Pediatric Myeloid Neoplasms With UBTF Tandem Duplications : Morphologic, Immunophenotypic, and Clinical Characterization

Abstract

Tandem duplications (TDs) in exons of upstream binding transcription factor ( UBTF -TD) are a rare recurrent alteration in pediatric and adult acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)/neoplasm. Although recently identified, AML with UBTF -TD is now considered a distinct subtype of AML. To further our understanding of myeloid neoplasms with UBTF -TD, we analyzed clinical, morphologic, and immunophenotypic characteristics of 27 pediatric patients with UBTF- TD-positive myeloid neoplasm, including 21 diagnosed as AML and 6 as MDS. Our data demonstrated that UBTF -TD is frequently associated with cytopenia, hypercellular marrow with erythroid hyperplasia, and trilineage dysplasia. Blasts and maturing myeloid cells show a characteristic dysplastic feature with condensed eosinophilic cytoplasm. Blasts have a myeloid or myelomonocytic immunophenotype with a variably dim expression of CD34 and/or CD117, and except for CD7 expression lack a consistent pattern of aberrant lineage-specific antigen expression. Patients with MDS had a lower blast count in the peripheral blood ( P = 0.03) and bone marrow ( P <0.001) but otherwise had no significant differences in other hematological parameters. Three patients with MDS rapidly progressed to AML in 33, 39, and 210 days from the initial diagnosis and there was no difference in overall survival between patients with MDS and AML ( P = 0.18). Our data suggest that MDS with UBTF-TD is prognostically equivalent to AML with UBTF -TD and thus should be considered as a continuum of the same molecularly defined myeloid neoplasm. These collective data also provide morphologic and immunophenotypic clues that can prompt screening for UBTF -TD in patients with MDS or AML.

FIGURE 1

Morphologic and immunophenotypic features of case #19 and morphologic features of case #32: Case ID #19 was initially diagnosed as AML-M2/AML with maturation (FAB classification), showing hypercellular marrow with increased blasts (A, hematoxylin and eosin). Aspirate smears show characteristic blasts, myeloid precursor cells with eosinophilic granules (B, Wright-Giemsa), dysplastic erythroid cells, and blasts with small Auer rods (C, Wright-Giemsa). Myeloperoxidase stain is brightly expressed in Myeloblasts with eosinophilic granules while dim to negative in other myeloblasts (D). Flow cytometry immunophenotyping shows blasts with high side scatter merging with granulocytes. Blasts are positive for CD7 (dim), CD13 (partial), CD33 (bright), CD34 (dim), CD117 (bright), CD123 (bright), CD133 (dim), and HLA-DR (moderate) (E). Case ID #32 was diagnosed as MDS with EBs, showing hypercellular marrow with a marked increase in megakaryocytes and osteosclerosis, features commonly seen in MDS with myelofibrosis (F, hematoxylin and eosin). Aspirate smears show characteristic myeloid precursor cells with eosinophilic granules (G, Wright-Giemsa) and small megakaryocytes (H, Wright-Giemsa). BM biopsy at post-stem cell transplant in the most recent follow-up is morphologically unremarkable and normocellular (I, hematoxylin and eosin).

FIGURE 2

Morphologic features of cases #2, 9, and 4: Case ID #2 was initially diagnosed as AML-M6a. BM biopsy is hypercellular, mainly composed of blasts and mature erythroid cells (A, hematoxylin and eosin). BM aspirates show many erythroblasts (blue arrow) and some myeloblasts (black arrow). Dyserythropoiesis and dysmegakaryopoiesis (red arrow) are prominent (B, Wright-Giemsa, and C, Wright-Giemsa). Case ID #9 was diagnosed initially as AML-M0/M7. Initial BM examination (D–F) showed a hypercellular marrow with an increased number of small-sized blasts, partially highlighted by CD61 immunohistochemical stain, consistent with megakaryocytic lineage ([D] hematoxylin and eosin, and [E] CD61 immunohistochemistry). BM aspirates showed morphologically different types of blasts, including some intermediate -large sized blasts with cytoplasmic granules (red arrowhead) and some small-sized blasts with scant agranular cytoplasm (black arrowhead) (F, Wright-Giemsa). During therapy, the BM biopsy showed persistent disease with foci of fibrosis and persistent blasts ([G] hematoxylin and eosin and [H] hematoxylin and eosin). There was an increased number of CD61-positive blasts compared with the initial diagnosis (I, CD61 immunohistochemistry), and the BM aspirate is mainly composed of small-sized blasts with scant agranular cytoplasm most consistent with AML-M7 (J, Wright-Giemsa). Case ID #4 presented with leukocytosis (K, Wright-Giemsa) and an increased number of circulating blasts and was diagnosed as AML-M4. The BM biopsy was hypercellular with increased blasts (L, hematoxylin, and eosin) and scattered small megakaryocytes (yellow arrowheads). BM aspirate smears show blasts with myelomonocytic features and scattered dysplastic erythroid cells (M, Wright-Giemsa).

FIGURE 3

Heatmap depicting the presence and absence of flow cytometry immunophenotype markers, selected mutations, and CG in pediatric patients with UBTF-TD. Absolute numbers are shown in the bars along the right side.