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* Myeloproliferative neoplasms
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The Updated WHO Classification of Hematological Malignancies| May 19, 2016
THE 2016 REVISION TO THE WORLD HEALTH ORGANIZATION CLASSIFICATION OF MYELOID
NEOPLASMS AND ACUTE LEUKEMIA
Daniel A. Arber,
Daniel A. Arber
1Department of Pathology, Stanford University, Stanford, CA;
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Attilio Orazi,
Attilio Orazi
2Department of Pathology, Weill Cornell Medical College, New York, NY;
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Robert Hasserjian,
Robert Hasserjian
3Department of Pathology, Massachusetts General Hospital, Boston, MA;
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Jürgen Thiele,
Jürgen Thiele
4Institute of Pathology, University of Cologne, Cologne, Germany;
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Michael J. Borowitz,
Michael J. Borowitz
5Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD;
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Michelle M. Le Beau,
Michelle M. Le Beau
6Section of Hematology/Oncology, University of Chicago, Chicago, IL;
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Clara D. Bloomfield,
Clara D. Bloomfield
7Comprehensive Cancer Center, James Cancer Hospital and Solove Research
Institute, The Ohio State University, Columbus, OH;
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Mario Cazzola,
Mario Cazzola
8Department of Molecular Medicine, University of Pavia, and Department of
Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; and
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James W. Vardiman
James W. Vardiman
9Department of Pathology, University of Chicago, Chicago, IL
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Blood (2016) 127 (20): 2391–2405.
https://doi.org/10.1182/blood-2016-03-643544
Article history
Submitted:
March 16, 2016
Accepted:
April 6, 2016
First Edition:
April 11, 2016
Connected Content
A related article has been published: Introduction to a review series: the 2016
revision of the WHO classification of tumors of hematopoietic and lymphoid
tissues
A companion article has been published: The 2016 revision of the World Health
Organization classification of lymphoid neoplasms
An erratum has been published: Arber DA, Orazi A, Hasserjian R, et al. The 2016
revision to the World Health Organization classification of myeloid neoplasms
and acute leukemia. Blood. 2016;127(20):2391-2405.
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Citation
Daniel A. Arber, Attilio Orazi, Robert Hasserjian, Jürgen Thiele, Michael J.
Borowitz, Michelle M. Le Beau, Clara D. Bloomfield, Mario Cazzola, James W.
Vardiman; The 2016 revision to the World Health Organization classification of
myeloid neoplasms and acute leukemia. Blood 2016; 127 (20): 2391–2405. doi:
https://doi.org/10.1182/blood-2016-03-643544
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ABSTRACT
The World Health Organization (WHO) classification of tumors of the
hematopoietic and lymphoid tissues was last updated in 2008. Since then, there
have been numerous advances in the identification of unique biomarkers
associated with some myeloid neoplasms and acute leukemias, largely derived from
gene expression analysis and next-generation sequencing that can significantly
improve the diagnostic criteria as well as the prognostic relevance of entities
currently included in the WHO classification and that also suggest new entities
that should be added. Therefore, there is a clear need for a revision to the
current classification. The revisions to the categories of myeloid neoplasms and
acute leukemia will be published in a monograph in 2016 and reflect a consensus
of opinion of hematopathologists, hematologists, oncologists, and geneticists.
The 2016 edition represents a revision of the prior classification rather than
an entirely new classification and attempts to incorporate new clinical,
prognostic, morphologic, immunophenotypic, and genetic data that have emerged
since the last edition. The major changes in the classification and their
rationale are presented here.
Subjects:
Free Research Articles, Myeloid Neoplasia, Review Articles, Review Series
Topics:
leukemia, acute, myelodysplastic syndrome, neoplasms, world health organization,
myeloproliferative disease, burkitt's lymphoma, mutation
INTRODUCTION
In collaboration with the Society for Hematopathology and the European
Association for Haematopathology, the World Health Organization (WHO) published
the third and fourth editions of the WHO Classification of Tumours of
Haematopoietic and Lymphoid Tissues, in 2001 and 2008, respectively, as part of
a series of WHO Classification of Tumours “blue book” monographs. In the spring
of 2014, a clinical advisory committee (CAC) composed of ∼100 pathologists,
hematologists, oncologists, and geneticists from around the world convened to
propose revisions to the fourth edition of the classification. The revision of
the fourth edition follows the philosophy of the third and fourth editions to
incorporate clinical features, morphology, immunophenotyping, cytogenetics, and
molecular genetics to define disease entities of clinical significance. The
fourth edition of the classification of hematopoietic and lymphoid tissues was
the second volume of the WHO “blue book” tumor series, and the series
publication is still in progress. A fifth edition series cannot begin until the
fourth edition series is completed; but after 8 years of information and
experience that have emerged from scientific and clinical studies, a revision of
these criteria for hematopoietic and lymphoid neoplasms was felt to be necessary
and timely. In relation to myeloid neoplasms and acute leukemia, this revision
has been influenced by several factors including the following:
1. The discovery of recently identified molecular features has yielded new
perspectives regarding diagnostic and prognostic markers that provide novel
insights for the understanding of the pathobiology of these disorders.
2. Improved characterization and standardization of morphological features
aiding in the differentiation of disease groups, particularly of the
BCR-ABL1− myeloproliferative neoplasms (MPNs), has increased the reliability
and reproducibility of diagnoses.
3. A number of clinical-pathological studies have now validated the WHO
postulate of an integrated approach that includes hematologic, morphologic,
cytogenetic, and molecular genetic findings.
For these reasons, the fourth edition is being updated, but this 2016
classification is not a major overhaul of the disease categories. Rather, it is
intended to incorporate new knowledge of these disorders obtained since the 2008
publication and is a revision of that classification. The purpose of this report
is to summarize the major changes in the revised WHO classification of myeloid
neoplasms and acute leukemia and to provide the rationale for those changes.
Table 1 lists the major subtypes of myeloid neoplasms and acute leukemias
according to the updated (2016) WHO classification.
Table 1
WHO classification of myeloid neoplasms and acute leukemia
WHO myeloid neoplasm and acute leukemia classification . Myeloproliferative
neoplasms (MPN) Chronic myeloid leukemia (CML), BCR-ABL1+ Chronic neutrophilic
leukemia (CNL) Polycythemia vera (PV) Primary myelofibrosis (PMF) PMF,
prefibrotic/early stage PMF, overt fibrotic stage Essential thrombocythemia
(ET) Chronic eosinophilic leukemia, not otherwise specified (NOS) MPN,
unclassifiable Mastocytosis Myeloid/lymphoid neoplasms with eosinophilia and
rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2 Myeloid/lymphoid
neoplasms with PDGFRA rearrangement Myeloid/lymphoid neoplasms with PDGFRB
rearrangement Myeloid/lymphoid neoplasms with FGFR1 rearrangement Provisional
entity: Myeloid/lymphoid neoplasms with
PCM1-JAK2 Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) Chronic
myelomonocytic leukemia (CMML) Atypical chronic myeloid leukemia (aCML),
BCR-ABL1− Juvenile myelomonocytic leukemia (JMML) MDS/MPN with ring
sideroblasts and thrombocytosis (MDS/MPN-RS-T) MDS/MPN,
unclassifiable Myelodysplastic syndromes (MDS) MDS with single lineage
dysplasia MDS with ring sideroblasts (MDS-RS) MDS-RS and single lineage
dysplasia MDS-RS and multilineage dysplasia MDS with multilineage
dysplasia MDS with excess blasts MDS with isolated del(5q) MDS,
unclassifiable Provisional entity: Refractory cytopenia of childhood Myeloid
neoplasms with germ line predisposition Acute myeloid leukemia (AML) and related
neoplasms AML with recurrent genetic abnormalities AML with
t(8;21)(q22;q22.1);RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or
t(16;16)(p13.1;q22);CBFB-MYH11 APL with PML-RARA AML with
t(9;11)(p21.3;q23.3);MLLT3-KMT2A AML with t(6;9)(p23;q34.1);DEK-NUP214 AML
with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM AML
(megakaryoblastic) with t(1;22)(p13.3;q13.3);RBM15-MKL1 Provisional entity:
AML with BCR-ABL1 AML with mutated NPM1 AML with biallelic mutations of
CEBPA Provisional entity: AML with mutated RUNX1 AML with
myelodysplasia-related changes Therapy-related myeloid neoplasms AML,
NOS AML with minimal differentiation AML without maturation AML with
maturation Acute myelomonocytic leukemia Acute monoblastic/monocytic
leukemia Pure erythroid leukemia Acute megakaryoblastic leukemia Acute
basophilic leukemia Acute panmyelosis with myelofibrosis Myeloid
sarcoma Myeloid proliferations related to Down syndrome Transient abnormal
myelopoiesis (TAM) Myeloid leukemia associated with Down syndrome Blastic
plasmacytoid dendritic cell neoplasm Acute leukemias of ambiguous lineage Acute
undifferentiated leukemia Mixed phenotype acute leukemia (MPAL) with
t(9;22)(q34.1;q11.2); BCR-ABL1 MPAL with t(v;11q23.3); KMT2A rearranged MPAL,
B/myeloid, NOS MPAL, T/myeloid, NOS B-lymphoblastic
leukemia/lymphoma B-lymphoblastic leukemia/lymphoma, NOS B-lymphoblastic
leukemia/lymphoma with recurrent genetic abnormalities B-lymphoblastic
leukemia/lymphoma with t(9;22)(q34.1;q11.2);BCR-ABL1 B-lymphoblastic
leukemia/lymphoma with t(v;11q23.3);KMT2A rearranged B-lymphoblastic
leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1 B-lymphoblastic
leukemia/lymphoma with hyperdiploidy B-lymphoblastic leukemia/lymphoma with
hypodiploidy B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3)
IL3-IGH B-lymphoblastic leukemia/lymphoma with
t(1;19)(q23;p13.3);TCF3-PBX1 Provisional entity: B-lymphoblastic
leukemia/lymphoma, BCR-ABL1–like Provisional entity: B-lymphoblastic
leukemia/lymphoma with iAMP21 T-lymphoblastic leukemia/lymphoma Provisional
entity: Early T-cell precursor lymphoblastic leukemia Provisional entity:
Natural killer (NK) cell lymphoblastic leukemia/lymphoma
WHO myeloid neoplasm and acute leukemia classification . Myeloproliferative
neoplasms (MPN) Chronic myeloid leukemia (CML), BCR-ABL1+ Chronic neutrophilic
leukemia (CNL) Polycythemia vera (PV) Primary myelofibrosis (PMF) PMF,
prefibrotic/early stage PMF, overt fibrotic stage Essential thrombocythemia
(ET) Chronic eosinophilic leukemia, not otherwise specified (NOS) MPN,
unclassifiable Mastocytosis Myeloid/lymphoid neoplasms with eosinophilia and
rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2 Myeloid/lymphoid
neoplasms with PDGFRA rearrangement Myeloid/lymphoid neoplasms with PDGFRB
rearrangement Myeloid/lymphoid neoplasms with FGFR1 rearrangement Provisional
entity: Myeloid/lymphoid neoplasms with
PCM1-JAK2 Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) Chronic
myelomonocytic leukemia (CMML) Atypical chronic myeloid leukemia (aCML),
BCR-ABL1− Juvenile myelomonocytic leukemia (JMML) MDS/MPN with ring
sideroblasts and thrombocytosis (MDS/MPN-RS-T) MDS/MPN,
unclassifiable Myelodysplastic syndromes (MDS) MDS with single lineage
dysplasia MDS with ring sideroblasts (MDS-RS) MDS-RS and single lineage
dysplasia MDS-RS and multilineage dysplasia MDS with multilineage
dysplasia MDS with excess blasts MDS with isolated del(5q) MDS,
unclassifiable Provisional entity: Refractory cytopenia of childhood Myeloid
neoplasms with germ line predisposition Acute myeloid leukemia (AML) and related
neoplasms AML with recurrent genetic abnormalities AML with
t(8;21)(q22;q22.1);RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or
t(16;16)(p13.1;q22);CBFB-MYH11 APL with PML-RARA AML with
t(9;11)(p21.3;q23.3);MLLT3-KMT2A AML with t(6;9)(p23;q34.1);DEK-NUP214 AML
with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM AML
(megakaryoblastic) with t(1;22)(p13.3;q13.3);RBM15-MKL1 Provisional entity:
AML with BCR-ABL1 AML with mutated NPM1 AML with biallelic mutations of
CEBPA Provisional entity: AML with mutated RUNX1 AML with
myelodysplasia-related changes Therapy-related myeloid neoplasms AML,
NOS AML with minimal differentiation AML without maturation AML with
maturation Acute myelomonocytic leukemia Acute monoblastic/monocytic
leukemia Pure erythroid leukemia Acute megakaryoblastic leukemia Acute
basophilic leukemia Acute panmyelosis with myelofibrosis Myeloid
sarcoma Myeloid proliferations related to Down syndrome Transient abnormal
myelopoiesis (TAM) Myeloid leukemia associated with Down syndrome Blastic
plasmacytoid dendritic cell neoplasm Acute leukemias of ambiguous lineage Acute
undifferentiated leukemia Mixed phenotype acute leukemia (MPAL) with
t(9;22)(q34.1;q11.2); BCR-ABL1 MPAL with t(v;11q23.3); KMT2A rearranged MPAL,
B/myeloid, NOS MPAL, T/myeloid, NOS B-lymphoblastic
leukemia/lymphoma B-lymphoblastic leukemia/lymphoma, NOS B-lymphoblastic
leukemia/lymphoma with recurrent genetic abnormalities B-lymphoblastic
leukemia/lymphoma with t(9;22)(q34.1;q11.2);BCR-ABL1 B-lymphoblastic
leukemia/lymphoma with t(v;11q23.3);KMT2A rearranged B-lymphoblastic
leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1 B-lymphoblastic
leukemia/lymphoma with hyperdiploidy B-lymphoblastic leukemia/lymphoma with
hypodiploidy B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3)
IL3-IGH B-lymphoblastic leukemia/lymphoma with
t(1;19)(q23;p13.3);TCF3-PBX1 Provisional entity: B-lymphoblastic
leukemia/lymphoma, BCR-ABL1–like Provisional entity: B-lymphoblastic
leukemia/lymphoma with iAMP21 T-lymphoblastic leukemia/lymphoma Provisional
entity: Early T-cell precursor lymphoblastic leukemia Provisional entity:
Natural killer (NK) cell lymphoblastic leukemia/lymphoma
View Large
MYELOPROLIFERATIVE NEOPLASMS
The categories of MPNs have not significantly changed since the 2008 fourth
edition of the classification, but discoveries of new mutations and improved
understanding of the morphologic features of some entities have impacted the
diagnostic criteria for the disease entities. Mastocytosis, however, is no
longer considered a subgroup of the MPNs due to its unique clinical and
pathologic features, ranging from indolent cutaneous disease to aggressive
systemic disease, and is now a separate disease category in the classification.
With regard to chronic myeloid leukemia (CML), BCR-ABL1+, most cases of CML in
chronic phase can be diagnosed from peripheral blood (PB) findings combined with
detection of t(9;22)(q34.1;q11.2) or, more specifically, BCR-ABL1 by molecular
genetic techniques. However, a bone marrow (BM) aspirate is essential to ensure
sufficient material for a complete karyotype and for morphologic evaluation to
confirm the phase of disease.1,2 In the era of tyrosine-kinase inhibitor (TKI)
therapy, newly diagnosed patients may have a nearly normal lifespan, but regular
monitoring for BCR-ABL1 burden and for evidence of genetic evolution and
development of resistance to TKI therapy is essential to detect disease
progression.3,4 Although the accelerated phase (AP) of CML is becoming less
common in the era of TKI therapy, there are no universally accepted criteria for
its definition. The criteria for AP in the revised WHO classification include
hematologic, morphologic, and cytogenetic parameters which are supplemented by
additional parameters usually attributed to genetic evolution,5 and manifested
by evidence of resistance to TKIs (see Table 2). These latter “response to TKI
therapy” criteria for AP are considered as “provisional” until further supported
by additional data. Diagnosis of blast phase (BP) still requires either at least
20% blasts in the blood or BM or the presence of an extramedullary accumulation
of blasts. However, because the onset of lymphoid BP may be quite sudden, the
detection of any bona fide lymphoblasts in the blood or marrow should raise
concern for a possible impending lymphoid BP, and prompt additional laboratory
and genetic studies to exclude this possibility.
Table 2
Criteria for CML, accelerated phase
CML, accelerated phase criteria . Any 1 or more of the following
hematologic/cytogenetic criteria or response-to-TKI criteria: • Persistent or
increasing WBC (>10 × 109/L), unresponsive to therapy “Provisional”
response-to-TKI criteria • Persistent or increasing splenomegaly, unresponsive
to therapy • Hematologic resistance to the first TKI (or failure to achieve a
complete hematologic response* to the first TKI) or • Persistent thrombocytosis
(>1000 × 109/L), unresponsive to therapy • Any hematological, cytogenetic, or
molecular indications of resistance to 2 sequential TKIs or • Persistent
thrombocytopenia (<100 × 109/L) unrelated to therapy • Occurrence of 2 or more
mutations in BCR-ABL1 during TKI therapy • 20% or more basophils in the PB •
10%-19% blasts† in the PB and/or BM • Additional clonal chromosomal
abnormalities in Ph+ cells at diagnosis that include “major route” abnormalities
(second Ph, trisomy 8, isochromosome 17q, trisomy 19), complex karyotype, or
abnormalities of 3q26.2 • Any new clonal chromosomal abnormality in Ph+ cells
that occurs during therapy
CML, accelerated phase criteria . Any 1 or more of the following
hematologic/cytogenetic criteria or response-to-TKI criteria: • Persistent or
increasing WBC (>10 × 109/L), unresponsive to therapy “Provisional”
response-to-TKI criteria • Persistent or increasing splenomegaly, unresponsive
to therapy • Hematologic resistance to the first TKI (or failure to achieve a
complete hematologic response* to the first TKI) or • Persistent thrombocytosis
(>1000 × 109/L), unresponsive to therapy • Any hematological, cytogenetic, or
molecular indications of resistance to 2 sequential TKIs or • Persistent
thrombocytopenia (<100 × 109/L) unrelated to therapy • Occurrence of 2 or more
mutations in BCR-ABL1 during TKI therapy • 20% or more basophils in the PB •
10%-19% blasts† in the PB and/or BM • Additional clonal chromosomal
abnormalities in Ph+ cells at diagnosis that include “major route” abnormalities
(second Ph, trisomy 8, isochromosome 17q, trisomy 19), complex karyotype, or
abnormalities of 3q26.2 • Any new clonal chromosomal abnormality in Ph+ cells
that occurs during therapy
Large clusters or sheets of small, abnormal megakaryocytes, associated with
marked reticulin or collagen fibrosis in biopsy specimens may be considered as
presumptive evidence of AP, although these findings are usually associated with
1 or more of the criteria listed above.
*
Complete hematologic response: WBC, <10 × 109/L; platelet count, <450 × 109/L,
no immature granulocytes in the differential, and spleen nonpalpable.
†
The finding of bona fide lymphoblasts in the blood or marrow, even if <10%,
should prompt concern that lymphoblastic transformation may be imminent and
warrants further clinical and genetic investigation; 20% or more blasts in blood
or BM, or an infiltrative proliferation of blasts in an extramedullary site is
CML, blast phase.
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In recent years, data have emerged that suggest the need for revisions to the
diagnostic criteria for the BCR-ABL1− MPNs,6 as many new findings have been
demonstrated to have diagnostic and/or prognostic importance:
1. The discovery of novel molecular findings in addition to JAK2 and MPL
mutations, in particular the CALR mutation, provide proof of clonality,
diagnostic importance, and influence prognosis.7,8
2. The CSF3R mutation is strongly associated with chronic neutrophilic leukemia
(CNL) (see also “Myelodysplastic/myeloproliferative neoplasms”).9
3. Polycythemia vera (PV) is possibly underdiagnosed using the hemoglobin
levels published in the fourth edition, and the utility of BM morphology as
a reproducible criterion for the diagnosis of PV is recognized.8,10,11
4. It is necessary to differentiate “true” essential thrombocythemia (ET) from
prefibrotic/early primary myelofibrosis (prePMF) by, among other features,
the morphologic findings in the BM biopsy, including the lack of reticulin
fibrosis at onset, and this distinction has prognostic implications.12-14
5. The minor clinical criteria in prePMF that may have a major impact not only
on accurate diagnosis but also on prognosis need to be explicitly
defined.14,15
6. Standardized morphologic criteria of MPNs are important to enhance
interobserver reproducibility of morphologic diagnoses (which currently
demonstrates consensus rates ranging between 76% and 88%, depending on the
study design).12,13,16-18
The revised criteria for CNL, PV, ET, PMF, and prePMF are listed in Tables 3-7
in addition to a slightly modified grading of reticulin and collagen BM fibers
(Table 8). It is important to emphasize that an accurate histologic diagnosis
has been proven to be key to predict prognosis in this group of diseases.13
Table 3
Diagnostic criteria for CNL
CNL diagnostic criteria . 1. PB WBC ≥25 × 109/L Segmented neutrophils plus band
forms ≥80% of WBCs Neutrophil precursors (promyelocytes, myelocytes, and
metamyelocytes) <10% of WBC Myeloblasts rarely observed Monocyte count <1 ×
109/L No dysgranulopoiesis 2. Hypercellular BM Neutrophil granulocytes
increased in percentage and number Neutrophil maturation appears
normal Myeloblasts <5% of nucleated cells 3. Not meeting WHO criteria for
BCR-ABL1+ CML, PV, ET, or PMF 4. No rearrangement of PDGFRA, PDGFRB, or FGFR1,
or PCM1-JAK2 5. Presence of CSF3R T618I or other activating CSF3R mutation or In
the absence of a CSFR3R mutation, persistent neutrophilia (at least 3 mo),
splenomegaly and no identifiable cause of reactive neutrophilia including
absence of a plasma cell neoplasm or, if present, demonstration of clonality of
myeloid cells by cytogenetic or molecular studies
CNL diagnostic criteria . 1. PB WBC ≥25 × 109/L Segmented neutrophils plus band
forms ≥80% of WBCs Neutrophil precursors (promyelocytes, myelocytes, and
metamyelocytes) <10% of WBC Myeloblasts rarely observed Monocyte count <1 ×
109/L No dysgranulopoiesis 2. Hypercellular BM Neutrophil granulocytes
increased in percentage and number Neutrophil maturation appears
normal Myeloblasts <5% of nucleated cells 3. Not meeting WHO criteria for
BCR-ABL1+ CML, PV, ET, or PMF 4. No rearrangement of PDGFRA, PDGFRB, or FGFR1,
or PCM1-JAK2 5. Presence of CSF3R T618I or other activating CSF3R mutation or In
the absence of a CSFR3R mutation, persistent neutrophilia (at least 3 mo),
splenomegaly and no identifiable cause of reactive neutrophilia including
absence of a plasma cell neoplasm or, if present, demonstration of clonality of
myeloid cells by cytogenetic or molecular studies
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Table 4
WHO criteria for PV
WHO PV criteria . Major criteria 1. Hemoglobin >16.5 g/dL in men Hemoglobin
>16.0 g/dL in women or, Hematocrit >49% in men Hematocrit >48% in
women or, increased red cell mass (RCM)* 2. BM biopsy showing hypercellularity
for age with trilineage growth (panmyelosis) including prominent erythroid,
granulocytic, and megakaryocytic proliferation with pleomorphic, mature
megakaryocytes (differences in size) 3. Presence of JAK2V617F or JAK2 exon 12
mutation Minor criterion Subnormal serum erythropoietin level Diagnosis of PV
requires meeting either all 3 major criteria, or the first 2 major criteria and
the minor criterion†
WHO PV criteria . Major criteria 1. Hemoglobin >16.5 g/dL in men Hemoglobin
>16.0 g/dL in women or, Hematocrit >49% in men Hematocrit >48% in
women or, increased red cell mass (RCM)* 2. BM biopsy showing hypercellularity
for age with trilineage growth (panmyelosis) including prominent erythroid,
granulocytic, and megakaryocytic proliferation with pleomorphic, mature
megakaryocytes (differences in size) 3. Presence of JAK2V617F or JAK2 exon 12
mutation Minor criterion Subnormal serum erythropoietin level Diagnosis of PV
requires meeting either all 3 major criteria, or the first 2 major criteria and
the minor criterion†
*
More than 25% above mean normal predicted value.
†
Criterion number 2 (BM biopsy) may not be required in cases with sustained
absolute erythrocytosis: hemoglobin levels >18.5 g/dL in men (hematocrit, 55.5%)
or >16.5 g/dL in women (hematocrit, 49.5%) if major criterion 3 and the minor
criterion are present. However, initial myelofibrosis (present in up to 20% of
patients) can only be detected by performing a BM biopsy; this finding may
predict a more rapid progression to overt myelofibrosis (post-PV MF).
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Table 5
WHO criteria for ET
WHO ET criteria . Major criteria 1. Platelet count ≥450 × 109/L 2. BM biopsy
showing proliferation mainly of the megakaryocyte lineage with increased numbers
of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant
increase or left shift in neutrophil granulopoiesis or erythropoiesis and very
rarely minor (grade 1) increase in reticulin fibers 3. Not meeting WHO criteria
for BCR-ABL1+ CML, PV, PMF, myelodysplastic syndromes, or other myeloid
neoplasms 4. Presence of JAK2, CALR, or MPL mutation Minor criterion Presence
of a clonal marker or absence of evidence for reactive thrombocytosis Diagnosis
of ET requires meeting all 4 major criteria or the first 3 major criteria and
the minor criterion
WHO ET criteria . Major criteria 1. Platelet count ≥450 × 109/L 2. BM biopsy
showing proliferation mainly of the megakaryocyte lineage with increased numbers
of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant
increase or left shift in neutrophil granulopoiesis or erythropoiesis and very
rarely minor (grade 1) increase in reticulin fibers 3. Not meeting WHO criteria
for BCR-ABL1+ CML, PV, PMF, myelodysplastic syndromes, or other myeloid
neoplasms 4. Presence of JAK2, CALR, or MPL mutation Minor criterion Presence
of a clonal marker or absence of evidence for reactive thrombocytosis Diagnosis
of ET requires meeting all 4 major criteria or the first 3 major criteria and
the minor criterion
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Table 6
WHO criteria for prePMF
WHO prePMF criteria . Major criteria 1. Megakaryocytic proliferation and
atypia, without reticulin fibrosis >grade 1*, accompanied by increased
age-adjusted BM cellularity, granulocytic proliferation, and often decreased
erythropoiesis 2. Not meeting the WHO criteria for BCR-ABL1+ CML, PV, ET,
myelodysplastic syndromes, or other myeloid neoplasms 3. Presence of JAK2,
CALR, or MPL mutation or in the absence of these mutations, presence of another
clonal marker,† or absence of minor reactive BM reticulin fibrosis‡ Minor
criteria Presence of at least 1 of the following, confirmed in 2 consecutive
determinations: a. Anemia not attributed to a comorbid condition b.
Leukocytosis ≥11 × 109/L c. Palpable splenomegaly d. LDH increased to above
upper normal limit of institutional reference range Diagnosis of prePMF requires
meeting all 3 major criteria, and at least 1 minor criterion
WHO prePMF criteria . Major criteria 1. Megakaryocytic proliferation and
atypia, without reticulin fibrosis >grade 1*, accompanied by increased
age-adjusted BM cellularity, granulocytic proliferation, and often decreased
erythropoiesis 2. Not meeting the WHO criteria for BCR-ABL1+ CML, PV, ET,
myelodysplastic syndromes, or other myeloid neoplasms 3. Presence of JAK2,
CALR, or MPL mutation or in the absence of these mutations, presence of another
clonal marker,† or absence of minor reactive BM reticulin fibrosis‡ Minor
criteria Presence of at least 1 of the following, confirmed in 2 consecutive
determinations: a. Anemia not attributed to a comorbid condition b.
Leukocytosis ≥11 × 109/L c. Palpable splenomegaly d. LDH increased to above
upper normal limit of institutional reference range Diagnosis of prePMF requires
meeting all 3 major criteria, and at least 1 minor criterion
*
See Table 8.
†
In the absence of any of the 3 major clonal mutations, the search for the most
frequent accompanying mutations (eg, ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1)
are of help in determining the clonal nature of the disease.
‡
Minor (grade 1) reticulin fibrosis secondary to infection, autoimmune disorder
or other chronic inflammatory conditions, hairy cell leukemia or other lymphoid
neoplasm, metastatic malignancy, or toxic (chronic) myelopathies.
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Table 7
WHO criteria for overt PMF
WHO overt PMF criteria . Major criteria 1. Presence of megakaryocytic
proliferation and atypia, accompanied by either reticulin and/or collagen
fibrosis grades 2 or 3* 2. Not meeting WHO criteria for ET, PV, BCR-ABL1+ CML,
myelodysplastic syndromes, or other myeloid neoplasms 3. Presence of JAK2,
CALR, or MPL mutation or in the absence of these mutations, presence of another
clonal marker,† or absence of reactive myelofibrosis‡ Minor criteria Presence of
at least 1 of the following, confirmed in 2 consecutive determinations: a.
Anemia not attributed to a comorbid condition b. Leukocytosis ≥11 × 109/L c.
Palpable splenomegaly d. LDH increased to above upper normal limit of
institutional reference range e. Leukoerythroblastosis Diagnosis of overt PMF
requires meeting all 3 major criteria, and at least 1 minor criterion
WHO overt PMF criteria . Major criteria 1. Presence of megakaryocytic
proliferation and atypia, accompanied by either reticulin and/or collagen
fibrosis grades 2 or 3* 2. Not meeting WHO criteria for ET, PV, BCR-ABL1+ CML,
myelodysplastic syndromes, or other myeloid neoplasms 3. Presence of JAK2,
CALR, or MPL mutation or in the absence of these mutations, presence of another
clonal marker,† or absence of reactive myelofibrosis‡ Minor criteria Presence of
at least 1 of the following, confirmed in 2 consecutive determinations: a.
Anemia not attributed to a comorbid condition b. Leukocytosis ≥11 × 109/L c.
Palpable splenomegaly d. LDH increased to above upper normal limit of
institutional reference range e. Leukoerythroblastosis Diagnosis of overt PMF
requires meeting all 3 major criteria, and at least 1 minor criterion
*
See Table 8.
†
In the absence of any of the 3 major clonal mutations, the search for the most
frequent accompanying mutations (eg, ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1)
are of help in determining the clonal nature of the disease.
‡
BM fibrosis secondary to infection, autoimmune disorder, or other chronic
inflammatory conditions, hairy cell leukemia or other lymphoid neoplasm,
metastatic malignancy, or toxic (chronic) myelopathies.
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Table 8
Grading of myelofibrosis
Myelofibrosis grading . MF-0 Scattered linear reticulin with no intersections
(crossovers) corresponding to normal BM MF-1 Loose network of reticulin with
many intersections, especially in perivascular areas MF-2 Diffuse and dense
increase in reticulin with extensive intersections, occasionally with focal
bundles of thick fibers mostly consistent with collagen, and/or focal
osteosclerosis* MF-3 Diffuse and dense increase in reticulin with extensive
intersections and coarse bundles of thick fibers consistent with collagen,
usually associated with osteosclerosis*
Myelofibrosis grading . MF-0 Scattered linear reticulin with no intersections
(crossovers) corresponding to normal BM MF-1 Loose network of reticulin with
many intersections, especially in perivascular areas MF-2 Diffuse and dense
increase in reticulin with extensive intersections, occasionally with focal
bundles of thick fibers mostly consistent with collagen, and/or focal
osteosclerosis* MF-3 Diffuse and dense increase in reticulin with extensive
intersections and coarse bundles of thick fibers consistent with collagen,
usually associated with osteosclerosis*
Semiquantitative grading of BM fibrosis (MF) with minor modifications concerning
collagen and osteosclerosis. Fiber density should be assessed only in
hematopoietic areas.
*
In grades MF-2 or MF-3 an additional trichrome stain is recommended.
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MASTOCYTOSIS
As mentioned, mastocytosis is no longer listed under the broad heading of MPNs.
Major advances in the understanding of mastocytosis have been made since the
2008 classification,19 and these are incorporated into the text of the
monograph. Table 9 20 lists the 2016 categories of mastocytosis, which includes
a shortening of the name of the 2008 category of “systemic mastocytosis with
associated clonal hematological non-mast-cell lineage disease (SH-AHNMD)” to the
2016 category of “systemic mastocytosis with an associated hematological
neoplasm (SM-AHN).” In many cases, the AHN is an aggressive neoplasm that must
be treated and the diagnosis should clearly and separately indicate the presence
of this disorder in a distinct diagnosis line.
Table 9
WHO classification of mastocytosis
WHO mastocytosis classification . 1. Cutaneous mastocytosis (CM) 2. Systemic
mastocytosis a. Indolent systemic mastocytosis (ISM)* b. Smoldering systemic
mastocytosis (SSM)* c. Systemic mastocytosis with an associated hematological
neoplasm (SM-AHN)† d. Aggressive systemic mastocytosis (ASM)* e. Mast cell
leukemia (MCL) 3. Mast cell sarcoma (MCS)
WHO mastocytosis classification . 1. Cutaneous mastocytosis (CM) 2. Systemic
mastocytosis a. Indolent systemic mastocytosis (ISM)* b. Smoldering systemic
mastocytosis (SSM)* c. Systemic mastocytosis with an associated hematological
neoplasm (SM-AHN)† d. Aggressive systemic mastocytosis (ASM)* e. Mast cell
leukemia (MCL) 3. Mast cell sarcoma (MCS)
*
These subtypes require information regarding B and C findings for complete
diagnosis,20 all of which may not be available at the time of initial tissue
diagnosis.
†
This category is equivalent to the previously described “systemic mastocytosis
with an associated clonal hematological non-mast cell lineage disease
(SM-AHNMD).” AHNMD and AHN can be used synonymously.
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MYELOID/LYMPHOID NEOPLASMS ASSOCIATED WITH EOSINOPHILIA AND REARRANGEMENT OF
PDGFRA, PDGFRB, OR FGFR1 OR WITH PCM1-JAK2
The criteria for the diagnosis of the eosinophilia-related proliferations
associated with specific molecular genetic changes are retained in the
classification, although it is noted that eosinophilia may be absent in a subset
cases. In the 2016 revision (Table 10), this disease group will incorporate the
myeloid neoplasm with t(8;9)(p22;p24.1);PCM1-JAK2 as a new provisional
entity.21,22 This rare entity is characterized by a combination of eosinophilia
with BM findings of left-shifted erythroid predominance, lymphoid aggregates,
and often myelofibrosis, at times mimicking PMF. It can also rarely present as
T- or B-lymphoblastic leukemia (acute lymphoblastic leukemia [ALL]) and responds
to JAK inhibition.23 Other JAK2-rearranged neoplasms, for example,
t(9;12)(p24.1;p13.2);ETV6-JAK2 and t(9;22)(p24.1;q11.2);BCR-JAK2 may have
similar features, but are uncommon and are not currently included as distinct
entities. Moreover, ETV6-JAK2 and BCR-JAK2–rearranged neoplasms present
primarily as B-cell ALL (B-ALL), and these are best considered as BCR-ABL1–like
B-ALL, a new provisional category of B-lymphoblastic leukemia/lymphoma.22
Table 10
Molecular genetic abnormalities in myeloid/lymphoid neoplasms associated with
eosinophilia
Disease . Presentation . Genetics . Treatment . PDGFRA Eosinophilia Cryptic
deletion at 4q12 Respond to TKI ↑Serum tryptase FIP1L1-PDGFRA, at least 66 other
partners ↑Marrow mast cells PDGFRB Eosinophilia t(5;12)(q32;p13.2) ETV6-PDGFRB,
at least 25 other partners Respond to TKI Monocytosis mimicking
CMML FGFR1 Eosinophilia Translocations of 8p11.2 Poor prognosis; do not respond
to TKI Often presents with T-ALL or AML FGFR1-various
partners PCM1-JAK2 Eosinophilia t(8;9)(p22;p24.1) PCM1-JAK2 May respond to JAK2
inhibitors Rarely presents with T-LBL or B-ALL Bone marrow shows left-shifted
erythroid predominance and lymphoid aggregates
Disease . Presentation . Genetics . Treatment . PDGFRA Eosinophilia Cryptic
deletion at 4q12 Respond to TKI ↑Serum tryptase FIP1L1-PDGFRA, at least 66 other
partners ↑Marrow mast cells PDGFRB Eosinophilia t(5;12)(q32;p13.2) ETV6-PDGFRB,
at least 25 other partners Respond to TKI Monocytosis mimicking
CMML FGFR1 Eosinophilia Translocations of 8p11.2 Poor prognosis; do not respond
to TKI Often presents with T-ALL or AML FGFR1-various
partners PCM1-JAK2 Eosinophilia t(8;9)(p22;p24.1) PCM1-JAK2 May respond to JAK2
inhibitors Rarely presents with T-LBL or B-ALL Bone marrow shows left-shifted
erythroid predominance and lymphoid aggregates
↑, Increased.
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MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS
The myelodysplastic syndrome (MDS)/MPN category was introduced in the third
edition to include myeloid neoplasms with clinical, laboratory, and morphologic
features that overlap between MDS and MPN.24 Based on accumulated scientific
evidence, a provisional entity within the MDS/MPN unclassifiable group,
refractory anemia with ring sideroblasts associated with marked thrombocytosis
(RARS-T), has been accepted as a full entity, now termed MDS/MPN with ring
sideroblasts and thrombocytosis in the 2016 revision. The 2016 revised criteria
for diseases in this category are summarized in Tables 11-14.25
Table 11
Diagnostic criteria for CMML
CMML diagnostic criteria . • Persistent PB monocytosis ≥1 × 109/L, with
monocytes accounting for ≥10% of the WBC count • Not meeting WHO criteria for
BCR-ABL1+ CML, PMF, PV, or ET* • No evidence of PDGFRA, PDGFRB, or FGFR1
rearrangement or PCM1-JAK2 (should be specifically excluded in cases with
eosinophilia) • <20% blasts in the blood and BM† • Dysplasia in 1 or more
myeloid lineages. If myelodysplasia is absent or minimal, the diagnosis of CMML
may still be made if the other requirements are met and • An acquired clonal
cytogenetic or molecular genetic abnormality is present in hemopoietic
cells‡ or • The monocytosis (as previously defined) has persisted for at least 3
mo and • All other causes of monocytosis have been excluded
CMML diagnostic criteria . • Persistent PB monocytosis ≥1 × 109/L, with
monocytes accounting for ≥10% of the WBC count • Not meeting WHO criteria for
BCR-ABL1+ CML, PMF, PV, or ET* • No evidence of PDGFRA, PDGFRB, or FGFR1
rearrangement or PCM1-JAK2 (should be specifically excluded in cases with
eosinophilia) • <20% blasts in the blood and BM† • Dysplasia in 1 or more
myeloid lineages. If myelodysplasia is absent or minimal, the diagnosis of CMML
may still be made if the other requirements are met and • An acquired clonal
cytogenetic or molecular genetic abnormality is present in hemopoietic
cells‡ or • The monocytosis (as previously defined) has persisted for at least 3
mo and • All other causes of monocytosis have been excluded
*
Cases of MPN can be associated with monocytosis or they can develop it during
the course of the disease. These cases may simulate CMML. In these rare
instances, a previous documented history of MPN excludes CMML, whereas the
presence of MPN features in the BM and/or of MPN-associated mutations (JAK2,
CALR, or MPL) tend to support MPN with monocytosis rather than CMML.
†
Blasts and blast equivalents include myeloblasts, monoblasts, and promonocytes.
Promonocytes are monocytic precursors with abundant light gray or slightly
basophilic cytoplasm with a few scattered, fine lilac-colored granules, finely
distributed, stippled nuclear chromatin, variably prominent nucleoli, and
delicate nuclear folding or creasing. Abnormal monocytes, which can be present
both in the PB and BM, are excluded from the blast count.
‡
The presence of mutations in genes often associated with CMML (eg, TET2, SRSF2,
ASXL1, SETBP1) in the proper clinical contest can be used to support a
diagnosis. It should be noted however, that many of these mutations can be
age-related or be present in subclones. Therefore, caution would have to be used
in the interpretation of these genetic results.
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Table 12
Diagnostic criteria for aCML, BCR-ABL1−
aCML diagnostic criteria . • PB leukocytosis due to increased numbers of
neutrophils and their precursors (promyelocytes, myelocytes, metamyelocytes)
comprising ≥10% of leukocytes) • Dysgranulopoiesis, which may include abnormal
chromatin clumping • No or minimal absolute basophilia; basophils usually <2% of
leukocytes • No or minimal absolute monocytosis; monocytes <10% of leukocytes •
Hypercellular BM with granulocytic proliferation and granulocytic dysplasia,
with or without dysplasia in the erythroid and megakaryocytic lineages • <20%
blasts in the blood and BM • No evidence of PDGFRA, PDGFRB, or FGFR1
rearrangement, or PCM1-JAK2 • Not meeting WHO criteria for BCR-ABL1+ CML, PMF,
PV, or ET*
aCML diagnostic criteria . • PB leukocytosis due to increased numbers of
neutrophils and their precursors (promyelocytes, myelocytes, metamyelocytes)
comprising ≥10% of leukocytes) • Dysgranulopoiesis, which may include abnormal
chromatin clumping • No or minimal absolute basophilia; basophils usually <2% of
leukocytes • No or minimal absolute monocytosis; monocytes <10% of leukocytes •
Hypercellular BM with granulocytic proliferation and granulocytic dysplasia,
with or without dysplasia in the erythroid and megakaryocytic lineages • <20%
blasts in the blood and BM • No evidence of PDGFRA, PDGFRB, or FGFR1
rearrangement, or PCM1-JAK2 • Not meeting WHO criteria for BCR-ABL1+ CML, PMF,
PV, or ET*
*
Cases of MPN, particularly those in accelerated phase and/or in
post-polycythemic or post-essential thrombocythemic myelofibrosis, if
neutrophilic, may simulate aCML. A previous history of MPN, the presence of MPN
features in the BM and/or MPN-associated mutations (in JAK2, CALR, or MPL) tend
to exclude a diagnosis of aCML. Conversely, a diagnosis of aCML is supported by
the presence of SETBP1 and/or ETNK1 mutations. The presence of a CSF3R mutation
is uncommon in aCML and if detected should prompt a careful morphologic review
to exclude an alternative diagnosis of CNL or other myeloid neoplasm.
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Table 13
Diagnostic criteria for MDS/MPN with ring sideroblasts and thrombocytosis
MDS/MPN diagnostic criteria . • Anemia associated with erythroid lineage
dysplasia with or without multilineage dysplasia, ≥15% ring sideroblasts,* <1%
blasts in PB and <5% blasts in the BM • Persistent thrombocytosis with platelet
count ≥450 × 109/L • Presence of a SF3B1 mutation or, in the absence of SF3B1
mutation, no history of recent cytotoxic or growth factor therapy that could
explain the myelodysplastic/myeloproliferative features† • No BCR-ABL1 fusion
gene, no rearrangement of PDGFRA, PDGFRB, or FGFR1; or PCM1-JAK2; no
(3;3)(q21;q26), inv(3)(q21q26) or del(5q)‡ • No preceding history of MPN, MDS
(except MDS-RS), or other type of MDS/MPN
MDS/MPN diagnostic criteria . • Anemia associated with erythroid lineage
dysplasia with or without multilineage dysplasia, ≥15% ring sideroblasts,* <1%
blasts in PB and <5% blasts in the BM • Persistent thrombocytosis with platelet
count ≥450 × 109/L • Presence of a SF3B1 mutation or, in the absence of SF3B1
mutation, no history of recent cytotoxic or growth factor therapy that could
explain the myelodysplastic/myeloproliferative features† • No BCR-ABL1 fusion
gene, no rearrangement of PDGFRA, PDGFRB, or FGFR1; or PCM1-JAK2; no
(3;3)(q21;q26), inv(3)(q21q26) or del(5q)‡ • No preceding history of MPN, MDS
(except MDS-RS), or other type of MDS/MPN
*
At least 15% ring sideroblasts required even if SF3B1 mutation is detected.
†
A diagnosis of MDS/MPN-RS-T is strongly supported by the presence of SF3B1
mutation together with a mutation in JAK2 V617F, CALR, or MPL genes.
‡
In a case which otherwise fulfills the diagnostic criteria for MDS with isolated
del(5q)-no or minimal absolute basophilia; basophils usually <2% of leukocytes.
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Table 14
Diagnostic criteria for JMML
JMML diagnostic criteria . I. Clinical and hematologic features (all 4 features
mandatory) • PB monocyte count ≥1 × 109/L • Blast percentage in PB and BM
<20% • Splenomegaly • Absence of Philadelphia chromosome (BCR/ABL1
rearrangement) II. Genetic studies (1 finding sufficient) • Somatic mutation in
PTPN11* or KRAS* or NRAS* • Clinical diagnosis of NF1 or NF1 mutation • Germ
line CBL mutation and loss of heterozygosity of CBL† III. For patients without
genetic features, besides the clinical and hematologic features listed under I,
the following criteria must be fulfilled: • Monosomy 7 or any other chromosomal
abnormality or at least 2 of the following criteria: • Hemoglobin F increased
for age • Myeloid or erythroid precursors on PB smear • GM-CSF
hypersensitivity in colony assay • Hyperphosphorylation of STAT5
JMML diagnostic criteria . I. Clinical and hematologic features (all 4 features
mandatory) • PB monocyte count ≥1 × 109/L • Blast percentage in PB and BM
<20% • Splenomegaly • Absence of Philadelphia chromosome (BCR/ABL1
rearrangement) II. Genetic studies (1 finding sufficient) • Somatic mutation in
PTPN11* or KRAS* or NRAS* • Clinical diagnosis of NF1 or NF1 mutation • Germ
line CBL mutation and loss of heterozygosity of CBL† III. For patients without
genetic features, besides the clinical and hematologic features listed under I,
the following criteria must be fulfilled: • Monosomy 7 or any other chromosomal
abnormality or at least 2 of the following criteria: • Hemoglobin F increased
for age • Myeloid or erythroid precursors on PB smear • GM-CSF
hypersensitivity in colony assay • Hyperphosphorylation of STAT5
Modified from Locatelli and Niemeyer25 with permission.
*
Germ line mutations (indicating Noonan syndrome) need to be excluded.
†
Occasional cases with heterozygous splice site mutations.
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In MDS/MPN, the karyotype is often normal or shows abnormalities in common with
MDS. Targeted sequencing of genes mutated in myeloid neoplasms detects mutations
in a high proportion of cases of chronic myelomonocytic leukemia (CMML) as well
as other MDS/MPN patients.26 The most commonly mutated genes in CMML are SRSF2,
TET2, and/or ASXL1 (>80% of cases).26,27 Other mutations which occur at lower
frequency include SETBP1, NRAS/KRAS, RUNX1, CBL, and EZH2.28,29 They can be
helpful adjunct studies in difficult cases, particularly given the frequently
normal karyotype of CMML, but should not be used alone as proof of neoplasia
because some of these mutations occur in healthy older patients as so-called
clonal hematopoiesis of indeterminate potential (CHIP)30,31 (for further
discussion, see “Myelodysplastic syndromes”). ASXL1 is a predictor of aggressive
disease behavior and has been incorporated into a prognostic scoring system for
CMML alongside karyotype and clinicopathologic parameters.27 Of note, NPM1
mutation is seen in a rare subset of CMML (3%-5%) and appears also to herald a
more aggressive clinical course.
CHRONIC MYELOMONOCYTIC LEUKEMIA
A diagnosis of CMML requires both the presence of persistent PB monocytosis ≥1 ×
109/L and monocytes accounting for ≥10% of the white blood cell (WBC)
differential count. Due to the discovery of molecular and clinical differences
between the so-called “proliferative type” of CMML (WBC count ≥13 × 109/L) and
the “dysplastic type” (WBC <13 × 109/L), particularly those differences related
to aberrancies in the RAS/MAPK signaling pathways,32-34 the separation of CMML
into these subtypes is warranted. In addition, blast percentage maintains clear
prognostic importance in CMML as initially suggested in the third edition and
later confirmed in the fourth edition. Recent evidence has shown that a more
precise prognostication can be obtained with 3 blast-based groupings: CMML-0, a
category for cases with <2% blasts in PB and <5% blasts in BM; CMML-1 for cases
with 2% to 4% blasts in PB and/or 5% to 9% blasts in BM; and CMML-2 for cases
with 5% to 19% blasts in PB, 10% to 19% in BM, and/or when any Auer rods are
present.33,35 The revision incorporates the CMML-0 category into the
classification scheme. In view of the importance of separating promonocytes
(blast equivalent cells) from monocytes, which can have abnormal features in
CMML, precise morphologic evaluation is essential, with the appropriate
integration of flow cytometry immunophenotyping and cytogenetic and molecular
genetic testing. Because other disorders must be excluded before a diagnosis of
CMML can be made, BCR-ABL1 rearrangement should be excluded in all cases and
PDGFRA, PDGFRB, FGFR1 rearrangements or PCM1-JAK2 fusions excluded if
eosinophilia is present. A prior well-documented diagnosis of a MPN would also
generally exclude CMML or another type of MDS/MPN.36,37
ATYPICAL CML, BCR-ABL1−
The rare MDS/MPN subtype atypical CML (aCML) is now better characterized
molecularly and can be more easily separated from CNL, a rare subtype of MPN
similarly characterized by neutrophilia. Although CNL is strongly associated
with the presence of CSF3R mutations, these appear to be very rare in aCML
(<10%).38 Conversely, aCML is associated with SETBP1 and/or ETNK1 mutations in
up to a third of cases.28,39,40 The so-called MPN-associated driver mutations
(JAK2, CALR, MPL) are typically absent in aCML.
MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM WITH RING SIDEROBLASTS AND
THROMBOCYTOSIS
The criteria for MDS/MPN with ring sideroblasts and thrombocytosis
(MDS/MPN-RS-T; previously known as RARS-T) include thrombocytosis (≥450 × 109/L)
associated with refractory anemia, dyserythropoiesis in the BM with ring
sideroblasts accounting for 15% or more of erythroid precursors, and
megakaryocytes with features resembling those in PMF or ET. After the discovery
that MDS/MPN-RS-T is frequently associated with mutations in the spliceosome
gene SF3B1 (which in turn are associated with the presence of ring
sideroblasts), there is now enough evidence to support MDS/MPN-RS-T as a full
entity.41-44 In MDS/MPN-RS-T, SF3B1 is often comutated with JAK2 V617F or less
frequently (<10%) with CALR, or MPL genes, thus providing a biological
explanation for the true hybrid nature of this rare myeloid neoplasm. Unlike MDS
with ring sideroblasts (see “Myelodysplastic syndromes”), the number of ring
sideroblasts required for a diagnosis of MDS/MPN-RS-T is not altered by the
presence or absence of a mutation in SF3B1. Because of changes in the MDS
terminology (see “Myelodysplastic syndromes”), the name RARS-T was changed to
MDS/MPN-RS-T.
JUVENILE MYELOMONOCYTIC LEUKEMIA
Juvenile myelomonocytic leukemia (JMML) is an aggressive clonal hematopoietic
disorder of infancy and early childhood characterized by an excessive
proliferation of cells of monocytic and granulocytic lineages that is included
as a MDS/MPN subtype.45,46 Approximately 90% of patients carry either somatic
or germ line mutations of PTPN11, KRAS, NRAS, CBL, or NF1. These genetic
aberrations are largely mutually exclusive and activate the RAS/MAPK pathway.
The clinical and pathological findings of JMML are not substantially changed
from the current WHO fourth edition (2008). However, molecular diagnostic
parameters have been refined. The updated diagnostic findings are listed in
Table 14.
MYELODYSPLASTIC SYNDROMES
The MDS are a group of clonal BM neoplasms characterized by ineffective
hematopoiesis, manifested by morphologic dysplasia in hematopoietic cells and by
peripheral cytopenia(s). The revised classification introduces refinements in
morphologic interpretation and cytopenia assessment and addresses the influence
of rapidly accumulating genetic information in MDS diagnosis and classification.
Cytopenia is a “sine qua non” for any MDS diagnosis and in prior
classifications, MDS nomenclature included references to “cytopenia” or to
specific types of cytopenia (eg, “refractory anemia”). However, the WHO
classification relies mainly on the degree of dysplasia and blast percentages
for disease classification and specific cytopenias have only minor impact on MDS
classification. Moreover, the lineage(s) manifesting significant morphologic
dysplasia frequently do not correlate with the specific cytopenia(s) in
individual MDS cases.47-49 For these reasons, the terminology for adult MDS has
changed to remove terms such as “refractory anemia” and “refractory cytopenia”
and replaces them with “myelodysplastic syndrome” followed by the appropriate
modifiers: single vs multilineage dysplasia, ring sideroblasts, excess blasts,
or the del(5q) cytogenetic abnormality (see Table 15). There are no changes to
childhood MDS; refractory cytopenia of childhood remains as a provisional entity
within this category.
Table 15
PB and BM findings and cytogenetics of MDS
Name . Dysplastic lineages . Cytopenias* . Ring sideroblasts as % of marrow
erythroid elements . BM and PB blasts . Cytogenetics by conventional karyotype
analysis . MDS with single lineage dysplasia (MDS-SLD) 1 1 or 2 <15%/<5%† BM
<5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS with
isolated del(5q) MDS with multilineage dysplasia (MDS-MLD) 2 or
3 1-3 <15%/<5%† BM <5%, PB <1%, no Auer rods Any, unless fulfills all criteria
for MDS with isolated del(5q) MDS with ring sideroblasts (MDS-RS) MDS-RS
with single lineage dysplasia (MDS-RS-SLD) 1 1 or 2 ≥15%/≥5%† BM <5%, PB <1%, no
Auer rods Any, unless fulfills all criteria for MDS with isolated
del(5q) MDS-RS with multilineage dysplasia (MDS-RS-MLD) 2 or 3 1-3 ≥15%/≥5%† BM
<5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS with
isolated del(5q) MDS with isolated del(5q) 1-3 1-2 None or any BM <5%, PB <1%,
no Auer rods del(5q) alone or with 1 additional abnormality except −7 or
del(7q) MDS with excess blasts (MDS-EB) MDS-EB-1 0-3 1-3 None or any BM
5%-9% or PB 2%-4%, no Auer rods Any MDS-EB-2 0-3 1-3 None or any BM 10%-19% or
PB 5%-19% or Auer rods Any MDS, unclassifiable (MDS-U) with 1% blood
blasts 1-3 1-3 None or any BM <5%, PB = 1%,‡ no Auer rods Any with single
lineage dysplasia and pancytopenia 1 3 None or any BM <5%, PB <1%, no Auer
rods Any based on defining cytogenetic abnormality 0 1-3 <15%§ BM <5%, PB <1%,
no Auer rods MDS-defining abnormality Refractory cytopenia of
childhood 1-3 1-3 None BM <5%, PB <2% Any
Name . Dysplastic lineages . Cytopenias* . Ring sideroblasts as % of marrow
erythroid elements . BM and PB blasts . Cytogenetics by conventional karyotype
analysis . MDS with single lineage dysplasia (MDS-SLD) 1 1 or 2 <15%/<5%† BM
<5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS with
isolated del(5q) MDS with multilineage dysplasia (MDS-MLD) 2 or
3 1-3 <15%/<5%† BM <5%, PB <1%, no Auer rods Any, unless fulfills all criteria
for MDS with isolated del(5q) MDS with ring sideroblasts (MDS-RS) MDS-RS
with single lineage dysplasia (MDS-RS-SLD) 1 1 or 2 ≥15%/≥5%† BM <5%, PB <1%, no
Auer rods Any, unless fulfills all criteria for MDS with isolated
del(5q) MDS-RS with multilineage dysplasia (MDS-RS-MLD) 2 or 3 1-3 ≥15%/≥5%† BM
<5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS with
isolated del(5q) MDS with isolated del(5q) 1-3 1-2 None or any BM <5%, PB <1%,
no Auer rods del(5q) alone or with 1 additional abnormality except −7 or
del(7q) MDS with excess blasts (MDS-EB) MDS-EB-1 0-3 1-3 None or any BM
5%-9% or PB 2%-4%, no Auer rods Any MDS-EB-2 0-3 1-3 None or any BM 10%-19% or
PB 5%-19% or Auer rods Any MDS, unclassifiable (MDS-U) with 1% blood
blasts 1-3 1-3 None or any BM <5%, PB = 1%,‡ no Auer rods Any with single
lineage dysplasia and pancytopenia 1 3 None or any BM <5%, PB <1%, no Auer
rods Any based on defining cytogenetic abnormality 0 1-3 <15%§ BM <5%, PB <1%,
no Auer rods MDS-defining abnormality Refractory cytopenia of
childhood 1-3 1-3 None BM <5%, PB <2% Any
*
Cytopenias defined as: hemoglobin, <10 g/dL; platelet count, <100 × 109/L; and
absolute neutrophil count, <1.8 × 109/L. Rarely, MDS may present with mild
anemia or thrombocytopenia above these levels. PB monocytes must be <1 × 109/L
†
If SF3B1 mutation is present.
‡
One percent PB blasts must be recorded on at least 2 separate occasions.
§
Cases with ≥15% ring sideroblasts by definition have significant erythroid
dysplasia, and are classified as MDS-RS-SLD.
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One of the biggest challenges in this category is separating MDS from reactive
causes of cytopenia and dysplasia. Although the threshold to define dysplasia
will remain as 10% dysplastic cells in any hematopoietic lineage, it is
recognized that dysplasia in excess of 10% may occur in some normal individuals
and even more frequently in nonneoplastic causes of cytopenia.50,51 Moreover,
identification of dysplasia is not always reproducible among even experienced
hematopathologists.52,53 For these reasons, possible reactive etiologies of
dysplasia should always be carefully considered prior to making a diagnosis of
MDS, particularly when the dysplasia is subtle and limited to 1 lineage. Some
dysplastic changes, particularly the presence of micromegakaryocytes (which can
be highlighted by immunostaining for megakaryocyte markers in the BM trephine),
are relatively specific for myelodysplasia and have high reproducibility.53
The myeloblast percentage, as determined by counting well-prepared, cellular BM
aspirate smears and/or touch preparations and a PB smear, remains critical in
defining the WHO MDS categories and as risk strata in the Revised International
Prognostic Scoring System (IPSS-R).54 The presence of 1% blasts in the PB, with
<5% BM blasts, defines 1 type of MDS, unclassifiable (MDS-U). However, because
1% blasts may not be reproducible as a single observation, this finding must now
be demonstrated on at least 2 separate occasions in order to diagnose MDS-U
according to this criterion. There is a major change in the diagnostic criteria
for myeloid neoplasms with erythroid predominance (erythroid precursors ≥50% of
all BM cells). In the updated classification, the denominator used for
calculating blast percentage in all myeloid neoplasms is all nucleated BM cells,
not just the “nonerythroid cells.” This will result in most cases previously
diagnosed as the erythroid/myeloid subtype of acute erythroid leukemia now being
classified as MDS with excess blasts, as discussed in “AML, not otherwise
specified” (see Table 16).
Table 16
Diagnostic approach to myeloid neoplasms when erythroid precursors comprise ≥50%
of BM nucleated cells
BM erythroid precursors . Myeloblast % of all cells in BM (or PB) . Prior
therapy? . Recurring WHO genetic abnormality? . Meets criteria for AML-MRC?
. Fourth edition diagnosis . Updated fourth edition diagnosis
. ≥50% NA Yes NA NA Therapy-related myeloid neoplasm Therapy-related myeloid
neoplasm ≥50% ≥20% No Yes NA AML with recurring genetic abnormality AML with
recurring genetic abnormality ≥50% ≥20% No No Yes AML with
myelodysplasia-related changes AML with myelodysplasia-related
changes ≥50% ≥20% No No No AML, NOS, acute erythroid leukemia (erythroid/myeloid
type) AML, NOS (non erythroid subtype) ≥50% <20%, but ≥20% of nonerythroid
cells No No* NA AML, NOS, acute erythroid leukemia (erythroid/myeloid
subtype) MDS† ≥50% <20%, and <20% of nonerythroid cells No No* NA MDS† MDS† >80%
immature erythroid precursors with ≥30% proerythroblasts <20% No No* NA AML,
NOS, acute erythroid leukemia (pure erythroid type) AML, NOS, acute erythroid
leukemia (pure erythroid type)
BM erythroid precursors . Myeloblast % of all cells in BM (or PB) . Prior
therapy? . Recurring WHO genetic abnormality? . Meets criteria for AML-MRC?
. Fourth edition diagnosis . Updated fourth edition diagnosis
. ≥50% NA Yes NA NA Therapy-related myeloid neoplasm Therapy-related myeloid
neoplasm ≥50% ≥20% No Yes NA AML with recurring genetic abnormality AML with
recurring genetic abnormality ≥50% ≥20% No No Yes AML with
myelodysplasia-related changes AML with myelodysplasia-related
changes ≥50% ≥20% No No No AML, NOS, acute erythroid leukemia (erythroid/myeloid
type) AML, NOS (non erythroid subtype) ≥50% <20%, but ≥20% of nonerythroid
cells No No* NA AML, NOS, acute erythroid leukemia (erythroid/myeloid
subtype) MDS† ≥50% <20%, and <20% of nonerythroid cells No No* NA MDS† MDS† >80%
immature erythroid precursors with ≥30% proerythroblasts <20% No No* NA AML,
NOS, acute erythroid leukemia (pure erythroid type) AML, NOS, acute erythroid
leukemia (pure erythroid type)
AML-MRC, acute myeloid leukemia with myelodysplasia-related changes; NA, not
applicable.
*
Cases of AML t(8;21)(q22;q22.1);RUNX1-RUNX1T1, AML with inv(16)(p13.1q22) or
t(16;16)(p13.1;q22);CBFB-MYH11 or APL with PML-RARA, may rarely occur in this
setting with <20% blasts and those diagnoses would take precedence over a
diagnosis of AML, NOS, or MDS.
†
Classify based on myeloblast percentage of all BM cells and of PB leukocytes and
other MDS criteria.
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Despite the lowering of the neutropenia prognostic threshold in the IPSS-R to
0.8 × 109/L,54 the WHO thresholds defining cytopenia will remain as in the
original IPSS (hemoglobin, <10 g/dL; platelets, <100 × 109/L; absolute
neutrophil count, <1.8 × 109/L); a diagnosis of MDS may be made in rare cases
with milder levels of cytopenia, but at least 1 cytopenia must be present in
order to make the diagnosis. It should be noted that some ethnic groups may have
a reference range for normal absolute neutrophil count that is lower than 1.8 ×
109/L, and thus caution should be exercised in interpreting neutropenia if it is
the only cytopenia. MDS-U will continue to include cases with single lineage
dysplasia or isolated del(5q) and pancytopenia, but in such cases all PB counts
must be below the WHO thresholds given in this paragraph.
The same cytogenetic abnormalities listed in the 2008 WHO classification55
remain MDS-defining in a cytopenic patient, even in the absence of diagnostic
morphologic dysplasia. In such cases, the abnormality must be demonstrated by
conventional karyotyping, not by fluorescence in situ hybridization (FISH) or
sequencing technologies. The presence of +8, −Y, or del(20q) is not considered
to be MDS-defining in the absence of diagnostic morphologic features of MDS. In
spite of the increased knowledge of the prognostic importance of genetic
findings in MDS, del(5q) remains as the only cytogenetic or molecular genetic
abnormality that defines a specific MDS subtype. Based on recent data showing no
adverse effect of 1 chromosomal abnormality in addition to the del(5q),56-58
the entity MDS with isolated del(5q) may be diagnosed if there is 1 additional
cytogenetic abnormality besides the del(5q), unless that abnormality is monosomy
7 or del(7q). Even though cytogenetic findings are not used to define other
specific subtypes of MDS, they are strongly correlated with prognosis, as
reflected in the 5 cytogenetic prognostic groups in the IPSS-R scheme54,58 ;
thus, a complete BM karyotype remains a critical test in any newly diagnosed MDS
case.
As with all the other myeloid neoplasms, a large amount of data has recently
become available on recurring mutations in MDS. Targeted sequencing of a limited
number of genes can detect mutations in 80% to 90% of MDS patients; the most
commonly mutated genes in MDS are SF3B1, TET2, SRSF2, ASXL1, DNMT3A, RUNX1,
U2AF1, TP53, and EZH2.59,60 Importantly, acquired clonal mutations identical to
those seen in MDS can occur in the hematopoietic cells of apparently healthy
older individuals without MDS, so-called “clonal hematopoiesis of indeterminate
potential” (CHIP).30,31,61 Although some patients with CHIP subsequently
develop MDS, the natural history of this condition is not yet fully understood;
thus, the presence of MDS-associated somatic mutations alone is not considered
diagnostic of MDS in this classification, even in a patient with unexplained
cytopenia, where these mutations may be commonly found.62 Further study is
required to determine the optimal management and monitoring of such patients and
to investigate possible links between specific mutations, mutant allele
fraction, or mutation combinations and subsequent development of bona fide
MDS.63 Rare cases of familial MDS are associated with germ line mutations,
which can be investigated by sequencing non-MDS patient tissue.
The number and types of specific mutations are strongly associated with disease
outcome in MDS, and the addition of mutation data improves the prognostic value
of existing risk-stratification schemes in MDS.64,65 TP53 mutation is associated
with aggressive disease in MDS in general66 and appears to predict poorer
response to lenalidomide in patients with del(5q).67-69 Evaluation for TP53
mutation is recommended in patients with MDS with isolated del(5q) to help
identify an adverse prognostic subgroup in this generally favorable prognosis
MDS entity.
With regard to MDS with ring sideroblasts (MDS-RS), recurrent mutations in the
spliceosome gene SF3B1 are frequent in MDS and are associated with the presence
of ring sideroblasts. A change in the classification of MDS is the inclusion now
of MDS cases with ring sideroblasts and multilineage dysplasia, lacking excess
blasts or an isolated del(5q) abnormality, into the category of MDS-RS. This
change is based largely on the link between ring sideroblasts and an SF3B1
mutation, which appears to be an early event in MDS pathogenesis, manifests a
distinct gene expression profile, and correlates with a favorable
prognosis.42,44,70-72 Recent studies have shown that in cases of MDS with any
ring sideroblasts, the actual percentage of ring sideroblasts is not
prognostically relevant.73 Thus, in the revised classification, if an SF3B1
mutation is identified, a diagnosis of MDS-RS may be made if ring sideroblasts
comprise as few as 5% of nucleated erythroid cells, whereas at least 15% ring
sideroblasts are still required in cases lacking a demonstrable SF3B1 mutation.
MDS-RS cases will be subdivided into cases with single lineage dysplasia
(previously classified as refractory anemia with ring sideroblasts) and cases
with multilineage dysplasia (previously classified as refractory cytopenia with
multilineage dysplasia). Although MDS-RS cases lacking SF3B1 mutation appear to
have an adverse prognosis compared with those with the mutation, the role of
multilineage dysplasia vs the SF3B1 mutation in influencing outcome in MDS-RS
remains controversial.72,73
MYELOID NEOPLASMS WITH GERM LINE PREDISPOSITION
Although most cases of MDS or acute leukemia are sporadic diseases, it is
becoming clear that a subgroup of cases is associated with germ line mutations
and is familial.74 A major change to the 2016 revision of the WHO
classification is the addition of a section on myeloid neoplasms with germ line
predisposition, which includes cases of MDS, MDS/MPN, and acute leukemias that
occur on the background of a predisposing germ line mutation. The presence of
the specific underlying genetic defect or predisposition syndrome should be
noted as part of the diagnosis. Of note, germ line genetic aberrations are not
unique to the patient with MDS or acute leukemia and should raise awareness of
the need to screen family members for these aberrations. The major categories of
such familial cases are summarized in Table 17.
Table 17
Classification of myeloid neoplasms with germ line predisposition
Myeloid neoplasm classification . Myeloid neoplasms with germ line
predisposition without a preexisting disorder or organ dysfunction AML with
germ line CEBPA mutation Myeloid neoplasms with germ line DDX41
mutation* Myeloid neoplasms with germ line predisposition and preexisting
platelet disorders Myeloid neoplasms with germ line RUNX1 mutation* Myeloid
neoplasms with germ line ANKRD26 mutation* Myeloid neoplasms with germ line
ETV6 mutation* Myeloid neoplasms with germ line predisposition and other organ
dysfunction Myeloid neoplasms with germ line GATA2 mutation Myeloid neoplasms
associated with BM failure syndromes Myeloid neoplasms associated with telomere
biology disorders JMML associated with neurofibromatosis, Noonan syndrome
or Noonan syndrome-like disorders Myeloid neoplasms associated with Down
syndrome*
Myeloid neoplasm classification . Myeloid neoplasms with germ line
predisposition without a preexisting disorder or organ dysfunction AML with
germ line CEBPA mutation Myeloid neoplasms with germ line DDX41
mutation* Myeloid neoplasms with germ line predisposition and preexisting
platelet disorders Myeloid neoplasms with germ line RUNX1 mutation* Myeloid
neoplasms with germ line ANKRD26 mutation* Myeloid neoplasms with germ line
ETV6 mutation* Myeloid neoplasms with germ line predisposition and other organ
dysfunction Myeloid neoplasms with germ line GATA2 mutation Myeloid neoplasms
associated with BM failure syndromes Myeloid neoplasms associated with telomere
biology disorders JMML associated with neurofibromatosis, Noonan syndrome
or Noonan syndrome-like disorders Myeloid neoplasms associated with Down
syndrome*
*
Lymphoid neoplasms also reported.
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ACUTE MYELOID LEUKEMIA
AML WITH RECURRENT GENETIC ABNORMALITIES
The WHO continues to define specific acute myeloid leukemia (AML) disease
entities by focusing on significant cytogenetic and molecular genetic subgroups.
A large number of recurring, balanced cytogenetic abnormalities are recognized
in AML, and most of those that are not formally recognized by the classification
are rare.75 The most common of these rare abnormalities that occur in pediatric
patients are summarized in supplemental Table 1 (available on the Blood Web
site), but these will not represent new disease categories. Minor refinements
related to updates in gene names (such as the change from MLL to KMT2A) are
included as well as recognition that the inv(3)(q21.3q26.2) or
t(3;3)(q21.3;q26.2) does not represent a fusion gene, but repositions a distal
GATA2 enhancer to activate MECOM expression and simultaneously confer GATA2
haploinsufficiency.76,77 In order to stress the significance of the PML-RARA
fusion, which may be cryptic or result from complex cytogenetic rearrangements
other than t(15;17)(q24.1;q21.2), acute promyelocytic leukemia (APL) with this
fusion is renamed as APL with PML-RARA. Finally, a new provisional category of
AML with BCR-ABL1 is added to recognize these rare de novo AML cases that may
benefit from TKI therapy.78,79 Although the diagnostic distinction between de
novo AML with BCR-ABL1 and blast transformation of CML may be difficult without
adequate clinical information, the significance of detecting this targetable
fusion is felt to warrant a provisional disease category. Preliminary data
suggest that deletion of antigen receptor genes (IGH, TCR), IKZF1 and/or CDKN2A
may support a diagnosis of de novo disease vs BP of CML.80
Although the WHO authors struggled with how to incorporate the recent
discoveries in gene mutations in AML,81-83 the text for all disease categories
is expanded to discuss the prognostic significance of various gene mutations and
their frequency in the different AML subtypes. An updated table further
summarizes the various genes mutated in AML and their significance (supplemental
Table 2). The finding that the improved prognosis associated with AML with
mutated CEBPA is associated with biallelic, but not single, mutations of the
gene84-88 has resulted in a change in that disease definition to require
biallelic mutations. Additionally, due to the lack of prognostic significance of
multilineage dysplasia in patients without MDS-associated cytogenetic findings
and with a mutation of NPM1 or biallelic mutation of CEBPA,89-91 these
mutations now supersede the presence of multilineage dysplasia in the
classification. Finally, a provisional category of AML with mutated RUNX1 has
been added to the classification for cases of de novo AML with this mutation
that are not associated with MDS-related cytogenetic abnormalities. This new
provisional disease category appears to represent a biologically distinct group
with a possibly worse prognosis than other AML types.92-95
AML WITH MYELODYSPLASIA-RELATED CHANGES
The category of AML with myelodysplasia-related changes has been retained, but
is refined to better incorporate cases with features suggesting a poor
prognosis. As mentioned, the presence of multilineage dysplasia alone will not
classify a case as AML with myelodysplasia-related changes when a mutation of
NPM1 or biallelic mutation of CEBPA is present.89-91 In cases lacking these
mutations, the morphologic detection of multilineage dysplasia (defined as the
presence of 50% or more dysplastic cells in at least 2 cell lines) remains a
poor prognostic indicator and is sufficient to make a diagnosis of AML with
myelodysplasia-related changes.90,96,97 A history of MDS remains as an
inclusion criterion for this category as does the presence of an MDS-related
cytogenetic abnormality with 1 exception: del(9q) has been removed as a defining
cytogenetic abnormality for AML with myelodysplasia-related changes because of
its association with NPM1 or biallelic CEBPA mutations98,99 and its apparent
lack of prognostic significance in those settings. Table 18 lists the
cytogenetic abnormalities that now define AML with myelodysplasia-related
changes.
Table 18
Cytogenetic abnormalities sufficient to diagnose AML with myelodysplasia-related
changes when ≥20% PB or BM blasts are present and prior therapy has been
excluded
Cytogenetic abnormalities . Complex karyotype (3 or more
abnormalities) Unbalanced
abnormalities −7/del(7q) del(5q)/t(5q) i(17q)/t(17p) −13/del(13q) del(11q) del(12p)/t(12p) idic(X)(q13) Balanced
abnormalities t(11;16)(q23.3;p13.3) t(3;21)(q26.2;q22.1) t(1;3)(p36.3;q21.2) t(2;11)(p21;q23.3) t(5;12)(q32;p13.2) t(5;7)(q32;q11.2) t(5;17)(q32;p13.2) t(5;10)(q32;q21.2) t(3;5)(q25.3;q35.1)
Cytogenetic abnormalities . Complex karyotype (3 or more
abnormalities) Unbalanced
abnormalities −7/del(7q) del(5q)/t(5q) i(17q)/t(17p) −13/del(13q) del(11q) del(12p)/t(12p) idic(X)(q13) Balanced
abnormalities t(11;16)(q23.3;p13.3) t(3;21)(q26.2;q22.1) t(1;3)(p36.3;q21.2) t(2;11)(p21;q23.3) t(5;12)(q32;p13.2) t(5;7)(q32;q11.2) t(5;17)(q32;p13.2) t(5;10)(q32;q21.2) t(3;5)(q25.3;q35.1)
View Large
THERAPY-RELATED MYELOID NEOPLASMS
Therapy-related myeloid neoplasms (t-MNs) remain as a distinct category in the
classification for patients who develop myeloid neoplasms following cytotoxic
therapy. The t-MNs may be further subdivided as therapy-related MDS or AML
(t-MDS or t-AML), but the associated cytogenetic abnormality, which is important
for determining therapy and prognosis, should be identified in the final
diagnosis. A number of t-MN cases have been shown to have germ line mutations in
cancer susceptibility genes; careful family histories to uncover cancer
susceptibility are warranted in t-MN patients.100
AML, NOT OTHERWISE SPECIFIED
Although the subcategories of AML, not otherwise specified (NOS) lack prognostic
significance when cases are classified based on NPM1 mutation and CEBPA
biallelic mutation status,101 the CAC agreed to keep the AML, NOS subcategories
with only a single change: the subcategory of acute erythroid leukemia,
erythroid/myeloid type (previously defined as a case with ≥50% BM erythroid
precursors and ≥20% myeloblasts among nonerythroid cells) has been removed from
the AML category. In the new classification, myeloblasts are always counted as a
percentage of total marrow cells and the majority of such cases have <20% total
blast cells and are now classified as MDS (usually MDS with excess blasts). This
change was based on the close biologic relationship of erythroid/myeloid type
acute erythroid leukemia to MDS in terms of its clinical presentation,
morphologic features, and genetic abnormalities, as well as the low
reproducibility of nonerythroid blast counts and an attempt to achieve
uniformity in expressing blast percentages across all myeloid neoplasms.102-106
Cases with ≥50% or more erythroid cells and ≥20% total myeloblasts usually meet
criteria for AML with myelodysplasia-related changes and should be diagnosed as
such; cases with ≥20% total myeloblasts not meeting criteria for AML with
myelodysplasia-related changes or AML with recurrent genetic abnormalities
should be categorized as 1 of the other subtypes of AML, NOS. Pure erythroid
leukemia remains as an AML, NOS subtype and is now the only type of acute
erythroid leukemia. Table 16 summarizes the current diagnostic approach to
neoplastic marrow specimens with 50% or more erythroid precursors.
MYELOID SARCOMA
Myeloid sarcoma remains in the classification as a unique clinical presentation
of any subtype of AML. Myeloid sarcoma may present de novo, may accompany PB and
marrow involvement, may present as relapse of AML, or may present as progression
of a prior MDS, MPN, or MDS/MPN.107 Although listed separately in the
classification, cases of myeloid sarcoma without evidence of marrow disease
should be investigated comprehensively so that they can be classified into a
more specific AML subtype.
MYELOID PROLIFERATIONS OF DOWN SYNDROME
The myeloid proliferations of Down syndrome include transient abnormal
myelopoiesis (TAM) and myeloid leukemia associated with Down syndrome.108,109
Both are usually megakaryoblastic proliferations, with TAM occurring at birth or
within days of birth and resolving in 1 to 2 months and myeloid leukemia
occurring later, but usually in the first 3 years of life with or without prior
TAM and persisting if not treated. The myeloid neoplasms of Down syndrome have a
similar behavior that is independent of blast cell count and these are not
subclassified into MDS or AML. Both TAM and myeloid leukemia associated with
Down syndrome are characterized by GATA1 mutations and mutations of the JAK-STAT
pathway, with additional mutations identified in the myeloid leukemia cases.110
ACUTE LEUKEMIAS OF AMBIGUOUS LINEAGE
No new entities will be defined within this subgroup of acute leukemias.
However, several studies have been published since the 2008 classification that
have confirmed both the clinical relevance of the entity and its subdivision
into genetic subgroups.111,112 Although data are still preliminary, it appears
that mixed phenotype acute leukemia (MPAL) with the t(9;22) can respond
favorably to treatment that includes a TKI.113,114
The small list of specific lineage markers useful for defining MPAL is unchanged
(Table 19), but it is now emphasized that in cases in which it is possible to
resolve 2 distinct blast populations, it is not necessary that the specific
markers be present, but only that each individual population would meet a
definition for either a B, T, or myeloid leukemia. Similarly, cases of ALL or
AML in which a diagnosis of MPAL is not being considered do not need to meet the
more strict MPAL criteria in order to assign lineage; these criteria do not
universally apply for the diagnosis of AML or ALL, but only for MPAL. It is also
now recognized that some cases of otherwise typical B-ALL with homogeneous
expression of lymphoid markers on a single blast population may express
low-level myeloperoxidase using immunophenotypic methods without other evidence
of myeloid differentiation. Because the clinical significance of this finding
has not yet been established, it is recommended that care be taken before making
a diagnosis of B/myeloid MPAL when low-intensity myeloperoxidase (MPO) is the
only myeloid-associated feature. Multiparameter flow cytometry is the method of
choice for recognizing MPAL; even when there are not 2 distinctly separable
populations, most cases of MPAL will show heterogeneity of expression of some
antigens such that MPO expression will be expressed on the subset of blasts that
show relatively brighter expression of myeloid markers and lower intensity of
B-cell–associated markers.
Table 19
Criteria for lineage assignment for a diagnosis of MPAL
Lineage assignment criteria . Myeloid lineage MPO* (flow cytometry,
immunohistochemistry, or cytochemistry) or Monocytic differentiation (at least
2 of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64,
lysozyme) T-lineage Strong† cytoplasmic CD3 (with antibodies to CD3 ε
chain) or Surface CD3 B-lineage Strong† CD19 with at least 1 of the following
strongly expressed: CD79a, cytoplasmic CD22, or CD10 or Weak CD19 with at
least 2 of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10
Lineage assignment criteria . Myeloid lineage MPO* (flow cytometry,
immunohistochemistry, or cytochemistry) or Monocytic differentiation (at least
2 of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64,
lysozyme) T-lineage Strong† cytoplasmic CD3 (with antibodies to CD3 ε
chain) or Surface CD3 B-lineage Strong† CD19 with at least 1 of the following
strongly expressed: CD79a, cytoplasmic CD22, or CD10 or Weak CD19 with at
least 2 of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10
*
See “Acute leukemias of ambiguous lineage” for caveats related to weaker antigen
expression, or to expression by immunohistochemistry only.
†
Strong defined as equal or brighter than the normal B or T cells in the sample.
View Large
B-CELL LYMPHOBLASTIC LEUKEMIA/LYMPHOMA (B-ALL)
Two important new provisional entities with recurrent genetic abnormalities have
been recognized and incorporated into the classification and these are discussed
in more detail in the following sections. In addition, the classification of
hypodiploid B-ALL now highlights the unique association between low hypodiploid
ALL and TP53 mutations that are often constitutional.115,116
B-ALL WITH INTRACHROMOSOMAL AMPLIFICATION OF CHROMOSOME 21.
This leukemia is characterized by amplification of a portion of chromosome 21,
characteristically detected by FISH with a probe for the RUNX1 gene that reveals
5 or more copies of the gene (or 3 or more extra copies on a single abnormal
chromosome 21 in metaphase FISH).117,118 It occurs in about 2% of children with
ALL, especially older children with low WBC counts. It is uncommon in adults.
This new entity is associated with an adverse prognosis which can, to some
extent, be overcome with more aggressive therapy.117
B-ALL WITH TRANSLOCATIONS INVOLVING TYROSINE KINASES OR CYTOKINE RECEPTORS
(“BCR-ABL1–LIKE ALL”).
This newly recognized entity is assuming increasing importance because of its
association with an adverse prognosis and responses of some cases to TKI
therapies; however, it has been difficult to define in the clinical setting. It
was originally described separately by different groups who demonstrated a
series of cases of poor-prognosis childhood ALL with gene expression profiles
similar to those seen in cases of ALL with BCR-ABL1,119,120 though different
algorithms applied to the same sets of cases did not classify all cases the same
way.121 Common features of BCR-ABL1–like ALL include translocations involving
other tyrosine kinases, or alternatively translocations involving either the
cytokine receptor-like factor 2 (CRLF2) or, less commonly, rearrangements
leading to truncation and activation of the erythropoietin receptor (EPOR).122
Cases with CRLF2 translocations are often associated with JAK gene mutations and
are particularly common in children with Down syndrome.123 This translocation
results in upregulation of the thymocyte stromal lymphopoietin receptor (TSLPR)
gene product of CRLF2 on leukemic cells that can readily be detected by flow
cytometry.
The cases with translocations involving tyrosine kinase genes involve many
different genes including ABL1 (with partners other than BCR), as well as other
kinases including ABL2, PDGFRB, NTRK3, TYK2, CSF1R, and JAK2.124 Over 30
different partner genes have been described. Some patients, especially those
with EBF1-PDGFRB translocations, have shown remarkable responses to TKI therapy,
even after failing conventional therapy.125
Patients with BCR-ABL1–like ALL show a high frequency of loss of IKZF1 and
CDKN2A/B, but these deletions also occur in high frequency in other types of ALL
as well.121
T-CELL LYMPHOBLASTIC LEUKEMIA/LYMPHOMA (T-ALL)
Although there has been considerable investigation into genetic mechanisms of
T-cell ALL (T-ALL) over the past decade, with the ability to identify
nonoverlapping genetic subgroups of T-ALL that can, to some extent, be matched
to stages of differentiation,126 assays to measure these are not yet standard
and the prognostic implications still controversial; thus, most differentiation
stage subgroups are not formally included in the classification. However, 1
subset with unique biology is recognized as a new provisional entity (see next
paragraph). Indolent T-lymphoblastic proliferation, which was briefly mentioned
in the fourth edition classification, is now a more readily recognized
nonneoplastic entity that may mimic T-lymphoblastic lymphoma.127 It typically
involves lymphoid tissue of the upper aerodigestive tract but may occur in other
locations. Local recurrences are common and systemic dissemination is rare.
Histologic examination of involved lymph nodes shows infiltration and sometimes
replacement by proliferations of lymphoblasts that are less cytologically
atypical than the usual T-lymphoblastic lymphoma. Although the blasts have an
immature thymic phenotype that can be demonstrated by TdT staining in lymph
nodes, the phenotype reflects a developmentally normal, nonaberrant phenotype
and the proliferations are not clonal. These latter features allow this indolent
entity to be distinguished from T-lymphoblastic lymphoma.
Early T-precursor (ETP) ALL leukemia has a unique immunophenotypic and genetic
makeup indicating only limited early T-cell differentiation, with retention of
some myeloid and stem cell characteristics at both the immunophenotypic and
genetic level.128-131 By definition, blasts in ETP ALL express CD7 but lack
CD1a and CD8, and are positive for 1 or more of the myeloid/stem cell markers
CD34, CD117, HLADR, CD13, CD33, CD11b, or CD65.128 They typically also express
CD2 and cytoplasmic CD3 and may express CD4, but these are not part of the
definition. CD5 is often negative and when positive is present on <75% of the
blast population. Myeloid-associated gene mutations, such as FLT3, NRAS/KRAS,
DNMT3A, IDH1, and IDH2, are reported at high frequency in ETP ALL,129,130
whereas more typical T-ALL–associated mutations such as activating mutations in
NOTCH1 or mutations in CDKN1/2 are infrequent.131 Although initial small series
of ETP ALL suggested that outcome was very poor,128,132 more recent larger
series with more effective therapy showed either a small but statistically
nonsignificant difference in outcome,133 or, in the largest series to date, no
prognostic significance.134
The online version of this article contains a data supplement.
ACKNOWLEDGMENTS
This work was supported by the Clinical Advisory Committee meeting (Chicago, IL,
March 31-April 1, 2014) from the following organizations: American Society of
Hematology, Joseph Carreras Foundation, Fondazione Italiana Linfomi (FIL),
Leukemia Clinical Research Foundation, University of Chicago Comprehensive
Cancer Center, Beckman Coulter Corporation, Celgene Corporation, Dako, Genentech
Corporation, Incyte Corporation, Leica Corporation, Millennium Pharmaceuticals,
Pharmacyclics, Seattle Genetics Corporation, Sysmex Corporation, and Ventana
Medical Systems, Inc, a member of the Roche Group.
AUTHORSHIP
Contribution: All authors were involved in the writing and editing of the
manuscript.
Conflict-of-interest disclosure: The authors declare no competing financial
interests.
Correspondence: Daniel A. Arber, Department of Pathology, Stanford University,
300 Pasteur Dr H1401 M/C 5627, Stanford, CA 94305; e-mail: darber@stanford.edu.
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