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