MYELODYSPLASTIC

• Myelodysplastic syndromes (MDS)


  A group of acquired clonal hematologic disorders characterized by progressive cytopenias in the peripheral blood, reflecting defects in erythroid, myeloid, and/or megakaryocytic maturation
• MDS


  • Increased risk, especially among certain subtypes, for the disease to transform into acute myeloid leukemia (AML)
  • Median age of diagnosis is 76 years old
  • Rarely affect individuals younger than age 50 unless preceded by chemotherapy or radiation used in the treatment of another malignancy
• The incidence of MDS seems to be increasing, but this apparent increase may be attributable in part to improved techniques for identifying these diseases and to improved classification
• Cell of origin for MDS

  Phenotypically normal hematopoietic stem cells (HSCs) that exist in low frequency in the bone marrow and may harbor one or more somatic mutations
• Clonal hematopoiesis of indeterminate potential (CHIP)


  A precursor state for many hematologic disorders, including MDS, even though the rate of transformation is low
• Approximately 10% of patients older than age 65 and nearly 20% older than age 90 have CHIP
• Therapy-related MDS (t-MDS)


  Develops in patients after treatment with chemotherapy and/or radiotherapy, usually 4 to 7 years after therapy was initiated
• 1. MDS is aggressive and may evolve quickly into AML
• Inherited bone marrow failure syndromes

  Fanconi anemia, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome are at a significantly increased risk for developing MDS, particularly in childhood or adolescence
• Morphologic abnormalities in MDS

  • Presence of progressive cytopenias despite cellular bone marrow
  • Dyspoiesis in one or more cell lines
• Dyserythropoiesis


  Abnormal morphologic findings in the erythroid cell line, including oval macrocytes, hypochromic microcytes, dimorphic red blood cell population, abnormal nuclear and cytoplasmic features in erythroid precursors, and ring sideroblasts
• Dysmyelopoiesis


  Abnormal morphologic findings in the myeloid cell line, including persistent basophilia, abnormal granulation, abnormal nuclear shapes, and uneven cytoplasmic staining
• Dysmegakaryopoiesis


  Abnormal morphologic findings in the megakaryocytic cell line, including micromegakaryocytes and abnormal platelet granulation
• Myelocyte


  Devoid of Granules
• Agranular Neutrophil


  Devoid of Granules
• The cytoplasm stained normally
• Abnormal granulation of the cytoplasm

  • Promyelocytes or myelocytes or both are devoid of primary granules
  • Primary granules may be larger than normal
  • Secondary granules may be reduced in number or absent
  • Occasional Auer rod
• Agranular promyelocytes


  May be mistaken for blasts, leading to misclassification of the disease in the AML scheme
• Abnormal nuclear findings


  • Hypersegmentation or hyposegmentation
  • Ring-shaped nuclei
• Bone marrow


  • Granulocytic hypoplasia or hyperplasia
  • Monocytic hyperplasia
• Abnormal localization of immature precursors

  • Myeloblasts and promyelocytes tend to cluster centrally in marrow sections
• Dysmegakaryopoiesis


  • Giant platelets
  • Platelets with abnormal granulation (hypogranulation or agranulation)
  • Platelets with large fused granules
  • Circulating micromegakaryocytes
• Megakaryocytic component of bone marrow

  • Large mononuclear megakaryocytes
  • Micromegakaryocytes
  • Micromegakaryoblasts
  • Abnormal nuclear shapes (bilobed or multiple small, separated nuclei)
• Dysplasia by itself is not sufficient evidence for MDS, as several other conditions can cause similar morphologic features
• Thorough history and physical examination, including questions about exposure to drugs and chemicals, are essential
• Abnormal cellular function


  • Decreased adhesion, deficient phagocytosis, decreased chemotaxis, or impaired microbicidal capacity in granulocytes
  • Shortened survival of RBCs
  • Decreased response to erythropoietin in erythroid precursors
  • Increased bleeding despite adequate platelet numbers
• The type and degree of dysfunction depend on the mutation present in the HSC
• FAB classification


  Standardized diagnosis of MDS with 5 classes based on morphology
• FAB classification did not view MDS in their totality as it did not address therapy-related MDS, hereditary forms, or childhood MDS
• WHO classification


  Maintains some FAB features while incorporating advances in medical knowledge such as clinical, molecular, cytogenetic, and immunologic characteristics
• WHO classification of MDS

  • MDS with single lineage dysplasia (MDS-SLD)
  • MDS with ring sideroblasts (MDS-RS)
  • MDS with multilineage dysplasia (MDS-MLD)
  • MDS with excess blasts (MDS-EB)
  • Myelodysplastic syndrome with isolated del(5q)
  • Myelodysplastic syndrome, unclassifiable
  • Childhood myelodysplastic syndrome
• MDS with single lineage dysplasia (MDS-SLD)


  • Presenting symptoms related to cytopenia
  • Less than 1% blasts in peripheral blood and less than 5% blasts in bone marrow
  • Dysplasia in at least one myeloid lineage
  • Median survival 5 years, 2-12% risk of transformation to AML
• MDS with multilineage dysplasia (MDS-MLD)

  • One or more cytopenias, dysplasia in two or more myeloid cell lines, less than 1% blasts in peripheral blood and less than 5% blasts in bone marrow
  • Median survival 31-38 months, 10-12% risk of transformation to AML within 5 years
• MDS with ring sideroblasts (MDS-RS)

  • Anemia and dyserythropoiesis, peripheral blood often shows dimorphic picture
  • If SF3B1 mutation detected, only 5% ring sideroblasts required
  • If no SF3B1 mutation, 15% ring sideroblasts required
• MDS-RS with single lineage dysplasia

  Unilineage dysplasia, less than 5% blasts, no Auer rods
• MDS-RS with multilineage dysplasia

  Multilineage dysplasia, less than 5% blasts, no Auer rods
• Rods


  Erythroid precursors that are ring sideroblasts
• Percentage of ring sideroblasts

  • <15%*
  • <5% if a mutation in SF3B1 is not detected
  • ≥15% if a mutation in SF3B1 is detected
• Percentage of blasts


  • 5%-9%; no Auer rods
  • 10%-19%; ± Auer rods+
• Dysplasia


  Unilineage or multilineage