Bone marrow neoplastic
Bone marrow - neoplastic myeloid
General
Transient abnormal myelopoiesis associated with Down syndrome
Resident / Fellow Advisory Board: Mario L. Marques-Piubelli, M.D.
Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.
Topic Completed: 20 May 2021
Minor changes: 9 June 2021
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PubMed Search: Transient abnormal myelopoiesis[title] associated with Down syndrome
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Cytology images | Peripheral smear description | Peripheral smear images | Positive stains | Negative stains | Flow cytometry description | Flow cytometry images | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: van den Akker TA, Geyer JT. Transient abnormal myelopoiesis associated with Down syndrome. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/leukemiaTAM.html. Accessed June 20th, 2021.
Definition / general
- Transient disorder of newborns with Down syndrome or phenotypically normal neonates with trisomy 21 mosaicism
- Presents within 3 - 5 days of birth and resolves spontaneously within 3 months
- Proliferation of nonerythroid blasts (commonly megakaryoblasts) in the peripheral blood or organs
- Morphologically indistinguishable from acute myeloid leukemia (AML), specifically acute megakaryoblastic leukemia (AMKL)
- Unique distinguishing clinical, immunophenotypic and molecular genetic features from AML not associated with Down syndrome
Essential features
- 10% of newborns with Down syndrome or trisomy 21 mosaicism
- Proliferation of nonerythroid blasts in the peripheral blood, bone marrow or organs
- Morphologically indistinguishable from other forms of AML
- Presents within first week of life and resolves within 3 months
- 20 - 30% may progress to nontransient AML (i.e. AMKL) within 1 - 3 years
- Associated with acquired GATA1 mutation
Terminology
- Transient abnormal myelopoiesis associated with Down syndrome (TAM)
- Transient myeloproliferative disorder (TMD)
- Transient leukemia (TL)
ICD coding
- ICD-O: 9898/1 - Transient abnormal myelopoiesis
Epidemiology
- Manifests in approximately 10% of neonates with Down syndrome
- 7 - 16% of TAM is seen in phenotypically normal neonates with trisomy 21 mosaicism
Sites
- Peripheral blood
- Common site of blasts, as fetal hematopoiesis occurs predominantly in the liver
- Peripheral blood involvement > bone marrow
- Bone marrow
- Less common site of fetal hematopoiesis
- Other organs
- Liver, spleen, skin, pancreas, kidneys, pleural fluid, pericardial fluid
Pathophysiology
- 3 step process (Curr Hematol Malig Rep 2016;11:333):
- Perturbation of fetal liver hematopoiesis by trisomy 21
- Acquired or somatic mutation of GATA1 (chromosome X), hematopoietic transcription factor
- 20 - 30% progress to AML with further acquisition of oncogenic mutations
Etiology
- Risk factors for Down syndrome
- Advanced maternal age
Clinical features
- Most diagnosed at 3 - 5 days of age
- Most patients are asymptomatic but may present with myeloblast organ infiltration:
- Hepatosplenomegaly (common)
- Ascites, pericardial or pleural effusions, hepatic fibrosis, disseminated intravascular coagulopathy (less common)
- Severe organ dysfunction causing renal, hepatic or cardiopulmonary failure (rare)
- If in utero, may present as hydrops fetalis secondary to cardiopulmonary failure and anemia
- References: Curr Hematol Malig Rep 2016;11:333, Silberstein: Hematology - Basic Principles and Practice, 7th Edition, 2017
Diagnosis
- No universal diagnostic criteria
- Children's Oncology Group (COG) (Blood 2011;118:6752):
- Detection of nonerythroid blasts in peripheral blood or organs
- Newborns < 90 days old
- Trisomy 21 or mosaicism
- Confirmation with:
- Second blood sample
- > 5% nonerythroid blasts in bone marrow
- Hepatosplenomegaly, lymphadenopathy or pericardial / pleural effusions
Laboratory
- Presence of megakaryoblasts in peripheral blood
- Thrombocytopenia is most common
- Moderate leukocytosis with myeloid left shift
- Basophilia
- Coagulopathy, specifically disseminated intravascular coagulation (DIC) (10%)
- Elevated conjugated bilirubin (common)
- Secondary to liver involvement
- References: Curr Hematol Malig Rep 2016;11:333, Silberstein: Hematology - Basic Principles and Practice, 7th Edition, 2017
Prognostic factors
- Majority resolve spontaneously over several weeks to 3 months
- Approximately 15 - 23% of patients may die as a result of secondary organ failure:
- Hepatic fibrosis
- Cardiopulmonary failure
- Poor prognostic factors for early death include:
- High WBC count
- Increased bilirubin
- Elevated liver function tests (LFTs)
- Failure to normalize blood counts
- 20 - 30% may develop nontransient AML (usually AMKL) within 1 - 3 years
- Greatest risk factors for AML progression are karyotypic abnormalities in addition to +21 in blast cells
- References: Curr Hematol Malig Rep 2016;11:333, Mycopathologia 2016;181:909
Case reports
- 7 day old neonate with TAM and severe multiorgan dysfunction (J Pediatr Hematol Oncol 2021;43:e292)
- 8 day old phenotypically normal newborn with TAM associated with Down syndrome mosaicism (Children (Basel) 2020;7:52)
- 14 day old newborn with TAM and pericardial effusion (Clin Case Rep 2019;7:1280)
- 2 neonates with TAM (J Pediatr Genet 2019;8:187)
Treatment
- Treatment is often supportive due to spontaneous remission
- In severe organ dysfunction, exchange transfusion, leukapheresis or chemotherapy may be necessary
- In TAM progression to AML, cytosine arabinoside is the most commonly used chemotherapeutic agent
- Favorable prognosis
- References: Curr Hematol Malig Rep 2016;11:333, Pediatr Int 2019;61:222
Microscopic (histologic) description
- Blasts are morphologically indistinguishable from those in AMKL associated with Down syndrome
- Features of megakaryoblasts
- Increased nuclear:cytoplasmic (N:C) ratio
- Dispersed nuclear chromatin
- Basophilic cytoplasm
- Coarse basophilic cytoplasmic granules
- Cytoplasmic blebbing
- Erythroid and megakaryocytic dysplasia are also seen
- Dyserythropoiesis with bi and trinucleated forms
- Dysmegakaryopoiesis with dysplastic small forms and micromegakaryocytes
Microscopic (histologic) images
Contributed by Julia T. Geyer, M.D.
Bone marrow biopsy
Cytology images
Contributed by Tayler A. van den Akker, M.D.
Blasts of TAM-DS
Blasts with hematopoietic elements
Cytoplasmic blebs
Peripheral smear description
- Features of megakaryoblasts in peripheral blood
- Increased N:C ratio
- Dispersed nuclear chromatin
- Basophilic cytoplasm
- Coarse basophilic cytoplasmic granules
- Cytoplasmic blebbing
- Basophilia
Peripheral smear images
Contributed by Julie Teruya-Feldstein, M.D.
Peripheral blood blasts
Positive stains
Flow cytometry description
- Expanded population of CD45+ myeloid blasts (left shift in myeloid maturation)
- Increased CD34+ myeloid population, may exceed 20% in peripheral blood, expressing CD117, CD33, CD38
- Aberrant expression of CD7 and CD56
- Expression of CD41 and CD61
- Reference: Cherian: Flow Cytometry in Evaluation of Hematopoietic Neoplasms, 1st Edition, 2012
Flow cytometry images
Contributed by Tayler A. van den Akker, M.D.
CD45+ dim population
CD34+, CD33+ dim population
CD34+,
HLA-DR+ partial population
CD33+ dim, CD117+ population
CD34+, CD235A- population
CD7+ heterogeneous, CD15- population
CD34+, CD38+ population
CD34+, MPO- population
Molecular / cytogenetics description
- Trisomy 21
- GATA1 mutation in blasts
- Expression of truncated protein, which promotes megakaryocytic and abnormal blast proliferation
- References: Curr Hematol Malig Rep 2016;11:333, Pediatr Int 2019;61:222
Sample pathology report
- Bone marrow, right posterior iliac crest and aspirate smears:
- Hypercellular marrow (100%), consisting predominantly of left shifted granulocytic precursors with focally interspersed small hypolobated megakaryocytes. Increased blasts (20%) with cytoplasmic blebs and prominent nucleoli. These findings are suspicious for transient abnormal myelopoiesis versus congenital AML (see comment).
- Comment: Flow cytometric analysis demonstrates an aberrant blast population (approximately 35% of total), exhibiting the following immunophenotype: CD45 moderate+, CD34+, CD33 dim+, HLA-DR partial+, CD117+, CD38+. CD7 heterogeneous+, CD4 dim+. These findings do not definitively distinguish between transient abnormal myelopoiesis and acute myeloid leukemia; clinical correlation is required.
- Bone marrow, left posterior iliac crest, trephine biopsy and clot: Quality: adequate. Cellularity: 100%. Normocellular marrow for age (~100%) consisting predominantly of left shifted granulocytic precursors. Megakaryocytes are increased, predominantly hypolobated forms and not seen in dense clusters. No granulomas. The bony trabeculae are unremarkable.
- Bone marrow aspirate smears: Quality: adequate. Blasts are increased, approximately 20% of total by manual differential count. Blasts with cytoplasmic blebs and prominent nucleoli.
Differential diagnosis
- AMKL in Down syndrome:
- Anemia, with preserved WBC count
- Occurs after the first year of life (versus first 3 - 5 days in TAM)
- May have a history of TAM
- Dyserythropoiesis and bone marrow fibrosis more common (versus TAM)
- Frequently negative for CD34, CD56, HLA-DR and positive for CD11b and CD13
- Complex karyotype and other cytogenetic abnormalities (i.e. JAK-STAT pathway) in addition to +21 and GATA1 mutation
- Acute myeloid leukemia not associated with Down syndrome:
- Commonly adults; median age: 65 - 68 years
- Poor prognosis compared with Down syndrome related AML (favorable prognosis)
- AMKL subtype is rare (< 5% AML)
- Absence of trisomy 21
Additional references
Board review style question #1
A 4 day old boy with Down syndrome is diagnosed with a transient myeloproliferative condition associated with the cells seen in the above image. Which genetic abnormality would be expected in addition to the additional chromosome 21?
- GATA1 mutation
- NPM1 mutation
- PDGFRA mutation
- t(9;22) with p190 breakpoint
Board review style answer #1
A. GATA1 mutation
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Reference: Transient abnormal myelopoiesis associated with Down syndrome
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Reference: Transient abnormal myelopoiesis associated with Down syndrome
Board review style question #2
Which immunophenotype is observed in AMKL associated with Down Syndrome?
- CD2+, CD4+, CD8- CD7-, CD10+, CXCL13+, BCL6+
- CD7+, CD3+, MPO-, CD4+, CD8+, TdT+, CD34+
- CD19+, Cd20+dim, CD5+, CD10-, FMC7-
- CD117+, CD34-, CD41+, CD7+, CD56-, CD61+, MPO-
Board review style answer #2
D. CD117+, CD34-, CD41+, CD7+, CD56-, CD61+, MPO-. Answer A is seen in AITL, answer B is seen in T-ALL and answer C is seen in CLL.
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Reference: Transient abnormal myelopoiesis associated with Down syndrome
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Reference: Transient abnormal myelopoiesis associated with Down syndrome
