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 WHO Classification of Tumours of
Haematopoietic and Lymphoid Tissues

Steven H. Swerdlow, Elias Campo, Nancy Lee Harris, Elaine S. Jaffe, Stefano A. Pileri,
Harald Stein, Jurgen Thiele, Daniel A. Arber, Robert P. Hasserjian,
Michelle M. Le Beau, Attilio Orazi, Reiner Siebert

WHO
World Health Organization Classification of Tumours

LeBoit P. E., Burg G., Weedon D., Kurman R.J., Carcangiu M.L., El-Naggar A. K., Chan J.K.C.,
Sarasin A. (Eds): World Health Herrington C.S., Young R.H. (Eds): Gradis J.R., Takata T., Slootweg P.J.
Organization Classification of WHO Classification of Tumours (Eds): WHO Classification of Head
Tumours. Pathology and Genetics of Female Reproductive and Neck Tumours (4th edition).
of Skin Tumours (3rd edition). Organs (4th edition). IARC: Lyon 2014. IARC: Lyon 2017.
IARC Press: Lyon 2006. ISBN 978-92-832-2435-8 ISBN 978-92-832-2438-9
ISBN 978-92-832-2414-0

Bosman F.T., Carneiro F., Travis W. D., Brambilla E., Burke A. P., Lloyd R.V., Osamura R.Y., Kloppel G.,
Hruban R. H., Theise N. D. (Eds): Marx A., Nicholson A. G. (Eds): Rosai J. (Eds): WHO Classification of
WHO Classification of Tumours of WHO Classification of Tumours of Tumours of Endocrine Organs
the Digestive System (4th edition). the Lung, Pleura, Thymus and Heart (4th edition). IARC: Lyon 2017.
IARC: Lyon 2010. (4th edition). IARC: Lyon 2015. ISBN 978-92-832-4493-6
ISBN 978-92-832-2432-7 ISBN 978-92-832-2436-5

Lakhani S.R., Ellis I.O., Schnitt S. J., Moch H., Humphrey P. A., Swerdlow S. H., Campo E., Harris N. L.,
Tan P. H., van de Vijver M.J. (Eds): Ulbright T.M., Reuter V.E. (Eds): Jaffe E.S., Pileri S.A., Stein H.,
WHO Classification of Tumours of the WHO Classification of Tumours of the Thiele J. (Eds): WHO Classification of
Breast (4th edition). IARC: Lyon 2012. Urinary System and Male Genital Tumours of Haematopoietic and Lym­
ISBN 978-92-832-2433-4 Organs (4th edition). IARC: Lyon 2016. phoid Tissues (Revised 4th edition).
ISBN 978-92-832-2437-2 IARC: Lyon 2017.
ISBN 978-92-832-4494-3

Fletcher C. D. M., Bridge J.A., Louis D. N., Ohgaki H., Wiestler O.D.,
Hogendoorn P.C.W., Mertens F. (Eds): Cavenee W. K. (Eds):
WHO Classification of Tumours WHO Classification of Tumours of
of Soft Tissue and Bone (4th edition). the Central Nervous System (Revised
IARC: Lyon 2013. 4th edition). IARC: Lyon 2016.
ISBN 978-92-832-2434-1 ISBN 978-92-832-4492-9

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World Health Organization Classification of Tumours

WHO OMS

International Agency for Research on Cancer (IARC)

Revised 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
Jurgen Thiele

International Agency for Research on Cancer

Lyon, 2017
 World Health Organization Classification of Tumours

Series Editors Fred T. Bosman, MD, PhD

Elaine S. Jaffe, MD
Sunil R. Lakhani, MD, FRCPath
Hiroko Ohgaki, PhD

WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues

Editors Steven H. Swerdlow, MD

Elias Campo, MD, PhD
Nancy Lee Harris, MD
Elaine S. Jaffe, MD
Stefano A. Pileri, MD, PhD
Harald Stein, MD
Jurgen Thiele, MD, PhD

Senior Advisors Daniel A. Arber, MD

Robert P. Hasserjian, MD
Michelle M. Le Beau, PhD
Attilio Orazi, MD
Reiner Siebert, MD

Project Coordinator Paul Kleihues, MD

Project Assistants Asiedua Asante

Anne-Sophie Hameau

Technical Editor Jessica Cox

Database Kees Kleihues-van Tol

Layout Markus Fessler

Printed by Maestro
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Publisher International Agency for

Research on Cancer (IARC)
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 Published by the International Agency for Research on Cancer (IARC),
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Format for bibliographic citations:

Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J (Eds):
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Revised 4th edition).
IARC: Lyon 2017

IARC Library Cataloguing in Publication Data

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, Jurgen Thiele. - Revised 4th edition.

(World Health Organization classification of tumours)

1. Hematologic Neoplasms - classification 2. Hematologic Neoplasms - genetics

3. Hematologic Neoplasms - pathology

I. Swerdlow, Steven H. II. Series

ISBN 978-92-832-4494-3 (NLM Classification: WH 525)

Contents
WHO classification of tumours of haematopoietic and 7 Myeloid neoplasms with germline predisposition 121
lymphoid tissues 10 Myeloid neoplasms with germline predisposition without a
pre-existing disorder or organ dysfunction 124
Introduction to the WHO classification of tumours of Acute myeloid leukaemia with germline
haematopoietic and lymphoid tissues 13 CEBPA mutation 124
Myeloid neoplasms with germline DDX41 mutation 125
1 Introduction and overview of the classification of the Myeloid neoplasms with germline predisposition and
myeloid neoplasms 15 pre-existing platelet disorders 125
Myeloid neoplasms with germline RUNX1 mutation 125
2 Myeloproliferative neoplasms 29 Myeloid neoplasms with germline ANKRD26 mutation 125
Chronic myeloid leukaemia, BCR-ABL1–positive 30 Myeloid neoplasms with germline ETV6 mutation 126
Chronic neutrophilic leukaemia 37 Myeloid neoplasms with germline predisposition
Polycythaemia vera 39 associated with other organ dysfunction 126
Primary myelofibrosis 44 Myeloid neoplasms with germline GATA2 mutation 126
Prefibrotic/early primary myelofibrosis 46 Myeloid neoplasms with germline predisposition associated
Overt primary myelofibrosis 48 with inherited bone failure syndromes and
Essential thrombocythaemia 50 telomere biology disorders 128
Chronic eosinophilic leukaemia, not otherwise specified 54
Myeloproliferative neoplasm, unclassifiable 57 8 Acute myeloid leukaemia and related precursor
neoplasms 129
3 Mastocytosis 61 Acute myeloid leukaemia with recurrent genetic
Cutaneous mastocytosis 65 abnormalities 130
Systemic mastocytosis 66 Introduction 130
Mast cell sarcoma 69 Acute myeloid leukaemia with t(8;21)(q22;q22.1);
RUNX1-RUNX1T1 130
4 Myeloid/lymphoid neoplasms with eosinophilia and Acute myeloid leukaemia with inv(16)(p13.1q22) or
gene rearrangement 71 t(16;16)(p13.1;q22); CBFB-MYH11 132
Myeloid/lymphoid neoplasms with PDGFRA rearrangement 73 Acute promyelocytic leukaemia with PML-RARA 134
Myeloid/lymphoid neoplasms with PDGFRB rearrangement 75 Acute myeloid leukaemia with t(9;11)(p21.3;q23.3);
Myeloid/lymphoid neoplasms with FGFR1 rearrangement 77 KMT2A-MLLT3 136
Myeloid/lymphoid neoplasms with PCM1-JAK2 78 Acute myeloid leukaemia with t(6;9)(p23;q34.1);
DEK-NUP214 137
5 Myelodysplastic/myeloproliferative neoplasms 81 Acute myeloid leukaemia with inv(3)(q21.3q26.2) or
Chronic myelomonocytic leukaemia 82 t(3;3)(q21.3;q26.2); GATA2, MECOM 138
Atypical chronic myeloid leukaemia, BCR-ABL1–negative 87 Acute myeloid leukaemia (megakaryoblastic) with
Juvenile myelomonocytic leukaemia 89 t(1;22)(p13.3;q13.1); RBM15-MKL1 139
Myelodysplastic/myeloproliferative neoplasm with ring Acute myeloid leukaemia with BCR-ABL1 140
sideroblasts and thrombocytosis 93 Acute myeloid leukaemia with gene mutations 141
Myelodysplastic/myeloproliferative neoplasm, unclassifiable 95 Acute myeloid leukaemia with mutated NPM1 141
Acute myeloid leukaemia with biallelic
6 Myelodysplastic syndromes 97 mutation of CEBPA 142
Overview 98 Acute myeloid leukaemia with mutated RUNX1 144
Myelodysplastic syndrome with single lineage dysplasia 106 Acute myeloid leukaemia with myelodysplasia-related
Myelodysplastic syndrome with ring sideroblasts 109 changes 150
Myelodysplastic syndrome with multilineage dysplasia 111 Therapy-related myeloid neoplasms 153
Myelodysplastic syndrome with excess blasts 113 Acute myeloid leukaemia, not otherwise specified 156
Myelodysplastic syndrome with excess blasts and Acute myeloid leukaemia with minimal differentiation 156
erythroid predominance 114 Acute myeloid leukaemia without maturation 157
Myelodysplastic syndrome with excess blasts Acute myeloid leukaemia with maturation 158
and fibrosis 114 Acute myelomonocytic leukaemia 159
Myelodysplastic syndrome with isolated del(5q) 115 Acute monoblastic and monocytic leukaemia 160
Myelodysplastic syndrome, unclassifiable 116 Pure erythroid leukaemia 161
Childhood myelodysplastic syndrome 116 Acute megakaryoblastic leukaemia 162
Refractory cytopenia of childhood 117 Acute basophilic leukaemia 164
Acute panmyelosis with myelofibrosis 165
Myeloid sarcoma 167
 Myeloid proliferations associated with Down syndrome 169 Heavy chain diseases 237
Transient abnormal myelopoiesis associated with Mu heavy chain disease 237
Down syndrome 169 Gamma heavy chain disease 238
Myeloid leukaemia associated with Down syndrome 170 Alpha heavy chain disease 240
Plasma cell neoplasms 241
9 Blastic plasmacytoid dendritic cell neoplasm 173 Non-IgM monoclonal gammopathy of undetermined
significance 241
10 Acute leukaemias of ambiguous lineage 179 Plasma cell myeloma 243
Acute undifferentiated leukaemia 182 Plasma cell myeloma variants 249
Mixed-phenotype acute leukaemia with Smouldering (asymptomatic) plasma cell myeloma 249
t(9;22)(q34.1;q11.2); BCR-ABL1 182 Non-secretory myeloma 250
Mixed-phenotype acute leukaemia with t(v;11q23.3); Plasma cell leukaemia 250
KMT2A-rearranged 183 Plasmacytoma 250
Mixed-phenotype acute leukaemia, B/myeloid, Solitary plasmacytoma of bone 250
not otherwise specified 184 Extraosseous plasmacytoma 251
Mixed-phenotype acute leukaemia, T/myeloid, Monoclonal immunoglobulin deposition diseases 254
not otherwise specified 185 Primary amyloidosis 254
Mixed-phenotype acute leukaemia, not otherwise specified, Light chain and heavy chain deposition diseases 255
rare types 186 Plasma cell neoplasms with associated
Acute leukaemias of ambiguous lineage, paraneoplastic syndrome 256
not otherwise specified 187 POEMS syndrome 256
TEMPI syndrome 257
11 Introduction and overview of the classification of the Extranodal marginal zone lymphoma of mucosa-associated
lymphoid neoplasms 189 lymphoid tissue (MALT lymphoma) 259
Nodal marginal zone lymphoma 263
12 Precursor lymphoid neoplasms 199 Paediatric nodal marginal zone lymphoma 264
B-lymphoblastic leukaemia/lymphoma, Follicular lymphoma 266
not otherwise specified 200 Testicular follicular lymphoma 268
B-lymphoblastic leukaemia/lymphoma with recurrent In situ follicular neoplasia 274
genetic abnormalities 203 Duodenal-type follicular lymphoma 276
B-lymphoblastic leukaemia/lymphoma with Paediatric-type follicular lymphoma 278
t(9;22)(q34.1;q11.2); BCR-ABL1 203 Large B-cell lymphoma with IRF4 rearrangement 280
B-lymphoblastic leukaemia/lymphoma with Primary cutaneous follicle centre lymphoma 282
t(v;11q23.3); KMT2A-rearranged 203 Mantle cell lymphoma 285
B-lymphoblastic leukaemia/lymphoma with Leukaemic non-nodal mantle cell lymphoma 290
t(12;21)(p13.2;q22.1); ETV6-RUNX1 204 In situ mantle cell neoplasia 290
B-lymphoblastic leukaemia/lymphoma with hyperdiploidy 205 Diffuse large B-cell lymphoma (DLBCL), NOS 291
B-lymphoblastic leukaemia/lymphoma with hypodiploidy 206 T-cell/histiocyte-rich large B-cell lymphoma 298
B-lymphoblastic leukaemia/lymphoma with Primary diffuse large B-cell lymphoma of the CNS 300
t(5;14)(q31.1;q32.1); IGH/IL3 206 Primary cutaneous diffuse large B-cell lymphoma, leg type 303
B-lymphoblastic leukaemia/lymphoma with EBV-positive diffuse large B-cell lymphoma, NOS 304
t(1;19)(q23;p13.3); TCF3-PBX1 207 EBV-positive mucocutaneous ulcer 307
B-lymphoblastic leukaemia/lymphoma, BCR-ABL1–like 208 Diffuse large B-cell lymphoma associated with
B-lymphoblastic leukaemia/lymphoma with iAMP21 208 chronic inflammation 309
T-lymphoblastic leukaemia/lymphoma 209 Fibrin-associated diffuse large B-cell lymphoma 311
Early T-cell precursor lymphoblastic leukaemia 212 Lymphomatoid granulomatosis 312
NK-lymphoblastic leukaemia / lymphoma 213 Primary mediastinal (thymic) large B-cell lymphoma 314
Intravascular large B-cell lymphoma 317
13 Mature B-cell neoplasms 215 ALK-positive large B-cell lymphoma 319
Chronic lymphocytic leukaemia/ Plasmablastic lymphoma 321
small lymphocytic lymphoma 216 Primary effusion lymphoma 323
Monoclonal B-cell lymphocytosis 220 HHV8-associated lymphoproliferative disorders 325
B-cell prolymphocytic leukaemia 222 Multicentric Castleman disease 325
Splenic marginal zone lymphoma 223 HHV8-positive diffuse large B-cell lymphoma, NOS 327
Hairy cell leukaemia 226 HHV8-positive germinotropic lymphoproliferative disorder 328
Splenic B-cell lymphoma/leukaemia, unclassifiable 229 Burkitt lymphoma 330
Splenic diffuse red pulp small B-cell lymphoma 229 Burkitt-like lymphoma with 11q aberration 334
Hairy cell leukaemia variant 230 High-grade B-cell lymphoma 335
Lymphoplasmacytic lymphoma 232 High-grade B-cell lymphoma with MYC and BCL2
IgM Monoclonal gammopathy of undetermined significance 236 and/or BCL6 rearrangements 335
High-grade B-cell lymphoma, NOS 340
 B-cell lymphoma, unclassifiable, with features intermediate 16 Immunodeficiency-associated lymphoproliferative
between DLBCL and classic Hodgkin lymphoma 342 disorders 443
Lymphoproliferative diseases associated with primary
14 Mature T- and NK-cell neoplasms 345 immune disorders 444
T-cell prolymphocytic leukaemia 346 Lymphomas associated with HIV infection 449
T-cell large granular lymphocytic leukaemia 348 Post-transplant lymphoproliferative disorders (PTLD) 453
Chronic lymphoproliferative disorder of NK cells 351 Non-destructive PTLD 456
Aggressive NK-cell leukaemia 353 Polymorphic PTLD 457
EBV–positive T-cell and NK-cell lymphoproliferative Monomorphic PTLD (B- and T/NK-cell types) 459
diseases of childhood 355 Monomorphic B-cell PTLD 459
Systemic EBV+ T-cell lymphoma of childhood 355 Monomorphic T/NK-cell PTLD 461
Chronic active EBV infection of T- and Classic Hodgkin lymphoma PTLD 462
NK-cell type, systemic form 358 Other iatrogenic immunodeficiency-associated
Hydroa vacciniforme–like lymphoproliferative disorder 360 lymphoproliferative disorders 462
Severe mosquito bite allergy 362
Adult T-cell leukaemia/lymphoma 363 17 Histiocytic and dendritic cell neoplasms 465
Extranodal NK/T-cell lymphoma, nasal type 368 Introduction 466
Intestinal T-cell lymphoma 372 Histiocytic sarcoma 468
Enteropathy-associated T-cell lymphoma 372 Tumours derived from Langerhans cells 470
Monomorphic epitheliotropic intestinal T-cell lymphoma 377 Langerhans cell histiocytosis 470
Intestinal T-cell lymphoma, NOS 378 Langerhans cell sarcoma 473
Indolent T-cell lymphoproliferative disorder of the Indeterminate dendritic cell tumour 474
gastrointestinal tract 379 Interdigitating dendritic cell sarcoma 475
Hepatosplenic T-cell lymphoma 381 Follicular dendritic cell sarcoma 476
Subcutaneous panniculitis-like T-cell lymphoma 383 Inflammatory pseudotumour-like follicular/fibroblastic
Mycosis fungoides 385 dendritic cell sarcoma 478
Sézary syndrome 390 Fibroblastic reticular cell tumour 479
Primary cutaneous CD30-positive T-cell Disseminated juvenile xanthogranuloma 480
lymphoproliferative disorders 392 Erdheim–Chester disease 481
Lymphomatoid papulosis 392
Primary cutaneous anaplastic large cell lymphoma 395
Primary cutaneous peripheral T-cell lymphomas,
rare subtypes 397 Contributors 484
Introduction 397
Primary cutaneous gamma delta T-cell lymphoma 397 Declaration of interests 493
Primary cutaneous CD8-positive aggressive
epidermotropic cytotoxic T-cell lymphoma 399 Clinical Advisory Committees 494
Primary cutaneous acral CD8-positive T-cell lymphoma 400
Primary cutaneous CD4+ small/medium T-cell IARC/WHO Commitee for ICD-O 496
lymphoproliferative disorder 401
Peripheral T-cell lymphoma, NOS 403 Sources of figures and tables 497
Angioimmunoblastic T-cell lymphoma and other nodal
lymphomas of T follicular helper (TFH) cell origin 407 References 504
Angioimmunoblastic T-cell lymphoma 408
Follicular T-cell lymphoma 411 Subject index 577
Nodal peripheral T-cell lymphoma with
TFH phenotype 412 List of abbreviations 585
Anaplastic large cell lymphoma, ALK-positive 413
Anaplastic large cell lymphoma, ALK-negative 418
Breast implant–associated anaplastic large cell lymphoma 421

15 Hodgkin lymphomas 423

Introduction 424
Nodular lymphocyte predominant Hodgkin lymphoma 431
Classic Hodgkin lymphoma 435
Nodular sclerosis classic Hodgkin lymphoma 435
Lymphocyte-rich classic Hodgkin lymphoma 438
Mixed-cellularity classic Hodgkin lymphoma 440
Lymphocyte depleted classic Hodgkin lymphoma 441
 WHO classification of tumours of haematopoietic
and lymphoid tissues

Myeloproliferative neoplasms Myeloid neoplasms with germline predisposition

Chronic myeloid leukaemia, BCR-ABL1-positive 9875/3 Acute myeloid leukaemia with germline CEBPA mutation
Chronic neutrophilic leukaemia 9963/3 Myeloid neoplasms with germline DDX41 mutation
Polycythaemia vera 9950/3 Myeloid neoplasms with germline RUNX1 mutation
Primary myelofibrosis 9961/3 Myeloid neoplasms with germline ANKRD26 mutation
Essential thrombocythaemia 9962/3 Myeloid neoplasms with germline ETV6 mutation
Chronic eosinophilic leukaemia, NOS 9964/3 Myeloid neoplasms with germline GATA2 mutation
Myeloproliferative neoplasm, unclassifiable 9975/3
Acute myeloid leukaemia (AML) and related
Mastocytosis precursor neoplasms
Cutaneous mastocytosis 9740/1
Indolent systemic mastocytosis 9741/1 AML with recurrent genetic abnormalities
Systemic mastocytosis with an associated AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 9896/3
haematological neoplasm 9741/3 AML with inv(16)(p13.1q22) or
Aggressive systemic mastocytosis 9741/3 t(16;16)(p13.1;q22); CBFB-MYH11 9871/3
Mast cell leukaemia 9742/3 Acute promyelocytic leukaemia with PML-RARA 9866/3
Mast cell sarcoma 9740/3 AML with t(9;11)(p21.3;q23.3); KMT2A-MLLT3 9897/3
AML with t(6;9)(p23;q34.1); DEK-NUP214 9865/3
Myeloid/lymphoid neoplasms with eosinophilia AML with inv(3)(q21.3q26.2) or
and gene rearrangement t(3;3)(q21.3;q26.2); GATA2, MECOM 9869/3
Myeloid/lymphoid neoplasms with AML (megakaryoblastic) with
PDGFRA rearrangement 9965/3 t(1;22)(p13.3;q13.1); RBM15-MKL1 9911/3
Myeloid/lymphoid neoplasms with AML with BCR-ABL1 9912/3*
PDGFRB rearrangement 9966/3 AML with mutated NPM1 9877/3*
Myeloid/lymphoid neoplasms with AML with biallelic mutation of CEBPA 9878/3*
FGFR1 rearrangement 9967/3 AML with mutated RUNX1 9879/3*
Myeloid/lymphoid neoplasms with PCM1―JAK2 9968/3*
AML with myelodysplasia-related changes 9895/3
Myelodysplastic/myeloproliferative neoplasms
Chronic myelomonocytic leukaemia 9945/3 Therapy-related myeloid neoplasms 9920/3
Atypical chronic myeloid leukaemia,
BCR-ABL1―negative 9876/3 Acute myeloid leukaemia, NOS 9861/3
Juvenile myelomonocytic leukaemia 9946/3 AML with minimal differentiation 9872/3
Myelodysplastic/myeloproliferative neoplasm AML without maturation 9873/3
with ring sideroblasts and thrombocytosis 9982/3 AML with maturation 9874/3
Myelodysplastic/myeloproliferative neoplasm, Acute myelomonocytic leukaemia 9867/3
unclassifiable 9975/3 Acute monoblastic and monocytic leukaemia 9891/3
Pure erythroid leukaemia 9840/3
Myelodysplastic syndromes Acute megakaryoblastic leukaemia 9910/3
Myelodysplastic syndrome with Acute basophilic leukaemia 9870/3
single lineage dysplasia 9980/3 Acute panmyelosis with myelofibrosis 9931/3
Myelodysplastic syndrome with ring sideroblasts
and single lineage dysplasia 9982/3 Myeloid sarcoma 9930/3
Myelodysplastic syndrome with ring sideroblasts
and multilineage dysplasia 9993/3* Myeloid proliferations associated with
Myelodysplastic syndrome with Down syndrome
multilineage dysplasia 9985/3 Transient abnormal myelopoiesis associated
Myelodysplastic syndrome with excess blasts 9983/3 with Down syndrome 9898/1
Myelodysplastic syndrome with isolated del(5q) 9986/3 Myeloid leukaemia associated with
Myelodysplastic syndrome, unclassifiable 9989/3 Down syndrome 9898/3
Refractory cytopenia of childhood 9985/3

10 WHO classification
Blastic plasmacytoid dendritic cell neoplasm 9727/3 Alpha heavy chain disease 9762/3
Plasma cell neoplasms
Acute leukaemias of ambiguous lineage Non-IgM monoclonal gammopathy of
Acute undifferentiated leukaemia 9801/3 undetermined significance 9765/1
Mixed-phenotype acute leukaemia with Plasma cell myeloma 9732/3
t(9;22)(q34.1;q11.2); BCR-ABL1 9806/3 Solitary plasmacytoma of bone 9731/3
Mixed-phenotype acute leukaemia with Extraosseous plasmacytoma 9734/3
t(v;11q23.3); KMT2A-rearranged 9807/3 Monoclonal immunoglobulin deposition diseases
Mixed-phenotype acute leukaemia, Primary amyloidosis 9769/1
B/myeloid, NOS 9808/3 Light chain and heavy chain
Mixed-phenotype acute leukaemia, deposition diseases 9769/1
T/myeloid, NOS 9809/3 Extranodal marginal zone lymphoma of mucosa-
Mixed-phenotype acute leukaemia, NOS, associated lymphoid tissue (MALT lymphoma) 9699/3
rare types Nodal marginal zone lymphoma 9699/3
Acute leukaemias of ambiguous lineage, NOS Paediatric nodal marginal zone lymphoma 9699/3
Follicular lymphoma 9690/3
Precursor lymphoid neoplasms In situ follicular neoplasia 9695/1*
B-lymphoblastic leukaemia/lymphoma, NOS 9811/3 Duodenal-type follicular lymphoma 9695/3
B-lymphoblastic leukaemia/lymphoma with Testicular follicular lymphoma 9690/3
t(9;22)(q34.1;q11.2); BCR-ABL1 9812/3 Paediatric-type follicular lymphoma 9690/3
B-lymphoblastic leukaemia/lymphoma with Large B-cell lymphoma with IRF4 rearrangement 9698/3
t(v;11q23.3); KMT2A-rearranged 9813/3 Primary cutaneous follicle centre lymphoma 9597/3
B-lymphoblastic leukaemia/lymphoma Mantle cell lymphoma 9673/3
with t(12;21)(p13.2;q22.1); ETV6-RUNX1 9814/3 In situ mantle cell neoplasia 9673/1*
B-lymphoblastic leukaemia/lymphoma Diffuse large B-cell lymphoma (DLBCL), NOS 9680/3
with hyperdiploidy 9815/3 Germinal centre B-cell subtype 9680/3
B-lymphoblastic leukaemia/lymphoma Activated B-cell subtype 9680/3
with hypodiploidy (hypodiploid ALL) 9816/3 T-cell/histiocyte-rich large B-cell lymphoma 9688/3
B-lymphoblastic leukaemia/lymphoma Primary DLBCL of the CNS 9680/3
with t(5;14)(q31.1;q32.1); IGH/IL3 9817/3 Primary cutaneous DLBCL, leg type 9680/3
B-lymphoblastic leukaemia/lymphoma EBV-positive DLBCL, NOS 9680/3
with t(1;19)(q23;p13.3); TCF3-PBX1 9818/3 EBV-positive mucocutaneous ulcer 9680/1*
B-lymphoblastic leukaemia/lymphoma, DLBCL associated with chronic inflammation 9680/3
BCR-ABL 1―like 9819/3* Fibrin-associated diffuse large B-cell
B-lymphoblastic leukaemia/lymphoma with lymphoma
iAMP21 9811/3 Lymphomatoid granulomatosis, grade 1,2 9766/1
T-lymphoblastic leukaemia/lymphoma 9837/3 Lymphomatoid granulomatosis, grade 3 9766/3*
Early T-cell precursor lymphoblastic Primary mediastinal (thymic) large
leukaemia 9837/3 B-cell lymphoma 9679/3
NK-lymphoblastic leukaemia/lymphoma Intravascular large B-cell lymphoma 9712/3
ALK-positive large B-cell lymphoma 9737/3
Mature B-cell neoplasms Plasmablastic lymphoma 9735/3
Chronic lymphocytic leukaemia (CLL)/ Primary effusion lymphoma 9678/3
small lymphocytic lymphoma 9823/3 Multicentric Castleman disease
Monoclonal B-cell lymphocytosis, CLL-type 9823/1* HHV8-positive DLBCL, NOS 9738/3
Monoclonal B-cell lymphocytosis, non-CLL-type 9591/1* HHV8-positive germinotropic lymphoproliferative
B-cell prolymphocytic leukaemia 9833/3 disorder 9738/1*
Splenic marginal zone lymphoma 9689/3 Burkitt lymphoma 9687/3
Hairy cell leukaemia 9940/3 Burkitt-like lymphoma with 11q aberration 9687/3*
Splenic B-cell lymphoma/leukaemia, unclassifiable 9591/3 High-grade B-cell lymphoma
Splenic diffuse red pulp small B-cell lymphoma 9591/3 High-grade B-cell lymphoma with MYC
Hairy cell leukaemia variant 9591/3 and BCL2 and/or BCL6 rearrangements 9680/3
Lymphoplasmacytic lymphoma 9671/3 High-grade B-cell lymphoma, NOS 9680/3
Waldentrom macroglobulinemia 9761/3 B-cell lymphoma, unclassifiable, with features
IgM monoclonal gammopathy of undetermined intermediate between DLBCL and classic
significance 9761/1* Hodgkin lymphoma 9596/3
Heavy chain diseases
Mu heavy chain disease 9762/3
Gamma heavy chain disease 9762/3

WHO classification 11
 Mature T- and NK-cell neoplasms Hodgkin lymphomas
T-cell prolymphocytic leukaemia 9834/3 Nodular lymphocyte predominant Hodgkin
T-cell large granular lymphocytic leukaemia 9831/3 lymphoma 9659/3
Chronic lymphoproliferative disorder of NK cells 9831/3 Classic Hodgkin lymphoma 9650/3
Aggressive NK-cell leukaemia 9948/3 Nodular sclerosis classic Hodgkin lymphoma 9663/3
Systemic EBV-positive T-cell lymphoma Lymphocyte-rich classic Hodgkin lymphoma 9651/3
of childhood 9724/3 Mixed cellularity classic Hodgkin lymphoma 9652/3
Chronic active EBV infection of Lymphocyte-depleted classic Hodgkin
T- and NK-cell type, systemic form lymphoma 9653/3
Hydroa vacciniforme-like lymphoproliferative
disorder 9725/1* Immunodeficiency-associated
Severe mosquito bite allergy lymphoproliferative disorders
Adult T-cell leukaemia/lymphoma 9827/3 Post-transplant lymphoproliferative disorders (PTLD)
Extranodal NK/T-cell lymphoma, nasal type 9719/3 Non-destructive PTLD
Enteropathy-associated T-cell lymphoma 9717/3 Plasmacytic hyperplasia PTLD
Monomorphic epitheliotropic intestinal Infectious mononucleosis PTLD
T-cell lymphoma 9717/3 Florid follicular hyperplasia
Intestinal T-cell lymphoma, NOS 9717/3 Polymorphic PTLD 9971/1
Indolent T-cell lymphoproliferative disorder Monomorphic PTLD
of the gastrointestinal tract 9702/1* Classic Hodgkin Lymphoma PTLD 9650/3
Hepatosplenic T-cell lymphoma 9716/3 Other iatrogenic immunodeficiency-
Subcutaneous panniculitis-like T-cell lymphoma 9708/3 associated lymphoproliferative disorders
Mycosis fungoides 9700/3
Sezary syndrome 9701/3 Histiocytic and dendritic cell neoplasms
Primary cutaneous CD30-positive T-cell Histiocytic sarcoma 9755/3
lymphoproliferative disorders Langerhans cell histiocytosis, NOS 9751/1
Lymphomatoid papulosis 9718/1* Langerhans cell histiocytosis, monostotic 9751/1
Primary cutaneous anaplastic Langerhans cell histiocytosis, polystotic 9751/1
large cell lymphoma 9718/3 Langerhans cell histiocytosis, disseminated 9751/3
Primary cutaneous gamma delta T-cell Langerhans cell sarcoma 9756/3
lymphoma 9726/3 Indeterminate dendritic cell tumour 9757/3
Primary cutaneous CD8-positive aggressive Interdigitating dendritic cell sarcoma 9757/3
epidermotropic cytotoxic T-cell lymphoma 9709/3 Follicular dendritic cell sarcoma 9758/3
Primary cutaneous acral CD8-positive Fibroblastic reticular cell tumour 9759/3
T-cell lymphoma 9709/3* Disseminated juvenile xanthogranuloma
Primary cutaneous CD4-positive small/medium Erdheim-Chester disease 9749/3
T-cell lymphoproliferative disorder 9709/1
Peripheral T-cell lymphoma, NOS 9702/3 The morphology codes are from the International Classification of Diseases
for Oncology (ICD-O) {1257A}. Behaviour is coded /0 for benign tumours;
Angioimmunoblastic T-cell lymphoma 9705/3 /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in
Follicular T-cell lymphoma 9702/3 situ and grade III intraepithelial neoplasia; and /3 for malignant tumours.
Nodal peripheral T-cell lymphoma with The classification is modified from the previous WHO classification, taking
into account changes in our understanding of these lesions.
T follicular helper phenotype 9702/3
Anaplastic large cell lymphoma, ALK-positive 9714/3 * These new codes were approved by the IARC/WHO Committee for
Anaplastic large cell lymphoma, ALK-negative 9715/3* ICD-O.
** These lesions are classified according to the lymphoma to which they
Breast implant-associated anaplastic
correspond, and are assigned the respective ICD-O code.
large cell lymphoma 9715/3*
Italics: Provisional tumour entities.

12 WHO classification
Introduction to the WHO classification of Harris N.L.
Arber D.A.
Pileri S.A.
Stein H.
tumours of haematopoietic and lymphoid Campo E.
Hasserjian R.P.
Swerdlow S.H.
Thiele J.
tissues Jaffe E.S. Vardiman J.W.
Orazi A.

Why classify? Classification is the language 130 pathologists and haematologists from The first component is the recognition that
of medicine; diseases must be described, around the world were involved in writing the underlying causes of these neoplasms
defined, and named before they can be the chapters. are often unknown and may vary. There­
diagnosed, treated, and studied. A con­ It has now been more than 8 years since fore, the WHO approach to classification
sensus on definitions and terminology is the publication of the 4th edition, and nu­ incorporates all available information ―
essential for both clinical practice and in­ merous basic and clinical investigations morphology, immunophenotype, genetic
vestigation. A classification should contain have since led to many advances in the features, and clinical features ― to define
diseases that are clearly defined, clinically field that warrant an update to the clas­ the diseases. The relative importance of
distinctive, and non-overlapping (i.e. mutu­ sification. Important contributions have each of these features varies by disease,
ally exclusive), and that together constitute been made through the application of depending on the current state of know­
all known entities (i.e. are collectively ex­ high-throughput genetic technologies ledge; there is no single gold standard by
haustive). A classification should provide such as gene expression profiling and which all diseases are defined.
a basis for future investigation and should next-generation sequencing. These tech­ The second important component of this
be able to incorporate new information as it nologies have led to new diagnostic tools classification process is the recognition
becomes available. Disease classification and have revealed new mechanisms of that the complexity of the field makes it
involves two distinct processes: class dis­ tumorigenesis and new potential therapeu­ impossible for any single expert or small
covery (the process of identifying catego­ tic targets. Because the 4th edition of the group of experts to be completely au­
ries of diseases) and class prediction (the WHO classification of tumours series is not thoritative; for a classification to be widely
process of determining to which category yet complete (with several volumes yet to accepted, broad agreement is necessary.
individual cases belong). The work of pa­ be released), the 5th edition cannot yet be Therefore, the WHO approach to clas­
thologists is essential for both processes. started, so the editors and authors have in­ sification relies on building a consensus
The 2008 WHO classification of tumours stead undertaken a major update to the ex­ on the definitions and nomenclature of
of the haematopoietic and lymphoid tis­ isting 4th edition of the WHO classification the diseases among as many experts as
sues (4th edition) {3848} was a collabora­ of tumours of the haematopoietic and lym­ possible. We recognize that compromise is
tive project of the European Association phoid tissues. This process has involved essential for establishing a consensus, but
for Haematopathology and the Society for many of the original editors as well as an we believe that even an imperfect single
Hematopathology. It was a revision and additional three senior advisors special­ classification is better than multiple com­
update of the 3rd edition {1820}, which izing in myeloid neoplasms and two senior peting classifications.
was the first true worldwide consensus advisors with expertise in molecular and The final important component of this clas­
classification of haematological malignan­ cytogenetic issues. Clinical advisory com­ sification process is the understanding that
cies. The 4th edition had an eight-member mittee meetings were held regarding both although pathologists must take primary
steering committee composed of members myeloid and lymphoid neoplasms, as was responsibility for developing a classifica­
of both societies. Through a series of meet­ done for prior editions. The key features of tion, the involvement of clinicians is also
ings and discussions, with input from both this revision have been summarized in re­ essential, to ensure the classification’s
societies, the steering committee agreed cent review articles {129A.3848A}. usefulness and acceptance in daily prac­
on a proposed list of diseases and chap­ The WHO classification of tumours of hae­ tice {1556}. When the 3rd edition of the
ters and chose authors. As was done for matopoietic and lymphoid tissues is based WHO classification was published, pre­
the 3rd edition, the advice of clinical hae- on the principles initially defined in the Re­ vious proponents of other classifications of
matologists and oncologists was obtained vised European-American classification of haematological neoplasms agreed to ac­
to ensure that the classification would be lymphoid neoplasms (REAL), proposed by cept and use the new classification, end­
clinically useful {1556}. Two clinical advi­ the International Lymphoma Study Group ing decades of controversy over the clas­
sory committees were convened: one for (ILSG) {1557}. In the WHO classification, sification of these tumours {338A,339,340,
myeloid neoplasms and other acute leu­ these principles have also been applied to 1165,1330A, 1643A, 2412A,2836,3310A}.
kaemias and one for lymphoid neoplasms. the classification of myeloid and histiocytic As stated above, there is no single gold
The meetings were organized around a se­ neoplasms. The guiding principle of both standard by which all diseases are defined
ries of questions, which addressed topics the REAL and the WHO classification is in the WHO classification. Morphology is al­
such as disease definitions, nomenclature, the importance of defining ‘real’ diseases ways important; many diseases have char­
grading, and clinical relevance. The com­ that can be recognized by pathologists acteristic or even diagnostic morphological
mittees were able to reach consensus on using the available techniques, and that features. Immunophenotype and genetic
most of the questions posed, and much of appear to be distinct clinical entities. There features are also important aspects of the
the input from the committees was incor­ are three important components of this definition of tumours of haematopoietic and
porated into the classification. More than process. lymphoid tissues, and the availability of this

Introduction to the WHO classification of tumours of haematopoietic and lymphoid tissues 13

 information means that it is now easier to been identified in some mature haemato- of cells with IGH/BCL2 rearrangement,
establish consensus definitions than it was lymphoid neoplasms. In addition, genetic and small populations of cells that have
when only subjective morphological crite­ abnormalities such as rearrangements in the immunophenotype of chronic lympho­
ria were available. Immunophenotyping is FGFR1, PDGFRA, and PDGFRB, or PCM1- cytic leukaemia or follicular lymphoma (i.e.
used in the routine diagnosis of the vast JAK2 fusion, can give rise to neoplasms monoclonal B-cell lymphocytosis, in situ
majority of haematological malignancies, of either myeloid or lymphoid lineage as­ follicular and mantle cell neoplasia, paedi­
both to determine lineage in malignant pro­ sociated with eosinophilia; these disor­ atric follicular hyperplasia with monoclonal
cesses and to distinguish between benign ders are recognized as a separate group. B cells, and more recently, mutations in
and malignant processes. Many diseases Precursor neoplasms (i.e. acute myeloid haematopoietic cells in older individuals,
have an immunophenotype so characteris­ leukaemias, lymphoblastic leukaemias/ without evidence of a haematological ma­
tic that it is essential (or nearly essential) for lymphomas, acute leukaemias of ambigu­ lignancy-so-called clonal haematopoiesis
the diagnosis; for other diseases, the im­ ous lineage, and blastic plasmacytoid of indeterminate potential {3772}). It is not
munophenotype plays a smaller diagnostic dendritic cel! neoplasm) are discussed always clear whether these clonal prolif­
role. For some lymphoid and many myeloid separately from more-mature neoplasms erations constitute early involvement by
neoplasms, a specific genetic abnormality (i.e. myeloproliferative neoplasms, masto­ a neoplasm, a precursor lesion, or an in­
is the key defining criterion, whereas other cytosis, myelodysplastic/myeloproliferative consequential finding. These situations are
neoplasms lack known specific genetic neoplasms, myelodysplastic syndromes, somewhat analogous to the identification
abnormalities. Some genetic abnormalities mature [peripheral] B-cell and T/NK-cell of small monoclonal immunoglobulin com­
are characteristic of a given disease or dis­ neoplasms, Hodgkin lymphomas, and his­ ponents in serum (i.e. monoclonal gam-
ease group but are not specific, such as tiocytic and dendritic cell neoplasms). The mopathy of undetermined significance).
MYC, CCND1, and BCL2 rearrangements mature myeloid neoplasms are classified The chapters on these neoplasms include
and JAK2 mutations; others are prognos­ according to their biological features (i.e. updated recommendations for dealing with
tic factors for several diseases, such as myeloproliferative neoplasms with effec­ these situations. The recommendations of
TP53 mutations and FLT3 internal tandem tive haematopoiesis vs myelodysplastic international consensus groups have also
duplication (FL73-ITD). The use of immu- neoplasms with ineffective haematopoie­ been updated, with regard to criteria for
nophenotypic features and genetic abnor­ sis), as well as by their genetic features. the diagnosis of chronic lymphocytic leu­
malities to define entities not only provides Within the category of mature lymphoid ne­ kaemia and plasma cell myeloma.
objective criteria for diagnosis, but has oplasms, the diseases are generally listed Any classification of diseases must be
also enabled the identification of antigens, according to their clinical presentation (i.e. periodically reviewed and updated to in­
genes, and pathways that can be targeted disseminated often leukaemic, extranodal, corporate new information. The Society for
for therapy. The success of the anti-CD20 indolent, or aggressive), and to some ex­ Hematopathology and the European Asso­
monoclonal antibody rituximab for the tent according to the stage of differentia­ ciation for Haematopathology now have a
treatment of B-cell neoplasms and the suc­ tion when this can be postulated. However, record of nearly two decades of collabora­
cess of the tyrosine kinase inhibitor imatinib the order in which the diseases are listed tion and cooperation in this effort. The soci­
for the treatment of leukaemias associated is in part arbitrary, and is not an integral eties are committed to updating and revis­
with rearrangements in ABL1 and other ty­ aspect of the classification. ing the classification as needed, with input
rosine kinase genes are testament to this This revised 4th edition of the WHO clas­ from clinicians and in collaboration with
approach. Finally, the diagnosis of some sification incorporates new information the International Agency for Research on
diseases requires knowledge of clinical that has emerged since the publication of Cancer (IARC) and WHO. The process of
features such as patient age, nodal versus the original 4th edition. It includes some developing and updating the WHO classi­
extranodal presentation, specific anatomi­ changes in terminology related to our im­ fication has generated a new and exciting
cal site, and history of cytotoxic and other proved understanding of certain disease degree of cooperation and communication
therapies. Most of the diseases described entities and presents revised defining among pathologists and oncologists from
in the WFIO classification are considered to criteria for some neoplasms. In addition, around the world, which will facilitate our
be distinct entities; however, some are not a number of previously provisional enti­ continued progress in the understanding
as clearly defined, and these are listed as ties have now been accepted as definite and treatment of haematological malig­
provisional entities. In addition, borderline entities, and new provisional entities have nancies. The multiparameter classifica­
categories have been created for cases been added ― some defined by genetic tion approach that has been adopted by
that do not clearly fit into a single category, criteria (particularly among the myeloid the WHO classification, with its emphasis
so that well-defined categories can be kept neoplasms) and others by a combination on defining real disease entities, has been
homogeneous and borderline cases can of morphology, immunophenotype, and shown in international studies to be repro­
be studied further. clinical features. The frequent application ducible; the diseases defined are clinically
The WHO classification classifies neo­ of immunophenotyping and genetic stud­ distinctive, and the uniform definitions and
plasms primarily according to lineage ― ies using peripheral blood, bone marrow, terminology used facilitate the interpreta­
myeloid, lymphoid, or histiocytic/dendrit- and lymph node samples has led to the tion of clinical and translational studies {1,
ic ― and a normal counterpart is postulated detection of small clonal populations in 148}. In addition, the accurate and precise
for each neoplasm. Although the goal is asymptomatic individuals. These clonal classification of disease entities has facili­
to define the lineage of each neoplasm, populations include small clones of cells tated the discovery of the genetic basis of
lineage plasticity can occur in precur­ with the BCR-ABL1 translocation seen in myeloid and lymphoid neoplasms in the
sor or immature neoplasms, and has also chronic myeloid leukaemia, small clones basic science laboratory.

14 Introduction to the WHO classification of tumours of haematopoietic and lymphoid tissues

CHAPTER

Introduction and
overview of the
classification of the
Myeloid neoplasms
Introduction and overview of the Arber D.A.
Orazi A.
Tefferi A.
Levine R.
classification of myeloid neoplasms Hasserjian R.P.
Brunning R.D.
Bloomfield C.D.
Cazzola M.
Le Beau M.M. Thiele J.
Porwit A.

The 2001 WHO Classification of Tumours: current revision explicitly acknowledges decision-making and that also provides a
Pathology and Genetics of Tumours of that recurrent genetic abnormalities not flexible framework for integration of new
Haematopoietic and Lymphoid Tissues only provide objective criteria for rec­ data.
(3rd edition) reflected a paradigm shift in ognition of specific entities but are also
the approach to the classification of my­ vital for the identification of abnormal
eloid neoplasms {1820}. For the first time, gene products and pathways that are Prerequisites for the
genetic information was incorporated into potential therapeutic targets. Several classification of myeloid
diagnostic algorithms provided for the disease subgroups and sets of defining
various entities. The publication was pref­ criteria have been expanded to include
neoplasms by WHO criteria
aced with a comment predicting future not only neoplasms associated with chro­ The WHO classification of myeloid neo­
revisions necessitated by rapidly emerg­ mosomal abnormalities recognizable by plasms relies on the morphological, cy-
ing genetic information relevant to the di­ conventional karyotyping, but also those tochemical, and immunophenotypic fea­
agnosis and classification of myeloid ma­ with gene mutations with or without a cy­ tures of the neoplastic cells to establish
lignancies. The 4th edition (published in togenetic correlate. However, the impor­ their lineage and degree of maturation,
2008) and the current 4th edition revision tance of careful clinical, morphological, and to determine whether the cellular
reflect the significant new molecular in­ and immunophenotypic characterization appearance is cytologically normal, dys-
sights that have become available since of every myeloid neoplasm, and correla­ plastic, or otherwise morphologically ab­
the publication of the 2001 edition. tion with the genetic findings, cannot be normal. The classification is based on cri­
The first entity described in this volume, overemphasized. The discoveries of acti­ teria applied strictly to initial specimens
chronic myeloid leukaemia, remains the vating JAK2 mutations and mutations in obtained prior to any therapy. Blast per­
prototype for the identification and clas­ CALR and MPL have revolutionized the centages in the peripheral blood, bone
sification of myeloid neoplasms. This leu­ diagnostic approach to myeloprolifera­ marrow, and other involved tissues re­
kaemia is recognized by its clinical and tive neoplasms (MPNs) {299,1831,2014, main of practical importance for catego­
morphological features, and its natural 2037,2099,2290,2823}. However, these rizing myeloid neoplasms and determin­
progression is characterized by an in­ mutations are not specific for any single ing their progression. Cytogenetic and
crease in blasts of myeloid, lymphoid, or clinical or morphological MPN pheno­ molecular genetic studies are required at
mixed myeloid-lymphoid immunophe- type, and some are also reported in cer­ the time of diagnosis not only for recogni­
notype. It is always associated with the tain cases of myelodysplastic syndromes tion of specific genetically defined enti­
BCR―ABL1 fusion gene, which results in (MDSs), myelodysplastic/myeloprolifera- ties, but also for establishing a baseline
the production of an abnormal protein ty­ tive neoplasms (MDS/MPNs), and acute against which follow-up studies can be
rosine kinase with enhanced enzymatic myeloid leukaemia (AML). Therefore, an interpreted to assess disease progres­
activity. This oncoprotein is sufficient to integrated, multimodality approach is sion. Given the integrated, multimodality
cause the disease and is also a target for necessary for the classification of all my­ approach required for diagnosing and
protein tyrosine kinase inhibitor therapy, eloid neoplasms. It is also critical to eluci­ classifying these neoplasms, it is recom­
which has prolonged the lives of thou­ date how molecular testing can be used mended that the various diagnostic stud­
sands of patients with this previously fatal to inform the diagnosis and treatment of ies be correlated with the clinical findings
illness {1040}. This successful integration myeloid malignancies, and to articulate and communicated in a single integrated
of clinical, morphological, and genetic in­ how these tests should be incorporated report. If a definitive classification cannot
formation embodies the goal of the WHO into clinical practice, on the basis of cur­ be determined, the report should indicate
classification scheme. rent and evolving scientific evidence. why and provide guidance for additional
In this revision, the combination of clini­ With so much yet to be learned, there studies that may clarify the diagnosis.
cal, morphological, immunophenotypic, may be some missteps as traditional For the purpose of achieving consist­
and genetic features continues to be approaches to categorization are fused ency, the following guidelines are recom­
used in an attempt to define disease enti­ with more molecularly oriented classifi­ mended for the evaluation of specimens
ties, such as chronic myeloid leukaemia, cation schemes. But the authors, senior when a myeloid neoplasm is suspected.
that are biologically homogeneous and advisors and editors of this revision of In this context, a standardized approach
clinically relevant ― the same approach the WHO classification, as well as the to the processing, documentation, and
used in the 3rd and 4th editions of the clinicians who served as members of reporting of bone marrow findings is
classification. The previous classifica­ its clinical advisory committees, have emphasized {2253}. It is assumed that
tion schemes opened the door to includ­ worked diligently to develop an updated, the evaluation will be performed with full
ing genetic abnormalities as criteria for evidence-based classification that can knowledge of the clinical history and per­
classifying myeloid neoplasms, and the be used in daily practice for therapeutic tinent laboratory data.

16 Introduction and overview of the classification of myeloid neoplasms

Morphology ommended that 500 nucleated bone mar­
row cells be counted on cellular aspirate
Peripheral blood smears in an area as close to the particle
A peripheral blood smear should be and as undiluted with blood as possible.
examined and correlated with the results Counting from multiple smears may reduce
of a complete blood count. Freshly made sampling error due to irregular distribution
smears should be stained with May-Grun- of cells. The cells to be counted include
wald-Giemsa or Wright-Giemsa stain and blasts and promonocytes (as defined be­
examined for white blood cell, red blood low), promyelocytes, myelocytes, meta­
Fig. 1.02 Bone marrow trephine biopsies of suspected
cell, and platelet abnormalities. It is im­ myelocytes, band neutrophils, segmented
myeloid neoplasms should be ≥ 1.5 cm in length and
portant to ensure that smears are well neutrophils, eosinophils, basophils, mono­ obtained at right angles to the cortical bone.
stained. Evaluation of neutrophil granular­ cytes, lymphocytes, plasma cells, eryth-
ity is important when a myeloid disorder is roid precursors, and mast cells. Megakary­
suspected; the designation of neutrophils ocytes (including dysplastic forms) should row biopsy sections for the diagnosis of
as abnormal on the basis of hypogranular not be counted. If a concomitant non-mye- myeloid neoplasms cannot be overstated.
cytoplasm alone should not be considered loid neoplasm (e.g. plasma cell myeloma) The bone marrow biopsy provides infor­
unless the stain is well controlled. Manual is present, it is reasonable to exclude those mation regarding overall (age-matched)
200-cell leukocyte differential counts are neoplastic cells from the count for the pur­ cellularity, histotopography, and the pro­
recommended as part of the peripheral pose of classifying the myeloid neoplasm. portion and maturation of haematopoietic
blood smear evaluation in patients with a If an aspirate cannot be obtained due to cells and also enables evaluation of bone
myeloid neoplasm when the white blood fibrosis or cellular packing, touch prepara­ marrow stroma and cancellous bone
cell count permits. The presence of abnor­ tions of the biopsy may yield valuable cy- structure. The biopsy also provides mate­
mal erythrocytes (e.g. tear-drop cells) as tological information, but differential counts rial for immunohistochemical studies that
well as platelet size and granularity should from touch preparations may not be repre­ may be of diagnostic and prognostic im­
also be taken into account. sentative. When performing touch prepara­ portance. A biopsy is essential whenever
tions, care must be taken to avoid crush there is myelofibrosis, and the classifica­
Bone marrow aspiration artefact or damage to the core biopsy. The tion of some entities, in particular MPNs,
Aspirate smears should be stained with differential counts obtained from marrow relies heavily on histology sections. The
May-Grunwald-Giemsa or Wright-Giemsa aspirates should be compared with an esti­ specimen must be adequate, be taken at
stain for optimal visualization of cytoplas­ mate of the proportions of cells observed in a right angle from the cortical bone, and
mic granules and nuclear chromatin. Be­ available corresponding biopsy sections. be ≥ 1.5 cm in length (to enable evalua­
cause the WHO classification relies on tion of ≥ 10 partially preserved intertra-
percentages of blasts and other specific Bone marrow trephine biopsy becular areas {2253}. It should be well
cells to categorize some entities, it is rec­ The importance of adequate bone mar­ fixed, thinly sectioned (at 3–4 pm), and
stained with H&E and/or a stain such as
Giemsa that allows for detailed morpho­
logical evaluation. A silver impregnation
method (including reticulin and collagen
assessment) is recommended for evalu­
ation for marrow fibrosis, which should be
graded according to the European con­
sensus scoring system {2148,3975}. Pe­
riodic acid-Schiff (PAS) staining may fa­
cilitate the detection of megakaryocytes.
Immunohistochemical study of the biop­
sy (discussed below) can be very useful
in the evaluation of myeloid neoplasms.

Blasts
The percentage of myeloid blasts is very
important for the diagnosis and classi­
fication of myeloid neoplasms. In the
peripheral blood, the blast percentage
should be determined from a 200-cell
leukocyte differential count and in the
bone marrow, from a 500-cell count using
cellular bone marrow aspirate smears as
described above. The blast percentage
Fig. 1.01 Myelodysplastic syndrome. Bone marrow biopsies should be well fixed, and thin (3―4 pm) sections should determined from the bone marrow aspi­
be stained with H&E and/or Giemsa stain to enable optimal evaluation of histological details. rate should correlate with an estimate of

Prerequisites for the classification of myeloid neoplasms by WHO criteria 17

the blast percentage in the trephine biop­ myelomonocytic leukaemia. Distinguish­
sy Immunohistochemical staining of the ing between monoblasts and promono­
bone marrow biopsy for CD34+ blasts is cytes is often difficult, but because both
often helpful in correlating aspirate and cell types are regarded as monoblasts
trephine biopsy findings (particularly fo­ for the purpose of rendering a diagno­
cal clusters or sheets of blasts), although sis of AML. the distinction between a
in some myeloid neoplasms the blasts do monoblast and a promonocyte is not
not express CD34. Flow cytometry deter­ always critical. Distinguishing promono­
mination of blast percentage should not cytes from more mature but abnormal
be used as a substitute for visual count­ leukaemic monocytes can also be dif­
ing of blasts: flow cytometry samples are ficult, but is critical, because the desig­
often haemodilute. and they can be af­ nation of a case as acute monocytic or
fected by a number of preanalytic vari­ acute myelomonocytic leukaemia versus
ables: in addition, as noted above, not all chronic myelomonocytic leukaemia of­
blasts express CD34. ten hinges on this distinction. Abnormal
Myeloblasts, monoblasts, and megakar- monocytes have more clumped chroma­
yoblasts are included in the blast count. tin than promonocytes, variably indented
Myeloblasts range from slightly larger folded nuclei, and grey cytoplasm with
than mature lymphocytes to the size of more abundant lilac-coloured granules.
monocytes or larger, with scant to abun­ Nucleoli are usually absent or indistinct
dant dark-blue to bluish-grey cytoplasm. Abnormal monocytes are not considered
The nuclei are round to oval, with finely to be monoblast equivalents.
granular chromatin and usually several Megakaryoblasts are usually small to
nucleoli: in some, nuclear irregularities medium-sized, with a round, indented, or Fig. 1.04 Monoblasts, promonocytes, and abnormal
are prominent. The cytoplasm may con­ irregular nucleus with fine reticular chro­ monocytes from a case of acute monocytic leukaemia.
matin and 1―3 nucleoli The cytoplasm Top: The monoblasts are large, with abundant cyto­
tain a few azurophilic granules.
plasm that may contain a few vacuoles or fine granules
Monoblasts are large cells with abundant is basophilic, is usually agranular, and
and have round nuclei with lacy chromatin and one or
cytoplasm that can be light grey to deep may show cytoplasmic blebs (see Acute more variably prominent nucleoli. Middle: Promono­
blue and may show pseudopod forma­ megakaryoblastic leukaemia, p. 162). cytes have more irregular and delicately folded nuclei,
tion. Their nuclei are usually round, with Small dysplastic megakaryocytes and with fine chromatin, small indistinct nucleoli, and finely
delicate, lacy chromatin and one or more micromegakaryocytes are not blasts. granulated cytoplasm. Bottom: Abnormal monocytes
large, prominent nucleoli. They are usu­ In acute promyelocytic leukaemia, the appear immature, but have more condensed nuclear
chromatin, convoluted or folded nuclei, and more
ally strongly positive for non-specific blast equivalent is the abnormal pro­
cytoplasmic granulation.
esterase (NSE), but have no or only myelocyte. Early erythroid precursors
weak myeloperoxidase (MPO) activity. (proerythroblasts) are not included in the
Promonocytes have a delicately convo­ blast count, except in the rare setting of be performed on histological sections of
luted. folded, or grooved nucleus with pure erythroid leukaemia. bone marrow or other tissues. Detection
finely dispersed chromatin; a small, in­ of MPO indicates myeloid differentiation
distinct. or absent nucleolus; and finely Cytochemistry and other special stains but its absence does not exclude a my­
granulated cytoplasm. Most promono­ Cytochemical studies are useful in deter­ eloid lineage, because early myeloblasts
cytes express NSE and have MPO activ­ mining the lineage of blasts, although in as well as monoblasts can lack MPO
ity. Promonocytes are considered to be some laboratories they have been sup­ The MPO activity in myeloblasts is usu­
monoblast equivalents when the requi­ planted by immunological studies using ally granular and is often concentrated
site percentage of blasts is tallied for the flow cytometry and/or immunohistochem- in the Golgi region, whereas monoblasts
diagnosis of acute monoblastic. acute istry. Cytochemical studies are usually (although usually MPO-negative) may
monocytic, or acute myelomonocytic performed on peripheral blood and bone show fine, scattered MPO-positive gran­
leukaemia and in subclassifying chronic marrow aspirate smears, but some can ules, a pattern that becomes more pro­
nounced in promonocytes. Erythroid
blasts, megakaryoblasts, and lympho­
blasts are also MPO-negative. Sudan
Black B staining parallels MPO staining
but is less specific. In the occasional cas­
es of lymphoblastic leukaemia that ex­
hibit Sudan Black B positivity, light-grey
granules are seen rather than the black
granules that characterize myeloblasts
The NSEs (alpha-naphthyl butyrate es­
terase and alpha-naphthyl acetate es­
terase) show diffuse cytoplasmic activity
Fig. 1.03 Acute myeloid leukaemia. A Agranular myeloblasts. B Granulated myeloblasts. in monoblasts and monocytes. Lympho-

18 Introduction and overview of the classification of myeloid neoplasms

Fig. 1.05 Antigen expression at various stages of normal myeloid differentiation

blasts may have focal punctate activity marily stains cells of the neutrophil line­ calcified) as well as on peripheral blood
with NSEs. but neutrophils are usually age and mast cells, enables identification or bone marrow aspirate smears. In pure
negative. Megakaryoblasts and erythroid of monocytes and immature and mature erythroid leucaemia, periodic acid-Schiff
blasts may have some multifocal, punc­ neutrophils simultaneously. Some cells, (PAS) staining may be helpful because
tate alpha-naphthyl acetate positivity, but particularly in myelomonocytic leukae­ the cytoplasm of the leukaemic pro­
the reactivity is partially resistant to sodi­ mias. may exhibit simultaneous activity erythroblasts may show large globu es of
um fluoride inhibition, whereas monocyte with NSEs and CAE. Although normal eo­ PAS positivity. Well-controlled iron stains
reactivity is totally inhibited by sodium sinophils lack CAE. it may be expressed should always be performed on the bone
fluoride. The combined use of an NSE by neoplastic eosinophils. CAE staining marrow aspirate to detect iron stores, nor­
and the specific esterase naphthol AS-D can be performed on tissue sections mal sideroblasts. and ring sideroblasts;
chloroacetate esterase (CAE), which pri­ (providing the sections are not acid de­ ring sideroblasts are defined as erythroid

Prerequisites for the classification of myeloid neoplasms by WHO criteria 19

precursors with ≥ 5 granules of iron, en­ phase. Among the AMLs with recurrent Genetics
circling one third or more of the nucleus genetic abnormalities, several have char­ The WHO classification includes a num­
acteristic phenotypes. These patterns, ber of entities defined in part by specific
Immunophenotype described in the respective sections, can genetic abnormalities, including gene
Immunophenotypic analysis by either facilitate the planning of molecular cy­ rearrangements due to chromosomal
multiparameter flow cytometry or im- togenetic (FISH) and molecular genetic translocations, deletions, and specific
munohistochemistry is an essential tool investigations for individual patients. The gene mutations; therefore, the determina­
in the characterization of myeloid neo­ immunophenotypic features of the other tion of genetic features of the neoplastic
plasms. Differentiation antigens that ap­ AML categories are extremely hetero­ cells is of critical importance for a com­
pear at various stages of haematopoi­ geneous. probably due to high genetic prehensive clinicopathological evalua­
etic development and in corresponding diversity. It has been suggested that the tion. A complete cytogenetic analysis
myeloid neoplasms are illustrated in expression of certain antigens (e.g. CD7. of bone marrow by conventional karyo­
Fig 1 05, and a thorough description of CD9. CD11b. CD14, CD56, and CD34) typing should be performed at the time
the lineage assignment criteria is provid­ could be associated with an adverse of initial evaluation to establish the cy­
ed in the sections on mixed-phenotype prognosis in AML, but their independ­ togenetic profile and at regular intervals
acute leukaemia (See Acute leukaemias ent prognostic value is still controversial, thereafter to detect evidence of genetic
of ambiguous lineage, p. 179). The tech­ and cytogenetic and molecular genetic evolution. Additional diagnostic genetic
niques used and the antigens analysed abnormalities are generally more reliable studies should be guided by the diag-
vary according to the myeloid neoplasm prognostic markers than is immunophe­ noss suspected on the basis of clinical,
suspected and the information required notype. With 8- or 10-colour flow cytom­ morphological, and immunophenotypic
to best characterize it. as well as by the etry, aberrant or unusual immunopheno- studies. In cases with variants of typi­
tissue available Immunophenotyping is types have been found in as many as cal cytogenetic abnormalities and cases
often important in the diagnosis of any 90% of cases of AML; these aberrancies in which the abnormality is cryptic (e.g.
haematological neoplasm; in myeloid include cross-lineage antigen expres­ the FIP1L1-PDGFRA fusion in myeloid
neoplasms, it is most commonly required sion. maturational asynchronous expres­ neoplasms associated with eosinophilia).
to identify mixed-phenotype acute leu­ sion of antigens, antigen overexpression, RT-PCR and/or FISH may detect gene re­
kaemia. to distinguish between AML with and the reduction or absence of antigen arrangements that are not apparent in the
minimal differentiation and lymphoblastic expression. Similar aberrancies have initial chromosomal analysis. Depending
leukaemia, to detect monocytic differ­ been reported in MDS, and their pres­ on the abnormality, quantitative PCR and/
entiation in AML, and in determining the ence can be used to support the diag­ or RT-PCR performed at the time of diag­
phenotype of blasts at the time of trans­ nosis in early or morphologically difficult nosis may also provide a baseline against
formation of chronic myeloid leukaemia. cases; however, aberrant flow cytom­ which the response to therapy can be
MDS. MDS/MPN. and MPN. etry immunophenotypes should not be monitored. In addition, the use of array-
Multiparameter flow cytometry is the used to diagnose MDS in the absence of based and next-generation sequencing
preferred method of immunophenotypic standard diagnostic criteria. technologies enables the sensitive and
analysis in AML due to the ability to ana­ Immunophenotyping by im mu nohisto­ accurate detection of many common
lyse large numbers of cells in a relatively chemistry on bone marrow biopsy sec­ gene rearrangements and has emerged
short period of time with simultaneous re­ tions can be performed, provided that as an alternative to RT-PCR and FISH for
cording of information about several an­ appropriate methods for fixation and the detection of pathogenic fusion genes
tigens for each individual cell. Extensive decalcification have been applied. Anti­ in haematological malignancies.
panels of monoclonal antibodies directed bodies reactive with paraffin-embedded A rapidly increasing number of somatic
against leukocyte differentiation antigens bone marrow biopsy tissue are available gene mutations detected by gene se­
are usually applied, due to the limited for many lineage-associated markers quencing. allele-specific PCR, and other
utility of individual markers in identify­ (e.g. MPO. KIT [CD117], CD33, CD68R. techniques have emerged as important
ing the commitment of leukaemic cells CD14, lysozyme, glycophorin A and C. diagnostic and prognostic markers for
to the various haematopoietic lineages. CD71, CD61. CD42b, CD19. CD3. PAX5. all categories of myeloid neoplasms
Evaluation of the expression patterns of CD79a, and tryptase) As noted previ­ Mutations in JAK2, MPL, CALR. NRAS
several antigens, both membrane and ously. CD34 staining of the biopsy can fa­ NF1, PTPN11, ASXL1, and KIT in MPN
cytoplasmic, is necessary for determin­ cilitate the detection of blasts and enable and MDS/MPN; TP53, SF3B1, ASXL1
ing lineage, identifying mixed-phenotype assessment of their distribution (provided RUNX1, EZH2, and ETV6 (among oth­
acute leukaemia, and detecting aberrant the blasts express CD34) {2989}. For cas­ ers) in MDS; and NPM1, CEBPA, FLT3.
phenotypes that will facilitate the evalu­ es rich in megaloblastoid erythroblasts. RUNX1, IDH1, IDH2, ASXL1, and KIT
ation of follow-up specimens for minimal immunohistochemistry for glycophorin, (among others) in AML are important for
residual disease. CD71, E-cadherin, or haemoglobin may diagnosis and prognosis. In particular
Immunophenotypic analysis has a central be helpful in distinguishing those cells JAK2, MPL, CALR, CSF3R, SF3B1, FLT3.
role in distinguishing between AML with from myeloblasts in MDS with excess NPM1, RUNX1, and CEBPA figure promi­
minimal differentiation and lymphoblas­ blasts or pure erythroid leukaemia, and nently in this revised classification. In
tic leukaemia, and in chronic myeloid CD61 or CD42b staining oflen facilitates addition, many recently characterized
leukaemia in distinguishing the myeloid the identification of abnormal megakaryo­ somatic disease alleles (e.g. recurrent
blast phase from the lymphoid blast cytes and megakaryoblasts. mutations in TET2, ASXL1, and DNMT3A)

20 Introduction and overview of the classification of myeloid neoplasms

can serve as definitive markers of clonal cal to establish methods for identifying set of genes tailored to a specific disease
haematopoiesis, which can be used as alleles with diagnostic, prognostic, and and/or clinical scenario, as well as panel-
an adjunct to the diagnosis of myeloid therapeutic relevance, and to use best based assays that query all genes im­
malignancies, despite the fact that these practices (including informational anno­ plicated in the pathogenesis of myeloid
alleles are neither specific for a particu­ tation and paired sequencing of tumour malignancies, or even more broadly, of
lar disease nor sufficient to diagnose a and normal material when possible) to all haematological malignancies. Both
myeloid neoplasm. These mutations and ascertain which alleles are present as ac­ approaches have clinical value in the
others seen in myeloid malignancies can quired mutations and which are present current context, but we expect the use of
also be observed in healthy individuals in the germline. In particular, given the panel-based assays and whole-genome/
with clonal haematopoiesis, which ap­ likelihood of tumour-derived contamina­ exome sequencing to increase as the
pears to constitute a premalignant, clonal tion of paired normal material collected cost and throughput of clinical genomic
state with a variable risk of progression at diagnosis and the frequent presence profiling continue to improve.
to overt, clinical disease, and has impor­ of antecedent, premalignant clonal hae­ Gene over- and underexpression, as
tant implications for interpreting genetic matopoiesis at the time of clinical remis­ well as loss of heterozygosity (LOH) and
profiling in the context of clinical, labora­ sion, the choice and timing of collection copy number variants detected by array-
tory, and pathological evaluation to make of non-haematopoietic reference DNA based approaches, are only now being
a specific diagnosis. are of critical importance for best-prac­ recognized as important abnormalities,
Next-generation sequencing continues tice genomic profiling. The current ap­ and may influence diagnostic and prog­
to emerge as a standard technology for proaches to genomic profiling include nostic models in the near future {2770}. It
mutational profiling; it is therefore criti­ focused, gene-specific tests for a small will be critical to develop gene-specific
and panel-based assays to query for dif­
ferential expression of specific biomark­
ers and to assess for copy number and
zygosity alterations at specific loci with
diagnostic, prognostic, and therapeutic
relevance.

Revised WHO classification of

myeloid neoplasms
Myeloproliferative neoplasms
The major subgroups of MPNs are
listed in the WHO classification table
at the beginning of this volume (p. 10).
Note that the name of the entity previ­
ously called ‘chronic myelogenous leu­
kaemia, BCR-ABL1 positive’ has been
changed to ‘chronic myeloid leukaemia,
BCR-ABL1-positive’.
The MPNs are clonal haematopoietic
stem cell disorders characterized by the
proliferation of cells of one or more of the
myeloid lineages (i.e. granulocytic, eryth-
roid, and megakaryocytic). They primari­
ly occur in adults, with incidence peaking
in the fifth to seventh decades of life, but
some subtypes are also reported in chil­
dren. The annual incidence of all subtypes
combined is 6 cases per 100 000 popula­
tion {1375,1864,2764,4010}.
Fig. 1.06 Mechanism of activation of JAK2 kinase activity by mutations in the JAK2 signalling pathway. A Cytokine Most MPNs are initially characterized by
ligands normally bind cytokine receptors, which results in JAK2 phosphorylation, recruitment of STAT signalling varying degrees of age-matched hyper-
proteins, and phosphorylation and activation of downstream signalling pathway components such as STAT cellularity of the bone marrow, with ef­
transcription factors, MAPK (ERK) signalling proteins, and the PI3K-AKT pathway. B The V617F-mutant and exon fective haematopoietic maturation and
12-mutant JAK2 kinases bind cytokine receptors and are phosphorylated in the absence of ligand, leading to ligand- increased numbers of granulocytes, red
independent activation of downstream signalling pathways. C In contrast, MPL W515L/K-mutant thrombopoietin
blood cells, and/or platelets in the pe­
receptors can phosphorylate wildtype JAK2 in the absence of thrombopoietin, resulting in the activation of signalling
pathways downstream of JAK2; negative regulation of JAK2 signalling is normally mediated by suppressor of cytokine ripheral blood. Splenomegaly and he­
signalling proteins, most notably SOCS1 and S0CS3; recent data indicate that the JAK2 V617F allele might escape patomegaly, caused by sequestration of
negative feedback by SOCS3. Reproduced from Levine RL et al. {2289}. excess blood cells and/or proliferation

Revised WHO classification of myeloid neoplasms 21

of abnormal haematopoietic progenitor ent on study design; for example, inclu­ pathways to promote transformation
cells, are common. Despite an insidi­ sion of all subtypes of MPN as opposed and proliferation of haematopoietic pro­
ous onset, each MPN has the potential to restriction to ET vs pre-PMF, inclusion genitors. The JAK2 V617F mutation is
to undergo a stepwise progression that of control cases with reactive changes, found in almost all patients with PV and
terminates in marrow failure due to mye­ and blinded morphological evaluation vs in nearly half of those with PMF and ET.
lofibrosis, ineffective haematopoiesis, or evaluation together with clinical data as In the few patients with PV who lack the
transformation to an acute blast phase. recommended by the WHO diagnostic JAK2 V617F mutation, activating JAK2
Evidence of genetic evolution usually guidelines {257,1361,1379,2433}. In this exon 12 mutations may be found; these
heralds disease progression, as may context, the learning effects of a work­ can be missense or insertion/deletion
increasing organomegaly, increasing or shop exercise including interobserver mutations that are not always detectable
decreasing blood counts, myelofibrosis, consensus among six haematopatholo- by standard JAK2 mutation assays. In a
and the onset of myelodysplasia. The gists included an increase in consensus small proportion of cases of PMF and ET,
finding of 10-19% blasts in the peripheral from 49% to 72% and an agreement rate an activating MPL W515L or W515K mu­
blood or bone marrow generally signifies of 83% between blinded histological and tation is seen, and somatic mutations in
accelerated disease, and a proportion clinical diagnoses {2434}. A number of CALR are found in most ET and PMF cas­
of ≥ 20% is sufficient for the diagnosis of problems and pitfalls associated with es with wildtype JAK2 and MPL. CALR
blast phase. assessing the fibrous matrix of the bone and MPL mutations are therefore impor­
marrow, including the differentiation be­ tant diagnostic criteria for JAK2-wildtype
Rationale for and problems with diagnosis tween reticulin and collagen fibres and ET and PMF. It is important to note that
and classification of myeloproliferative the grading of osteosclerosis, must be JAK2 V617F is not specific for any MPN,
neoplasms taken into account {2148}. A multicentre nor does its absence exclude MPN. The
The revisions to the 2008 criteria for the study that compared the results of fibre mutation can also be found in some cas­
classification of MPNs have been influ­ grading between local pathologists and es of MDS/MPN and in rare cases of de
enced by three main factors {258}: a panel of experts showed an overall novo AML and MDS, and can occur in
1. The recent discovery of genetic ab­ agreement rate of only 56%, supporting combination with other well-defined ge­
normalities has provided diagnostic and the concept of central pathology review netic abnormalities, such as BCR-ABL1
prognostic markers and novel insights for clinical studies {3228}. {1872}. Therefore, the diagnostic algo­
into the pathobiology of BCR-ABL1-neg­ Most (if not all) MPNs are associated rithms for PV, ET, and PMF have been up­
ative MPNs {3920,3932}. with clonal abnormalities either involv­ dated to take into account the mutational
2. Improved characterization and stand­ ing genes that encode cytoplasmic or status of JAK2, MPL, and CALR, as well
ardization of morphological features aid­ receptor protein tyrosine kinases (result­ as to summarize the additional labora­
ing in histological pattern recognition ing in the constitutive activation of onco­ tory and histological findings required to
and differentiation of disease groups genic signalling pathways) or occurring accurately classify cases, regardless of
has increased the reliability and repro­ in regulators of these pathways (resulting whether a mutation is present.
ducibility of diagnosis {257,1361,1379, in similar biological consequences). The The role that altered protein tyrosine ki­
2433,3977}. abnormalities described to date include nases play in the pathogenesis of chronic
3. A number of clinicopathological stud­ translocations, insertions, deletions, and myeloid leukaemia, PV, ET, and PMF sup­
ies have now validated the WHO postu­ point mutations of genes resulting in ports the inclusion of similar chronic mye­
late of an integrated approach that in­ abnormal, constitutively activated pro­ loid proliferations related to protein tyros­
cludes haematological, morphological, tein tyrosine kinases that activate signal ine kinase abnormalities under the MPN
and molecular genetic findings {251,266, transduction pathways, leading to abnor­ umbrella; however, the molecular patho­
1363,1379,1380,2433,3977}. mal proliferation. In some cases, these genesis of some cases of ET and PMF, a
Reports of controversial aspects have genetic abnormalities (e.g. the BCP- subset of chronic neutrophilic leukaemia
mainly focused on subjectivity and lack ABL1 fusion gene in chronic myeloid cases that lack CSF3P mutation, and a
of interobserver reproducibility regard­ leukaemia) are associated with consist­ number of myeloid neoplasms associ­
ing the morphological criteria, especially ent clinical, laboratory, and morphologi­ ated with eosinophilia remains unknown.
their validity in distinguishing essential cal findings, which enables their use as For these cases, clinical, laboratory, and
thrombocythaemia (ET) from prefibrotic/ major criteria for classification; other ge­ morphological features remain essential
early phases of primary myelofibrosis netic abnormalities provide proof that the for diagnosis and classification.
(pre-PMF) and polycythaemia vera (PV). myeloid proliferation is neoplastic rather
A critical evaluation of these studies sug­ than reactive. Mastocytosis
gests that the failure to use a standard­ Acquired somatic mutations in JAK2, Due to its unique clinical and pathologi­
ized approach to recognizing the dis­ at chromosome band 9p24, have been cal features, mastocytosis (which ranges
tinctive bone marrow features of these shown to play a pivotal role in the patho­ from indolent cutaneous disease to ag­
disorders resulted in incorrect histologi­ genesis of many cases of BCR-ABL1- gressive systemic disease) is no longer
cal pattern recognition {255,257,3977}. negative MPNs {1831,2045,2099,2289, considered a subgroup of the MPNs. It is
However, several studies on large cohorts 2290}. The most common mutation, now a separate disease category in the
of patients have reported consensus JAK2 V617F, results in a constitutively WHO classification.
rates for the correct diagnosis of MPNs of active cytoplasmic JAK2, which acti­
76-88%, which are significantly depend­ vates STAT, MAPK, and PI3K signalling

22 Introduction and overview of the classification of myeloid neoplasms

Myeloid/lymphoid neoplasms with ter chemotherapy should not be placed another myeloid subgroup, they remain in
eosinophilia and gene rearrangement in this category. Rarely, MPNs may pre­ this mixed category, which acknowledg­
This category of the classification re­ sent as accelerated phase in which the es the overlap that may occur between
mains largely unchanged, except for chronic phase was not recognized, and MDS and MPN.
the addition of the provisional entity of may have findings that suggest they In the original version of the 4th edi­
myeloid/lymphoid neoplasms with t(8;9) belong to the MDS/MPN group. In such tion of the WHO classification, refrac­
(p22;p24.1) resulting in PCM1-JAK2 cases, if clinical and laboratory studies tory anaemia with ring sideroblasts as­
{230,3108}. The finding of a rearrange­ fail to reveal the nature of the underlying sociated with marked thrombocytosis
ment of PDGFRA, PDGFRB, or FGFR1, process, the designation ‘MDS/MPN un- was proposed as a provisional entity to
or of PCM1-JAK2 places a case in this classifiable’ may be appropriate. Cases encompass cases with the clinical and
category regardless of the morphologi­ with BCR-ABL1; with rearrangement of morphological features of MDS with ring
cal classification; eosinophilia is absent PDGFRA, PDGFRB, or FGFR1; or with sideroblasts but also with thrombocytosis
in a subset of cases. Myeloid neoplasms PCM1-JAK2 should not be categorized associated with abnormal megakaryo­
with eosinophilia that lack all of these as MDS/MPNs. Mutations in non-kinase cytes similar to those observed in BCR-
abnormalities and that meet the crite­ genes, including in epigenetic regulators ABL1-negative MPNs. More recently,
ria for chronic eosinophilic leukaemia, such as TET2 and ASXL1, are very com­ and in particular after the discovery of a
not otherwise specified (NOS), should mon in MDS/MPNs; they can be used to strong association with SF3B1 and con­
be placed in that MPN subgroup. Other establish clonality, but are neither dia­ current JAK2 V617F, MPL, or CALR mu­
JAK2-rearranged neoplasms, such as gnostic nor specific for this disease sub­ tations, MDS/MPN with ring sideroblasts
those with t(9;12)(p24.1;p13.2), resulting set {1795,2779}. and thrombocytosis, the new term for
in ETV6-JAK2, and t(9;22)(p24.1;q11.2), the former refractory anaemia with ring
resulting in BCR-JAK2, may have similar Rationale for diagnosis and classification sideroblasts associated with marked
features, but are uncommon and are not of myelodysplastic/myeloproliferative thrombocytosis category, has become
included as formal entities in this clas­ neoplasms a distinct, well-characterized MDS/MPN
sification. Many cases with BCR-JAK2 A diagnosis of chronic myelomono- overlap entity {2460,2461,3102}.
present primarily as B-lymphoblastic leu­ cytic leukaemia (CMML) requires both The classification of myeloid neoplasms
kaemia, and these are best classified as the presence of persistent periph­ that carry an isolated isochromosome
B-lymphoblastic leukaemia/lymphoma, eral blood monocytosis (monocyte of 17q and that have < 20% blasts in the
BCR-ABL1-like (a new provisional cat­ count ≥ 1 x 109/L) and monocytes ac­ peripheral blood and bone marrow has
egory of B-lymphoblastic leukaemia/lym­ counting for ≥ 10% of white blood cells proven difficult {1913}. Some authors
phoma) {230}. on the differential count. As a result of the suggest that this cytogenetic defect de­
discovery of molecular and clinical differ­ fines a unique disorder characterized
Myelodysplastic/myeloproliferative ences between the so-called proliferative by mixed MDS and MPN features asso­
neoplasms type (white blood cell count ≥ 13 x 109/L) ciated with prominent pseudo-Pelger-
The MDS/MPNs include clonal myeloid and the dysplastic type (white blood cell Huet anomaly of the neutrophils, a low
neoplasms that at the time of initial pre­ count < 13 x 109/L) {620,3349,3827}, bone marrow blast count, and a rapidly
sentation are associated with some find­ these cases have been separated into progressive clinical course. A proportion
ings that support the diagnosis of an MDS two subtypes, myeiodyspiastic and mye­ of cases are reported to have prominent
and other findings more consistent with loproliferative, in this classification up­ monocytosis that meets the criteria for
an MPN {2987}. These neoplasms are date. Cases of CMML with eosinophilia CMML, but in some, the peripheral blood
usually characterized by hypercellularity associated with PDGFRB rearrangement monocyte count does not reach the
of the bone marrow due to proliferation are excluded, but rare cases of CMML threshold for that diagnosis {1220,2594}.
in one or more of the myeloid lineages. with eosinophilia that do not exhibit such For cases that do not fulfil the criteria
Often, the proliferation is effective in rearrangement are included in this cat­ for CMML or another well-defined mye­
some lineages, with increased numbers egory. The category ‘CMML-0’ has also loid neoplasm category, designation as
of circulating cells that may be morpho­ been added, for cases with low periph­ MDS/MPN, unclassifiable, with isolated
logically and/or functionally dysplastic. eral blood and bone marrow blast cell isochromosome 17q abnormality is most
Simultaneously, one or more of the other counts {2978,3587,3805}. appropriate {1912}.
lineages may exhibit ineffective prolifera­ In juvenile myelomonocytic leukaemia,
tion, so that cytopenia may be present as nearly 80% of cases demonstrate mutu­ Myeiodyspiastic syndromes
well. The blast percentage in the bone ally exclusive mutations of PTPN11, NRAS These neoplasms are characterized by
marrow and blood is always < 20%. Al­ or KRAS, or NF1 {2382,3796,3906}, all the simultaneous proliferation and apop­
though hepatosplenomegaly is common, of which encode components of RAS- tosis of haematopoietic cells that result
the clinical and laboratory findings vary dependent pathways; approximately in a normocellular or hypercellular bone
along a continuum between those usually 30-40% of cases of CMML and atypi­ marrow and peripheral blood cytopenia.
associated with MDSs and those usually cal chronic myeloid leukaemia, BCR- MDSs are among the most diagnostically
associated with MPNs. Cases of well-de­ ABL1-negative, exhibit NRAS mutations challenging of the myeloid neoplasms,
fined MPNs in which dysplasia and inef­ {3053,4152,4329}. Given the lack of any both in terms of their distinction from the
fective haematopoiesis develop as part specific genetic abnormality to suggest numerous other (often non-neoplastic)
of the natural history of the disease or af­ that these entities should be relocated to causes of cytopenia and in terms of the

Revised WHO classification of myeloid neoplasms 23

Table 1.01 Diagnostic approach to myeloid neoplasms in which erythroid precursors constitute ≥ 50% of the nucleated bone marrow (BM) cells
Percentage of BM cells Percentage of BM Prior Defining Meets criteria 4th Edition diagnosis Revised 4th edition
that are erythroid (or PB) cells therapy WHO genetic for AML with myelo­ (2008) diagnosis (2017)
precursors that are myeloblasts abnormality dysplasia-related
present changes

≥ 50% n/a yes n/a n/a Therapy-related Therapy-related

myeloid neoplasm myeloid neoplasm

≥ 50% ≥ 20% no yes n/a AML with recurrent AML with recurrent genetic
genetic abnormality abnormality

≥ 50% ≥ 20% no no yes AML with myelodysplasia- AML with myelodysplasia-

related changes related changes

≥ 50% ≥ 20% no no no AML, NOS; AML, NOS

acute erythroid leukaemia (a non-erythroid subtype)
(erythroid/myeloid subtype)

≥ 50% < 20%, but no no a n/a AML, NOS; MDS b

≥ 20% of acute erythroid leukaemia
non-erythroid cells (erythroid/myeloid subtype)

≥ 50% < 20%, and no no a n/a MDS b MDS b

< 20% of
non-erythroid cells

> 80% immature erythroid < 20% no no a n/a AML, NOS; AML, NOS;
precursors with acute erythroid leukaemia pure erythroid leukaemia
> 30% proerythroblasts (pure erythroid subtype)

AML, acute myeloid leukaemia; BM, bone marrow; MDS, myelodysplastic syndrome; n/a, not applicable; NOS, not otherwise specified; PB, peripheral blood.
a Cases of AML with t(8;21)(q22;q22.1) resulting in the RUNX1-RUNX1T1 fusion protein, AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) resulting in the CBFB-MYH11
fusion protein, or acute promyelocytic leukaemia with the PML-RARA fusion protein may rarely occur in this setting with < 20% blasts, and those diagnoses take
precedence over the diagnosis of either AML, NOS or MDS.
b Classify according to the myeloblast percentage of all BM cells and PB leukocytes, along with other MDS criteria.

proper classification to guide the clini­ fied: single lineage versus multilineage this revision that affects MDS diagnosis
cal approach. The general features of dysplasia, ring sideroblasts, excess is in the diagnostic criteria for myeloid
MDS, as well as specific guidelines for blasts, or the defining del(5q) cytogenet­ neoplasms in which ≥ 50% of the bone
their diagnosis and classification, are ic abnormality. No new disease entities marrow cells are erythroid precursors. In
outlined in Chapter 6, Myeiodyspiastic have been introduced, but the diagnostic the original 4th edition WHO classifica­
syndromes: Overview (p. 98). criteria for some entities have been re­ tion, erythroid/myeloid-type acute eryth­
In this revised WHO classification, new fined, as detailed in Table 6.01 (p. 101) in roid leukaemia (erythroleukaemia) was
terminology has been introduced. In the the Myeiodyspiastic syndromes chapter diagnosed if blasts accounted for ≥ 20%
original 4th edition, MDS disease names and in the sections on each MDS entity. of the non-erythroid cells in the bone
included references to cytopenia or spe­ MDS cases with multilineage dysplasia, marrow; if blasts accounted for < 20%
cific types of cytopenia (e.g. refractory ring sideroblasts, and no excess of blasts of the non-erythroid cells, the case was
anaemia). Although cytopenia is a sine or isolated del(5q) cytogenetic abnormal­ considered to be MDS and subclassified
qua non of any MDS diagnosis, the WHO ity are now categorized as a subgroup of on the basis of the blast count among all
classification relies mainly on the degree MDS with ring sideroblasts rather than nucleated bone marrow cells. Due to the
of dysplasia and blast percentages for being grouped with MDS with multiline­ apparent close biological relationship of
MDS classification; specific cytopenias age dysplasia lacking ring sideroblasts erythroleukaemia to MDS and the poor
have only a minor impact on classifica­ as in the original 4th edition. MDS in chil­ reproducibility and potential lability of
tion. Moreover, the lineage(s) manifesting dren has features that differ from those of non-erythroid blast counts, and in an at­
significant morphological dysplasia often most MDS in adults, and the provisional tempt to achieve consistency in express­
do not correlate with the specific cytope­ entity refractory cytopenia of childhood ing blast percentages across all myeloid
nias seen in individual MDS cases. For remains in this updated classification. neoplasms, non-erythroid blast counting
these reasons, the updated MDS names Although this entity is still provisional, its has been eliminated from the diagnostic
do not refer to cytopenia. All diagnostic morphological features and distinction criteria for all myeloid neoplasms. For
entity names start with ‘myeiodyspiastic from severe aplastic anaemia are now all cases (even those with ≥ 50% bone
syndrome’, with further qualifiers speci­ better defined. An important change in marrow erythroid cells), the bone mar­

24 Introduction and overview of the classification of myeloid neoplasms

 row blast percentage is now expressed there is an associated t(8;21)(q22;q22.1), often characterized by loss of genetic
as a percentage of all nucleated marrow inv(16)(p13.1q22), or t(16;16)(p13.1;q22) material and haploinsufficiency of genes.
cells. This will result in most cases that chromosomal abnormality or PML-RARA Within the past few years, novel genetic
previously would have been classified fusion. Although the line between AML mutations have also been identified in
as erythroleukaemia (i.e. those in which and MDS when other recurrent cytoge­ essentially all types of AML {545,2774},
blasts constitute < 20% of all nucleated netic abnormalities are present is in­ and our approach to and understanding
marrow cells) now being classified as creasingly blurred, such cases continue of gene mutations in AML has evolved
MDS with excess blasts, rather than as to be classified on the basis of peripheral (see Table 1.02, p.26). Some of the mu­
a subtype of AML. The diagnostic ap­ blood and bone marrow blast cell counts. tations, such as those of CEBPA and per­
proach to dealing with myeloid prolifera­ The revised classification also continues haps NPM1, involve transcription factors;
tions with increased numbers of erythroid to place a high proportion of cases into others, including those of FLT3, NRAS,
cells is summarized in Table 1.01. the AML, NOS category, for which the and KRAS, affect signal transduction. An
The prognostic relevance of many so­ prognosis is variable. This is particularly emerging class of mutations in epigenetic
matic mutations in MDS has led to the in­ true in paediatric AML {3503}, but studies regulators, including TET2, IDFH, IDH2,
creasing use of genomic profiling in this seeking additional prognostic markers in ASXL1, DNMT3A, and cohesin complex
clinical context; the optimal integration of all age groups are probably warranted. family members, are seen in nearly half
mutational information into existing MDS Although the diagnosis of AML accord­ of all AML cases. These discoveries
risk-stratification schemes and its impact ing to the above guidelines is operation­ have improved our understanding of the
on clinical management are evolving is­ ally useful by indicating an underlying de­ pathogenesis of AML and suggest that
sues. Specifically, mutations in SF3B1 fect in myeloid maturation, the diagnosis many cases are driven by mutations in
are now considered in the diagnosis of does not necessarily confer a mandate to ≥ 3 distinct biological pathways, which
MDS with ring sideroblasts. treat the patient for AML; clinical factors, act in concert to induce progression from
The revised classification of MDS is including the pace of progression of the normal haematopoietic stem/progeni-
shown in the WHO classification table at disease, must always be taken into con­ tor cells to clonal, preleukaemic stem/
the beginning of this volume (p. 10); the sideration when choosing therapy. progenitor cells, to overtly transformed
rationale for the changes is provided in leukaemic cells. Not only have these
the sections on each MDS entity. Rationale for the diagnosis and mutations informed our understanding
classification of acute myeloid leukaemia of leukaemogenesis in cytogenetically
Acute myeloid leukaemia The 3rd edition of the WHO classification normal AML, they have also proved to be
AML results from the clonal expansion ushered in the era of formal incorporation powerful prognostic factors {2774}. Ge­
of myeloid blasts in the peripheral blood, of genetic abnormalities in the diagnos­ netic abnormalities in AML elucidate the
bone marrow, or other tissue. It is a heter­ tic algorithms for AML. The abnormali­ pathogenesis of the neoplasm, provide
ogeneous disease clinically, morphologi­ ties included were mainly chromosomal the most reliable prognostic information,
cally, and genetically and can involve a translocations involving transcription fac­ and will likely lead to the development
single or all myeloid lineages. Worldwide, tors and associated with characteristic of more-successful targeted therapies.
the annual incidence is approximately clinical, morphological, and immunophe­ Therefore, the use of genomic profiling
2.5―3 cases per 100 000 population notypic features that defined a clinico- is a critical aspect of the evaluation and
per year, and is reportedly highest in pathological and genetic entity. As our risk stratification of AML in the clinical
Australia, western Europe, and the USA. knowledge about leukaemogenesis has context.
The median patient age at diagnosis is increased, so has the acceptance that One of the challenges in this revision
65 years, and there is a slight male pre­ the genetic abnormalities leading to leu­ and in the original 4th edition has been
dominance in most countries. In children kaemia are not only heterogeneous, but how to incorporate important and/or re­
aged < 15 years, AML constitutes 15- also complex; multiple aberrations often cently acquired genetic information into
20% of all cases of acute leukaemia, with contribute in a multistep process to initi­ a classification scheme for AML and yet
peak incidence in the first 3―4 years of ate the complete leukaemia phenotype. adhere to the WHO principle of defining
life {960,4409}. Experimental evidence suggests that in homogeneous, biologically relevant enti­
The requisite blast percentage for a dia­ cases with rearrangements or mutations ties based not only on genetic studies or
gnosis of AML is ≥ 20% myeloblasts, in genes (e.g. RUNX1, CBFB, and RARA) their prognostic value, but also on clini­
monoblasts/promonocytes, and/or mega- that encode transcription factors impli­ cal, morphological, and/or immunophe­
karyoblasts in the peripheral blood or cated in myeloid differentiation, an ad­ notypic studies. This was particularly
bone marrow. The diagnosis of mye­ ditional genetic abnormality is necessary problematic with the most frequent and
loid sarcoma is synonymous with AML to promote proliferation or survival of the prognostically important mutations in
regardless of the number of blasts in the neoplastic clone {1984}. Often, this addi­ cytogenetically normal AML: mutations in
peripheral blood or bone marrow. If there tional abnormality is a mutation of a gene FLT3, NPM1, RUNX1 and CEBPA. Cases
is a prior history of MPN or MDS/MPN, (e.g. FLT3 or KIT) that encodes proteins with these mutations have few or variably
myeloid sarcoma is evidence of acute that activate signal transduction path­ consistent morphological, immunophe­
transformation (blast phase). A dia­ ways to promote proliferation/survival. notypic, and clinical features reported to
gnosis of AML can also be made when A similar multistep process is also evi­ date, and the mutations are not mutually
the blast percentage in the peripheral dent in AML that evolves from MDS or exclusive. For the most part, the frame­
blood and/or bone marrow is < 20% if that has myelodysplasia-related features, work established in the 3rd edition and

Revised WHO classification of myeloid neoplasms 25

Table 1.02 Functional complementation groups of genetic alterations in acute myeloid leukaemia
Period Before 2008 2008-2012 From 2013

Analysis Cytogenetic and molecular Next-generation sequencing The Cancer Genome Atlas (TCGA) project {545}
genetic analysis approaches

Class 1 - Transcription factor fusions

e.g. t(8;21), inv(16), and t(15;17)

Class I
Class 2 - Nucleophosmin 1
Activated signalling
NPM1 mutations
Class I e.g. FLT3, KIT, and RAS
Activated signalling mutations
Class 3 - Tumour suppressor genes
e.g. FLT3, KIT, RAS mutations
e.g. TP53 and PHF6 mutations

Class 4 - DNA methylation—related genes

DNA hydroxymethylation e.g. TET2, IDH1, and IDH2
DNA methyltransferases e.g. DNMT3A
Class II
Functional Transcription and differentiation
groups Class 5 - Activated signalling genes
e.g. t(8;21), inv(16), t(15;17),
CEBPA and RUNX1 mutations e.g. FLT3, KIT, RAS mutations

Class 6 - Chromatin-modifying genes

e.g. ASXL1 and EZH2 mutations, KMT2A fusions, KMT2A-PTD

Class II
Class 7 - Myeloid transcription factor genes
Transcription and differentiation
e.g. CEBPA, RUNX1 mutations
e.g. t(8;21), inv(16), t(15;17),
and CEBPA mutations Epigenetic modifiers
(so-called ‘Class III’) Class 8 - Cohesin complex genes
e.g. TET2, DNMT3A, and ASXL1 e.g. STAG2, RAD21, SMC1, SMC2 mutations
mutations
Class 9 - Spliceosome-complex genes
e.g. SRSF2, U2AF1, ZRSR2 mutations

used in the 4th edition proved flexible studies have shown no difference in de assigned to this category if they evolve
enough to incorporate the new entities novo cases with and without this find­ from previously documented MDS, have
proposed by members of the WHO and ing {211,975,1145}. Lastly, the provisional specific myelodysplasia-related cytoge­
clinical advisory committees. The origi­ category of AML with mutated RUNX1 netic abnormalities, or exhibit morpho­
nal entities described in the subgroup has been added for de novo cases with logical multilineage dysplasia. However,
‘acute myeloid leukaemia with recurrent this mutation that are not associated with these features do not supersede therapy-
genetic abnormalities’ remain (with only MDS-related cytogenetic abnormalities. related disease or the defined cytoge­
minor modifications), and two provisional This provisional category appears to rep­ netic categories of AML. As mentioned
entities have been added. A new provi­ resent a biologically distinct form of AML above, de novo cases with NPM1 or bi­
sional category, AML with BCR-ABL1, {1274,2627,3576,3897}. AML with mu­ allelic CEBPA mutation with no MDS-re­
has been added to recognize these rare tated FLT3 is not included as a separate lated cytogenetic abnormalities, but with
de novo cases {2082,2801,3740}, which entity, because FLT3 mutation occurs multilineage dysplasia, are now classi­
may benefit from tyrosine kinase inhibi­ across multiple AML subtypes; however, fied as either AML with mutated NPM1
tor therapy and must be distinguished the significance of this mutation should or AML with biallelic mutation of CEBPA.
from blast transformation of chronic my­ not be underestimated, and it should be The cytogenetic abnormalities that de­
eloid leukaemia. AMLs with mutated tested for in essentially all cases, includ­ fine MDS-associated disease have also
NPM1 and CEBPA are now full entities, ing those with NPM1 or CEBPA mutation been modified: del(9q), which does not
but a biallelic mutation is required for the or other recurrent genetic abnormali­ appear to have prognostic significance
revised category now known as AML ties. Broader gene panels are becom­ in the setting of NPM1 or biallelic CEBPA
with biallelic mutation of CEBPA. Addi­ ing increasingly available and are prob­ mutation, has been removed from the list
tionally, multilineage dysplasia alone no ably indicated in most, if not all, types {1511,3562}, as has monosomy 5; del(5q)
longer supersedes a diagnosis of AML of AML. Modifications have been made and unbalanced translocation involving
with mutated NPM1 or AML with bial­ to the AML with myelodysplasia-related 5q remain {1559,4209}.
lelic mutation of CEBPA, because recent changes subgroup. Cases should still be

26 Introduction and overview of the classification of myeloid neoplasms

Therapy-related myeloid neoplasms ample, therapy-related AML with t(9;11) peripheral blood or bone marrow involve­
(i.e. therapy-related AML, MDS, and (p21.3;q23.3). ment, the immunophenotype should be
MDS/MPN) remain in the revised classi­ The category ‘acute myeloid leukaemia, ascertained by flow cytometry and/or
fication as a distinct subgroup. Most pa­ NOS’ encompasses the cases that do immunohistochemistry, and the geno­
tients who develop therapy-related neo­ not fulfil the specific criteria for any of the type determined by cytogenetic analy­
plasms have received therapy with both other entities. This group currently ac­ sis or (in the absence of fresh tissue) by
alkylating agents and topoisomerase II counts for 25―30% of all AML cases. If FISH or molecular analysis for recurrent
inhibitors, so division according to type of cases of AML with mutated NPM1 or bial­ genetic abnormalities. Myeloid sarcoma
therapy remains impractical. It has been lelic mutation of CEBPA are removed from may also be the initial indication of re­
argued that ≥ 90% of cases of therapy- this group as is advocated in this revised lapse in a patient previously diagnosed
related AML have cytogenetic abnor­ classification, the subtypes of AML, NOS, with AML, or may indicate disease pro­
malities similar to those seen in AML with no longer have prognostic significance gression to AML or to the blast phase in
recurrent genetic abnormalities or AML {4233}. The number of cases that fall into patients with a prior diagnosis of MDS,
with myelodysplasia-related changes, the AML, NOS, category will continue MDS/MPN, or MPN.
and could be assigned to those catego­ to diminish as more genetic subgroups As in the original 4th edition, the unique
ries. However, in most reported series, are identified. As mentioned above, the features of myeloid proliferations associ­
therapy-related myeloid neoplasms — category ‘acute erythroid leukaemia (ery- ated with Down syndrome are addressed
except therapy-related AML with inv(16) throid/myeloid)’ has been removed from in a separate category, which encom­
(p13.1q22), t(16;16)(p13.1;q22), or PML- the classification, and most of these cas­ passes transient abnormal myelopoiesis
RARA — have a significantly worse es are now classified as MDS. associated with Down syndrome and
clinical outcome than do their de novo Myeloid sarcoma, an extramedullary tu­ myeloid leukaemia associated with Down
counterparts with the same genetic ab­ mour mass consisting of myeloid blasts, syndrome.
normalities {94,392,3435,3699,3709}, is included in the classification as a dis­ A section on myeloid neoplasms with
suggesting some biological differences tinct pathological entity. However, when germline predisposition {1390,4301}
between the two groups. The study of myeloid sarcoma occurs de novo, the has been added to the classification
therapy-related neoplasms may provide diagnosis is equivalent to a diagnosis to address cases of AML, MDS, and
valuable insight into the pathogenesis of of AML, and further evaluation (includ­ MDS/MPN that have germline genetic
de novo disease by providing clues as to ing genetic analysis) is necessary to abnormalities. The recognition of such
why certain patients develop leukaemia determine the appropriate classification cases should lead to screening of fam­
whereas most patients treated with the of the leukaemia {3177}. When the peri­ ily members, which may enable earlier
same therapies do not. Therefore, cases pheral blood and/or bone marrow are disease detection in affected individuals.
of therapy-related neoplasms should al­ concurrently involved by AML, these
ways be designated as such, and any specimens can be used for analysis and
specific genetic abnormality should also further classification. However, when the
be listed as part of the diagnosis; for ex­ myeloid sarcoma precedes evidence of

Revised WHO classification of myeloid neoplasms 27

Exploring the Variety of Random
Documents with Different Content
 Tyytyväisenä vastaukseen, joka niin hyvin soveltui ujolle neidolle,
läksi Neta-täti keittiöstä.

Mutta Alma ajatteli: "Ei majuria, ei majuria ilmoisna ikänä — — —"

VIII.

Samalla aikaa kun tämä tapahtui ylijahtimestarin virkatalossa vaelsi

Karl August haaveellisempana kuin koskaan ennen takaisin
Hevossaareen.
Alman kuva ei nyt ainoastaan liihoitellut hänen ympärillään; se oli
myöskin kirkkaana ja selvänä syöpynyt hänen sisäiseen
näkemykseensä.

Isän omituinen ja — mikäli Karl Augustin oli syytä päätellä —

karkea käytös saattoi hänet levottomaksi ainoastaan mikäli se
vaikeutti tyttären tapaamista, ja tältä näkökannalta hän oli ylen
pahoillaan siitä onnettomuudesta, ettei hän ollut vähääkään
mieluinen vanhalle herralle. Kuitenkin oli Karl Augustilla kyllin
arvostelukykyä voidakseen olla vakuutettu siitä, että sellainen mies,
miksi ylijahtimestari oli osoittautunut, ei ollut ilkeä eikä sivistymätön,
vaan ainoastaan erilainen kuin muut: omituinen, samalla äreä ja
pirteä ukko, joka tahtoi taivuttaa koko maailman oman mielensä
mukaan.

Päättäen joka tapauksessa jäädä Hevossaareen pariksi päiväksi

Karl August laittoi olonsa mahdollisimman mukavaksi; ja juuri
aikoessaan ottaa esille kirjoitusneuvonsa huomasi hän ikkunasta
pojan, jolla oli kirje kädessä. Aavistaen parasta Karl August juoksi
pihalle, missä sanantuoja kysyi "tämäkö se herra on?"

— Niin, se on minulle, — sanoi Karl August luettuaan

päällekirjoituksen: "K.K.H. Raunioilla vaeltavalle ritarille"… —
Odotappa hetkinen, poikani! — pyysi hän ja kiiruhti sisälle lukemaan
äkkiarvaamatta saamaansa sanomaa, miettien mielessään, olisiko
siinä anteeksipyyntö vaiko uusi onnentoivotus. Sinetti singahti auki,
ja Karl August silmäsi seuraavat rivit:

"Koska en tiedä, kenelle minulla on kunnia kirjoittaa, saatte, hyvä

herra, tyytyä siihen, että sekä päällekirjoitukseen että otsikkoon
merkitsen K.K.H. Tämän lipun tarkoituksena on kuitenkin pyyntö,
että Te, hyvä herra, jos oleskelunne Ombergissa kestää yli
huomispäivän, silloin suvaitsisitte läsnäolollanne kunnioittaa
yksinkertaista päivällispöytääni. Syön päivällisen täsmälleen kello
2; ja ilman ollessa suotuisa on minulla iltapäivällä ilo näyttää Teille,
hyvä herra, paikkakunnan merkillisyyksiä.

Nils B."

Joskaan tätä ei suinkaan saattanut sanoa onnentoivotukseksi

enempää kuin anteeksipyynnöksikään, oli Karl August kuitenkin
sydämensä pohjasta tyytyväinen, sillä hän piti sellaista kirjettä, kun
se oli tuollaisen miehen lähettämä, oikeana sovinnontarjouksena.
Mutta nyt hänen täytyi hillitä ilonsa ajatellessaan vastausta.

Mihin tapaan hän sen kirjoittaisi vai riittäisikö suullinen kiitos? Ei,
se ei käynyt päinsä, kirjoittaa hänen täytyi! Ja ensi kerran eläissään
Karl August tunsi olevansa pulassa sen johdosta, ettei hänellä ollut
mitään arvonimeä. Kuuluihan "Karl August Kemner" kovin tyhjältä,
varsinkin kun ylijahtimestarin oli mahdoton tietää, että sille antoi
merkityksen ruukki ja kaksikymmentä tilaa. Ja pelko, että hän vielä
kerran joutuisi epäedulliseen asemaan, sai hänet ottamaan sen
arvonimen, joka hänelle jo kotona kohteliaisuudesta ja hänen
kiusakseen oli annettu: ruukinpatruuna Kemner ei kuulunut niinkään
hullulta; ja vaikkakin Karl August punastui korviaan myöten siitä, että
vasta tänään oli tehnyt sen keksinnön, mukautui hän kuitenkin
siihen. Ruukkihan oli joka tapauksessa joutuva hänelle, ja niinpä
vastaus oli seuraava:

"Koska olen päättänyt oleskella tällä paikkakunnalla viikon ajan,

saan mitä nöyrimmin kiittää Teitä, herra ylijahtimestari, kohteliaasta
kutsustanne ja ilmoittaa, että minä suurimmalla ilolla olen saapuva.

K
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e
r
,
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 u
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k
i
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a
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u
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.
"

Kirjelipun ohella sai lähetti, jonka tuli jättää kirje tai oikeammin joka
oli tuonut kutsukortin, juomarahaa kaksi pankkoriksiä, jotka
sivumennen sanoen pojan palatessa selvästi ilmenivätkin
ylijahtimestarille.

Tärkeän postin lähdettyä Karl August koetti kuluttaa aikaansa

mietiskelyllä — kirjettä vanhemmille ei nyt kannattanut ajatella —
mutta hänellä ei ollut mitään rauhaa sisällä eikä ulkona; koskaan hän
ei ollut vielä tuntenut sellaista sielunjännitystä.

Yöllä, saman levottomuuden pitäessä häntä valveilla, tuotti hänelle

suuria huolia keksimänsä ruukinpatruunan arvonimi ja ne ikävyydet,
joita se saattoi hänelle tuottaa, jos ylijahtimestari, kuten oli varsin
luultavaa, tekisi hänelle kaikenlaisia pulmallisia kysymyksiä ruukin
oloista, jotka hänen luonnollisesti arveltiin tuntevan — hänen, joka ei
tiennyt juuri mitään, ei edes raudan nykyisin käypää hintaa. Mitä Karl
August, joka niin usein oli ollut kuuro isänsä perinpohjaisille
esityksille, olisikaan tahtonut antaa saadakseen vielä tämän yön
keskustella hänen kanssaan! Karl August olisi nyt ollut isänsä
tarkkaavaisin kuuntelija. Minkä riemun se olisikaan tuottanut!

Uneton yö auttoi häntä ainakin aamu-unella lyhentämään osan

seuraavassa aamupäivästä. Loppuosan hän käytti pukemiseen, ja
kello yhdeltä hän läksi matkaan majatalon parhailla rattailla.

Samassa kun hevonen rattaineen oli kääntynyt takaisin

ylijahtimestarin virkatalon portilta ja paraikaa hölkytti kotiin, avasi
Karl August varsin hiljaa kaipaamansa Edenin pääsytien.

Hän sekä toivoi että pelkäsi, että Alma olisi hänen ensimäinen
vastaantulijansa. Mutta siinä hänen sekä toivonsa että pelkonsa oli
turha, sillä ylijahtimestari itse seisoi kuistilla, hienona, muhoilevana ja
kumarrellen.

— Päivää, herra ruukinpatruuna, tervetuloa arkiaterialle! En tiedä

mitä hyvää Neta-neiti — hän on kotihirviöni… kodinhoitajattareni piti
minun sanoa — aikoo meille antaa; mutta sen verran voin jo
edeltäkäsin kavaltaa, että hän ei koskaan tee itseänsä syypääksi
ylellisyyteen.

— Yksinkertaisinkin ateria, — vakuutti Karl August sillaikaa kun

hänellä oli kunnia pudistaa ylijahtimestarin kättä, — on ylellisyyttä
minulle: en suurestikaan harrasta pöytänautintoja.

— Vai niin, vai ette — herra ruukinpatruuna on sitten kenties sitä

suurempi muitten huvien harrastaja, mitä, häh? Niin, niin, tunnen
kyllä nykyaikaiset nuoret herrat… Mutta astukaa sisälle, astukaa
sisälle, minulla on täällä eräs, joka tahtoo sanoa herralle jonkun
ystävällisen sanan eilispäivän tapauksen johdosta.

Karl August tunsi veren kiivaasti kuohahtavan suonissaan. Oi,

miltä hän näyttäisikään, tuo viehättävä Alma, — tulisiko hän ujona ja
arkana vaiko kohotetuin katsein häntä vastaan?

Itse uskalsi Karl August tuskin silmiänsä nostaa seuratessaan

isäntää vierashuoneeseen. Hän ei kyennyt eroittamaan yhtään
esinettä. — Ruukinpatruuna Kemner! — esitteli ylijahtimestari. Vasta
silloin Karl August rohkaisi mielensä ja avasi silmänsä, mutta
punastui ja nolostui sanomattomasti, kun tytön sijasta kookas,
vanhahko soturi reippaasti ojensi kätensä ja esittelyn jälkiosa suhisi
hänen korvissaan: — Majuri Kling, naapurini ja paras ystäväni!

— Minua ilahduttaa, — sanoi majuri äänellä, jossa oli mitä

hyväntahtoisin sävy, — että saan lausua herra ruukinpatruunalle
ottavani osaa mitä lämpimimmin siihen kiitollisuuteen, jonka tämä
hyvä ystäväni arvatakseni jo aikaa sitten on lausunut.

— Kas niin, kas niin, — keskeytti ylijahtimestari, — emme puhu

enää viimevuotisesta lumesta: älköön koskaan vatvottako samaa
asiaa niin kauan, että se käy väsyttäväksi! Pakisin eilen pari sanaa
kahden kesken ylä-ilmojen isälle — (ylijahtimestari viittasi taivaalle)
— ja pöydässä juomme maljan: olen sanonut Neta-neidille, että hän
saattaa kustantaa meille pullollisen oikeata vanhaa madeiraa!

— Kelpo isännällämme on omat pikku omituisuutensa, mutta

jospa, herra ruukinpatruuna, tuntisitte hänet niin hyvin kuin minä ja…

— Ohoh, ei, ei, — puuttui ylijahtimestari innokkaasti päätään

nyökytellen puheeseen, — älkäämme huoliko tehdä
anteeksipyyntöjä isännän puolesta — mitä, häh, majuri, enkö osaa
itse puhua puolestani? No, herra ruukinpatruuna, rautaako vai
paperia vai mitä hyvää teidän ruukissanne valmistetaan?

— Rautaa, herra ylijahtimestari.

— No, sehän on käypää tavaraa — ja missä on ruukki?

— Södermanlannissa. Vanhempani asuvat siellä. Maatila on

kauan kulkenut sukuperintönämme, ja korkein toivomukseni on, että
olisi vielä kaukana se aika, jolloin se siirtyy minulle. Olen iloinen siitä,
että isäni hallitsee kaikkea — olen pikemmin oppilas kuin hänen
täydellinen auttajansa, ja pidän sen vuoksi arvonimeä enemmän
turhanpäiväisenä koristeena, jonka kernaammin unohdan, milloin en
käytä sitä ilmoituksena.

— Se on miehekäs ja avoin huomautus meidän aikamme nuorison

lausumaksi.
Oletteko ainoa lapsi, herra Kemner?

— Olen ainoana elossa neljästä sisaruksesta.

— Aivan samoin kuin minun tyttäreni. Vaimo-vainajani — oivallisin

nainen, mitä maa on koskaan kantanut — lahjoitti minulle neljä
tytärtä. Juuri siinä kohden hän teki enimmin minun mieltäni vastaan.
Minä sanoin joka kerta, etten hyväksynyt mitään tytön tynkiä, vaan
tahdoin pojan; mutta hän niskuroitsi, ja niin sain pitää hyvänäni
pelkkiä hameita — no, enpä olisi pahoillani, jos ne olisivat minulla nyt
kaikkityyni. Mutta hinkuyskä, tulirokko ja mitä hittoja ne kaikki
ovatkaan, poimi pois toisen toisensa perään, kunnes minulla vihdoin
oli ainoastaan Alma jäljellä. Ja minä pelkäsin kuin jänis, että
hänenkin kävisi samoin; mutta Herra näki, miten kaduin entistä
nurinaani, ja antoi minun pitää tyttölapsen, joka puhuakseni suuni
puhtaaksi on minun silmäteräni… — Näin sanoen ylijahtimestari veti
kellon taskustaan, — Kello on nyt kolme minuuttia vailla kaksi, on
aika katsoa, totellaanko minua talossani!

Herrat astuivat saliin, missä Neta-neiti niiaillen seisoi toisessa

päässä pöytää, tulenvärisillä nauhoilla somistetussa myssyssä ja
musta bomaseehame yllänsä. Mutta ketään muuta ei näkynyt, ja
luodessaan pöytään nopean silmäyksen Karl August huomasi
ihmeekseen, että se oli katettukin ainoastaan neljälle hengelle.

— Puuttuuko mitään? — kysyi ylijahtimestari, ja mustat silmät

loivat veitikkamaisen katseen nuoreen vieraaseen. Perin nolona
tämä tarttui vesikarahviin, ja ylijahtimestari kuvasi kaunopuheisesti
viinapöydän ääressä Ombergin veden oivallisuutta;! siitä hän sai
taas aihetta kertoa jutun metsänneidoista, joiden sanottiin joka aamu
hautelevan pienoisia jalkojaan herttaisessa lähteessä, mistä vesi
noudettiin.

— No, veli on kai käynyt heitä tervehtämässä pukeutumishetkellä?

— kysyi majuri pöytään istuttaessa.

— Olen kyllä lähtenyt ulos epälukuisina aamuina, mutta noilla

viehkeillä neitosilla on omat tähystäjänsä, jotka ovat huomanneet
seitsemänkymmentä ikävuottani, ja näin vanhalle eivät metsän-,
veden- tahi maanneidot enää juuri välitä keimailla. En ole silti
menettänyt ryhtiäni, vaan lohdutan sensijaan itseäni viehättävällä
ystävälläni, kotoisella Neta-neidollani, joka myöskin puolestaan
osoittaa minulle kaikkea sitä myötätuntoisuutta, mitä olen ansainnut.

— Ylijahtimestari on aina leikkisä sekä sopivaan että

sopimattomaan aikaan, — vastasi Neta-neiti säilyttäen kaiken
mahdollisen mielenmalttinsa, mutta käsi vapisi kuitenkin, niin että
lihaliemi, jota hän oli ammentamassa lautasille, oli vähällä läikkyä
pöytäliinalle.

— Luulen totisesti lihaliemen joutuneen lainehtimaan, — sanoi

ylijahtimestari tekeytyneen ystävällisellä äänellä. — Onkohan ruuvi
irtautunut liemikauhan varresta?

Neta-neiti ei vastannut sanaakaan, varoessaan vastaamasta liian

paljoa.

Ylijahtimestari siirtyi toiseen aineeseen: hän alkoi jutella

metsästyksestä ja kertoi, miten hän kerran itse oli tehnyt matkan
Tukholmaan, mukanaan pari ammuttua hirveä, joilla hänen
entisaikaisen sukkeluutensa mukaan oli aivan yhtä komeat sarvet
kuin…

Kaikeksi onneksi Neta-neidillä oli se hyvä ymmärrys, että hän

joudutti paistia, jota ukko aina itse leikkasi, ja siten tarina keskeytyi
alkuunsa, Karl Augustin mielihyväksi, hän kun ei pitänyt
eräänlaatuisista väljähtyneistä kaskuista.

Paistin mukana tuli luvattu madeira, jonka näkeminen elähdytti

isännän pitämään hilpeän puheen; sen loppuna oli kuitenkin
muutamia vakavia, sydämestä lähteneitä sanoja vieraalle.

Mutta Alman poissaolosta ei puhuttu; ja turhaan Karl August odotti

saavansa iltapäivällä jotakin valaistusta asiaan. Hän ei enää
ollenkaan pelännyt tytön tapaamista. Ylijahtimestari kävi sillävälin
yhä kohteliaammaksi ja kohteliaammaksi. Herrat kutsuttiin hänen
yksityishuoneeseensa juomaan kahvia ja tupakoimaan. Kaikki
harvinaisuudet katseltiin, jokaisella esineellä oli vaiheensa, jotka
omistaja muisti kertoa. Kun oli tehty retki vuorelle, päättyi viimein ilta,
— eikä Almaa vieläkään näkynyt.

Karl Augustin oli mahdoton kysyä. Hänen täytyi vihdoin sanoa

hyvästi ja ilman paluun toivoa, sillä joskin hän pari kertaa oli
maininnut oleskelevansa vielä viikon paikkakunnalla, ei
ylijahtimestari ollut sitä kuulevinansakaan, vaan portilla erottaessa
muitta mutkitta toivotti vieraalleen onnellista matkaa, ilmaisten ilonsa
tämän lyhyen tuttavuuden johdosta ja pyytäen, että herra
ruukinpatruuna palauttaessaan mieleensä Ombergin matkan
myöskin muistelisi vanhaa ylijahtimestaria.

— En koskaan, — sanoi Karl August jonkun verran kiihkeästi, —

en koskaan saata unohtaa Ombergissa käyntiäni enkä… enkä
tapausta Alvastrassa. — — Toivoakseni ei mikään pahoinvointi…

— Ei, ei, ei, ainoastaan vähän säikähdyksen jälkivaikutusta, joka

ei merkitse sen enempää… Mutta harvoinpa näkee taivasta
tuollaisena! Tiedättekö, herra ruukinpatruuna, minä olen aina
väittänyt: missään muualla ei saa nähdä niin ihanaa iltaruskoa ja niin
kirkasta vettä kuin täällä. Omberg on paratiisi.

— Ja herra ylijahtimestari vartioi itse sen porttia, — uskalsi Karl

August lausua.

Ylijahtimestari nauroi ja näytti olevan huomautuksesta hyvillään:

hän siveli leukaansa ja veti kokoon suupielensä, kuten aina hyvällä
päällä ollessaan, ja sanoi leikillisesti: — Portinvartijan tehtävä ei
olekaan ihan helppo. Mutta tulkaa vuoden kuluttua, niin kaikki
paratiisin portit ovat selkoselällään.
 — Mitä se merkitsee? — kysyi Karl August huonosti salaten
kiivauttaan.

— Oh, ei mitään muuta, — sanoi ylijahtimestari, — kuin että

paratiisilintu lienee silloin muuttanut majaa… Mutta minä viivytän
herra ruukinpatruunaa — kiitos vielä kerran hauskasta seurasta!

Ja paiskaten voimakkaasti kättä ukko kääntyi takaisin, jättäen Karl

Augustin portille, mihin hän hetkiseksi jäi seisomaan haluttomana
lähtemään paikasta, johon hän jo oli niin suuresti kiintynyt. Mutta
pelko, että hänet huomattaisiin, voitti lopullisesti viipymishalun; portti
sulkeutui hiljaa — ja Karl August seisoi karkoitettuna Edenistä.
IX.

— Miten pikku tyttöseni tänä iltana jaksaa, — onko hän niin reipas,
että saatamme tehdä pienen kävelyretken? — kysyi ylijahtimestari
astuessaan Alman huoneeseen.

— Minähän voin erinomaisesti, isä, — vastasi Alma. — Ja olenhan

makuulla ainoastaan sen vuoksi, että sinä käskit minun levätä!

— Eikä isä käske mitään muuta kuin minkä hänen viisautensa

hyväksyy. Vuoteesta ei nousta äkkiä aamulla, kun illalla on juonut
pari kuppia juhannuskukka-teetä, — sellaista on kartettava, jos
tahtoo säilyttää terveytensä ja poskiensa ruusut.

— No, nyt saan siis nousta ylös, isä-kulta? Minun on ihan ikävä
Kultakäpälää — (tämä oli Alman pikku vuohen nimi) — ja olenpa
varma, että sekin on ikävissään, kun ei ole nähnyt minua eilisestä
saakka.

— On toinenkin, joka sinua kaipaa, nimittäin kunnon majurimme

täällä. Niin, ja tosiaankin, olin vähällä unohtaa sanoa, että vieras,
joka auttoi sinut raunioista, on myöskin ollut päivällisellä.

— Eihän — lasket leikkiä, isä?

 — Miksi niin? Lähetin hänelle eilis-iltana kirjelipun ja kutsuin hänet
yksinkertaiselle päivälliselle.

— Onko hän vielä täällä?

— Ei, hän läksi äsken. Hän on ruukinpatruunan poika

Södermanlannista.

— Ja miksi minä en saanut tietää, että hän oli täällä, — miksi en

saanut pukeutua mennäkseni sisälle häntä kiittämään?

Eikä Alma saattanut pidättää mielipahansa ilmettä: se ilmeni

hänen äänensä harvinaisesta noususta ja poskiensa väristä.

— Mitä nyt? — huudahti ylijahtimestari ällistyneenä. — Tahtooko

neiti pitää kotikuulustelua isänsä kanssa, jos tämä uskaltaa kutsua
luokseen vieraan, kysymättä neuvoa tyttäreltään, tahi unohtaa
kutsua häntä mukaan milloin se ei ole tarpeellista!

— Mutta miksi, isä, se tänään oli vähemmän tarpeellista kuin

muulloin?
Olethan, isä, usein sanonut, että pöydästä puuttuu jotakin, milloin
Almasi ei ole läsnä!

— Niinpä kyllä, niinpä kyllä; mutta ei liene liian aikaista totuttautua

siihen kaipuuseen. Eiväthän tytöt ole luodut iän kaiken olemaan
kotona isiensä huvitukseksi: he ovat muuttuvaista tavaraa, joka
kulkee kädestä käteen — luonnollisesti isän kädestä aviomiehelle…
Mutta nouse ylös, lapseni — me odotamme sinua!

Ylijahtimestari jätti tyttärensä, ja neljännestunnin kuluttua oli Alma

isänsä huoneessa, jossa majuri Kling istui sohvalla sanomalehtien
ympäröimänä.
 Majuri oli viisikymmen-vuotias mies. Nuoruudessa oli kolme
ominaisuutta tehnyt hänet kuuluisaksi: hän pelasi korttia, vaihtoi
hevosia eikä koskaan viihtynyt kotona. Mutta miehuudeniässään hän
kammosi näitä nuoruudenhuvituksiaan: nyt hän ei koskaan pelannut
korttia, ei koskaan vaihtanut hevosia ja rakasti intohimoisesti kotiaan,
josta vaimoa lukuunottamatta ei puuttunut mitään.

Majurilla ei ollut ylijahtimestarin halua seurata aikaansa kaikessa,

paitsi pakinoimisessa ja juttujen kertomisessa. Sanomalehdille hän
antoi kolmannen tahi neljännen sijan, ja muita kirjoja hän ei lukenut
kuin maataloutta koskevia. Mutta joskaan majuri ei halunnut lukea
kirjoista ihmisten suruja ja kärsimyksiä, niin hän sitä useammin etsi
niitä tosielämästä, antaakseen apua hyväntahtoisesta sydämestä. Ja
siinä ylijahtimestari ja hän usein kohtasivat toisensa, niin että he
vihdoin olivat tulleet aivan välttämättömiksi toisilleen.

Ylijahtimestarin ja majurin kesken ei tähän asti ollut tapahtunut

mitään lähempää selvittelyä Almasta. Mutta ylijahtimestari tunsi, että
majurin kaikkein korkein toivomus oli saada sanoa tyttöä
vaimokseen, samaten kuin majuri tiesi, että ylijahtimestari — juuri
nähdäkseen tämän avioliiton toteutuvan — pidätteli kaikkia nuoria
miehiä talostaan.

Ja tässä molemminpuolisessa levollisessa vakaumuksessa he

antoivat asian mennä tavallista menoaan. Almahan oli lapsellinen,
vaikkakin Neta-neidin huomautuksen mukaan jo täysi
kahdeksantoista-vuotias ihminen; ja sen vuoksi hänen piti vielä
saada nauttia riemuaan rauhassa: maailma oli hänet kyllä ajoissa
löytävä! "Kun ei vaan". puheli joskus ylijahtimestari itsekseen, —
"joku onnenonkija tulisi ennen sitä ja nipistäisi sydämeen."
 Kohta kun Alma oli astunut kynnyksen yli, nousi majuri
kiiruhtamaan häntä vastaan. Vanhan tavan mukaan, joka oli
juurtunut tytön lapsuudesta saakka, suuteli majuri nuorta tyttöä
otsalle, samalla kun tämä kumartui tavallista syvemmälle ja nyt
omaksi levottomuudekseen tunsi punastuvansa.

Miksi hän punastui? Vuoden toisensa jälkeen majuri oli tervehtänyt

häntä samalla tavalla, hänen edes sitä ajattelemattaan; niin, olipa
hän usein ojentanutkin otsansa, kun majuri myöhempinä aikoina
jonkinmoisella kömpelyydellä oli tahtonut suudella hänen kättään.
Mutta nyt Alma tiesi sen, mitä hän ennen ei ollut aavistanut, nimittäin
että majurin matkoilla oli "tarkoitus". Se säikytti ja punastutti häntä,
vieläpä sai hänet vapisemaankin, kun kunnon majuri tavallista
hellemmin ilmein katsoi häntä silmiin.

— Jumalan kiitos, — sanoi hän lämpimästi, — että Alma pelastui

uhkaavasta vaarasta. Oli onni, että nuori matkustavainen oli siellä.

— Hm, hm, hm, — mutisi ylijahtimestari, ja tämähän merkitsi

suunnilleen samaa kuin: "Hitto ties, oliko suurikaan onni, että mies
oli nuori!"

— Niin, niinpä kylläkin, — vastasi Alma. — Mutta juuri senvuoksi

olen kovin pahoillani, etten saanut virkkaa hänelle yhtään sanaa.

— Isäsi on lausunut hänelle sitä useampia, — kiiruhti

ylijahtimestari lisäämään. — Hän oli erittäin tyytyväinen, vai mitä,
majuri, — velihän näki itse?

Majuri myhäili eikä sanonut olevansa siitä niin perinpohjin

vakuutettu.
Hän oli Alman puolella; tytön itsensä olisi pitänyt saada kiittää.
 — Vai niin, vai niin, tässä on kysymys kapinasta, kyllä ymmärrän!
— lausui ylijahtimestari ja vilkui niin vikkelästi mustilla silmillään, että
Alma tuskin tiesi, puhuiko hän piloillaan vai tosissaan. — Veli yllyttää
tyttöä: hän tulee uppiniskaiseksi kuin… kuin…

— Kuin kyyhkynen, joka vähimmästä tuulenpuuskasta pistää

päänsä siipien suojaan, — täydensi majuri.

— Siunaa ja varjele, — huudahti ylijahtimestari, — onkohan

todellakaan pahempaa kuin kyyhkysmäinen haikailu, olkoonpa se
untuvissa tai hameessa! No, nosta silmäsi, Alma, näytä että olet
sellaisen miehen tyttö, joka saattaa katsoa ihmisiä ja itse
paholaistakin silmiin. Sano suoraan, ettet ole mikään kyyhkynen,
sillä silloin, vieköön minut se ja se, saattaisit yhtä hyvin olla harakka,
varis tahi… tahi… Mutta sanalla sanoen, minä en tahdo tietää
mistään kyyhkysistä talossani!

Mutta silloin Alma nauroi ja kapsahti isänsä kaulaan. — Minä en

ole mikään kyyhkynen, en ollenkaan, isä-kulta — kun vain olisin
rahtusen rohkeampi! Mutta vanhemmaksi tultuani kai asia muuttuu,
ja silloin saattaa tapahtua, että minulla on oikea oma tahto.

Alma tuli lausuneeksi nämä sanat lapsellisen ilon puuskauksena.

Vasta myöhemmin hän huomasi, mitä ne saattoivat merkitä, ja
hämmästyi ajatellessaan, että hänen tahtonsa todellakin kerran voisi
joutua ristiriitaan isän tahdon kanssa.

Mutta neitonen ei ehtinyt ajatella enempää. Ylijahtimestari sanoi:

— Veli huomaa, että tyttö alkaa luontua… Mutta ota nyt hattu, ja
menkäämme puutarhaan katsomaan, ovatko kukat kasvaneet paljon
sateen jälkeen! — — —
 Ylijahtimestari teki kävelyretken toisaanne, ja majuri ja Alma jäivät
kahden kesken.

— Meidän ei olisi sopinut lähteä näin pitkälle — sanoi majuri; —

pelkään Alman vilustuvan.

— En suinkaan. Tänä iltana on niin suloista. En luule koko maan

pinnalla olevan paikkaa, jota saattaisin rakastaa yhtä paljon kuin
tätä!

— Kenties kuitenkin, — virkkoi toinen erityisellä äänenpainolla, —

jos Almaa kerran kiinnittävät toiseen paikkaan yhtä hellät siteet kuin
tähän!

Alma katseli poispäin pyökkilehtoihin ja vastasi hiljaa: — Silloin

täytyy monen asian muuttua!
X.

Eräällä Hevossaaren rannan viereisellä kalliolla seisoi Karl August

samana iltana, luoden miettivän katseen Vetterin yli.

Hän ajatteli menneen päivän pettyneitä toiveita, haluttomuutta

jatkaa alottamaansa kirjettä vanhemmille, mahdollisuutta nähdä
jälleen Alma, mahdollisuutta keksiä onnellista keinoa siihen, lyhyesti
sanoen: hän pohti kaikkea tuollaista vähäpätöistä, joka vihdoin
muodostuu varmaksi taipumukseksi. Mutta silloin hänen huomionsa
kiintyi mitä merkillisimpään ilmestykseen. Hän alkoi tuijottaa vesille ja
luuli näkevänsä unta.

Autereessa näkyi kokonainen voimallisen jättiläisen kuva, ainakin

kahdenkymmenen kyynärän korkuinen, ja jotakin sanomattoman
kamalaa oli tuon harmaankalpean ilmaolennon edestakaisessa
liitelyssä. Se oli ollut näkyvissä noin viisi minuuttia ja kolme tahi neljä
kertaa muuttanut asentoaan, milloin kohottaen käsivarsiaan ja
milloin, kuten näytti, nyökäyttäen päätänsä; ja sitten hirviön takaa
vähitellen kohosi punertava muuri päätyineen ja torneineen, jotka
kuitenkin pian muuttuivat korkeiksi puiksi ja tuuheiksi lehdoiksi. Koko
tätä näytelmää kesti noin neljännestunnin, jonka jälkeen se katosi.
Jättiläinen jäi paikoilleen viimeiseksi, mutta hävisi äkkiä, kun kova
vihuri kiiti pitkin vedenpintaa ja lakaisi pois koko haavekuvan.

Sanattomassa hämmästyksessään Karl August seisoi kauan

paikoillaan; mutta käännyttyään vihdoin lähtemään vetäytyi hän
äkkiä taaksepäin: jättiläinen seisoi aivan hänen edessään! Mutta
pian hän huomasi tällä kertaa olevansa tekemisissä veren ja lihan
kanssa, joskin olento oli laatuaan harvinainen.

Aivan Karl Augustin edessä seisoi tavattoman kookas mies

suureen ryhmysauvaansa nojaten. Hänen pikimusta tukkansa riippui
tuuheana, leveänä ja tasaiseksi leikattuna tupsuna aina kulmille asti.
Syvällä kuopissaan olevat silmät tuskin näkyivät harjamaisten
kulmakarvojen alta. Hänen ihonsa väri vivahti oliivinkeltaiseen ja
kuparinruskeaan, ja tuuhea parta alkoi poskipäiltä ja ulottui hyvän
matkaa leuan ja merimies-kaulaliinan alapuolelle, joka
viimeksimainittu sekä hurstinuttu osoittivat, että hän oli merimies tai
oli ollut siinä ammatissa.

— Hyvää iltaa, — sanoi Karl August nyökäyttäen päätänsä

miehelle, jonka kasvoilla oli hiljaisen raskasmielisyyden ilme.

— Iltaa, — oli miehen lyhyt vastaus; ja ääni, jolla tämä

yksinkertainen sana lausuttiin, kuului kumealta kuin haljenneen
kellon.

— Huomasitko kangastusta, kummitusta tuolla? — kysyi Karl

August viitaten Vetteriin päin.

— Huomasin kyllä, — vastasi vanhus, — senlaisia olen täällä

nähnyt usein. Hän varoitta myrskyn tullen.
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