Characterization and Treatment Outcomes of Malignant Histiocytoses in a Retrospective Series of 141 Cases in France

Malignant histiocytoses (MH) are rare and poorly understood cancers, with no established therapeutic guidelines. We conducted a national retrospective study of MH diagnosed in France between 2000 and 2023. All cases underwent centralized histological review, and several malignant tumors with a stroma highly enriched in histiocytes were excluded. In total, 141 patients were included, with a median age of 62 years (range, 1 to 87 years). The cases comprised either primary MH (64%) or MH associated with other hematologic malignancies (36%). Phenotypes corresponded to histiocytic (43%), interdigitating dendritic cell (37%) or Langerhans cell (12%) sarcomas, or high grade indeterminate dendritic cell tumors (10%) as per the WHO classification. Tumor cells were almost universally positive for CSF1R and PU.1, and 85% showed phosphor-ERK positivity. NGS was performed on 75 cases. Mutations in the MAPK pathway were more frequent in secondary compared to primary MH (90% versus 55%, p=0.0012). PTPN11 mutations were exclusively observed in primary MH (p=0.0035). Mutations in genes related to DNA methylation mechanisms (TET2, ASXL1, DNMT3A) and TP53 were present in 20% and 14% of cases, respectively. Although therapeutic regimens varied considerably, our results demonstrated that surgical resection in localized cases, and the use of BRAF or MEK inhibitors achieved the highest complete response rates, at 63% and 21%, respectively. The prognosis remains poor with a five-year overall survival rate of 31%, which is comparable to that of T/NK cell lymphomas. Prospective follow-up and a standardized treatment approach in specialized reference centers are crucial to improving patient survival.