Myelodysplastic Syndrome (MDS) with Multilineage Dysplasia

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This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.

Primary Author(s)*

Xiaoli Du, Ph.D; Teresa A. Smolarek, Ph.D, FACMG

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.

Cancer Category/Type

Myelodysplastic Syndrome

Cancer Sub-Classification / Subtype

Myelodysplastic Syndrome (MDS) with Multilineage Dysplasia (MLD)

Definition / Description of Disease

Myelodysplastic syndrome (MDS) with multilineage dysplasia (MDS-MLD), called Refractory Cytopenia with Multilineage Dysplasia (RCMD) in the 2008 edition of WHO book, is a frequent subtype of myelodysplastic syndrome (MDS) characterized by one or more cytopenias and dysplastic changes in two or more of the myeloid lineages (erythroid, granulocytic, and megakaryocytic), <5% of blasts in bone marrow and <1% blasts in peripheral blood, non-Auer rods[1][2]. The presences of 1% blasts in the peripheral blood excludes a diagnosis of MDS-MLD. Cases with multilineage dysplasia and ≥15% ring sideroblasts or ≥5% ring sideroblasts and SF3B1 mutation is classified as MDS with ring sideroblasts and multilineage dysplasia (MDS-RS-MLD). While cases with multilineage dysplasia or ≥5% but <15% ring sideroblasts with unknown SF3B1 mutation status is classified as MDS-MLD[1]. MDS-MLD has a variable clinical course and prognosis, which is associated with karyotype and degree of cytopenia and dysplasia.

Synonyms / Terminology

Refractory cytopenia with multilineage dysplasia, RCMD, MDS-MLD

Epidemiology / Prevalence

Exact prevalence is unknown but MDS-MLD accounts for about 30% of patients with MDS[1].

  • Occurs mainly in older patients
  • Median age is 65-70 years
  • Male predominance

Clinical Features

Patients usually present with evidence of bone marrow failure. Most patients present with unicytopenia or bicytopenia[3]. The recommended thresholds for cytopenia suggested by International Prognostic Scoring System (IPSS)[4]:

  • Hemoglobin concentration: <10 g/dL
  • Absolute neutrophil count: <1.8 x109/L AND
  • Platelet count: <100 x109/L

However, some patients present with pancytopenia or milder cytopenia above this threshold levels in the IPSS[5].

Sites of Involvement

Peripheral blood and bone marrow

Morphologic Features

Categories Morphologic Features
Neutrophil Nuclear clumping, lack of lobation (pseudo-Pelger-Huet anomaly), cytoplasmic hypogranularity
Erythroid precursors Increased number, cytoplasmic vacuole, nuclear irregularity (nuclear budding, multinucleation, internuclear chromatin bridging)
Megakaryocyte Non-lobated nuclei, binucleation or multinucleation, micromegakaryocytes (most reliable marker for dysplastic megakaryocyte)[6]

Immunophenotype

Same as the MDS immunophenotype and the CD34+ cells are typical <5. However, definitive morphological and/or cytogenetic findings can help establish the diagnosis. Reporting flow cytometry findings in MDS should be done in an integrated diagnostic report, together with morphological, cytogenetic and/or molecular findings[7][8][9].

Chromosomal Rearrangements (Gene Fusions)

No

Characteristic Chromosomal Aberrations / Patterns

Trisomy 8, monosomy 7, del(7q), del(5q) or t(5q) Del(20q) and complex karyotypes[10].

Genomic Gain/Loss/LOH

  • Nonspecific cytogenetic abnormalities have been observed in 50% of MDS-SLD cases.
  • Trisomy 8, monosomy 7, del(7q), del(5q) or t(5q) Del(20q) and complex karyotypes[11].

Gene Mutations (SNV/INDEL)

  • More than 50% of MDS-MLD cases share the same gene mutations with MDS with excess blasts.
  • Most frequent mutations: STAG2, ASXL1, SRSF2, RUNX1, CBL, TP53 and TET2[12][13][14].
  • SF3B1: 1) MDS-MLD: multilineage dysplasia or ≥5% but <15% ring sideroblasts with unknown SF3B1 mutation status 2) MDS-RS-MLD: multilineage dysplasia and ≥15% ring sideroblasts or ≥5% ring sideroblasts and SF3B1 mutation[15].

Other Mutations

No

Epigenomics (Methylation)

TET2 mutations: altered DNA methylation, have been found to be an independent prognostic indicator with a high response rate to hypomethylating agents[16].

Genes and Main Pathways Involved

  • STAG2: involved in the separation of sister chromatids during cell division
  • ASXL1: involved in chromatin remodeling
  • SRSF2: involved in pre-mRNA splicing
  • RUNX1: transcription factor for hematopoiesis cells
  • CBL: involved in targeting substrates for degradation by the proteasome
  • TP53: tumor suppressor and TP53 pathway regulates the pathways of cell cycle arrest, apoptosis, and DNA repair
  • TET2: involved in regulating transcription
  • SF3B1: involved in pre-mRNA splicing

Diagnostic Testing Methods

  • Quantification of dysplasia: Microscopy
  • Pathology: Immunophenotyping by flow cytometry
  • Genetics: Conventional karyotyping, fluorescence in situ hybridization analysis (FISH), microarray and sequencing

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • Diagnosis: One or more cytopenias and dysplastic changes in two or more of the myeloid lineages. The blast percentage is <1% in the peripheral blood and <5% in the bone marrow.
  • Prognosis: International Prognostic Scoring System (IPSS) was adopted and accepted introduced by the Myelodysplastic Syndrome Working Group[17]. The clinical course of the patients with a diagnosis of MDS-MLD varies from case to case, which is related to the karyotype and degree of cytopenia and dysplasia[18]. Median survival of patients with MDS-MLD is approximately 36 months with the rate of progression to acute myeloid leukemia 28% at 5 years[19][1].
  • Therapeutic: Supportive care is important for MDS-MLD patients regardless of whether other treatments are planned. However, patients with MDS-MLD are often evaluated for immunosuppressive treatment. The antithymocyte globulin (ATG) treatment is recommended for MDS-MLD patient with symptomatic anemia and/or thrombocytopenia and/or neutropenia with increased susceptibility to infections[20].

Familial Forms

None

Other Information

None

Links

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References

  1. ↑ 1.0 1.1 1.2 1.3 Arber DA, et al., (2016). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J Editors. IARC Press: Lyon, France, p106-109.
  2. ↑ Rosati, S.; et al. (1996-01). "Refractory cytopenia with multilineage dysplasia: further characterization of an 'unclassifiable' myelodysplastic syndrome". Leukemia. 10 (1): 20–26. ISSN 0887-6924. PMID 8558932. Check date values in: |date= (help)
  3. ↑ Maassen, Anna; et al. (2013-01). "Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts". Leukemia Research. 37 (1): 64–70. doi:10.1016/j.leukres.2012.09.021. ISSN 1873-5835. PMID 23122806. Check date values in: |date= (help)
  4. ↑ Greenberg, Peter L.; et al. (2012-09-20). "Revised international prognostic scoring system for myelodysplastic syndromes". Blood. 120 (12): 2454–2465. doi:10.1182/blood-2012-03-420489. ISSN 1528-0020. PMC 4425443. PMID 22740453.
  5. ↑ Maassen, Anna; et al. (2013-01). "Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts". Leukemia Research. 37 (1): 64–70. doi:10.1016/j.leukres.2012.09.021. ISSN 1873-5835. PMID 23122806. Check date values in: |date= (help)
  6. ↑ Matsuda, A.; et al. (2007-04). "Improvement of criteria for refractory cytopenia with multilineage dysplasia according to the WHO classification based on prognostic significance of morphological features in patients with refractory anemia according to the FAB classification". Leukemia. 21 (4): 678–686. doi:10.1038/sj.leu.2404571. ISSN 0887-6924. PMID 17268513. Check date values in: |date= (help)
  7. ↑ Porwit, A.; et al. (2014-09). "Revisiting guidelines for integration of flow cytometry results in the WHO classification of myelodysplastic syndromes-proposal from the International/European LeukemiaNet Working Group for Flow Cytometry in MDS". Leukemia. 28 (9): 1793–1798. doi:10.1038/leu.2014.191. ISSN 1476-5551. PMID 24919805. Check date values in: |date= (help)
  8. ↑ van de Loosdrecht, Arjan A.; et al. (2013-07). "Cutting edge: flow cytometry in myelodysplastic syndromes". Journal of the National Comprehensive Cancer Network: JNCCN. 11 (7): 892–902. doi:10.6004/jnccn.2013.0106. ISSN 1540-1413. PMID 23847222. Check date values in: |date= (help)
  9. ↑ Xu, Lan; et al. (2014-06-10). "Genomic landscape of CD34+ hematopoietic cells in myelodysplastic syndrome and gene mutation profiles as prognostic markers". Proceedings of the National Academy of Sciences of the United States of America. 111 (23): 8589–8594. doi:10.1073/pnas.1407688111. ISSN 1091-6490. PMC 4060725. PMID 24850867.
  10. ↑ Maassen, Anna; et al. (2013-01). "Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts". Leukemia Research. 37 (1): 64–70. doi:10.1016/j.leukres.2012.09.021. ISSN 1873-5835. PMID 23122806. Check date values in: |date= (help)
  11. ↑ Maassen, Anna; et al. (2013-01). "Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts". Leukemia Research. 37 (1): 64–70. doi:10.1016/j.leukres.2012.09.021. ISSN 1873-5835. PMID 23122806. Check date values in: |date= (help)
  12. ↑ Haferlach, T.; et al. (2014-02). "Landscape of genetic lesions in 944 patients with myelodysplastic syndromes". Leukemia. 28 (2): 241–247. doi:10.1038/leu.2013.336. ISSN 1476-5551. PMC 3918868. PMID 24220272. Check date values in: |date= (help)
  13. ↑ Muscedere, John; et al. (2013-11). "The clinical impact and preventability of ventilator-associated conditions in critically ill patients who are mechanically ventilated". Chest. 144 (5): 1453–1460. doi:10.1378/chest.13-0853. ISSN 1931-3543. PMID 24030318. Check date values in: |date= (help)
  14. ↑ Xu, Lan; et al. (2014-06-10). "Genomic landscape of CD34+ hematopoietic cells in myelodysplastic syndrome and gene mutation profiles as prognostic markers". Proceedings of the National Academy of Sciences of the United States of America. 111 (23): 8589–8594. doi:10.1073/pnas.1407688111. ISSN 1091-6490. PMC 4060725. PMID 24850867.
  15. ↑ Malcovati, Luca; et al. (2015-07-09). "SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts". Blood. 126 (2): 233–241. doi:10.1182/blood-2015-03-633537. ISSN 1528-0020. PMC 4528082. PMID 25957392.
  16. ↑ Ganguly, Bani Bandana; et al. (2016-07). "Mutations of myelodysplastic syndromes (MDS): An update". Mutation Research. Reviews in Mutation Research. 769: 47–62. doi:10.1016/j.mrrev.2016.04.009. ISSN 1388-2139. PMID 27543316. Check date values in: |date= (help)
  17. ↑ Greenberg, P.; et al. (1997-03-15). "International scoring system for evaluating prognosis in myelodysplastic syndromes". Blood. 89 (6): 2079–2088. ISSN 0006-4971. PMID 9058730.
  18. ↑ Maassen, Anna; et al. (2013-01). "Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts". Leukemia Research. 37 (1): 64–70. doi:10.1016/j.leukres.2012.09.021. ISSN 1873-5835. PMID 23122806. Check date values in: |date= (help)
  19. ↑ Maassen, Anna; et al. (2013-01). "Validation and proposals for a refinement of the WHO 2008 classification of myelodysplastic syndromes without excess of blasts". Leukemia Research. 37 (1): 64–70. doi:10.1016/j.leukres.2012.09.021. ISSN 1873-5835. PMID 23122806. Check date values in: |date= (help)
  20. ↑ Bennett, John M. (2016-11). "Changes in the Updated 2016: WHO Classification of the Myelodysplastic Syndromes and Related Myeloid Neoplasms". Clinical Lymphoma, Myeloma & Leukemia. 16 (11): 607–609. doi:10.1016/j.clml.2016.08.005. ISSN 2152-2669. PMID 27693133. Check date values in: |date= (help)

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