Bone marrow neoplastic

Bone marrow - neoplastic myeloid

Other AML entities defined by the WHO

Myeloid leukemia associated with Down syndrome

Editorial Board Member: Patricia Tsang, M.D., M.B.A.
Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.
Rashmi Manur, M.D., M.P.H.
Alexa J. Siddon, M.D.

Last author update: 16 November 2020
Last staff update: 10 May 2021

Copyright: 2001-2024,, Inc.

PubMed Search: Myeloid leukemia [title] associated with Down syndrome

Rashmi Manur, M.D., M.P.H.
Alexa J. Siddon, M.D.
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Cite this page: Manur R, Siddon AJ. Myeloid leukemia associated with Down syndrome. website. Accessed April 15th, 2024.
Definition / general
  • Myeloid proliferations seen in individuals with Down syndrome (DS) include:
    • Transient abnormal myelopoiesis (TAM) is a hematopoietic stem cell disorder of newborns with Down syndrome which presents with clinical and morphological findings of acute myeloid leukemia but is self limiting; this entity is discussed separately
    • Myeloid leukemia associated with Down syndrome
Essential features
  • Myeloid proliferations associated with Down syndrome include transient abnormal myelopoiesis which is self limiting and acute myeloid leukemia, specifically, acute megakaryoblastic leukemia
  • Trisomy 21 and GATA1 mutations are implicated in pathogenesis
  • Prognosis is better than in cases with other pediatric acute leukemias
ICD coding
  • ICD-10: C92.Z - Other myeloid leukemia
  • ICD-O: 9898/3 - Myeloid leukemia associated with Down syndrome
  • Individuals with Down syndrome have 10 - 100 times the risk of acute leukemia as compared with the general population (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised Edition, 2017)
  • 1 - 2% of children with Down syndrome will develop acute myeloid leukemia before 5 years of age
  • If patient is a neonate, consider the diagnosis transient abnormal myelopoiesis associated with Down syndrome
  • 20 - 30% of children with history of transient abnormal myelopoiesis get acute myeloid leukemia within 1 - 3 years following transient abnormal myelopoiesis
  • Primary sites: peripheral blood and bone marrow
  • Extramedullary: spleen and liver, usually present
  • Trisomy 21 in fetal hematopoietic precursors followed by acquired GATA1 mutations is implicated in the development of myeloid proliferations associated with Down syndrome
  • Secondary epigenetic and genetic events lead to acute myeloid leukemia in individuals with transient abnormal myelopoiesis
  • Trisomy 21 affects fetal hematopoietic stem cell biology and leads to defective megakaryocytic, erythroid and B lymphoid lineage development
  • N terminal truncating mutations in the key megakaryocyte erythroid transcription factor, GATA1, are commonly seen in association with trisomy 21; mutated GATA1 gene affects megakaryocytic lineage in the fetal liver
  • Some of the secondary events that lead to acute leukemia in patients with transient abnormal myelopoiesis are gain of function mutation in myeloid cytokine receptor CSF2RB and tyrosine kinases such as JAK1, JAK2 and JAK3; loss of function mutations in genes encoding cohesion core subunits - CTCF, NIPBL, JAK1-3, SRSF2 and SF3B (Cancer Cell 2019;36:123)
Clinical features
  • Often a prolonged preleukemic or myelodysplastic phase may be present when patient presents with refractory cytopenias
Prognostic factors
  • Individuals with Down syndrome and GATA1 mutated acute myeloid leukemia have a better prognosis than those with other pediatric acute myeloid leukemias (must use Down specific treatment protocols)
  • Older age at diagnosis is associated with poor prognosis
Case reports
Microscopic (histologic) description
  • Preleukemic phase has morphologic features of refractory cytopenia of childhood; no increase in blasts
  • Acute megakaryoblastic leukemia accounts for ≥ 50% of cases
  • Bone marrow:
    • Variable blast count
    • Leukemic blasts have round to slightly irregular nuclei and a moderate amount of basophilic cytoplasm, basophilic granules; cytoplasmic blebs (megakaryoblastic features)
    • Erythroid, granulocytic and megakaryocytic dysplasia
    • Variable degree of reticulin fibrosis
  • Reference: Arch Pathol Lab Med 2020;144:466
Microscopic (histologic) images

Contributed by Alexa J. Siddon, M.D.

Hypercellular bone marrow

Bone marrow with CD34+ blasts

Bone marrow with CD61+ megakaryocytes and blasts

Peripheral smear description
  • Circulating blasts are typically present in blood; may have cytoplasmic blebs
  • Macrocytic red cells with anisopoikilocytosis including dacrocytes
  • Thrombocytopenia with giant platelets
Peripheral smear images

Contributed by Alexa J. Siddon, M.D.

Megakaryoblasts in peripheral blood

Positive stains
Negative stains
Flow cytometry description
  • Similar to stains
  • Can be helpful to show that the blasts are positive for both CD34 and platelet markers
Molecular / cytogenetics description
Sample pathology report
  • Bone marrow, biopsy, aspirate and peripheral smear:
    • Acute megakaryoblastic leukemia (see comment)
    • Comment: The overall features, including smear morphology, immunophenotype of the blast population and detection of a GATA1 mutation are most consistent with myeloid leukemia associated with Down syndrome in this 3 year old child with trisomy 21.
  • Peripheral smear:
    • The peripheral blood shows anemia and scattered intermediate sized blasts with basophilic cytoplasm, a subset of which has cytoplasmic blebs.
  • Bone marrow biopsy:
    • Cellular marrow for age (100% cellular). The marrow shows marked fibrosis, clusters of immature cells and frequent dysplastic megakaryocytes which are small with hypolobated nuclei. Residual trilineage hematopoiesis is markedly decreased. A reticulin stain reveals that reticulin is markedly increased (MF 3 of 3). Trabecular bone is unremarkable and there are no lymphoid aggregates. The clot section consists predominantly of clotted blood admixed with rare marrow elements.
  • Immunostains:
    • CD34 highlights abundant blasts, accounting for 50% of cellularity, which are negative for myeloperoxidase. CD61 highlights abundant dysplastic megakaryocytes as well as blasts.
  • Bone marrow aspirate:
    • The aspirate smear is aparticulate hemodilute; a formal differential count was not performed. Frequent blasts similar to those in blood are noted. They are medium in size and have a high N/C ratio. The nuclei are round or irregular with moderately delicate chromatin and inconspicuous nucleolus. The cytoplasm is scant and blue staining with occasional cytoplasmic blebs. Prussian blue iron stain on diluted smear is inconclusive for storage iron assessment; no increase in ring sideroblasts is seen.
  • Flow cytometry:
    • Flow cytometric analysis reveals approximately 44% of analyzed cells are blasts with a megakaryoblastic immunophenotype: CD45dim+ CD34+ CD117+ CD7dim+ CD41a(var)+ CD42+ CD61+ CD14- CD64- CD13dim+ CD33dim CD4- HLADR- CD19- CD10- CD79a- TDT- surfaceCD3- CD56(var) CD235a- MPO- cytoCD3-. The differential based on immunophenotype alone includes acute megakaryoblastic leukemia (AMKL) and transient abnormal myelopoiesis of Down syndrome. Blasts cannot be reliably differentiated by flow cytometry for these two entities but age is more consistent with AMKL. Please correlate with core biopsy analysis and molecular/cytogenetic results as available.
  • Cytogenetics:
    • Karyotype: 47,XY,+21[20]
Differential diagnosis
Board review style question #1

A 29 month old child with Down syndrome presents to the clinic with easy bruising. Peripheral blood smear is significant for thrombocytopenia, anisopoikilocytosis and blasts (~ 30%). A flow cytometry analysis of peripheral blood specimen is pending. What is the most likely immunophenotype of the blasts?

  1. CD34-, CD117+, HLADR-, MPO++, CD33,
  2. CD34+, CD33+, CD11b+, CD41+, CD61+, MPO-, CD71-
  3. CD34+, CD117+, CD33+, HLA-DR+, CD41-, CD61-
  4. CD34-, CD4+, CD7+, CD33+, CD123+, CD56+
  5. CD34+, CD19+, CD20-, CD10+, TdT+
Board review style answer #1
B. CD34+, CD33+, CD11b+, CD41+, CD61+, MPO-, CD71-

Comment Here

Reference: Myeloid leukemia associated with Down syndrome
Board review style question #2
The 29 month old child has been diagnosed with myeloid leukemia associated with Down syndrome. Which of the following will likely be positive?

  1. Monosomy 7
  2. t(1;22)
  3. t(1;19)
  4. t(2;5)
  5. GATA1 mutation
Board review style answer #2
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