WHO 2008


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WHO Classification of tumors of hematologic and lymphoid tissue 2008 (4th Ed)

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WHO 2008

  1. 1. World Health Orga nization Classifica tion of Tumours Hamilton SR. Aartonen LA (Eds.) : Fletcher C.D.. Unni KK., Tavassoli F A .. Devilee P. (Eds .): World Health Organization Mertens F. (Eds,): World Health World Health Organization Classification of Tumours , Organization Classification 01 Classification 01 Tumours . Patholog y and Genetics of Tumours Tumours. Patho logy and Genetics 01 Pathology and Genetics of Tumours of the Digestive System (3rd edition) . Tumours of Soft Tissue and Bone of the Breast and Female Genital IARC Press: lyon 2000 (3rd edition). Organs (3rd edition). ISBN 92 832 241 0 8 IARC Press : lyon 2002 IARC Press : lyon 2003 ISBN 92 832 2413 2 ISBN 92 832 2412 4 Eble J .N., Sauter G .• Epstein J E., Travis wo., Brambilla E., Muller· Delellis A.A., lloyd A.V, Heitz, P.U., Sesterreon l.A . (Eds.) World Health Hermelink H.K ., Harris C .C. (Eds.): Eng C . (Eds.): World Hea lth Organization Classification of World Health Organization Organization Classification of Tumours. Pathology and Genetics of Classification 01 Tumours. Pathology TlJTlOUrs. Pathology and Genetics ot Tumours althe Urinary System and and Genetics of Tumours of lung TlJTlOUrs of Endocrine Organs (3rd Male Genital Organs (Jrd ed ition) P1eu"a. Thyrrus and Heart (3I"d edilon), edition). fARe Press : lyon 2004 IARC Press : lyon 2004 IARC Press : lyon 2004 ISBN 92 832 2415 9 ISBN 92 832 2418 3 ISBN 92 832 2416 7 Barnes L , Eveson J .W , Reichart P" leBoit P.E.. Burg G , Weedon D., louis D.N" Ohgaki H ., WiesUer D.O., Sidransky 0 (Eds.): World Health Sarasm A . (Ed s.): World Health Cavenee WK (Ed s.) : World Health Organization Classification of Organization Classification of Organization Classification of Tumours. Pathology and Genetics of Tumours. Pathology and Genetics of Tumours . Tumours of the Central Head and Neck Tumours (3I"d edition) . Skin Tumou rs (3rd edition). Nervous System (4th edition ). IARC Press : lyon 2005 IA RC Press : lyon 2006 IARC, lyon 2007 ISBN 92 832 24 17 5 ISBN 92 832 2414 0 ISBN 92 832 2430 2This book and all other volumes of the series can be purchased from: From all countries WHO PRESS World Health Organization 20 Avenu e Appia 1211 Geneva 27 Switzer land www. who intlbookord ers/ Tei. + 4 1 22 791 3264 Fax +41 22 791 4857 bcokoroersewno.ot From USA I Canada WHO Publications Center 5 San d Creek Road Albany, NY 1205- 1400 Tel. +15184369686 Fax . + 1518436 7433 qcorpeconouserve.com Renouf Pub lishing Co. lid http://www.renoufbooks.comJ From USA : Tel.+18885517470 Fax +18885517471 From Canada: Tel. + 1 866 767 6766 Fax +16137457660
  2. 2. -.I
  3. 3. •I WH O OMS International Agency for Research on Cancer (IARC) 4th Edition WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues Edited by Steven H. Swe rdlow Elias Campo Nancy Lee Harris Elaine S. Jaffe Stefano A. Pileri Harald Stein JOrgen Thiele James W. Vardiman Intern ational Agency for Resea rch 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. JOrg en Thiele, M.D. James W. Vardi man, M.D. Layout Sebastien Antoni Marlen Grassinger Pascale Collard Printed by Participe Present 69250 Neuville s/SaOne, France Publisher International Agency for Research on Cance r (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 Grou p 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 cou rs 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: +4 1 22 791 3264; Fax: +4 1 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 ot the 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 01 its frontiers or ccooca-ee. The mootion ol scecac companies or 01 certain manufacturers products does not imply that they are encIorned or fecorrmellded by the World Health Organization in preference to others of a smilar nature that are not mentioned Errors and omissions excepted, the rwnes 01 proprietary 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 01 charts 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 Lympho id Tissues,IARC: Lyon 2008IARC Ubrary Cataloguing in Publication DataWHO Classific ation of Tumou rs of Haematopo ietic and Lymp hoid TissuesEdited by Swerdlow S.H.. Campo E., Harris NL , Jaffe E.S.• Piled SA, Stein H., Thiele J .. Vardiman JW.1. Haematopoie hc System Neop lasms - genetics2. Haematopoielic System Neop lasms - pathologyI. Swerdlow. Steven H.ISBN 978-92-832-243 1-0
  7. 7. ContentsWHO Classifjcatioo 9 AML with mutated NPM 1 120 Summary table 10 AMLwith mutated CEBPA 122 Introduction to the classification of tumours of AML with myelo dysplas ia-related changes 124 haematopoietic and lymphoid tissues 14 Therapy -relate d myeloid neoplasms 127 Acu te myeloid leukaemia, NOS 130 Introduction and overview of the classification of AML with minimal diff erentiation 130 the myeloid neoplasms 17 AML withOut matu ration 131 AML with maturabon 1312 Myeloproliferative neoplasms 31 Acute myelomonocytic leukae mia 132 Chronic myelogenous leukaemia. BCR-ABL 1 positive 32 Acute monoblastic and monocytic leukaem ia 133 Chronic neutrophilic leukaemia 38 Acute erythroid leukaemia 134 PoIycythaemia vera 40 Acu te megakaryoblastic leukaemia 136 Primary myelofibrOsis 44 Acute basophilic leukaemia 137 Essenliallhrombocythaemia 48 Acu te paomveosrs with myelofibros is 138 Chronic eosinophilic leukaemia. NOS 51 Myeloid sarcoma 140 Mastocytosis 54 Myeloid proli ferations related 10 Down synd rome 142 Cutaneous mastocytosis 57 Transient abnOrmal myelopoiesis 142 Systemic mastocytosis 58 Myeloid leukaemia associated with Masl cell leukaemia 61 Dc:rwn syndrome 143 Mast cell sarcoma 61 Blastic plasmacytoid dendritic cell neoplasm 145 Extracutaneous mastocytoma 61 Myeloproliferative neoplasm, unc lassi fiable 64 7 Acute leukaemiasof ambiguous lineage 149 Acute undlHerentiated leukaemia 1513 Myeloid and lymphoid neoplasms with Mixed phenotype acute leukaemia wilh eosinophilia and abnormalities of PDGFRA. t(9;22)(q34;q 11.2): BCR-ABL 1 15 1 PDGFRB Of FGFRl 67 Mixed phenotype acute leukaemia with t(v:11q 23): MLL rear ranged 1524 MyelodysplasticJmyeloproliferative neoplasms 75 Mixed phenotype acute leukaemia , B/myeloid, NOS 152 Chronic mveiomonocync leukaemia 76 Mixed phenotype ac ute leukaemia , T/myeloid , NOS 153 Atypical ctYonic myeloid leukaEmia. BCR- ABL 1 negative 80 Mixed phenoty pe acu te leukaemia, NOS· rare Juvenile myelomonocytic leuk aemia 82 types 154 MyelodysplastiC/myeloproliferali ve neoplasm , Other ambiguous lineage reukaerraes t 55 urclasaifiable 85 Natura! killer (NK)-celilympho blastic leukaemi a/lymphoma 1555 Myelodysplastic syndromes 87 Myelodysplastic synd romes/n eo plasms , overview 88 8 Introduction and overview 01 the c lassification of Refractory cytope nia with unilineage dysplasia 94 the lymphoid neoplasms 157 Refractory anaemia with ring side rob lasts 96 Refractory cytopenia with multilineage dysplasia 98 9 Precu rsor lymphoid neoplasms 167 Refractory anaemia with exc ess b lasts 100 B lymp hob lastic leukaemia/lymphoma, NOS 168 Myelodysp lastic synd rome with isolated de l(5q) 102 B lymphob lastic leukaemia/ lymphoma Myelodysp lastic synd rome, uncrasslttabte 103 with recu rrent gene tic abn orma lities 171 Childhood mye lodysp lastic synd rome 104 B lymphob lastic leukaem iallymphoma with Refractory c ytopenia of c hild hood 104 t(9 :22)(q 34;q 11.2): BCR-ABL 1 171 B lymp hoblastic leukaemia/ly mpho ma with6 Acute myeloid leukaemia (AML) and l(v:11q 23): ML L rearranged 171 related precursor neoplasms 109 B lympho blastic leukaemiall ymphom a with AML with recurrent genet ic abn or malities 11 0 t(12:2 1)(p1 3;q22 ): TEL-AMLl (ETV6--RUNX 1) 172 AML with t(8:21 )(q22:q22); RUNX1 -RUNX1T1 11 0 B lymphoblastic leukaemia/lymphoma with AML with inv( 16)( p 13.1q22) or hyperdi ploi dy 173 1(16:t6)(p 13.1;q22): CBFB-MYH 11 11 1 B lymphoblastic leukaemiallymphom a with Acute orornveiocvnc leukaem ia with hypodiplOi dy (Hypodiploi d ALL) 174 t(15:17)(q22 :q 12): PML- RARA 11 2 B lymphoblastic leukaemiallymphoma with AML with us.11)(p 22:q 23): MLLT3-MLL 114 t(5; 14)(q31;q32); IL3-IGH 174 AML with t(6:9)(p23 :q34); DEK-NU P2 14 115 B lymphoblastic leukaemiallymphoma with AML with inv(3)( q2 1q26 .2) or t(3;3)( q2 1;q26.2); t( 1;19) (q23:P13.3): E2A-PBX1( TCF3-PBXI) 175 RPNt ·EVI1 116 T lymphoblastic leukaemiallymphoma 176 AML (megakaryoblastic) with t( 1;22)(p13;q 13): RBM15-MKL 1 117
  8. 8. 10 Mature B-ceUneoplasms 179 Enteropathy -associated t-een lymphoma 289 Chronic lymphocytic leukaemia Ismail Hepatosplenlc t -een lymphoma 292 Iymptlocytic lymphoma :f 180 Subcutaneous panniculitis-like t-een lymphoma 294 s-een prolyrT¢lhocytic leukaemia 183 Mycosis fungoi des 296 Splenic B-cell marginal zone lymphoma 185 Sezary syndrome 299 Hairy cell leukaemia 188 Primary cutaneous CD30 posi tive t-een Splenic B-cell Iymphomalleukaemia, unclassiliable 191 Iymphoprolilerative disorders 300 Splenic diffuse red pulp small B-ceil lymphoma 191 Primary cutaneous per ipheral t-een lymphoma s, Hairy cenleckaeme-....anent 192 rare subtypes 302 lymphoplasmacytic lymphoma 194 Primary cutaneous garnna-della T-cen lymphoma 302 Heavy chain diseases 196 Primary cutaneous COB positive agg ressive Gamma heavy chain disease 196 ep idermotrop ic cytotoxic T-celt lymphoma 303 Mu heavy chain disease 197 Primary cutaneou s CD4 positive Alpha heavy chain disease 198 small/medium T-cell lymphoma 304 Plasma cell neoplasms 200 Peripheral t-een lymphoma. NOS 306 Monoc lonal gammop athy 01 undetermined Ang ioimmunoblastic t -een lymphoma 309 significance (MGUS) 200 Anaplastic large cell lymphoma. AlK positive 312 Plasma ce ll myeloma 202 Anapla stic large cell lymphoma . ALK negat ive 317 Solitary plasmacytoma of bone 208 Extraosseous plasmacytoma 208 12 Hod gkin lymphoma 32 1 Monoclonal immunoglobulin deposition diseases 209 Introduction 322 Extranodat marginal zone lymphoma of mucosa- Nodular lymphocyte predominant Hodgkin Iymptuna 323 associa ted lymphoid tissue (MALT lymphoma) 214 Classical Hodgk in lymp homa. introduction 326 Nodal marg inal zone lymphoma 218 Nodular sclerosis classical Hodgkin lymphoma 330 Follicular lymphoma 220 Mixed ce llularity classical Hodgkin lymphoma 331 Primary cutaneous follicle centre lymphoma 227 Lymphoc yte-rich classical Hodgkin lymphoma 332 Mantle cell lymphoma 229 lymphocyte-depleted classical Hodgkin lymphoma 334 Diffuse large B-celllymphoma (DLBCl), NOS 233 T celilhi stiocyte-rich large B-ce ll lymphoma 238 13 1rnmunode ficiency-assoc iated Primary DlBCL of the CNS 240 Iymphoproliferative disorde rs 335 Primary cutaneous DlBCl . leg type 242 Lymp hoproliferative diseases associated with EBV positive DLBCl of the elderly 243 primary immune disorders 336 DLBCL assoc iated with chronic inflammation 245 Lymphomas associa ted with HIV infection 340 Lymphomatoid granulomatosis 247 Post-nansotanttsmpnooronterauve disorders (PTlD) 343 Primary med iastinal (thymic) large B-celilymphoma 250 Plasmacytic hyperp lasia and infectious- Intrav escurer large B-celi lymphoma 252 rroooo ocieose-uke PTlD 345 ALK positive large Been lymphoma 254 Polymorphic PTlO 346 Plasmablastic lymphoma 256 Monomorph ic PTlO 347 large a-ceu lymphoma arising in HHV8-associated Classical Hodgkin lymphoma type PTLO 349 multicent ric Castleman disease 258 Other iatrogenic immunodeficiency-assoc iated Primary effusion lymphoma 260 Iymphoproliferative disorders 350 Burkitllymp homa 262 B-cel1lymphoma, unclassiliab le, with features 14 Histiocytic and dendritic cell neoplasms 353 intermediate between DLBCL and Introd uction 354 Burkitllymphoma 265 Histiocyt ic sarcoma 3S6 B-ceillymphoma, unctessmebie. with features Tumours der ived from langerhans cells 358 intermediate between OLBCl and Langerhans cell histiocytosis 3S8 clas sica l Hodgkin lymphoma 267 Langerhans ce ll sarcoma 360 Interdigitating dendrit ic cell sarcoma 36 1 11 Mature T- and NK-cell neoplasms 269 Follicular de ndritic ce ll sarcoma 363 r-cea prolymphocytic leukaemia 270 Other rare dendritic cell tumours 365 t- een large granular lymphocytic leukaemia 272 Disseminated juvenile xanthogranuloma 366 Chronic Iymphoproliferative disorder of NK cells 274 Aggressive NK cell leukaemia 276 Contributors 369 Epstein-Barr virus (EBV) positive t-een Clinical advi sory oorrrnittee 374 Iymphoprol ilerative diseases of ch ildhood 278 Source of Charts and photographs 376 Systemic EBV+ t-een Iymphoproliferalive disease of childhood 278 References 300 Hydroa vacclnrtorrne-uk e lymphoma 280 Subject index 429 Adull T-ceil leukaemia/lymphoma 281 Extranodal NK/T-cell lymphoma. nasal type 285 NOS, no! otherwise specifi ed,•
  9. 9. WHO Classification 4th Edition- / / -.,.e" / , ...,...,... ~ /,f / - ~ ~~ - -~ ~ _....i? ~.,.~-
  10. 10. WHO Classification of tumours of haematopoieticand lymphoid tissues MYELOPROLIFERATIVE NEOPLASMS MYELODYSPLASTIC SYNDROMES Chronic myelogenous leukaemia , Refractory cytopenia with unilineage dysplasia BCR-ABL 1 positive 987513 Refractory anaemia 9980/3 Chronic neutrophilic leukaemia 996 3/3 Refractory neutropenia 999 1/3 Polycythaemia vera 995 0/3 Refractory thrombocytopenia 9992/3 Primary myelofibrosis 996 1/3 Refractory anaemia with ring sideroblasts 9962/3 Essential thrombocythaemia 996213 Refractory cytopenia with Chronic eosinophilic leukaemia, NOS 9964 /3 multitineage dysplasia 9965/3 Mastocytosis Refractory anaemia with excess blasts 9983/3 Cutaneous mastocytosis 9 74011 MyelodysplasU syndrome c associated with isolated del(Sq) 9966/3 Systemic mastocytosis 9 74 1/3 Myelodysplasticsyndrome, uncJassifiable 9969/3 Mast cell leukaemia 974 213 Mast cell sarcoma 974 0/3 Childhood myelodyspla suc syndrome Extracutaneous mastocytoma 974 0/1 Refractory cytopenia of childhood 996513 Myeloproliferative neoplasm , unctassitlable 9975/3 ACUTE MYELOID LEUKAEMIA (AML) AND RELATED PRECURSOR NEOPLASMS MYELOID AND LYMPHOID NEOPLASMS WITH EOSINOPHILIA AND ABNORMALITIES OF AML with recurr ent genetic abnormalities PDGFRA, PDGFRB OR FGFRI AML with t(6 ;21)(q22;q2 2); Myeloid and lymphoid neoplasms RUNXI-RUNX1Tl 9696/3 with PD GFRA rearrangement 9965/3 AML with inv(16)(pI 3.1q22 ) Myeloid neoplasms or t(16;16)(pI3.1;q2 2); CBFB-MYHl1 9671/3 with PDGFRB rearrangement 9966/3 Acute promyelccytlc leukaemia Myeloid and lymphoid neoplasms with t(15 ;17)(q22 ;qI2); PML-RARA 9666/3 with FGFR1 abnormalities 9967/3 AML with t(9 ;11)(p22 ;q23); MLLT3-MLL 9697/3 AML with 1(6;9)(p2 3;q34 ); DEK-NUP214 986513 MYELODYSPLASTIC/MYELOPROLIFERAnVE AML with inv( 3)(q2 1q26.2) NEOPLASMS ort(3; 3)(q21;q 26.2); RPNI -EV/1 9869/3 Chronic myetcmonocytic leukaemia 9945/3 AML (megakaryoblastic) with t(I ;22)(p I 3;q I 3); RBMI5-MKLI 9911/3 Atypical chronic myeloid leukaemia. BCR-ABL 1 negative 967613 AML with mutated NPM1 986 1/3 Juvenile myelomonocytic leukaemia 9946/3 AML wrlh mutated CEBPA 9661/3 Myelodysplasticlmyeloproliferative neoplasm. unclassifiable 9975/3 AML with myelodysplasia-related changes 969513 Refractory anaemia with ring sideroblasts Therapy-re lated myeloid neoplasm s 99 2013 associated WI h marked thrombocyt t osis 99 621310 WHO ctassrtceton
  11. 11. Acute myeloid leukaemla",NOS 9861/3 B lymphoblastic leukaemia/lymphoma with recurrent genetic abnormalities AML with minimal differentiation 987213 B lymphoblastic leukaemiaflymphoma AML without maturation 9873/3 with 1(9;22)(q 34;q l 1.2); BCR-ABU 9812/3 AML with maturation 9874 /3 B lymphoblastic leukaemiall ymphoma Acute myelomonocytic leukaemia 9867 /3 with t(v;11q23); MLL rearranged 981Y3 Acute monob lastic and monocytic leukaemia 9891 /3 B lymphoblastic leukaemiall ymphoma Acute erythroid leukaemia 984013 with 1 12;21)(p13;q22); TEL-AMU ( (ETV6-RUNX1) 9814/3 Acute megakaryoblastic leukaemia 99 10/3 B lymphoblastic leukaemiallymphoma Acute basoph ilic leukaemia 987013 w ith hyperdiploidy 981513 Acute panmyelosis with myelofibrosis 9931 13 B lymphoblastic leukaemiallymphoma with hypod iploidy (hypod iploid ALL) 981613Myeloid sarcoma 993013 B lymphoblastic leukaemiallymphoma with t(5;14 Xq31 ;q32 ); IL3-IGH 9817/3 B lymphoblastic leukaemia/lymphoma withMyeloid proliferations related to Down syndrome t(1;19 )(q23 ;p13 .3); E2A-PBXlTransient abnormal myelopoiesis 989811 (TCF3-PBX1) 9818/3Myeloid leukaemia associated with Down syndrome 9898/3 T lymphoblastic leukaemia/lymphoma 9837/3Blastic plasmacytoid dendritic cell neoplasm 9727/3 MATURE B-CELL NEOPLASMS Chronic lym phocytic leukaemia! small lymphocytic lymphoma 982313ACUTE LEUKAEMIAS OF AMBIGUOUS LINEAGE B-cell prolymphocytic leukaemia 983313Acute undifferentiated leukaemia 980 1/3 Splenic Bccell marginal zone lymphoma 968913Mixed phenotype ac ute leukaemia Hairy cell leukaemia 9940/3 with t(9;22)(q3 4;q 11.2); BCR-ABL1 980613Mixed phenotype ac ute leuka em ia Splenic B-cell fymphomalleukaemia, unclassifiable 959 1/3 with t{v;11q23); MLL rea rranged 9807/3 Splenic diffuse red pulp small B-cell lymphoma 9591/3Mixed phenotype ac ute leukaemia, Hairy eel/leukaemia-variant 959 1/3 B/myeloid, NO S 9808/3 Lymphoplasmacytic lymphoma 9671/3Mixed phenotype ac ute leukaemia, Tfmyeloid, NOS 9809/3 waldenstrom macroglobulinemia 9761/3Natural killer (NK) cell lymphoblastic Heavy chain diseases 9762/3 !euKaemiallymphoma Alpha heavy chain disease 9762/3 Gamma heavy chain disease 9762/3 Mu heavy cha in disease 9762/3PRECURSOR LYMPHOID NEOPLASMS Plasma cell myeloma 9732/3B lymphoblastic leukaemiaflymphoma Solitary plasmacytoma of bone 9731/3B lymphoblastic leukaemiall ymphoma, NO S 98 11/3 Extraosseous plasmacytoma 9734/3 WHO classification 11
  12. 12. - Extranodal marginal zone lymphoma Systemic EBV positive T-celllymphoproliferative of mucosa-associated lymphoid tissue disease of childhood 9724/3 (MALT lymphoma) 9699/3 Hydroa vaccin iforme-like lymp homa 972513 Nodal marginal zone lymphom a 9699/3 Adult T-cell ieukaemia/lymphoma 9827/3 Paediatric nodal marginal zone lymphoma 9699/3 Extranodal NKIT cell lym phoma, nasal type 9719 /3 Follicular lymphoma 9690/3 Enteropamy-associated T-cell lymphoma 9717/3 Paediatric folliculaf lymphoma 9690/3 Hepatosplenic T-cell lymp homa 971613 Primary cutaneous follicle centre lym phoma 959713 Subcutaneous panniculitis-like T-cell lymphoma 970813 Mantle cell lymphoma 967313 Mycosis fungoides 970013 Diffuse large B-eelllymphoma (OlBCl), NOS 968013 Sezary syndrome 970113 T-ceillhistiocyte rich large B-eelilymphorna 9688/3 Primary cutaneous CD30 positive F-eel! Primary DLBCl of the CNS 968013 Iymphoproliferative disorders Primary cutaneous DlBCl. leg type 9680/3 9718/1 lymphomatoid papulosis EBV positive OLBCL of the elderly 9680/3 Primary cutaneous anaplastic large cell Ol BCl associated with chro nic inflammation 968013 lymphoma 9718/3 l ymphomatoid granulomatosis 9766 /1 Primary cutaneous qamma-delta r -ceuivmpncma 9726/3 Primary med iastinal (thym ic) large B-celllym phoma 9679/3 Primary cutaneous COB positive aggressive epidermotropic cytotoxic T-cefl lymphoma 9709/3 Intravascular large B-cell lymphoma 971213 Primary cutaneous CD4 positive smalVmedium AlK positive large B-cell lym phoma 9737/3 T-cell lymphoma 9709/3 Plasmablastic lymphoma 973 5/3 Peripheral Tccelllympboma, NOS 970213 l arge Bccell lymp homa arising in HHV8- Angioimmunoblastic l-cetl Iyrnphoma 970513 associated multicentric Castleman disease 9738/3 Anaplastic large cell lymp homa, ALK positive 97 14/3 Primary effusio n lymphoma 9678/3 968 7/3 Anaplastic large cell lymphoma, ALK negative 970213 Burkitt lymph oma B-ceillym phom a, uncl assifiable, with feature s intermediate between diffuse large g-ceu lymph oma and Burkitt lymph oma 968 0/3 HODGKIN LYMPHOMA B-ceil lymph oma , unclassifiable, with feat ures Nodular lymphocyte predomi nant intermediate betwee n diffuse large 8-cell 9659/3 Hodgkin lymp homa lymphoma and classica l Hodgkin lymphoma 9596/3 Classical Hodgkin lymp homa 9650/3 Nodular sclerosis classical Hodgkin lymphoma 9663/3 MATURE T-CELL AND NK·CELL NEOPLASMS l ymphocyte-rich classica l j-cen prolymphocytic leukaemia 9834/3 Hodgkin lymphoma 965113 f-celllarqe granular lym phocytic leukaemi a 983 1/3 Mixed cellularity classica lI Chronic Iymphoproliferative disorder of NK..cells 983113 Hodgkin lymphoma l ymphocyte-depleted classical 965213~l.. Aggressive NK cell leukaemia 9948/3 Hodgkin lymphoma 965313 12 WHO ciassitcenon _
  13. 13. HISTIOCYTIC AND DENDRITIC CELL NEOPLASMSHistiocytic sarcoma 9755 /3l angerhans cell histiocytosis 975 1/3langerhans cell sarcoma 9756/3Interdigitating dendritic cell sarcoma 9757/3Follicular dendritic cell sarcoma 975813Fibroblastic reticu lar cell tumour 9759/3Indeterminate dendritic cell tumour 9757/3Disseminated juvenile xanthogranulomaPOST·TRANS PLANT LYMPHOPROUFERATIVEDISORDERS (PTLO)Early lesi ons P1asmacytic hyperplasia 9971/1 Infectious mononucleosis-like PTLD 9971 /1Polymorphic PTLO 9971/3Monomorphic PTlO (B- and TINK-cell types)Classical Hodgkin lym phoma type PTLO"NOS, not otherwise speci fied .The italicized numbers are provi siona l cod es for the 4thedition of lCD -D . While they are expected to be incorpo-rated in the next ICD -O editi on , they currentty remainsubjectto changes.The italicized histologi c type s are provisional enti ties , forwhich the WHO Working Group fe ll the re was insufficientevidence to recognize as distinct diseases at this time."These lesions are classi fied according to the leukaemia orlymphoma to which they correspond, and are assigned therespective tCO-G code. WHO classification 13
  14. 14. Introduction to the WHO classification NL Harris E. Campo H. Stein S.H. Swerdlow of tumours of-haernatopoletlc E.S. Jaffe SA Pileri J Thiele J w. Vardiman and lymphoid tissues Why classify? Classification is the lan- committees was incorporated into the classification , involvement of clinicians is guage of medic ine: diseases must be class ification. Over 130 pa thologists and essential to ensure its usefulness and ac- described , defin ed and named before the y haem ato logis ts from around the world ceptance in daily practice 18971. At the lime can be diagnosed , treated and stud ied . were involved in writing the chap ters. A of publication of the WHO classi fication A consensus on definition s and termin ol- consensus meeting was held at the head - (3rd edition), prop onents of other cla ssifi- og y is essent ial for both clinic al practice quarters of the IARC in Lyon, France. to cations of haematologic neoplasms agreed and investigation . A cl assification should make final d eci sions on the classi ficatio n to use the new cl assification, thus ending contain diseases thai are clearly defin ed . and the con tent of the book. decad es of cont roversy over the classifi- c linically d istinc tive . norKlVerlappi ng (mu- cation of these tumo urs 147. 478 . t 89. tually excllsive) and that together comprise The WHO cl assification of tumours of the 1B9A, 190, 673,7750 , 1344A. 18198 1 , all known entities (collectively e xha ustive). haematopoietic an d lymphoid system is II should serve as a ba sis lor future inves- based on the principles initially d efined in As indicated above , there is no one -gold tigation . and should be able to incorporate the "Revised Europe an-Amer ican Classi- stand ard ," by which all diseases are new information as it becomes ava ilab le. fica tion of Lymp hoid Neoplasms" (REAL). def ined in the WHO cl assific ation. Mor- Classification has two aspects: clas s dis- from the Interna tiona l Lymphoma Stud y pholog y is alway s important, and many covery - the proces s of identifying cate- Group (ILSG) 18981. In the WHO classifi- diseases have ch aracteristic or even di- gories of diseases, and class pre diction cation, these p rinciples have also been agnosti c morphologic featu res, Immune- - the process of determining which cere- appl ied to the class ification of myeloid phe notype and genetic features are an gory an individual case belongs to. Pamer- and his tiocy tic neoplasms, The gu id ing important part of the definition of tumours ogi sts are critical to both processes . prin cip le of the REAL and WHO cl assifi- of the naematopolettc and lymphoid c ations is the attempt to define "real" tissues , and the av ailability of this infor- The World Hea lth Org anizati on (WHO) d iseases that c an be recognized by mation makes arriving at conse nsus defi- Classi fication of Tumours of the Haema- pa tholo gi sts with availabl e techniques. nitions easier now than it was when only topoietic and Lymp hOid Tissues (4th Edi- and that appear be distinct clinical enti- subjec tive morphologic criteria were tion ) was a coll aborative project of the ties . There are 3 important com ponents to available . lrrmunophenotyping studies are European Association for Haematopathol- this p rocess First. recognizing tha t the used in routine diagnosis in the vast ogy and the Society lor Hematopatholog y. underlying c auses of these neo plasms majority of haematolog ic mali gn ancies, It is a revision and update of the 3rd Edi- are often unknown and may vary, this ap- both to d etermine lineage in malig nant tion 11039 }. which was the first true proa ch to cl assifica tion uses all available processes and to dis tinguish be nig n lrom worldwide consensus c lassific ation of information - morpholog y, immunop he- ma lignant processes . Many disea ses baematoiocic malignancies. The update, notype, genetic features, and cl inical fea- have a chara ct eristic immunophenotype. which began in 2006, had an a-me mbe r tures- to define diseases. The relative such that one would hesitate to make the steering committee composed of membe rs impo rtance of eac h of these features diagnosis in the abse nce of the immune- of both societies, The Steering Comminee, varies among diseases, d epend ing upon p henot yp e, while in others the immuno- in a series of meetings and discussions, the state of current knowledge, and there onenotvpe is only part of the diagnosis, In agreed on a proposed list of diseases is therefore no one "g old standard ," by some lymphoi d and in many myeloid ne0- and chapters and selec ted authors. with which all di seases are defined . Second. p lasms a speci fic genetic abnorma lity is input from both soc ieties. As with the rec ognizing that the com plexity 01 the the key defining criterion, while etters lack WHO 3fd ed ition 1 71. the advice of clin - 89 field makes it impossib le for a single specific known genet ic ebnomantes. ical haematologists and oncologists was expert Of small g roup to be comptet ely Some g enetic abnormalities, while char- obtained . in order to ensure that the clas- authoritative, and that broad agreement is acteri stic of one dis ea se, are not specific sifica tion will be clinica lly useful. Two Clin- necessary if a classificati on is to be ac - (such as MYC. CCND 1or BCl2 rearrange- ic al Adv isory Committee s (CAG). one for cep ted, this cta ssrncanon relies on bu ild - ments or mutations in JAK2). and others myeloid neoplasm s and other acut e ing a consensus among as many experts are prognostic factors in several diseases leukaemias and one for lym phoid neo- as possible on the def inition and nomen- (such as TP mutations or FLT3-ITO) , 53 plasms. were convened, The mee tings clatu re of the diseases, We recognize that The inc lusion of jr munoohenotvoc lea- were org anized aroun d a ser ies of com promise is essential in orde r to arrive tures and genetic abnormalities to define questions, inc luding disease definitions, at a consensus, but bel ieve that the only entities not only provides ob jective criteria nomenclature, grading. and clinical rele- thing worse than an imperfect classifica- for disease recogni tion but has identified vance. The committ ees were able to tion is multiple competing classifi cati ons . antigens, genes or pathways that can be reach consensus on mos t of the ques- Finally. wh ile patholog ists must take targeted for therapy; the success of tions po sed . and muc h of the inp ut of the pr imary respon sib ility for developing a rituxima b , an anti-CD20 molecule, in the 14 Introduction to the classification.. .
  15. 15. treatment of. B-cel! neoplasms, and 01 ord er of listing is in part arb itrary, and is the WHO classification has produced aimatinib in the treatment of leukaemias as- not an integral part of the cl assification. new and exciting degree of cooperationsociated with ABL 1 and oth re!lrrange- and conmunic ation among patholog istsments inv olving tryoene kinase genes are The 4th ed ition of the WHO classification and oncologists from around the world .testament to this approach. Finally. some inc orpo rates new information that has which stould facilitate con tinued progressdiseases require know ledge of clinical emerged from basic and clinic al in....estr- in the understand ing and treatment offeatures - age, nodal versus extranodal gat ions in the interva l since pu b lication of haema totog ic manqnaocies . The mullipa-presentan on. specific anatomic site . and the 3rd edition . It inc ludes new defining rameter approach to c lassification, withhistory 01 cytotoxic and other therapies criter ia for some disease s, as well as a an emphasis on defining real disease- to make the diagnosis. Most 01 the dis- number of new entities. some def ined by entites. tha t has be en ad opted by theeases described in the WHO classification genetic criteria - particul arly among the WHO classification, has been shown inare considered to be distinct enti ties ; myeloid neoplasm s- and others by a inte rnational studi es 10 be reproducible:howev er. some are not as clearly defined, combination of morpholog y. immunoph e- the disea ses d efined are c linically dis-and these are listed as prov isional entities, ootype . and clinic al features. The frequent ttnct iv e. and the uniform definitions andIn addition . borderline categories ha....e application of immunophenotyping and terminology facilitate the interpretation ofbeen created in this edition for cases that genetic stud ies to peripheral blood, bone clinical and translational stud ies 1 1, 791 . 5do not c learly fit into one category, so that ma rrow, and lym ph node samp les has In addition, accurate and precise classifi -well-de fined categories ca n be kept also led to the de tection of small clonal c ation of d isease entities has facilitatedhomogeneous, and the borderline cases populations in asy mptomatic pe rsons . the discovery of the genetic bas is ofcan be stud ied further. These include small clones of cells with the my eloid and lymphoid neoplasms in the BCR-ABL 1 translocation seen in chronic ba sic science laboratoryThe WHO classification stratifiesneoplasms myelogenous leukaemia. small cl ones ofprimarily ac cording to lineag e: myeloid, ce lls with BCL2-IGH rearrangement. andlymphoid, and histiocyticfdendritic c ell. A small populat ions of c ells that have thenormal c ounterpart is postulaled lor each imm uoopheootype of chronic lymp hocyticneoplasm. While the goal is to define the leukaemia (e l l ) or folli cu lar lymphomalineag e of each neoplasm, lineage pla s- (mo noc lonal B lymphocytosis, follicularticity may occur in precursor or imma ture lymphoma-in Situ , paediatric follicul ar hy-neoplasms, and has recently been identi- perplas ia WIth monoclonal B c ells). Infied in some mature haematotymphoid man y case s. it is not clear whether theseneoplasms , In addition, genetic atooe - represent earty involvement by a neoplasm,rreuues suc h as FGFR1, PDGFA and a precursor iesoo. or an inconsequentialPDGFB rearrangements may give rise to find ing. These situations have someneoplasms 01 either myel oid or lymphoid ana logies to the identification of smalllineage associated with eosinophilia ; monoclonal immunoglobulin componentsthese disorders are now recognized as a in serum (monoclonal gammopathy ofseparate group. Precursor neoplasms unknown significance), The ch apters on(acute myeloid reukaemes. lymphoblastic these neoplasms include recommenda-Iymphomasfleukaemias, acute reukaerraas tions for dea ling with these situations. The01 amb iguo us lineag e, and blast ic p las- rec omm end ations of international con -macytoid de nd ritic ce ll neop lasm ) are sens us group s have bee n co nsidered.considered separately from mo re mature with regard to criteria for the d iagnosis ofneoplasms [myeloproliferative neoplasms e ll, plasma cell myeloma, Waldenstr6m(MPN). myelodysplastic/myeloproliterative macroglobulinemia, and new subtypes ofneoplasms, myelodysplastic syndromes , cutaneous lymphomas, as well as in themature (peripheral) B-cell and T/NK -cell development of new algorithms for the neoplasms, Hodgkin lymphoma. and his- diagnosis of MPN .Iiocyteldeodritic-c ell neoplasms] . The ma- ture myeloid neoplasms are stratified A critic al feature of any class ification of according to the ir bi ologica l features diseases is that it be periodically reviewed (myeIoploIiferative, with effective baereio- and updated to incorpor ate new informa- poiesis. ....ersus myelodysplastic , with in- tion. TheSocietyfor Haematopathology and effective neematcootesfs . as welt a s by the European Association for Haemato- genetiC feature s). Within the mature lym- pathology now have a more than to-year phoid neop lasms , the diseases are listed record of couebceaton and coo pe ration in broadly ac cord ing to clinical presentation this effort. The societies are comm itted to (disseminated often leukaemi c, extran - updating and revising the classification coat. indolent. aggressiv e). and to some as needed . with input lrom clinicians and extent according to stage of differentiation with the collaboration of the WHO . The when this can be postulated: howe....er the experience of developing and updating Introdu ction to the cl assification 15
  16. 16. • ) CHAPTER 1 Introduction and Overview of the Classification of the Myeloid Neoplasms •-, "
  17. 17. Introduction and overview of the J.w. Vardiman A.D. Brunning A. Porwit A . retten classification of the myeloid neoplasms D.A . Arter M.M.Le Beau C.D. Bloomfield J. Thiele The WHO Classification of Tumours of the by its c linic al and morphologic features, genetic features is used in an anerrctt c Haematopoietic and Lymphoid Tissue s and its natural progression is charac ter- define d isease entities , such as CML, that (3rd edition) published in 200 1 reflected ized by an inc rease in blasts of myeloid , are biolog ically homogeneous and clini- a pa radigm shift in the approach to c las- lymphoid or m ixed myeloid/lymphoid cally relevant - the same approach used sification of myeloid neoplasms { 1039). For immunop henotype. It is always associ- in the 3rd ed ition of the classification. the first time. genetic information was in- ated with the BCR·ABL 1 fusion gen e that Altho ugh the previous scheme began to cor porated into diagnostic algorithms results in the production 01 an abnormal open the door to including genetic ab- provided lor the vario us en tities. The pub- protein tyros ine kinase (PTK) with en- normalities as c riteria to classi fy myeloid licat ion was prefac ed with a comment hance d enzyma tic ac tivity. This p rotein is neoplasms, this rev ision firmly acknow l- pred icti ng future revisions nec essitated sut tcrentto ca use the leukaem ia and also edges that as in CML, recu rring ge netic by rapidly eme rg ing gen el ic information. provides a targ et for prote in tyrosi ne abno rmali ties provi de not onl y objec tive The cu rrent revision is a commentary on kinase inhibi tor (PTKI) the ra py tha t has c rite ria for recognition of speci fic entities the significant ne w molecular insights mat prolonge d the lives of thousands of pa - but also identification of abnormal gene have bec ome avail abl e since the publi- tients with this often tatal illness {6 151. product s or pathways that are potent ial cation of the last ctassncauon . This successful integ ratio n of cl inical , targets for therapy. One example in this The first entity described in this mono- morphologi c and genetic information em- revised sc heme is the addition of a new graph . chronic myelogenous leukaemia bodies the goal of the WHO classific ation subgroup of mye loid neoplasm s (Tabte (CML) rema ins the prototype for the iden- scheme. 1.01) assoc iated with eos inoph ilia and tification and c lassific atio n of myeloid In th is revis ion . a combination of c linica l, chromo somal ab normalities that involve neoplasms This leukaemia is recognized morpholog ic . imm uno phe noty pic and the oiateiet-oenved growth factor rece ptor .- Table 1.01 Themyeloid neoplasms major sul:9OUJlS and dal;U::i tstic features at ~ .........., .... """" - -- 0..... 8M ctllularity 10 MIrfOW bluts HatrnatopOitsit MPN Usually increased. En-. VanabIe; 008 or Co<m>oo often normalin ET tbmaJ or sIighlIy increased: <10% in dIonic phase """" G••,,,, relabYe/y normal, """..- IifIeage usually """""""", """""" irullallyincreased MyeIoidIIymphoid Increased Normal or $IigM~ Present Relatively normal Elfectrve Eosinophilia Com~ neoplasmswith increased: <20% irl j~t 5x10ir1.) eosinophilia and abriof· cnronc phase malilies of PDGFRA. PDGFRB Of FGFRI MOS Nom1al or incr eased: Preserlt ~lasia inoreor Inel!&CtiIe Cytopenia(s) U_ "as." =- "". more myeloid lineage -,,- -- ~aror """""" """... MPN _"" incleased;<2010 """" Usually oneormae ...... ...... Moy""Y ...... IariabIe. WBC ..-- Co<m>oo - rrft!lal cIyspIaSIa """" ....... ......, ........ ..-...... WllC_ -...... _>2ll%. "",", May Of may JIOl be """- """"""" ......... eQPl in some cases or e"ect1ve lIllh specific cybJeneIlc abnorrnaIilies or in -... dyspIaslailoneor some cases of erylhroIeukaemia Mf)N, myeloproliferative neoplasms: MDS, myelod)spla:slic syndromes; MDSlMf)N, myeIodysplasbcJmyeloprolifefalive neoplasms: AMl, ICIJIe myeloid leukaemia; ET, esseflIlaj Ihfombocylhaemia, JMML. ju¥&nile myelomonocytic leukaemia, wec. wniIe bloocI e&II$. 18 Introduction and overview of the c lassif ication of the mye loid neoplasms..
  18. 18. ] alpha (PDG FflA) Of platelet de rived growth is based on cr iteria applied 10 initial spec- factor recep tor beta (PDGFRB) genes imen s obtained prior to any definitive ther- -a subgroup defined larg er9 by genetic apy, includ ing growth lactor therapy, for the events that lead to consti tutive act ivat ion myeloid neoplasm. The blast percentage in of the receptor tyrosine kinase, PDGFA, the per ip her al b lood , bone ma rrow an d and that respond to PTKI therapy {13 1, other involved tissues remains of p ractica l 466. 8121 . Similar examples are found impo rtance to categorize myeloid neo- througho ut the classification in each plas ms and to judge their progression . 11111111 111I 1111 1111 111111 major subgroup, and inclu de not only Cytogenetic and molecular genetic stud- neoplasms assoc iated with rmcroscopr- ies are requ ired at the time of d iag nosis 456 cally rec og niza ble chromosomal abnor- not only for recoq r n ton 01 specific genet- FS!. 1.01 Bone marrow tIeI:Me biopsy, Bone marfOW malities but also with gene mutations ically d efined entities, but for establiShing bephinebiopsies should be alleast 1. em in length and 5 without a cytogenetic correlate as weu. a baseline against which futu re studies ollt<w1ed at right angles10 the cortical bone. On the other hand . the importance 01 can be judged to assess disease pro- careful clinical, morphological and im- gression. Beca use of the multidisciplinary munophenotypic characterization of each approach req uired to diagnose and clas- cells to categorize some eoutes. it is rec- myeloid neoplasm and coeretanoo with sify myeloid neoplasms it is recomnended ommended that 500 nucleated BM cells the genetic findings cannot be over- thaI the various diagnostic studies be be counted on cellular aspirate smears in emphasized. The discovery of activating correlated with the clinical findings and an area as close to the particle and as JAK2 mutations has revolutionized the reported in a single, integ rated report. If undiluted with blood as possible. Countll"lQ approach to the diagnosis of the myelo- a definitive classification cannot be from multiple smears may reduce sam- proliferative neoplasms (MPN) 1163, 1044 , reached the report should indicate the pling error due to irregular distribution of 1186,12681. Yet JAK2mutatiQns are not reasons why and provide guidelines for cells. The cells to be counted include specific for any single clinical or morpho- additional studies that may clarify the blasts and promonocytes (see definition logic MPN phenotype, and are also diagnosis. below) . pronveocvtes. myelocytes, meta- reported in some cases 01 myelodysplas- To obtain consistency, the following myelocytes, band neutrophils, segmented tic syndromes (MDS), myeiooysplasnc/ guidelines are recommended for the eval- neutrophils, eosiropnns. basophils, fTlQIlO- myeloproliferative neoplasms (MDSlMPN) uation of specimens when a myeloid neo- cytes , lymphocytes. plasma cells , erythrOid and ac ute mye loid leu kaemia (AMl). plasm is suspected to be present. It is precursors and mas t cells. Megakaryo- Thus, an integ rate d, multidisciplinary assu me d tha t this evalua tion will be pe r- cvtes. including dysplastic forms. are not approach is necessary for the classification formed with full knowled ge of the clinical inc lude d. If a concomitant non-mye loid of myeloid neoplasms. history and pertinent laboratory data. neoplasm is present, such as p lasma ceu With so muc h yet 10 learn, there may be myeloma, it is reasonable to exclude some missteps" as trad itional approaches Morphology tho se neo plastic cells from the coun t to categorization are fused with more Periphera l blood: A perip heral b lood (PB) used to evaluate the myeloid neop lasm. If rrcecuarfy-orentec clessifcaton schemes , smea r sho uld be exa mined and co rre- an aspirate ca nnot be obta ined du e to Nevertheless, thi s revi sion of th e WHO late d with result s of a co mple te b loo d fibrosis Of ce llular packing, touch prepa- classification is an attempt by the authors, c ount. Freshly mad e smea rs shou ld be ratio ns of the b iop sy may yield valuable editors and the c linic ians who served as sta ined with May-Gnmwald -Giernsa or c yto log ic informa tion, but d ifferential members of the Clinica l Advisory Com- Wright-G iemsa and examined for wh ite co unts from touc h preparations may not mittee (CAC ) to p rovide an "evidence- bloo d ce ll (WBC) , red b lood ce ll (AB C) be repr esentative . The d ifferential co unts based" c lass ifica tion that ca n be used in and plate let abnormal ities It is impo rtant obta ined from marrow aspi rate s should daily p ractic e for therap euti c deci sions to ascerta in that the smears are we ll- be compared to an estimate of the p ro- and yet pr ovide a flexib le framework for stained, Evaluation of neutrophil g ranularity po rtions of cells o bserved in avai lab le integration of new data , is imp ortant when a myelo id d isor der is biop sy sections, suspected; de signat ion of neut rophils as Bone marrow trephine biopsy: The contri- abnormal b ased o n hypog ranular cyto- but ion of adequate 8M bio psy sections in Prerequisites for classification plasm alo ne shoul d not be conside red the diagnosis of myeloi d neoplasms can- unless the stain is well-controlled . Manual not be overstated. The tre phine biopsy ofmyeloid neoplasms by 2OO-cell leukocyte di fferentials of PB provides information rega rdin g overall WHO criteria smea rs are recommended in patients with cellularity and the to pog raphy, propo rtion a myeloid neoplasm when the WBC count and maturation of baematopolenc cells , The WHO c lassification of myeloid neo- permits. and allows evalu ation of 8M stroma. The plasms relies on the morphologic, cyto- Bone manowaspirate: Bone marrow (BM) biopsy also provid es material for immuno- chemical and immunophenotypic features as pi rate smears should also be stained histochemical studies th at may have of the neop lastic cells to esta bl ish thei r with May-G rQnwald-G iemsa or Wright- diagnostic and prognostic importance. A lineage and deg ree 01 ma turation and to Gie msa for optimal visua lization of cyto- biopsy is essential whenever there is decide whether cellular p rolife ration is plas mic g ranules and nuclear chromatin. myelofibrosis, and the classification of sore q101ogica lly normal or dysplastic or Because the WHO Classification relies on entities , partiCularly MPN, relies heavily on esecuve or ineffec tive . The classification percentages of blasts and other specific trephine sections, The specimen must be Introduction and overview of the ctassncauoo at the myeloid neoplasms 19
  19. 19. adeq uate, Iake n at rig ht angle from thecortica l bone and at least 1.5 cm in lengthto enable the evaluation of at least 10 par-tially preserved inter-trabecular areas. Itshould be well-fixed, thinly sectioned at3-4 micra, and stained with haematoxylinand eosin and/o r a stain such as Giemsathat allows lor detailed morphologic eval-uation . A silver impreg nation method forreticulin fibres is recommended andmarrow fibrosis graded according to theEuropean consensus scoring system122141, A periodic acid-Schitt (PAS) stainmay aid in detection 01 megakaryocytes.Immunohistoc hemical (IHe) study of thebiopsy is often indispensable in the eva l-uation of myeloid neoplasms and is dis-cussed belOw,Blas ts: The percentage of myeloid blastsis important for dl8gnosis and ctasstcatonof myeloid neoplasms , In the PB the blastpercentage should be derived from a200-cell leukocyte differential and in the8M from a 500-cell count of cellular 8 Maspirate smears as described above . The biopsy. not all blasts express CD34 . They are usually strongly positive for n0n-blast percentage derived rom the 8 M Myeloblas ts. monoblasts and megakary<> specific esterase(NSE) but have no or onlyaspirate should correlate With an estimate blasts are included in the blast count. weak myeloperoxidase (MPO) activity,of the blast percentage in the trephine Myeloblasts vary from slightly larger than Promonocytes are considered as rrooo-biop sy. although large foca l clusters or mature lymphocytes to the size of mono- blast equivalents " when the requisite per-sheets 01 blasts in the biopsy should be cvtes or larger. with moderate to abun- centage 01 blasts is tallied for theregarded as possible disease progression. dant dark blue to blue-grey cytoplasm. diagnosis of acute monoblastic . acuteImmunohistochemical staining of the BM The nuclei are round to oval with finely monoc ytic and acute myerorronocyncbiopsy for CD34+ blasts often aids in the granul ar chromatin and usually several leukaemia. Promonoc vtes have a deli-correlation of aspirate and trephine biopsy nucleoli. but in some nuclear irregularities cately convoluted. folded or groovedfindings, although in some myeloid neo- may be prominent. The cytoplasm may nucleus with finely dispersed chromatin,plasms the blasts do not express CD34 , contain a few azurophil granules (Fig 1,03), a small , indistinct or absent nucleolus,Flow cyto metry determination of blast Monob lasts are large cells with abundant and finely granulated cytoplasm (Fig 1.04percentage should not be used as a sub- c ytoplasm that can be light grey to deeply C, 0), Most promonocytes express NSEstitute for visual inspection. The spec imen blue and may show pseudopod formation and are likely to have MPO activ ity. Thefor flow c ytometry is otten haemoouute. (Fig 1.04 A. S). Their nuc lei are usually distinct ion between mono brasts andand may be affected by a number of pre- round with deli cate , lacy chromatin and prornonocvte s is often difficu lt. butanalytic variabl es. and as noted for the one or more large prominent nucleoli. because the two cell types are summated ... ., •20 Introduction and overview of the classification of the myeloid neoplasms
  20. 20. as rr onootasf s in making the diagnosis ofAML, the distinction between a monoblastand promonocyte is not aly,.ogys critical.On the other hand , distinguishin g pro-monocvtes from mo re matu re b ut ab-normal leukaemic monocytes can also bedilficult, but is critical, because the des-ignation 01 a case as acu te monocytic oracute myelomonocytic leukaemia versuschronic myelomonocytic leukaemia oltenhinges on this distinclion . Abnormal A Brrooocv tes have more clumped chromatinthan a p romonocyte, variably indented.folded nucl ei 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 rotconsider ed as monoblast eouvaeots.Megakaryoblasts are usually 01rreoen tolarge size with a round , indented or ~~ - .irregular nucleu s with finefy reticularchromatin and one to three nucleoli. ThecytOplasm is basophiliC, usually agranular,and may show cytoplasmic blebs (See • •Chapter 6 on acute myeloid leukaemia,NOS). Small dysplastic megakaryocytes c oand micrornegal<.aryocyt es are not blasts.Inacute promyelocytic leukaemia, the blastequivalent is the abnormal promyelocyte .Erythroid precursors (erythroblasts) arerot included in the blast count except inthe rare instance of "pure" acute erythroidleukaemia, in which case they are cons id-ered as blast equiva lents (See Chap ter 6on acute myeloi d leukaemia, NOS).Cytochemistry and other special steins:Cytochemical stud ies are used to deter-mine the lineage 01 blasts, althou gh insome laboratories they have bee n sup- E Fplanted by immun ologi c studies usin gflow cytometry an d/or immunohistochem - Fig. 1.04 Monoblasts, promonocytes and abnormal mcnccytea from a case of acute monocytic laukaemia.istry. They are usu ally perform ed on PB A, B Monoblas tsarelarge with abundant cylOlJlasm that ma y contain a few vacuoles Of fine granules and have roullCland 8M aspirate smears but some can be nuclei withlacy chroma~n and one Of more variably prominent nucleoli. C, D Prornor.ocytes have more irregular anclperformed on sections 01 treph ine b iop - delicately folded n~ withfine chroma~n, small indistinct nucleoli and finely granulated cytoplasm. E, F Abnormalsies or other tissues . Detec tion 01 MPO monocytes appear immature, yet have mo condensed nuclear chroma tin, conoQ/uled Of fdded nuclai, and more re cylopIasmiC granulaboo (Courtesy of Or. J. Goasguen).indicates myeloid d ifferentia tion b ut itsabsence does not exclude a myeloid lin-eage because early myelobl asts as well case light grey granules are seen rather inhibi ted by NaF, The combination of NSEasmonoblasts may lack MPO. The MPO than the deeply black granules that char- and the specific esterase , naph thol-ASD-activity in rrweiobtasrs is usually granular acterize mverobrasts. The non-specific chloroaceta te esterase (CAE), which stainsand etten concentrated in the Golgi region este rases . u nap hthyl butyrate (ANB) and primarily cells 01 the neutroph il lineagewhereas monobtasts. although usually (,( naphthyl acetate (ANA). show diffuse and mast cells, permits ident ification ofnegative,may show line, scattered MPO+ cytoplasmic activity in monoblasts and monccvtes and immature and maturegranules, a pattern tha t becomes mo re monocytes. Lymphoblasts may have foca l neutroph ils simultaneously. Some cells ,pronounced in prcmonocvtes . Erythroid punctate activity with NSE but neutrophils particularty in myeIornonocytic leukaemias,blasts, megakaryoblasts and Iymphoblasts are usually negative. Megakaryoblasts may exhib it NSE and CAE simultaneously.are MPO negat ive . Sudan Black B (SSBl and erythroid b lasts may have some mul- While norma l eosinoph ils lack CAE, it maystaining parallels M PO but is less spe- titocal. punctate ANA positivity, b ut it is be expressed by neop lastic eosooohne.etc. Occ asional cases of lymphoblastic partia lly resistant to natrium ffuorid e (NaF) CAE can be performed on tissue sections leult.aemia exhibit SSB POSitiVIty in which , inhibition whereas monocyte NSE is totally as well as PB ()( marrow asp irate smears. Introduction and overview 01 the ctass.tcanoo 01 the myeloid neoplasms 21
  21. 21. In acute erythroid leukaemia. a PAS stain an essential tool in the cha racterization of immunophenotyping in myeloid neoplasmsmay be helpful in that the cytoplasm of myeloid neoplasms. Differootiation antigens is most com monly required in AML and inthe leukaemic oroervmrobreate may show that appear at various stages of haemato- determining the phe notype of blasts atlarge globules of PAS positivity. Well- ooeuc develo pment and in correspon- the lime of transfo rmation of MOS.controlled iron stains should always be ding myeloid neoplasms are illustrated in MOS!MPN and MPN,per formed on the 8M aspirate to detect Fig . 1.05. and a thorough descriplion of Mulliparameter flow cytometry is theiroo stores. normal side roblasts and ring lineage assignment criteria is provided in prefer red method of immuno phenotypicside robrasts. the latter of which are de- the chapters on mixed phenotype acute analysis in AML due to the ability to ana-fined as erythroid precursors with 5 or leukaemia, The techn iques employed and lyze high numbers of cells in a relativelymore granules of iron encircling one-third the antigens anafyzed may vary accord- short period of time with simultaneousor more of the nuc leus. ing to the myeloid neoplasm suspected recording of information about severer and the information required 10 best char- antigens for each individual cell. Usually.Immunop henotype acterize it as well as by the tissue avail- rather extensive panels of monoclonal an-Immunophenotypic analysis using either able. Although often important in the tibodies directed against leukocyte differ-multiparameter flow cytometry or IHe is diagnosis ol any haematoiogicaJ neoplasm. entiation antigens are applied because <-U II 7+ - C U 1I7+ c m l 7- lib- llb-I+ C U,J. - C O lJ5.- C D.l6- CDIJ ~- fh+ C DJ6 - Cll1J~.- "" CD l 6 - C D235. - prvQ)"lbn>bla. 1 b ....p bllk: pc.ol ycbrvm.lk tory l b rub l.,. toryl h ruh l• • 1 C U lM- + C I)l63+ C IUJ+ C IU+ C O}4... C O IS+ C OU + C IU + C IU J + C O l5-+- C D36-+ COll ++ C D U" C I)6" + C DJ .... IIr"",,::7:-:-~01 liLA-DR" C IU 3" HL- -DR + C OM+ C U34_ C O ll b+ IH...A-O R + liLA -DR t-tl L -"-LO"--l,. C D I 4+ C O l lb++ C U.H++ • • C O l -t-t mon.. hl . ~1 p rumo"ucy m nmx: yl f ,-------, r----, em s- C O Il 7 +1- C IH J d lm C lU J " C ll1 J+ C IU J + MO+ C D 33 + MPO+ C D6 5+ MPO+ C ))65+ C U15+ C:0 6 5+ C D I5 + C D I I II+ C D I5+/· C U ll b+_ C1U 5tlim C D 3.. +-+ e m s- 1I1.A.-UR C D .N+-+ Un _ C D J ..... C IH M+ C D U J- C1U5R A+ _n_ C UJ4+I. C DJ4· C U.14- C D3.. + C DJ M., _ C DJ8+ ClHM _ C O. II++ C D61+ C 06 1+ C I)6 I++ C D IlJ-. C I).&I+ C 04I + C I).& 1-+-+ C1 U 5 HA - ce-e- C04 l +I· C U" l+ TIO -R+22 mtrocucuco and overview of lhe classification of the myeloid neoplasms