Early Prediction and Streamline of Nucleophosmin Mutation Status in Acute Myeloid Leukemia Using Cup-Like Nuclear Morphology.

: With the advent of novel therapies for nucleophosmin gene ()-mutated acute myeloid leukemia (AML), there is a growing need for the reliable prediction of mutations. This study explored the role of cytomorphological features in the early prediction of -mutated AML. : Altogether, 212 de novo AML cases with normal karyotypes, diagnosed and treated at a single institution within 5 years (2018-2023), were retrospectively evaluated. A final diagnosis of -mutated AML, based on the World Health Organization (WHO) integrated criteria, including real-time based identification of mutation and normal karyotype, was established in 83/212 (39.15%) cases. : Cup-like blasts (CLBs), a cytomorphological feature suggestive of -mutated AML, were detected in 56/83 (67%) patients. Most cases (44/56, 78.6%) had CLB ≥ 10%. In total, 27 of 83 AML -mutated patients had no CLB morphology (missed call). Additionally, two of 212 had CLB morphology without confirmed mutation (wrong call). The positive/negative predictive values of cytomorphological evaluation for CLB ≥ 10% were 95.7%/75.6%, with sensitivity/specificity of 53%/98.5%, while the accuracy was 80.7%. We noted an increased percentage of CLBs (≥15%) in 77.8% and 50% of patients with AML without and with granulocytic maturation, respectively (the specificity for mutation prediction was 100%). CLB was associated with fms-like tyrosine kinase 3 () mutation ( = 0.03), but, without statistical significance for CLB ≥ 10% and CLB ≥ 15%. : Our investigation confirmed that the morphological identification of CLB at diagnosis represents a reliable and easily reproducible tool for the early prediction of mutations, enabling a streamlined genetic work-up for its confirmation. This may facilitate considering the early administration of individualized therapies by clinicians for specific patients.