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

2. World Health Orga nization Classifica tion of Tumours
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3. -.I

4. •
I
WH O OMS
International Agency for Research on Cancer (IARC)
4th Edition
WHO Classification of Tumours of
Haematopoietic and Lymphoid Tissues
Edited by
Steven H. Swe rdlow
Elias Campo
Nancy Lee Harris
Elaine S. Jaffe
Stefano A. Pileri
Harald Stein
JOrgen Thiele
James W. Vardiman
Intern ational Agency for Resea rch on Cancer
Lyon , 2008

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.
JOrg en Thiele, M.D.
James W. Vardi man, M.D.
Layout Sebastien Antoni
Marlen Grassinger
Pascale Collard
Printed by Participe Present
69250 Neuville s/SaOne, France
Publisher International Agency for
Research on Cance r (IARC)
69008 Lyon. France

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 Grou p are indicated
in the List of Contributors on pages 369-374.

7. Published by the International Agenc y for Research 00 Cancer (IARC),
150 cou rs Albert Thomas, 69372 Lyon ceoex 08, France
C International Agency for Research on Cancer, 2008
Distributed by
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The authors alone are responsible fOf the views expressed in this pubhcatlQfl.
The copyright of figures and charts remains with the authors
(see source 01 charts and photographs. page 376--379)
Format for bibliographic citations:
Swerdlow S.H., Campo E., Harris N,L., Jaffe E.S" Pileri S.A., Stein H" Thiele J , Vardiman J.w. (Eds.):
WHO Classification of Tumours of Haematopoietic and Lympho id Tissues,
IARC: Lyon 2008
IARC Ubrary Cataloguing in Publication Data
WHO Classific ation of Tumou rs of Haematopo ietic and Lymp hoid Tissues
Edited by Swerdlow S.H.. Campo E., Harris NL , Jaffe E.S.• Piled SA, Stein H., Thiele J .. Vardiman JW.
1. Haematopoie hc System Neop lasms - genetics
2. Haematopoielic System Neop lasms - pathology
I. Swerdlow. Steven H.
ISBN 978-92-832-243 1-0

8. Contents
WHO Classifjcatioo 9 AML with mutated NPM 1 120
Summary table 10 AMLwith mutated CEBPA 122
Introduction to the classification of tumours of AML with myelo dysplas ia-related changes 124
haematopoietic and lymphoid tissues 14 Therapy -relate d myeloid neoplasms 127
Acu te myeloid leukaemia, NOS 130
Introduction and overview of the classification of AML with minimal diff erentiation 130
the myeloid neoplasms 17 AML withOut matu ration 131
AML with maturabon 131
2 Myeloproliferative neoplasms 31 Acute myelomonocytic leukae mia 132
Chronic myelogenous leukaemia. BCR-ABL 1 positive 32 Acute monoblastic and monocytic leukaem ia 133
Chronic neutrophilic leukaemia 38 Acute erythroid leukaemia 134
PoIycythaemia vera 40 Acu te megakaryoblastic leukaemia 136
Primary myelofibrOsis 44 Acute basophilic leukaemia 137
Essenliallhrombocythaemia 48 Acu te paomveosrs with myelofibros is 138
Chronic eosinophilic leukaemia. NOS 51 Myeloid sarcoma 140
Mastocytosis 54 Myeloid proli ferations related 10 Down synd rome 142
Cutaneous mastocytosis 57 Transient abnOrmal myelopoiesis 142
Systemic mastocytosis 58 Myeloid leukaemia associated with
Masl cell leukaemia 61 Dc:rwn syndrome 143
Mast cell sarcoma 61 Blastic plasmacytoid dendritic cell neoplasm 145
Extracutaneous mastocytoma 61
Myeloproliferative neoplasm, unc lassi fiable 64 7 Acute leukaemiasof ambiguous lineage 149
Acute undlHerentiated leukaemia 151
3 Myeloid and lymphoid neoplasms with Mixed phenotype acute leukaemia wilh
eosinophilia and abnormalities of PDGFRA. t(9;22)(q34;q 11.2): BCR-ABL 1 15 1
PDGFRB Of FGFRl 67 Mixed phenotype acute leukaemia with
t(v:11q 23): MLL rear ranged 152
4 MyelodysplasticJmyeloproliferative neoplasms 75 Mixed phenotype acute leukaemia , B/myeloid, NOS 152
Chronic mveiomonocync leukaemia 76 Mixed phenotype ac ute leukaemia , T/myeloid , NOS 153
Atypical ctYonic myeloid leukaEmia. BCR-
ABL 1 negative 80 Mixed phenoty pe acu te leukaemia, NOS· rare
Juvenile myelomonocytic leuk aemia 82 types 154
MyelodysplastiC/myeloproliferali ve neoplasm , Other ambiguous lineage reukaerraes t 55
urclasaifiable 85 Natura! killer (NK)-celilympho blastic
leukaemi a/lymphoma 155
5 Myelodysplastic syndromes 87
Myelodysplastic synd romes/n eo plasms , overview 88 8 Introduction and overview 01 the c lassification of
Refractory cytope nia with unilineage dysplasia 94 the lymphoid neoplasms 157
Refractory anaemia with ring side rob lasts 96
Refractory cytopenia with multilineage dysplasia 98 9 Precu rsor lymphoid neoplasms 167
Refractory anaemia with exc ess b lasts 100 B lymp hob lastic leukaemia/lymphoma, NOS 168
Myelodysp lastic synd rome with isolated de l(5q) 102 B lymphob lastic leukaemia/ lymphoma
Myelodysp lastic synd rome, uncrasslttabte 103 with recu rrent gene tic abn orma lities 171
Childhood mye lodysp lastic synd rome 104 B lymphob lastic leukaem iallymphoma with
Refractory c ytopenia of c hild hood 104 t(9 :22)(q 34;q 11.2): BCR-ABL 1 171
B lymp hoblastic leukaemia/ly mpho ma with
6 Acute myeloid leukaemia (AML) and l(v:11q 23): ML L rearranged 171
related precursor neoplasms 109 B lympho blastic leukaemiall ymphom a with
AML with recurrent genet ic abn or malities 11 0 t(12:2 1)(p1 3;q22 ): TEL-AMLl (ETV6--RUNX 1) 172
AML with t(8:21 )(q22:q22); RUNX1 -RUNX1T1 11 0 B lymphoblastic leukaemia/lymphoma with
AML with inv( 16)( p 13.1q22) or hyperdi ploi dy 173
1(16:t6)(p 13.1;q22): CBFB-MYH 11 11 1 B lymphoblastic leukaemiallymphom a with
Acute orornveiocvnc leukaem ia with hypodiplOi dy (Hypodiploi d ALL) 174
t(15:17)(q22 :q 12): PML- RARA 11 2 B lymphoblastic leukaemiallymphoma with
AML with us.11)(p 22:q 23): MLLT3-MLL 114 t(5; 14)(q31;q32); IL3-IGH 174
AML with t(6:9)(p23 :q34); DEK-NU P2 14 115 B lymphoblastic leukaemiallymphoma with
AML with inv(3)( q2 1q26 .2) or t(3;3)( q2 1;q26.2); t( 1;19) (q23:P13.3): E2A-PBX1( TCF3-PBXI) 175
RPNt ·EVI1 116 T lymphoblastic leukaemiallymphoma 176
AML (megakaryoblastic) with t( 1;22)(p13;q 13):
RBM15-MKL 1 117

9. 10 Mature B-ceUneoplasms 179 Enteropathy -associated t-een lymphoma 289
Chronic lymphocytic leukaemia Ismail Hepatosplenlc t -een lymphoma 292
Iympt'locytic lymphoma :f 180 Subcutaneous panniculitis-like t-een lymphoma 294
s-een prolyrT¢lhocytic leukaemia 183 Mycosis fungoi des 296
Splenic B-cell marginal zone lymphoma 185 Sezary syndrome 299
Hairy cell leukaemia 188 Primary cutaneous CD30 posi tive t-een
Splenic B-cell Iymphomalleukaemia, unclassiliable 191 Iymphoprolilerative disorders 300
Splenic diffuse red pulp small B-ceil lymphoma 191 Primary cutaneous per ipheral t-een lymphoma s,
Hairy cenleckaeme-....anent 192 rare subtypes 302
lymphoplasmacytic lymphoma 194 Primary cutaneous garnna-della T-cen lymphoma 302
Heavy chain diseases 196 Primary cutaneous COB positive agg ressive
Gamma heavy chain disease 196 ep idermotrop ic cytotoxic T-celt lymphoma 303
Mu heavy chain disease 197 Primary cutaneou s CD4 positive
Alpha heavy chain disease 198 small/medium T-cell lymphoma 304
Plasma cell neoplasms 200 Peripheral t-een lymphoma. NOS 306
Monoc lonal gammop athy 01 undetermined Ang ioimmunoblastic t -een lymphoma 309
significance (MGUS) 200 Anaplastic large cell lymphoma. AlK positive 312
Plasma ce ll myeloma 202 Anapla stic large cell lymphoma . ALK negat ive 317
Solitary plasmacytoma of bone 208
Extraosseous plasmacytoma 208 12 Hod gkin lymphoma 32 1
Monoclonal immunoglobulin deposition diseases 209 Introduction 322
Extranodat marginal zone lymphoma of mucosa- Nodular lymphocyte predominant Hodgkin Iymptuna 323
associa ted lymphoid tissue (MALT lymphoma) 214 Classical Hodgk in lymp homa. introduction 326
Nodal marg inal zone lymphoma 218 Nodular sclerosis classical Hodgkin lymphoma 330
Follicular lymphoma 220 Mixed ce llularity classical Hodgkin lymphoma 331
Primary cutaneous follicle centre lymphoma 227 Lymphoc yte-rich classical Hodgkin lymphoma 332
Mantle cell lymphoma 229 lymphocyte-depleted classical Hodgkin lymphoma 334
Diffuse large B-celllymphoma (DLBCl), NOS 233
T celilhi stiocyte-rich large B-ce ll lymphoma 238 13 1rnmunode ficiency-assoc iated
Primary DlBCL of the CNS 240 Iymphoproliferative disorde rs 335
Primary cutaneous DlBCl . leg type 242 Lymp hoproliferative diseases associated with
EBV positive DLBCl of the elderly 243 primary immune disorders 336
DLBCL assoc iated with chronic inflammation 245 Lymphomas associa ted with HIV infection 340
Lymphomatoid granulomatosis 247 Post-nansotanttsmpnooronterauve disorders (PTlD) 343
Primary med iastinal (thymic) large B-celilymphoma 250 Plasmacytic hyperp lasia and infectious-
Intrav escurer large B-celi lymphoma 252 rroooo ocieose-uke PTlD 345
ALK positive large Been lymphoma 254 Polymorphic PTlO 346
Plasmablastic lymphoma 256 Monomorph ic PTlO 347
large a-ceu lymphoma arising in HHV8-associated Classical Hodgkin lymphoma type PTLO 349
multicent ric Castleman disease 258 Other iatrogenic immunodeficiency-assoc iated
Primary effusion lymphoma 260 Iymphoproliferative disorders 350
Burkitllymp homa 262
B-cel1lymphoma, unclassiliab le, with features 14 Histiocytic and dendritic cell neoplasms 353
intermediate between DLBCL and Introd uction 354
Burkitllymphoma 265 Histiocyt ic sarcoma 3S6
B-ceillymphoma, unctessmebie. with features Tumours der ived from langerhans cells 358
intermediate between OLBCl and Langerhans cell histiocytosis 3S8
clas sica l Hodgkin lymphoma 267 Langerhans ce ll sarcoma 360
Interdigitating dendrit ic cell sarcoma 36 1
11 Mature T- and NK-cell neoplasms 269 Follicular de ndritic ce ll sarcoma 363
r-cea prolymphocytic leukaemia 270 Other rare dendritic cell tumours 365
t- een large granular lymphocytic leukaemia 272 Disseminated juvenile xanthogranuloma 366
Chronic Iymphoproliferative disorder of NK cells 274
Aggressive NK cell leukaemia 276 Contributors 369
Epstein-Barr virus (EBV) positive t-een Clinical advi sory oorrrnittee 374
Iymphoprol ilerative diseases of ch ildhood 278 Source of Charts and photographs 376
Systemic EBV+ t-een Iymphoproliferalive
disease of childhood 278 References 300
Hydroa vacclnrtorrne-uk e lymphoma 280 Subject index 429
Adull T-ceil leukaemia/lymphoma 281
Extranodal NK/T-cell lymphoma. nasal type 285 NOS, no! otherwise specifi ed
,
•

10. WHO Classification
4th Edition
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11. WHO Classification of tumours of haematopoietic
and lymphoid tissues
MYELOPROLIFERATIVE NEOPLASMS MYELODYSPLASTIC SYNDROMES
Chronic myelogenous leukaemia , Refractory cytopenia with unilineage dysplasia
BCR-ABL 1 positive 987513
Refractory anaemia 9980/3
Chronic neutrophilic leukaemia 996 3/3
Refractory neutropenia 999 1/3
Polycythaemia vera 995 0/3
Refractory thrombocytopenia 9992/3
Primary myelofibrosis 996 1/3
Refractory anaemia with ring sideroblasts 9962/3
Essential thrombocythaemia 996213
Refractory cytopenia with
Chronic eosinophilic leukaemia, NOS 9964 /3 multitineage dysplasia 9965/3
Mastocytosis Refractory anaemia with excess blasts 9983/3
Cutaneous mastocytosis 9 74011 MyelodysplasU syndrome
c
associated with isolated del(Sq) 9966/3
Systemic mastocytosis 9 74 1/3
Myelodysplasticsyndrome, uncJassifiable 9969/3
Mast cell leukaemia 974 213
Mast cell sarcoma 974 0/3
Childhood myelodyspla suc syndrome
Extracutaneous mastocytoma 974 0/1
Refractory cytopenia of childhood 996513
Myeloproliferative neoplasm , unctassitlable 9975/3
ACUTE MYELOID LEUKAEMIA (AML)
AND RELATED PRECURSOR NEOPLASMS
MYELOID AND LYMPHOID NEOPLASMS
WITH EOSINOPHILIA AND ABNORMALITIES OF
AML with recurr ent genetic abnormalities
PDGFRA, PDGFRB OR FGFRI
AML with t(6 ;21)(q22;q2 2);
Myeloid and lymphoid neoplasms
RUNXI-RUNX1Tl 9696/3
with PD GFRA rearrangement 9965/3
AML with inv(16)(pI 3.1q22 )
Myeloid neoplasms
or t(16;16)(pI3.1;q2 2); CBFB-MYHl1 9671/3
with PDGFRB rearrangement 9966/3
Acute promyelccytlc leukaemia
Myeloid and lymphoid neoplasms with t(15 ;17)(q22 ;qI2); PML-RARA 9666/3
with FGFR1 abnormalities 9967/3
AML with t(9 ;11)(p22 ;q23); MLLT3-MLL 9697/3
AML with 1(6;9)(p2 3;q34 ); DEK-NUP214 986513
MYELODYSPLASTIC/MYELOPROLIFERAnVE AML with inv( 3)(q2 1q26.2)
NEOPLASMS ort(3; 3)(q21;q 26.2); RPNI -EV/1 9869/3
Chronic myetcmonocytic leukaemia 9945/3 AML (megakaryoblastic)
with t(I ;22)(p I 3;q I 3); RBMI5-MKLI 9911/3
Atypical chronic myeloid leukaemia.
BCR-ABL 1 negative 967613 AML with mutated NPM1 986 1/3
Juvenile myelomonocytic leukaemia 9946/3 AML wrlh mutated CEBPA 9661/3
Myelodysplasticlmyeloproliferative neoplasm.
unclassifiable 9975/3 AML with myelodysplasia-related changes 969513
Refractory anaemia with ring sideroblasts Therapy-re lated myeloid neoplasm s 99 2013
associated WI h marked thrombocyt
t osis 99 6213
10 WHO ctassrtceton

12. Acute myeloid leukaemla",NOS 9861/3 B lymphoblastic leukaemia/lymphoma
with recurrent genetic abnormalities
AML with minimal differentiation 987213
B lymphoblastic leukaemiaflymphoma
AML without maturation 9873/3
with 1(9;22)(q 34;q l 1.2); BCR-ABU 9812/3
AML with maturation 9874 /3
B lymphoblastic leukaemiall ymphoma
Acute myelomonocytic leukaemia 9867 /3 with t(v;11q23); MLL rearranged 981Y3
Acute monob lastic and monocytic leukaemia 9891 /3 B lymphoblastic leukaemiall ymphoma
Acute erythroid leukaemia 984013 with 1 12;21)(p13;q22); TEL-AMU
(
(ETV6-RUNX1) 9814/3
Acute megakaryoblastic leukaemia 99 10/3
B lymphoblastic leukaemiallymphoma
Acute basoph ilic leukaemia 987013 w ith hyperdiploidy 981513
Acute panmyelosis with myelofibrosis 9931 13 B lymphoblastic leukaemiallymphoma
with hypod iploidy (hypod iploid ALL) 981613
Myeloid sarcoma 993013 B lymphoblastic leukaemiallymphoma
with t(5;14 Xq31 ;q32 ); IL3-IGH 9817/3
B lymphoblastic leukaemia/lymphoma with
Myeloid proliferations related to Down syndrome
t(1;19 )(q23 ;p13 .3); E2A-PBXl
Transient abnormal myelopoiesis 989811 (TCF3-PBX1) 9818/3
Myeloid leukaemia
associated with Down syndrome 9898/3
T lymphoblastic leukaemia/lymphoma 9837/3
Blastic plasmacytoid dendritic
cell neoplasm 9727/3
MATURE B-CELL NEOPLASMS
Chronic lym phocytic leukaemia!
small lymphocytic lymphoma 982313
ACUTE LEUKAEMIAS OF AMBIGUOUS LINEAGE
B-cell prolymphocytic leukaemia 983313
Acute undifferentiated leukaemia 980 1/3
Splenic Bccell marginal zone lymphoma 968913
Mixed phenotype ac ute leukaemia
Hairy cell leukaemia 9940/3
with t(9;22)(q3 4;q 11.2); BCR-ABL1 980613
Mixed phenotype ac ute leuka em ia Splenic B-cell fymphomalleukaemia, unclassifiable 959 1/3
with t{v;11q23); MLL rea rranged 9807/3 Splenic diffuse red pulp small B-cell lymphoma 9591/3
Mixed phenotype ac ute leukaemia, Hairy eel/leukaemia-variant 959 1/3
B/myeloid, NO S 9808/3
Lymphoplasmacytic lymphoma 9671/3
Mixed phenotype ac ute leukaemia,
Tfmyeloid, NOS 9809/3 waldenstrom macroglobulinemia 9761/3
Natural killer (NK) cell lymphoblastic Heavy chain diseases 9762/3
!euKaemiallymphoma
Alpha heavy chain disease 9762/3
Gamma heavy chain disease 9762/3
Mu heavy cha in disease 9762/3
PRECURSOR LYMPHOID NEOPLASMS
Plasma cell myeloma 9732/3
B lymphoblastic leukaemiaflymphoma
Solitary plasmacytoma of bone 9731/3
B lymphoblastic leukaemiall ymphoma, NO S 98 11/3
Extraosseous plasmacytoma 9734/3
WHO classification 11

13. -
Extranodal marginal zone lymphoma Systemic EBV positive T-celllymphoproliferative
of mucosa-associated lymphoid tissue disease of childhood 9724/3
(MALT lymphoma) 9699/3 Hydroa vaccin iforme-like lymp homa 972513
Nodal marginal zone lymphom a 9699/3 Adult T-cell ieukaemia/lymphoma 9827/3
Paediatric nodal marginal zone lymphoma 9699/3 Extranodal NKIT cell lym phoma, nasal type 9719 /3
Follicular lymphoma 9690/3 Enteropamy-associated T-cell lymphoma 9717/3
Paediatric folliculaf lymphoma 9690/3 Hepatosplenic T-cell lymp homa 971613
Primary cutaneous follicle centre lym phoma 959713 Subcutaneous panniculitis-like
T-cell lymphoma 970813
Mantle cell lymphoma 967313
Mycosis fungoides 970013
Diffuse large B-eelllymphoma (OlBCl), NOS 968013
Sezary syndrome 970113
T-ceillhistiocyte rich large B-eelilymphorna 9688/3
Primary cutaneous CD30 positive F-eel!
Primary DLBCl of the CNS 968013 Iymphoproliferative disorders
Primary cutaneous DlBCl. leg type 9680/3
9718/1
lymphomatoid papulosis
EBV positive OLBCL of the elderly 9680/3
Primary cutaneous anaplastic large cell
Ol BCl associated with chro nic inflammation 968013 lymphoma 9718/3
l ymphomatoid granulomatosis 9766 /1 Primary cutaneous qamma-delta
r -ceuivmpncma 9726/3
Primary med iastinal (thym ic) large
B-celllym phoma 9679/3 Primary cutaneous COB positive aggressive
epidermotropic cytotoxic T-cefl lymphoma 9709/3
Intravascular large B-cell lymphoma 971213
Primary cutaneous CD4 positive smalVmedium
AlK positive large B-cell lym phoma 9737/3
T-cell lymphoma 9709/3
Plasmablastic lymphoma 973 5/3
Peripheral Tccelllympboma, NOS 970213
l arge Bccell lymp homa arising in HHV8-
Angioimmunoblastic 'l-cetl Iyrnphoma 970513
associated multicentric Castleman disease 9738/3
Anaplastic large cell lymp homa, ALK positive 97 14/3
Primary effusio n lymphoma 9678/3
968 7/3
Anaplastic large cell lymphoma, ALK negative 970213
Burkitt lymph oma
B-ceillym phom a, uncl assifiable, with feature s
intermediate between diffuse large g-ceu
lymph oma and Burkitt lymph oma 968 0/3
HODGKIN LYMPHOMA
B-ceil lymph oma , unclassifiable, with feat ures
Nodular lymphocyte predomi nant
intermediate betwee n diffuse large 8-cell 9659/3
Hodgkin lymp homa
lymphoma and classica l Hodgkin lymphoma 9596/3
Classical Hodgkin lymp homa 9650/3
Nodular sclerosis classical
Hodgkin lymphoma 9663/3
MATURE T-CELL AND NK·CELL NEOPLASMS
l ymphocyte-rich classica l
j-cen prolymphocytic leukaemia 9834/3 Hodgkin lymphoma 965113
'f-celllarqe granular lym phocytic leukaemi a 983 1/3 Mixed cellularity classica l
I Chronic Iymphoproliferative disorder of
NK..cells 983113
Hodgkin lymphoma
l ymphocyte-depleted classical
965213
~l..
Aggressive NK cell leukaemia 9948/3 Hodgkin lymphoma 965313
12 WHO ciassitcenon
_

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 reticu lar cell tumour 9759/3
Indeterminate dendritic cell tumour 9757/3
Disseminated juvenile xanthogranuloma
POST·TRANS PLANT LYMPHOPROUFERATIVE
DISORDERS (PTLO)
Early lesi ons
P1asmacytic hyperplasia 9971/1
Infectious mononucleosis-like PTLD 9971 /1
Polymorphic PTLO 9971/3
Monomorphic PTlO (B- and TINK-cell types)'
Classical Hodgkin lym phoma type PTLO'"
NOS, not otherwise speci fied .
The italicized numbers are provi siona l cod es for the 4th
edition of lCD -D . While they are expected to be incorpo-
rated in the next ICD -O editi on , they currentty remain
subjectto changes.
The italicized histologi c type s are provisional enti ties , for
which the WHO Working Group fe ll the re was insufficient
evidence to recognize as distinct diseases at this time.
"These lesions are classi fied according to the leukaemia or
lymphoma to which they correspond, and are assigned the
respective tCO-G code.
WHO classification 13

15. Introduction to the WHO classification NL Harris
E. Campo
H. Stein
S.H. Swerdlow
of tumours of-haernatopoletlc E.S. Jaffe
SA Pileri
J Thiele
J w. Vardiman
and lymphoid tissues
Why classify? Classification is the lan- committees was incorporated into the classification , involvement of clinicians is
guage of medic ine: diseases must be class ification. Over 130 pa thologists and essential to ensure its usefulness and ac-
described , defin ed and named before the y haem ato logis ts from around the world ceptance in daily practice 18971. At the lime
can be diagnosed , treated and stud ied . were involved in writing the chap ters. A of publication of the WHO classi fication
A consensus on definition s and termin ol- consensus meeting was held at the head - (3rd edition), prop onents of other cla ssifi-
og y is essent ial for both clinic al practice quarters of the IARC in Lyon, France. to cations of haematologic neoplasms agreed
and investigation . A cl assification should make final d eci sions on the classi ficatio n to use the new cl assification, thus ending
contain diseases thai are clearly defin ed . and the con tent of the book. decad es of cont roversy over the classifi-
c linically d istinc tive . norKlVerlappi ng (mu- cation of these tumo urs 147. 478 . t 89.
tually excllsive) and that together comprise The WHO cl assification of tumours of the 1B9A, 190, 673,7750 , 1344A. 18198 1 ,
all known entities (collectively e xha ustive). haematopoietic an d lymphoid system is
II should serve as a ba sis lor future inves- based on the principles initially d efined in As indicated above , there is no one -gold
tigation . and should be able to incorporate the "Revised Europe an-Amer ican Classi- stand ard ," by which all diseases are
new information as it becomes ava ilab le. fica tion of Lymp hoid Neoplasms" (REAL). def ined in the WHO cl assific ation. Mor-
Classification has two aspects: clas s dis- from the Interna tiona l Lymphoma Stud y pholog y is alway s important, and many
covery - the proces s of identifying cate- Group (ILSG) 18981. In the WHO classifi- diseases have ch aracteristic or even di-
gories of diseases, and class pre diction cation, these p rinciples have also been agnosti c morphologic featu res, Immune-
- the process of determining which cere- appl ied to the class ification of myeloid phe notype and genetic features are an
gory an individual case belongs to. Pamer- and his tiocy tic neoplasms, The gu id ing important part of the definition of tumours
ogi sts are critical to both processes . prin cip le of the REAL and WHO cl assifi- of the naematopolettc and lymphoid
c ations is the attempt to define "real" tissues , and the av ailability of this infor-
The World Hea lth Org anizati on (WHO) d iseases that c an be recognized by mation makes arriving at conse nsus defi-
Classi fication of Tumours of the Haema- pa tholo gi sts with availabl e techniques. nitions easier now than it was when only
topoietic and Lymp hOid Tissues (4th Edi- and that appear be distinct clinical enti- subjec tive morphologic criteria were
tion ) was a coll aborative project of the ties . There are 3 important com ponents to available . lrrmunophenotyping studies are
European Association for Haematopathol- this p rocess First. recognizing tha t the used in routine diagnosis in the vast
ogy and the Society lor Hematopatholog y. underlying c auses of these neo plasms majority of haematolog ic mali gn ancies,
It is a revision and update of the 3rd Edi- are often unknown and may vary, this ap- both to d etermine lineage in malig nant
tion 11039 }. which was the first true proa ch to cl assifica tion uses all available processes and to dis tinguish be nig n lrom
worldwide consensus c lassific ation of information - morpholog y, immunop he- ma lignant processes . Many disea ses
baematoiocic malignancies. The update, notype, genetic features, and cl inical fea- have a chara ct eristic immunophenotype.
which began in 2006, had an a-me mbe r tures- to define diseases. The relative such that one would hesitate to make the
steering committee composed of membe rs impo rtance of eac h of these features diagnosis in the abse nce of the immune-
of both societies, The Steering Comminee, varies among diseases, d epend ing upon p henot yp e, while in others the immuno-
in a series of meetings and discussions, the state of current knowledge, and there onenotvpe is only part of the diagnosis, In
agreed on a proposed list of diseases is therefore no one "g old standard ," by some lymphoi d and in many myeloid ne0-
and chapters and selec ted authors. with which all di seases are defined . Second. p lasms a speci fic genetic abnorma lity is
input from both soc ieties. As with the rec ognizing that the com plexity 01 the the key defining criterion, while etters lack
WHO 3fd ed ition 1 71. the advice of clin -
89 field makes it impossib le for a single specific known genet ic ebnomantes.
ical haematologists and oncologists was expert Of small g roup to be comptet ely Some g enetic abnormalities, while char-
obtained . in order to ensure that the clas- authoritative, and that broad agreement is acteri stic of one dis ea se, are not specific
sifica tion will be clinica lly useful. Two Clin- necessary if a classificati on is to be ac - (such as MYC. CCND 1or BCl2 rearrange-
ic al Adv isory Committee s (CAG). one for cep ted, this cta ssrncanon relies on bu ild - ments or mutations in JAK2). and others
myeloid neoplasm s and other acut e ing a consensus among as many experts are prognostic factors in several diseases
leukaemias and one for lym phoid neo- as possible on the def inition and nomen- (such as TP mutations or FLT3-ITO) ,
53
plasms. were convened, The mee tings clatu re of the diseases, We recognize that The inc lusion of jr munoohenotvoc lea-
were org anized aroun d a ser ies of com promise is essential in orde r to arrive tures and genetic abnormalities to define
questions, inc luding disease definitions, at a consensus, but bel ieve that the only entities not only provides ob jective criteria
nomenclature, grading. and clinical rele- thing worse than an imperfect classifica- for disease recogni tion but has identified
vance. The committ ees were able to tion is multiple competing classifi cati ons . antigens, genes or pathways that can be
reach consensus on mos t of the ques- Finally. wh ile patholog ists must take targeted for therapy; the success of
tions po sed . and muc h of the inp ut of the pr imary respon sib ility for developing a rituxima b , an anti-CD20 molecule, in the
14 Introduction to the classification
.. .

16. treatment of. B-cel! neoplasms, and 01 ord er of listing is in part arb itrary, and is the WHO classification has produced a
imatinib in the treatment of leukaemias as- not an integral part of the cl assification. new and exciting degree of cooperation
sociated with ABL 1 and oth re!lrrange- and conmunic ation among patholog ists
ments inv olving tryoene kinase genes are The 4th ed ition of the WHO classification and oncologists from around the world .
testament to this approach. Finally. some inc orpo rates new information that has which stould facilitate con tinued progress
diseases require know ledge of clinical emerged from basic and clinic al in....estr- in the understand ing and treatment of
features - age, nodal versus extranodal gat ions in the interva l since pu b lication of haema totog ic manqnaocies . The mullipa-
presentan on. specific anatomic site . and the 3rd edition . It inc ludes new defining rameter approach to c lassification, with
history 01 cytotoxic and other therapies criter ia for some disease s, as well as a an emphasis on defining real disease
- to make the diagnosis. Most 01 the dis- number of new entities. some def ined by entites. tha t has be en ad opted by the
eases described in the WHO classification genetic criteria - particul arly among the WHO classification, has been shown in
are considered to be distinct enti ties ; myeloid neoplasm s- and others by a inte rnational studi es 10 be reproducible:
howev er. some are not as clearly defined, combination of morpholog y. immunoph e- the disea ses d efined are c linically dis-
and these are listed as prov isional entities, ootype . and clinic al features. The frequent ttnct iv e. and the uniform definitions and
In addition . borderline categories ha....e application of immunophenotyping and terminology facilitate the interpretation of
been created in this edition for cases that genetic stud ies to peripheral blood, bone clinical and translational stud ies 1 1, 791 .
5
do not c learly fit into one category, so that ma rrow, and lym ph node samp les has In addition, accurate and precise classifi -
well-de fined categories ca n be kept also led to the de tection of small clonal c ation of d isease entities has facilitated
homogeneous, and the borderline cases populations in asy mptomatic pe rsons . the discovery of the genetic bas is of
can be stud ied further. These include small clones of cells with the my eloid and lymphoid neoplasms in the
BCR-ABL 1 translocation seen in chronic ba sic science laboratory
The WHO classification stratifiesneoplasms myelogenous leukaemia. small cl ones of
primarily ac cording to lineag e: myeloid, ce lls with BCL2-IGH rearrangement. and
lymphoid, and histiocyticfdendritic c ell. A small populat ions of c ells that have the
normal c ounterpart is postulaled lor each imm uoopheootype of chronic lymp hocytic
neoplasm. While the goal is to define the leukaemia (e l l ) or folli cu lar lymphoma
lineag e of each neoplasm, lineage pla s- (mo noc lonal B lymphocytosis, follicular
ticity may occur in precursor or imma ture lymphoma-in Situ , paediatric follicul ar hy-
neoplasms, and has recently been identi- perplas ia WIth monoclonal B c ells). In
fied in some mature haematotymphoid man y case s. it is not clear whether these
neoplasms , In addition, genetic atooe - represent earty involvement by a neoplasm,
rreuues suc h as FGFR1, PDGFA and a precursor iesoo. or an inconsequential
PDGFB rearrangements may give rise to find ing. These situations have some
neoplasms 01 either myel oid or lymphoid ana logies to the identification of small
lineage associated with eosinophilia ; monoclonal immunoglobulin components
these disorders are now recognized as a in serum (monoclonal gammopathy of
separate group. Precursor neoplasms unknown significance), The ch apters on
(acute myeloid reukaemes. lymphoblastic these neoplasms include recommenda-
Iymphomasfleukaemias, acute reukaerraas tions for dea ling with these situations. The
01 amb iguo us lineag e, and blast ic p las- rec omm end ations of international con -
macytoid de nd ritic ce ll neop lasm ) are sens us group s have bee n co nsidered.
considered separately from mo re mature with regard to criteria for the d iagnosis of
neoplasms [myeloproliferative neoplasms e ll, plasma cell myeloma, Waldenstr6m
(MPN). myelodysplastic/myeloproliterative macroglobulinemia, and new subtypes of
neoplasms, myelodysplastic syndromes , cutaneous lymphomas, as well as in the
mature (peripheral) B-cell and T/NK -cell development of new algorithms for the
neoplasms, Hodgkin lymphoma. and his- diagnosis of MPN .
Iiocyteldeodritic-c ell neoplasms] . The ma-
ture myeloid neoplasms are stratified A critic al feature of any class ification of
according to the ir bi ologica l features diseases is that it be periodically reviewed
(myeIopl'oIiferative, with effective baereio- and updated to incorpor ate new informa-
poiesis. ....ersus myelodysplastic , with in- tion. TheSocietyfor Haematopathology and
effective neematcootesfs . as welt a s by the European Association for Haemato-
genetiC feature s). Within the mature lym- pathology now have a more than to-year
phoid neop lasms , the diseases are listed record of couebceaton and coo pe ration in
broadly ac cord ing to clinical presentation this effort. The societies are comm itted to
(disseminated often leukaemi c, extran - updating and revising the classification
coat. indolent. aggressiv e). and to some as needed . with input lrom clinicians and
extent according to stage of differentiation with the collaboration of the WHO . The
when this can be postulated: howe....er the experience of developing and updating
Introdu ction to the cl assification 15

17. •
)
CHAPTER 1
Introduction and Overview
of the Classification
of the Myeloid Neoplasms
•
-,
"

18. Introduction and overview of the J.w. Vardiman
A.D. Brunning
A. Porwit
A . retten
classification of the myeloid neoplasms D.A . Arter
M.M.Le Beau
C.D. Bloomfield
J. Thiele
The WHO Classification of Tumours of the by its c linic al and morphologic features, genetic features is used in an anerrctt c
Haematopoietic and Lymphoid Tissue s and its natural progression is charac ter- define d isease entities , such as CML, that
(3rd edition) published in 200 1 reflected ized by an inc rease in blasts of myeloid , are biolog ically homogeneous and clini-
a pa radigm shift in the approach to c las- lymphoid or m ixed myeloid/lymphoid cally relevant - the same approach used
sification of myeloid neoplasms { 1039). For immunop henotype. It is always associ- in the 3rd ed ition of the classification.
the first time. genetic information was in- ated with the BCR·ABL 1 fusion gen e that Altho ugh the previous scheme began to
cor porated into diagnostic algorithms results in the production 01 an abnormal open the door to including genetic ab-
provided lor the vario us en tities. The pub- protein tyros ine kinase (PTK) with en- normalities as c riteria to classi fy myeloid
licat ion was prefac ed with a comment hance d enzyma tic ac tivity. This p rotein is neoplasms, this rev ision firmly acknow l-
pred icti ng future revisions nec essitated sut tcrentto ca use the leukaem ia and also edges that as in CML, recu rring ge netic
by rapidly eme rg ing gen el ic information. provides a targ et for prote in tyrosi ne abno rmali ties provi de not onl y objec tive
The cu rrent revision is a commentary on kinase inhibi tor (PTKI) the ra py tha t has c rite ria for recognition of speci fic entities
the significant ne w molecular insights mat prolonge d the lives of thousands of pa - but also identification of abnormal gene
have bec ome avail abl e since the publi- tients with this often tatal illness {6 151. product s or pathways that are potent ial
cation of the last ctass'ncauon . This successful integ ratio n of cl inical , targets for therapy. One example in this
The first entity described in this mono- morphologi c and genetic information em- revised sc heme is the addition of a new
graph . chronic myelogenous leukaemia bodies the goal of the WHO classific ation subgroup of mye loid neoplasm s (Tabte
(CML) rema ins the prototype for the iden- scheme. 1.01) assoc iated with eos inoph ilia and
tification and c lassific atio n of myeloid In th is revis ion . a combination of c linica l, chromo somal ab normalities that involve
neoplasms This leukaemia is recognized morpholog ic . imm uno phe noty pic and the oiateiet-oenved growth factor rece ptor
.-
Table 1.01 Themyeloid neoplasms' major sul:9'OUJlS and dal;U::i tstic features at ~
.........., .... """" -
--
0..... 8M ctllularity '10 MIrf'OW bluts HatrnatopOitsit
MPN Usually increased. En-. VanabIe; 008 or Co<m>oo
often normalin ET
tbmaJ or sIighlIy
increased: <10% in
dI'onic phase
"""'" G••,,,''''''',
relabYe/y normal, """..-
IifIeage usually
"""""""",
"""""'"
irullallyincreased
MyeIoidIIymphoid Increased Normal or $IigM~ Present Relatively normal Elfectrve Eosinophilia Com~
neoplasmswith increased: <20% irl j~t 5x10ir1.)
eosinophilia and abriof· cnronc phase
malilies of PDGFRA.
PDGFRB Of FGFRI
MOS Nom1al or incr
eased: Preserlt ~lasia inoreor Inel!&Cti'Ie Cytopenia(s) U_
"''''as."
=- ""'. more myeloid lineage
-,,- --
~aror
"""""'"
"""'...
M''''''PN
_""
incl'eased;<20'10 """'" Usually oneormae
......
......
Moy""Y ...... IariabIe. WBC
..-- Co<m>oo
-
rrft'!lal cIyspIaSIa
"""" ....... ......, ........ ..-......
WllC_
-......
_>2ll%. "",", May Of may J'IOl be """'-
""""""'"
.........
eQPl in some cases or e"ect1ve
'l'Illh specific cybJeneIlc
abnorrnaIilies or in
-... dyspIaslai'loneor
some cases of
erylhroIeukaemia
Mf)N, myeloproliferative neoplasms: MDS, myelod)'spla:slic syndromes; MDSlMf)N, myeIodysplasbcJmyeloprolifefalive neoplasms: AMl, ICIJIe myeloid leukaemia; ET, esseflIlaj
Ihfombocylhaemia, JMML. ju¥&nile myelomonocytic leukaemia, wec. wniIe bloocI e&II$.
18 Introduction and overview of the c lassif ication of the mye loid neoplasms
.. '

19. ]
alpha (PDG FflA) Of platelet de rived growth is based on cr iteria applied 10 initial spec-
factor recep tor beta (PDGFRB) genes imen s obtained prior to any definitive ther-
-a subgroup defined larg er9 by genetic apy, includ ing growth lactor therapy, for the
events that lead to consti tutive act ivat ion myeloid neoplasm. The blast percentage in
of the receptor tyrosine kinase, PDGFA, the per ip her al b lood , bone ma rrow an d
and that respond to PTKI therapy {13 1, other involved tissues remains of p ractica l
466. 8121 . Similar examples are found impo rtance to categorize myeloid neo-
througho ut the classification in each plas ms and to judge their progression . 11111111 111I 1111 1111 111111
major subgroup, and inclu de not only Cytogenetic and molecular genetic stud-
neoplasms assoc iated with rmcroscopr- ies are requ ired at the time of d iag nosis 456
cally rec og niza ble chromosomal abnor- not only for recoq r n ton 01 specific genet-
F'S!. 1.01 Bone marrow tIeI:Me biopsy, Bone marfOW
malities but also with gene mutations ically d efined entities, but for establiShing
b'ephinebiopsies should be alleast 1. em in length and
5
without a cytogenetic correlate as weu. a baseline against which futu re studies ollt<w1ed at right angles10 the cortical bone.
On the other hand . the importance 01 can be judged to assess disease pro-
careful clinical, morphological and im- gression. Beca use of the multidisciplinary
munophenotypic characterization of each approach req uired to diagnose and clas- cells to categorize some eoutes. it is rec-
myeloid neoplasm and coeretanoo with sify myeloid neoplasms it is recomnended ommended that 500 nucleated BM cells
the genetic findings cannot be over- thaI the various diagnostic studies be be counted on cellular aspirate smears in
emphasized. The discovery of activating correlated with the clinical findings and an area as close to the particle and as
JAK2 mutations has revolutionized the reported in a single, integ rated report. If undiluted with blood as possible. Countll"lQ
approach to the diagnosis of the myelo- a definitive classification cannot be from multiple smears may reduce sam-
proliferative neoplasms (MPN) 1163, 1044 , reached the report should indicate the pling error due to irregular distribution of
1186,12681. Yet JAK2mutatiQns are not reasons why and provide guidelines for cells. The cells to be counted include
specific for any single clinical or morpho- additional studies that may clarify the blasts and promonocytes (see definition
logic MPN phenotype, and are also diagnosis. below) . pronveocvtes. myelocytes, meta-
reported in some cases 01 myelodysplas- To obtain consistency, the following myelocytes, band neutrophils, segmented
tic syndromes (MDS), myeiooysplasnc/ guidelines are recommended for the eval- neutrophils, eosiropnns. basophils, fTlQIlO-
myeloproliferative neoplasms (MDSlMPN) uation of specimens when a myeloid neo- cytes , lymphocytes. plasma cells , erythrOid
and ac ute mye loid leu kaemia (AMl). plasm is suspected to be present. It is precursors and mas t cells. Megakaryo-
Thus, an integ rate d, multidisciplinary assu me d tha t this evalua tion will be pe r- cvtes. including dysplastic forms. are not
approach is necessary for the classification formed with full knowled ge of the clinical inc lude d. If a concomitant non-mye loid
of myeloid neoplasms. history and pertinent laboratory data. neoplasm is present, such as p lasma ceu
With so muc h yet 10 learn, there may be myeloma, it is reasonable to exclude
some 'missteps" as trad itional approaches Morphology tho se neo plastic cells from the coun t
to categorization are fused with more Periphera l blood: A perip heral b lood (PB) used to evaluate the myeloid neop lasm. If
rrcecuarfy-orentec clessifcaton schemes , smea r sho uld be exa mined and co rre- an aspirate ca nnot be obta ined du e to
Nevertheless, thi s revi sion of th e WHO late d with result s of a co mple te b loo d fibrosis Of ce llular packing, touch prepa-
classification is an attempt by the authors, c ount. Freshly mad e smea rs shou ld be ratio ns of the b iop sy may yield valuable
editors and the c linic ians who served as sta ined with May-Gnmwald -Giernsa or c yto log ic informa tion, but d ifferential
members of the Clinica l Advisory Com- Wright-G iemsa and examined for wh ite co unts from touc h preparations may not
mittee (CAC ) to p rovide an "evidence- bloo d ce ll (WBC) , red b lood ce ll (AB C) be repr esentative . The d ifferential co unts
based" c lass ifica tion that ca n be used in and plate let abnormal ities It is impo rtant obta ined from marrow aspi rate s should
daily p ractic e for therap euti c deci sions to ascerta in that the smears are we ll- be compared to an estimate of the p ro-
and yet pr ovide a flexib le framework for stained, Evaluation of neutrophil g ranularity po rtions of cells o bserved in avai lab le
integration of new data , is imp ortant when a myelo id d isor der is biop sy sections,
suspected; de signat ion of neut rophils as Bone marrow trephine biopsy: The contri-
abnormal b ased o n hypog ranular cyto- but ion of adequate 8M bio psy sections in
Prerequisites for classification plasm alo ne shoul d not be conside red the diagnosis of myeloi d neoplasms can-
unless the stain is well-controlled . Manual not be overstated. The tre phine biopsy
ofmyeloid neoplasms by
2OO-cell leukocyte di fferentials of PB provides information rega rdin g overall
WHO criteria smea rs are recommended in patients with cellularity and the to pog raphy, propo rtion
a myeloid neoplasm when the WBC count and maturation of baematopolenc cells ,
The WHO c lassification of myeloid neo- permits. and allows evalu ation of 8M stroma. The
plasms relies on the morphologic, cyto- Bone manowaspirate: Bone marrow (BM) biopsy also provid es material for immuno-
chemical and immunophenotypic features as pi rate smears should also be stained histochemical studies th at may have
of the neop lastic cells to esta bl ish thei r with May-G rQnwald-G iemsa or Wright- diagnostic and prognostic importance. A
lineage and deg ree 01 ma turation and to Gie msa for optimal visua lization of cyto- biopsy is essential whenever there is
decide whether cellular p rolife ration is plas mic g ranules and nuclear chromatin. myelofibrosis, and the classification of sore
q101ogica lly normal or dysplastic or Because the WHO Classification relies on entities , partiCularly MPN, relies heavily on
esecuve or ineffec tive . The classification percentages of blasts and other specific trephine sections, The specimen must be
Introduction and overview of the ctassncauoo at the myeloid neoplasms 19

20. adeq uate, Iake n at rig ht 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/o r a stain such as Giemsa
that allows lor detailed morphologic eval-
uation . A silver impreg nation 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.
Immunohistoc hemical (IHe) study of the
biopsy is often indispensable in the eva l-
uation of myeloid neoplasms and is dis-
cussed belOw,
Blas ts: 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 8 M
aspirate smears as described above . The biopsy. not all blasts express CD34 . They are usually strongly positive for n0n-
blast percentage derived 'rom the 8 M Myeloblas ts. monoblasts and megakary<> specific esterase(NSE) but have no or only
aspirate should correlate With an estimate blasts are included in the blast count. weak myeloperoxidase (MPO) activity,
of the blast percentage in the trephine Myeloblasts vary from slightly larger than Promonocytes are considered as ' rrooo-
biop sy. although large foca l clusters or mature lymphocytes to the size of mono- blast equivalents " when the requisite per-
sheets 01 blasts in the biopsy should be cvtes or larger. with moderate to abun- centage 01 blasts is tallied for the
regarded as possible disease progression. dant dark blue to blue-grey cytoplasm. diagnosis of acute monoblastic . acute
Immunohistochemical staining of the BM The nuclei are round to oval with finely monoc ytic and acute myerorronocync
biopsy for CD34+ blasts often aids in the granul ar chromatin and usually several leukaemia. Promonoc vtes have a deli-
correlation of aspirate and trephine biopsy nucleoli. but in some nuclear irregularities cately convoluted. folded or grooved
findings, although in some myeloid neo- may be prominent. The cytoplasm may nucleus with finely dispersed chromatin,
plasms the blasts do not express CD34 , contain a few azurophil granules (Fig 1,03), a small , indistinct or absent nucleolus,
Flow cyto metry determination of blast Monob lasts are large cells with abundant and finely granulated cytoplasm (Fig 1.04
percentage should not be used as a sub- c ytoplasm that can be light grey to deeply C, 0), Most promonocytes express NSE
stitute for visual inspection. The spec imen blue and may show pseudopod formation and are likely to have MPO activ ity. The
for flow c ytometry is otten haemoouute. (Fig 1.04 A. S). Their nuc lei are usually distinct ion between mono brasts and
and may be affected by a number of pre- round with deli cate , lacy chromatin and prornonocvte s is often difficu lt. but
analytic variabl es. and as noted for the one or more large prominent nucleoli. because the two cell types are summated
...
.,
•
20 Introduction and overview of the classification of the myeloid neoplasms

21. as rr onootasf s 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 mo re matu re b ut ab-
normal leukaemic 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 A B
rrooocv tes have more clumped chromatin
than a p romonocyte, variably indented.
folded nucl ei and grey cytoplasm with
,
rrore abundant lilac -colored granules . Nu-
cleoli are usually absent or indi stinct (Ftg
1.04 E.F). Abnormal monocytes are rot
consider ed as monoblast eouvaeots.
Megakaryoblasts are usually 01rreoen to
large size with a round , indented or
~~
- .
irregular nucleu s 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 c o
and micrornegal<.aryocyt es 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 cons id-
ered as blast equiva lents (See Chap ter 6
on acute myeloi d leukaemia, NOS).
Cytochemistry and other special steins:
Cytochemical stud ies are used to deter-
mine the lineage 01 blasts, althou gh in
some laboratories they have bee n sup- E F
planted by immun ologi c studies usin g
flow cytometry an d/or immunohistochem - Fig. 1.04 Monoblasts, promonocytes and abnormal mcnccytea from a case of acute monocytic laukaemia.
istry. They are usu ally perform ed on PB A, B Monoblas tsarelarge with abundant cylOlJlasm that ma y contain a few vacuoles Of fine granules and have roullCl
and 8M aspirate smears but some can be nuclei withlacy chroma~n and one Of more variably prominent nucleoli. C, D Prornor.ocytes have more irregular ancl
performed on sections 01 treph ine b iop - delicately folded n~ withfine chroma~n, small indistinct nucleoli and finely granulated cytoplasm. E, F Abnormal
sies or other tissues . Detec tion 01 MPO monocytes appear immature, yet have mo condensed nuclear chroma tin, con'o'Q/uled Of fdded nuclai, and more
re
cylopIasmiC granulaboo (Courtesy of Or. J. Goasguen).
indicates myeloid d ifferentia tion b ut its
absence does not exclude a myeloid lin-
eage because early myelobl asts as well case light grey granules are seen rather inhibi ted by NaF, The combination of NSE
asmonoblasts may lack MPO. The MPO than the deeply black granules that char- and the specific esterase , naph thol-ASD-
activity in rrweiobtasrs is usually granular acterize mverobrasts. The non-specific chloroaceta te esterase (CAE), which stains
and etten concentrated in the Golgi region este rases . u nap hthyl butyrate (ANB) and primarily cells 01 the neutroph il lineage
whereas monobtasts. although usually (,( naphthyl acetate (ANA). show diffuse and mast cells, permits ident ification of
negative,may show line, scattered MPO+ cytoplasmic activity in monoblasts and monccvtes and immature and mature
granules, a pattern tha t becomes mo re monocytes. Lymphoblasts may have foca l neutroph ils simultaneously. Some cells ,
pronounced in prcmonocvtes . Erythroid punctate activity with NSE but neutrophils particularty in myeIornonocytic leukaemias,
blasts, megakaryoblasts and Iymphoblasts are usually negative. Megakaryoblasts may exhib it NSE and CAE simultaneously.
are MPO negat ive . Sudan Black B (SSBl and erythroid b lasts may have some mul- While norma l eosinoph ils lack CAE, it may
staining parallels M PO but is less spe- titocal. punctate ANA positivity, b ut it is be expressed by neop lastic eosooohne.
etc. Occ asional cases of lymphoblastic partia lly resistant to natrium ffuorid e (NaF) CAE can be performed on tissue sections
leult.aemia exhibit SSB POSitiVIty in which
, inhibition whereas monocyte NSE is totally as well as PB ()( marrow asp irate smears.
Introduction and overview 01 the ctass.tcanoo 01 the myeloid neoplasms 21

22. In acute erythroid leukaemia. a PAS stain an essential tool in the cha racterization of immunophenotyping in myeloid neoplasms
may be helpful in that the cytoplasm of myeloid neoplasms. Differootiation antigens is most com monly required in AML and in
the leukaemic oroervmrobreate may show that appear at various stages of haemato- determining the phe notype of blasts at
large globules of PAS positivity. Well- oo'euc develo pment and in correspon- the lime of transfo rmation of MOS.
controlled iron stains should always be ding myeloid neoplasms are illustrated in MOS!MPN and MPN,
per formed on the 8M aspirate to detect Fig . 1.05. and a thorough descriplion of Mulliparameter flow cytometry is the
iroo stores. normal side roblasts and ring lineage assignment criteria is provided in prefer red method of immuno phenotypic
side robrasts. the latter of which are de- the chapters on mixed phenotype acute analysis in AML due to the ability to ana-
fined as erythroid precursors with 5 or leukaemia, The techn iques employed and lyze high numbers of cells in a relatively
more granules of iron encircling one-third the antigens anafyzed may vary accord- short period of time with simultaneous
or more of the nuc leus. ing to the myeloid neoplasm suspected recording of information about severer
and the information required 10 best char- antigens for each individual cell. Usually.
Immunop henotype acterize it as well as by the tissue avail- rather extensive panels of monoclonal an-
Immunophenotypic analysis using either able. Although often important in the tibodies directed against leukocyte differ-
multiparameter flow cytometry or IHe is diagnosis ol any haematoiogicaJ neoplasm. entiation antigens are applied because
<-U II 7+
- C U 1I7+ c m l 7-
lib- llb-I+
C U,J. -
C O lJ5.-
C D.l6-
CDIJ ~'-
' fh+
C DJ6 -
Cll1J~.-
"'"
CD l 6 -
C D235. -
prvQ')"lbn>bla. 1 b ....p bllk: pc.ol ycbrvm.lk
tory l b rub l.,. toryl h ruh l• • 1
C U lM-
+ C I)l63+
C IUJ+ C IU+
C O}4... C O IS+ C OU +
C IU + C IU J + C O l5-+-
C D36-+ COll ++
C D U'"
C I)6" + C DJ ....
IIr"",,::7:-:-~01 liLA-DR'"
' C IU 3'" HL- -DR + C OM+
C U34_ C O ll b+ IH...A-O R +
liLA -DR t-tl L -"-LO"--l,. C D I 4+ C O l lb++
C U.H++
• • C O l -t-t
mon.. hl . ~1 p rumo"ucy'' m nmx: yl f'
,------''-, r'----,
em s-
C O Il 7 +1- C IH J d lm C lU J '"
C ll1 J+ C IU J + M''O+
C D 33 + MPO+ C D6 5+
MPO+ C ))65+ C U15+
C:0 6 5+ C D I5 + C D I I II+
C D I5+/· C U ll b+'_ C1U 5tlim
C D 3.. +-+ e m s-
1I1.A.-UR
C D .N+-+
Un _
C D J .....
C IH M+
C D U J-
C1U5R A+
_n_
C UJ4+I. C DJ4· C U.14-
C D3.. + C DJ M., _ C DJ8+
ClHM _ C O. II++
C D61+ C 06 1+ C I)6 I++
C D IlJ-. C I).&I+ C 04I + C I).& 1-+-+
C1 U 5 HA - ce-e- C04 l +I· C U"' l+
TI'O -R+
22 mtrocucuco and overview of lhe classification of the myeloid neoplasms