Case of the Month: Transient Abnormal Myelopoiesis

A 38-week-gestation boy was born to a 38-year-old mother. Pertinent physical exam findings included up-slanting eyes, webbed toes, and a murmur consistent with a ventricular septal defect. 

At birth the patient had the following CBC data:

Master List

• Reactive lymphocytosis
• Acute monocytic leukemia
• Transient abnormal myelopoiesis
• Infectious mononucleosis

The patient’s blood smear shows abnormal cells. Image 1 is a low magnification view. Many of the cells (46% by manual differential counts) are similar to Image 2. Additional cells similar to Image 3 are present.

This material was originally released as the 2014 CPIP-B Case 2: Circulating Blasts in Neonates.

This infant has transient abnormal myelopoiesis (TAM), which is seen in infants with trisomy 21 (Down syndrome (DS)).

The peripheral smear reveals a leukocytosis with increased blasts (Image 1), including medium-sized blasts with scant cytoplasm, large blasts, and blasts with cytoplasmic blebbing (Image 2). Micromegakaryocytes, small binucleate megakaryocytes, and giant platelets are present (sequentially shown on Image 3). Combined with the clinical features of Down syndrome (DS), these findings are most consistent with transient abnormal myelopoiesis (TAM).

TAM is a clonal myeloproliferative condition that occurs in up to 10% of newborns with DS. As the name implies, the process is transient in nature with the majority of cases resolved within three months.1,2

Clinically, up to 25% of patients can be asymptomatic. Hepatosplenomegaly is the most common physical exam finding. In some cases, severe complications such as hepatic fibrosis and cardiopulmonary failure can occur. Many antenatal cases of TAM terminate due to fetal hydrops.1 Although uncommon, TAM can be seen in trisomy 21 mosaics.3 These patients may appear phenotypically normal, so it is important to keep TAM in the differential diagnosis. Testing for trisomy 21 should be performed when other findings are suggestive of TAM.1

TAM is characterized by leukocytosis with increased circulating blasts. Thrombocytopenia is often present (40% of cases). Abnormal platelet morphology, including giant platelets and megakaryocytic cytoplasmic fragments may also be seen. Anemia and neutropenia are uncommon. Basophilia is occasionally present. Morphologically the blasts are heterogeneous. Blasts may have megakaryocytic differentiation, being medium to large in size with basophilic cytoplasm, basophilic granules, and cytoplasmic blebbing. Nuclei are slightly irregular or indented with fine chromatin and one to three nucleoli.2 In comparison to other lineages, binucleation is frequently seen with megakaryocytic differentiation. However, blasts may be nondescript and morphologically lack megakaryocytic features making immunophenotyping critical for specific lineage characterization. More mature megakaryocytic cells may be seen, especially micromegakaryocytes or binucleate forms. Bone marrow biopsies are generally not considered necessary and typically reveal a smaller blast fraction than seen in the peripheral blood.1 Dysplasia of the megakaryocytic (micromegakaryocytes) and erythroid lineages are often present.2

By flow cytometry, the blasts have a characteristic immunophenotype, expressing CD34, CD56, CD117, CD13, CD33, CD7, dim CD4, CD41, CD42, TPO-R, IL-3R, CD36, CD61, and CD71. They are commonly negative for MPO, CD15, CD14, and glycophorin A. Thirty percent of cases are positive for HLA-DR.2

Cytogenetics abnormalities aside from trisomy 21 are uncommon in TAM. The detection of new cytogenetic abnormalities along the course of TAM maybe indicate progression to acute myeloid leukemia (AML). The presence of an additional 21 (+21) is a common cytogenetic abnormality seen in AML. Thus, in order to confirm DS, it is important to prove the presence of trisomy 21 in more than just leukemic cells.3

Somatic mutations of GATA1 are directly involved in the pathogenesis of TAM and DS-associated acute megakaryoblastic leukemia (DS-AMKL). The gene encodes the GATA1 transcription factor, which is necessary for development of erythroid and megakaryocytic lineages.3 This mutation is pathognomic for TAM and DS-AMKL, and is not found in non-DS related AMKL involving t(1;22). 

Eighty percent of TAM cases resolve spontaneously within three months without treatment. Fatal complications do occur and include hepatic fibrosis, cardiopulmonary, splenic necrosis, or hyperviscosity. Patients with life threatening complications or evidence of clonal abnormalities have shown some benefit to treatment with cytosine arabinoside.1 Twenty to thirty percent of patients develop DS-AMKL within the next one to three years. DS-AMKL is morphologically, phenotypically, and genetically similar to TAM.2

In summary, TAM occurs almost exclusively in newborns with DS and is characterized by increased circulating blasts that resolves spontaneously within three months. In TAM, patients may be asymptomatic. Cytopenias, with the exception of thrombocytopenia, are unusual in TAM. The percentage of blasts in the peripheral blood usually exceeds the percentage seen in the bone marrow (usually <60%). Morphologically, the blasts in TAM can be diverse but usually have megakaryocytic features. Cytogenetic abnormalities other than trisomy 21 are uncommon in TAM. GATA1 mutations are present.

It is important to distinguish congenital leukemia from TAM. Congenital leukemia can present in both non-DS and DS newborns, and is defined as leukemia within the first 30 days of life. Patients with congenital leukemia usually present with leukocytosis. Anemia, neutropenia, and thrombocytopenia are common. Patients are often clinically ill, and many show signs or symptoms of skin and CNS involvement.^4,5 In congenital leukemia blasts in the bone marrow are dramatically increased, replacing the marrow space and exceeding the fraction of blasts in the peripheral blood.⁶ Blasts tend to be morphologically more homogeneous than in TAM. The majority of congenital leukemia is myeloid or monocytic in nature, which is often reflected in the morphology and immunophenotype. The majority of congenital leukemia involve translocations of 11q23 (MLL gene).^4,5 Cases of AMKL in non-DS patients in neonates usually harbor t(1;22).² GATA1 mutations are not present.

Congenital leukemia is an aggressive disease with poor prognosis. Prompt diagnosis allows for initiation of intensive chemotherapy. Due to the rarity of congenital leukemia, standard protocols are not established, but tend to parallel lineage-specific treatments used in pediatric leukemias. The overall three-year survival for congenital AML is estimated at 25% to 35%, with a relapse rate of 50%. The overall survival rate for congenital acute lymphoblastic leukemia (ALL) is worse (<10%), with a relapse rate of up to 73%.^4,5

1. Transient abnormal myelopoiesis occurs almost exclusively in newborns with Down’s syndrome (DS).
   1. True
   2. False
2. All of the following statements regarding transient abnormal myelopoiesis (TAM) are true except:
   1. Morphologically the blasts in TAM can be diverse, but usually have megakaryocytic features. 
   2. Cytogenetics usually shows the t(1;22) abnormality.
   3. Somatic mutations of GATA1 are directly involved in the pathogenesis of TAM. 
   4. Eighty percent of TAM cases resolve spontaneously within three months, without treatment.

1. Roy A, Roberts I, Vyas P. Biology and management of transient abnormal myelopoiesis (TAM) in children with Down syndrome. Semin Fetal Neonatal Med. 2012;17:196-201. (4)
2. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. 4th ed. Lyon, France: IARC Press; 2008. (5) 
3. Proytcheva MA, ed. Diagnostic Pediatric Hematopathology. Cambridge, NY: Cambridge University Press; 2011. (1)
4. Isaacs H. Fetal and neonatal leukemia. J Pediatr Hematol Oncol. 2003;25:348-61. (6)
5. van der Linden MH, Creemers S, Pieters R. Diagnosis and management of neonatal leukemia. Semin Fetal Neonatal Med. 2012;17(4):192-5. (7)
6. Kesler MV, Gewirtz AS. Increased blasts in a neonate with trisomy 21. LabMedicine. 2001;32:509-11.

1. True
2. Cases of AMKL in non-DS patients in neonates usually harbor t(1;22) (b)

Julia S. Manny, MD
Hematopathology Fellow at Wake Forest Baptist Medical Center

Excerpted for Case of the Month by:
Vandita P. Johari, MD, FCAP
Associate Professor, Department of Pathology, UMMS-Baystate
Clinical Pathology Education Committee

This material was originally released as the 2014 CPIP-B Case 2: Circulating Blasts in Neonates.