title: Detection of papillary thyroid carcinoma by analysis of BRAF and RET/PTC1 mutations in fine-needle aspiration biopsies of thyroid nodules.
abstract: BACKGROUND
  Activating mutations of the oncogene BRAF or rearrangements of the tyrosine kinase receptor RET are observed in up to 80% of papillary thyroid carcinomas (PTCs). The predominant BRAF V600E mutation has not been detected in benign thyroid tissue so far, so consequently, this assumedly pathognomonic alteration is qualified to improve the preoperative diagnosis of PTC.
  
  
  METHODS
  Two hundred ninety preoperatively harvested fine-needle aspiration biopsies (FNABs) underwent routine cytologic assessment. BRAF V600E mutation analysis was performed by mutation-specific PCR using the same cell material; a hybrid-specific RT-PCR assay was used for detection of RET/PTC1 rearrangements. Detected genetic alterations were verified by direct sequencing. Definitive histopathology was obtained in 93/290 lesions following surgery of the respective thyroid nodule.
  
  
  RESULTS
  While cytology alone diagnosed 13/30 malignancies (22 PTCs, 4 FTCs, 1 MTC, 1 UTC, 2 metastases), five additional malignancies were identified by supplementary mutation analysis. Cytology classified eight FNABs as benign, while postoperative histology demonstrated a thyroid malignancy (6 PTCs, 1 FTC, 1 metastasis). In four of these eight cases, the genetic analysis detected a BRAF V600E mutation or a RET/PTC1 rearrangement. Classifying both suspicious and malignant FNAB results as positive cytology results, supplementary genetic testing increased the overall sensitivity of FNAB from 70.4 to 85.7%, the positive predictive value (PPV) from 59.4 to 64.9%, and the negative predictive value (NPV) from 84.0 to 91.3%.
  
  
  CONCLUSIONS
  Supplementary mutation analysis of RET and especially of the BRAF V600E mutation in FNABs is a fast and probably cost-effective assay in routine diagnostic setting. Mutation analyses of PTC-specific genetic alterations improve the preoperative identification and prognostic assessment of thyroid malignancies and therefore enable an optimized surgical strategy.
authors.affiliation: Endocrine Surgery, University Medical Center, Gutenberg University Mainz, Langenbeckstr. 1, 55101, Mainz, Germany. musholt@uni-mainz.de
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Musholt
authors.forename: Christian
authors.initials: C
authors.lastname: Fottner
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Weber
authors.forename: Waltraud
authors.initials: W
authors.lastname: Eichhorn
authors.forename: Joachim
authors.initials: J
authors.lastname: Pohlenz
authors.forename: Petra B
authors.initials: PB
authors.lastname: Musholt
authors.forename: Erik
authors.initials: E
authors.lastname: Springer
authors.forename: Arno
authors.initials: A
authors.lastname: Schad
mesh_terms: D000231:Adenocarcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D044963:Biopsy, Fine-Needle; D006801:Humans; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D016606:Thyroid Nodule / Q000235:genetics / Q000473:pathology
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf