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Surgical Pathology Criteria

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Refractory Cytopenia with Multilineage Dysplasia (RCMD)


  • Myelodysplastic syndrome characterized by bi- or trilineage dysplasia

Diagnostic Criteria

  • Exclusions
  • Cytopenias in 1 or more lineages
  • Dysplasia in >10% of more than one cell lineage (see below for criteria for dysplasia)
  • 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 half of refractory anemia cases
      • Incidence in other refractory cytopenias is currently unknown
    • If no clone present, patient must be observed for 6 months before diagnosis of MDS is given
  • Marrow fibrosis and/or hypocellularity may cause problems with diagnosis
    • If present, add to the diagnosis as a modifier
      • (i.e. RCUD with fibrosis or hypocellular RCUD)

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 abnormalities are found in about 50% of RCMD cases
  • Other causes must be actively excluded clinically (see Differential Diagnosis at left)

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


  • 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 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


Hairy Cell Leukemia Aplastic Anemia Hypocellular (Hypoplastic) MDS Hypocellular AML
Variable cellularity Low cellularity Low cellularity Low cellularity
No dysplasia Mild erythroid dyspoiesis allowed but no ring sideroblasts Dysplasia present Variable dysplasia
Marrow blasts <5% Marrow blasts ≤1%, no ALIP Marrow blasts <20%, ALIP Marrow blasts ≥20%
Blood blasts rare No blood blasts Blood blastsl <20% Blood blasts ≥20%
Cytogenetics nonspecific May have cytogenetic abnormalities May have defining abnormalities May have defining abnormalities
Clonal B cells No B cell clone No B cell clone No B cell clone
ALIP = abnormal localization of immature precursors


Primary Myelofibrosis, Fibrotic Phase MDS with Fibrosis Post-Polycythemia Vera Myelofibrosis
JAK2V617F mutations in 50% JAK2V617F mutations rare JAK2V617F mutations in almost 100%
Tightly clustered hyperchromatic megakaryocytes Increased but non-clustered dysplastic megakaryocytes Variable size and increase in megakaryocytes
Prominent splenomegaly Rare splenomegaly Prominent splenomegaly
Does not meet criteria for MDS or PV Commonly multilineage dysplasia and increased blasts History of polycythemia vera
Myelofibrosis grade 2-3 and cytogenetic abnormalities are common in all three


  • Can occur at any age but most frequent in older adults
  • RCMD has a moderate (10%) rate of transformation to acute leukemia at 2 years
  • Median survival 30 months

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



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