Potential clinical implications of BRAF mutations in histiocytic proliferations

// Anna-Maria Bubolz 1 , Stephanie E. Weissinger 1 , Albrecht Stenzinger 2 , Annette Arndt 3 , Konrad Steinestel 3,4 , Silke Bruderlein 1 , Holger Cario 5 , Anneli Lubatschofski 5 , Claudia Welke 6 , Ioannis Anagnostopoulos 7 , Thomas F. E. Barth 1 , Ambros J. Beer 8 , Peter Moller 1 , Martin Gottstein 8 , Andreas Viardot 9* and Jochen K. Lennerz 1* 1 Institute of Pathology, University Ulm, Ulm, Germany 2 Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany 3 Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, Ulm, Germany 4 Bundeswehr Institute of Radiobiology, Munich, Germany 5 Department of Pediatric Oncology, Children’s Hospital, University Ulm, Ulm, Germany 6 Comprehensive Cancer Center Ulm, Ulm Germany 7 Institute of Pathology, Charite University Hospital, Berlin, Germany 8 Department of Nuclear Medicine, University Ulm, Ulm, Germany 9 Department of Internal Medicine III, University Ulm, Ulm, Germany * These authors contributed equally to this work Correspondence: Jochen K. Lennerz, email: // Keywords : Langerhans, Biomarker, Erdheim-Chester, V600E Received : April 8, 2014 Accepted : June 5, 2014 Published : June 6, 2014 Abstract For a growing number of tumors the BRAF V600E mutation carries therapeutic relevance. In histiocytic proliferations the distribution of BRAF mutations and their relevance has not been clarified. Here we present a retrospective genotyping study and a prospective observational study of a patient treated with a BRAF inhibitor. Genotyping of 69 histiocytic lesions revealed that 23/48 Langerhans cell lesions were BRAF -V600E-mutant whereas all non-Langerhans cell lesions (including dendritic cell sarcoma, juvenile xanthogranuloma, Rosai-Dorfman disease, and granular cell tumor) were wild-type. A metareview of 29 publications showed an overall mutation frequency of 48.5%; and with N=653 samples, this frequency is well defined. The BRAF mutation status cannot be predicted based on clinical parameters and outcome analysis showed no difference. Genotyping identified a 45 year-old woman with an aggressive and treatment-refractory, ultrastructurally confirmed systemic BRAF -mutant LCH. Prior treatments included glucocorticoid/vinblastine and cladribine-monotherapy. Treatment with vemurafenib over 3 months resulted in a dramatic metabolic response by FDG-PET and stable radiographic disease; the patient experienced progression after 6 months. In conclusion, BRAF mutations in histiocytic proliferations are restricted to lesions of the Langerhans-cell type. While for most LCH-patients efficient therapies are available, patients with BRAF mutations may benefit from the BRAF inhibitor vemurafenib.