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

[erdheim-chester disease]

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 V 600 E mutations in 35 % to 60 % of cases . Tumor protein p 53 (TP 53 ) 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 V 600 E 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 V 600 E 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 .

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erdheim-chester disease

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