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Refractory Anemia with Ring Sideroblasts

Definition

  • Myelodysplastic syndrome characterized by erythroid dysplasia with ring sideroblasts

Diagnostic Criteria

  • Should be distinguished from RCUD because of longer median survival and lower rate of leukemic transformation
  • Exclusions
  • Refractory anemia - Hemoglobin <10 mg/dL
    • Dysplasia limited to erythroid lineage (see below for criteria for dysplasia)
      • Must involve ≥10% of erythroids
      • If ≥10% of other lineage(s) involved see RCUD or RCMD
        • RCMD with ring sideroblasts is not distinct category in WHO 2008
          • Clinical course is similar to RCMD without ring sideroblasts
    • Ring sideroblasts (see definition below) ≥15% of total erythroid precursors (if <15% see RCUD)
    • If >450x103/μL platelets in peripheral blood with marrow megakaryocytic proliferation, consider RARS-T
      • This is a provisional mixed MDS/MPN entity that is commonly JAK2V617E mutated
  • Peripheral blood blasts <1%, based on 200 leukocyte differential
  • Bone marrow blasts <5%, based on 500 nucleated cell differential
  • Cytogenetics should be performed on every patient to verify the presence of a clonal abnormality
    • Present in about 10% of patients
    • If no clone present, patient must be observed for 6 months before diagnosis of MDS is given

Morphologic features of erythroid dysplasia

  • Dyserythropoeisis
    • Dimorphic red blood cells (RBC)
      • Mixture of normal or macrocytic RBC and hypochromic microcytic RBC
      • High RDW
      • Basophilic stippling (Pappenheimer bodies)
    • Bone marrow erythroid lineage abnormalties
      • Ring sideroblasts
        • ≥5 iron granules encircling ≥1/3 of the nucleus
        • Must involve ≥15% of erythroids to make the diagnosis of RARS
          • Usually either many or none
      • Erythroid hyperplasia
        • Megaloblastoid / megaloblastic changes
          • Dyssynchronous maturation of nucleus and cytoplasm of erythroid precursors
            • Nucleus lags behind cytoplasm
      • Cytoplasmic vacuoles
        • Also seen in copper deficiency
      • Nuclear changes
        • Multinuclearity
        • Nuclear budding, hyperlobulation and satellite nuclei
        • Internuclear bridging
    • Often increased iron in histiocytes
      • Due to lysis of defective erythrocytes

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 abnormalities are identified in fewer (about 10%) RARS patients than in other MDS
    • Presence important for prognosis
  • If >450x103/μL platelets in peripheral blood with marrow megakaryocytic proliferation, consider JAK2V617F
    • Frequently mutated in RARS-T
  • Serum iron and ferritin show iron overload

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)

Flow immunophenotyping

  • Often shows decreased hematogones
  • May show immunophenotypic abnormalities
    • e.g. CD56 on blasts and monocytes
  • Paroxysmal Nocturnal Hemoglobinuria clone may be present, particularly in RCUD
    • CD55 and CD59 deficient RBC

Immunohistochemistry

  • CD34+ blast clusters
    • ≥3 clusters of ≥3 cells each
    • Confers worse prognosis in MDS with <5% blasts

Bone marrow reticulin/trichrome stains

  • Dense, diffuse fibrosis confers worse prognosis independent of IPSS
    • Grade 2-3 per the European consensus scale (Thiele 2005)

Differential Diagnosis

Non-neoplastic causes of sideroblastic anemia

  • Congenital
    • May be unmasked with discontinuation of pyridoxine (vitamin B6) in multivitamins
  • Acquired
    • Alcohol
    • Isoniazid
    • Chloramphenicol
    • Lead poisoning

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

  • RARS has a low (1-2%) rate of transformation to acute leukemia
  • Overall median survival 69-108 months
  • Increased risk of iron overload with hepatosplenomegaly

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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