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More than a century after its first description, Langerhans cell histiocytosis (LCH) still remains an intriguing disease. Considerable progress in understanding its biology has been achieved recently. Description of the V600E BRAF mutation in samples of LCH tissue in 2010 was followed by description of additional mutations, all leading to constitutive ERK activation. Current experimental data suggest that LCH is a myeloid neoplasia with inflammatory properties, yet the exact pathophysiology remains poorly understood. Disease management paradigms have changed over time, closely reflecting the evolving view of the nature of the disease. The international Histiocyte Society have conducted three prospective clinical studies on multisystem LCH since the early 1990s. The standard frontline therapy for patients with multisystem LCH based on the cumulative knowledge of those trials consists of 6-12 weeks of initial therapy (daily oral steroids and weekly vinblastine injections), followed by pulses of prednisolone/vinblastine every 3 weeks, for a total treatment duration of 12 months. A currently ongoing study (LCH-IV) with a complex design (five interventional and two observational strata) targets further reduction of mortality and morbidity by tailoring treatment intensity depending on expected risk, as well as by exploring treatment regimens for special locations. Current knowledge on LCH pathobiology opens opportunities for improvement in the patient outcome. The activating BRAF and MAP2K1 mutations collectively accounting for about 75% of the LCH population as well as the resulting constitutive activation of downstream ERK offer an opportunity for targeted treatment. Related issues (eg, finding most effective and less toxic drugs or combinations, appropriate dosage, and optimal treatment duration) must be addressed in controlled prospective trials. Additional mechanisms, such as the interactions of the mutated dendritic cell clone with other inflammatory cells and key cytokines and chemokines, still remain attractive targets for therapeutic intervention, particularly in patients with localized, less aggressive disease.

Insights into the pathogenesis of Langerhans cell histiocytosis: the development of targeted therapies