Mixed-phenotype acute leukemia with trilineage differentiation presenting as a non-leukemic mediastinal tumor

Mixed-phenotype acute leukemia (MPAL) is an uncommon hematological malignancy, and cases exhibiting trilineage differentiation are extraordinarily rare. Here, we report the case of a 63-year-old male patient who presented with severe dyspnea secondary to a massive anterior mediastinal mass and pleural effusion, in the absence of detectable abnormal cells in the peripheral blood. Immunophenotypic analysis of pleural fluid and tumor biopsy revealed an unprecedented trilineage phenotype with concurrent expression of T-lymphoid (cytoplasmic CD3⁺ and CD7⁺), B-lymphoid (CD19⁺ and CD22⁺), myeloid (cytoplasmic MPO⁺ and CD33⁺) markers, along with stem cell (CD34⁺ and HLA-DR⁺), and lymphoblastic (TdT⁺) markers. B-lineage commitment was further confirmed by immunoglobulin heavy chain gene rearrangement. These findings established a diagnosis of T/B/myeloid triphenotypic MPAL presenting as an aleukemic disease with minimal bone marrow infiltration (<1%). Initial treatment with acute myeloid leukemia-directed induction therapy (daunorubicin plus cytarabine) proved refractory. However, the hyperCVAD regimen, which is an acute lymphoblastic leukemia (ALL)-directed approach, achieved a complete metabolic response. Subsequent consolidation with cord blood transplantation resulted in durable remission lasting 2 years before a late relapse, which occurred in the mediastinal region. This is the first reported case of non-leukemic, triphenotypic MPAL presenting as a primary mediastinal tumor, highlighting the diagnostic complexity and therapeutic challenges associated with this rare malignancy. Based on our experience, intensive ALL-directed chemotherapy followed by allogeneic stem cell transplantation may offer an effective therapeutic strategy for this exceptionally rare clinical entity.