Multi-omics profiling supports the diagnosis of histiocytic sarcoma and mesenchymal mimics

In a “real-life” diagnostic setting, we explore their diagnostic relevance, applying a comprehensive, multi-platform approach, including immunophenotyping, high-throughput sequencing, gene expression profiling, and methylome analysis. We demonstrated a substantial morphophenotypic overlap among the three neoplasms, while also identifying distinct features within each group. Histiocytic sarcoma samples were enriched for mutations in the MAPK pathway, along with other recurrent mutations characteristic of myeloid neoplasms, and exhibited a functional genetic signature consistent with derivation from mononuclear phagocytes.

In contrast, soft tissue sarcomas showed a markedly higher tumor mutational burden and evidence of Hippo pathway activation, as well as FGF/FGFR signaling. Our work represents an initial step toward establishing a comprehensive diagnostic framework for malignant histiocytosis, facilitating the identification of relevant therapeutic and prognostic factors, and ultimately improving the clinical management of these rare patients.