Molecular Pathogenesis and Targeted Therapeutic Advances in Langerhans Cell Histiocytosis: A Systematic Review

Abstract

Introduction: Langerhans Cell Histiocytosis (LCH) is a rare myeloid neoplasm characterized by clonal proliferation of immature dendritic cells, primarily driven by constitutive activation of the MAPK signaling pathway through mutations in BRAFV600E, MAP2K1, and ARAF. Recent genomic and therapeutic advances have reshaped the understanding of LCH pathophysiology, highlighting differences between pediatric and adult presentations, particularly regarding skeletal involvement and prognosis. Aim: To systematically review the literature published between 2015 and 2025 addressing genetic alterations, immunopathogenic mechanisms, orthopedic manifestations, and targeted therapies in pediatric and adult Langerhans Cell Histiocytosis. Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines. Searches were performed in PubMed/MEDLINE, SciELO, and the Virtual Health Library (BVS). After screening, duplicate removal, and eligibility assessment, 38 studies were included. Due to methodological heterogeneity, data were synthesized through qualitative analysis, and no meta-analysis was performed. Results: The included studies demonstrated a predominance of BRAFV600E mutations (52–65%) and MAP2K1 mutations (15–25%), leading to sustained MAPK pathway activation and chronic inflammation. Pediatric patients more frequently presented with multifocal skeletal involvement, while adults predominantly exhibited unifocal disease with favorable prognosis. Targeted therapy with BRAF and MEK inhibitors achieved high response rates, with radiological regression and functional improvement; however, disease relapse after treatment discontinuation remained common in a subset of patients. Conclusion: Activation of the MAPK pathway is central to LCH pathogenesis and clinical behavior. Incorporation of molecular profiling enables precision-based therapeutic strategies, particularly with BRAF and MEK inhibitors. Orthopedic manifestations, especially in pediatric patients, require conservative and multidisciplinary management. Despite significant advances, randomized clinical trials and standardized treatment protocols are still needed to define optimal therapy duration and reduce relapse risk.