Systemic Histiocytosis (Langerhans Cell Histiocytosis, Erdheim–Chester Disease, Destombes–Rosai–Dorfman Disease): from Oncogenic Mutations to Inflammatory Disorders

Purpose of Review Provide an overview of recent progress in decoding the pathogenesis and treatment of systemic histiocytoses. Recent Findings Advances in molecular techniques over the last few years, enabling the identification of several MAPK mutations in lesion histiocytes, have revolutionized our understanding of histiocytosis that led to a revised classification and new treatments. Summary Since the 2010 discovery of the BRAF V600E mutation in 57% of Langerhans cell histiocytosis (LCH) lesions, several other kinase mutations have been found, mostly in the MAPK pathway, and also in other key signaling pathways, in LCH, Erdheim–Chester Disease (ECD) and, less frequently, Destombes–Rosai–Dorfman disease (RDD). Those revolutionary breakthroughs enhanced our understanding of the pathogenesis of histiocytosis and led to trials with targeted therapies that demonstrated notable efficacy.