https://orcid.org/0000-0002-7767-755X
Key Points
KRAS, NRAS, BRAF or MAP2K1 mutations are more prevalent in secondary MH, whereas PTPN11 mutations are exclusive to primary MH.
Surgical ablation and BRAF or MEK inhibitors demonstrated the highest response rates, yet the prognosis of MH remains poor.
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.
