic medulary reticulosis Haemophagocytic syndromes
Malignant histiocytosis ALCLHaemophagocytic syndromes
Regressing atypical histiocytosis Primary cutaneous CD30‐positive T‐cell lymphoma
Intestinal malignant histiocytosis Enteropathy‐type T‐cell lymphoma
Histiocytic cytopathic panniculitis Subcutaneous panniculitis‐like T‐cell lymphoma with Haemophagocytosis
Post‐Transplant Lymphoproliferative Disorders
21
Table B12: Post-Transplant Lymphoproliferative Disorders (PTLD)
WHO Preferred Term ICD-O-3
Early lesions No Code
Classical Hodgkin lymphoma type PTLD *
Infectious mononucleosis-like PTLD 9971/1
Monomorphic PTLD (B- and T/NK-cell types) *
Plasmacytic hyperplasia 9971/1
Polymorphic PTLD 9971/3
*These lesions are classified according to the leukemia or lymphoma to which they correspond, and are assigned the respective ICD-O code.
Disease definitions and symptoms
22
Tumors Primary in Tissue
Lymphoma: Malignant tumor in lymph nodes or lymphoid tissue
Myeloid sarcoma: Solid tumor of immature white blood cells
Plasma cell tumor (MM, extraosseous, osseous): Tumors comprised of plasma cells
23
Lymphoma Presentation
Not specific to diseaseSwollen lymph nodesChest pain/breathing problemsUnexplained weight lostRecurring fevers/night sweatsRashesLower back painSore LN after alcohol consumption
24
Tests That Identify Specific Lymphoid Histologies
25
2008 WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues
Basic principle: Classification for all neoplasms based on:
• Morphology and biologic features
• Genetic• Immunophenotype
• Clinical features
26
Genetic Testing
Laboratory studies of blood, bone marrow, or tissue to analyze DNA to identify chromosome abnormalities which diagnose specific neoplasms
27
Normal Chromosomes
46 in each cellEach chromosome has a specific number
Example: (1;2)
Short arm “p” and a long arm “q”
Example: (p13;q22)
28
Genetic Abnormalities
1. Translocation: t(1;2)
2. Inversion: inv16
3. Deletion: ‐7 or 7‐
4. Addition: +8 or 8+
29
Gene Translocation
30Courtesy: National Human Genome Research Institute
Gene Inversion
31Diego Diez, Ph, Bioinformatics Center, Institute for Chemical Research, Kyoto University.Gokasho, Uji, Kyoto 611-0011 JAPAN [email protected]
Gene Deletion
32
Courtesy: National Human Genome Research Institute
Gene Addition
33
Walters L, Palmer JG. “The Ethics of Human Gene Therapy.” Oxford University Press. 1997.
Genetic Testing
FISH: Identifies genetic changes and translocations.
Polymerase chain reaction (PCR): Measures cancer cells that cannot be detected by FISH.
Karyotyping: To arrange and classify chromosomes based on number, size, shape, and other characteristics.
34
FISH to Identify NPM/ALK Fusion Gene
35http://www.pathologyoutlines.com
Genetic Testing/Cytogenetics
36Appelbaum, MD, Frederick R. Leukemia [Internet]. Version 5. Knol. 2008 Jul 28. Available from: http://knol.google.com/k/frederick-r-appelbaum-md/leukemia/pOIC0j0O/gRxHJw
Karyotype
37http://www.pathologyoutlines.com
Immunophenotyping
Cells from blood, BM, tissue used to determine types of antigens or markers on surface of cell. Referred to as CD
CD; cluster of differentiation: Used to define the findings in immunophenotyping .
38
Additional Immunophenotyping
Flow cytometry: Cells from blood, BM, tissue are treated with antibodies and passed in front of a laser beam.
Immunocytochemistry (IHC): Shows specific antigens in cells from blood, BM, by using either fluorescent dyes or enzymes as markers
39
Immunohistochemistry
40
http://www.pathologystudent.com/?tag=acute-myeloid-leukemia
Staging
41
Stage
• Stage IStage I NHL means involvement of a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE).
• Stage IIStage II NHL means involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ or site and its regional lymph nodes with or without other lymph node regions on the same side of the diaphragm (IIE). [Note: The number of lymph node regions involved may be indicated by a subscript (e.g., II3).]
Stage
• Stage IIIStage III NHL means involvement of lymph node regions on both sides of the diaphragm (III) that may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE), by involvement of the spleen (IIIS), or both (IIIS+E).
• Stage IVStage IV NHL means disseminated (multifocal) involvement ofone or more extralymphatic sites with or without associated lymph node involvement or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement.
Stage
• adult NHL can be subclassified into A and B categories :
A for those without such symptoms
B for those with well‐defined generalized symptoms
B symptom
• B designation is given to patients with any of the following symptoms:
I. Unexplained loss of more than 10% of body weight in the 6 months before diagnosis.
II. Unexplained fever with temperatures above 38°C.
III. Drenching night sweats.
Stage I & II
Stage IIE & III
Stage IV & Bone marrow aspiration
Stage I lymphoma‐ PET
Upstaged from stage II to stage IIIs
Stage IV lymphoma
Cancer registry
52
Most Common Lymphomas
Armitage JO, et al. J Clin Oncol. 1998;16:2780-2795.
Diffuse large B cell: 31%
Follicular: 22%Marginal zone, extranodal: 8%
Peripheral T cell: 7%
Small lymphocytic/CLL: 7%
Mantle cell: 6%
Mediastinal large B cell: 2%
Anaplastic large cell: 2%
Burkitt: 2%
Marginal zone, nodal: 2%
T lymphoblastic: 2%Other: 9%
Cancer registry
• USA
• New cases: 63,190.
• Deaths: 18,660.
• Taiwan
• New cases: 1,902
• Deaths: 1,298
非何杰金氏淋巴瘤
非何杰金氏淋巴瘤
年齡別發生率 , 96年 年齡別死亡率, 96年
組織形態
首次療程
何杰金氏淋巴瘤
何杰金氏淋巴瘤
年齡別發生率 , 96年 年齡別死亡率, 96年
組織形態
首次療程
Treatment and prognosis
63
Indolent lymphomas
• Relatively good prognosis with a median survival as long as 10 years
• Usually are not curable in advanced clinical stages
• Early stage (stage I and stage II) can be effectively treated with radiation therapy alone
Aggressive lymphomas
• Shorter natural history
• Significant number of these patients can be cured with intensive combination chemotherapy
Treatment Option Overview
• Radiation therapy : varies from 25 Gy to 50 Gy
• Combination chemotherapy
• Aggressive consolidation with marrow or stem cell support
Treatment Options for Advanced Low‐Grade Lymphoma
• Observation (watch and wait)
• Radiation
• Single‐agent therapy
• Combination chemotherapy
• Interferon
• Monoclonal antibodies
• Hematopoietic transplantation
• Antisense molecules
• Vaccines
• Targeted agents
Treatment Option Overview
• Treatment of non‐Hodgkin lymphoma (NHL) depends on the histologic type and stage.
• Late effects of treatment of NHL :permanent sterility elevated risk for second primary cancers Left ventricular dysfunction Myelodysplastic syndrome and acute myelogenous leukemia
Evolving Standards of Care in Non-Hodgkin’s Lymphomaclinicaloptions.com/oncology
CHOP ± Rituximab in DLBCL: 7-Yr Survival Results (GELA LNH-98.5 Study)
Coiffier B, et al. ASCO 2007. Abstract 8009.
OS (N = 399) Parameter, % Low Risk
High Risk
Age, < 70 vs ≥ 70 yrs 58.0 49.0
LDH, NI vs > NI 69.0 45.0*
Stage, I/II vs III/IV 67.0 50.0
Bone marrow, yes vs no 60.0 34.5*
Tumor size, < 10 vs ≥ 10 cm 60.0 36.5
β2-microglobulin, NI vs > NI 64.5 39.0*
Serum albumin, ≥ 35 vs < 35 g/L 60.0 40.0
*P < .05 (multivariate analysis).
Surv
ival
Pro
babi
lity
Yrs
0
0.2
0.4
0.6
0.8
1
0 1 3 5 7 82 4 6
CHOPR-CHOP
P = .0004
Prognosis
• Overall survival at 5 years is approximately 50% to 60%
• Aggressive NHL, 30% to 60% can be cured
• Vast majority of relapses occur in the first 2 years after therapy
• Asymptomatic patients with indolent forms of advanced NHL, treatment may be deferred until the patient becomes symptomatic as the disease progresses
The Follicular Lymphoma International Prognostic Index (FLIPI)
• FLIPI score used to predict outcomes of therapy based on adding number of risk factors (each factor = 1 point)– Older than 60 yrs of age– Ann Arbor stage III/IV disease
– Hb < 12 g/L
– LDH > ULN
– > 4 involved nodal sites
Solal‐Céligny P, et al. Blood. 2004;104:1258‐1265. © The American Society of Hematology.
FLIPI Risk Group
Risk Factors, n
Patients, % 5-Yr OS, % 10-Yr OS, % Relative Risk
Low 0-1 36 90.6 70.7 1.0
Intermediate 2 37 77.6 50.9 2.3
High ≥ 3 27 52.5 35.5 4.3
DLBCL: Prognostic FactorsRisk Group Risk
Factors, n
CR, %
5-Yr OS, %
Patients (all ages)
Low 0-1 87 73
Low intermediate 2 67 51
High intermediate 3 55 43
High 4-5 44 26
Patients 60 yrs of age or younger
Low 0 92 83
Low intermediate 1 78 69
High intermediate 2 57 46
High 3 46 32
• Adverse risk factors correlated with response to chemotherapy and survival– Older than 60 yrs of age– LDH > normal– PS ≥ 2– Ann Arbor stage III/IV– Extranodal involvement > 1 site*
International NHL Prognosis Factors Project. N Engl J Med. 1993;329:987‐994.*Prognostic for patients older than 60 yrs of age only
clinicaloptions.com/oncologyClinical Advances and Practical Applications in Lymphoma
Prop
ortio
n R
emai
ning
Aliv
e
YrsIPI Score Censor Fail Total Media
0/1 36 47 83 5.032 36 67 103 2.103 20 53 73 1.41
4/5 9 38 47 0.68
00.10.20.30.40.50.60.70.80.91.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
OS in PTCL by IPI Score
Vose J, et al. J Clin Oncol. 2008;26:4124-4130.Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.
19 20
Summary
• Heterogeneous group of lymphoproliferative malignancies
• Usually originates in lymphoid tissues and can spread to other organs
• Far greater predilection to disseminate to extranodal sites
Thank you for your attention !
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