Blood Res 2021; 56(S1):
Published online April 30, 2021
https://doi.org/10.5045/br.2021.2021010
© The Korean Society of Hematology
Correspondence to : Yoon Hwan Chang, M.D., Ph.D.
Department of Laboratory Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
E-mail: cyh1969@snu.ac.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological neoplasms characterized by ineffective hematopoiesis, morphologic dysplasia, and cytopenia. MDS overlap syndromes include various disorders, such as myelodysplastic/myeloproliferative neoplasms and hypoplastic MDS with aplastic anemia characteristics. MDS overlap syndromes share the characteristics of other diseases, which make differential diagnoses challenging. Advances in genomic studies have led to the discovery of frequent mutations in MDS and overlap syndromes; however, most of the mutations are not specific for the diagnosis of these diseases. The molecular characteristics of the overlap syndromes usually do not show a just “in-between” form but rather heterogeneous features. Established diagnostic criteria for these diseases based on clinical, morphologic, and laboratory features are still useful when combined with genomic data. It is expected that further studies for MDS and overlap syndromes will place emphasis on the roles of mutations as therapeutic targets and prognostic indicators.
Keywords Myelodysplastic syndromes, Overlap syndromes, Myelodysplastic/myeloproliferative neoplasms, Hypoplastic MDS, Genomic, Mutation
Blood Res 2021; 56(S1): S51-S64
Published online April 30, 2021 https://doi.org/10.5045/br.2021.2021010
Copyright © The Korean Society of Hematology.
Yoon Hwan Chang
Department of Laboratory Medicine, Seoul National University Hospital, Seoul, Korea
Correspondence to:Yoon Hwan Chang, M.D., Ph.D.
Department of Laboratory Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
E-mail: cyh1969@snu.ac.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological neoplasms characterized by ineffective hematopoiesis, morphologic dysplasia, and cytopenia. MDS overlap syndromes include various disorders, such as myelodysplastic/myeloproliferative neoplasms and hypoplastic MDS with aplastic anemia characteristics. MDS overlap syndromes share the characteristics of other diseases, which make differential diagnoses challenging. Advances in genomic studies have led to the discovery of frequent mutations in MDS and overlap syndromes; however, most of the mutations are not specific for the diagnosis of these diseases. The molecular characteristics of the overlap syndromes usually do not show a just “in-between” form but rather heterogeneous features. Established diagnostic criteria for these diseases based on clinical, morphologic, and laboratory features are still useful when combined with genomic data. It is expected that further studies for MDS and overlap syndromes will place emphasis on the roles of mutations as therapeutic targets and prognostic indicators.
Keywords: Myelodysplastic syndromes, Overlap syndromes, Myelodysplastic/myeloproliferative neoplasms, Hypoplastic MDS, Genomic, Mutation
Table 1 . Diagnostic criteria for myelodysplastic syndrome (MDS) entities [5, 6]..
Name | Dysplastic lineages | Cytopeniasa) | RS (%)b) | BM and PB blasts (%) | Cytogeneticsc) |
---|---|---|---|---|---|
MDS-SLD | 1 | 1 or 2 | <15/<5d) | BM <5, PB <1, no Auer rods | Any, unless fulfills all criteria for MDS with isolated del(5q) |
MDS-MLD | 2 or 3 | 1–3 | <15/<5d) | BM <5, PB <1,no Auer rods | Any, unless fulfills all criteria for MDS with isolated del(5q) |
MDS-RS | |||||
MDS-RS-SLD | 1 | 1 or 2 | ≥15/≥5d) | BM <5, PB <1,no Auer rods | Any, unless fulfills all criteria for MDS with isolated del(5q) |
MDS-RS-MLD | 2 or 3 | 1–3 | ≥15/≥5d) | 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-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-U | |||||
1% blood blasts | 1–3 | 1–3 | None or any | BM <5, PB=1e), no Auer rods | Any |
SLD and pancytopenia | 1 | 3 | None or any | BM <5, PB <1,no Auer rods | Any |
Defining cytogenetic abnormality | 0 | 1–3 | <15f) | BM <5, PB <1,no Auer rods | MDS-defining abnormalityg) |
Refractory cytopenia of childhood | 1–3 | 1–3 | None | BM <5, PB <2 | Any |
a)Cytopenias defined as hemoglobin concentration <10 g/dL, platelet count <100×109/L, and absolute neutrophil count <1.8×109/L, although MDS can present with mild anemia or thrombocytopenia above these levels; PB monocytes must be <1×109/L. b)Ring sideroblasts as the percentage of marrow erythroid elements. c)Cytogenetics by conventional karyotype analysis. d)If
Abbreviations: BM, bone marrow; EB, excess blasts; MDS-U, MDS, unclassifiable; MLD, multilineage dysplasia; PB, peripheral blood; RS, ring sideroblasts; SLD, single lineage dysplasia..
Table 2 . Recurrent chromosomal abnormalities and their frequencies in myelodysplastic syndrome (MDS) at diagnosis [5, 14]..
Chromosomal abnormality | Frequency | Prognosisb) | |
---|---|---|---|
MDS overall | Therapy-related MDS | ||
Unbalanced | |||
Gain of chromosome 8a) | 10% | Intermediate | |
Loss of chromosome 7 or del(7q) | 10% | 50% | Intermediate |
del(5q) | 10% | 40% | Good |
del(20q)a) | 5–8% | Good | |
Loss of Y chromosomea) | 5% | Very good | |
Isochromosome 17q or del(17p) | 3–5% | 25–30% | Intermediate |
Loss of chromosome 13 or del(13q) | 3% | Intermediate | |
del(11q) | 3% | Very good | |
del(12p) or t(12p) | 3% | Good | |
del(9q) | 1–2% | Intermediate | |
idic(X)(q13) | 1–2% | Intermediate | |
Balanced | |||
t(11;16)(q23.3;p13.3) | 3% | Intermediate | |
t(3;21)(q26.2;q22.1) | 2% | Poor | |
t(1;3)(p36.3;q21.2) | 1% | Poor | |
t(2;11)(p21;q23.3) | 1% | Intermediate | |
inv(3)(q21.3q26.2)/t(3;3)(q21.3;q26.2) | 1% | Poor | |
t(6;9)(p23;q34.1) | 1% | Intermediate |
a)As a sole cytogenetic abnormality in the absence of morphological criteria, gain of chromosome 8, del(20q) and loss of Y chromosome are not considered definitive evidence of MDS; in the setting of persistent cytopenia of undetermined origin, the other abnormalities shown in this table are considered as presumptive evidence of MDS, even in the absence of definitive morphological features. b)Normal karyotype: Good; Double including del(5q): Good; Double including -7/del(7q): Poor; Any other double: Intermediate; Complex karyotype (3 abnormalities): Poor; Complex karyotype (>3 abnormalities): Very poor..
Table 3 . Gene mutation profiles for MDS/MPNs, MDS, and MPN [modified from 5, 27, 28]..
Functional class | Gene | CMML | JMML | aCML | MDS/MPN-RS-T | MDS/MPN-U | MDS | MPN |
---|---|---|---|---|---|---|---|---|
Epigenetic regulation | 50–60% | 0 | 20–40% | 10–25% | 20–25% | 20–30% | 10–20% | |
<5% | Rare | ∼5% | ∼15% | 5–10% | ∼10% | 5–10% | ||
40–45% | ∼5% | ∼30% | 15–30% | 30–50% | 15–20% | PMF 25%, | ||
ET/PV 1–3% | ||||||||
5–10% | <5% | ∼20% | ∼5% | ∼15% | 5–10% | PMF 5–10% | ||
<5% | 0 | <5% | <5% | ∼5% ( | 1–3% | |||
∼5% | 0 | <5% | <5% | <5% | ∼5% ( | 1–3% | ||
RNA splicing | 45–50% | 0 | 30–40% | 5–10% | ∼25% | ∼15% | PMF 10–15%, | |
ET <2% | ||||||||
∼5% | 5–10% | 80–90% | 10–15% | 20–30% | ET <3% | |||
5–10% | 5–10% | ∼5% | 10–15% | 5–10% | PMF 10–15% | |||
5–10% | <5% | <5% | <5% | 5–10% | 5–10% | |||
Cell signaling | 20–30% | 25–35% | 25–35% | Rare | 10–15% | ∼5% ( | NRAS: PMF Rare | |
5–10% | 0 | ∼5% | ∼50% | ∼25% | PV 95%, | |||
PMF and ET 50–60% | ||||||||
5–15% | ||||||||
10–20% | 10–15% | 5–10% | <5% | ∼5% | ∼5% | PMF 4% | ||
<5% | 35–45% | <5% | <5% | |||||
Rare | 10–15% | Rare | PMF Rare | |||||
Rare | <5% | ∼5% | PMF 25–30%, | |||||
ET 20–25% | ||||||||
<5% | ∼5% | ET 2–3%, | ||||||
PMF 3–5% | ||||||||
<5% | 5–10% | Rare | <5% | |||||
<5% | <5% | <5% | <3% | |||||
Transcription | 10–20% | <5% | 10–20% | <5% | 5–10% | ∼10% | <3% (sAML 10%) | |
<5% | 4% | <5% | ||||||
<5% | <5% | <5% | <3% | |||||
Rare | Rare | Rare | 8–9% | 5–10% | <5% (sAML 20%) | |||
Rare | ||||||||
Cohesin complex | <10% | 5–10% | 5–7% | |||||
Others | <5% | ∼8% | Rare | <5% | ||||
5–10% | 5–15% | 25–40% | ∼10% | 10–15% | ||||
<5% | Rare | 0 | <5% |
a)These genes are also reported to be mutated in clonal hematopoietic cells in a subset of healthy individuals (clonal hematopoiesis of indeterminate potential)..
Abbreviations: aCML, atypical chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; ET, essential thrombocythemia; JMML, juvenile myelomonocytic leukemia; MDS, myelodysplastic syndrome; MDS/MPN, myelodysplastic/myeloproliferative neoplasm; MDS/MPN-RS-T, MDS/MPN with ring sideroblasts and thrombocytosis; MDS/MPN-U, MDS/MPN unclassifiable; MPN, myeloproliferative neoplasm; PMF, primary myelofibrosis; PV, polycythemia vera; sAML, secondary acute myeloid leukemia..
Unknown
< 10%
10-20%
20-30%
30-50%
>50%.
Table 4 . Proposed diagnostic criteria for the myelodysplastic syndrome (MDS) with mutated
Cytopenia defined by standard hematologic values |
Somatic |
Isolated erythroid or multilineage dysplasiaa) |
Bone marrow blasts <5% and peripheral blood blasts <1% |
WHO criteria for MDS with isolated del(5q), MDS/MPN-RS-T or other MDS/MPNs, and primary myelofibrosis or other MPNs are not met |
Normal karyotype or any cytogenetic abnormality other than del(5q); monosomy 7; inv(3) or abnormal 3q26, complex (≥3) |
Any additional somatically mutated gene other than |
a)RS are not required for the diagnosis. b)Additional
Table 5 . Diagnostic criteria for chronic myelomonocytic leukemia (CMML) [5, 39]..
1. Persistent peripheral blood monocytosis (≥1×109/L) with monocytes accounting for ≥10% of the leukocytes |
2. WHO criteria for |
3. No rearrangement of |
4. Blastsb) constitute <20% of the cells in the peripheral blood and bone marrow |
5. Dysplasia involving ≥1 myeloid lineages orIf myelodysplasia is absent or minimal, criteria 1-4 are met and: |
-An acquired, clonal cytogenetic or molecular genetic abnormality is present in hematopoietic cellsc) or |
-Monocytosis has persisted for ≥3 months and all other causes of monocytosis (e.g., malignancy, infection, and inflammation) have been excluded. |
a)Myeloproliferative neoplasms (MPN) can be associated with monocytosis or it can develop during the course of the disease; such cases can mimic CMML. In these rare instances, a documented history of MPN excludes CMML, whereas the presence of MPN features in the bone marrow and/or MPN-associated mutations (in
Table 6 . Diagnostic criteria for atypical chronic myeloid leukemia,
- Peripheral blood leukocytosis ≥13×109/L, due to increased numbers of neutrophils and their precursors (i.e., promyelocytes, myelocytes, and metamyelocytes), with neutrophil precursors constituting ≥10% of the leukocytes |
- Dysgranulopoiesis, which may include abnormal chromatin clumping |
- No or minimal absolute basophilia; basophils constitute <2% of the peripheral blood leukocytes |
- No or minimal absolute monocytosis; monocytes constitute <10% of the peripheral blood leukocytes |
- Hypercellular bone marrow with granulocytic proliferation and granulocytic dysplasia, with or without dysplasia in the erythroid and megakaryocytic lineages |
- <20% blasts in the blood and bone marrow |
- No evidence of |
- The WHO criteria for |
a)Myeloproliferative neoplasms (MPNs), in particular those in the accelerated phase and/or in post-polycythemia vera or post-essential thrombocythemia myelofibrosis, if neutrophilic, may simulate aCML. A history of MPN, the presence of MPN features in the bone marrow, and/or MPN-associated mutations (in
Table 7 . Diagnostic criteria for juvenile myelomonocytic leukemia (JMML) [5, 87]..
Clinical and hematological criteria (all 4 criteria are required) |
- Peripheral blood monocyte count ≥1×109/L |
- Blast percentage in peripheral blood and bone marrow of <20% |
- Splenomegaly |
- No Philadelphia (Ph) chromosome or |
Genetic criteria (any 1 criterion is sufficient) |
- Somatic mutationa) in |
- Clinical diagnosis of neurofibromatosis type 1 or |
- Germline |
Other criteria |
Cases that do not meet any of the genetic criteria above must meet the following criteria in addition to the clinical and hematological criteria above: |
- Monosomy 7 or any other chromosomal abnormality or |
- ≥2 of the following: |
- Increased hemoglobin F for age |
- Myeloid or erythroid precursors on peripheral blood smear |
- Granulocyte-macrophage colony-stimulating factor (also called CSF2) hypersensitivity in colony assay |
- Hyperphosphorylation of STAT5 |
a)If a mutation is found in
Table 8 . Diagnostic criteria for myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) [5]..
- Anemia associated with erythroid-lineage dysplasia, with or without multilineage dysplasia; ≥15% ring sideroblastsa), <1% blasts in the peripheral blood, and <5% blasts in the bone marrow |
- Persistent thrombocytosis, with platelet count ≥450×109/L |
- |
- No |
- No history of myeloproliferative neoplasm, myelodysplastic syndrome (except myelodysplastic syndrome with ring sideroblasts), or other myelodysplastic/myeloproliferative neoplasm |
a)≥15% ring sideroblasts is a required criterion even if
Table 9 . Diagnostic criteria for myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U) [5]..
Myeloid neoplasm with mixed myeloproliferative and myelodysplastic features at onset, not meeting the WHO criteria for any other myelodysplastic/myeloproliferative neoplasm, myelodysplastic syndrome, or myeloproliferative neoplasm - <20% blasts in the peripheral blood and bone marrow |
- Clinical and morphological features of one of the categories of myelodysplastic syndromea) |
- Clinical and morphological myeloproliferative features manifesting as a platelet count of ≥450×109/L associated with bone marrow megakaryocytic proliferation and/or a white blood cell count of ≥13×109/La) |
- No history of recent cytotoxic or growth factor therapy that could explain the myelodysplastic/myeloproliferative features |
- No |
a)Cases that meet the criteria for myelodysplastic syndrome with isolated del(5q) are excluded irrespective of the presence of thrombocytosis or leukocytosis..
Table 10 . Semiquantitative comparison of laboratory and genetic features among hMDS, AA, and normo/hypercellular MDS (modified from 117)..
Properties | Normo/hypercellular MDS | hMDS | AA |
---|---|---|---|
Laboratory features | |||
Cytopenia and macrocytosis | + | ++ | ++ |
LDH | +/- | + | ++ |
BM blasts | =/+ | - | -- |
Associated conditions | |||
PNH clone | +/ | + | ++ |
LGL clone | + | ++ | +/- |
Extrahematologic autoimmunity | - | ++ | +/- |
Cytogenetic abnormalities | ++ | +/- | Rare |
Somatic mutations | |||
Splicing: | +++ | + | +/- |
DNA methylation: | ++ | + | +/- |
Chromatin modification: | ++ | + | +/- |
Cohesin: | + | +/- | Rare |
Tumor suppressor: | + | +/- | Rare |
Signaling: | +/- | +/- | Rare |
Transcription: | +/- | Rare | |
Pathogenic germline | - | +/- | + |
Abbreviations: AA, aplastic anemia; BM, bone marrow; hMDS, hypoplastic myelodysplastic syndrome; LDH, lactate dehydrogenase; LGL, large granular lymphocytes; MDS, myelodysplastic syndrome; PNH, paroxysmal nocturnal hemoglobinuria..
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