Pathology of Myeloid Proliferations Related to Down Syndrome

Updated: Dec 06, 2015
  • Author: Cherie H Dunphy, MD, FCAP, FASCP; Chief Editor: Cherie H Dunphy, MD, FCAP, FASCP  more...
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Overview

Overview

For individuals with Down syndrome (DS), the risk of developing acute leukemia is increased 10- to 100-fold. Children with Down syndrome are at increased risk for developing acute myeloid leukemia (AML) (approximately 1-2% of children with Down syndrome develop AML, the great majority < 5 y) rather than acute lymphoblastic leukemia (ALL), which is a more common form of leukemia in children. The great majority of pediatric AML cases (ie, 70%) are of acute megakaryoblastic leukemia. Transient abnormal myelopoiesis (TAM) and myeloid leukemia associated with Down syndrome are the disorders associated trisomy 21.

Transient abnormal myelopoiesis (TAM) is a unique disorder that occurs in newborns with Down syndrome. It is characterized by an increase in the number of myeloblasts—cases often meet the diagnostic criteria for AML. TAM has morphologic and immunophenotypic features characteristic of megakaryoblastic leukemia. [1, 2] See the following images.

Blasts from the peripheral blood of 1-day-old pati Blasts from the peripheral blood of 1-day-old patient with trisomy 21 and transient abnormal myelopoiesis.
Megakaryoblasts of pediatric acute megakaryoblasti Megakaryoblasts of pediatric acute megakaryoblastic leukemia.

Although TAM is most often reported in newborns with Down syndrome (10%), this condition is occasionally found in phenotypically normal neonates [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21] ; some of these neonates are found to be mosaic for trisomy 21. [4, 5, 6, 7, 8, 10, 11, 12] Although in the majority of cases, TAM resolves spontaneously (thus, the term transient abnormal myelopoiesis), up to 20% of cases develop into AML that requires treatment.

In addition, a significant percentage of those cases of TAM that do not resolve spontaneously (ie, 20-30%) progress to acute megakaryoblastic leukemia within 1-3 years from the time of diagnosis. As mentioned above, AML associated with Down syndrome is most often of the acute megakaryoblastic type. It should be recognized that both myelodysplastic syndrome (MDS) and AML that arise in a patient with Down syndrome are classified as myeloid leukemia associated with Down syndrome.

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Clinical and Morphologic Features

Patients with transient abnormal myelopoiesis (TAM) most commonly present with thrombocytopenia; anemia and neutropenia are less common. One should keep in mind that the percentage of blasts in the peripheral blood (PB) may exceed the percentage of blasts in the bone marrow (BM). Patients may present with hepatosplenomegaly.

If transient, TAM usually resolves spontaneously within the first 3 months of life. As previously mentioned, children with acute myeloid leukemia (AML) are usually younger than 5 years at the time of presentation (the disease is usually diagnosed during the first 3 y of life). Cases in which there are fewer than 20% blasts in the bone marrow follow a more indolent course (as a myelodysplastic syndrome [MDS]) and may be associated with thrombocytopenia.

The morphologic and immunophenotypic features of TAM are often identical with those of the majority of cases of Down syndrome-associated AML (see the image below). TAM is characterized by cells resembling megakaryoblasts; the basophilic cytoplasm contains coarse basophilic granules and associated cytoplasmic blebs. There may be associated peripheral blood basophilia. In addition, erythroid and megakaryocytic dysplasia may be present in the bone marrow.

Blasts from the peripheral blood of 1-day-old pati Blasts from the peripheral blood of 1-day-old patient with trisomy 21 and transient abnormal myelopoiesis.

In the MDS-type of myeloid leukemias associated with Down syndrome, the blasts represent fewer than 20% of the bone marrow cells. Dyserythropoiesis associated with macrocytic erythroid cells is often present.

AML may be associated with leukoerythroblastosis. The blasts are often similar to those described in TAM. There is often associated dyserythropoiesis, and there may be dysgranulopoiesis and dysmegakaryopoiesis as well. Bone marrow fibrosis may also be present. Cases of acute megakaryoblastic leukemia may show markedly increased clusters of megakaryocytes, clusters of dysplastic, small forms (ie, micromegakaryocytes), and an increase in the number of promegakaryocytes, as shown in the following image.

Megakaryoblasts of pediatric acute megakaryoblasti Megakaryoblasts of pediatric acute megakaryoblastic leukemia.
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Immunophenotypic Features

The blasts of transient abnormal myelopoiesis (TAM) most commonly demonstrate the following characteristic immunophenotype: CD34+, CD56+, CD117+, CD13+, CD33+, CD7+, CD4(dim+), CD41+ , CD42+, CD61+, CD36+, CD71+, HLA-Dr(var+), CD14–, CD15–, MPO–, and glycophorin A–. [22] Most often, these markers are analyzed by flow cytometric analysis, but CD41 and CD61 may also be analyzed by immunohistochemical analysis of paraffin-embedded bone marrow biopsy sections; this latter technique may be particularly helpful in cases in which aspiration is not possible or is not effective.

The leukemic blasts in acute megakaryoblastic leukemia of Down syndrome display an immunophenotype similar to that of TAM. However, in acute megakaryoblastic leukemia, CD34 is expressed in only 50% of cases; in addition, CD56 and CD41 are absent in up to 30% of cases.

The blasts of all TAM and Down syndrome-associated acute megakaryoblastic leukemia are positive for thrombopoietin receptor (TPO-R) and interleukin (IL)-3R, whereas erythropoietin receptor (EPO-R) and IL-6R are absent. The absence of EPO-R on the blasts may be a sign of the high expression of the mutated -- and less active --GATA1 gene in Down syndrome (described in Molecular/Genetic Features). [22]

In the other AML subtypes that arise in Down syndrome, the blasts display the characteristic immunophenotypic features of that particular subtype of AML (ie, links to AML not otherwise specified and AML with recurring cytogenetic abnormalities).

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Molecular/Genetic Features

Along with abnormalities of chromosome 21, a few patients with transient abnormal myelopoiesis (TAM) have other clonal chromosomal abnormalities at presentation. [3, 17, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33] These additional abnormalities usually disappear at the time of remission, except in rare cases. [24] Acute leukemia may develop later; when it does, the disorder may show either a different type of chromosomal aberration [27, 28] or the same chromosomal aberration seen in the original TAM clone. [24, 33]

In addition to trisomy 21, the blasts of TAM and myeloid proliferations associated with Down syndrome contain acquired GATA1 mutations; such mutations are considered pathognomonic of these disorders. [34, 35, 36]

Microarray transcript profiling is able to distinguish TAM from acute megakaryoblastic leukemia in patients with Down syndrome. [37] Among the significant differences, CDKN2C, the effector of GATA1 -mediated cell cycle arrest, is increased in acute megakaryoblastic leukemia but not in TAM, despite the similar level of GATA1. In contrast, MYCN (a neuroblastoma-derived oncogene) is expressed in TAM at a significantly greater level than in acute megakaryoblastic leukemia.

Finally, the tumor antigen preferentially expressed antigen of melanoma (PRAME) has been identified as a specific marker for acute megakaryoblastic leukemia; PRAME is not expressed in TAM.

Trisomy 8 is another common cytogenetic abnormality in myeloid leukemias associated with Down syndrome, occurring in approximately in 13-44% of cases. [38, 39] By contrast, monosomy 7 is very rare in these disorders.

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Prognosis

As mentioned previously, although the majority of cases of transient abnormal myelopoiesis (TAM) resolve spontaneously, up to 20% develop into acute myeloid leukemia (AML). In addition, of those patients whose disease does resolve spontaneously, a significant percentage (ie, 20-30%) develop acute megakaryoblastic leukemia within the next 1-3 years.

The prognosis for children with myeloid leukemia associated with Down syndrome is better than the prognosis for children with AML that is not associated with Down syndrome. [40, 41] However, the prognosis for older children with myeloid proliferations associated with Down syndrome (ie, those with GATA1 mutations) is poorer in comparison with the prognosis of children with myeloid proliferations that are not associated with Down syndrome. [42]

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