1. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (2008) 경희의대 종양혈액내과 교수 조경삼

2. Why classify? Classification is the language of medicine –Diseases must be described, defined and named before they can be diagnosed, treated and studied. –A classification should contain diseases that are clearly defined, clinically distinctive, non-overlapping (mutually exclusive) and that together comprise all known entities (collectively exhaustive).

3. Previous classification of hematologic malignancies Clinical features Morphology Leukemia : acute, chronic FAB classification CMPD : PV, ET, IMF Lymphoma : HD, NHL Plasma cell dyscrasia

4. 만성 골수구성 백혈병 (CML) Leukemia (chronic) – acute transform Myeloproliferative neoplasms Ph 1 positive CML Ph negative CML BCR/ABL positive CML : imatinib Atypical CML Chronic myelomonocytic leukemia

5. Harrison’s Internal Medicine (17 th Ed. 2008) Chap. 102 Aplastic Anemia, Myelodysplasia, and Related BM Failure Syndrome Chap. 103 PV and other Myeloproliferative Diseases(MPD) Chap. 104 Acute and Chronic Myeloid Leukemia Chap. 105 Malignancies of Lymphoid cells Chap. 106 Plasma cell disorders

6. Classification of Lymphoma Hodgkin’s disease Non-Hodgkin’s Lymphoma –Rappaport classification –Working fomulation –Real (Revised European-American Classification of Lymphoid Neoplasms) classification –WHO classification

7. Classification of MDS FAB –Refractory anemia –RA with ringed sideroblasts (RARS) –RA with excess blasts –RAEB in transformation (blast : 20 – 30%) –Chronic myelomonocytic leukemia WHO (2001) Refractory anemia (RA) RA with multilineage dysplasia (RCMD) RA with ringed sideroblasts (RARS) RCMD-RS RA with excess blasts-1 (RAEB-I) RAEB-II MDS, unclassified (MDS-U) MDS associated with isolated del(5q)

8. MDS (WHO: 2008) Refractory cytopenia with unilineage dysplasia –Refractory anemia –Refractory neutropenia –Refractory thrombocytopenia Refractory anemia with ring sideroblasts Refractory cytopenia with multineage dysplasia Refractory anemia with excess blasts Myelodysplastic syndrome associated with isolated del(5q) Myelodysplastic syndrome, unclassifiable Childhood myelodysplastic syndrome –Refractory cytopenia of childhood

9. Classification of AML (FAB) M0: minimally differentiated: CD13 or 33 M1: myeloblast without maturation: CD13,33,34, HLA-DR+ M2: myeloblastic with maturation: CD13,15,33,34, HLA-DR+, t(8;21) M3: promyelocytic: CD13,15,33,HLA-DR-, t(15;17) M4: myelomonocytic: CD11b,13,14,15,33, HLA-DR+, inv(16)-M4Eo M5: monocytic: CD11b,13,14,15,33, HLA-DR+, 11q23 M6: Erythroleukemia: CD33, HLA-DR+ M7: Megakaryoblastic: CD33,41

10. WHO classification (3 rd Ed.) Pathology and Genetics of Tumors of Haematopoietic and lymphoid Tissues (2001) The first true worldwide consensus classification of hematologic malignancies

12. WHO classification (3 rd Ed.) Pathology and Genetics of Tumors of Haematopoietic and lymphoid Tissues (2001) The first true worldwide consensus classification of hematologic malignancies The European association for Haematopathology The Society of Hematopathology Steering Committee in 1995 CAC (Clinical Advisory Committee) meeting in 1997 2006 update began

13. Classification principles REAL (Revised European-American Classification of Lymphoid Neoplasms) from the ILSG (International Lymphoma Study Group) 1994 : define “real” diseases that can be recognized by pathologists with available techniques, and that appear be distinct clinical entities 1. No one gold standard : morphology, immunophenotype, genetic features and clinical features 2. Consensus : only thing worse than an imperfect classification is multiple competing classifications 3. Pathologists and clinicians : pathologists must take primary responsibilities for developing a classification, involvement of clinicians is essential

14. WHO classification (3 rd Ed.) CMPD Myelodysplastic/myeloproliferative dideases MDS AML –AML with recurrent cytogenetic abnormalities –AML with multilineage dysplasia –AML and MDS, therapy related –AML not otherwise categorized –Acute leukemia of ambiguous lineage

15. WHO classification (3 rd Ed.) B-cell neoplasms –Precursor B-cell neoplasms –Mature B-cell neoplasms –B-cell proliferations of uncertain malignant potential T-cell and NK-cell neoplasms –Precursor T-cell neoplasms –Mature T-cell and NK-cell neoplasms –T-cell proliferations of uncertain malignant potential Hodgkin lymphoma Histiocytic and dendritic-cell neoplasms –Macrophage/histiocytic neoplasm –Dendritic cell neoplasms Mastocytosis

16. WHO classification (4 th Ed.) Europian association for Haematopathology Society of Hematopathology Two Clinical advisory Committees (CAC) –Myeloid neoplasm and other acute leukemia –Lymphoid neoplasm 130 pathologists and hematologists International Agency for Research on Cancer (IARC), Lyon, France October 25-27, 2007

18. Bases of classification Morphology : most important part but sometimes not objective Immunophenotype : lineage, objective, target (ex. CD20) Genetic abnormalities : objective –Characteristic but not specific : MYC, CCND, BCL2 rearrangement, JAK2 mutation –Prognostic : TP53 mutation or FLT3-ITD Clinical features : age, nodal versus extranodal presentation, specific anatomic site and history of cytotoxic and other therapies Provisional entities, borderline categories

19. Stratification according to Lineages : –myeloid, lymphoid, and histiocytic/dendritic cell –Lineage plasticity –FGFR1, PDGFA, and PDGFB rearrangement Maturation : precursor, mature Biologic features : MPN, MDS Clinical presentation : mature lymphoid –Disseminated, extranodal, indolent, aggressive –Stage of differentiation

20. Myeloid neoplasms Acute leukemia of ambiguous lineage Lymphoid neoplasms Histiocytic and dendritic cell neoplasms WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (2008)

21. Myeloid neoplasms –Myeloproliferative neoplasms (MPN) –Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 –Melodysplastic/Myeloproliferative neoplasms (MDA/MPN) –Myelodysplastic syndrome (MDS) –Acute myeloid leukemia (AML) and related precursor neoplasms Acute leukemia of ambiguous lineage

24. Myeloproliferative neoplasms (MPN) Chronic myelogenous leukemia, BCR-ABL 1 positive Chronic neurophilic leukemia Polycythemia vera Primary myelofibrosis Essential thrombocythemia Chronic eosinophilic leukemia, NOS (CEL/hypereosinophilic synd) Mastocytosis –Cutaneous mastocytosis –Systemic mastocytosis –Mast cell leukemia –Mast cell sarcoma –Extracutaneous matocytoma Myeloproliferative neoplasm, unclassifiable

26. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 Myeloid and lymphoid neoplasms with PDGFRA rearrangement Myeloid neoplasms with PDGFRB rearrangement Myeloid and lymphoid neoplasms with FGFR1 rearrangement

27. Myelodysplastic syndrome Refractory cytopenia with unilineage dysplasia –Refractory anemia –Refractory neutropenia –Refractory thrombocytopenia Refractory anemia with ring sideroblasts Refractory cytopenia with multineage dysplasia Refractory anemia with excess blasts Myelodysplastic syndrome associated with isolated del(5q) Myelodysplastic syndrome, unclassifiable Childhood myelodysplastic syndrome –Refractory cytopenia of childhood

28. Melodysplastic/Myeloproliferative neoplasms Chronic myelomococytic leukemia Atypical chronic myeloid leukemia, BCR-ABL1 negative Juvenile myelomonocytic leukemia Myelodysplastic/Myeloproliferative neoplasms, unclassifiable –Refractory anemia with ring sideroblasts associated with marked thrombocytosis

29. Acute myeloid leukemia (AML) and related precursor neoplasms AML with recurrent genetic abnormalities AML with myelodysplasia-related changes Therapy-related myeloid neoplasms Acute myeloid leukemia, NOS Myeloid sarcoma Myeloid proliferations related to Down syndrome Blastic plasmacytoid dendritic cell neoplasm

30. AML with recurrent genetic abnormalities AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 Acute promyelocytic leukemia with t(15;17)(q22;q12); PML-RARA AML with t(9;11)(q22;q23); MLLT3-MLL AML with t(6;9)(p23;q34); DEK-NUP214 AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1 AML with mutated NPM1 AML with mutated CEBPA

31. Acute myeloid leukemia, NOS AML with minimal differentiation AML without maturation AML with maturation Acute myelomonocytic leukemia Acute monoblastic and monocytic leukemia Acute erythroid leukemia Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis (Myeloid sarcoma)

32. Acute myeloid leukemia (AML) and related precursor neoplasms AML with myelodysplasia-related changes Therapy-related myeloid neoplasms Myeloid sarcoma Myeloid proliferations related to Down syndrome –Transient abnormal myelopoiesis –Myeloid leukemia with Down syndrome Blastic plasmacytoid dendritic cell neoplasm

34. Acute leukemias of ambiguous lineage Acute undifferntiated leukemia Mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1 Mixed phenotype acute leukemia with t(v;11q23); MLL rearranged Mixed phenotype acute leukemia, B/myeloid, NOS Mixed phenotype acute leukemia, T/myeloid, NOS Natural killer (NK) cell lymphoblastic leukemia/lymphoma

35. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (2008) Lymphoid neoplasms –Precursor lymphoid neoplasms –Mature B-cell neoplasms –Mature T-cell and NK-cell neoplasms –Hodgkin Lymphoma –Post-transplant lymphoproliferative disorders (PTLD) Histiocytic and dendritic cell neoplasms

36. Lymphoid neoplasms Precursor lymphoid neoplasms Mature B-cell neoplasms Mature T-cell and NK-cell neoplasms Hodgkin Lymphoma Post-transplant lymphoproliferative disorders (PTLD)

37. Precursor lymphoid neoplasms B lymphoblastic leukemia/lymphoma –B lymphoblastic leukemia/lymphoma, NOS –B lymphoblastic leukemia/lymphoma, with recurrent genetic abnormalities B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2); BCR-ABL1 B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22); TEL- AML1(ETV6-RUNX1) B lymphoblastic leukemia/lymphoma with hyperdiploidy B lymphoblastic leukemia/lymphoma with hypodiploidy (hypodiploid ALL) B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32); IL3-IGH B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); E2A- PBX1(TCF3-PBX1) T lymphoblastic leukemia/lymphoma

38. Mature B-cell neoplasms Chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia Splenic marginal zone lymphoma Hairy cell leukemia Splenic B-cell lymphoma/leukemia, unclassifiable –Splenic diffuse red pulp small B-cell lymphoma –Hairy cell leukemia-variant

39. Mature B-cell neoplasms Lymphoplasmacytic lymphoma –Waldenström macroglobulinemia Heavy chain diseases –Alpha heavy chain disease –Gamma heavy chain disease –Mu heavy chain disease Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma

40. Mature B-cell neoplasms Extranodal marginal zone lymphoma of mucosa- associated lymphoid tissue (MALT lymphoma) Nodal marginal zone lymphoma –Pediatric nodal marginal zone lymphoma Follicular lymphoma –Pediatric follicular lymphoma Primary cutaneous follicle centre lymphoma Mantle cell lymphoma

41. Mature B-cell neoplasms Diffuse large B-cell Lymphoma (DLBCL), NOS –T-cell/histiocyte rich large B-cell lymphoma –Primary DLBCL of the CNS –Primary cutaneous DLBCL, leg type –EBV positive DLBCL of the elderly DLBCL associated with chronic inflammation Lymphomatoid granulomatosis Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma

42. Mature B-cell neoplasms ALK positive large B-cell lymphoma Plasmablastic lymphoma Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease Primary effusion lymphoma Burkitt lymphoma B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma

43. Mature T-cell and NK-cell neoplasms T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphoproliferative disorder of NK-cell Aggressive NK cell leukemia Systemic EBV positive T-cell lymphoproliferative disease of childhood Hydroa vacciniforme-like lymphoma Adult T-cell leukemia/lymphoma Extranodal NK/T cell lymphoma, nasal type

44. Mature T-cell and NK-cell neoplasms Enteropathy-associated T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sezary syndrome Primary cutaneous CD30 positive T-cell lymphoproliferative disorders –Lymphomatoid papulosis –Primary cutaneous anaplastic large cell lymphoma

45. Mature T-cell and NK-cell neoplasms Primary cutaneous gamma-delta T-cell lymphoma Primary cutaneous CD8 positive aggressive epidermotropic cytotoxic T-cell lymphoma Primary cutaneous CD4 positive small/medium T-cell lymphoma Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Anaplalstic large cell lymphoma, ALK positive Anaplastic large cell lymphoma, ALK negative

46. Hodgkin Lymphoma Nodular lymphocyte predominant Hodgkin lymphoma Classical Hodgkin lymphoma –Nodular sclerosis classical Hodgkin lymphoma –Lymphocyte-rich classical Hodgkin lymphoma –Mixed cellularity classical Hodgkin lymphoma –Lymphocyte-depleted classical Hodgkin lymphoma

47. Histiocytic and dendritic cell neoplasms Histiocytic sarcoma Langerhans cell histiocytosis Langerhans cell sarcoma Interdigitating dendritic cell sarcoma Follicular dendritic cell sarcoma Fibroblastic reticular cell tumour Indeterminate dendritic cell tumour Disseminated juvenile xanthogranuloma

48. Post-transplant lymphoproliferative disorders (PTLD) Early lesions –Plasmacytic hyperplasia –Infectious mononucleosis-like PTLD Polymorphic PTLD Monomprphic PTLD (B- and T/NK-cell types) * Classical Hodgkin lymphoma type PTLD *