BRAF Deletion in Adult Patients with Langerhans Cell Histiocytosis Correlates with Multisystem Disease and Poor Outcomes

PURPOSE: Langerhans cell histiocytosis (LCH) is a rare and highly heterogeneous histiocytosis. There are currently few studies examining the correlation between molecular profiling and clinical phenotype or outcomes in adult patients with LCH. The objective of this study was to characterize the genomic landscape of adult LCH and correlate molecular findings with clinical features and patient outcomes. EXPERIMENTAL DESIGN: This study included 254 patients, ages ≥18 years, with biopsy-proven LCH from January 2000 to December 2023. All patients underwent next-generation sequencing or fluorescence qPCR for the BRAFV600E mutation. Patient demographics, disease characteristics, and treatments were collected through electronic medical records. Patient outcomes were collected through clinical and telephone follow-up. RESULTS: 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 multisystem (MS) involvement than single-system disease (24.5% vs. 6.6%, P < 0.001). Overall, BRAFindel was associated with inferior overall survival (3-year overall survival 89.6% vs. 99.0%, P = 0.014) and progression-free survival (PFS) (3-year PFS 50.0% vs. 78.6%, P < 0.001). In patients with MS LCH, BRAFindel was associated with worse PFS (3-year PFS 47.8% vs. 76.0%, P = 0.001). CONCLUSIONS: This large study provides molecular and clinical pathologic characterization of adult LCH. BRAFindel was highly correlated with MS LCH and was associated with worse outcomes.