Immunophenotypic aberrancies in molecularly confirmed acute promyelocytic leukemia: lessons from two cases

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by PML::RARA fusion, typical morphology, and a characteristic flow cytometric immunophenotype that enables rapid diagnosis. However, immunophenotypic aberrancies may occur and can mimic mixed phenotype acute leukemia (MPAL), leading to diagnostic and therapeutic dilemmas. We report two adult male patients with APL confirmed by fluorescence in situ hybridization (FISH) demonstrating PML::RARA fusion. Both cases exhibited unusual immunophenotype. In the first case, peripheral blood flow cytometry revealed blasts with bright cMPO, CD34, dim HLA-DR, along with aberrant expression of CD19 (moderate), cCD79a (dim), cCD3 (heterogeneous), and CD7, raising a suspicion for MPAL. However, lineage defining criteria for T- and B-lineages were not fulfilled. Marrow showed abnormal promyelocytes with bundles of Auer rods, and molecular studies confirmed APL. In the second case, morphology suggested microgranular variant APL. Flow cytometry demonstrated aberrant expression of lymphoid and monocytic markers, including CD19 (dim), sCD3 (moderate), CD7, and CD14 (moderate), in addition to cMPO. Cytogenetics and molecular studies confirmed t(15;17)/PML::RARA in both cases, along with FLT3-ITD mutations. One patient developed differentiation syndrome and responded to all-trans-retinoic acid, while the follow-up of the second patient is unavailable. APL may exhibit immunophenotypic aberrancies mimicking MPAL. Molecular confirmation of PML::RARA and an integrated diagnostic approach are essential to avoid misclassification and ensure timely therapy.