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
B-cell Differentiation B Antigen-Induced B-Cell Maturation Immature/transitional B cell Marginal-zone B cell Follicular B cell T-cell-independent antigen Outside germinal center V-gene mutation Not obligatory T-cell-dependent antigen Inside germinal center Obligatory Plasma cell Memory cell Plasma cell Memory cell With or without V-gene mutations V-gene mutations 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 cell Differentiation 6
T cell Differentiation 7 Major Types of B Cell Lymphoma Aggressive or high grade Indolent or low grade Lymphoplasmacytic NHL B-ALL subtypes Indolent B-CLL Mantle cell NHL Immunoblastic Burkitt Large B lymphoma Follicular center cells Small cleaved Marginal zone NHL B-CLL Myeloma
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 smallcleaved 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, 4 th 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 Table B7: Precursor Lymphoid Neoplasms WHO Preferred Term B lymphoblastic leukemia/lymphoma ICD-O-3 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 14
Mature B Cell Neoplasms part I 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 9596/3 lymphoma and classical Hodgkin lymphoma 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 9699/3 lymphoma) 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 15 Mature B Cell Neoplasms part II WHO Preferred Term Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease ICD-O-3 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 16
Mature T Cell and NK Cell Neoplasms Table B9: Mature T-Cell and NK-Cell Neoplasm WHO 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 17 T-cell prolymphocytic leukemia 9834/3 Hodgkin Lymphoma 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 18
Histiocytic Cell and Dendritic Cell Neoplasms Table B11: Histiocytic and Dendritic Cell Neoplasm WHO Preferred Term Disseminated juvenile xsanthogranuloma ICD-O-3 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 19 Histiocytic Cell Neoplasms Table 14.01 True histiocytic malignancy, a vanishing diagnosis. Original diagnosis Histiocytic lymphoma, nodular and diffuse Histiocytic medulary reticulosis Malignant histiocytosis Regressing atypical histiocytosis Intestinal malignant histiocytosis Histiocytic cytopathic panniculitis Currently considered Diffuse large B cell lymphoma Follicular lymphoma, grade 3 Peripheral T cell lymphoma Histiocyte rich variants of B cell, T cell, and Hodgkin lymphoma Anaplastic large cell lymphoma Haemophagocytic syndromes ALCL Haemophagocytic syndromes Primary cutaneous CD30 positive T cell lymphoma Enteropathy type T cell lymphoma Subcutaneous panniculitis like T cell lymphoma with Haemophagocytosis 20
Post Transplant Lymphoproliferative Disorders Table B12: Post-Transplant Lymphoproliferative Disorders (PTLD) WHO Preferred Term Early lesions ICD-O-3 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. 21 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 disease Swollen lymph nodes Chest pain/breathing problems Unexplained weight lost Recurring fevers/night sweats Rashes Lower back pain Sore 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 cell Each 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 Courtesy: National Human Genome Research Institute 30
Gene Inversion Diego Diez, Ph, Bioinformatics Center, Institute for Chemical Research, Kyoto University. Gokasho, Uji, Kyoto 611-0011 JAPAN diez@kuicr.kyoto-u.ac.jp 31 Gene Deletion Courtesy: National Human Genome Research Institute 32
Gene Addition Walters L, Palmer JG. The Ethics of Human Gene Therapy. Oxford University Press. 1997. 33 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 http://www.pathologyoutlines.com 35 Genetic Testing/Cytogenetics Appelbaum, MD, Frederick R. Leukemia [Internet]. Version 5. Knol. 2008 Jul 28. Available from: http://knol.google.com/k/frederick-r-appelbaummd/leukemia/poic0j0o/grxhjw 36
Karyotype http://www.pathologyoutlines.com 37 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 http://www.pathologystudent.com/?tag=acutemyeloid-leukemia 40
Staging 41 Stage Stage I Stage I NHL means involvement of a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE). Stage II Stage 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 III Stage 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 IV Stage IV NHL means disseminated (multifocal) involvement of one 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 : Afor 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 T lymphoblastic: 2% Marginal zone, nodal: 2% Other: 9% Burkitt: 2% Anaplastic large cell: 2% Mediastinal large B cell: 2% Diffuse large B cell: 31% Mantle cell: 6% Small lymphocytic/cll: 7% Peripheral T cell: 7% Marginal zone, extranodal: 8% Follicular: 22% Armitage JO, et al. J Clin Oncol. 1998;16:2780-2795. USA New cases: 63,190. Deaths: 18,660. Cancer registry 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
Survival Probability Evolving Standards of Care in Non-Hodgkin s Lymphoma clinicaloptions.com/oncology CHOP ± Rituximab in DLBCL: 7-Yr Survival Results (GELA LNH-98.5 Study) 1 0.8 0.6 0.4 0.2 0 P =.0004 OS (N = 399) Parameter, % Yrs CHOP R-CHOP 0 1 2 3 4 5 6 7 8 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 β 2 -microglobulin, NI vs > NI 64.5 39.0* Serum albumin, 35 vs < 35 g/l 60.0 40.0 *P <.05 (multivariate analysis). Coiffier B, et al. ASCO 2007. Abstract 8009. 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) LDH > ULN Older than 60 yrs of age > 4 involved nodal sites Ann Arbor stage III/IV disease Hb < 12 g/l 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 Solal Céligny P, et al. Blood. 2004;104:1258 1265. The High American Society of 3Hematology. 27 77.6 52.5 50.9 35.5 2.3 4.3 DLBCL: Prognostic Factors Risk Group Patients (all ages) Risk Factors, n CR, % 5-Yr OS, % 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 International *Prognostic for NHL patients Prognosis older Factors than Project. 60 yrs of N Engl J Med. 1993;329:987 994. age only 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*
Clinical Advances and Practical Applications in Lymphoma clinicaloptions.com/oncology OS in PTCL by IPI Score Proportion Remaining Alive 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Yrs IPI Score Censor Fail Total Media 0/1 36 47 83 5.03 2 3 36 20 67 53 103 73 2.10 1.41 4/5 9 38 47 0.68 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
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