Original Paper

Acta Neuropathologica

, Volume 123, Issue 2, pp 223-233

Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with brain metastases

  • David CapperAffiliated withDepartment of Neuropathology, Institute of Pathology, Ruprecht-Karls-UniversityClinical Cooperation Unit Neuropathology, German Cancer Research Center
  • , Anna Sophie BerghoffAffiliated withDepartment of Medicine I, Medical University of ViennaComprehensive Cancer Center—CNS Tumors Unit, Medical University of Vienna
  • , Manuel MagerleAffiliated withDepartment of Medicine I, Medical University of ViennaComprehensive Cancer Center—CNS Tumors Unit, Medical University of Vienna
  • , Aysegül IlhanAffiliated withDepartment of Medicine I, Medical University of ViennaComprehensive Cancer Center—CNS Tumors Unit, Medical University of Vienna
  • , Adelheid WöhrerAffiliated withComprehensive Cancer Center—CNS Tumors Unit, Medical University of ViennaInstitute of Neurology, Medical University of Vienna
  • , Monika HacklAffiliated withAustrian National Cancer Registry, Statistics Austria
  • , Josef PichlerAffiliated withLandes-Nervenklinik Wagner-Jauregg
  • , Stefan PuschAffiliated withDepartment of Neuropathology, Institute of Pathology, Ruprecht-Karls-UniversityClinical Cooperation Unit Neuropathology, German Cancer Research Center
  • , Jochen MeyerAffiliated withDepartment of Neuropathology, Institute of Pathology, Ruprecht-Karls-UniversityClinical Cooperation Unit Neuropathology, German Cancer Research Center
    • , Antje HabelAffiliated withDepartment of Neuropathology, Institute of Pathology, Ruprecht-Karls-University
    • , Peter PetzelbauerAffiliated withDepartment of Dermatology, Medical University of Vienna
    • , Peter BirnerAffiliated withComprehensive Cancer Center—CNS Tumors Unit, Medical University of ViennaClinical Institute of Pathology, Medical University of Vienna
    • , Andreas von DeimlingAffiliated withDepartment of Neuropathology, Institute of Pathology, Ruprecht-Karls-UniversityClinical Cooperation Unit Neuropathology, German Cancer Research Center Email author 
    • , Matthias PreusserAffiliated withDepartment of Neuropathology, Institute of Pathology, Ruprecht-Karls-UniversityDepartment of Medicine I, Medical University of ViennaComprehensive Cancer Center—CNS Tumors Unit, Medical University of ViennaInstitute of Neurology, Medical University of Vienna Email author 

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Abstract

Brain metastases (BM) are frequent and carry a dismal prognosis. BRAF V600E mutations are found in a broad range of tumor types and specific inhibitors targeting BRAF V600E protein exist. We analyzed tumoral BRAF V600E-mutant protein expression using the novel mutation-specific antibody VE1 in a series of 1,120 tumor specimens (885 BM, 157 primary tumors, 78 extra-cranial metastases) of 874 BM patients. In 85 cases, we performed validation of immunohistochemical results by BRAF exon 15 gene sequencing. BRAF V600E protein was expressed in BM of 42/76 (55.3%) melanomas, 1/15 (6.7%) ovarian cancers, 4/72 (5.5%) colorectal cancers, 1/355 (0.3%) lung cancers, 2/6 thyroid cancers and 1/2 choriocarcinomas. BRAF V600E expression showed high intra-tumoral homogeneity and was similar in different tumor manifestations of individual patients. VE1 immunohistochemistry and BRAF exon 15 sequencing were congruent in 68/70 (97.1%) cases, but VE1 immunostaining identified small BRAF V600E expressing tumor cell aggregates in 10 cases with inconclusive genetic results. Melanoma patients with BRAF V600E mutant protein expressing tumors were significantly younger at diagnosis of the primary tumor and at operation of BM than patients with non-mutated tumors. In conclusion, expression of BRAF V600E mutant protein occurs in approximately 6% of BM and is consistent in different tumor manifestations of the same patient. Thus, BRAF V600E inhibiting therapies seem feasible in selected BM patients. Immunohistochemical visualization of V600E-mutant BRAF protein is a promising tool for patient stratification. An integrated approach combining both, VE1 immunohistochemistry and genetic analysis may increase the diagnostic accuracy of BRAF mutation analysis.

Keywords

Brain metastases BRAF V600E Mutation Immunohistochemistry VE1