title: Histopathologic and Clinical Characterization of Thyroid Tumors Carrying the BRAF(K601E) Mutation.
abstract: BACKGROUND
  While the association of the BRAF(V600E) mutation with aggressive histopathological tumor features and clinical behavior has been extensively studied in papillary thyroid carcinoma (PTC), the BRAF(K601E) mutation has not been well characterized. This study reports what is currently the largest series of BRAF(K601E) mutated thyroid nodules.
  
  
  METHODS
  Histopathologic, cytologic, and molecular reports over a period of seven years (June 2007 to June 2014) were reviewed to identify thyroid cases with various types of BRAF mutations. All cases positive for the BRAF(K601E) mutation were reviewed to confirm histopathologic diagnosis and establish tumor variant, and clinical charts were reviewed to obtain clinical characteristics and follow-up information.
  
  
  RESULTS
  The BRAF(K601E) mutation was identified in 39 patients and comprised 5.3% of all BRAF mutations noted in thyroidectomy specimens. Twenty-seven out of 29 nodules (93%) with BRAF(K601E) mutated tumors with surgical pathology results available for review were PTC, one (3.4%) was a follicular thyroid carcinoma, and one (3.4%) was a follicular adenoma. The majority of K601E-mutant PTCs (20 cases) were follicular variant PTC. Encapsulation was present in all but one case, and one case showed capsular invasion. Coexisting mutations overall were not identified in BRAF(K601E) mutated thyroid nodules except in a case that exhibited a complex K601E + T599I mutation and had a classic PTC phenotype. The majority of K601E mutant nodules were T1 lesions (69%) and T2 lesions (28%) by TNM staging. With a median follow-up of 19.6 months, no structural or biochemical recurrence or metastases were found in patients with an isolated BRAF(K601E) mutation.
  
  
  CONCLUSIONS
  The BRAF(K601E) mutation is the second most common BRAF mutation found in thyroid nodules. Unlike BRAF(V600E), the most common mutation, K601E is strongly associated with follicular-patterned cancer, particularly with the encapsulated follicular variant of PTC, and may also be found in follicular thyroid carcinomas. Overall, BRAF(K601E) mutant tumors show better clinical outcomes than BRAF(V600E) positive tumors, and preoperative BRAF(K601E) analysis may provide important prognostic information for use in clinical management.
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania.
authors.forename: Michelle
authors.initials: M
authors.lastname: Afkhami
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania.
authors.forename: Arivarasan
authors.initials: A
authors.lastname: Karunamurthy
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania.
authors.forename: Simion
authors.initials: S
authors.lastname: Chiosea
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania.
authors.forename: Marina N
authors.initials: MN
authors.lastname: Nikiforova
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania.
authors.forename: Raja
authors.initials: R
authors.lastname: Seethala
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania.
authors.forename: Yuri E
authors.initials: YE
authors.lastname: Nikiforov
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania.
authors.forename: Christopher
authors.initials: C
authors.lastname: Coyne
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000175:diagnosis / Q000235:genetics; D000236:Adenoma / Q000175:diagnosis / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf