From Non-Advanced Disease to Mast Cell Leukemia: Diagnostic, Morphologic, and Molecular Heterogeneity of Systemic Mastocytosis in a Single-Center Real-World Series

Background/Objectives: Systemic mastocytosis (SM) is a heterogeneous clonal mast-cell neoplasm requiring integrated clinical, biochemical, morphological, immunophenotypic, and molecular assessment. This study aimed to characterize the diagnostic and biological heterogeneity of SM across different disease phenotypes. Methods: We retrospectively reviewed six patients with SM diagnosed and managed between 2018 and 2022 at a single center. Clinical presentations, organ involvement, serum tryptase concentrations, bone marrow morphology, immunophenotypic and molecular findings, treatment, and outcomes were analyzed. Results: The cohort included four males and two females aged 16–86 years. Cutaneous manifestations occurred in five patients and frequently preceded diagnosis. All patients had bone marrow involvement, with variable mast-cell infiltration and aberrant CD25 and/or CD2 expression. Serum tryptase concentrations ranged from 15.8 to 348 μg/L. The highest concentration occurred in Patient 5, who had a FIP1L1::PDGFRA-positive myeloid/lymphoid neoplasm with eosinophilia and prominent systemic mast-cell involvement. In contrast, Patient 6, diagnosed with mast cell leukemia, had a tryptase concentration of 28.5 μg/L despite extensive marrow and peripheral blood involvement. KIT mutations were detected in five patients, while Patient 6 tested negative. Conclusions: This series highlights the marked clinical and biological heterogeneity of SM and the potential discordance between serum tryptase concentrations, mast-cell burden, molecular findings, and disease aggressiveness. Accurate diagnosis and disease characterization require an integrated multidisciplinary approach.