Pediatric Langerhans cell histiocytosis: state of the science and future directions.

Langerhans cell histiocytosis (LCH) is an inflammatory neoplasm of myeloid origin characterized by the presence of classic CD1a+/CD207+ cells. An ongoing debate over the grouping of LCH was finally settled in favor of neoplasm after the discovery of the BRAF V600E mutation in 2010. The pathologic cells were found to involve an almost universal activation of the MAPK/ERK pathway, with mutations identified in most kinases upstream of ERK (RAS/RAF/MEK). The clinical presentation of LCH is a mixed bag, ranging from self-resolving localized disease to fulminant, fatal disseminated disease. The current standard of care for patients with multisystem LCH, who have high relapse rates, continues to be combination treatment with vinblastine and prednisone. Patients treated with BRAF and MEK inhibitors have shown a significant and sustained response in early-phase trials. During the current decade, researchers have described an extensive genomic landscape for LCH that has significantly enlarged our understanding of the biology and pathogenesis of this disease, especially neurodegenerative LCH. These advances have opened the door to studies of precision medicine and targeted therapy in LCH. Disease reactivation, long-term sequelae, very high-risk disease, and neurodegenerative LCH represent ongoing challenges. A renewed understanding of the biology of this disease, coupled with targeted therapies, may help in overcoming most of these challenges.