ABSTRACT: The differential diagnosis between histiocytic sarcoma (HS) and undifferentiated pleomorphic sarcoma (UPS) remains an underexplored area of histopathological and oncological relevance. Both entities are rare, high-grade neoplasms that may arise in soft tissue, skin, the nervous system, and the gastrointestinal tract, among other sites, predominantly in adult patients. Their clinical and morphological overlap may be underrecognized, partly due to the subspecialized structure of contemporary surgical pathology practice. Comparative data on their natural history, treatment, and prognosis remain limited. Furthermore, while UPS is managed according to established international guidelines, no standardized treatment approach exists for HS. In this study, we compared the clinical, histopathological, and genetic features of three patient groups diagnosed with HS, UPS, and dedifferentiated liposarcoma (DLS) – control group. 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.
