Clinical characteristics, molecular aberrations, treatments, and outcomes of malignant histiocytosis

Abstract

Malignant histiocytosis (MH) is an extremely rare neoplasm of the macrophage-dendritic cell lineage. We report the clinical characteristics, molecular aberrations, treatments, and outcomes of patients with MH seen at two referral centers from January 2000 to May 2023. We identified 43 patients with MH, of which 26 had histiocytic sarcoma (MH-H), 9 interdigitating dendritic cell sarcoma (MH-IDC), and 8 Langerhans cell sarcoma (MH-LC). The median age at diagnosis was 61 years (range, 3-83). Thirty-three patients (77%) had multifocal disease, while 10 had unifocal involvement. Tumor specimens from 22 patients (51%) underwent targeted next generation sequencing, and 19 of 22 (86%) had at least one pathogenic mutation, including mutations in MAPK pathway genes (73%). The median overall survival (OS) among the entire cohort was 16 months (95% CI: 8-50). The outcomes of those with multifocal disease were significantly shorter than their unifocal counterpart: median OS of 10 months versus 50 months (p = .07). Patients with risk organ involvement (bone marrow, spleen, or liver) had significantly inferior outcomes. Chemotherapy and surgery were the most common first-line treatments for multifocal and unifocal disease, respectively. While the outcome for patients with multifocal disease was poor, there was a subset of patients who had durable responses to treatment. Our study highlights that MH has heterogeneous clinical presentation, frequent oncogenic mutations, and prognosis, which is strongly tied to disease extent and type of organ involvement.

Figure 1A.

Pathogenic mutations and fusions involved in malignant histiocytosis. Figure 1B. Heat map illustrating the mutations involved in patients with malignant histiocytosis who underwent next-generation sequencing.

Figure 2.. Swimmer plot depicting disease course, treatment outcomes, and adverse effects in patients with malignant histiocytosis.

The bar graphs show the time from date of diagnosis to date of last known follow up. Additional details on the specific treatments utilized can be found in Supplementary Table 1 and 4.

Figure 3.

Survival analysis of patients with malignant histiocytosis. (A): Overall survival of the entire cohort. (B) Progression-free survival of the entire cohort. (C) Overall survival comparing patients with unifocal vs. multifocal involvement. (D) Overall survival comparing patients with primary vs. secondary malignant histiocytosis.