Myeloid Proliferations of Down Syndrome

Abstract

Individuals with Down syndrome (DS) have a markedly increased risk of developing unique myeloid proliferations such as transient abnormal myelopoiesis (TAM) and myeloid leukemia associated with Down syndrome (ML-DS) [1, 2]. These proliferations occur in the first 3 years of life and are a result of several transforming genetic events that arise during the fetal and newborn period. The initial event, an additional chromosome 21, leads to increased megakaryocytic proliferation in the fetal liver. Subsequent mutation of GATA-binding protein 1 (GATA1) results in the development of TAM. Further acquisition of additional mutations of epigenetic regulators and common signaling pathways such as JAK family kinases, MPL, and multiple RAS pathway genes leads to the transformation to MS-DS [3].

Individuals with Down syndrome (DS) have a markedly increased risk of developing unique myeloid proliferations such as transient abnormal myelopoiesis (TAM) and myeloid leukemia associated with Down syndrome (ML-DS) [1, 2]. These proliferations occur in the first 3 years of life and are a result of several transforming genetic events that arise during the fetal and newborn period. The initial event, an additional chromosome 21, leads to increased megakaryocytic proliferation in the fetal liver. Subsequent mutation of GATA-binding protein 1 (GATA1) results in the development of TAM. Further acquisition of additional mutations of epigenetic regulators and common signaling pathways such as JAK family kinases, MPL, and multiple RAS pathway genes leads to the transformation to ML-DS [3].

While the time of presentation varies, TAM typically occurs shortly after birth, whereas ML-DS typically occurs between 3 months and 3 years of age. The morphologic and immunophenotypic features of the myeloid proliferations of DS are essentially indistinguishable , (Table 12.1, Figs. 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 12.10, and 12.11).

Table 12.1 The myeloid proliferations of Down syndrome

Fig. 12.1

The peripheral blood smear in transient abnormal myelopoiesis (TAM) typically shows leukocytosis , with increased blasts exhibiting megakaryoblastic morphology, although the morphology may be variable. The neoplastic cells characteristically show high N:C ratio, with fine chromatin and prominent nucleoli. The basophilic cytoplasm may be scant to moderate and may demonstrate occasional peripheral “blebs.” Small vacuoles may also be present [Wright-Giemsa, 100×]

Fig. 12.2

The platelet count in TAM may be increased or decreased, and the peripheral blood smear may show numerous large platelets (pictured) in addition to megakaryocytic fragments. A circulating blast is also illustrated in the center of the image [Wright-Giemsa, 100×]

Fig. 12.3

Numerous polychromatophilic cells and circulating nucleated red cells are often seen in the peripheral blood in TAM. Other changes involving the red cells that may be seen in Down syndrome (in the absence of TAM) include an increase in the mean corpuscular hemoglobin (MCH) and mean cell volume (MCV), usually evident at 9 to 12 months of age [13, 14] [Wright-Giemsa, 100×]

Fig. 12.4

The blasts in TAM are shown to be positive for nonspecific esterase (a) and negative for myeloperoxidase (b), with the latter showing strong positivity in an adjacent granulocyte precursor. Myeloperoxidase may show weak staining in some cases [nonspecific esterase and myeloperoxidase cytochemical stains, 100×]

Fig. 12.5

By flow cytometry , the blasts in TAM show moderate to bright CD45 expression, in addition to expression of immature marker CD34, myeloid marker CD33, and megakaryocyte marker CD61. CD7 and CD56 are also aberrantly expressed on the blasts. HLA-DR and MPO are negative. The intensity of CD34 expression appears uniformly heterogeneous. Also demonstrated is a pattern of loss of CD34 expression with increasing expression of CD61 (bottom right plot), suggestive of “maturation” of the neoplastic cells. The phenotype is consistent overall with megakaryocytic differentiation

Fig. 12.6

The circulating blasts in myeloid leukemia associated with Down syndrome (ML-DS) also typically exhibit megakaryoblastic morphology, characterized by fine chromatin and prominent nucleoli. The cytoplasm is typically deeply basophilic and may show occasional cytoplasmic blebbing and vacuolation. The blasts usually circulate in relatively low numbers [Wright-Giemsa, 100×]

Fig. 12.7

The bone marrow aspirate in ML-DS shows increased numbers of megakaryoblasts, with relatively reduced background hematopoietic elements. In some instances, the presence of marked bone marrow fibrosis may produce a “dry tap” [Wright-Giemsa, 100×]

Fig. 12.8

There may be prominent dysplasia present in ML-DS, here shown to affect the red cell lineage in a bone marrow aspirate. Mature red cell precursors show multinucleation and nuclear budding [Wright-Giemsa, 100×]

Fig. 12.9

The bone marrow core biopsy in acute megakaryoblastic leukemia typically shows a hypercellular bone marrow with sheets of blasts showing pale, fine chromatin, visible nucleoli, and variable amounts of cytoplasm. Background hematopoietic elements are reduced. Reticulin fibrosis may also be prominent in some cases (not shown) [H&E, 40×]

Fig. 12.10

The blasts in the bone marrow core biopsy in ML-DS can be highlighted by a CD61 immunostain, which also highlights occasional larger background megakaryocytes [CD61, 40×]

Fig. 12.11

The blasts in acute megakaryoblastic leukemia show a similar phenotype to that seen in TAM, here showing expression of immature marker CD34, myeloid markers CD13 and CD33, and megakaryocyte marker CD61. There is also bright aberrant expression of CD56. HLA-DR and MPO are negative. In contrast to TAM, the CD34 expression shown here is bright, with a more discrete population showing relatively little heterogeneity. Furthermore, there does not appear to be the same “phenotypic” maturation pattern (i.e., loss of CD34 with increasing CD61 expression) as illustrated previously in the case of TAM (Fig. 12.5)

Approximately 4% to 18% of individuals with DS develop TAM, although the true incidence of TAM is difficult to discern in view of the fact that most infants are asymptomatic, so blood counts or morphologic evaluation may not be performed [4]. TAM typically occurs at the time of birth (or within the first few days following birth) and is defined as an increase in peripheral blasts that have morphologic and phenotypic features of megakaryocytic lineage. There is no internationally agreed-upon definition of a percentage blast threshold for diagnosis, however, and circulating blasts are also frequently seen in DS individuals without TAM. The blasts in TAM harbor acquired N-terminal truncating mutations in the key hematopoietic transcription factor gene GATA1 [5, 6]; this mutation is considered a molecular hallmark of these disorders. A subset of patients with so-called silent TAM may also have acquired GATA1 mutations despite lacking clinical or overt hematologic manifestations of disease [7]. In most cases (75–90%), the peripheral blasts resolve spontaneously by approximately 3 months of age without the need for chemotherapy, although a few children may experience life-threatening or even fatal complications.

Approximately 20% of patients with clinically apparent TAM subsequently develop nonremitting acute myeloid leukemia (AML) , when persistent GATA1-mutant cells acquire additional oncogenic mutations [8,9,10,11,12]. ML-DS encompasses cases of both myelodysplastic syndrome (MDS) and overt AML, which behave in a similar fashion regardless of the absolute blast count [1]. ML-DS occurs later than TAM, usually in the first 3 years of life, and is usually preceded by TAM. In most cases, the acute leukemia is a megakaryoblastic leukemia, in contrast to the relatively low incidence of this leukemia in non-DS individuals . ML-DS has a relatively favorable prognosis with enhanced chemotherapeutic responsiveness.