Purpose. Malignant histiocytoses (MHs) including Langerhans cell sarcoma (LCS), interdigitating dendritic cell sarcoma (IDCS), and histiocytic sarcoma (HS) are rare, aggressive neoplasms of the macrophage-dendritic cell lineage. Prognosis is generally poor, particularly in disseminated disease. While mutation-specific therapies are increasingly used in indolent histiocytic neoplasms, their role in MH remains unclear due to the frequent presence of complex mutational profiles. Our understanding of the genomic landscape of MH is limited. This study aimed to comprehensively characterize the molecular alterations in MH.Methods. We conducted a retrospective chart review of MH patients seen at Mayo Clinic and the University of Alabama at Birmingham who underwent comprehensive next-generation sequencing (NGS), including DNA ± RNA analysis. A systematic literature review using PubMed identified additional MH cases with available molecular data.Results. We identified 17 institutional MH cases (3 IDCS, 3 LCS, 11 HS) and 72 cases from the literature (6 IDCS, 11 LCS, 55 HS) with NGS data. Among the 89 total patients, 26 (29%) had DNA-only sequencing and 63 (71%) had combined DNA/RNA sequencing. Twelve patients (n=12; 13%) had a single mutation; the majority had multiple alterations. The most frequently mutated genes were: RAS (n=26; 29%), CDKN1/2 (n=26; 29%), MAP2K1 (n=15; 17%), PTEN (n=11; 12%), BRAF non-V600E (n=8; 9%), PTPN11 (n=8; 9%), CREBBP (n=8; 9%), TET2 (n=8; 9%), DNMT3A (n=7; 8%), fusions (n=7; 8%), BRAFV600E (n=6; 7%), and NF1 (n=4; 4%). Fusions included BRAF::NRF11, BRAF::CLIP2, BRAF::MBP, EGFR::CYTOR, CDKN2A::ADGRG6, IGH::BCL6, and CLIP2-BRAF. Two patients had no alteration detected. Non-V600E BRAF mutations included D594G (n=3), G596R (n=1), G466A (n=1), N581T (n=1), N581I (n=1), and N581S (n=1). Common co-mutations with BRAF included CDKN2A/B (n=9), TP53 (n=6), KRAS/NRAS (n=5), and PDGFR (n=1). Only 2 of 15 MAP2K1-mutated patients (13%) had isolated mutations; the rest had co-mutations, most frequently TP53 (n=3) and BCL2 (n=3). MAP2K1 mutations included F53I (n=2), C121S (n=2), I103N (n=1), Q56P(n=3), E203K (n=1), F53-K57del (n=1), and F53-Q58del (n=1).NRAS mutations (n=6) included Q16K (n=2), G12C (n=1), Q61R (n=1), and 2 unspecified.

KRAS mutations (n=20) included G13D (n=3), Q61H (n=3), G12V (n=2), K117N (n=1), V14I (n=1), and 10 unspecified. The most frequent co-mutational pattern (24%) was RAS plus another gene: BRAF (n=3), TP53 (n=6), MAP2K1 (n=2), PTEN (n=4), and CDKN2A/B (n=6).Twelve patients (12/26; 46%) were treated with targeted therapies. Responses included 6 partial and 5 complete responses. Median duration of response was 27.5 months (range 7–54). The sole non-responder had co-occurring NRASand TP53 mutations and received trametinib. Responders received a range of agents matched to their mutations: trametinib (BRAFV600E, MAP2K1F53I, KRASQ16H/PTEND24G/EPHB1R327C, MAP2K1F53I/BCL2/CDKN1B/KIT, and CALR), dabrafenib + trametinib(BRAFG596R/KRASQ61H), imatinib (MAP2K1C121S/METG28881T/DUSP2G137D/HIST1H3BC97Y/GRIN2AS1216C and PTPN11/STK11/GNA11/JAK2), chidamide + sintilimab(IDH2G515A/RHOAG50T/TET23344delC), sirolimus(PTEN/FGFR3/SETD2) and sorafenib (BRAFD594G/KRASK117N/TP53). Most responders (8/11) had multiple mutations; only 3 had single alterations, suggesting multi-mutant MH may still be targetable. Common complex patterns included BRAF+CDKN2A + CDKN2B (n=4), BRAF + CDKN2A + TP53 (n=2), and BRAF + CDKN2A + KRAS (n=2).Conclusion. The MAPK pathway (BRAF, MAP2K1, RAS) is the most altered signaling axis in MH, often accompanied by mutations in tumor suppressors and cell cycle regulators such as TP53, CDKN2A/B, and PTEN. Most MH patients exhibit multiple genomic alterations. Despite this complexity, durable clinical responses to targeted agents are achievable, even in heavily mutated cases. These findings support the use of comprehensive genomic profiling in MH to identify therapeutic targets and guide precision treatment strategies.

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2025
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