title: Follicular variant of papillary carcinoma: reproducibility of histologic diagnosis and utility of HBME-1 immunohistochemistry and BRAF mutational analysis as diagnostic adjuncts.
abstract: BACKGROUND
  Despite the recognition of the follicular variant of papillary carcinoma of the thyroid (FVPTC) for over 50 years, reproducibility of this diagnostic category has remained poor. Architectural features have been of variable utility as some FVPTC seem encapsulated, whereas others are multifocal and may be confused with nodular hyperplasia. Nuclear features are important for diagnosis of FVPTC, but some authors have discounted the utility of nuclear grooves and inclusions. More recently, BRAF and HBME-1 (Human Bone Marrow Endothelial Cell-1) have been suggested as markers for FVPTC.
  
  
  OBJECTIVE
  To investigate the frequency of BRAF mutations and HBME-1 immunopositivity, in a series of FVPTCs in which the diagnosis was established by 100% consensus among a panel of 6 surgical pathologists.
  
  
  METHODS
  Twenty-eight specimens with an original diagnosis of FVPTC and 10 cases with other diagnoses were obtained from the surgical pathology files of the University of Utah School of Medicine. All specimens were independently reviewed by 6 surgical pathologists. Tissue blocks were analyzed for BRAF exon 15 mutations and HMBE-1 expression.
  
  
  RESULTS
  Complete agreement among pathologists for the diagnosis of FVPTC was obtained in 28.6% (8/28) of cases originally diagnosed as FVPTC. Mutations in BRAF exon 15 were found in 25% (2/8) of cases with a 100% consensus diagnosis of FVPTC and 32% (6/19) of cases unanimously diagnosed as a type of papillary carcinoma (classic or follicular variant). HBME-1 was expressed in 87.5% (7/8) of lesions with a 100% consensus diagnosis of FVPTC and 84.2% (16/19) of lesions with a unanimous diagnosis of a type of papillary carcinoma of the thyroid (classic or follicular variant).
  
  
  CONCLUSIONS
  Interobserver agreement for the diagnosis of FVPTC is poor and testing for the BRAF mutation is only marginally helpful because a minority of FVPTCs possess the mutation. HBME-1 expression when coupled with a BRAF mutation, results in 100% specificity but low sensitivity for the presence of papillary carcinoma of the thyroid including the follicular variant.
authors.affiliation: Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Wallander
authors.forename: Lester J
authors.initials: LJ
authors.lastname: Layfield
authors.forename: Elke
authors.initials: E
authors.lastname: Jarboe
authors.forename: Lyska
authors.initials: L
authors.lastname: Emerson
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.forename: Harshwardhan
authors.initials: H
authors.lastname: Thaker
authors.forename: Joseph
authors.initials: J
authors.lastname: Holden
authors.forename: Sheryl
authors.initials: S
authors.lastname: Tripp
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism*; D002291:Carcinoma, Papillary / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D020518:Focal Nodular Hyperplasia / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D015588:Observer Variation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013964:Thyroid Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000951:Antigens, Neoplasm
chemical_list: D014408:Biomarkers, Tumor; D048493:Proto-Oncogene Proteins B-raf; C432845:HBME-1 antigen; D000951:Antigens, Neoplasm; C482119:BRAF protein, human