Refractory Cytopenia with Unilineage Dysplasia (RCUD)

Definition

• Myelodysplastic syndrome characterized by dysplasia limited to one lineage

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 as RAEB-2 or AML)
• Cytopenias in 1-2 lineages
• Dysplasia in ≥10% of 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 >1 lineage, see Refractory Cytopenia with Multilineage 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 unilineage refractory cytopenias is currently unknown
  • If no clone present, patient may need to be observed for 6 months before diagnosis of MDS is given
• Marrow fibrosis (grade 2-3) and/or hypocellularity (<30% if ≤60 years old, <20% if >60) 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 30% of Refractory Anemia MDS cases
  • No data for new RCUD category
• 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

Clinical

• Can occur at any age but most frequent in older adults
• RCUD has a low (2%) rate of transformation to acute leukemia
• Median survival 70 months
• May respond to immunosuppressive therapy

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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