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Myelodysplastic Syndromes (MDS)

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Differential Diagnosis

The myelodysplastic syndromes (MDS) are a heterogenous group of neoplastic disorders of clonal hematopoietic stem cells characterized by dysplasia of major blood cell lines and ineffective hematopoiesis resulting in cytopenia. Clinical features include an increased percentage of blasts in the bone marrow and peripheral blood accounting for less than 20% of nucleated cells.1,2 

MDS can be difficult to diagnose because of overlap with other syndromes and clinical similarities, particularly cytopenia. Comprehensive diagnostic testing, including blood tests, bone marrow aspiration and biopsy, and karyotyping, is required to rule out other potential causes of cytopenia.3

Common mimics of MDS that cause cytopenia or morphologic abnormalities of blood cells include the following3:

  • Cobalamin, copper, or folate deficiencies
  • Congenital syndromes such as Fanconi anemia and X-linked sideroblastic anemia
  • Excessive alcohol consumption
  • HIV infection
  • Immune-mediated cytopenias, such as aplastic anemia and large granular lymphocytic leukemia
  • Medications such as methotrexate 
  • Myeloproliferative neoplasms (some of which may co-occur with MDS in overlap syndromes)

Many entities should be considered in the differential diagnosis during an evaluation for MDS.

Anemia

The most common cytopenia in MDS is anemia.1 Anemia in MDS must occur in the absence of blood loss, hemolysis, and other conditions that decrease the production of erythrocytes.4 

Deficiencies of cobalamin (vitamin B12), folate (vitamin B9), copper, and thiamine (vitamin B1) may contribute to the production of abnormal, dysfunctional erythrocytes.5-7 Testing for these deficiencies should be a part of the diagnostic workup.  

Read more about MDS testing

Aplastic Anemia

In aplastic anemia (AA), which is a syndrome of chronic primary hematopoietic failure due to stem cell injury, hematopoietic precursors in the bone marrow are diminished or absent. Etiologic theories of AA include extrinsic immune-mediated suppression of hematopoietic stem cells and intrinsic abnormalities of bone marrow progenitors. AA is characterized by pancytopenia and hypocellularity on a bone marrow biopsy specimen, which is devoid of marrow progenitors.8 

In contrast, a bone marrow biopsy specimen in an individual with MDS is generally hypercellular; however, between 10% and 15% of MDS specimens are hypocellular. Cases of low blast or hypoplastic MDS share immune-mediated pathogenic mechanisms with acquired idiopathic AA.9 Abnormal karyotypes occur more frequently in hypocellular MDS than in AA, particularly trisomy 1q and 20q deletions, which are detected by fluorescence in situ hybridization (FISH) testing. FISH abnormalities predicted a poor prognosis in patients with hypocellular MDS, whereas an abnormal karyotype in AA did not predict the prognosis.9,10 In addition, hypocellular MDS was more likely than AA to undergo transformation to leukemia.10

Morphological differences between AA and hypoplastic MDS are subtle. An increased percentage of CD34+ cells in the bone marrow, the presence of dysplastic granulocytes or megakaryocytes, and the presence of ring sideroblasts may help distinguish hypocellular MDS from AA.11

Read more about MDS histology

Megaloblastic Anemia

Thiamine-responsive megaloblastic anemia (TRMA) syndrome, also known as Rogers syndrome, is characterized by the onset of megaloblastic anemia during childhood (infancy through adolescence) along with progressive sensorineural hearing loss and diabetes mellitus. Treatment with thiamine corrects the anemia.7

Myelophthisic Anemia

Myelophthisic anemia is a form of anemia in which immature erythrocytes circulate in the peripheral blood as a consequence of infiltration or displacement of the bone marrow by abnormal fibrotic tissue, a space-occupying cancer, a lipid storage disease, or other lesions. The reticulocyte count is usually lower than in anemia caused by blood loss or hemolysis.12 

Moderate-to-severe bone marrow fibrosis occurs in only a minority of cases of MDS (10% to 20%). These cases must be differentiated from myelophthisic anemia as well as from primary myelofibrosis, acute megakaryoblastic leukemia, acute panmyelosis with myelofibrosis, and the MDS overlap syndrome — chronic myelomonocytic leukemia (CMML).11

Bone Marrow Failure Disorders

The bone marrow failure syndromes are a group of inherited or acquired disorders characterized by the inadequate production of blood cells from hematopoietic stem cells. They affect any or all of the 3 blood cell lineages.13

Inherited bone marrow disorders include Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia, dyskeratosis congenita, reticular dysgenesis, and telomere biology disorders.13 Individuals in whom an inherited bone marrow syndrome is diagnosed have a germline predisposition, or increased risk, for MDS.14

Read more about MDS risk factors

Genetic testing can identify specific germline mutations causing inherited bone marrow failure disorders.15

Leukemias

Acute Myeloid Leukemia

Approximately one-third of MDS cases, especially treatment-related MDS (t-MDS), transform to acute myeloid leukemia (AML). A blast count in the bone marrow or peripheral blood that reaches or exceeds 20% reflects transformation of MDS to AML.1 

However, in 2008, the World Health Organization (WHO) stipulated that the 20% blast threshold is not the only criterion for treating patients as if they have AML or blast transformation. The WHO suggests that therapeutic decisions should be based on the clinical situation, with all available information taken into consideration.16,17 

Chronic Myelogenous Leukemia (Chronic Myeloid Leukemia)

Chronic myelogenous leukemia, also known as chronic myeloid leukemia (CML), accounts for approximately 20% of all cases of leukemia. CML is characterized by proliferation of the granulocytic blood cell line without loss of differentiation. Often, immature blast cells and an increased number of granulocytes circulate in the peripheral blood.18 

CML is characterized by the Philadelphia chromosome, in which abnormal translocation of the long arms of chromosomes 9 and 22 results in the formation of the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) fusion oncogene.19 The Philadelphia chromosome is extremely rare in MDS; however, it may occur during treatment for AML or MDS.20,21

Hairy Cell Leukemia

Hairy cell leukemia (HCL) is a chronic lymphoid leukemia in which microscopic examination reveals hairlike cytoplasmic projections on abnormal B cells. This feature is a morphologic differentiator of HCL from MDS.22

Neutropenia

Causes of neutropenia other than MDS must be ruled out, including hereditary and acquired conditions, drug-related direct toxicity, immune system effects, and autoimmune conditions. In hereditary conditions that cause neutropenia, specific genetic mutations can be identified with genetic testing to differentiate the conditions from MDS.23,24

Autoimmune neutropenia may be associated with24:

  • Crohn’s disease
  • Rheumatoid arthritis with or without Felty syndrome
  • Sjögren’s syndrome
  • Systemic lupus erythematosus
  • Thymoma 
  • Hodgkin lymphoma
  • Goodpasture disease
  • Chronic autoimmune hepatitis
  • Granulomatosis with polyangiitis 
  • Pure red blood cell aplasia
  • Large granular lymphocyte proliferation or leukemia
  • Transfusion reactions

Read more about MDS genetics

Felty Syndrome

Felty syndrome is characterized by the triad of rheumatoid arthritis, splenomegaly, and granulocytopenia.25 Splenomegaly is rare but may cause complications in MDS.26 Rheumatoid arthritis may co-occur with MDS but often precedes the diagnosis of MDS by a median of 9 months.27 Dysregulated immune function in patients with rheumatoid arthritis may contribute to the development of MDS.28

Platelet Disorders

Thrombocytopenia with causes other than MDS must be ruled out, including autoimmune thrombocytopenias, gestational thrombocytopenia, drug-induced thrombocytopenias, thrombotic thrombocytopenic purpura, and other conditions.29 MDS must also be distinguished from conditions that result in easy bleeding, such as Glanzmann thrombasthenia, von Willebrand disease, and Bernard-Soulier syndrome. These platelet disorders are caused by defects or deficiencies in various clotting factors, proteins, and protein complexes that disrupt platelet aggregation.30

Immune Thrombocytopenia

Immune thrombocytopenia (ITP), an autoimmune condition caused by autoantibodies to platelets, results in the sequestration of platelets in the spleen and inhibition of platelet production.29 In ITP, thrombocytopenia is isolated; the bone marrow is normal, and other potential causes of thrombocytopenia are absent.31 In contrast, one of the hallmark characteristics of MDS is dysplasia of the bone marrow, which is confirmed with bone marrow aspiration and biopsy.32

Read more about MDS clinical features

Myeloproliferative Disease

MDS and myeloproliferative neoplasms (MPNs) both begin with abnormal changes or mutations in hematopoietic stem cells in the bone marrow.33,34 In MDS, these changes result in the production of dysplastic or immature blood cells and cytopenia in one or more of the 3 major blood cell lines.33 In MPN, the stem cell changes result in the overproduction of any combination of red blood cells, white blood cells, and platelets.34 Sometimes, features of both MDS and MPN are present, resulting in subtypes called MDS/MPN overlap syndromes.35

Pre-MDS Conditions

In recent literature, the characteristics of several potential pre-MDS conditions have been described. The WHO has proposed terminology to avoid misdiagnosis or overdiagnosis of early stages of cancer development, as these conditions can persist without further signs or progression. However, as they may also develop into MDS, these categories are used as a provisional diagnosis, to be replaced by a final diagnosis after follow-up.36

Idiopathic Cytopenia of Undetermined Significance

The WHO proposed a category — idiopathic cytopenia of undetermined significance (ICUS) —  in which patients are classified as having possible MDS that is difficult to prove. Further diagnostic testing may be required to confirm a diagnosis of MDS. To meet the criteria for ICUS, patients must demonstrate persistent peripheral cytopenia in one or more blood cell lineages for at least 6 months that cannot be unexplained by any other cause or disease process.37 

The diagnostic criteria for MDS are not fulfilled in ICUS for the following reasons36:

  • Dysplasia is absent or mild (<10%)
  • The percentage of blast cells is less than 5%
  • No MDS-related genetic mutations are found

Idiopathic Dysplasia of Undetermined Significance

The WHO proposed a second category — idiopathic dysplasia of undetermined significance (IDUS) —  in which patients are classified as having possible MDS that is difficult to prove. Further or repeated testing may be needed to confirm a diagnosis of MDS.36

In IDUS, dysplasia in 10% or more of neutrophilic, erythroid, and/or megakaryocytic cell lines is found. However, the diagnostic criteria for MDS are not fulfilled in IDUS for the following reasons36:

  • Peripheral cytopenia is absent
  • No MDS-related genetic mutations are found
  • The percentage of blast cells is less than 5%

Other pre-MDS conditions that do not meet the MDS diagnostic criteria but must also be considered during a diagnostic workup for MDS include clonal cytopenia of undetermined significance (CCUS) and clonal hematopoiesis of indeterminate potential (CHIP). CCUS presents with peripheral cytopenias and one or more MDS-related genetic mutations, but the percentage of blast cells is fewer than 5% and dysplasia is absent or very mild, at less than 10%. CHIP presents with one or more MDS-related genetic mutations, but it does not present with peripheral cytopenias, the percentage of blast cells is fewer than 5%, and dysplasia is absent or very mild, at less than 10%.36

Read more about MDS diagnosis

References

  1. Dotson JL, Lebowicz Y. Myelodysplastic syndrome. StatPearls [Internet. Updated July 18, 2022. Accessed June 22, 2023. 
  2. Kennedy AL, Shimamura A. Genetic predisposition to MDS: clinical features and clonal evolution. Blood. 2019;133(10):1071-1085. doi:10.1182/blood-2018-10-844662
  3. Bejar R, Steensma DP. Recent developments in myelodysplastic syndromes. Blood. 2014;124(18):2793-2803. doi:10.1182/blood-2014-04-522136
  4. Maakaron JE. Anemia: practical essentials. Medscape. Updated September 27, 2021. Accessed June 22, 2023.
  5. Vitamin B12 or folate deficiency anaemia. NHS Inform. Accessed June 22, 2023.
  6. Wazir SM, Ghobrial I. Copper deficiency, a new triad: anemia, leucopenia, and myeloneuropathy. J Community Hosp Intern Med Perspect. 2017;7(4):265-268. doi:10.1080/20009666.2017.1351289
  7. Sako S, Tsunogai T, Oishi K. Thiamine-responsive megaloblastic anemia syndrome. GeneReviews® [Internet]. Updated July 28, 2022. Accessed June 22, 2023. 
  8. Moore CA, Krishnan K. Aplastic anemia. StatPearls [Internet]. Updated July 18, 2022. Accessed June 22, 2023.
  9. Serio B, Risitano A, Giudice V, Montuori N, Selleri C. Immunological derangement in hypocellular myelodysplastic syndromes. Transl Med UniSa. 2014;8:31-42.
  10. Koh Y, Lee HR, Song EY, et al. Hypoplastic myelodysplastic syndrome (h-MDS) is a distinctive clinical entity with poorer prognosis and frequent karyotypic and FISH abnormalities compared to aplastic anemia (AA). Leuk Res. 2010;34(10):1344-1350. doi:10.1016/j.leukres.2010.03.001
  11. Malcovati L, Hellström-Lindberg E, Bowen D, et al. 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
  12. Ashorobi D, Munakomi S. Myelophthisic anemia. StatPearls [Internet]. Updated February 12, 2023. Accessed June 22, 2023.
  13. Moore CA, Krishnan K. Bone marrow failure. StatPearls [Internet]. Updated July 11, 2022. Accessed June 21, 2023.
  14. Myelodysplastic syndromes – MDS: risk factors. Cancer.Net. Accessed June 22, 2023.
  15. Kim HY, Kim HJ, Kim SH. Genetics and genomics of bone marrow failure syndrome. Blood Res. 2022;57(Suppl 1):86-92. doi:10.5045/br.2022.2022056
  16. Estey E, Hasserjian RP, Döhner H. Distinguishing AML from MDS: a fixed blast percentage may no longer be optimal. Blood. 2022;139(3):323-332. doi:10.1182/blood.2021011304
  17. 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
  18. Besa EC. Chronic myelogenous leukemia (CML): practice essentials. Medscape. Updated June 15, 2023. Accessed June 22, 2023. 
  19. Sampaio MM, Santos MLC, Marques HS, et al. Chronic myeloid leukemia–from the Philadelphia chromosome to specific target drugs: a literature review. World J Clin Oncol. 2021;12(2):69-94. doi:10.5306/wjco.v12.i2.69
  20. Chelapareddy LR, Sen S. Philadelphia translocation in MDS: a case report and a brief review of the literature looking at its prevalence, disease progression, and treatment options. Case Rep Hematol. 2018;2018:5865321. doi:10.1155/2018/5865321
  21. Kurt H, Zheng L, Kantarjian HM, et al. Secondary Philadelphia chromosome acquired during therapy of acute leukemia and myelodysplastic syndrome. Mod Pathol. 2018;31(7):1141-1154. doi:10.1038/s41379-018-0014-x
  22. Besa EC. Hairy cell leukemia: practice essentials. Medscape. Updated October 25, 2022. Accessed June 22, 2023.
  23. DeFaria C. Neutropenia: practice essentials. Medscape. Updated October 31, 2022. Accessed June 22, 2023.
  24. DeFaria C. Neutropenia: etiology. Medscape. Updated October 31, 2022. Accessed June 22, 2023.
  25. Keating RM. Felty syndrome: practice essentials. Medscape. Updated July 19, 2022. Accessed June 22, 2023.
  26. Nalluru SS, Jindal V, Piranavan P, Kate Y, Siddiqui AD. Splenic infarction secondary to myelodysplastic syndrome: unravelling more etiologies. AME Case Rep. 2019;3:31. doi:10.21037/acr.2019.07.11
  27. Mekinian A, Braun T, Decaux O, et al. Inflammatory arthritis in patients with myelodysplastic syndromes. Medicine (Baltimore). 2014;93(1):1-10. doi:10.1097/MD.0000000000000011
  28. Sun C, Luo Y, Tong H, Xu G, Lin J. Usefulness of tocilizumab for treating rheumatoid arthritis with myelodysplastic syndrome. Medicine (Baltimore). 2018;97(25):e11179. doi:10.1097/MD.0000000000011179
  29. Thiagarajan P. Platelet disorders: overview of platelet disorders – autoimmune thrombocytopenias. Medscape. Updated November 19, 2021. Accessed June 22, 2023. 
  30. Thiagarajan P. Platelet disorders: overview of platelet disorders – disorders of platelet function. Medscape. Updated November 19, 2021. Accessed June 22, 2023. 
  31. Silverman MA. Immune thrombocytopenia (ITP) in emergency medicine: practice essentials. Medscape. Updated September 13, 2021. Accessed June 22, 2023.
  32. What are myelodysplastic syndromes (MDS)? Cancer Research UK. Accessed June 22, 2023.
  33. Myelodysplastic syndromes. Leukemia & Lymphoma Society. Accessed June 22, 2023.
  34. Myeloproliferative neoplasms. Leukemia & Lymphoma Society. Accessed June 22, 2023.
  35. 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
  36. Valent P. ICUS, IDUS, CHIP and CCUS: diagnostic criteria, separation from MDS and clinical implications. Pathobiology. 2019;86(1):30-38. doi:10.1159/000489042
  37. Malcovati L, Cazzola M. The shadowlands of MDS: idiopathic cytopenias of undetermined significance (ICUS) and clonal hematopoiesis of indeterminate potential (CHIP). Hematology. 2015;2015(1):299-307. doi:10.1182/asheducation-2015.1.299

Reviewed by Hasan Avcu, MD, on 6/23/2023.

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