A Biologically Distinctive Subgroup of Acute Myelogenous Leukemia with Characteristic Nuclear Morphology and a High Frequency of FLT3 Mutation.

Acute myelogeneous leukemia (AML) is a heterogeneous group of diseases. Mutations of the fms-like tyrosine kinase-3 (FLT3) gene of internal tandem duplication (ITD) type have been identified as one of the most frequent molecular defects in AML. However, even within FLT3 mutated/ITD positive cases, there is heterogeneity in clinical outcomes. In this study, we describe a biologically distinctive subgroup of AML in which blasts exhibit prominent nuclear invagination with frequent fishmouth-like nuclear indentation and had tendency of high frequency of FLT3/ITD. We identified 23 AML, FAB-M1 cases with fishmouth morphologic feature (study series, SS) diagnosed between 1998 and mid-2005 at our institution, which represents approximately 20% of AML, M1 cases and 1% of the entire AML cases. The age-matched control series (CS) of 20 AML, M1 cases without this nuclear feature were established to compare the incidence of FLT3 mutations, cytogenetics (CG), immunophenotype by multiparameter flow cytometry and clinical outcome. All the laboratory tests were performed on the bone marrow (BM) samples except one case using peripheral blood.

As illustrated in the table, AML cases with fishmouth-like nuclear morphology are significantly associated with female gender and lack of expression of CD34 and HLA-DR. There is statistical trend toward high frequencies of normal cytogenetics (68% diploid by conventional karyotyping) and FLT3 mutation of ITD type (86%) in the study series. The white cell count, bone marrow blast percentage (82–98%, median 90% in SS vs. 76–97%, median 85% in CS) and expression of CD13, CD33 and CD117 are not significantly different. Electron microscopic examination demonstrated condensed collections of mitochondriae within the indented/invaginated nuclear pockets. Complete remission rate was higher in AML cases with fishmouth-like nuclear morphology (73% vs. 40%, p=0.032). However, there was no difference in the overall survival rate between these two groups (1-year survival of 38% in SS vs. 39% in CS). In conclusion, AML cases with fishmouth-like nuclear morphology may represent a rare but distinctive AML subgroup with specific clinical, immunophenotypic and genetic features. Further prospective studies of larger cohorts of patients are required to confirm the prognosis of this entity.