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Refractory Anemia with Excess Blasts (RAEB)

Definition

  • Myelodysplastic syndrome characterized by elevated blasts, but below leukemic levels

Diagnostic Criteria

  • Exclusions
  • Elevated blasts, but not to leukemic levels in either:
    • Peripheral blood blasts 2-19%, based on 200 leukocyte differential, OR
    • Bone marrow blasts 5-19%, based on 500 nucleated cell differential
    • Divided into two prognostic groups:
      • RAEB 1
        • 2-4% peripheral blood blasts AND/OR
        • 5-9% bone marrow blasts
      • RAEB 2
        • 5-19% peripheral blood blasts AND/OR
        • 10-19% bone marrow blasts AND/OR
        • Auer rods
          • Presence should raise suspicion for AML (see Differential Diagnosis)
  • Hypercellular marrow with dysplasia in >10% of one or more cell lineage
  • Abnormal localization of immature precursors (ALIP) frequently present
    • Aggregates (3-5%) or clusters (>5%) of immature cells located in center portion of marrow
      • Away from normal perivascular or endosteal locations
  • Cytogenetics should be performed on every patient to verify the presence of a clonal abnormality
    • Present in about half
  • Marrow fibrosis and/or hypocellularity may cause problems with diagnosis
    • If present, add to the diagnosis as a modifier

Myelodysplasia is defined by morphologic features of abnormal cellular maturation in at least one bone marrow lineage

  • Not all features are applicable to all disorders
  • Dyserythropoeisis
    • Peripheral blood erythrocyte abnormalities
      • Normocytic, normochromic anemia
      • Macrocytosis
      • Dimorphic red blood cells (RBC)
      • Basophilic stippling
      • Poikilocytosis
        • Varying shapes, frequently macro-ovalocytes
    • Bone marrow erythroid lineage abnormalties
      • Erythroid hyperplasia or hypoplasia
        • Megaloblastoid / megaloblastic changes
          • Dyssynchronous maturation of nucleus and cytoplasm of erythroid precursors
            • Nucleus lags behind cytoplasm
      • Ring sideroblasts
        • ≥5 iron granules encircling ≥1/3 of the nucleus
        • Usually either many or none
      • Cytoplasmic vacuoles
        • Also seen in copper deficiency
      • Nuclear changes
        • Multinuclearity
        • Nuclear budding, hyperlobulation and satellite nuclei
        • Internuclear bridging
  • Dysgranulopoiesis
    • Peripheral blood and/or bone marrow findings (easier seen in peripheral blood)
      • Hypogranularity
        • Pale cytoplasm almost indistinguishable from background on slide
      • Nuclear hypolobation or irregular hypersegmentation (>5 lobes)
        • Pseudo Pelger-Huet anomaly
          • Two equal size nuclear lobes connected by a thin strand of chromatin
      • Infrequent findings
        • Abnormal cytoplasmic granules (pseudo Chediak-Higashi granules)
          • Giant grey to red granules
        • Dohle bodies
          • Small blue cytoplasmic inclusions
          • Often found at periphery of cell
        • Auer rods
          • Rod-like structures formed by fusion of primary granules
          • May be found in blasts or maturing granulocytes
  • Dysmegakaryopoiesis
    • Peripheral blood platelet abnormalities
      • Giant
        • Larger than a red blood cell
      • Bizarre
        • Irregular shapes and protrusions
      • Hypogranularity
        • Compare to normal platelets with purple granules
    • Bone marrow megakaryocyte abnormalities
      • Micromegakaryocytes
        • Smaller than a promyelocyte
      • Nuclear hypolobation
        • Prominent in 5q- syndrome
        • A single lobe is typically seen in a small megakaryocyte
      • Multinucleation
        • Distinct nuclei without a connecting strand of chromatin
      • Cytoplasmic hypogranularity

Dita Gratzinger MD PhD
Tracy I George MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting: 10/23/11

Supplemental studies

Cytogenetic studies should be performed in all cases of myelodysplasia or suspected myelodysplasia

  • FISH for MDS associated abnormalities is not indicated for screening but is helpful if <20 metaphases were examined on karyotyping
  • In the setting of persistent cytopenia in the absence of definitive morphologic features of MDS:
    • The following abnormalities are considered presumptive evidence of MDS
      • Deletions
        • -5, del(5q)
        • -7, del(7q)
        • del(9q)
        • del(11q)
        • del(12p)
        • t(12p)
        • -13, del(13q)
        • i(17q), t(17p)
        • idic(X)(q13)
      • Translocations
        • t(1;3)(p36.3;q21.2)
        • t(2;11)(p21;q23)
        • t(3;21)(q26.2;q22.1)
        • inv(3)(q21q26.2) and t(6;9)(p23;q24)
          • Most frequently present as AML and need to be closely monitored for overt transformation
        • t(11;16)(q23;p13.3)
    • The following are commonly found in MDS but are not by themselves considered definitional for MDS
      • +8
      • -Y
      • del(20q)

Differential Diagnosis

Refractory Anemia with Excess Blasts Acute Myelogenous Leukemia
Blasts <20% in both peripheral blood and bone marrow Blasts frequently ≥20% in peripheral blood and/or bone marrow
AML defining translocations not present May have AML defining translocations t(8;21)(q22;q22) or inv or t(16)(p13.1;q22)

Non-neoplastic disorders may simulate myelodysplasia

  • Vitamin/micronutrient deficiencies
    • B12/folate
    • Copper
      • Ring sideroblasts present
      • Cytoplasmic vacuoles
      • May be due to
        • Zinc excess
        • Gastrectomy
        • Total parenteral nutrition
  • Infections
    • HIV
    • Parvovirus
    • HHV-6 in children
  • Toxins
    • Ethanol
    • Heavy metals
  • Growth factors
    • Granulocyte-macrophage colony-stimulating factor (GMCSF)
    • Erythropoietin
  • Drugs (numerous)
    • Chemotherapeutic agents
      • e.g. megaloblastoid change with folate antagonists
    • Valproic acid, MMF (mycophenolate mofetil), Ganciclovir
      • Pseudo-Pelger-Helger anomaly
  • Autoimmune/rheumatologic
    • e.g. systemic lupus erythematosus
  • Congenital
    • Congenital dyserythropoietic anemias
    • Inherited bone marrow failure syndromoes (Fanconi etc.)
    • Monocytopenia immunodeficiency syndrome

Myelodysplastic Syndromes

  Circulating Blasts Marrow Blasts Ring Sideroblasts Dysplastic Lineages Cytopenias
RCUD <1% <5% <15% Any 1 lineage 1 or 2
RARS 0 <5% ≥15% Only erythroid 1 or 2
RCMD <1% <5% Variable 2 or more lineages 1, 2 or 3
RAEB-1 <5% 5-9% Variable 1 or more 1, 2 or 3
RAEB-2 5-19% 10-19% or Auer rods Variable 1 or more 1, 2 or 3
del(5q) <1% <5% Variable Frequently hypolobated small megakaryocytes Usually 1 (anemia)
  • RCUD = refractory cytopenia (anemia, neutropenia or thrombocytopenia) with unilineage dysplasia; RARS = refractory anemia with ringed sideroblasts; RCMD = refractory cytopenia with multilineage dysplasia; RAEB = refractory anemia with excess blasts; del(5q) = 5q- syndrome
  • All MDS must not have absolute monocytosis
  • If chemotherapy or radiation therapy related, should be reported as "therapy-related myeloid neoplasm"
  • In children, consider provisional WHO entity "refractory cytopenia of childhood" for low blast count MDS
  • Myelodysplastic syndrome unclassifiable (MDS-U)
    • Must not meet criteria of any specific WHO category
    • Persistent cytopenia(s) with any of the following:
      • Unilineage marrow dysplasia with pancytopenia OR
      • <1% blasts in blood, <5% blasts in marrow and cytogenetic abnormalities but no lineage with ≥10% dysplastic forms OR
      • Findings of RCUD or RCMD but with 1% blasts in peripheral blood
        • (2-4% blasts would be classified as RAEB-1)
    • Nonclonal causes must be excluded

 

Clinical

  • Includes approximately 40% of MDS patients
  • Most over age 50 years
  • RAEB1
    • Median survival 16 months
    • 25% transformation to AML
  • RAEB 2
    • Median survival 9 months
    • 33% transformation to AML

International Prognostic Scoring System (IPSS)

Points are assigned based on abnormal findings

Points: 0 0.5 1 1.5 2
BM blast % <5 5-10 - 11-20 21-30
Cytogenetic Group Good Intermediate Poor    
Number of cytopenic lineages 0-1 2-3      
  • Cytogenetic groups
    • Good: Normal, -Y, del(5q), del(20q)
    • Intermediate: All others
    • Poor: Complex, chromosome 7 abnormalities
  • Cytopenias
    • Hemoglobin <10 mg/dl
    • Absolute neutrophil count <1.8 x 103/μL
    • Platelets <100 x 103/μL

Risk groups are determined based on points assigned as above

Risk Group Points Median Survival Evolution to Acute Leukemia
Low 0 5.7 years 9.4 years
Intermediate-1 0.5-1.0 3.5 years 3.3 years
Intermediate-2 1.5-2.0 1.2 years 1.1 years
High >2.5 0.4 years 0.2 years
  • Treatment based on risk group assigned and ability to tolerate therapy including
    • Supportive care
    • Immunosuppressive agents
    • Bone marrow transplantation
    • Intensive cytotoxic treatment
    • Demethylating agents
    • Farnesyl transferase inhibitors

Blood 89:2079, 1997

 

Classification / Lists

WHO 2008 Classification of Myeloid Neoplasms

Myeloproliferative Neoplasms (MPN)

Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1

Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)

Myelodysplastic Syndromes (MDS)

Therapy Related Myeloid Neoplasms

 

Bibliography

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