Refractory Cytopenia with Multilineage Dysplasia (RCMD)

Definition

• Myelodysplastic syndrome characterized by bi- or trilineage dysplasia

Diagnostic Criteria

• Exclusions
  • Non-clonal causes for dysplasia must be excluded (see Differential Diagnosis)
  • If chemotherapy or radiation therapy related, should be reported as "therapy-related myeloid neoplasm"
  • <1 x 10³/μL monocytes (if present consider Chronic Myelomonocytic Leukemia)
  • Lack of neutrophilia (if present consider BCR-ABL1+CML or atypical CML)
  • Lack of Auer rods (if present, diagnose asRAEB-2 or AML)
• Cytopenias in 1 or more lineages
• Dysplasia in >10% of more than one cell lineage (see below for criteria for dysplasia)
  • Refractory anemia - Hemoglobin <10 mg/dL
    • Ring sideroblasts <15% of erythroid lineage cells (if ≥15% see Refractory Anemia with Ring Sideroblasts)
  • Refractory neutropenia - Absolute neutrophil count <1.8 x 10³/μL
  • Refractory thrombocytopenia - Platelet count <100 x 10³/μL
  • If dysplasia present in only 1 lineage, see Refractory Cytopenia with Unilineage 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)
      • Mixture of normal RBC and hypochromic microcytic RBC
        • Often seen in Sideroblastic Anemia (RARS)
    • 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

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

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 simulators
• Other myelodysplastic disorders

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

• 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 present, consider chronic myelomonocytic leukemia
• 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

Clinical

• 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

• 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

• 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)

• Chronic myeloid leukemia, BCR-ABL1 pos
• Chronic neutrophilic leukemia
• Chronic eosinophilic leukemia NOS
  • (see also Idiopathic hypereosinophilic syndrome)
• Polycythemia vera
• Essential thrombocythemia
• Primary myelofibrosis
• Mastocytosis
• Myeloproliferative neoplasm unclassifiable

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

Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)

• Chronic myelomonocytic leukemia (CMML)
• Atypical chronic myeloid leukemia, BCR-ABL1 negative
• Juvenile myelomonocytic leukemia
• Myelodysplastic / myeloproliferative neoplasm, unclassifiable
• Refractory anemia with ring sideroblasts associated with marked thrombocytosis
• Myelodysplastic / myeloproliferative neoplasm with isolated isochromosome 17q

Myelodysplastic Syndromes (MDS)

• Refractory cytopenia with unilineage dysplasia (RCUD)
  • Refractory anemia
  • Refractory neutropenia
  • Refractory thrombocytopenia
• Refractory cytopenia with multilineage dysplasia (RCMD)
• Refractory anemia with ring sideroblasts (RARS)
• Refractory anemia with excess blasts (RAEB)
• MDS associated with isolated del(5q)
• Childhood myelodysplastic syndrome
  • Refractory cytopenia of childhood
• MDS unclassifiable
• Additional features that may be superimposed on above classification:
  • MDS with fibrosis
  • MDS, hypocellular

Therapy Related Myeloid Neoplasms

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