Mast Cell Sarcoma Progressing to Aleukemic Mast Cell Leukemia with Secondary Hemophagocytic Lymphohistiocytosis: A Case Report with Complex Cytogenetic and Molecular Profile

Background: Mast cell sarcoma is an exceptionally rare and highly aggressive neoplasm characterized by a localized, destructive proliferation of atypical mast cells, most frequently involving bone. It may progress to mast cell leukemia (MCL), a systemic and often rapidly fatal disease. Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome that can occur secondary to hematologic malignancies. The coexistence of mast cell neoplasms and HLH is exceedingly uncommon and poses significant diagnostic and therapeutic challenges.

Aims: To describe the clinical, morphologic, immunophenotypic, cytogenetic, and molecular features of a patient with mast cell sarcoma evolving to aleukemic mast cell leukemia in association with secondary HLH.

Results: A 77-year-old woman presented with constitutional symptoms and lytic bone lesions. Laboratory evaluation revealed cytopenias and marked hyperferritinemia. Initial bone marrow examination showed hemophagocytosis and 10% atypical cells, with normal karyotype, supporting a diagnosis of secondary HLH related to an occult neoplasm. Vertebral biopsy demonstrated a neoplastic proliferation positive for CD45, CD68, CD117, CD43, and tryptase, consistent with mast cell sarcoma.

Six weeks later, bone marrow showed 24.2% atypical mast cells with toluidine blue positivity and an aberrant immunophenotype (CD117+, CD13+, CD33+, CD203c+, MPO−, CD34−). Cytogenetics revealed a complex karyotype with multiple chromosomal gains and losses. Molecular studies identified mutations in RUNX1, NF1, ATRX, TP53, and IKZF1 (germline origin excluded). A diagnosis of aleukemic mast cell leukemia was established. Despite treatment with dexamethasone and midostaurin, rapid progression occurred, with 87% marrow mast cells and fatal outcome.

Conclusion: This case documents the rare progression of mast cell sarcoma to mast cell leukemia with concomitant HLH, highlighting its aggressive biology, complex genomic profile, and dismal prognosis despite targeted therapy.

Dr. Ada Esteban-Figuerola is a consultant hematologist at Hospital Universitario San Pedro (La Rioja, Spain), specializing in diagnostic hematology and myeloid neoplasms. She completed her residency in Hematology at Hospital Joan XXIII (Tarragona) and holds advanced postgraduate degrees in hematopoietic transplantation, myelodysplastic syndromes, and acute leukemias. Dr. Esteban-Figuerola is an active member of PETHEMA, GESMD, and GECH (SEHH), with a strong focus on integrated morphologic and molecular diagnosis. She has authored numerous peer-reviewed publications and congress presentations and is actively involved in teaching and multidisciplinary molecular pathology programs.