Biological and therapeutic implications of the BRAF pathway in histiocytic disorders.

Langerhans cell histiocytosis (LCH) has historically evolved in its classification from a primary immune dysregulatory disorder to what current evidence supports as a dendritic cell neoplasm with an immune-inflammatory component. A key part of the classification of LCH as a neoplasm has been the identification of BRAF V600E mutations in 35% to 60% of cases. Tumor protein p53 (TP53) and RAS mutations have also been identified, albeit in less than 2% of reported cases. Of note, over 50% of patients with another dendritic cell disease, Erdheim-Chester Disease, have also been shown to have BRAF V600E mutations. Although the BRAF mutations have not been shown to be associated with extent of disease, they may still provide a target for a molecularly guided approach to therapy. In cases of LCH in which no BRAF mutations were identified, there was evidence for activation of the RAS-RAF-MEK-extracellular signal-regulated kinases (ERK) pathway, suggesting that similar to other tumors, this pathway may be therapeutically exploitable. Anecdotal responses have been reported in a few patients with LCH and Erdheim-Chester Disease to vemurafenib, a BRAF V600E inhibitor. Although these results pave the way for careful, prospective clinical testing, selection of the optimal groups in which to test such inhibitors, alone or in combination, will be critical based on the toxicity profile thus far observed in adults with melanoma and other BRAF mutated tumors.