Diagnostic features in paediatric MDS-EB with UBTF-internal tandem duplication: defining a unique subgroup

Abstract

Aim: Tandem-duplications of the UBTF gene (UBTF-TDs) have recently been identified as a new genetic driver in young individuals with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Disease in these newly defined subgroups is characterized by poor response to standard intensive chemotherapy and inferior survival of the affected patients. However, a thorough analysis of bone marrow histomorphology of UBTF-mutated neoplasia has not been undertaken thus far.

Methods and results: In this retrospective study, we investigated the characteristic histopathological features of a cohort comprising 14 paediatric MDS patients with an excess of blasts (MDS-EB) and UBTF-TD. Bone marrow biopsies from these patients revealed hypercellularity and severe dysplasia across all three haematopoietic lineages. In particular, a marked hyperplastic megakaryopoiesis characterized by the presence of frequent micromegakaryocytes and a high number of monolobulated cells forming small clusters was observed. Additionally, erythropoiesis was left-shifted, with numerous blastoid precursors. The granulopoietic precursors displayed prominent UBTF-positive nucleoli.

Conclusion: The unique combination of these histomorphological features strongly suggests a possible UBTF aberration. It will allow initiating the appropriate genetic testing to confirm the presence of UBTF-TD and identify potential additional genetic alterations. Such molecular profiling will not only contribute to a better understanding of the disease mechanism, but also facilitate more rational treatment approaches for these high-risk paediatric MDS patients.

Keywords: UBTF‐TD; diagnostic features; paediatric MDS.

Figure 1

Cytomorphology and histomorphology of UBTF‐TD. (A) Blood smear with normoblast. (B–D) Bone marrow smears showing dysplastic erythropoiesis with megaloblastoid changes (B), an increase of myeloid blasts (C), and hypolobulated megakaryocytes (D). Bone marrow biopsies are hypercellular (E, H&E) with effaced architecture. Immature myeloid precursors are increased centromedullary (F; H&E). EWOG ID‐number D1113. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Immunohistochemistry and special stain of UBFT‐TD bone marrow biopsy. (A) Naphthol‐Chloracetatesterase stain shows a reduced granulopoeisis (red). (B) Erythropoiesis is atypically located, with expanded erythroid islets and an increased presence of immature cell forms (E‐cadherin immunohistochemistry). (C) Megakaryopoiesis is hyperplastic with small groups of hypolobulated cell forms and micromegakaryocytes (CD42b immunohistochemistry). Myeloblasts are negative for CD34 (D; CD34 immunohistochemistry) and positive for CD33 (E; CD33 immunohistochemistry). MPO‐positive myeloid precursors show prominent UBTF‐positive nucleoli (F; UBTF and MPO double‐immunofluorescence). Dispersed CD3‐positive T‐lymphocytes and CD20‐positive B‐lymphocytes are visible (G; CD3 immunohistochemistry and H; CD20 immunohistochemistry). Small aggregates of CD123‐positive plasmocytoid dendritic cells are shown (I; CD123 immunohistochemistry). EWOG ID number D1000. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Molecular landscape of UBTF‐TD. [Color figure can be viewed at wileyonlinelibrary.com]