Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.
Myelodysplastic syndromes (MDS) are a group of hematological cancers characterized by the inability of hematopoietic stem cells in the bone marrow to produce healthy blood cells.1
The DNA of the stem cells becomes damaged, resulting in acquired mutations that affect the stem cells from functioning normally and producing mature, healthy blood cells. The blood cells that are produced are abnormally sized or shaped, which is classified as dysplasia.2
History of MDS Subtype Classification
The World Health Organization (WHO) has published several iterations of MDS subtype classification guidelines — in 1997, 2002, 2008, and 20163-6 — categorizing MDS into various subtypes based on how the cells within the bone marrow and peripheral blood appear under microscopic evaluation.7
As understanding of MDS grew, classification of the subtypes became based on the following factors:7
- Number of dysplastic lineages: the number of blood cell types, including red blood cells, white blood cells, and platelets, that demonstrate dysplasia
- Cytopenias: the number of low blood cell counts
- Ring sideroblasts: the proportion of immature red blood cells that contain rings of iron deposits surrounding the center of the erythrocyte
- Blasts: the percentage or proportion of immature forms of blood cells both in the bone marrow and circulating in the peripheral blood
- Chromosomal abnormalities: changes to certain chromosomes may result in specific forms of MDS
In addition to the WHO classification system for MDS, the Society for Hematopathology and the European Association for Haematopathology developed the International Consensus Classification (ICC) system to classify MDS subtypes. It also denotes 6 MDS subtypes.8
Discerning a patient’s exact MDS subtype can help guide treatment decisions and predict prognosis.8
Read more about MDS prognosis
Recent Updates to Myelodysplastic Syndromes Subtype Classifications
The ICC and the WHO have published their most recent revisions to the classification of myeloid neoplasms — both in 2022.9,10
According to the most recent 5th edition WHO classification guidelines, the number of dysplastic lineages is now optional as a differentiator since this reflects the clonal evolution of the MDS disease process more than it defines specific subtypes. The WHO specified in the 2022 classification system for MDS that the threshold for dysplasia is set at 10% for all lineages.10
The WHO also added 2 main subgroups to the list: MDS with defining genetic abnormalities and MDS that is morphologically defined. Additionally, the MDS, unclassifiable (MDS-U) subtype present in previous iterations of the WHO classification system was removed.10
Myelodysplastic syndromes with low blasts and isolated 5q deletion, MDS with low blasts and SF3B1 mutation, and MDS with biallelic TP53 inactivation were listed under MDS with defined genetic abnormalities.10
Myelodysplastic syndromes with hypoplasia (MDS-h), MDS with fibrosis (MDS-f), MDS with low blasts (MDS-LB), and MDS with increased blasts (MDS-IB) were all classified within the new MDS, morphologically defined group. The WHO defined clarifying cutoffs for MDS-LB and MDS-IB.10
Read more about MDS guidelines
Current MDS Subtypes and Overlap Syndromes
As some clinicians still refer to and use the older classifications of MDS subtypes, the following is a comprehensive list of the WHO MDS subtypes and overlap syndromes from both the 2016 and 2022 guidelines:
Myelodysplastic Syndromes With Multilineage Dysplasia
Myelodysplastic syndromes with multilineage dysplasia (MDS-MLD) is characterized by 1 or more cytopenias and 2 or more dysplastic changes in the myeloid lineage (erythroid, granulocytic, and/or megakaryocytic).11
Myelodysplastic Syndromes With Single Lineage Dysplasia
Myelodysplastic syndromes with single lineage dysplasia (MDS-SLD) is characterized by unilineage dysplasia affecting the erythroid series.12
Myelodysplastic Syndromes With Ring Sideroblasts
Myelodysplastic syndromes with ring sideroblasts (MDS-RS) is characterized by13:
- Morphological dysplasia; and
- Ring sideroblasts that typically make up at least 15% of the bone marrow erythroid precursor cells.
MDS-RS may occur in MDS types with either single or multiple lineage dysplasia. Patients with MDS-RS-MLD demonstrate any number of cytopenias and 2 or more dysplastic lineages.13
Myelodysplastic Syndromes With Excess Blasts
Myelodysplastic syndromes with excess blasts (MDS-EB) is subdivided into 2 types: refractory anemia with excess blasts (RAEB)-1 (type 1) and RAEB-2 (type 2).14 RAEB-1 is characterized by 5% to 9% blasts present in the bone marrow and less than 5% blasts in the peripheral blood.14 RAEB-2 is characterized by 10% to 19% blasts present in the bone marrow.14
RAEB-2 and RAEB with Auer rods (RAEB in transformation) may be characterized by 5% to 19% blasts in the peripheral blood and less than 10% blasts in the bone marrow.14
Myelodysplastic Syndromes, Unclassifiable
Myelodysplastic syndromes, unclassifiable was removed from the 2022 WHO classification system for MDS.10
Myelodysplastic Syndromes With Defining Genetic Abnormalities
Myelodysplastic Syndromes With Low Blasts and Isolated 5Q Deletion
Myelodysplastic syndromes with isolated 5q deletion (MDS-5q) is characterized by10:
- Less than 5% blasts in the bone marrow;
- Less than 2% blasts in the peripheral blood; and
- 5q deletion alone or with 1 more abnormality, other than monosomy 7 or 7q deletion, upon cytogenetic analysis.
Myelodysplastic Syndromes With Low Blasts and SF3B1 Mutation
Myelodysplastic syndromes with low blasts and SF3B1 mutation (MDS-SF3B1) is characterized by10:
- Less than 5% blasts in the bone marrow;
- Less than 2% blasts in the peripheral blood;
- Absence of the 5q deletion, monosomy 7, or complex karyotype upon cytogenetic analysis; and
- SF3B1 gene mutation.
Myelodysplastic Syndromes With Biallelic TP53 Inactivation
Myelodysplastic syndromes with biallelic TP53 inactivation (MDS-biTP53) is characterized by10:
- Less than 20% blasts in the bone marrow and peripheral blood;
- Typically complex cytogenetics; and
- 2 or more TP53 gene mutations, or 1 mutation with evidence of TP53 copy number loss or copy neutral loss of heterozygosity.
Read more about MDS genetics
Myelodysplastic Syndromes, Morphologically Defined
Myelodysplastic Syndromes With Low Blasts
Myelodysplastic syndromes with low blasts is characterized by less than 5% blasts in the bone marrow and less than 2% blasts in the peripheral blood.10
Myelodysplastic Syndromes, Hypoplastic
Myelodysplastic syndromes, hypoplastic, is characterized by less than 5% blasts in the bone marrow and less than 2% blasts in the peripheral blood. There is also ≤25% bone marrow cellularity, age adjusted.10
Myelodysplastic Syndromes With Increased Blasts
Myelodysplastic syndromes with increased blasts is subdivided into 2 categories: MDS-IB1 and MDS-IB2.10 MDS-IB1 is characterized by 5% to 9% blasts in the bone marrow and 2% to 4% blasts in the peripheral blood.10 MDS-IB2 is characterized by 10% to 19% blasts in the bone marrow and 5% to 19% blasts in the peripheral blood or Auer rods.10
Myelodysplastic Syndromes With Fibrosis
Myelodysplastic syndromes with fibrosis is characterized by 5% to 19% blasts in the bone marrow and 2% to 19% blasts in the peripheral blood.10
Read more about MDS clinical features
Childhood MDS is a clonal hematopoietic stem cell neoplasm occurring in children and adolescents under the age of 18. Yearly incidence is between 1 and 2 cases per every million children. It is characterized by10:
- Cytopenia or cytopenias;
- Ineffective blood cell production; and
- Possible progression to acute myeloid leukemia.
Childhood MDS is subdivided into two groups: childhood MDS with low blasts (cMDS-LB) and childhood MDS with increased blasts (cMDS-IB).10
Childhood MDS with low blasts is further subdivided into two groups: childhood MDS with low blasts, not otherwise specified and childhood MDS with low blasts, hypocellular. Around 80% of cMDS-LB cases demonstrate hypocellular bone marrow with similar features to severe aplastic anemia and other bone marrow failure syndromes. Germline pathogenic variants, bone marrow failure syndromes, metabolic diseases, nutritional deficiencies, and infections must be ruled out first to reach a diagnosis of cMDS-LB.10
Between 10% to 25% of childhood MDS cases involve those with increased blasts. This subtype is characterized by10:
- greater than or equal to 5% blasts in the bone marrow;
- greater than or equal to 2% blasts in the peripheral blood; and
- acquired cytogenetic abnormalities and RAS-pathway mutations.
Read more about MDS diagnosis
Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes are types of clonal myeloid malignancies that share both MDS and MPN clinical, pathological, and therapeutic features. These syndromes may require similar treatments to MDS when features of MDS predominate over features of MPN.15,16
The WHO published diagnostic criteria for MDS/MPN overlap syndromes in 2016.17
Chronic Myelomonocytic Leukemia
Chronic myelomonocytic leukemia (CMML) is characterized by17:
- Adult onset;
- Sustained peripheral blood monocytosis ≥1×109/L;
- Dysplasia in 1 or more lineages or molecular TET2 (60%), SRSF2 (50%), ASXL1 (40%), and/or SETBP1 (15%) gene mutations;
- RAS pathway mutations; and
- Enriched JAK2V617F (in proliferative cases).
Juvenile Myelomonocytic Leukemia
Juvenile myelomonocytic leukemia (JMML) is characterized by17:
- Pediatric onset;
- Peripheral blood monocytosis ≥1×109/L; and
- Somatic mutations in PTPN11 (38%), NRAS (18%), KRAS (14%), CBL (12% to 18%), or NF1 (5% to 10%) or diagnosis of neurofibromatosis-1.
Atypical Chronic Myeloid Leukemia, BCR-ABL Negative
Atypical chronic myeloid leukemia, BCR-ABL negative (aCML), also known as myelodysplastic/myeloproliferative neoplasm with neutrophilia, is characterized by17:
- White blood cell count >13×109/L with increased and dysplastic neutrophils;
- No or minimal absolute basophils and monocytosis; and
- Hypercellular bone marrow with granulocytic proliferation and dysplasia (neutrophil precursors ≥10%).
Myelodysplastic/Myeloproliferative Neoplasm With SF3B1 Mutation and Thrombocytosis
Myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis, also known as MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), is characterized by17:
- Platelet count ≥450×109/L;
- 15% ring sideroblasts in the bone marrow or >5% ring sideroblasts in the bone marrow along with SF3B1 mutation; and
- Presence of megakaryocytic atypia resembling essential thrombocythemia or myelofibrosis.
Myelodysplastic/Myeloproliferative Neoplasm, Not Otherwise Specified
Myelodysplastic/myeloproliferative neoplasm, not otherwise specified (or unclassifiable) is characterized by myeloid neoplasms with mixed MDS/MPN features that do not meet WHO criteria for other MDS/MPN overlap neoplasms, MDS, or MPN.17
Read more about MDS differential diagnosis
- Myelodysplastic syndromes treatment (PDQ®)–patient version. National Cancer Institute. Updated March 31, 2023. Accessed June 7, 2023.
- Myelodysplastic syndromes. Leukemia & Lymphoma Society. Accessed June 7, 2023.
- Harris NL, Jaffe ES, Diebold J, et al. World Health Organization Classification of Neoplastic Diseases of the Hematopoietic and Lymphoid Tissues: Report of the Clinical Advisory Committee Meeting—Airlie House, Virginia, November 1997. JCO. 1999;17(12):3835-3849. doi:10.1200/JCO.1918.104.22.16835
- Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100(7):2292-2302. doi:10.1182/blood-2002-04-1199
- Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937-951. doi:10.1182/blood-2009-03-209262
- 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. doi:10.1182/blood-2016-03-643544
- MDS subtypes. Leukemia & Lymphoma Society. Accessed June 7, 2023.
- Myelodysplastic syndromes – MDS: subtypes and classification. Cancer.Net. Accessed June 7, 2023.
- Lee C, Kim HN, Kwon JA, et al. Implications of the 5th edition of the World Health Organization classification and International Consensus Classification of myeloid neoplasm in myelodysplastic syndrome with excess blasts and acute myeloid leukemia. Ann Lab Med. 2023;43(5):503-507. doi:10.3343/alm.2023.43.5.503
- Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1
- Myelodysplastic syndrome with multilineage dysplasia. National Cancer Institute: Surveillance, Epidemiology, and End Results Program (SEER). Accessed June 7, 2023.
- Myelodysplastic syndrome with single lineage dysplasia. National Cancer Institute: Surveillance, Epidemiology, and End Results Program (SEER). Accessed June 7, 2023.
- Myelodysplastic syndrome with ring sideroblasts and multilineage dysplasia. National Cancer Institute: Surveillance, Epidemiology, and End Results Program (SEER). Accessed June 7, 2023.
- Myelodysplastic syndrome with excess blasts. National Cancer Institute: Surveillance, Epidemiology, and End Results Program (SEER). Accessed June 7, 2023.
- Pati H, Kundil Veetil K. Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes: molecular pathogenetic mechanisms and their implications. Indian J Hematol Blood Transfus. 2019;35(1):3-11. doi:10.1007/s12288-019-01084-y
- Foster MC. Myelodysplastic syndromes staging. Medscape. Updated November 3, 2022. Accessed June 7, 2023.
- Patnaik MM, Lasho T. Myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes: a focused review. Hematology Am Soc Hematol Educ Program. 2020;2020(1):460-464. doi:10.1182/hematology.2020000163
Reviewed by Harshi Dhingra, MD, on 6/13/2023.