Bone marrow neoplastic

Bone marrow - neoplastic myeloid

General

Transient abnormal myelopoiesis associated with Down syndrome

Authors: Tayler A. van den Akker, M.D., Julia T. Geyer, M.D.

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

Copyright: 2001-2021, PathologyOutlines.com, Inc.

PubMed Search: Transient abnormal myelopoiesis[title] associated with Down syndrome

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Table of Contents

Cite 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 September 22nd, 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

CD34, CD117 (KIT), CD13, CD33, CD41, CD42, CD110 (TPOR), IL3R, CD36, CD38, CD61, CD71
Dim CD4
CD41, CD42b, CD61 help identify megakaryocytic lineage
Aberrant expression of CD7, CD56
HLA-DR (30%)

Negative stains

MPO, CD14, CD15, CD16, CD11a, CD235a (glycophorin A)

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

Campo: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017

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

Comment Here

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.

Comment Here

Reference: Transient abnormal myelopoiesis associated with Down syndrome