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 01Classification 01 Tumours . Patholog y and Genetics of TumoursTumours. 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 2002IARC Press : lyon 2003 ISBN 92 832 2413 2ISBN 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 HealthHermelink H.K ., Harris C .C. (Eds.): Eng C . (Eds.): World Hea lth Organization Classification ofWorld Health Organization Organization Classification of Tumours. Pathology and Genetics ofClassification 01 Tumours. PathologyTlJTlOUrs. Pathology and Genetics ot Tumours althe Urinary System andand 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 2004IARC Press : lyon 2004IARC Press : lyon 2004 ISBN 92 832 2415 9ISBN 92 832 2418 3ISBN 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 HealthSarasm A . (Ed s.): World HealthCavenee WK (Ed s.) : World Health Organization Classification ofOrganization Classification ofOrganization Classification of Tumours. Pathology and Genetics ofTumours. Pathology and Genetics ofTumours . Tumours of the Central Head and Neck Tumours (3I"d edition) .Skin Tumou rs (3rd edition).Nervous System (4th edition ). IARC Press : lyon 2005IA RC Press : lyon 2006 IARC, lyon 2007 ISBN 92 832 24 17 5 ISBN 92 832 2414 0ISBN 92 832 2430 2This book and all other volumes of the series can be purchased from: From all countriesWHO 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 6766Fax +16137457660

2. -.I 3. I WH O OMSInternational Agency for Research on Cancer (IARC)4th EditionWHO Classification of Tumours ofHaematopoietic and Lymphoid Tissues Edited bySteven H. Swe rdlow Elias Campo Nancy Lee HarrisElaine S. JaffeStefano A. Pileri Harald SteinJOrgen ThieleJames W. Vardiman Intern ational Agency for Resea rch on CancerLyon , 2008 4. World Health Organization Classification of TumoursSeries 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. LayoutSebastien Antoni Marlen Grassinger Pascale Collard Printed byParticipe Present 69250 Neuville s/SaOne, FrancePublisherInternational Agency for Research on Cance r (IARC) 69008 Lyon. France 5. This volume was produced with support from the Associazione S.P.E.S. Onlus, BolognaFriends of Jose Carreras International Leukemia FoundationLeukemia Clinical Research FoundationMEDIC FoundationNational Cancer Institute, USA National Institutes of Health Office of Rare Diseases, USAUniversity of Chicago Cancer Research CenterThe WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues presented in this book reflects the views of a Working Groupthat convened for an Editorial and Consensus Conference at theInternational Agency for Research on Cancer (fARC), LyonOctober 25-27. 2007. Members of the Working Grou p are indicated in the List of Contributors on pages 369-374. 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 byWHO 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 theexpression 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 thedelimitatiOn 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 aredistmguished 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. ContentsWHO Classifjcatioo9 AML with mutated NPM 1120Summary table 10AMLwith mutated CEBPA 122Introduction to the classification of tumours of AML with myelo dysplas ia-related changes124 haematopoietic and lymphoid tissues14 Therapy -relate d myeloid neoplasms127 Acu te myeloid leukaemia, NOS130Introduction and overview of the classification ofAML with minimal diff erentiation 130the myeloid neoplasms 17AML withOut matu ration 131AML with maturabon1312 Myeloproliferative neoplasms31Acute myelomonocytic leukae mia 132Chronic myelogenous leukaemia. BCR-ABL 1 positive 32Acute monoblastic and monocytic leukaem ia133Chronic neutrophilic leukaemia38Acute erythroid leukaemia 134PoIycythaemia vera40Acu te megakaryoblastic leukaemia 136Primary myelofibrOsis 44Acute basophilic leukaemia137Essenliallhrombocythaemia 48Acu te paomveosrs with myelofibros is 138Chronic eosinophilic leukaemia. NOS 51 Myeloid sarcoma140Mastocytosis54 Myeloid proli ferations related 10 Down synd rome142 Cutaneous mastocytosis 57Transient abnOrmal myelopoiesis 142Systemic mastocytosis 58Myeloid leukaemia associated withMasl cell leukaemia 61Dc:rwn syndrome 143Mast cell sarcoma 61 Blastic plasmacytoid dendritic cell neoplasm 145Extracutaneous mastocytoma61Myeloproliferative neoplasm, unc lassi fiable 647 Acute leukaemiasof ambiguous lineage149 Acute undlHerentiated leukaemia1513 Myeloid and lymphoid neoplasms withMixed phenotype acute leukaemia wilheosinophilia and abnormalities of PDGFRA. t(9;22)(q34;q 11.2): BCR-ABL 115 1PDGFRB Of FGFRl 67 Mixed phenotype acute leukaemia witht(v:11q 23): MLL rear ranged1524 MyelodysplasticJmyeloproliferative neoplasms75 Mixed phenotype acute leukaemia , B/myeloid, NOS 152Chronic mveiomonocync leukaemia 76 Mixed phenotype ac ute leukaemia , T/myeloid , NOS 153Atypical ctYonic myeloid leukaEmia. BCR- ABL 1 negative 80 Mixed phenoty pe acu te leukaemia, NOS rareJuvenile myelomonocytic leuk aemia82types 154MyelodysplastiC/myeloproliferali ve neoplasm , Other ambiguous lineage reukaerraest 55 urclasaifiable 85 Natura! killer (NK)-celilympho blasticleukaemi a/lymphoma 1555 Myelodysplastic syndromes 87Myelodysplastic synd romes/n eo plasms , overview 888 Introduction and overview 01 the c lassification ofRefractory cytope nia with unilineage dysplasia 94 the lymphoid neoplasms 157Refractory anaemia with ring side rob lasts 96Refractory cytopenia with multilineage dysplasia989 Precu rsor lymphoid neoplasms 167Refractory anaemia with exc ess b lasts100B lymp hob lastic leukaemia/lymphoma, NOS 168Myelodysp lastic synd rome with isolated de l(5q)102B lymphob lastic leukaemia/ lymphomaMyelodysp lastic synd rome, uncrasslttabte 103 with recu rrent gene tic abn orma lities 171Childhood mye lodysp lastic synd rome104B lymphob lastic leukaem iallymphoma with Refractory c ytopenia of c hild hood104 t(9 :22)(q 34;q 11.2): BCR-ABL 1 171B lymp hoblastic leukaemia/ly mpho ma with6 Acute myeloid leukaemia (AML) andl(v:11q 23): ML L rearranged 171related precursor neoplasms109B lympho blastic leukaemiall ymphom a withAML with recurrent genet ic abn or malities11 0t(12:2 1)(p1 3;q22 ): TEL-AMLl (ETV6--RUNX 1)172AML with t(8:21 )(q22:q22); RUNX1 -RUNX1T1 11 0 B lymphoblastic leukaemia/lymphoma withAML with inv( 16)( p 13.1q22) or hyperdi ploi dy173 1(16:t6)(p 13.1;q22): CBFB-MYH 11 11 1 B lymphoblastic leukaemiallymphom a withAcute orornveiocvnc leukaem ia withhypodiplOi dy (Hypodiploi d ALL) 174 t(15:17)(q22 :q 12): PML- RARA11 2 B lymphoblastic leukaemiallymphoma withAML with us.11)(p 22:q 23): MLLT3-MLL114 t(5; 14)(q31;q32); IL3-IGH 174AML with t(6:9)(p23 :q34); DEK-NU P2 14115B lymphoblastic leukaemiallymphoma withAML 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 EVI1116T lymphoblastic leukaemiallymphoma176AML (megakaryoblastic) with t( 1;22)(p13;q 13): RBM15-MKL 1 117 8. 10 Mature B-ceUneoplasms179Enteropathy -associated t-een lymphoma 289 Chronic lymphocytic leukaemia IsmailHepatosplenlc t -een lymphoma292 Iymptlocytic lymphoma :f180Subcutaneous panniculitis-like t-een lymphoma294 s-een prolyrTlhocytic leukaemia 183Mycosis fungoi des 296 Splenic B-cell marginal zone lymphoma185Sezary syndrome299 Hairy cell leukaemia 188Primary cutaneous CD30 posi tive t-een Splenic B-cell Iymphomalleukaemia, unclassiliable191 Iymphoprolilerative disorders 300 Splenic diffuse red pulp small B-ceil lymphoma 191Primary cutaneous per ipheral t-een lymphoma s, Hairy cenleckaeme-....anent192 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 disease196 ep idermotrop ic cytotoxic T-celt lymphoma303 Mu heavy chain disease 197 Primary cutaneou s CD4 positive Alpha heavy chain disease198small/medium T-cell lymphoma 304 Plasma cell neoplasms200Peripheral t-een lymphoma. NOS 306 Monoc lonal gammop athy 01 undetermined Ang ioimmunoblastic t -een lymphoma309significance (MGUS) 200Anaplastic large cell lymphoma. AlK positive 312 Plasma ce ll myeloma 202Anapla stic large cell lymphoma . ALK negat ive317 Solitary plasmacytoma of bone208 Extraosseous plasmacytoma208 12 Hod gkin lymphoma32 1 Monoclonal immunoglobulin deposition diseases209Introduction 322 Extranodat marginal zone lymphoma of mucosa-Nodular lymphocyte predominant Hodgkin Iymptuna323 associa ted lymphoid tissue (MALT lymphoma)214Classical Hodgk in lymp homa. introduction 326Nodal marg inal zone lymphoma 218Nodular sclerosis classical Hodgkin lymphoma 330Follicular lymphoma 220Mixed ce llularity classical Hodgkin lymphoma331Primary cutaneous follicle centre lymphoma227Lymphoc yte-rich classical Hodgkin lymphoma332Mantle cell lymphoma229lymphocyte-depleted classical Hodgkin lymphoma 334Diffuse large B-celllymphoma (DLBCl), NOS 233T celilhi stiocyte-rich large B-ce ll lymphoma238 13 1rnmunode ficiency-assoc iated Primary DlBCL of the CNS 240Iymphoproliferative disorde rs 335 Primary cutaneous DlBCl . leg type 242Lymp hoproliferative diseases associated with EBV positive DLBCl of the elderly243primary immune disorders 336DLBCL assoc iated with chronic inflammation 245Lymphomas associa ted with HIV infection 340Lymphomatoid granulomatosis 247Post-nansotanttsmpnooronterauve disorders (PTlD) 343Primary med iastinal (thymic) large B-celilymphoma250Plasmacytic hyperp lasia and infectious-Intrav escurer large B-celi lymphoma252 rroooo ocieose-uke PTlD 345ALK positive large Been lymphoma254Polymorphic PTlO 346Plasmablastic lymphoma256Monomorph ic PTlO347large a-ceu lymphoma arising in HHV8-associatedClassical Hodgkin lymphoma type PTLO 349multicent ric Castleman disease 258Other iatrogenic immunodeficiency-assoc iatedPrimary effusion lymphoma 260Iymphoproliferative disorders350Burkitllymp homa262B-cel1lymphoma, unclassiliab le, with features14 Histiocytic and dendritic cell neoplasms 353intermediate between DLBCL and Introd uction354Burkitllymphoma 265Histiocyt ic sarcoma 3S6B-ceillymphoma, unctessmebie. with featuresTumours der ived from langerhans cells 358intermediate between OLBCl and Langerhans cell histiocytosis3S8clas sica l Hodgkin lymphoma267Langerhans ce ll sarcoma 360 Interdigitating dendrit ic cell sarcoma36 111 Mature T- and NK-cell neoplasms269Follicular de ndritic ce ll sarcoma363 r-cea prolymphocytic leukaemia 270Other rare dendritic cell tumours365 t- een large granular lymphocytic leukaemia272Disseminated juvenile xanthogranuloma366 Chronic Iymphoproliferative disorder of NK cells 274 Aggressive NK cell leukaemia 276 Contributors369 Epstein-Barr virus (EBV) positive t-eenClinical advi sory oorrrnittee374 Iymphoprol ilerative diseases of ch ildhood278 Source of Charts and photographs376 Systemic EBV+ t-een Iymphoproliferalivedisease of childhood278 References300 Hydroa vacclnrtorrne-uk e lymphoma 280 Subject index 429 Adull T-ceil leukaemia/lymphoma281 Extranodal NK/T-cell lymphoma. nasal type285 NOS, no! otherwise specifi ed, 9. WHO Classification4th Edition-//-.,.e"/,...,...,...~ /,f /- ~ ~~- -~~ _....i? ~.,.~- 10. WHO Classification of tumours of haematopoieticand lymphoid tissues MYELOPROLIFERATIVE NEOPLASMSMYELODYSPLASTIC SYNDROMES Chronic myelogenous leukaemia , Refractory cytopenia with unilineage dysplasia BCR-ABL 1 positive 987513Refractory anaemia9980/3 Chronic neutrophilic leukaemia 996 3/3Refractory neutropenia999 1/3 Polycythaemia vera 995 0/3Refractory thrombocytopenia 9992/3 Primary myelofibrosis996 1/3 Refractory anaemia with ring sideroblasts9962/3 Essential thrombocythaemia 996213 Refractory cytopenia with Chronic eosinophilic leukaemia, NOS9964 /3multitineage dysplasia 9965/3 MastocytosisRefractory anaemia with excess blasts9983/3Cutaneous mastocytosis9 74011MyelodysplasU syndromec associated with isolated del(Sq) 9966/3Systemic mastocytosis 9 74 1/3 Myelodysplasticsyndrome, uncJassifiable9969/3Mast cell leukaemia 974 213Mast cell sarcoma 974 0/3 Childhood myelodyspla suc syndromeExtracutaneous mastocytoma974 0/1Refractory 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 FGFRIAML with t(6 ;21)(q22;q2 2); Myeloid and lymphoid neoplasmsRUNXI-RUNX1Tl 9696/3 with PD GFRA rearrangement 9965/3AML with inv(16)(pI 3.1q22 ) Myeloid neoplasmsor t(16;16)(pI3.1;q2 2); CBFB-MYHl1 9671/3 with PDGFRB rearrangement9966/3Acute promyelccytlc leukaemia Myeloid and lymphoid neoplasms with t(15 ;17)(q22 ;qI2); PML-RARA9666/3 with FGFR1 abnormalities 9967/3AML with t(9 ;11)(p22 ;q23); MLLT3-MLL9697/3AML with 1(6;9)(p2 3;q34 ); DEK-NUP214986513 MYELODYSPLASTIC/MYELOPROLIFERAnVEAML with inv( 3)(q2 1q26.2) NEOPLASMSort(3; 3)(q21;q 26.2); RPNI -EV/1 9869/3 Chronic myetcmonocytic leukaemia 9945/3AML (megakaryoblastic)with t(I ;22)(p I 3;q I 3); RBMI5-MKLI9911/3 Atypical chronic myeloid leukaemia. BCR-ABL 1 negative 967613 AML with mutated NPM1986 1/3 Juvenile myelomonocytic leukaemia9946/3 AML wrlh mutated CEBPA 9661/3 Myelodysplasticlmyeloproliferative neoplasm. unclassifiable 9975/3 AML with myelodysplasia-related changes 969513Refractory anaemia with ring sideroblastsTherapy-re lated myeloid neoplasm s99 2013associated WI h marked thrombocyt t osis 99 621310WHO ctassrtceton 11. Acute myeloid leukaemla",NOS9861/3B lymphoblastic leukaemia/lymphomawith recurrent genetic abnormalities AML with minimal differentiation 987213 B lymphoblastic leukaemiaflymphoma AML without maturation 9873/3with 1(9;22)(q 34;q l 1.2); BCR-ABU 9812/3 AML with maturation9874 /3 B lymphoblastic leukaemiall ymphoma Acute myelomonocytic leukaemia 9867 /3 with t(v;11q23); MLL rearranged 981Y3 Acute monob lastic and monocytic leukaemia 9891 /3B lymphoblastic leukaemiall ymphoma Acute erythroid leukaemia984013with 1 12;21)(p13;q22); TEL-AMU ((ETV6-RUNX1)9814/3 Acute megakaryoblastic leukaemia 99 10/3 B lymphoblastic leukaemiallymphoma Acute basoph ilic leukaemia987013 w ith hyperdiploidy981513 Acute panmyelosis with myelofibrosis 9931 13B 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 syndromet(1;19 )(q23 ;p13 .3); E2A-PBXlTransient abnormal myelopoiesis 989811(TCF3-PBX1) 9818/3Myeloid leukaemia associated with Down syndrome9898/3T lymphoblastic leukaemia/lymphoma9837/3Blastic plasmacytoid dendriticcell neoplasm 9727/3MATURE B-CELL NEOPLASMSChronic lym phocytic leukaemia!small lymphocytic lymphoma982313ACUTE LEUKAEMIAS OF AMBIGUOUS LINEAGEB-cell prolymphocytic leukaemia 983313Acute undifferentiated leukaemia980 1/3Splenic Bccell marginal zone lymphoma 968913Mixed phenotype ac ute leukaemiaHairy cell leukaemia9940/3with t(9;22)(q3 4;q 11.2); BCR-ABL1 980613Mixed phenotype ac ute leuka em iaSplenic B-cell fymphomalleukaemia, unclassifiable 959 1/3with t{v;11q23); MLL rea rranged9807/3 Splenic diffuse red pulp small B-cell lymphoma 9591/3Mixed phenotype ac ute leukaemia,Hairy eel/leukaemia-variant959 1/3B/myeloid, NO S 9808/3Lymphoplasmacytic lymphoma9671/3Mixed phenotype ac ute leukaemia,Tfmyeloid, NOS9809/3 waldenstrom macroglobulinemia9761/3Natural killer (NK) cell lymphoblasticHeavy chain diseases9762/3 !euKaemiallymphoma Alpha heavy chain disease9762/3 Gamma heavy chain disease9762/3 Mu heavy cha in disease9762/3PRECURSOR LYMPHOID NEOPLASMSPlasma cell myeloma 9732/3B lymphoblastic leukaemiaflymphomaSolitary plasmacytoma of bone 9731/3B lymphoblastic leukaemiall ymphoma, NO S 98 11/3Extraosseous plasmacytoma 9734/3 WHO classification11 12. -Extranodal marginal zone lymphoma Systemic EBV positive T-celllymphoproliferativeof mucosa-associated lymphoid tissue disease of childhood 9724/3(MALT lymphoma) 9699/3Hydroa vaccin iforme-like lymp homa972513Nodal marginal zone lymphom a 9699/3Adult T-cell ieukaemia/lymphoma9827/3Paediatric nodal marginal zone lymphoma 9699/3Extranodal NKIT cell lym phoma, nasal type 9719 /3Follicular lymphoma 9690/3Enteropamy-associated T-cell lymphoma9717/3Paediatric folliculaf lymphoma9690/3Hepatosplenic T-cell lymp homa 971613Primary cutaneous follicle centre lym phoma 959713Subcutaneous panniculitis-likeT-cell lymphoma970813Mantle cell lymphoma967313Mycosis fungoides970013Diffuse large B-eelllymphoma (OlBCl), NOS 968013Sezary syndrome970113T-ceillhistiocyte rich large B-eelilymphorna9688/3Primary cutaneous CD30 positive F-eel!Primary DLBCl of the CNS968013 Iymphoproliferative disordersPrimary cutaneous DlBCl. leg type 9680/3 9718/1 lymphomatoid papulosisEBV positive OLBCL of the elderly 9680/3 Primary cutaneous anaplastic large cellOl BCl associated with chro nic inflammation 968013lymphoma9718/3l ymphomatoid granulomatosis9766 /1 Primary cutaneous qamma-deltar -ceuivmpncma 9726/3Primary med iastinal (thym ic) large B-celllym phoma9679/3Primary cutaneous COB positive aggressiveepidermotropic cytotoxic T-cefl lymphoma 9709/3Intravascular large B-cell lymphoma 971213Primary cutaneous CD4 positive smalVmediumAlK positive large B-cell lym phoma 9737/3 T-cell lymphoma 9709/3Plasmablastic lymphoma973 5/3Peripheral Tccelllympboma, NOS 970213l arge Bccell lymp homa arising in HHV8-Angioimmunoblastic l-cetl Iyrnphoma 970513 associated multicentric Castleman disease 9738/3Anaplastic large cell lymp homa, ALK positive 97 14/3Primary effusio n lymphoma9678/3968 7/3Anaplastic large cell lymphoma, ALK negative 970213Burkitt lymph omaB-ceillym phom a, uncl assifiable, with feature sintermediate between diffuse large g-ceulymph oma and Burkitt lymph oma 968 0/3HODGKIN LYMPHOMAB-ceil lymph oma , unclassifiable, with feat uresNodular lymphocyte predomi nantintermediate betwee n diffuse large 8-cell 9659/3Hodgkin lymp homalymphoma and classica l Hodgkin lymphoma 9596/3Classical Hodgkin lymp homa9650/3 Nodular sclerosis classical Hodgkin lymphoma9663/3MATURE T-CELL AND NKCELL NEOPLASMS l ymphocyte-rich classica lj-cen prolymphocytic leukaemia9834/3Hodgkin lymphoma 965113f-celllarqe granular lym phocytic leukaemi a 983 1/3Mixed cellularity classica lI Chronic Iymphoproliferative disorder ofNK..cells 983113 Hodgkin lymphoma l ymphocyte-depleted classical 965213~l..Aggressive NK cell leukaemia9948/3Hodgkin lymphoma 965313 12WHO ciassitcenon _ 13. HISTIOCYTIC AND DENDRITIC CELL NEOPLASMSHistiocytic sarcoma9755 /3l angerhans cell histiocytosis 975 1/3langerhans cell sarcoma9756/3Interdigitating dendritic cell sarcoma 9757/3Follicular dendritic cell sarcoma975813Fibroblastic reticu lar cell tumour9759/3Indeterminate dendritic cell tumour9757/3Disseminated juvenile xanthogranulomaPOSTTRANS PLANT LYMPHOPROUFERATIVEDISORDERS (PTLO)Early lesi ons P1asmacytic hyperplasia 9971/1 Infectious mononucleosis-like PTLD9971 /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. Introduction to the WHO classification NL HarrisE. Campo H. SteinS.H. Swerdlow of tumours of-haernatopoletlcE.S. JaffeSA PileriJ ThieleJ 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 beclass ification. Over 130 pa thologists andessential to ensure its usefulness and ac- described , defin ed and named before the y haem ato logis ts from around the worldceptance in daily practice 18971. At the lime can be diagnosed , treated and stud ied . were involved in writing the chap ters. Aof 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 practicequarters of the IARC in Lyon, France. to cations of haematologic neoplasms agreed and investigation . A cl assification shouldmake 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 compriseThe WHO cl assification of tumours of the1B9A, 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 inAs indicated above , there is no one -gold tigation . and should be able to incorporatethe "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 theties . There are 3 important com ponents toavailable . 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 trueproa 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 rtures- to define diseases. The relativesuch 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 uponp henot yp e, while in others the immuno- in a series of meetings and discussions,the state of current knowledge, and thereonenotvpe is only part of the diagnosis, In agreed on a proposed list of diseases is therefore no one "g old standard ," bysome lymphoi d and in many myeloid ne0- and chapters and selec ted authors. withwhich 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 - 89field makes it impossib le for a singlespecific 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 forcep 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 expertsare 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 tingsclatu re of the diseases, We recognize thatThe inc lusion of jr munoohenotvoc lea- were org anized aroun d a ser ies ofcom 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 taketargeted 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. treatment of. B-cel! neoplasms, and 01 ord er of listing is in part arb itrary, and isthe 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 areThe 4th ed ition of the WHO classification and oncologists from around the world .testament to this approach. Finally. someinc orpo rates new information that haswhich stould facilitate con tinued progressdiseases require know ledge of clinicalemerged from basic and clinic al in....estr- in the understand ing and treatment offeatures - age, nodal versus extranodalgat ions in the interva l since pu b lication of haema totog ic manqnaocies . The mullipa-presentanon. specific anatomic site . andthe 3rd edition . It inc ludes new definingrameter 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 classificationgenetic criteria - particul arly among the WHO classification, has been shown inare considered to be distinct enti ties ;myeloid neoplasm s- and others by ainte 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 frequentttnct iv e. and the uniform definitions andIn addition . borderline categories ha....eapplication of immunophenotyping and terminology facilitate the interpretation ofbeen created in this edition for cases thatgenetic 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 hasIn addition, accurate and precise classifi -well-de fined categories ca n be keptalso led to the de tection of small clonal c ation of d isease entities has facilitatedhomogeneous, and the borderline casespopulations 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 chronicba 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 theleukaemia (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 haematotymphoidman 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 anda precursor iesoo. or an inconsequentialPDGFB rearrangements may give rise tofind 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 ain serum (monoclonal gammopathy ofseparate group. Precursor neoplasmsunknown significance), The ch apters on(acute myeloid reukaemes. lymphoblasticthese neoplasms include recommenda-Iymphomasfleukaemias, acute reukaerraastions 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 maturewith regard to criteria for the d iagnosis ofneoplasms [myeloproliferative neoplasmse ll, plasma cell myeloma, Waldenstr6m(MPN). myelodysplastic/myeloproliterativemacroglobulinemia, and new subtypes ofneoplasms, myelodysplastic syndromes , cutaneous lymphomas, as well as in themature (peripheral) B-cell and T/NK -celldevelopment 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 listedrecord of couebceaton and coo pe ration in broadly ac cord ing to clinical presentationthis 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 differentiationwith the collaboration of the WHO . The when this can be postulated: howe....er the experience of developing and updating Introdu ction to the cl assification15 16. )CHAPTER 1 Introduction and Overview of the Classification of the Myeloid Neoplasms -, " 17. Introduction and overview of the J.w. VardimanA.D. Brunning A. Porwit A . retten classification of the myeloid neoplasmsD.A . ArterM.M.Le BeauC.D. Bloomfield J. Thiele The WHO Classification of Tumours of theby its c linic al and morphologic features,genetic features is used in an anerrctt c Haematopoietic and Lymphoid Tissue sand its natural progression is charac ter- define d isease entities , such as CML, that (3rd edition) published in 200 1 reflectedized 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/lymphoidcally relevant - the same approach used sification of myeloid neoplasms { 1039). Forimmunop henotype. It is always associ- in the 3rd ed ition of the classification. the first time. genetic information was in- ated with the BCRABL 1 fusion gen e thatAltho ugh the previous scheme began to cor porated into diagnostic algorithmsresults 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 commenthance 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 alsoedges 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 neabno rmali ties provi de not onl y objec tive The cu rrent revision is a commentary onkinase 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 recognizedmorpholog ic . imm uno phe noty pic andthe oiateiet-oenved growth factor rece ptor.- Table 1.01 Themyeloid neoplasms major sul:9OUJlS and dal;U::i tstic features at ~..........,.... """" ---0..... 8M ctllularity10 MIrfOW blutsHatrnatopOitsitMPNUsually increased.En-. VanabIe; 008 orCooo often normalin ET tbmaJ or sIighlIyincreased: bla. 1b ....p bllk: pc.ol ycbrvm.lk tory l b rub l.,. toryl h ruh l 1C 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 . ~1p rumo"ucy m nmx: yl f,-------, r----,em s- C O Il 7 +1- C IH J d lmC 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 5tlimC D 3.. +-+ e m s-1I1.A.-URC D .N+-+ Un _ C D J ..... C IH M+ C D U J- C1U5R A+ _n_ C UJ4+I. C DJ4C 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 22. Jthe utility o f in,s:livid ual markers in identify- in the id entification of abnormal mega-Revised WHO classification ofing commitme nt of leukaemic c ells intoka rvoc ytes.myeloid neoplasmsthe different haemat op oieti c tlneages islimited Evaluation of exp ress ion patternsGenetic studi esof several antige ns, bo th membrane and The WHO classi fication includes a num-Table 1,0 1 lists the major subgroup s ofcytoplasmic, is necessary for lineagebe r of entities defined in part by scecmc myelold neop lasms and their characteristicassignment. to d etect mixed phenotype genetic abnormalities. including genefeatures at diagnosis. The nomenclatureacute leu kaemia, and 10 detect aberran trearrangemen ts due 10 chromosomal for the myeloprolife rative entities has beenphenotypes allowing lor follow-up of nansrccarrons and to specific gene muta- c hanged from "c hronic mye lopro liferat iveminimal re sidua l d ise ase . tions. so de term ination of genet ic features diseases" to myeIoproIiferative neoplasms"Irrmunopheootypic analysis has a ce ntral of the neoplastic cells must be performed and the subgroup formerly designated asrole in disting uishing be tween minimally if possible. A complete cytogenetic ana ly-"myelod ys pl as ticfm y e lo p ro li fe rati v edllferentiated acut e myeloid leu kaemia sis of 8M shou ld be perlormed at the time dis eases" has been ch ang ed toand acute lymphoblastic leukaemia, andof init ial eva luat ion to establish the cyto- "myelod ysplasticJmyelo proliferative ne0-in CML between myeloid blast pha se genetic profile, and at regu lar intervalsprasms" to und erscore the ir neoplast icand lymphoid blas t phase. Among AM L thereafter to detect evidence of geneticnature . Beside s the addition of the newWIth recurrent genetic abnormalities , sev -evolution . Additional d iag nosti c geneticsubgroup. "Myeloi d and lymp hoid ne0-eral have characteristic phenotypes. Thesestudies should be guided by the diagnosis plasms with eosinophil ia and abnormalitiespatterns. described in the respective suspected on clinica l, morpholog ic a nd of PDGFRA, PDGFR8 and FGFRt , newsections, can help to plan molecularcvto- imTulophenotypi studies. In some cases, entities have been added and/or diag-genetIC {lluorescence in situ hybrid izationreverse transc rip tase-pol ymerase c hainnost ic criteria updated with in each sub-(FISHlI and molecular inv estigation s in reaction (AT-PCR) and/or FISH may de- group.individual patie nts, lm munophe notyp ic tect gene rearrangements thai are pres-features or the other AMl categor ies are ent in low frequency and not observed inMyeloproliferative neoplasms (MPN)extremely heterog eneo us. probably due the initial chromosomal ana lysis, in c asesThe MPN (Table 1.02) are c lonal haeretc-to high genetic d iver sity. Although it haswith var iants of typical cytogenetic porenc stem cell d isorders Characterizedbeen sugges ted that express ion of c er- abnormalities, and in cases in which theby pr oliferation of one or more of thetam antiqens, such as CD?, COO, C Ol lb,abnormality is cryptic , such as themyel oid lineages (l.e. granulocytic , ery -C014. CD56 and CD34 cou ld be associ- PDGFRA-FIP1L 1 fusion in myeloid neo- thro id . megakaryocytic and mast cell).ated with an adver se prognosis in AMl, plasms associated with eos inophilia, De- They are primarily neoplasms of ad ultstheir independe nt prognostic value is stillpending on the abnormality, qu ant itativethat peak in frequency in the 5th to 7thcontroversial. Aberrant or unusual omoro- PCR performe d at the time of diagnosis decade, but some subtypes. parti cu larlyphenotypes have been found in atmay also p rovide a baseline againstCM l and essential thrombocythaemialeast 75% of ca ses of AMl. These c an be whic h the response to therapy c an be(ET), are reported in children as well. Thedescribed as c ross-lineage antigen ex- monitored . A num ber of gene mutations inc id enc e of all sub types combined ispression, matura tional as ync hronousd etect ed by gene sequencing, allele-6-10/ 100,000 population annually {1053,expression of antigens , antigen overex-spe cific Pe A and othe r techniq ues have1059. 1060 f,pression, and the red uction or abse nce of em erge d as importa nt diagnostic andInitially. MPN is cha racterized by hyper-antigen expressio n, Sim ilar aberra nciesprognostic ma rkers in all ca tegories of cellularity of the BM with effective have also been reported in MDS as well.mye loid neoplasm s, Mutat ion s of JAK2, naematoporetc maturation and increased and their presence ca n be used to sup portMPL , NRAS, NFl , PTPN 11, and KI T innumbers of gra nulocytes, red blood ce lls the diagnosis in ear ly o r morpholog ica llyMPN and MDS/MPN, and NPM1, CEBPA, and/o r plate lets in the PB. Splenomegaly ambiguous cases of MDS (See Chapter 5).FLT3, RUNX1 and KIT, among others. in and hep atomeg aly a re co mmon and lm11unophenotyping by IHC on 8 M b iopsy AMl are impo rta nt for d iagnosis andcaused by sequestration of excess b lood sections can be applied if ma rrow cellp rognosis. and some. particularly JAK2,cells or proliferation of abnormal raemato- suspensions are nol available for flow cy- FLT3, NPM 1 an d CE8PA figure impor-poietic cells, Despite an insidious onset tcmetry analysis. Antibodies reactive with tantly in this revised classification . Fur-each MPN has the potential to undergo a paraffin-embedded BM biopsy tissue are thermore , the role of gene over- and available for many lineage-associatedunde r-expression as well as loss of het- Table 1.02 ~live neoplasms (MPN) . markers (e,g. MPO.lysozyme, CD3, PAX:s,e rozygosity and copy number variants C033, etc.). As noted previously, CD34 detected by array-based approaches areChrtncITl)9logenous 1Bukaenia, BCR-ABI. posibYe (CMl) staining of the biop sy can fac ilitate theon ly now being recognized as impo rtant detection of blasts and their distribution , abnormalities that may well influence Clwtlnic. neutrophilic leubeml8 (CNL) provided the blasts expres s CD341 1650/.d iagnostic and prognostic models in the ~oefil (PV} For cases rich in megalob lastoid erythro- near future 11531AI . Nevertheless,"""" _ _ (PM~ blasts. immunohistolog y for glycophorin m icroarray prof iling studies. alt hough ESSoElIIUl ~ (ET)"-or haemoglobin may be helpful in dist in- import ant in the research setting , have not Oworic eosnophic Ieukaerru. NOS lea NOS)guishing those cells from myeicotasts yet been tested in cl inic al practice . (eg. in cases of RAEB or acute erythro- MyelqiltMaabYeneoplasm,loIldasslJable (UPN,U)1eI.Memia), and COOl or CD42 oflen aidintroouctco and overview of the ctassrncanon of the myek>id neoplasms23 23. CML ABUMyeloid neoplasmsPDGFRA,PDGFRB,FGFR1 with eosinoph iliaPVJAK2 V617F, JAK exon 12PMF JAK2V617F, MPL W15 1UK ET JAK2V617F, MPL W151 UK Mastocytosis KITD816VFig..06 Myeloprololerative neoplasms (t.4PN)and oIhet myeloid neoplasms associated W11t1 mutaliOnlrearrangement of tyrosine kinase genes.stepwise pr ogr ession that term inate s insubtypes of MPN from each other butthese genetic abnormalities. such as themarrow failur e d ue to myelofib rosis , inef- from reacti ve granulocyt ic . erythroid andl BCR-ABL1 fusion gene in CMl . are esso-fective haemat opoi esis or Iransformalion or megakaryocyt ic hyperplasia .cia ted with consistent clinical, laboratcry1 an acu te blast phase. Evid ence of ge - 0 Revisions in the criteria for cla ssification and morp hologic find ing s that allow themnetic evo lution usually heralds disease of MPN in the cu rrent scheme have been to be utilized as major criteria for classfi-progression as may increasing organa-influen ced by two fac tors - the recen t cation, whereas others provide proof thatmegaly, increasing or decreasing blood discovery of gen etic abnorm alities in-the myeloid prolifera tion is neoplasticcounts , myelofi brosis and onset 01myelo- volved in the pathogenesis of BCR-ABL 1 rather than reactive.dysplasia. The finding of 10-19% b lasts negative MPN and the wide r appreciationAc quired somat ic mutations of JAK2. atin the P8 Of 8M generally signi fies accel-that histologic features (megakaryocyticchromosome 9p24. have been shown);)erated disease and 20% or more ismorp hology and topograph y, marrow playa p ivotal role in the pathogenesis dsuHicient for a di ag nosis 01bla st pha se .stromal changes, id entific ation 01specificmany cases of BCR-ABL 1 negative MPH cell lineages involved in the proliferation)11 04 4, 1163, 1186, 1287A , 12881 The.Rationale for tho diagnosis andcor relate with clin ical features and c an bemost comm on mutation , JAK2 V6 17F, re-classification of MPNused as criteria to identi fy MPN subtypessults in a constitutively active cytoplasmicIn previous cl assification schemes the{2 177. 22 16, 22221. JAK2 that activates signal transducer anddetect ion of the Philadel phi a chromo- Mo st if not all MPN are assoc iated with ac tivator of transcription (STAT), mitogensome and/or BCR-ABL 1 fusion g ene was clona l abnormalities involving g enes that activated p rotein kinase (MAPK) and[ used to coolirm the diagnosis of C Mlwher eas the remaining MPN sub types encode c ytoplasmic or receptor PTKs. The abnormalities described to da te phospholidyllnositol a-kmase (P13K) sigo naling pathways to prorote transforma1Olwere diagnosed by their cli nical andinclude transicc anons Of point mutations and proliferation of baemaroooenc pro.j labo ratory features with relatively minorcontributions to the diagnosis from mor- of genes that result in abnormal, co nstitu- tively abnormal PTKs that activate signal g enitors (Fig. 1.07). The JAK2V617Fmu- tation is found In almost all patients wit~ph ologi c findings. A number of criteriatransdu cti on pathw ays leading to the polycythaemia vera (PV) and in n ear~were required not only to distinguishabnormal proliferation . In some c ases,one-half of those with primary myelofil:Jrosis24Introdu::tion and overview of the classi fication of the myeloid neoplasms 24. (PfvlF) and wit~ esseotelmoroocvmaeraaand ab normalities 01 PDGFRA. PDGFRB or their relevan ce are in progress and revi-(ET), In the few PV patients wno lack the FGFR1 , If none of the se rearrangementssions may be necessary.JAK2 V6 17F, an acti vat ing JAK2exon 12are d etec ted, and there is no BCR-ABL 7mutation may be fou nd , and in a small fusio n gene , they should be ca tego rized Myeloid and lymphoid neoplasms withproportion of cas es of PMF and ET, an ac-as GEL, not otherwise specified eosinophilia and abnormalitie s oftivating mutation 0 1 MPL W5 15l or W5 15K4. The d iagnostic al go rithms for PV, ET PDGFRA, PDGFRB or FGFR1is seen. It is important 10 no te that JAK2 and PMF ha ve been substantiallyDe termi ning the ca use of marked , per-V617F is not specific for any MPN nor c hanged to incl ude infor mation rega rd ing sistent eosinophilia (~ 1 .5x1()9/l) in thedoes its absence exd ude MPN . Further- JAK2 and similar ac tivat ing mutations asblood can be challengi ng and is some-more, it has been reported in some caseswell as pertinent histolog ic featu res 01 thetimes cli nically urg ent beca use 01 theof MDS/MPN, in rare cases of AMl, and 8M biopsy as d iag nostic Criteri a.potential damage to the heart, lungs , cen-incombination w ith other well-defined ge-5. The threshold of the p latelet count for tral nervous and other organ systemsnetic abnormalities such as the BCR-A8L 7 the di ag nos is of ET has been lowered tocaused by the eosinophilic infiltration and110641. Thus, diagnostic algorittvns for PIl, ~4 5Ox 1 Q91l.release of cvtocnes. enzymes and other ET and PMF have been altered to take the 6. Crit er ia for CMl in accelerated phaseproteins. The eoeoooous may be derivedmutationalstatus of JAK2 into account ashave been suggested w ith the caveat that from the neoplastic clone of a myeloid weN as 10outline the additional laboratory they have not been fully evaluated in the neoplasm, such as GEL, GMl or AMl, or and histo6ogic "ndi~JS required to reach era of PTKI therapy: studies 10 determine lhey may be reactive due to abnormal an accurate classification 01 c ases, re- gardless 01 whe ther the mu tation is or is not present. In addition to the changes in the cr iteria B lor N , ET and PMF, information reg ardi ng A abnormal PTK toncnon due to rearrange- mentsof the POGFRA, PDGFRBor FGFR1 genes in patients with myeloid neoplasms associated with eosinop hilia led to reap- praisaland new diag 1ostiC algorithms for those syndromes as well (see below). The appreciation 01 the role altered PTKs pla y in the pathogenesis of C Ml, PV, ET and PMF also argues lor the inclusion of simi- lar chronic myelo id pronteranons related ~I 10 PTK abnormalities under the MPN um-Ibrella. Thus, systemic ma stocytosis, wh ich Akt (0has many features in common with otherIMPN entities and is alm ost always asso-ciated with D816V mutation in the KIT TO "FoxO " -., E0geneencoding the recep tor PTK, KIT, hasIbeen added to this categ ory 121761 St ill,tI"1e molecular pathogenesis of nearly halfof all cases of ET and PMF, of all cases of I X ~0 @jJIchronic neutrophilic leukaemia and am ber of myeloid neo plasms ass oc iated mwith eosinophilia remai n unkn ow n . For these reliance on cli nical, laboratory and -- ----- -- Activation of gene!o Important in proliferation and survival morphologic features is essenti al for diagnosis and classification, Stmnary 01major c hanges in the classilication of MPN orFig. 1.07 MecRanism activatiOn aI JA11 of 3 consblulional symploms: >1 0%weighlloss il611lC111tts, iWJhI sweats.6phase, megakaryocytes seen in theunexplained IeoeI (>31.S C)poIycythaemic stag e 01 PV are clearlydi st inguishable from those seen in ET.42 MyeloproliferatIve neoplasms 42. "Spent phase"and postpolycythaemicmyelofibrosis (oost-Pv MF)During the later phases of PV, e rythro-poiesis progressively decreases. As aconsequence, the red blood cell massnormalizes and then decreases, and thespleen further enlarges. Usually theseChanges are accompanied by correspon-ding 8M aneranons 1641 . 20711. The mostcommon pattern of disease progressionis posf-Pv MF accompanied by myeloidmetaplasia which is characterized by aIeukoerythroblastic PB smear, poikilocyioss wil h teard rop-shaped red bloodcells. and splenomegaly due to EMH , asdefined in Table 203 {143A). The mor-phological hallmark of th is slage of thedisease is overt reticulin aOO collagenfbrosisofthe BM 1641 . 775 , 2203, 22221,The CelkJarity varies in this terminal stage.tu: hy1:loceIIular specimens are coreroo.Fig. 2.19 ~ Yllla, ~ rnyelofbosis (pos&-PV MF) and"lbd metaplasia , splerJedoi"rCUsters of megakaryocytes, olten with specinen. The splenic enlarvement in the ~ ptIase isdue IlIMlIy b eJb"ameOJlary Ilaema!DpoIesishyperchromatic and very dysmorphic!hat Cll:X:ln II1 It1e splenic sftlses , as wei 11$Iibrosis.-.d lll1trapmenl d platelets and tIaernalopoieli eels II1lhe splenicnuclei, are prominent Eryth ropoiesis and coosgranulopoiesis are decreased in amount.and are sometimes foun d . along withmegakaryocytes, lying within dila ted mar-iower freq uencvltea. 1044 ,1 186 , 12881.Postulated cell of ori gi nrcw srcsocs 12203 1. Osteosclerosis may The mutation occurs in a haematopoielic Heemetopoteuc stem cel l.also occur 1 1, 775 1 The splenic en-64 ,stem cell , and is found in all of thelargement is a consequence of EMH , myeloid lineages. Hence cells that utilizeProg nosi s and pred ictive fact ors....nich is characterized by the presence ofJAK2 kinase in the intr acellular signaling With currently available treatment, medianerythroid. granu locylic and megakary-path way may be hyp ersen sitive to g rowth survival li mes > 10 ye ars are commonlyccvnc elements in the splenic sinuses fa ct ors a nd other cvtokmes. inc lud ingrepor ted {SO, 1215 , 1548,2071/ . although and cords of Billrot h. An increase in the EPO . A fun ct ionally similar mutat io n incontroversy persists about the risk factors number of immature cells may be ob-exon 12 of JAK2 has also been reportedother than olde r age {1215, 1389, 17021 . served in these stages, butme finding of 11981/. so that virtually all patient s with PV Most p atients d ie from thrombosis or ) 10% blasts in the PB or 8 M or the pre s-have a JAK2 aber ration , St ill, no ge ne tichaemorrhage , but up to 20% succumb to ence of signific ant my e lodysp lasia isdefect enti rely specif ic to PV has been myelodysplasia or acute mye loid leukaemia unusual, and mosl likely sig nals tran sfor- ide ntified . At diagnosis, c yto ge ne tic ISO, 1389, 207 11, mation to an acce lerated phase and/or a ab normal ities are detectab le in ab out The factors tha t p red ict the risk of throm- myelodysplastic synd rome (MD S), Cases20% of pa t ients. The mo st c ommonbo sis or haemorrhage are not well inwhich 20% or more blasts are found are rec urring abnormalities inc lude +8, +9, d efined 11389, 1700,20711, The incid encecnsoerecAML 117 2071, 2203, 2222). 01,del(20Q), de l( 13q) and de l{9p) : some- of MDS and ac ute leukaemic transforma-times +8 and +9 are found tog ether 142,tion is only 2-3% in patients who hav e not""""phenotype 2394/. There is no Philade lphi a c hromo-been treated with cy totoxic agents , butNo abnormal phenotype has been reosome or BCR-ABL 1 fusi on g ene . The seincreases to 10% or more follow ing"",eo c hromosomal ab normalities are seen with ce rtai n types of c hemot hera py {704 ,increasi ng frequency with d isea se pro- 1389 , 1548 , 170 1, 1702 1_Goo"gression and in near ly 80-90% of thoseThe mosf frequent genetic ab normality in w ith post-PV MF 1421, Almost 100 % o fPV is the somatic qam-ot-tuncnon mut a- those wh o develop MDS or AMl havetoo JAK2 V617F. Altho ug h il occurs in cyt ogenetic abnormalities. inclu ding those> of patients with PV, it is not specific 95%commonly o bserved in the rapy-relatedand is found in other MPN as well. but in MD S and AMl (See Chapter 6 ).PoIycythaemlCl vera43 43. Primary myelofibrosis J . ThieleH M . KvasnickaA. TefferiG. BarosiA. OraziJW. Vardi manDefinition ICD-O code 9961 /3 in yo ung chil d ren have been reportedPrimary myelofibrosis (PMF) 11464 1 is aHow often this represents an MPN is ~clonal myeloproliferative neoplasm (MPN) Synonyms known. but at least some cases appear 10characterized by a proliferation of pre- Chronic idiopathic myelofibros is (CIMF);represent an autoscmal recessive imenteddominantly megakaryocytes and granulo- Agnogenic myeloid metaplasia (A MM); oondilioo 118731 In oee-families with acytes in the bone marrow (8M) that in fullyMyelofib rosiS/scl erosis with myeloid meta- somewhat later age of onset . the leal1.Xesdeveloped d isease is associated withplasia (MMM) ; Id iopathic myelofibrosis . havebeen consistent withan MPN, suggest-reactive deposition of fibrous connec tiveing a familial predisposition to PMF 13691.tissue and with extramedul lary haema- Epidemiologytopoiesis (EM H) . There is a step wise evo- The overt fibrotic pha se is estimated toSites of involveme ntlution from an initial prefibrotic phase oc cur at 0.5- 1,5 per 100 000 persons per Blood and BM are always invo lved. In the121771 cha rac terized b y a hypercell ularyear {1060,21671. It occur s most C()fTVTK)ll1y later stages of the d isease , EMH (alsoBM wit h absent or minimal reticulin fibrosisin the sixth 10 seventh decade of life, andkno wn as myeloid metaplasia) becomesto a fibrotic phase with marked reticulinboth sexes are nearty equally affected prominent, in particular in the spleenor collagen ubrosrs in lhe 8M and often121671. Children are rarely affected 136n117731. In the initial stages. randomly dis-osteosclerosis. This fibrot ic stage of PMF tnbcted C034+ prOlJenitors are slightly in-is characterized by ieukoervtbrobiastosisEtiology creased in the 8 M. but not in thein the booo witll teardrop-shaped red cel ls.Exposure to benzene or ionizing radi ation pe ripheral b lood {PBl Only in the tateand by hepatome galy and sp lenomegaly has been documented in some casesstag es they ap pear in large numbers pe-(Tabl e 2,0 4 ). {5881 Rare familial c ases of 8 M fibrosis riphe rally (1592, 22091 This increase ofCD3 4 + ce lls in the PB is a ph enomenonlarge ly restric ted to overt PMF and is notseen in non-fib rotic po lycythaemia vera fibrosis: 50% of the 8 Mspace. With exception of allogenei c stern~~~) ..Fig. 2.23 Primary myelofibros fibrotic stage WlIIl ellrameduallary haemalopoiesis in Iivet A In the Mr, tie is,, .cell transplan tation 11592. 22131 develop-- ,sirtUSOids are prominenUy involved by bilineage prolilerallOll. B Megakaryotyles are the hallrnart. 01 abnonnllment of myelofibrosis in PMF is not signifi-irltrasinusoidal haematopoiesis.can tly influence d by treatment modalities.an d is obviously related to disease p ro-gression 1295. 22 17, 22181 In patients withan a normal endosteal loc ation in the 8M acute phase . In cases with 20% Of morea previously established diagnosis of PMF,12204. 22091. ind ica te an accelerated blasts in the PB and/Of 8 M at presentationthe finding of 10-19% bl asts in the P8 p hase of the disease, whereas ~% in which other find ing s may suggest PMF,Iand/or 8M and the oerectco by immuno- b lasts is consid ered as acute uanstome- the diagnosis 0 1 acute leukaemia shOOdhistochemistry of an increased number ofIteo. Patients with PMF may also present be made with only mentiOnof the possibleCD34+ cells With cluste r formation and/orinitially in an accelerated phase Of an derivation from PMF.46 Myeloproliferative neoplasms 46. Extramedullary baenatoooleeta The most common site of EMH is the spleen , followed by the liver 117731. Thespleen shows an expansion of the redpulp by erythroid, granulocytic an dmegakaryocytic cells. Their identificationcan be aided by immunohistochemistry [ 16 13, 2 1991. which also allows an ap-preciation of an increase in neoanqioqen-esis / 144 . Megakaryocytes are often themost conspicuous component of theEMH. Occasionally large aggregates ofrreqakeryocytes. growing COhesively can.ooocce macroscopically evident tt.mOUrallesions. In the presence of nodular lesionsand , in general. in any advanced stagedisease with large amounts of EMH, thePQS&bility 01 a myebd sarcoma should bec:onsidefed and carefully excluded by per-laming irrmunohistological studies withCD34 117731. The red pu lp cords mayexhibit fibrosis as well as pooling 01 Fig.2.24 PrWncwy myeIoIilrosis. 6brollc stage . A ThIs penrtIerBl bloodsme70 years . Hb 10% weight bss in 6 month$. right sweats, I,Il8lplBined illver{>37.5-C150MyeloproliferatIVe neoplasms 50. Chronic eosinophilic leukaemia,BJ. Bain D.G. Gi llilandnot otherwise specifiedJ W , Vardiman H .-P. Horny-Ctwooic eosinophilic leukaemia (CEL) is amyeloproliferative neoplasm (MPN) inwhich anautonomous. clonal proliferation01 eosinophil precursors results In per-can be fou nd , and w hich is associatedwith sig ns of organ involveme nt and dys-function 1443, 23821; there is no evidencefor eosinophil clonality. It is a diagnosis 01exclusio n. and may inc lude some cases pa rt. The epidemiological features of cases of HES that rema in idio pathic have not vet been c learly d efined. Sites of involvementSistently increased numbers of eosiro-of true eosinophilic leukaemia that cannot eElis a multisystem disorder. The PBptliIs in the peripheral blood (PS), bone currently be reccqnrzeo. as we ll as cases and BM are alwa ys involved . TIssue infil-matrON(BM) and penooerarnssoes. with01 cytokin e-d riven eo sino philia that are tration by theeos.roonns.and release ofeoSKlOPh~ia being the dominant baema- due to the ab normal release of eosinophil cytokines and humoral factors from thek*lgical abnormality. Organ damage cc-gr owth fa ctors, e.q . interleukin (IL) 2. 3eosinophil g ranules lead to tissue dam-ClSS asa result oueceaemc infilt ration orand 5, fOf unknown reason s (128 , 443 , age in a number of organs, but the heart.ee releaseof cytokines, enzymes Of other1971. 2072 , 238 21. lungs , central nervous system, skin andproteins by the eosinoctas. Chronicgastrointestinal tract are commonly in-eosinophilic leukaemia . not otherwiseico-oeeee 9964/3 voiveo. Evidenc e of sp lenic and hepaticspecified, (GEl. NOS) excludes patientsinvo lvement is p rese nt in 30-50% ofWIth a Philadelphia (Ph) chromosome,Synonympatients 1443. t97 1. 2072 , 23821 .BCR-ABL llusion gene or rearrangement Hypereosinophilic synd rome (not recom-01 PDGFRA, PDGFRB or FGFR1. mend ed) . Clinical featuresIn eEL, NOS the eosinophil count isSometimes eosinophilia is detectedn5xl ~1L in the blood. There are fewe r Ep idemiologyinc identally in patients who are otherwisethan20% blasts in the PB or 8M . To makeDue 1 the p revious dilfic ulty in d istin-0asymptoma tic . In othe r pa tients, co nstitu-adiagnosis 01CEl. there should be evi-gu ishing CEL f rom idiopat hic HES. the tiona l symp toms , such as fever, fatigue ,dence/or clonality of the eosiropbus or antrue inc id enc e of these di seases iscough, ang ioed ema . musc le pa ins, pr uri-ecreese in myeloblasts in the PB or 8 M.unknown, althou g h th ey are rare . Manytus and d iarr hoea are found . The mo stIn many cases however, it is impossible topatients wh o wou ld until rec ently haveserious clinical findings relate to endomyo-proyeclonalrty 01 the eosoo ptuls. in w hichbee n c lassified as hav ing idiopathic HESc ardi al fibrosis . with ensu ing restrictivecase, if there is no inc rease in blast ca n now be show n to have C El assoc i- ca rdiomeg aly. Scarring 01the mitralltricu -cells, the diagnosis of "id iopathic hyper- ated w ith a FJPtL 1-PDGFRA fusion genespid valves leads to valvula r regurgitationeosinophilic syndrome" is made . The{466 1 Since this co ndition oc cur s mainl y.and formation of intrac ard iac thro mbi,idiopathic hypereosinophilic synd romein ad ult me n, the male dominanc e and thew hich may embouze to the brain or else-(idiopathic HES) is de fined as eosi no-peak inc ide nce in the four th decad ew here, Perip heral ne urop athy, cen tra lphilia (~1.5~ 1CfJ/L) persisting for at least 6 prev iously descr ibed in "HES" {443 , 1971 ,nervou s syste m dy sfu nction, pulmonarymonths, for which no und erlying ca use 2072, 2382 ) are now exp lained , at least insymptoms due to lung infiltration, and Chronic eosinophilic leukaemia. not otherwise specdied 51 51. rheoma toroptcar findings are other fre-qu ent ma nifestations (443, 1971 , 2072 ,-2382 1In CEL, NOS the most striking feature inthe PB is eosinophilia, there being mainlyma ture eosinophils with only small num-bers of eosi no p hi lic myelocytes orpromyelocytes {443. 710, 12OJ. 1971, 2072,23821. There may be a range of eosinophilabnormalities, including sparse granulationwith clear areas of cytoplasm, cytoplasmicvacuolation, nuclear hype rseg men tationor hyposeg me ntati on, and enlarg ed size,These c hanges ma y be seen in cases ofreec uve as well as of neoplastic eosino-philia, however, and are thus not veryhe lpful in deciding whether a case is likelyto be CEl {1281. Neutrophilia often ac-,,.com pani es the eosinophili a , an d some Fig. 2.31 Ch ron ic~oop/l i l ic ~uk.aem ia . Peripheral blood smear from a patient With ahistory ofpersjstent eosi1c?*ec ases have monocytosis, M ild basoph iliaImmatureaswell as mature eosinophilsarepresent CyloQenebc arlalysis showed trisomy of chromosome 10, tiChas been reported 17101, Blast cells maybe present but are less than 20%.The BM is nvoercenotar due in part to disease 1128. 19311. In addition, a num- are immunophenotypical1y aberranl an:! 1meosinophilic proliferation 1289, 443. 710,ber of neoplastic disorders such ast-een tha t mayor may not be clonal 1286, 1156.Nc1200, 2382 1 In most cases, eosinophilmaturation is orderly, w ithout a d isp ro por-lym phoma, Hodgkin lymphoma, sys tem icma stocytosi s, acute lym p hob last ic leuk 202 41. When such an aberran t T-c ell pop. ulati on is presen t, the case is not CEl00m,tio na te inc rease in m ye loblasts. Ch arcot- aemia and other MPN may be associatedis it idiopathic HES. If the monocyte conG.l eyden crystals are often present. with abnormal release of Il2, 1l3, ILS oris > 1x1r:P1L a diagnosis of chronic mye;o.NoEryttTopoiesiS and megakaryOCytopoiesis GM-CSF and a secondary eosinophiliamonocytic leukaemia with eosinoptlUare usually normal. The finding of in-c reased num bers of m yelob lasts (5-19%)tha t mimics CEll 128 , 1168, 1172, 1450,1616. 1924, 1931,246 11: in systemic mas - may be more appropriate, but if there are dysplastic features and> 10% neutrophl"";da, supports a di agn osis of CEl, as does thetocytosis there can also b e eosinop hilsprecu rsor s in the PB and no rnonccytoss. Faob servation of dysp lastic features in other be looging to the neo pl astic clone. The BM a d iag nosis of atypical chronic myebdcell linea g es. M ar row fibrosis IS seen in should be carefully inspected for anyleukaemia with eosinophilia should Sifn. lusome cases 1289, 7101. Any tissue may process which might explain the eosino-larly be considered. cashow eosinophilic infiltration and Charcot- philia as a secondary reaction, such asThe distinction between GEl. NOS. arcwitleyden crystals are often present. Fibro- vasculitis, lymphoma, acute lymphoblas-idiopattuc HES is important. IdiopattlcGElsis is a common find ing . an d is caused bytic leukaemia , sys tem ic m as toc ytosis o r HES can be diag nosed onl y in fUlly inves-conthe d egr anu lati on of the eo sin op hile wit h gran ulomatou s d isorders. Some cases oftigated pa tients and on ly when (i) there,maOthe release of eosinophil basic protein persistent eosinophilia are due to the ab- an eosinophil count of warU. I( Sollar. ~ $perl. P V8Ienl. .IN laid.. 50% of SM pat ients, and are more often cutaneous mastocytosis This variant ocanam:..man. K WOlIf observed in those with an indol ent course. exdusiYely in d*eIl54MyeloproliferatIVe neoplasms. 54. In contrast. aggress ive va riants of SMoften present without skin lesion s [97 11 .However, some SM patients withou t skinescos may on occasion present wit h anindolent form of SM, most often isolated8M mastocytosis.ICIricaI featuresCutaneous mastocyt osis includes severalcetrct cmco- nistocettoicqcar en tities.l esions of all form s 01 CM may urticate Fig. 2.36 Indolent syslelTllt mastocytosis. Densewhen stroked ("Dariers sign 4 ) and most infiltrate conSisting mainly 01 spind~ stitJ1Iysnow intraepidermal accumulation of~nUar mast eels.melanin pigment. The term wtcana 4ptgmentosa mac roscop ically describessesetwo clinical features. Blister ing("b.bJs mastocytosis") does n:lI representa separate subtype but rather an exaq-geralion 01 urticaria. Blistering is usuallyseen IrIpatients less than 3 years of age.m may be assoc iated with all forms ofceeoanc CM 11 68 7, 2055, 24361.Symptoms in SM at presentation havebeefl grouped into 4 c ategor ies: 1) con-SbtUtIOO8! symptoms (fat igue, weight loss,Mr, diaphoresis). 2) skin manifestationsFig. 2.38 Indolent systellic mastoeylOSis. A loo5eIy scattered spmdHhaped tlypograrlular mast cells WJlhooI(prurituS, urticaria, dermatographism). tendency III awegate. Diagnosis is lacihlatedIfhen addibonal imrrI.rnostaHWI and moIeaJIar analysis n performed.B IrrITlIAlOSlain withCD25 shows an atypical ~ 01 mast eels with rnentlralle assooated reactivity. 31mediator-related systemic events (ab- dcminal pain. gastrointestinal d istress ,Dushing. syncope, headache. nvpoienson. tachycardia. respira tory symptoms) and 4) musculoskeletal complaints (bone pain. oeteoceora steoporoers. frac tu res,o 25%ollhe mast eels r11he 2056,20571 , In contrast, the presenced infihle are ~ orhaveatypocaIlll(llllI1CJIog or, d aI mas! eels n bone m.arrtMasprate rruttifocal compact mast cell infiltrates ora smeaR, :>25% aremnalln oratypical. diffuse-compact mast cell infiltration pattern.........2. Deleclion of an ICtiYaIIlg poI"It rnutalI:Wl at c:odor1816 of KIT~ bone manow. blocdor anolher eJ:lraCula.3. MastOBIs itI bone marrow. blocdor oItler eJhcutaneous organs express CO2 andorC025 in adl;1itlOII ~ is highly compatible with the diagnosis d mastocytosis during first inspection. H0w- ever, additional immunohistochemical aId nonnat mast 011 maR-eB. molecular studies are strongly reccn- 20 ng/mLthe mast cell infiltrate may vary according and round or oval nuclei. In norrnarreaois suggestive of SM and is used as a to the tissue sampled 1130, 290 , 7 13, 966,tive states, mast cells are easily dislilo"minor" criterion for diagnosis, unless there968 ,973, 1162, 1466 1. A d iffuse interstitial guished from the smaller metactvonacFig. 2.40 Typical skin lesion of a dIld WIlh ur1icatiapigm&nIosa. Aggregales of mast cells Iil Ihe papIIafydemIII ald edllnd as 5he8ls into Ile f8tJCWr clemis.56Myeloprol!ferative neoplasms 56. TIIbIt 2.11 SubdaSSlf?tiOn 01cutaneous mastocy1osis,Table 2.12 Criteria lor variants 01 systemic mastocytosis I1. ~ pioJnenIosa (UP V~ 1.IndolentsystemicmlStoeytosis(ISM) ewneous mastoeylosis (MPCM)Meets arteria b" SM. No"C" findings (see below). No evldence of afl associated non.roastc:ellileage cJonaj2 DIuse l:lJWoeou$ mastocylO$ls I1aematOOgicaI mali1laflc.yldlsonlel" (AHNMOI In !hisvanant. !he mast cellMOefllS low and skin3, Sl*arI mamcytomaof skinlesions areaWnosI ilVaria ~ present 1. BDnemarrow mastocytosisbasophils which have segmented nuclei, As above (ISMI wiIIl bone marrow involvement. but noskin lesions.and larger and fewer granules. With en- 1.2 Smouldering systemicmastocytosiszyme cytochemistry. mast cells reac t As above (ISM), but wItl 2 oc ITIOle "8 fn:l1llgS but no "C" ffldings. strongly wrth naphtholASD-chlofoacetateesterase (CAE) but do not express 2. Sptemie mastocytosis with n soeiBted clonal hMmaI~ norHnUt c:.Illl. . . . disease (SM-rnye!operoxidase In mastocytosis. the AHNMO)cylOIogy of mast cells vanes, but aboor-Meets CriIeria torSU and cntenalor an assoaaled. donIlIlIIemaloklgicI flOIloITIaII eel lineage disorder .!tal cyIo1ogic features are almost always AHNMO !MOS, MPN .AJ.IL,~ . oc ott. ~ neopasm tIal meets !he aliena b" aoetected. nckJdlllQ marked spindling anddisbnd~ " tie WHO cIasslticaIm ).hypOgrarJJlarrty 122901.Cytanorpnoiogical atypia is pronounced3.AggrlSSivt systemic: mastocylosis (ASM)11 higtl-gfade lesions 01 mastocytosis.* ee occurrence of metachromatic ......Meets c:nena b SM. 30% infinratkin bymast cells (focal, ceose aggregates) andlor serumlolal s taimng fortryptase/chymase and CD 117lryptase level >20 nglmL. and, for neoplastic mast ce lls. C0 2 and 2. Signs of dysplasia or myeloproliferation. in ten-mast ceil lineage(s). but insufficient criteria for definitive CD25, The morpholog ic features of th e diagnosis of a haematopoietic neoplasm(AHNMD), with nonnal or only slightly abnormal bloodcooors common subtypes of mas toc ytos is are3. Hepatomega ly withoutimpairment 01 ~v&r function , andlO!" palpatlle splenomegaly without hypersplenism,tescnoeobelow.and/or lymphadenopathyon palpalfon or imaging "C" findings 1_ Bone marrow- dyslunction mal1lfasted by ooe Of mor cyOI)a!1ia (ANe rim of eos inop hilic cytop lasm. The cyto- acut e leukaemia {48. 682, 683. 833. 2102.c yto pen ia is often pre sent. Atypical , large p lasm ic membrane is usua lly d istinc t.2 170. 24431. Thus. it is recommelldecl platelets may be ob served 148. 13961with we ll-defined cyto plas mic borders. that CMML be furt her d ivided into twoThe BM is hyperc e llular in ove r 75% ofThis imparts a c ohe sive ap pearanc e to subcategories. dependil"lQ on the runt:lEJcases. bu t rorrrcc enorer and even hypo-the infilt ratin g c ells. Apoptonc bodies. of blasts (plus promonocytes) found ilc ellula r sp ecimen s also occur (1471, often within star ry sky testrocvtes. are PS and 8M . as follows :21021. Granu loc ytic prol iferation is oftenfrequently pre sent. The rela tionship of thethe mos t striking find ing in the BM biop syplasmacytoid dendritic cell proliferation 1 0 CMML- 1but an increa se in erythroid pr ecursor s the leuka emic ce lls has been consider edBlasts (including promonocytes)