BRAF deletion in adult patients with Langerhans cell histiocytosis correlates with multisystem disease and poor outcome

Abstract Langerhans cell histiocytosis (LCH) is a rare and highly heterogeneous histiocytosis. The objective of this study was to characterize the genomic landscape of adult LCH and correlate molecular findings with clinical features and patient outcomes. This study included 254 patients aged ≥18 years with biopsy-proven LCH from January 2000 to December 2023. All patients underwent next-generation sequencing (NGS) or fluorescence quantitative PCR (qPCR) for the BRAFV600E mutation. Overall, 254 patients were enrolled. MAPK/PI3K pathway alterations were observed in 77.6%（n=197）of the patients. BRAFV600E mutation was the most common (30.7%, n=78), followed by BRAFindel (18.1%, n=46) and MAP2K1 mutations (12.6%, n=32). The proportion of BRAFindel was much higher in patients with MS involvement than single system disease (24.5% vs 6.6%, p＜0.001). In overall patients, BRAFindel was associated with inferior overall survival (3-year OS 90.0% vs 98.0%, p=0.038) and progression-free survival (3-year PFS 46.7% vs 77.6%, p＜0.001). In MS LCH patients, BRAFindel was associated to worse PFS (3-year PFS 44.6% vs 74.2%, p＜0.001). In summary, this large study provides molecular and clinical pathologic characterization of adult LCH. BRAFindel appeared almost exclusively in MS patients, and was associated to worse outcome.