Recurrent BRAF mutations in Langerhans cell histiocytosis

Abstract

Langerhans cell histiocytosis (LCH) has a broad spectrum of clinical behaviors; some cases are self-limited, whereas others involve multiple organs and cause significant mortality. Although Langerhans cells in LCH are clonal, their benign morphology and their lack (to date) of reported recurrent genomic abnormalities have suggested that LCH may not be a neoplasm. Here, using 2 orthogonal technologies for detecting cancer-associated mutations in formalin-fixed, paraffin-embedded material, we identified the oncogenic BRAF V600E mutation in 35 of 61 archived specimens (57%). TP53 and MET mutations were also observed in one sample each. BRAF V600E tended to appear in younger patients but was not associated with disease site or stage. Langerhans cells stained for phospho-mitogen-activated protein kinase kinase (phospho-MEK) and phospho-extracellular signal-regulated kinase (phospho-ERK) regardless of mutation status. High prevalence, recurrent BRAF mutations in LCH indicate that it is a neoplastic disease that may respond to RAF pathway inhibitors.

Figure 1

Immunofluorescence analysis of BRAF pathway activation in LCH. (A) LCH sample stained with DAPI (blue), anti-CD1a (green), antiphospho-MEK (red), and a merged image of all 3 stains. (B) LCH sample stained with DAPI (blue), anti-CD1a (green), antiphospho-ERK (red), and a merged image of all 3 stains. Arrowheads indicate CD1a-negative cells that are also negative for phospho-MEK and phospho-ERK. (Technical details described in supplemental Methods.)