Clasificación de leucemias - OMS 2008

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Clasificación de leucemias - OMS 2008

  1. 1. World Health Organization Classification of Tumours Hamilton SR. Aartonen LA (Eds.): World Health Organization Classificationof Tumours, Pathology and Genetics of Tumours of the Digestive System (3rd edition) . IARC Press: lyon 2000 ISBN 92 832 2410 8 Fletcher C.D.. Unni KK., Mertens F. (Eds,): World Health Organization Classification 01 Tumours. Pathology and Genetics 01 Tumours of Soft Tissue and Bone (3rd edition). IARC Press : lyon 2002 ISBN 92 832 2413 2 Tavassoli F A.. Devilee P.(Eds.): World Health Organization Classification 01 Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs (3rd edition). IARC Press: lyon 2003 ISBN 92 832 2412 4 Eble J.N., Sauter G.• Epstein J E., Sesterreon l.A. (Eds.) World Health Organization Classification of Tumours. Pathology and Genetics of Tumours althe Urinary Systemand Male Genital Organs (Jrd ed ition) fARe Press : lyon 2004 ISBN 92 832 2415 9 Travis wo., Brambilla E., Muller· Hermelink H.K ., Harris C.C. (Eds.): World Health Organization Classification 01 Tumours. Pathology and Genetics of Tumours of lung P1eu"a. Thyrrus and Heart (3I"dedilon), IARC Press : lyon 2004 ISBN 92 832 2418 3 Delellis A.A., lloyd A.V, Heitz, P.U., Eng C. (Eds.): World Health Organization Classification of TlJTlOUrs. Pathology and Genetics ot TlJTlOUrs of Endocrine Organs(3rd edition). IARC Press: lyon 2004 ISBN 92 832 2416 7 Barnes L , Eveson J.W , Reichart P" Sidransky 0 (Eds.): World Health OrganizationClassification of Tumours. Pathology and Genetics of Head and Neck Tumours (3I"d edition) . IARC Press: lyon 2005 ISBN 92 832 24 17 5 leBoit P.E.. Burg G , Weedon D., Sarasm A. (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Skin Tumou rs (3rd edition). IARC Press: lyon 2006 ISBN 92 832 2414 0 louis D.N" Ohgaki H., WiesUerD.O., Cavenee WK (Eds.): World Health Organization Classification of Tumours. Tumours of the Central Nervous System (4th edition ). IARC, lyon 2007 ISBN 92 832 2430 2 This book and all other volumes of the series can be purchased from: From all countries WHO PRESS World Health Organization 20 Avenue Appia 1211 Geneva 27 Switzerland www.who intlbookord ers/ Tei. +41 22 791 3264 Fax +41 22 791 4857 bcokoroersewno.ot From USA I Canada WHO Publications Center 5 Sand Creek Road Albany, NY 1205-1400 Tel. +15184369686 Fax. +1518436 7433 qcorpeconouserve.com Renouf Publishing Co. lid http://www.renoufbooks.comJ From USA: Tel.+18885517470 From Canada: Tel. + 1 866 767 6766 Fax +18885517471 Fax +16137457660
  2. 2. -.I
  3. 3. • I WHO OMS International Agency for Research on Cancer (IARC) 4th Edition WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues Edited by Steven H. Swerdlow Elias Campo Nancy Lee Harris Elaine S. Jaffe Stefano A. Pileri Harald Stein JOrgen Thiele James W. Vardiman International Agency for Research on Cancer Lyon, 2008
  4. 4. World Health Organization Classification of Tumours Series Editors Fred T. Bosman, M.D. Elaine S. Jaffe. M.D. Sunil R. Lakhani. M.D. Hiroko Onqaki, Ph.D. WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues Editors Sleven H. Swerdlow, M.D. Elias Campo. M.D. Nancy Lee Harris, M.D. Elaine S. Jaffe, M D. Stefano A. Pileri. M.D. Harald Stein, M.D. JOrgen Thiele, M.D. James W. Vardiman, M.D. Layout Sebastien Antoni Marlen Grassinger Pascale Collard Printed by Participe Present 69250 Neuville s/SaOne, France Publisher International Agency for Research on Cancer (IARC) 69008 Lyon. France
  5. 5. • This volume was produced with support from the Associazione S.P.E.S. Onlus, Bologna Friends of Jose Carreras International Leukemia Foundation Leukemia Clinical Research Foundation MEDIC Foundation National Cancer Institute, USA National Institutes of Health Office of Rare Diseases, USA University of Chicago Cancer Research Center The WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues presented in this book reflects the views of a Working Group that convened for an Editorial and Consensus Conference at the International Agency for Research on Cancer (fARC), Lyon October 25-27. 2007. Members of the Working Group are indicated in the List of Contributors on pages 369-374.
  6. 6. Published by the International Agenc y for Research 00 Cancer (IARC), 150 cours Albert Thomas, 69372 Lyon ceoex 08, France C International Agency for Research on Cancer, 2008 Distributed by WHO Press, World Health Organization , 20 Avenue Appia, 1211 Geneva 27, Switzerland (Tel: +41 22 791 3264; Fax: +41 22 791 4857; e-mail: bookordersOwholnt). PubliCations Of the World Health Organization enjoy copyright crotectco in accordance with the proviecos of Protocol 2 of the Universal Copyright Coeventoo. All rights reserved. The designatiOns employed and the presentation otthe material in this publicatiOn do not imply the expression ot any opiniOn whatsoever on the part of the secretarial 01 the WOOd Health OrganiZatiOn concerning the legal status 01 any country , territory. city. or area or 01 its authonltes, or concerning the delimitatiOn 01its frontiers or ccooca-ee. The mootion ol scecac companies or 01certain manufacturers' products does not imply that they are encIornedor fecorrmellded by the World Health Organization in preference to others of a smilar nature that are not mentioned Errors and omissions excepted, the rwnes 01proprietary products are distmguished by initial capnatjetters. The authors alone are responsible fOf the views expressed in this pubhcatlQfl. The copyright of figures and charts remains with the authors (see source 01charts and photographs. page 376--379) Format for bibliographic citations: Swerdlow S.H., Campo E., Harris N,L., Jaffe E.S" Pileri S.A., Stein H" Thiele J , Vardiman J.w. (Eds.): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC: Lyon 2008 IARC Ubrary Cataloguing in Publication Data WHO Classification of Tumours of Haematopo ietic and Lymphoid Tissues Edited by Swerdlow S.H.. Campo E., Harris NL , Jaffe E.S.• Piled SA, Stein H., Thiele J.. Vardiman JW. 1. Haematopoiehc System Neop lasms - genetics 2. Haematopoielic System Neop lasms - pathology I. Swerdlow. Steven H. ISBN 978-92-832-2431-0
  7. 7. Contents WHO Classifjcatioo 9 Summary table 10 Introduction to the classification of tumours of haematopoietic and lymphoid tissues 14 Introduction and overview of the classification of the myeloid neoplasms 17 2 Myeloproliferative neoplasms 31 Chronic myelogenous leukaemia. BCR-ABL 1positive 32 Chronic neutrophilic leukaemia 38 PoIycythaemia vera 40 Primary myelofibrOsis 44 Essenliallhrombocythaemia 48 Chronic eosinophilic leukaemia.NOS 51 Mastocytosis 54 Cutaneous mastocytosis 57 Systemic mastocytosis 58 Masl cell leukaemia 61 Mast cell sarcoma 61 Extracutaneous mastocytoma 61 Myeloproliferative neoplasm, unclassifiable 64 3 Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA. PDGFRBOf FGFRl 67 4 MyelodysplasticJmyeloproliferative neoplasms 75 Chronic mveiomonocync leukaemia 76 Atypical ctYonicmyeloid leukaEmia. BCR-ABL1negative 80 Juvenile myelomonocytic leukaemia 82 MyelodysplastiC/myeloproliferalive neoplasm, urclasaifiable 85 5 Myelodysplastic syndromes 87 Myelodysplastic syndromes/neoplasms, overview 88 Refractory cytopenia with unilineage dysplasia 94 Refractory anaemia with ring side roblasts 96 Refractory cytopenia with multilineage dysplasia 98 Refractory anaemia with excess blasts 100 Myelodysplastic syndrome with isolated de l(5q) 102 Myelodysplastic syndrome, uncrasslttabte 103 Childhood myelodysplastic syndrome 104 Refractory cytopenia of childhood 104 6 Acute myeloid leukaemia (AML) and related precursor neoplasms 109 AML with recurrent genetic abnormalities 110 AML with t(8:21 )(q22:q22); RUNX1-RUNX1T1 110 AML with inv( 16)(p 13.1q22) or 1(16:t6)(p 13.1;q22): CBFB-MYH11 11 1 Acute orornveiocvnc leukaemia with t(15:17)(q22:q 12): PML-RARA 11 2 AML with us.11)(p22:q23): MLLT3-MLL 114 AML with t(6:9)(p23 :q34); DEK-NUP214 115 AML with inv(3)(q2 1q26.2) or t(3;3)( q2 1;q26.2); RPNt ·EVI1 116 AML (megakaryoblastic) with t(1;22)(p13;q13): RBM15-MKL 1 117 AML with mutated NPM 1 120 AMLwith mutated CEBPA 122 AML with myelodysplasia-related changes 124 Therapy-related myeloid neoplasms 127 Acu te myeloid leukaemia, NOS 130 AML with minimal differentiation 130 AML withOut maturation 131 AML with maturabon 131 Acute myelomonocytic leukaemia 132 Acute monoblastic and monocytic leukaemia 133 Acute erythroid leukaemia 134 Acute megakaryoblastic leukaemia 136 Acute basophilic leukaemia 137 Acute paomveosrs with myelofibrosis 138 Myeloid sarcoma 140 Myeloid proliferations related 10 Down synd rome 142 Transient abnOrmal myelopoiesis 142 Myeloid leukaemia associated with Dc:rwn syndrome 143 Blastic plasmacytoid dendritic cell neoplasm 145 7 Acute leukaemiasof ambiguous lineage 149 Acute undlHerentiated leukaemia 151 Mixed phenotype acute leukaemia wilh t(9;22)(q34;q 11.2): BCR-ABL 1 151 Mixed phenotype acute leukaemia with t(v:11q23): MLL rearranged 152 Mixed phenotype acute leukaemia , B/myeloid, NOS 152 Mixed phenotype acute leukaemia , T/myeloid, NOS 153 Mixed phenotype acute leukaemia, NOS· rare types 154 Other ambiguous lineage reukaerraes t 55 Natura! killer (NK)-celilympho blastic leukaemia/lymphoma 155 8 Introduction and overview 01 the classification of the lymphoid neoplasms 157 9 Precursor lymphoid neoplasms 167 B lymp hob lastic leukaemia/lymphoma, NOS 168 B lymphoblastic leukaemia/lymphoma with recurrent gene tic abn ormalities 171 B lymphoblastic leukaemiallymphoma with t(9:22)(q34;q 11.2): BCR-ABL 1 171 B lymphoblastic leukaemia/lymphoma with l(v:11q23): MLL rearranged 171 B lympho blastic leukaemiall ymphoma with t(12:21)(p13;q22): TEL-AMLl (ETV6--RUNX1) 172 B lymphoblastic leukaemia/lymphoma with hyperdiploidy 173 B lymphoblastic leukaemiallymphoma with hypodiplOidy (Hypodiploid ALL) 174 B lymphoblastic leukaemiallymphoma with t(5; 14)(q31;q32); IL3-IGH 174 B lymphoblastic leukaemiallymphoma with t(1;19) (q23:P13.3): E2A-PBX1(TCF3-PBXI) 175 T lymphoblastic leukaemiallymphoma 176
  8. 8. Enteropathy-associated t-een lymphoma 289 Hepatosplenlc t -een lymphoma 292 Subcutaneous panniculitis-like t-een lymphoma 294 Mycosis fungoides 296 Sezary syndrome 299 Primary cutaneous CD30 positive t-een Iymphoprolilerative disorders 300 Primary cutaneous peripheral t-een lymphomas, rare subtypes 302 Primary cutaneous garnna-della T-cenlymphoma 302 Primary cutaneous COB positive aggressive epidermotrop ic cytotoxic T-celt lymphoma 303 Primary cutaneous CD4 positive small/medium T-cell lymphoma 304 Peripheral t-een lymphoma. NOS 306 Angioimmunoblastic t-een lymphoma 309 Anaplastic large cell lymphoma. AlK positive 312 Anapla stic large cell lymphoma . ALK negative 317 12 Hodgkin lymphoma 321 Introduction 322 Nodular lymphocyte predominant Hodgkin Iymptuna 323 Classical Hodgkin lymphoma. introduction 326 Nodular sclerosis classical Hodgkin lymphoma 330 Mixed cellularity classical Hodgkin lymphoma 331 Lymphocyte-rich classical Hodgkin lymphoma 332 lymphocyte-depleted classical Hodgkin lymphoma 334 13 1rnmunodeficiency-associated Iymphoproliferative disorders 335 Lymphoproliferative diseases associated with primary immune disorders 336 Lymphomas associated with HIV infection 340 Post-nansotanttsmpnooronterauve disorders (PTlD) 343 Plasmacytic hyperp lasia and infectious- rrooooocieose-uke PTlD 345 Polymorphic PTlO 346 Monomorphic PTlO 347 Classical Hodgkin lymphoma type PTLO 349 Other iatrogenic immunodeficiency-associated Iymphoproliferative disorders 350 , • 10 Mature B-ceUneoplasms 179 Chronic lymphocytic leukaemia Ismail Iympt'locytic lymphoma:f 180 s-een prolyrT¢lhocytic leukaemia 183 Splenic B-cell marginal zone lymphoma 185 Hairy cell leukaemia 188 Splenic B-cell Iymphomalleukaemia, unclassiliable 191 Splenic diffuse red pulp small B-ceil lymphoma 191 Hairy cenleckaeme-....anent 192 lymphoplasmacytic lymphoma 194 Heavy chain diseases 196 Gamma heavy chain disease 196 Mu heavy chain disease 197 Alpha heavy chain disease 198 Plasma cell neoplasms 200 Monoclonal gammopathy 01undetermined significance (MGUS) 200 Plasma cell myeloma 202 Solitary plasmacytoma of bone 208 Extraosseous plasmacytoma 208 Monoclonal immunoglobulin deposition diseases 209 Extranodat marginal zone lymphoma of mucosa- associated lymphoid tissue (MALT lymphoma) 214 Nodal marginal zone lymphoma 218 Follicular lymphoma 220 Primary cutaneous follicle centre lymphoma 227 Mantle cell lymphoma 229 Diffuse large B-celllymphoma (DLBCl), NOS 233 T celilhistiocyte-rich large B-cell lymphoma 238 Primary DlBCL of the CNS 240 Primary cutaneous DlBCl . leg type 242 EBV positive DLBCl of the elderly 243 DLBCL associated with chronic inflammation 245 Lymphomatoid granulomatosis 247 Primary mediastinal (thymic) large B-celilymphoma 250 Intravescurer large B-celi lymphoma 252 ALK positive large Been lymphoma 254 Plasmablastic lymphoma 256 large a-ceu lymphoma arising in HHV8-associated multicentric Castleman disease 258 Primary effusion lymphoma 260 Burkitllymphoma 262 B-cel1lymphoma, unclassiliable, with features intermediate between DLBCL and Burkitllymphoma 265 B-ceillymphoma, unctessmebie.with features intermediate between OLBCl and classical Hodgkin lymphoma 267 11 Mature T- and NK-cell neoplasms 269 r-cea prolymphocytic leukaemia 270 t-een large granular lymphocytic leukaemia 272 Chronic Iymphoproliferative disorder of NK cells 274 Aggressive NK cell leukaemia 276 Epstein-Barr virus (EBV) positive t-een Iymphoprolilerative diseases of childhood 278 Systemic EBV+ t-een Iymphoproliferalive disease of childhood 278 Hydroa vacclnrtorrne-uke lymphoma 280 Adull T-ceil leukaemia/lymphoma 281 Extranodal NK/T-cell lymphoma. nasal type 285 14 Histiocytic and dendritic cell neoplasms Introduction Histiocytic sarcoma Tumours derived from langerhans cells Langerhans cell histiocytosis Langerhans cell sarcoma Interdigitating dendrit ic cell sarcoma Follicular dendritic cell sarcoma Other rare dendritic cell tumours Disseminated juvenile xanthogranuloma Contributors Clinical advisory oorrrnittee Source of Charts and photographs References Subject index NOS, no! otherwise specified 353 354 3S6 358 3S8 360 361 363 365 366 369 374 376 300 429
  9. 9. - WHO Classification 4th Edition / / - -.,.e" / , ~ ~~...,...,... -~ /,f / -~ ~ _....i? ~.,.~ -
  10. 10. WHO Classification of tumours of haematopoietic and lymphoid tissues MYELOPROLIFERATIVE NEOPLASMS MYELODYSPLASTIC SYNDROMES Chronic myelogenous leukaemia, BCR-ABL 1 positive Chronic neutrophilic leukaemia Polycythaemia vera Primary myelofibrosis Essential thrombocythaemia Chronic eosinophilic leukaemia, NOS Mastocytosis Cutaneousmastocytosis Systemic mastocytosis Mast cell leukaemia Mastcell sarcoma Extracutaneous mastocytoma Myeloproliferative neoplasm, unctassitlable 987513 9963/3 9950/3 9961/3 996213 9964/3 974011 9741/3 974 213 9740/3 9740/1 9975/3 Refractory cytopenia with unilineage dysplasia Refractoryanaemia Refractory neutropenia Refractory thrombocytopenia Refractoryanaemia with ring sideroblasts Refractory cytopenia with multitineage dysplasia Refractoryanaemia with excess blasts MyelodysplasUc syndrome associated with isolated del(Sq) Myelodysplasticsyndrome, uncJassifiable Childhood myelodysplasuc syndrome Refractorycytopenia of childhood 9980/3 9991/3 9992/3 9962/3 9965/3 9983/3 9966/3 9969/3 996513 MYELODYSPLASTIC/MYELOPROLIFERAnVE NEOPLASMS 9869/3 9696/3 9666/3 9697/3 986513 9671/3 9911/3 9861/3 9661/3 AML with recurrent genetic abnormalities AML with t(6;21)(q22;q22); RUNXI-RUNX1Tl AML with inv(16)(pI 3.1q22 ) or t(16;16)(pI3.1;q22); CBFB-MYHl1 Acute promyelccytlc leukaemia with t(15;17)(q22;qI2); PML-RARA AML with t(9;11)(p22 ;q23); MLLT3-MLL AML with 1(6;9)(p23;q34); DEK-NUP214 AML with inv(3)(q21q26.2) ort(3;3)(q21;q26.2); RPNI-EV/1 AML (megakaryoblastic) with t(I ;22)(pI 3;qI 3); RBMI5-MKLI AML withmutated NPM1 AML wrlh mutatedCEBPA ACUTE MYELOID LEUKAEMIA (AML) AND RELATED PRECURSOR NEOPLASMS 9965/3 9967/3 9966/3 967613 9946/3 9945/3Chronic myetcmonocytic leukaemia Atypical chronic myeloidleukaemia. BCR-ABL 1negative Juvenile myelomonocyticleukaemia MYELOID AND LYMPHOID NEOPLASMS WITH EOSINOPHILIA AND ABNORMALITIES OF PDGFRA, PDGFRB OR FGFRI Myeloid and lymphoid neoplasms with PD GFRA rearrangement Myeloid neoplasms with PDGFRB rearrangement Myeloid and lymphoid neoplasms with FGFR1 abnormalities 996213 Myelodysplasticlmyeloproliferative neoplasm. unclassifiable 9975/3 Refractoryanaemia with ringsideroblasts associated WIth marked thrombocytosis AML with myelodysplasia-related changes 969513 Therapy-related myeloid neoplasm s 992013 10 WHOctassrtceton
  11. 11. Myeloid proliferations related to Down syndrome Transient abnormal myelopoiesis 989811 Myeloid leukaemia associated with Down syndrome 9898/3 Acute myeloid leukaemla",NOS 9861/3 AML with minimal differentiation 987213 AML without maturation 9873/3 AML with maturation 9874/3 Acute myelomonocytic leukaemia 9867/3 Acute monoblastic and monocytic leukaemia 9891/3 Acute erythroid leukaemia 984013 Acute megakaryoblastic leukaemia 99 10/3 Acute basophilic leukaemia 987013 Acute panmyelosis with myelofibrosis 993113 Myeloid sarcoma 993013 B lymphoblastic leukaemia/lymphoma with recurrent genetic abnormalities B lymphoblastic leukaemiaflymphoma with 1(9;22)(q34;ql 1.2); BCR-ABU 9812/3 B lymphoblastic leukaemiallymphoma with t(v;11q23); MLL rearranged 981Y3 B lymphoblastic leukaemiallymphoma with 1(12;21)(p13;q22); TEL-AMU (ETV6-RUNX1) 9814/3 B lymphoblastic leukaemiallymphoma with hyperdiploidy 981513 B lymphoblastic leukaemiallymphoma with hypodiploidy (hypodiploid ALL) 981613 B lymphoblastic leukaemiallymphoma with t(5;14Xq31;q32); IL3-IGH 9817/3 B lymphoblastic leukaemia/lymphoma with t(1;19)(q23 ;p13.3); E2A-PBXl (TCF3-PBX1) 9818/3 T lymphoblastic leukaemia/lymphoma 9837/3 982313 983313 968913 9940/3 9591/3 9591/3 9591/3 9671/3 9761/3 9762/3 9762/3 9762/3 9762/3 9732/3 9731/3 9734/3 Splenic B-cell fymphomalleukaemia, unclassifiable Splenic diffuse red pulp small B-cell lymphoma Hairy eel/leukaemia-variant MATURE B-CELL NEOPLASMS Chronic lymphocytic leukaemia! small lymphocytic lymphoma B-cell prolymphocytic leukaemia Splenic Bccell marginal zone lymphoma Hairy cell leukaemia Lymphoplasmacytic lymphoma waldenstrom 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 9727/3 98 11/3 9807/3 980613 9808/3 9809/3 Mixed phenotype acute leukaemia with t{v;11q23); MLL rearranged Mixed phenotype acute leukaemia, B/myeloid, NOS Mixed phenotype acute leukaemia, Tfmyeloid, NOS Natural killer (NK) cell lymphoblastic !euKaemiallymphoma ACUTE LEUKAEMIAS OF AMBIGUOUS LINEAGE Acute undifferentiated leukaemia 9801/3 Mixedphenotype acute leukaemia with t(9;22)(q34;q 11.2); BCR-ABL1 PRECURSOR LYMPHOID NEOPLASMS B lymphoblastic leukaemiaflymphoma B lymphoblastic leukaemiall ymphoma, NOS Blastic plasmacytoid dendritic cell neoplasm WHOclassification 11
  12. 12. - 965313 965213 965113 9663/3 9659/3 9650/3 9718/3 9726/3 9709/3 9709/3 970213 970513 9714/3 970213 970813 970013 970113 9718/1 HODGKIN LYMPHOMA Nodular lymphocyte predominant Hodgkin lymp homa Classical Hodgkin lymphoma Nodular sclerosis classical Hodgkin lymphoma l ymphocyte-rich classica l Hodgkin lymphoma Mixed cellularity classical Hodgkin lymphoma l ymphocyte-depleted classical Hodgkin lymphoma Primary cutaneous CD30 positive F-eel! Iymphoproliferative disorders lymphomatoid papulosis Primary cutaneous anaplastic large cell lymphoma Primary cutaneous qamma-delta r -ceuivmpncma Primary cutaneous COB positive aggressive epidermotropic cytotoxic T-cefl lymphoma Primary cutaneous CD4 positive smalVmedium T-cell lymphoma Peripheral Tccelllympboma, NOS Angioimmunoblastic 'l-cetl Iyrnphoma Anaplastic large cell lymphoma, ALK positive Anaplastic large cell lymphoma, ALK negative Systemic EBV positive T-celllymphoproliferative disease of childhood 9724/3 Hydroa vacciniforme-like lymphoma 972513 Adult T-cell ieukaemia/lymphoma 9827/3 Extranodal NKIT cell lymphoma, nasal type 9719/3 Enteropamy-associated T-cell lymphoma 9717/3 Hepatosplenic T-cell lymphoma 971613 Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sezary syndrome 983113 9948/3 9678/3 9687/3 968 0/3 9679/3 971213 9737/3 9735/3 9699/3 9699/3 9699/3 9690/3 9690/3 959713 967313 Aggressive NK cell leukaemia MATURE T-CELL AND NK·CELL NEOPLASMS j-cen prolymphocytic leukaemia 9834/3 'f-celllarqe granular lymphocytic leukaemia 9831/3 Chronic Iymphoproliferative disorder of NK..cells Primary effusion lymphoma Burkitt lymphoma B-ceillymphoma, unclassifiable, with features intermediate between diffuse large g-ceu lymphoma and Burkitt lymphoma B-ceil lymph oma , unclassifiable, with features intermediate between diffuse large 8-cell lymphoma and classical Hodgkin lymphoma 9596/3 Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Diffuse large B-eelllymphoma (OlBCl), NOS 968013 T-ceillhistiocyte rich large B-eelilymphorna 9688/3 Primary DLBCl of the CNS 968013 Primary cutaneous DlBCl. leg type 9680/3 EBV positive OLBCL of the elderly 9680/3 Ol BCl associated with chronic inflammation 968013 l ymphomatoid granulomatosis 9766 /1 Primary mediastinal (thymic) large B-celllymphoma Intravascular large B-cell lymphoma AlK positive large B-cell lymphoma Plasmablastic lymphoma l arge Bccell lymphoma arising in HHV8- associated multicentric Castleman disease 9738/3 Nodal marginal zone lymphoma Paediatric nodal marginal zone lymphoma Follicular lymphoma Paediatric folliculaf lymphoma Primary cutaneous follicle centre lymphoma Mantle cell lymphoma 12 WHO ciassitcenon I ~l.. _
  13. 13. HISTIOCYTIC AND DENDRITIC CELL NEOPLASMS Histiocytic sarcoma 9755/3 l angerhans cell histiocytosis 975 1/3 langerhans cell sarcoma 9756/3 Interdigitating dendritic cell sarcoma 9757/3 Follicular dendritic cell sarcoma 975813 Fibroblastic reticular cell tumour 9759/3 Indeterminate dendritic cell tumour 9757/3 Disseminated juvenile xanthogranuloma POST·TRANSPLANT LYMPHOPROUFERATIVE DISORDERS (PTLO) Early lesions P1asmacytic hyperplasia 9971/1 Infectious mononucleosis-like PTLD 9971/1 Polymorphic PTLO 9971/3 Monomorphic PTlO (B- and TINK-cell types)' Classical Hodgkin lymphoma type PTLO'" NOS, not otherwise specified. The italicized numbers are provisiona l codes for the 4th editionof lCD-D. While they are expected to be incorpo- ratedin the next ICD-O edition, they currentty remain subjectto changes. Theitalicized histologic types are provisional entities , for which the WHO Working Group fell there was insufficient evidence to recognize as distinct diseases at this time. "These lesions are classified according to the leukaemia or lymphoma to which they correspond, and are assigned the respectivetCO-G code. WHO classification 13
  14. 14. Introduction to the WHO classification of tumours of-haernatopoletlc and lymphoid tissues NL Harris E. Campo E.S. Jaffe SA Pileri H. Stein S.H. Swerdlow J Thiele Jw. Vardiman ... . Why classify? Classification is the lan- guage of medicine: diseases must be described , defin ed and named before they can be diagnosed, treated and studied. A consensus on definitions and terminol- og y is essential for both clinical practice and investigation. A classification should contain diseases thai are clearly defined. clinically distinctive. norKlVerlappi ng (mu- tually excllsive) and that together comprise all known entities (collectively exhaustive). II should serve as a basis lor future inves- tigation. and should be able to incorporate new information as it becomes available. Classification has two aspects: clas s dis- covery - the proces s of identifying cate- gories of diseases, and class prediction - the process of determining which cere- gory an individualcase belongs to. Pamer- ogi sts are critical to both processes. The World Health Organization (WHO) Classification of Tumours of the Haema- topoietic and Lymp hOid Tissues (4th Edi- tion) was a coll aborative project of the European Association for Haematopathol- ogyand the Society lor Hematopathology. It is a revision and update of the 3rd Edi- tion 11039}. which was the first true worldwide consensus classification of baematoiocic malignancies. The update, which began in 2006, had an a-membe r steering committee composed of members of both societies, The Steering Comminee, in a series of meetings and discussions, agreed on a proposed list of diseases and chapters and selected authors. with input from both societies. As with the WHO 3fd edition 18971. the advice of clin - ical haematologists and oncologists was obtained. in order to ensure that the clas- sification will be clinically useful. TwoClin- ical Advisory Committees (CAG). one for myeloid neoplasms and other acut e leukaemias and one for lymphoid neo- plasms. were convened, The mee tings were organized around a series of questions, inc luding disease definitions, nomenclature, grading. and clinical rele- vance. The committees were able to reach consensus on most of the ques- tions posed. and muc h of the input of the 14 Introduction to the classification committees was incorporated into the class ification. Over 130 pathologists and haem atologists from around the world were involved in writing the chapters. A consensus meeting was held at the head- quarters of the IARC in Lyon, France. to make final decisions on the classification and the content of the book. The WHO classification of tumours of the haematopoietic and lymphoid system is based on the principles initially defined in the "Revised European-American Classi- fication of Lymphoid Neoplasms" (REAL). from the Interna tional Lymphoma Study Group (ILSG) 18981. In the WHO classifi- cation, these principles have also been applied to the class ification of myeloid and histiocy tic neoplasms, The gu iding principle of the REAL and WHO classifi- cations is the attempt to define "real" d iseases that can be recognized by pathologists with available techniques. and that appear be distinct clinical enti- ties. There are 3 important components to this process First. recognizing that the underlying causes of these neo plasms are often unknown and may vary, this ap- proach to classifica tion uses all available information - morphology, immunophe- notype, genetic features, and cl inical fea- tures- to define diseases. The relative impo rtance of each of these features varies among diseases, depend ing upon the state of current knowledge, and there is therefore no one "gold standard," by which all diseases are defined . Second. recognizing that the com plexity 01 the field makes it impossible for a single expert Of small g roup to be comptetely authoritative, and that broad agreement is necessary if a classificati on is to be ac- cepted, this ctassrncanon relies on build- ing a consensus among as many experts as possible on the definition and nomen- clature of the diseases, We recognize that com promise is essential in order to arrive at a consensus, but believe that the only thing worse than an imperfect classifica- tion is multiple competing classifi cations. Finally. while pathologists must take primary responsibility for developing a classification, involvement of clinicians is essential to ensure its usefulness and ac- ceptance in daily practice 18971. At the lime of publication of the WHO classi fication (3rd edition), proponents of other classifi- cations of haematologic neoplasms agreed to use the new classification, thus ending decad es of controversy over the classifi- cation of these tumours 147. 478. t 89. 1B9A, 190, 673,7750 , 1344A. 181981, As indicated above , there is no one -gold standard ," by which all diseases are defined in the WHO classification. Mor- pholog y is always important, and many diseases have characteristic or even di- agnosti c morphologic features, Immune- phe notype and genetic features are an important part of the definition of tumours of the naematopolettc and lymphoid tissues, and the availability of this infor- mation makes arriving at consensus defi- nitions easier now than it was when only subjective morphologic criteria were available. lrrmunophenotyping studies are used in routine diagnosis in the vast majority of haematolog ic malignancies, both to determine lineage in malignant processes and to distinguish benign lrom malignant processes. Many diseases have a characteristic immunophenotype. such that one would hesitate to make the diagnosis in the absence of the immune- phenotype, while in others the immuno- onenotvpe is only part of the diagnosis, In some lymphoid and in many myeloid ne0- plasms a specific genetic abnorma lity is the key defining criterion, while etters lack specific known genetic ebnomantes. Some genetic abnormalities, while char- acteri stic of one disease, are not specific (such as MYC. CCND 1or BCl2rearrange- ments or mutations in JAK2). and others are prognostic factors in several diseases (such as TP53 mutations or FLT3-ITO), The inc lusion of jr munoohenotvoc lea- tures and genetic abnormalities to define entities not only provides objective criteria for disease recogni tion but has identified antigens, genes or pathways that can be targeted for therapy; the success of rituximab, an anti-CD20 molecule, in the
  15. 15. treatment of. B-cel! neoplasms, and 01 imatinib in the treatment of leukaemias as- sociated with ABL 1 and oth re!lrrange- ments involving tryoene kinase genes are testament to this approach. Finally. some diseases require knowledge of clinical features - age, nodal versus extranodal presentanon. specific anatomic site. and history 01 cytotoxic and other therapies - to make the diagnosis. Most 01 the dis- eases described in the WHO classification are considered to be distinct enti ties; however. some are not as clearly defined, and these are listed as provisional entities, In addition . borderline categories ha....e been created in this edition for cases that do not c learly fit into one category, so that well-defined categories can be kept homogeneous, and the borderline cases can be studied further. The WHO classification stratifiesneoplasms primarily according to lineage: myeloid, lymphoid, and histiocyticfdendritic cell. A normal counterpart is postulaled lor each neoplasm. While the goal is to define the lineage of each neoplasm, lineage plas- ticity may occur in precursor or immature neoplasms, and has recently been identi- fied in some mature haematotymphoid neoplasms , In addition, genetic atooe- rreuues such as FGFR1, PDGFA and PDGFB rearrangements may give rise to neoplasms 01either myeloid or lymphoid lineage associated with eosinophilia; these disorders are now recognized as a separate group. Precursor neoplasms (acute myeloid reukaemes. lymphoblastic Iymphomasfleukaemias, acute reukaerraas 01ambiguo us lineag e, and blastic plas- macytoid dendritic ce ll neoplasm) are considered separately from more mature neoplasms [myeloproliferative neoplasms (MPN). myelodysplastic/myeloproliterative neoplasms, myelodysplastic syndromes , mature (peripheral) B-cell and T/NK-cell neoplasms, Hodgkin lymphoma. and his- Iiocyteldeodritic-cell neoplasms]. The ma- ture myeloid neoplasms are stratified according to their biological features (myeIopl'oIiferative, with effective baereio- poiesis. ....ersus myelodysplastic, with in- effective neematcootesfs. as welt as by genetiC features). Within the mature lym- phoid neoplasms, the diseases are listed broadly accord ing to clinical presentation (disseminated often leukaemic, extran - coat. indolent. aggressive). and to some extent according to stage of differentiation when this can be postulated: howe....er the order of listing is in part arbitrary, and is not an integral part of the classification. The 4th edition of the WHO classification incorpo rates new information that has emerged from basic and clinical in....estr- gations in the interval since publication of the 3rd edition. It includes new defining criteria for some disease s, as well as a number of new entities. some defined by genetic criteria - particularly among the myeloid neoplasms- and others by a combination of morphology. immunophe- ootype . and clinical features. The frequent application of immunophenotyping and genetic studies to peripheral blood, bone marrow, and lymph node samp les has also led to the detection of small clonal populations in asymptomatic pe rsons. These include small clones of cells with the BCR-ABL 1 translocation seen in chronic myelogenous leukaemia. small clones of cells with BCL2-IGH rearrangement. and small populations of cells that have the immuoopheootype of chronic lymphocytic leukaemia (e l l ) or follicular lymphoma (monoc lonal B lymphocytosis, follicular lymphoma-in Situ, paediatric follicular hy- perplasia WIth monoclonal B cells). In many case s. it is not clear whether these represent earty involvement by a neoplasm, a precursor iesoo. or an inconsequential find ing. These situations have some analogies to the identification of small monoclonal immunoglobulin components in serum (monoclonal gammopathy of unknown significance), The chapters on these neoplasms include recommenda- tions for dealing with these situations. The recommendations of international con - sensus groups have bee n considered. with regard to criteria for the d iagnosis of e ll, plasma cell myeloma, Waldenstr6m macroglobulinemia, and new subtypes of cutaneous lymphomas, as well as in the development of new algorithms for the diagnosis of MPN . A critical feature of any class ification of diseases is that it be periodically reviewed and updated to incorporate new informa- tion. TheSocietyfor Haematopathology and the European Association for Haemato- pathology now have a more than to-year record of couebceaton and cooperation in this effort. The societies are comm itted to updating and revising the classification as needed. with input lrom clinicians and with the collaboration of the WHO. The experience of developing and updating the WHO classification has produced a new and exciting degree of cooperation and conmunication among patholog ists and oncologists from around the world . which stould facilitate continued progress in the understand ing and treatment of haematotogic manqnaocies . Themullipa- rameter approach to classification, with an emphasis on defining real disease entites. that has been adopted by the WHO classification, has been shown in international studies 10 be reproducible: the diseases defined are clinically dis- ttnct ive. and the uniform definitions and terminology facilitate the interpretation of clinical and translational studies 151, 791. In addition, accurate and precise classifi- cation of d isease entities has facilitated the discovery of the genetic bas is of myeloid and lymphoid neoplasms in the basic science laboratory Introdu ction to the classification 15
  16. 16. -, CHAPTER 1 Introduction and Overview of the Classification of the Myeloid Neoplasms • " ) •
  17. 17. Introduction and overview of the classification of the myeloid neoplasms J.w. Vardiman A.D. Brunning D.A. Arter M.M.Le Beau A. Porwit A. retten C.D. Bloomfield J. Thiele The WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues (3rd edition) published in 200 1 reflected a paradigm shift in the approach to clas- sification of myeloid neoplasms {1039). For the first time. genetic information was in- corporated into diagnostic algorithms provided lor the various entities. The pub- lication was prefac ed with a comment pred icting future revisions necessitated by rapidly emerg ing gen elic information. The cu rrent revision is a commentary on the significant new molecular insights mat have become avail abl e since the publi- cation of the last ctass'ncauon. The first entity described in this mono- graph. chronic myelogenous leukaemia (CML) remains the prototype for the iden- tification and classification of myeloid neoplasms This leukaemia is recognized by its c linical and morphologic features, and its natural progression is character- ized by an increase in blasts of myeloid, lymphoid or mixed myeloid/lymphoid immunophenotype. It is always associ- ated with the BCR·ABL 1fusion gene that results in the production 01 an abnormal protein tyros ine kinase (PTK) with en- hanced enzymatic activity. This protein is sut tcrentto cause the leukaemia and also provides a targ et for protein tyrosi ne kinase inhibi tor (PTKI) therapy that has prolonged the lives of thousands of pa- tients with this often tatal illness {6151. This successful integration of cl inical , morphologic and genetic information em- bodies the goal of the WHO classification scheme. In this revision. a combination of clinical, morpholog ic . immunophenotypic and genetic features is used in an anerrcttc define disease entities , such as CML, that are biolog ically homogeneous and clini- cally relevant - the same approach used in the 3rd ed ition of the classification. Although the previous scheme began to open the door to including genetic ab- normalities as criteria to classi fy myeloid neoplasms, this revision firmly acknowl- edges that as in CML, recurring genetic abno rmalities provide not only objec tive criteria for recognition of speci fic entities but also identification of abnormal gene product s or pathways that are potential targets for therapy. One example in this revised scheme is the addition of a new subgroup of mye loid neoplasms (Tabte 1.01) assoc iated with eos inoph ilia and chromosomal ab normalities that involve the oiateiet-oenved growth factor receptor ..' Table 1.01 Themyeloid neoplasms' majorsul:9'OUJlS and dal;U::i tstic features at~ 0..... 8Mctllularity '10 MIrf'OW bluts .- .........., HatrnatopOitsit ...."""" -MPN Usually increased. tbmaJ or sIighlIy """'" G••,,,''''''', En-. VanabIe;008 or Co<m>oo often normalin ET increased: <10%in -- """..-dI'onic phase relabYe/y normal, IifIeage usually """""""", irullallyincreased """""'"MyeIoidIIymphoid Increased Normal or $IigM~ Present Relatively normal Elfectrve Eosinophilia Com~ neoplasmswith increased: <20% irl j~t 5x10ir1.) eosinophiliaand abriof· cnronc phase maliliesof PDGFRA. PDGFRB Of FGFRI MOS "''''as." Nom1al or increased: Preserlt ~lasia inoreor Inel!&Cti'Ie Cytopenia(s) U _ =- ""'. more myeloid lineage ~aror """""'"M''''''PN """'... -,,- """'" Usually oneormae Moy""Y ...... IariabIe. WBC Co<m>oo incl'eased;<20'10 -- ...... ..--......_""rrft'!lal cIyspIaSIa """"....... _>2ll%. "",", MayOf may J'IOl be ........ WllC_ """'- eQPl in some cases ......, """"""'" ore"ect1ve ..-......'l'Illh specific cybJeneIlc -... dyspIaslai'loneor ...-abnorrnaIilies or in -...... ......some cases of erylhroIeukaemia Mf)N, myeloproliferative neoplasms: MDS, myelod)'spla:slic syndromes;MDSlMf)N, myeIodysplasbcJmyeloprolifefalive neoplasms: AMl, ICIJIe myeloid leukaemia; ET, esseflIlaj Ihfombocylhaemia, JMML.ju¥&nile myelomonocytic leukaemia, wec.wniIe bloocI e&II$. 18 Introduction and overview of the c lassification of the myeloid neoplasms
  18. 18. ] alpha (PDGFflA) Ofplatelet derived growth factor receptor beta (PDGFRB) genes -a subgroup defined larger9 by genetic events that lead to constitutive act ivation of the receptor tyrosine kinase, PDGFA, and that respond to PTKI therapy {13 1, 466. 8121. Similar examples are found throughout the classification in each major subgroup, and include not only neoplasms associated with rmcroscopr- cally recog nizable chromosomal abnor- malities but also with gene mutations without a cytogenetic correlate as weu. On the other hand . the importance 01 careful clinical, morphological and im- munophenotypic characterization of each myeloid neoplasm and coeretanoo with the genetic findings cannot be over- emphasized. The discovery of activating JAK2 mutations has revolutionized the approach to the diagnosis of the myelo- proliferative neoplasms (MPN) 1163, 1044, 1186,12681. Yet JAK2mutatiQns are not specific for any single clinical or morpho- logic MPN phenotype, and are also reported in some cases 01 myelodysplas- tic syndromes (MDS), myeiooysplasnc/ myeloproliferative neoplasms (MDSlMPN) and acute myeloid leukaemia (AMl). Thus, an integ rate d, multidisciplinary approach is necessary for the classification of myeloid neoplasms. With so much yet 10 learn, there may be some 'missteps" as traditional approaches to categorization are fused with more rrcecuarfy-orentec clessifcatonschemes, Nevertheless, this revi sion of the WHO classification is an attempt by the authors, editors and the clinic ians who served as members of the Clinica l Advisory Com- mittee (CAC ) to provide an "evidence- based" classification that can be used in daily practice for therap eutic decisions and yet provide a flexible framework for integration of new data, Prerequisites for classification ofmyeloid neoplasms by WHO criteria The WHO classification of myeloid neo- plasms relies on the morphologic, cyto- chemical and immunophenotypic features of the neoplastic cells to establish thei r lineage and deg ree 01 maturation and to decide whether cellular prolife ration is q101ogically normal or dysplastic or esecuve or ineffective . The classification is based on cr iteria applied 10 initial spec- imens obtained prior to any definitive ther- apy, including growth lactor therapy, for the myeloid neoplasm. The blast percentage in the peripheral blood , bone marrow and other involved tissues remains of practical impo rtance to categorize myeloid neo- plasms and to judge their progression. Cytogenetic and molecular genetic stud- ies are requ ired at the time of diagnosis not only for recoqr nton 01 specific genet- ically defined entities, but for establiShing a baseline against which futu re studies can be judged to assess disease pro- gression. Beca use of the multidisciplinary approach required to diagnose and clas- sify myeloid neoplasms it is recomnended thaI the various diagnostic studies be correlated with the clinical findings and reported in a single, integ rated report. If a definitive classification cannot be reached the report should indicate the reasons why and provide guidelines for additional studies that may clarify the diagnosis. To obtain consistency, the following guidelines are recommended for the eval- uation of specimens when a myeloid neo- plasm is suspected to be present. It is assumed that this evalua tion will be per- formed with full knowledge of the clinical history and pertinent laboratory data. Morphology Peripheral blood: A perip heral blood (PB) smear should be exa mined and co rre- lated with results of a co mplete blood count. Freshly mad e smea rs should be sta ined with May-Gnmwald -Giernsa or Wright-Giemsa and examined for wh ite blood ce ll (WBC) , red blood ce ll (ABC) and platelet abnormalities It is important to ascerta in that the smears are well- stained, Evaluation of neutrophil granularity is important when a myeloid disorder is suspected; designation of neutrophils as abnormal based on hypog ranular cyto- plasm alone shoul d not be considered unless the stain is well-controlled . Manual 2OO-cell leukocyte di fferentials of PB smears are recommended in patients with a myeloid neoplasm when the WBC count permits. Bone manowaspirate: Bonemarrow (BM) aspirate smears should also be stained with May-GrQnwald-Giemsa or Wright- Giemsa for optimal visualization of cyto- plasmic granules and nuclear chromatin. Because the WHO Classification relies on percentages of blasts and other specific 11111111 111I 1111 1111 111111 4 5 6 F'S!. 1.01 Bone marrow tIeI:Me biopsy, Bone marfOW b'ephinebiopsies should be alleast 1.5em inlength and ollt<w1ed at right angles10 the cortical bone. cells to categorize some eoutes. it is rec- ommended that 500 nucleated BM cells be counted on cellular aspirate smears in an area as close to the particle and as undiluted with blood as possible. Countll"lQ from multiple smears may reduce sam- pling error due to irregular distribution of cells. The cells to be counted include blasts and promonocytes (see definition below) . pronveocvtes. myelocytes, meta- myelocytes, band neutrophils, segmented neutrophils, eosiropnns. basophils, fTlQIlO- cytes , lymphocytes. plasma cells, erythrOid precursors and mast cells. Megakaryo- cvtes. including dysplastic forms. are not included. If a concomitant non-myeloid neoplasm is present, such as plasma ceu myeloma, it is reasonable to exclude those neoplastic cells from the coun t used to evaluate the myeloid neoplasm. If an aspirate ca nnot be obtained due to fibrosis Of ce llular packing, touch prepa- rations of the biopsy may yield valuable cytolog ic information, but differential co unts from touch preparations may not be representative . The differential counts obtained from marrow aspi rates should be compared to an estimate of the pro- portions of cells observed in available biopsy sections, Bone marrow trephine biopsy: The contri- bution of adequate 8M biopsy sections in the diagnosis of myeloid neoplasms can- not be overstated. The trephine biopsy provides information rega rding overall cellularity and the topog raphy, proportion and maturation of baematopolenc cells , and allows evaluation of 8M stroma. The biopsy also provides material for immuno- histochemical studies that may have diagnostic and prognostic importance. A biopsy is essential whenever there is myelofibrosis,and the classificationof sore entities, partiCularly MPN, relies heavily on trephine sections, Thespecimen must be Introduction and overview of the ctassncauoo at the myeloid neoplasms 19
  19. 19. adeq uate, Iaken at right angle from the cortica l bone and at least 1.5 cm in length to enable the evaluation of at least 10 par- tially preserved inter-trabecular areas. It should be well-fixed, thinly sectioned at 3-4 micra, and stained with haematoxylin and eosin and/or a stain such as Giemsa that allows lor detailed morphologic eval- uation. A silver impregnation method for reticulin fibres is recommended and marrow fibrosis graded according to the European consensus scoring system 122141, A periodic acid-Schitt (PAS) stain may aid in detection 01 megakaryocytes. Immunohistochemical (IHe) study of the biopsy is often indispensable in the eval- uation of myeloid neoplasms and is dis- cussed belOw, Blasts: The percentage of myeloid blasts is important for dl8gnosis and ctasstcaton of myeloid neoplasms, In the PB the blast percentage should be derived from a 200-cell leukocyte differential and in the 8M from a 500-cell count of cellular 8M aspirate smears as described above. The blast percentage derived 'rom the 8M aspirate should correlate With an estimate of the blast percentage in the trephine biopsy. although large focal clusters or sheets 01blasts in the biopsy should be regarded as possible disease progression. Immunohistochemical staining of the BM biopsy for CD34+ blasts often aids in the correlation of aspirate and trephine biopsy findings, although in some myeloid neo- plasms the blasts do not express CD34, Flow cytometry determination of blast percentage should not be used as a sub- stitute for visual inspection. The specimen for flow cytometry is otten haemoouute. and may be affected by a number of pre- analytic variables. and as noted for the biopsy. not all blasts express CD34. Myeloblasts. monoblasts and megakary<> blasts are included in the blast count. Myeloblasts vary from slightly larger than mature lymphocytes to the size of mono- cvtes or larger. with moderate to abun- dant dark blue to blue-grey cytoplasm. The nuclei are round to oval with finely granul ar chromatin and usually several nucleoli. but in some nuclear irregularities may be prominent. The cytoplasm may contain a few azurophil granules(Fig 1,03), Monoblasts are large cells with abundant cytoplasm that can be light grey to deeply blue and may show pseudopod formation (Fig 1.04 A.S). Their nuclei are usually round with delicate , lacy chromatin and one or more large prominent nucleoli. . , They are usually strongly positive for n0n- specific esterase(NSE)but have noor only weak myeloperoxidase (MPO) activity, Promonocytes are considered as ' rrooo- blast equivalents" when the requisite per- centage 01 blasts is tallied for the diagnosis of acute monoblastic . acute monocytic and acute myerorronocync leukaemia. Promonoc vtes have a deli- cately convoluted. folded or grooved nucleus with finely dispersed chromatin, a small, indistinct or absent nucleolus, and finely granulated cytoplasm (Fig 1.04 C, 0), Most promonocytes express NSE and are likely to have MPO activity. The distinction between monobrasts and prornonocvte s is often difficult. but because the two cell types are summated ... • 20 Introduction and overview of the classification of the myeloid neoplasms
  20. 20. B o F inhibited by NaF, The combination of NSE and the specific esterase, naphthol-ASD- chloroacetate esterase (CAE), which stains primarily cells 01 the neutrophil lineage and mast cells, permits identification of monccvtes and immature and mature neutroph ils simultaneously. Some cells, particularty in myeIornonocytic leukaemias, may exhibit NSE and CAE simultaneously. While normal eosinoph ils lack CAE, it may be expressed by neoplastic eosooohne. CAE can be performed on tissue sections as well as PB ()( marrow aspirate smears. , - ~~ . • • A E c Fig. 1.04 Monoblasts, promonocytes and abnormal mcnccytea from a case of acute monocytic laukaemia. A, B Monoblastsarelarge withabundant cylOlJlasm that maycontain afew vacuoles Of fine granules and have roullCl nuclei withlacy chroma~n and oneOfmore variablyprominent nucleoli. C, DPrornor.ocytes have more irregular ancl delicately folded n~ withfine chroma~n, small indistinct nucleoli and finely granulated cytoplasm. E, FAbnormal monocytes appear immature, yet have more condensed nuclear chromatin, con'o'Q/uledOf fddednuclai, and more cylopIasmiC granulaboo (Courtesyof Or. J.Goasguen). case light grey granules are seen rather than the deeply black granules that char- acterize mverobrasts. The non-specific esterases .u naphthyl butyrate (ANB) and (,( naphthyl acetate (ANA). show diffuse cytoplasmic activity in monoblasts and monocytes. Lymphoblasts may have focal punctate activity with NSE but neutrophils are usually negative. Megakaryoblasts and erythroid blasts may have some mul- titocal. punctate ANA positivity, but it is partially resistant to natrium ffuoride (NaF) inhibition whereas monocyte NSE is totally as rronootasfs in making the diagnosis of AML, the distinction between a monoblast and promonocyte is not aly,.ogys critical. On the other hand, distinguishin g pro- monocvtes from more mature but ab- normalleukaemic monocytes can also be dilficult, but is critical, because the des- ignation 01 a case as acu te monocytic or acute myelomonocytic leukaemia versus chronic myelomonocytic leukaemia olten hinges on this distinclion. Abnormal rrooocvtes havemore clumped chromatin than a promonocyte, variably indented. folded nuclei and grey cytoplasm with rrore abundant lilac-colored granules . Nu- cleoli are usually absent or indi stinct (Ftg 1.04 E.F). Abnormal monocytes are rot considered as monoblast eouvaeots. Megakaryoblasts are usually 01rreoen to large size with a round , indented or irregular nucleus with finefy reticular chromatin and one to three nucleoli. The cytOplasm is basophiliC, usually agranular, and may show cytoplasmic blebs (See Chapter 6 on acute myeloid leukaemia, NOS). Small dysplastic megakaryocytes andmicrornegal<.aryocytes are not blasts. Inacute promyelocytic leukaemia, the blast equivalent is the abnormal promyelocyte. Erythroid precursors (erythroblasts) are rot included in the blast count except in the rare instance of "pure" acute erythroid leukaemia, in which case they are consid- ered as blast equiva lents (See Chapter 6 onacute myeloid leukaemia, NOS). Cytochemistry and other special steins: Cytochemical studies are used to deter- mine the lineage 01 blasts, although in some laboratories they have bee n sup- planted by immun ologic studies using flow cytometry and/or immunohistochem- istry. They are usually performed on PB and8M aspirate smears but some can be performed on sections 01trephine biop - sies or other tissues. Detec tion 01 MPO indicates myeloid d ifferentia tion but its absence does not exclude a myeloid lin- eage because early myeloblasts as well asmonoblasts may lack MPO. The MPO activity in rrweiobtasrs is usually granular and etten concentrated in the Golgi region whereas monobtasts. although usually negative,may show line, scattered MPO+ granules, a pattern that becomes more pronounced in prcmonocvtes. Erythroid blasts, megakaryoblasts and Iymphoblasts are MPO negative. Sudan Black B (SSBl staining parallels MPO but is less spe- etc. Occasional cases of lymphoblastic leult.aemia exhibit SSB POSitiVIty, in which Introduction and overview 01 the ctass.tcanoo 01 the myeloid neoplasms 21
  21. 21. In acute erythroid leukaemia. a PAS stain may be helpful in that the cytoplasm of the leukaemic oroervmrobreatemay show large globules of PAS positivity. Well- controlled iron stains should always be per formed on the 8M aspirate to detect iroo stores. normal sideroblasts and ring siderobrasts. the latter of which are de- fined as erythroid precursors with 5 or more granules of iron encircling one-third ormore of the nucleus. Immunophenotype Immunophenotypic analysis using either multiparameter flow cytometry or IHe is an essential tool in the characterization of myeloid neoplasms. Differootiation antigens that appear at various stages of haemato- oo'euc develo pment and in correspon- ding myeloid neoplasms are illustrated in Fig. 1.05. and a thorough descriplion of lineage assignment criteria is provided in the chapters on mixed phenotype acute leukaemia, The techniques employed and the antigens anafyzed may vary accord- ing to the myeloid neoplasm suspected and the information required 10 best char- acterize it as well as by the tissue avail- able. Although often important in the diagnosis ol any haematoiogicaJ neoplasm. immunophenotyping in myeloid neoplasms is most commonly required in AML and in determining the phenotype of blasts at the lime of transfo rmation of MOS. MOS!MPN and MPN, Mulliparameter flow cytometry is the prefer red method of immuno phenotypic analysis in AML due to the ability to ana- lyze high numbers of cells in a relatively short period of time with simultaneous recording of information about severer antigens for each individual cell. Usually. rather extensive panels of monoclonal an- tibodies directed against leukocyte differ- entiation antigens are applied because C U lM- C I)l63+ C IU+ COU+ C O l5-+- COll ++ C DJ .... C OM+ IH...A-OR+ C O l lb++ C O l -t-t "'"CDl6- C D235.- • C U.14- C O.II++ C I)6 I++ C I).&1-+-+ C U"' l+ em s- C lU J '" M''O+ C D65+ C U15+ C D IIII+ C1U 5tlim e m s- m nmx: ylf' pc.olycbrvm.lk toryl hruh l• • 1 c m l 7- ' fh+ C DJ6 - Cll1J~.- C IH Jd lm C IU J + MPO+ C))65+ C D I5+ C U ll b+'_ C DJ4· C DJ8+ C 061+ C 04I+ C04l +I· • C U1I7+ llb-I+ C D.l6- CDIJ ~'- b ....p bllk: torylb rub l.,. C O Il 7+1- C ll1 J+ CD33+ MPO+ C:0 65+ C D I5+/· p rumo"ucy'' ,------''-, r'----, + C IUJ+ CO IS+ C IU J + C D36-+ C I)6"+ HL- -DR+ CO ll b+ C D I4+ mon..hl . ~1 C UJ4+I. C DJ M.,_ C D61+ C I).&I+ ce-e- _ n _ C D3.. + ClHM_ C D IlJ-. C1 U 5 HA - TI'O -R+ C D3.. +-+ 1I1.A.-UR C D.N+-+ Un_ C DJ..... C IH M+ C D U J- C1U5RA+ C U34_ liLA-DR t-tlL -"-LO"--l,. C U.H++ C O}4... C IU + C D U'" ' r"",,::7:-:-~01 C IU 3'"II liLA-DR'" <--U II 7+ lib- C U,J.- C OlJ5.- prvQ')"lbn>bla. 1 22 mtrocucuco and overview of lhe classification of the myeloid neoplasms
  22. 22. J the utility of in,s:livid ual markers in identify- ing commitment of leukaemic cells into the different haemat opoietic tlneages is limited Evaluation of expression patterns of several antigens, both membrane and cytoplasmic, is necessary for lineage assignment. to detect mixed phenotype acute leukaemia, and 10 detect aberrant phenotypes allowing lor follow-up of minimal residual d isease . Irrmunopheootypic analysis has a central role in disting uishing between minimally dllferentiated acute myeloid leukaemia and acute lymphoblastic leukaemia, and in CML between myeloid blast phase andlymphoid blast phase. Among AM L WIth recurrent genetic abnormalities, sev- eral have characteristicphenotypes. These patterns. described in the respective sections,can help to plan molecular cvto- genetIC {lluorescence in situ hybrid ization (FISHlI and molecular investigations in individual patients, lm munophenotypic features or the other AMl categor ies are extremely heterogeneous. probably due tohigh genetic diversity. Although it has been suggested that expression of cer- tam antiqens, such as CD?, COO, COl lb, C014. CD56 and CD34 could be associ- ated with an adver se prognosis in AMl, their independent prognostic value is still controversial. Aberrant orunusual omoro- phenotypes have been found in at least 75%of cases of AMl. These can be described as cross-lineage antigen ex- pression, maturational async hronous expression of antigens, antigen overex- pression, and the reduction or abse nce of antigen expressio n, Similar aberrancies have also been reported in MDS as well. and their presencecan be used to support the diagnosis in early or morpholog ically ambiguouscases of MDS (See Chapter 5). lm11unophenotyping by IHC on8 M biopsy sections can be applied if ma rrow cell suspensions are nol available for flow cy- tcmetry analysis. Antibodies reactive with paraffin-embedded BM biopsy tissue are available for many lineage-associated markers (e,g. MPO.lysozyme, CD3, PAX:s, C033, etc.). As noted previously, CD34 staining of the biopsy can fac ilitate the detection of blasts and their distribution , provided the blasts express CD341 1650/. For casesrich in megalob lastoid erythro- blasts. immunohistolog y for glycophorin or haemoglobin may be helpful in dist in- guishing those cells from myeicotasts (eg. in cases of RAEB or acute erythro- 1eI.Memia), and COOl or CD42 oflen aid in the identification of abnormal mega- karvocytes. Genetic studies The WHO classification includes a num- ber of entities defined in part by scecmc genetic abnormalities. including gene rearrangements due 10 chromosomal nansrccarrons and to specific gene muta- tions. so determination of genet ic features of the neoplastic cells must be performed if possible. A complete cytogenetic analy- sis of 8M should be perlormed at the time of initial evaluation to establish the cyto- genetic profile, and at regu lar intervals thereafter to detect evidence of genetic evolution . Additional d iagnostic genetic studies should be guided by the diagnosis suspected on clinica l, morphologic and imTulophenotypi studies. In some cases, reverse transcriptase-polymerase chain reaction (AT-PCR) and/or FISH may de- tect gene rearrangements thai are pres- ent in low frequency and not observed in the initial chromosomal analysis, in cases with var iants of typical cytogenetic abnormalities, and in cases in which the abnormality is cryptic , such as the PDGFRA-FIP1L 1 fusion in myeloid neo- plasms associated with eosinophilia, De- pending on the abnormality, quantitative PCR performed at the time of diagnosis may also provide a baseline against which the response to therapy can be monitored . A number of gene mutations detected by gene sequencing, allele- specific Pe A and other techniques have emerge d as important diagnostic and prognostic markers in all categories of mye loid neoplasms, Mutations of JAK2, MPL, NRAS, NFl, PTPN 11, and KIT in MPN and MDS/MPN, and NPM1, CEBPA, FLT3, RUNX1 and KIT, among others. in AMl are important for d iagnosis and prognosis. and some. particularly JAK2, FLT3, NPM 1 and CE8PA figure impor- tantly in this revised classification. Fur- thermore, the role of gene over- and unde r-expression as well as loss of het- erozygosity and copy number variants detected by array-based approaches are only now being recognized as important abnormalities that may well influence diagnostic and prognostic models in the near future 11531AI. Nevertheless, microarray prof iling studies. although important in the research setting , have not yet been tested in clinical practice. Revised WHO classification of myeloid neoplasms Table 1,0 1 lists the major subgroups of myelold neoplasms and their characteristic features at diagnosis. The nomenclature for the myeloproliferative entities has been changed from "chronic myeloproliferative diseases" to ·myeIoproIiferative neoplasms" and the subgroup formerly designated as "myelod ys pl as ticfmyelo p ro li fe rati ve diseases" has been changed to "myelodysplasticJmyeloproliferative ne0- prasms" to underscore their neoplastic nature. Besides the addition of the new subgroup. "Myeloid and lymphoid ne0- plasms with eosinophilia and abnormalities of PDGFRA, PDGFR8 and FGFRt ,· new entities have been added and/or diag- nostic criteria updated within each sub- group. Myeloproliferative neoplasms (MPN) The MPN (Table 1.02) are clonal haeretc- porenc stem cell disorders Characterized by proliferation of one or more of the myeloid lineages (l.e. granulocytic , ery- throid . megakaryocytic and mast cell). They are primarily neoplasms of ad ults that peak in frequency in the 5th to 7th decade, but some subtypes. particularly CMl and essential thrombocythaemia (ET), are reported in children as well. The incidence of all sub types combined is 6-10/100,000 population annually {1053, 1059. 1060 f, Initially. MPN is cha racterized by hyper- cellularity of the BM with effective naematoporetc maturation and increased numbers of gra nulocytes, red blood ce lls and/o r plate lets in the PB. Splenomegaly and hepatomegaly are common and caused by sequestration of excess blood cells orproliferation of abnormal raemato- poietic cells, Despite an insidious onset each MPN has the potential to undergo a Table 1.02 ~live neoplasms (MPN). ChrtncITl)9logenous1Bukaen'ia, BCR-ABI.posibYe (CMl) Clwtlnic. neutrophilic leubeml8 (CNL) ~'o'efil (PV} """'" _ _ (PM~ ESSoElI'IUl ~ (ET) Oworic eosnophic Ieukaer'ru.NOS lea NOS) "'-MyelqiltMaabYeneoplasm,loI'ldasslJable (UPN,U) introouctco and overview of the ctassrncanon of the myek>id neoplasms 23
  23. 23. CML Myeloid neoplasms with eosinophilia PV PMF ET Mastocytosis ABU PDGFRA,PDGFRB,FGFR1 JAK2 V617F, JAK exon 12 JAK2V617F, MPL W15 1UK JAK2V617F, MPL W151 UK KITD816V Fig. ' .06 Myeloprololerative neoplasms (t.4PN)andoIhet myeloid neoplasms associated W11t1 mutaliOnlrearrangementoftyrosine kinase genes. [ j stepwise progression that terminate s in marrow failure due to myelofibrosis, inef- fective haematopoiesis or Iransformalion 10 an acute blast phase. Evidence of ge- netic evolution usually heralds disease progression as may increasing organa- megaly, increasing or decreasing blood counts, myelofi brosis and onset 01myelo- dysplasia. The finding of 10-19% blasts in the P8 Of 8M generally signifies accel- erated disease and 20% or more is suHicient for a diagnosis 01blast phase. Rationale for tho diagnosis and classification of MPN In previous classification schemes the detection of the Philadelphi a chromo- some and/or BCR-ABL1fusion gene was used to coolirm the diagnosis of CMl whereas the remaining MPN subtypes were diagnosed by their clinical and labo ratory features with relatively minor contributions to the diagnosis from mor- phologic findings. A number of criteria were required not only to distinguish subtypes of MPN from each other but from reactive granulocytic. erythroid andl or megakaryocytic hyperplasia. Revisions in the criteria for cla ssification of MPN in the current scheme have been influenced by two factors - the recent discovery of genetic abnormalities in- volved in the pathogenesis of BCR-ABL1 negative MPN and the wider appreciation that histologic features (megakaryocytic morphology and topograph y, marrow stromal changes, identification 01specific cell lineages involved in the proliferation) correlate with clinical features and can be used as criteria to identi fy MPN subtypes {2177. 2216, 22221. Most if not all MPN are associated with clona l abnormalities involving genes that encode cytoplasmic or receptor PTKs. The abnormalities described to da te include transiccanons Of point mutations of genes that result in abnormal, constitu- tively abnormal PTKs that activate signal transducti on pathways leading to the abnormal proliferation. In some cases, these genetic abnormalities. such as the BCR-ABL1fusion gene in CMl . areesso- cia ted with consistent clinical, laboratcry and morphologic findings that allow them to be utilized as major criteria for classfi- cation, whereas others provide proof that the myeloid prolifera tion is neoplastic rather than reactive. Acquired somat ic mutations of JAK2. at chromosome 9p24. have been shown);) playa pivotal role in the pathogenesisd many cases of BCR-ABL 1negative MPH 11044, 1163, 1186, 1287A, 12881. The most common mutation, JAK2 V617F, re- sults in a constitutively active cytoplasmic JAK2 that activates signal transducer and activator of transcription (STAT), mitogen activated protein kinase (MAPK) and phospholidyllnositol a-kmase(P13K) sigo naling pathways to prorote transforma1Ol and proliferation of baemaroooenc pro. genitors (Fig. 1.07). The JAK2V617Fmu- tation is found In almost all patients wit~ polycythaemia vera (PV) and in near~ one-half of those with primary myelofil:Jrosis 24 Introdu::tion and overview of the classi fication of the myeloid neoplasms
  24. 24. Activation of gene!o Important in proliferation andsurvival their relevan ce are in progress and revi- sions may be necessary. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 Determi ning the cause of marked , per- sistent eosinophilia (~ 1 .5x1()9/l) in the blood can be challengi ng and is some- times cli nically urgent because 01 the potential damage to the heart, lungs , cen- tral nervous and other organ systems caused by the eosinophilic infiltration and release of cvtocnes. enzymes and other proteins. The eoeoooous may be derived from the neoplastic clone of a myeloid neoplasm, such as GEL, GMl orAMl, or lhey may be reactive due to abnormal ~ I (0 I E0 I ~0 I @jJ -- ------- IX B I Akt ¥ ""'-.,TO FoxO A and abnormalities 01 PDGFRA. PDGFRBor FGFR1 , If none of these rearrangements are detected, and there is no BCR-ABL 7 fusion gene, they should be categorized as GEL, not otherwise specified 4. The diagnostic algorithms for PV, ET and PMF ha ve been substantially changed to incl ude information regarding JAK2 and similar activating mutations as well as pertinent histolog ic features 01the 8M biopsy as diag nostic Criteria. 5. The threshold of the platelet count for the diagnosis of ET has been lowered to ~45Ox 1 Q91l. 6. Criteria for CMl in accelerated phase have been suggested with the caveat that they have not been fully evaluated in the era of PTKI therapy: studies 10 determine Fig. 1.07 MecRanism oractivatiOn aIJA1<2 kinaseactMtyby rn.rtaIiOns in the JAK2 Signalirg pathway. It.Cytokile ligalldsnormaHy bind cytokine recepIors, .tlich resultsinJaI'llS kiase 2 (JAK2) pIlosphoryIatio, recruilmenI aIsq.at rcInsduc:er and actrvator allJansaipbon (Stal) signaling protelns and pIlospholyIation alld activatiOn ofdownstream SigRaIing pathways ind.I:lIng SIal ~ lactor&,lTIlogefIlIdMlled proIeIn U1ase(MAPK) sigMWlg proteins , arIl the phosphotidyinos 3-kinase (Pl3K)--Akt pathway B The JAK2 Vfi17F alld JAK2 ewn 121Tl11anl kilases bind cytokine recepIors, are phosphorylated il the absence alligand and lead to~ activation aI0JwIn. streamsignaing palhways. C Bycontrast, MPl. W515lA(rrUal'lllhiOi'~ recepb$ are able 10 phospI1Oi'yale ri1-Iype JAK2lithe absence 01 hanbopoleIi., and red IItle aetwabon ofsignaling paltrways <townstream01IN<2. Negativeregulation 01 JAX2 sigNIng is nonnaIy medIaIed bysuwessorofcytome s9laIilg (Socs) proWls, most notably SOCSl alld SOCS3; recent dala i'ldic3IeIhalthe JAK2 V617F aIeIe night escape negatiYe IeectIacll by SOCS3. Repro:U;:ed from {1287AI Stmnary 01major changes in the classilication of MPN I. The nomenclature , 'mveiopronteranve disease" has been changed to "myelo- proliferative neoplasm" 2, Mastocytosishas been included in the MPN category 3 Some cases previously meeting the Cfllena forchronic eosinophilic leukaemia (CEllmay now be categorized as myeloid (J ~d neoplasms with eosinophilia (PfvlF) and wit~ esseotelmoroocvmaeraa (ET), In the few PV patients wnolack the JAK2 V617F, an acti vating JAK2exon 12 mutation may be found , and in a small proportion of cas es of PMF and ET, an ac- tivating mutation 01 MPL W515l or W5 15K is seen. It is important 10 note that JAK2 V617F is not specific for any MPN nor does its absence exd ude MPN . Further- more, it has been reported in some cases of MDS/MPN, in rare cases of AMl, and incombination with other well-defined ge- netic abnormalities such as the BCR-A8L 7 110641. Thus, diagnostic algorittvns for PIl, ET and PMF have been altered to take the mutationalstatus of JAK2 into account as weN as 10outline the additional laboratory and histo6ogic "ndi~JS required to reach anaccurate classification 01 cases, re- gardless 01 whether the mutation is or is notpresent. In addition to the changes in the criteria lorN, ET and PMF, information reg arding abnormal PTK toncnon due to rearrange- mentsofthe POGFRA, PDGFRBor FGFR1 genes in patients with myeloid neoplasms associated with eosinophilia led to reap- praisaland new diag'1ostiCalgorithms for thosesyndromes as well (see below). The appreciation01the role altered PTKs play in the pathogenesis of CMl, PV, ET and PMFalso argues lor the inclusion of simi- lar chronic myeloid pronteranons related 10 PTK abnormalities under the MPN um- brella.Thus,systemic mastocytosis, which hasmany features in common with other MPN entities and is almost always asso- ciated with D816V mutation in the KIT geneencoding the recep tor PTK, KIT, has beenadded to this category 121761 Still, tI"1e molecular pathogenesis of nearly half of all cases of ET and PMF, of all cases of chronic neutrophilic leukaemia and a mm berof myeloid neoplasms associated with eosinophilia remai n unkn own. For thesereliance on clinical, laboratory and morphologic features is essenti al for diagnosis and classification, Introduction and overview of the classification 01 the myeloid neoplasms 25
  25. 25. cytoki ne release from reactive or neo- plastic r-ceus. In a number of cases. no underlying cause can be fOund and the clonahty of the eosinophils cannot be proven: these cases are app ropriately termed "idiopathic hypereosinophilic ssn- drome" (See Chapters 2 and 3). Rationale for diagnosis and classification of myeloid and lymphoid disorders with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR, Since the last edition of the WHO classifi- cation it has been recognized that many cases of eosinophilia, including a sub- stantial number considered as "idiopathic" are clonal myeloid neoplasms caused by abnormalities in genes that encode the alpha or beta chains 01 the receptor PTKs, platelet derived growth factor receptor (PDGFR) or fibroblast growth factor reo ceptor 1 (FGFR1), Rearrangements 01 PDGFRB at chromosome band 5q33 that lead to constitutive activation of the beta moiety of PDGFA were first recogni zed in cases variably reported as CEL or chronic myelomonocytic leukaemia (CMML) with eosinophilia 1131, 812. 20851. More re- cently the gene that encodes the alpha moiety of the PDGFR, PDG FRA, at chro- mosome band 4q12. was found to be involved in cryptic translocat ions in CEl and in nearty one-half of cases reported as idiopathic hypereosinophilic syndrome 14661· In addition, rearrangements of the FGFR 1 tyrosine kinase gene have also been implicated in myeiooronteratrons with prominent eosinophilia 13, 13541. However, the clinical and morphologic presentations associat ed with FGFR 1 rearrangement are variable, and include not only presentation as a myeloprolifera- tive neop lasm with eosinophilia, bul also as AML and they may even present as, or evolve to. precursor T or B lymphoblastic leukaemia/lymphoma with prominent eo- sinophits Cases associated with PDGFRA rearrangements can likewise present as AMl or precursor t-een neoplasms 114691. Tlb.. 1.03 Myeloid and lymphoid neoplasms W11t1 eosmphi liaard abnormal~m ol POOFRA,POOFRB,or FGFR1. Myeloid and lymphoid neoplasms with PDGFRA real1"angement Myeloid nooplasms withPDGFRB rearrangemeot Myeloid aooIylTVIOid neoplasms wiltl FGFRf abnormallbes Although it might seem most efficient to categorize these cases as CEl within MPN, this would ignOfe cases WIth PDGFRB abnormalities that present as CMML as well as cases of FGFR1 and PDGFRA rearrangements that may even have a lymphoid conoooenr. To accom- modate Ihese transiccatons. a new sub- group defined largely by the genetic abnormalities of PDGFRA, PDGFRB or FGFR1 has been added (Table 1.03). Detection of one of these abnormalities places the case in this category, regard- less at the morpholog ic classification. Cases of myeloid neoplasms with eosinophilia that lack all of these abnor- malities and that meet the criteria for CEL. NOS, in the MPN catecov should be placed in that group. Myelodysplastic/myeloproliferative neoplasms (MDSlMPN) The MDS/MPN (Table 1.04) include clonal myeloid neoplasms that at the time of ini- tial presentation have some clinical, labo- ratory or morphologic findings that support a diagnosis of MDS, and other findings more consistent with MPN They are usually characterized by bvpercenu- larity of the BM due to proliferation in one or more of the myeloid lineages. Fre- quently, the proliferation is effective in some lineages with increased numbers of circulating cells that may be morphologi- cally and/or func tionally dysplastic. Si- multaneously, one or more 01 the other lineages may exhibit ineffective prolifera- tion so that cytopenlate) may be present as well. The blast percentage in the BM and blood is always <20%, Although hepatosplenomegaly is common, the clin- ical and laboratory findings vary and lie along a continuum between those usually associ ated with MDS or those usually associated with MPN Patients with a well- defined MPN who develop dysplasia and ineffective haematopoiesis as part of the natural history of their disease or after chemotherapy should not be placed in this category. Rarely, some patients may present in a transformed stage of an MPN entity in which the chronic phase was not recognized, and may have findings that suggest that they belong to the MDS/MPN group. In such cases, if clinical and labo- ratory stud ies fail to reveal the nature of the underlying process, the designation of MDS/MPN, unclassifiable may be ap· orcorare.Paneotswro havethe BCR·ABL 1 fusion gene or rearrangementsof PfX3FRA TableU4 ~neopIasms (MDSlMPN). cmnc myelomonocyllc leukaenU (CMMl) Atypocal chrooiC myeloid leukae~ , BCR-ABLI negative (aCMl) JIMIrIiIe myelomooocytic leukaemia (""'Ml) MyekldysplastcIMyeloproliferative neoplasm, undassdiable (MDSlMPN ,U) Provisional entity: Refractory anaemia wittlMrlg sideroblasts and ltJramt>ocytasis (RARS-n should not be categorized as MDS/MPN. and in contrast to the criteria used in the 3rd edition of the WHO classification, cases of CMML with PDGFRB rearrange- ments are also excluded Rationale for diagnosis and classification of MDSlMPN This diagnostic category was introduced in the 3rd edition amidst controversy as to wl1ether some entities, particularly CMML, would be better categorized as either MDS or MPN depending on the extent of myeloprol iferation as evidenced by the WBC count. Some cases of CMML have low neutrophil counts and only modestly elevated monocyte counts and resemble MDS clinically and morphologically whereas others have markedly elevated WBC counts and organomegaly more in keeping with MPN. yet criteria that clearly distinguish biologiCally relevant subtypes of CMML remain to be defined . To date, a lew cases of CMML and atypi- cal chronic myeloid leukaemia, BCR-ABL1 negative (aCML) have been reported to demonstrate JAK2mutations that charac- terize BCR-ABL 1 negative MPN, but the prol iferative aspec ts of most cases of MPD/MPN are related to aberrancies in the AAS/MAPK signaling pathways. In ju- venile myelQmonocyticleukaemia (JMML) nearly 80% of patients demonstrate mutually exclusive mutations 01 PTNPN1', NRAS or KRAS, or NFl 11329. 2096, 21621. all of wl1ichencode signaling pro- teins in AAS dependent pathways, and approximately 30- 40% of cases of CMML and aCML exhibit NRAS mutations {1686, 2311, 24171. In view of the lack of any specific genetic abnormality 10 suggest that these entities should be relocated 10 another myeloid subgroup, they remainin this "mixed" category which acknowledges the overlap that may occur between MDS and MPN.Casesof CMML with eosinophilia associated with PfX3FRB rearrangements are excluded , but rare cases of CMML nurooocuoo and overview 01 the classification of the myeloid neoplasms
  26. 26. witheosinophilia that do not exhibit such rearrangements should be cJassified in thiscategOry Themost controverstat issue in the sub- groupatMDSIMPN is the provisional entity. refractory anaemia with ring sideroblasts andthrombocytosis (RAR5-T). The major- ity(SO- 60%) 01 cases of RARS-T studied lor JAK2V617F carry this mutation 1234. 354.762 , 1835. 1839. 1969,2081,2139. 23581. This has prompted the notion that RARS-T should be moved to the MPN group of myeloid neoplasms. whereas othershave argued thaI RARS-Tis not an entity at all but merely one of the better recogniZed MPN entities, such as PMF or ET. i'l which genetic evolution has led to a dysplasticteanse. ring sideroblasls 11966. 2139. 23581. In a few cases reported. hl:1Never.the cells of patients with RARS-T. when studied by in vitro cul ture tech- niques, have growth characteristic more in keeping with MOS than MPN 1234, 18351. An additional question is hOw to clearlydistinguish RAR5-T from RARS, in which moderately elevated pla telet counts are etten reported . This question ismorepressing in view of the revised cri- teria for RARS-T that lowers the platelet threshold from ~x lrJl/L to ~450x 1rPlL, in parallel with the revised threshold lor Ef It is important to note that the diag- nostic criteria for RARS-T include not only theIinding of an elevated platelet coun t in conjunction with anaemia and ring elder- oblasts in the 8M, but also morphologi- callyabnormal megakaryoc ytes similar to thoseof ET or PMF. Only a few patient s with RARS and plate let counts in the 450,500x W9/L range have been studi ed for JAK2 mutations and in most with plateletcounts in the lower rang es no mu- tations have been found . Neverth eless, more studies are need ed , and we recom- mend to test for JAK2 mutations in pa- tents whohave RARS and platelet counts above the normal range. The sum of cur- rent informationregarding RAR5-T argues for its continued placement in the MDS/MPN category. but in view of the debate regarding its precise definition and nature, it is best regarded as a 'provisional entity" until more data are available, lastly. classification of myeloid neoplasms that carry an isolated isochromosome t 7q andthat have less than 20% blasts in the P8or BM may prove difficult. Some au- thOrs suggesl this cytogenetic defect defines a unique disorder characterized by mixed MOS and MPN features associ- ated with prominent pseuoo-Percer-Hoet anomaly of me neutroot urs. low 8M blast count, and a rapidly progressive clinical course. Most cases reported have a prominent monocytic component and meet the criteria lor CMML, but in some, the PB monocyte coun t may not reach the lower threshold for that dia gnosis 1708, 14371· In cases that do not fu"ill the criteria lor CMML or another well defined myeloid category. designation as MOSIMPN. un- classifiable. with isolated isochromosome 17q abnormality, is most appropriate. $urTmary of major changes in MDSIMPN 1. Some cases of CMML with eosinophilia are relocated to the category, "Myeloid neoplasms with PDGFRB rearrangement" 2. The category, "Atypical CML" has been renamed as •Atypical CML. BCR-ABL 1 negative" to emphasize this disease is not merely a variant of BCR-ABL 1 positive CML. 3. RAR$-T remains as a provisional enlity, classified as MDS/MPN . uncrassiuabre. until further data clarifies its appropriate designation. The criteria for its recognition have been modified. The platelet thresh- old has been lowered to ~45Ox 1rPll, and megakaryocytes with morphology similar to those seen in ETor PMF must be present Myeladysplastic syndromes (MOS) These disorders, usually characterized by the simultaneous proliferation and apop- tests of baematopoienc cells that lead to a normal or nvoerceuurar BM biop sy and PB cytopenia(s), remain among the most challenging of the myeloid neoplasms for prope r diagnosis and classification , The general features of MOS, as well as specific gu ide lines for diagnosis and classification are outlined in Chapter 5. An impo rtant addition to the MOS cate- go ry (Table 1.05) is the provisional entity, refractory cytopenia of childhood (RCG), This category is reserved for children with MOS who have <2% blasts in their PB and <5% in their 8M and persistent cvtope- nia(s) with dysp lasia, In contrast to MDS with refractory cvtcoentee in eoutts. the majority of cases of ACC have hypocellular 8M biopsy specimens, and the distinction from acquired aplastic anaemia and inherited BM failure syndromes is often challenging 117841, An issue appropriate 10 menton at this point is the cntene used for ctassmcatco of myeloid neoplasms in which more lhan 50% of the BM cells are erythroid precut- sors. and for which acute erythroid leukaemia is considered a possible diag- nosis. In such cases. if blasts account for fewer than 20% of WBC in the PB and 01 all nucleated 8 M cells, and for less than 20% of the non-erythroid cells in the BM (lymphocytes, plasma cells, etc. are also excluded in this latter calculation), the case is considered as MOS. In this sce- nario. there is lack of consensus among members of the WHO committee as to whether the MOS should then be classi- fied according to !he blast perceotace of all nucleated 8 M cells or according 10the blast percentage of all non-erythroid BM cells. but the majority recommends that the MOS be classified using the blast per- centage of all marrow nucleated cells. Many cases of refractory anaemia with ring sioerobrests as well as refractory anaemia have marked erythroid prolifera- tionand using the blast percentage of the non-erythroid cells lor classification of such cases might cause these to be placed in an unnecessarily high-risk cat- egory. On the other hand , if there is severe multilineage dysplasia, very bizarre erythroid morphology. and/or minimal or no maturation to segmented neutroobus. and the btast percentage of total 8M cells is not sufficienl to place the case into a high-g rade MOS category, the case shoul d be flagged tor clinical correlation and discussion, with careful follow-up (Tab le 1.06). More studies are needed however to cla rify this controversial issue. Acute myeloid leukaemia (AML) AML is a disease resulting from the clonal expansion of myeloid blasts in the PB, 8M , or other tissue, It is a heterogeneous disease clinically, morphologically and ge netically and may involve only one or Tabl. 1.05 Myelodysplastcsyndromes, Reffacto!y ~nia wlltlll1 iWleage dysfllas48 (RCUD) Reffa<:byanaemia (RA) Refracloty neutropenia (RN) Refradcry ltuQmbocytopenia (RT) Re!fadclry allaemia with ri1gSiderObIasts (RARS) Relractory cytlpenia with ITIJlblineage dysplasia (RCMD) Refractory all8e/l'M8 wiII1 excess bIasls (ME B) MyelodyspIa$llc syncWmewilI1 iSOIatecI dfll(Sq) Myelodysplllsbc syndrcIme. undas.sJliable (J.I>S.U) C*hood ~ syrw:lrome Pn:MsicnaInty Refra:t:ry ~ ~ d*hlod (ROC) Introduction and overview of me classification 01 the myelOId neoplasms 27
  27. 27. Table1.06 PMSib1e d~ when erythroid precursors ~50'10 ofbone marrow nucleatedcells. %Erythroid ~ Blocdhnarrowfindirlgl. 0ltIer f1odlng& DIagnosis ......- • Erythroid precursors, lymphoid cellsandplasmacens aresubtracledfroma" nlJdeatedmarrowcells to calDJlate the"noo-erythroid eels"inthebone marrow. - ~ blasts inblood or Case meets alterialor AML With fl'lyelodyspIaSia ofallnucleatedmarrow AMLwith my8lOdysplasia· related changes - related changes ~ inmatln IJyIIwid Few • lit'{ myeIclt:Qsts Miwnall <Wly PIn 8I)tWIlid IeWemia """""...,"""'" """""'"matlJflllJon _01 >5011 -_.- fIm.>MiKi1I -,--blasts <m d II ~celsll ....... """"""""""- .." """"" '50' <20% blastsinblood, Blasts<20% 01 all MDS: classifyMDS blasts <20% ofall ~roid' cells in acx:oroing 10 number of """'"'"""""- ...""""" blasts inbloodandblasts as pen:entIge d II """""""""""- pathways to promote proliferation/survival A similar multistep process is also evident in AMl that evolves from MDS orthat has myelodyspl asia-related features, often characterized by loss of genetic material and haploinsufliciency of genes. Within the last few years, genetic mutations have also been identilied in cytogenetically normal AML 115321. Sane of therrutations, such as those of CEBPA and perhaps NPM1invdve transcriplion faclors. whereas erne-e. including those of FlT.J and NRASIKRAS. affect signal transduction. Not only have these mutations led to an unde rstand ing of leukaemocenests in cytogenetically normal AML, bul they have proved to be powerful prognostic factors 115321. In summary, genetic ab- normalities in AML elucidate the patho- genesis of the neoplasm, provide the most reliable prognoslic information, and will likely lead 10 development of more successful targeled therapy. One of the challenges in this revision has been how to incorporate important and/or recently acquired genetic information into a classification scheme of AMl and yel adhere to tile WHO principle of defining horoogeneOuS, biologically relevant entities based not only on genetic studies or their prognostic value, but also on clinical, morphologic and/or immunophenotypic studies . This was particularly problematic for the most frequent and prognostically impo rtant mutat ions in cytogenetically normal AML, mutated FLT3, NPM 1 and CEBPA. They have few or variably con- sistent morphologic, irrwnunophenotypic and clinical features reported to dale , and the mutation s are not mutually exclusive. For the most par t, the framework coo- structec in the 3rd edition proved flexible enough to incorporate the new entities proposed by members of the WHO c0m- rmtteeand the CAC (Table 107). The en- tities initially described in the subgroup ·AML with recurring genetic abnormal- nee' remain with only minor modifications (Table 1.07) and three more entities, char- acterized by chromosomal transtocatioos associated with fairly unilorm morpholog- ical and clinical features have been added. Cases with mutated NPMl and CEBPA are added to the same subgroup as ' provisional entities' indicating that more study is needed 10 lully characterize and estab lish them as unique entities Although mutated FLT3is not included as a separate entity because it is found to be associated with a number of other entities, maturation, the diagnosis does not nec- essarily translate into a mandate to treat the patient for AML; clinical factors. in- cluding the pace of prog ression of the disease, most atways be taken into con- sloerenon when deciding therapy. Rationale for the WHO diagnosis and classification of AML The 3rd edition 01the WHO ctassrncatoo ushered in the era of formal incorporation of genetic abnormalities in the diagnostic algorithms for the diagnosis of AML. The abnormalities included were mainly chro- mosomal transiocenoee involVing tran- scription factors and associated with charac teristic clinical, morphologic and immunophenotypic features Ihat formed a ·clinico-pathologic-genelic· entity. As knowledge regarding leukaemogenesis has increased, so has the acceptance that the genetic abnormal ities leading to leukaemia are not only heterogeneous, but complex, and multiple aberrations often cooperate in a multistep process to initiate the comple te leukaemia pheno- type. Experimental evidence suggests mat in many cases, although rearrange- ment of genes such as RUNX1, CBFB or RARA that encode transcncuon factors impair myeloid differentiation, a second genetic abnormality is necessary to pro- mote proliferation or survival of the neo- plastic clone (Fig. 1.08) 11135AI. Often. the additional abnormalities are mutations 01genes such as FLT30r KITthat encode proteins that activate signal transduction all myeloid lineages. Worldwide the inci- dence is app roximately 2.5-3 cases per 100,000 popu lation per year, and is reportedly highest in Australia. Western Europe and the United States. The me- dian age at diagnosis is 65 years, with a slight male predominance in most coun- tries. In Children less than 15 years of age, AML com prises 15- 20% of all cases of acute leukaemia, with a peak incidence in the first 3-4 years of lite 1559A, 2463AI. The requisite blast perce ntage for a diag· rosrs of AML is 20% or more mveiobtasts and/or monoblastslpromonocytes and/or megakaryoblasts in the P8 or BM. The di - agnosis of myeloid sarcoma is synony- mous with AML regardless of the number of blasts in the PB or BM, unless the patient has a prior history of MPN or MDS/MPN, in which case myeloid sarcoma is evidence of acute transforma- tion. The diagnosis of AML can also be made when the blast percentage in the PB and/or BM is less than 20% if there is an associated t(8;21XQ22;Q22), inv(16)(p13.1Q22), t(16:16XP13.1;Q22) or t(15;17)(Q22:q 12) chromosomal abnor- mality, and in some cases of acute ery- throid IeuI<aemia when eryttvoid precursors account for more than SO% of the BM cells and blasts account for more than 20% of the non-erythroid marrow cells (See Chapter on acute myeloid leukaemia, NOS). Although the diagnosis of AML using the above guidelines is operationally useful to indicate an underlying defec t in myeloid 28 IntroductIOn and overvIew of the ctassuceuoo of the myeloid neoplasms
  28. 28. to their genetic abnormalities, but until more data are available, we recommend thai such cases be classified as AML with myelodysplasia-related changes (multilin- eage dysplasia) with the mutational status of the gene appended, Therapy-related myeloid neoplasms (t-AMLJ t·MDS and t-AMlIt-MDSlMPN) remain in the revised classification as a distinct subgroup. However, most patients who develop therapy-related neoplasms have received therapy with both alkylating agents as well as with topoisomerase II inhibitors, so that a division according to the type of therapy is usually not practical and not recommended in this revision. It has been argued that 90% or more 01 cases with I-AMLIt-MDS or t-AMl/t-MDSI MPN have cytogenetic abnormalities similar to those seen in AML with recur- rent genetic abnormalities or AML with myelodyspiasia-relaled features and could be assigned to those categories. However, except for patients with t-AML who have inv(16Xp 13.1q22), t(16;16XP13.1;q22)or t(15 :17Xq22;q 12), in most reported series those with therapy-related myeloid neo- plasms have a significantly worse clinical outcome Ihan their de novo counterparts with the same genetic abnormalities 136, Impaired haematopoietic differentiation and .ub- HqUent .poptos~ PML-RARA RUNX1-RUNX1Tl CBFB-MYH11 MLL fusions CEBPA NPM11 Class II mutations Atutt myeloidIeukaemi,with recurrent gtllllIlIt Ibnormalitles AMLwith~8;2 1 )(Q22:Q22): RUNXt-RUNXm AML withinv{16)(p13.1q22}c.(16:16Kpl3.1:q22); CBFB-MYHIt APl with (15;17)(q22:Q12); PML-RARA AMLwitht(9:11){p22:q23}: MLLT3-MLL AMl witht(6:9)(p23;Q34): OEK-NUP214 AMl withinv(3KQ21Q26.2) ort(3:3J(Q21;q26,2); RPN1·EVll AML(megakeryoblastic)with 1(1;22)(p13;q13): RBMI5-MKL 1 Provisional entity:AMl with mutatedNPM1 Provisional entity:AMLwith mutatedCEBPA Acutemyeloid leukaemia with mye!ody,plilil-related changes Therapy-related myeloid neoplil5m, Acutemyeloid leukaemia, no! otherwl$l spec;lrted AMLwith minimal diffe!lll1tialiorl AML without maturation AMLwithmallJ"aUon Acute m~ leukaemia Acute roonoblasticJmooocytic Ieukaemla Acute ~ IeukaelBas PIseerythroid leukaemia EIythroleukaemia, 8I')1hroidfmyeloid Acute megakaryoblas.lic Ieukaetnia Acute basophl1ic Ieukaen'Ha Acute panmyeIosis withmyebfibrosis Myeloidsarcoma Myeloidproliferations related to Down syndrome Transaent abnormal myelopoiesis Myeloid leukaemia ISSOCiaIed withDown syndrome Blastic plil5maC}'loid dendritic u1llll1oplalms Table 1.07 Acutemyeloid leukaemia andrelatedmyeloidneoplasms, should be evaluated for FLT3, NPMI and CEBPA rnutanons. Currently, however, the clinical significance of a mutalion of one or more of these genes in the setting of morphologic multilineage dysplasia is not clear. Future studies may well prove that such cases are better classified according FLT3-ITD FLT3-TKO KIT RAS PTPN11 JAK2 Class I mutations Proliferation and/or survival advantage; not affecting differentiation its siqrsbcance should not be uoderest- mated, and it is essential that it be tested for in all cytogenetically normal patients, including those who demonstrate NPM1 and CEBPA mutations. Modifications have been made in the subgroup previously ter med "AML with multilineage ovsprasta." Initially, it was envisioned that this group would encom- pass biologically unique AML charac ter- ized by MD$-like fea tures, incl ud ing unfavourable cytogenetics, a higher lnc t- oence of ove rexpressfon 01 multidrug resistance gfycoprotein (AS CS1or MDR-1) andan unfavou rable response to therapy. Dysplasia in ~50% of ce lls in two or more heematopoienc lineages was used as a universally-applicable surrogate marker for the myelodysplasia- relate d featu res. Although the clinical significance of this grOl.lp has been verified in some stud ies , it has been disputed in othe rs in which multivariate analysis showed that multilin- eage dyspla sia had no independent sig- nificance in predi c ting clinical outcome wen cytogenetic findings were mcorpo- rated in tne analysis 169, 869, 2356, 24651. Accordingly, in this revision, this group has been renamed as "AML with myelodysplasia- related changes," Pa- tientsmay be assigned 10this category if theyevolve Irom previously documented MOS. have specific myelodysplasia- relatedcytogenetic abnormalities. or lastly, if they exhibit morphologic mu ltilineage dysplasia as def ined above. Patients in Ianer group with a normal karyotype Introduction and overview of lhe classification 01the myeloid neoplasms 29

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