Clinical Research Papers:
Potential clinical implications of BRAF mutations in histiocytic proliferations
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Anna-Maria Bubolz1, Stephanie E. Weissinger1, Albrecht Stenzinger2, Annette Arndt3, Konrad Steinestel3,4, Silke Brüderlein1, Holger Cario5, Anneli Lubatschofski5, Claudia Welke6, Ioannis Anagnostopoulos7, Thomas F. E. Barth1, Ambros J. Beer8, Peter Möller1, Martin Gottstein8, Andreas Viardot9* and Jochen K. Lennerz1*
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, Charité 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
Jochen K. Lennerz, email:
Keywords: Langerhans, Biomarker, Erdheim-Chester, V600E
Received: April 8, 2014 Accepted: June 5, 2014 Published: June 6, 2014
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.
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