Myelodysplastic Syndromes (MDS)

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell neoplasms affecting blood cell synthesis in the bone marrow. Changes to stem cell DNA result in the production of immature, abnormal blood cells, causing various clinical features, including cytopenias, ineffective hematopoiesis, dysplasia in 1 or more myeloid cell lineages, and increased risk of transformation into acute myeloid leukemia (AML).1 

Differential Diagnosis of MDS

A comprehensive diagnostic workup is necessary to differentiate between types of MDS, guide treatment decisions, and rule out other differential diagnoses. Differential diagnoses include2,3

  • Clonal hematopoiesis of indeterminate potential (CHIP)
  • Clonal hematopoiesis of oncogenic potential (CHOP)
  • Idiopathic cytopenia of unknown significance (ICUS)
  • Idiopathic dysplasia of unknown significance (IDUS)
  • Clonal cytopenia of undetermined significance (CCUS)
  • Aplastic anemia (AA)
  • Paroxysmal nocturnal hemoglobinuria (PNH)
  • Chronic infections
  • Acute myeloid leukemia and other similar malignancies

Read more about MDS differential diagnosis 

Guidelines for Diagnosis of MDS

National and international working groups have developed consensus statements and clinical practice guidelines for the diagnosis and treatment of MDS.2 In the United States, clinicians follow MDS diagnostic guidelines set forth by the National Comprehensive Cancer Network (NCCN).2,4 In Europe, the European Society for Medical Oncology (ESMO), the European Leukemia Net (ELN), and several European countries have published MDS guidelines.2,3,5,6 The European Hematology Association (EHA) collaborated with and endorsed ESMO’s most recent MDS guidelines, first published online in November 2020.3,7 

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Diagnostic Workup for MDS

Clinical Assessments for MDS Diagnosis

Guidelines suggest that the following processes are required to confirm an MDS diagnosis2-8:

  • Detailed medical and family history, including possible environmental or occupational exposures, comorbidities, current medications, and past medical treatments, such as chemotherapy and/or radiation
  • Comprehensive physical examination to assess for dyspnea, bruising, tachycardia, vascular events, petechiae, pleural or pericardial effusions, inflammation, constitutional symptoms, lymphadenopathy, and organomegaly 

Read more about MDS clinical features

Laboratory Testing for MDS Diagnosis

Guidelines suggest that the following tests are required to confirm an MDS diagnosis2-8:

  • Examination of blood, including a complete blood count and repeated peripheral blood smears to assess dysplasia and other hematologic abnormalities
  • Microscopic examination of bone marrow aspirate and biopsy specimens
  • Cytomorphological assessments of peripheral blood and bone marrow specimens
  • Flow cytometry
  • Immunophenotyping

The recommended number of cells to be reviewed per slide is 200 cells for peripheral blood and 500 for the bone marrow to confirm a diagnosis of MDS. The marrow blast count is critical as it includes promonocytes, agranular blasts, and myeloblasts. Staining for iron with Prussian blue is recommended to evaluate the presence of ring sideroblasts in lower-risk MDS patients.3,8

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Genetic Testing for MDS Diagnosis

Guidelines suggest that the following tests are required to confirm an MDS diagnosis2-8:

  • Cytogenetic analysis
  • Karyotype and mutation analysis of blood and bone marrow cells via fluorescence in situ hybridization (FISH), next-generation sequencing, polymerase chain reaction (PCR) testing, whole exome analysis, or targeted gene panel testing—a critical step in determining MDS subtype and patient prognosis

Read more about MDS genetics

Diagnostic Criteria for MDS

Central features for MDS diagnosis include the following3,4:

  • Well-defined dysplasia (the presence of ≥10% abnormal cells) in 1 or more of the 3 major bone marrow and/or peripheral blood cell lineages (erythroid, megakaryocytic, and neutrophilic)
  • Cytopenia(s) persisting for at least 4 to 6 months (2 months if accompanied by a particular MDS-related karyotype or bilineage dysplasia)
  • Absence of underlying conditions explaining the cytopenia or dysplasia

Other MDS diagnostic criteria in addition to dysplasia in 1 or more cell lineages include4,7:

  • Blast cell counts between 5% and 19% on bone marrow smears and/or 2% to 19% blasts on peripheral blood smears
  • Specific MDS-related karyotypes, such as del(5q), del(20q), +8, or −7/del(7q).

Diagnostic Distinction Between Overlap Syndromes and Myelodysplastic Syndromes

Accurate diagnosis of MDS overlap syndromes leads to improved estimation of patient prognosis, which is driven largely by different genetic profiles and pathobiology.9

Chronic Myelomonocytic Leukemia

Chronic myelomonocytic leukemia (CMML) is the most common MDS/myeloproliferative neoplasm (MPN) overlap disease with the distinct feature of monocytosis plus 1 or more cytopenias (usually anemia) and bone marrow results that meet MDS diagnostic criteria. Somatic mutations in the TET2ASXL1SRSF2EZH2NRASKRAS, and CBL genes frequently occur in patients with CMML.9

MDS/MPN With Ring Sideroblasts and Thrombocytosis

MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is the second most common overlap disease. MDS/MPN-RS-T is identified by the distinctive features of ≥15% ring sideroblasts and a persistently elevated platelet count of ≥450 × 109/L while also meeting MDS diagnostic criteria. Around 80% of cases demonstrate SF3B1 mutations. Other frequently occurring mutations affect the JAK2 (50% to 70%), CALR (10% to 20%), and MPL (2% to 5%) genes, although mutations in other genes, such as TET2DNMT3AASXL1, and SETBP1, may be noted.9

Atypical Chronic Myeloid Leukemia

Atypical chronic myeloid leukemia (aCML) is another MDS/MPN overlap syndrome with the distinctive feature of leukocytosis with some degree of dysgranulopoiesis and minimal to no absolute basophilia and monocytosis. Mutations in SETBP1 (25% of aCML cases) and CSF3R (<10% of aCML cases) may occur.9

Juvenile Myelomonocytic Leukemia

One of the least common MDS overlap syndromes is juvenile myelomonocytic leukemia (JMML). The identifying feature of this overlap syndrome is the age of onset, as JMML occurs in early childhood at a median age of 2 years. Approximately 95% of children with JMML exhibit germline mutations in a RAS pathway gene, including CBL, KRAS, NF1, NRAS, and PTPN11.9

Read more about MDS prognosis


  1. Gupta G, Singh R, Kotasthane DS, Kotasthane VD. Myelodysplastic syndromes/neoplasms: recent classification system based on World Health Organization Classification of Tumors – International Agency for Research on Cancer for Hematopoietic and Lymphoid Tissues. J Blood Med. 2010;1:171-182. doi:10.2147/JBM.S12257
  2. Kasprzak A, Kaivers J, Nachtkamp K, et al. Guidelines for myelodysplastic syndromes: converting evidence into action? Int J Environ Res Public Health. 2021;18(14):7629. doi:10.3390/ijerph18147629
  3. Fenaux P, Haase D, Santini V, Sanz GF, Platzbecker U, Mey U; ESMO Guidelines Committee. Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(2):142-156. doi:10.1016/j.annonc.2020.11.002
  4. Greenberg PL, Stone RM, Al-Kali A, et al. Myelodysplastic syndromes, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2017;15(1):60-87. doi:10.6004/jnccn.2017.0007
  5. Malcovati L, Hellström-Lindberg E, Bowen D, et al; European Leukemia Net. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943-2964. doi:10.1182/blood-2013-03-492884
  6. Stojkov K, Silzle T, Stussi G, et al. Guideline-based indicators for adult patients with myelodysplastic syndromes. Blood Adv. 2020;4(16):4029-4044. doi:10.1182/bloodadvances.2020002314
  7. van de Loosdrecht AA, Mandac Smoljanović I. EHA endorsement of ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up for myelodysplastic syndromes. Hemasphere. 2022;6(3):e695. doi:10.1097/HS9.0000000000000695
  8. Valent P, Orazi A, Steensma DP, et al. Proposed minimal diagnostic criteria for myelodysplastic syndromes (MDS) and potential pre-MDS conditions. Oncotarget. 2017;8(43):73483-73500. doi:10.18632/oncotarget.19008
  9. Tanaka TN, Bejar R. MDS overlap disorders and diagnostic boundaries. Blood. 2019;133(10):1086-1095. doi:10.1182/blood-2018-10-844670

Reviewed by Debjyoti Talukdar, MD, on 6/21/2023.