Is the Association of "Cup-like" Nuclei With Mutation of the NPM1 Gene in Acute Myeloid Leukemia Clinically Useful?

University of Rochester, Rochester, New York, United States
American Journal of Clinical Pathology (Impact Factor: 3.01). 10/2010; 134(4):648-52. DOI: 10.1309/AJCPULO8SLW0RKJL
Source: PubMed

ABSTRACT Cup-like nuclear invaginations (NIs) in acute myeloid leukemia (AML) blasts have been associated with NPM1 mutations. Precision for enumeration of NI blasts has not been previously studied. Furthermore, the sensitivity and specificity for the morphologic prediction of NPM1 mutations have been variously reported. By using 66 AML specimens (17 with NPM1 mutations and 49 without), we found that interobserver reproducibility for enumeration of NI blasts was high (r = 0.98) and that identification of this feature was teachable (r = 0.96). No NPM1 mutation-negative case had greater than 7% NI blasts. The fraction of NI blasts was highly variable among 17 NPM1 mutation-positive cases, ranging from 0% to greater than 40%. These data indicate that an NI blast fraction of more than 10% is highly specific for NPM1 mutation-positive cases but with a sensitivity of about 30%. Therefore, although NI blasts can be reliably identified in routine smears and although they are a specific marker of NPM1 mutation-positive cases, the majority of NPM1 mutation-positive cases lack this distinctive finding.

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    ABSTRACT: The purpose of this study was to investigate the correlation of mutations of the fms-like tyrosine kinase (FLT3) and nucleophosmin (NPM1) genes with the cup-like nuclear morphology of blasts in patients with acute myeloid leukemia (AML). We retrospectively reviewed peripheral blood (PB) and bone marrow (BM) slides of 208 patients prepared at the time of diagnosis of AML based on the results of testing for mutations of both NPM1 exon 12 and FLT3. We investigated the association between this phenotype and hematologic findings, disease markers, and mutations in NPM1 exon 12, FLT3-internal tandem duplication (ITD), and tyrosine kinase domain (TKD) genes. Cup-like nuclei were found in 44 patients (21.2 %) diagnosed with AML. This morphology was associated with high blast counts in the PB and BM; AML type, especially AML M1 (FAB classification); low CD34 expression; and mutation of FLT3-ITD, -TKD, NPM1 regardless of other mutations (p < 0.05 for all). However, FLT3-ITD or TKD mutation alone (nine cases, p = 0.228) was not associated, and NPM1 mutation alone (14 cases, p = 0.036) was weakly associated with cup-like nuclei. Mutation of both NPM1 and FLT3-ITD or TKD (17 cases, p < 0.001) was strongly correlated with the cup-like nuclear morphology. AML with cup-like nuclei is strongly associated with co-occurring mutations of both NPM1 and FLT3-ITD or TKD. Therefore, testing for both mutations is recommended for patients with the cup-like nuclear morphology.
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