title: Potential clinical implications of BRAF mutations in histiocytic proliferations.
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.
authors.affiliation: Institute of Pathology, University Ulm, Ulm, Germany.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Bubolz
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Weissinger
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.forename: Annette
authors.initials: A
authors.lastname: Arndt
authors.forename: Konrad
authors.initials: K
authors.lastname: Steinestel
authors.forename: Silke
authors.initials: S
authors.lastname: Brüderlein
authors.forename: Holger
authors.initials: H
authors.lastname: Cario
authors.forename: Anneli
authors.initials: A
authors.lastname: Lubatschofski
authors.forename: Claudia
authors.initials: C
authors.lastname: Welke
authors.forename: Ioannis
authors.initials: I
authors.lastname: Anagnostopoulos
authors.forename: Thomas F E
authors.initials: TF
authors.lastname: Barth
authors.forename: Ambros J
authors.initials: AJ
authors.lastname: Beer
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.forename: Martin
authors.initials: M
authors.lastname: Gottstein
authors.forename: Andreas
authors.initials: A
authors.lastname: Viardot
authors.affiliation: Institute of Pathology, University Ulm, Ulm, Germany.
authors.forename: Jochen K
authors.initials: JK
authors.lastname: Lennerz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006644:Histiocytes / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D055815:Young Adult
chemical_list: D048493:Proto-Oncogene Proteins B-raf