title: Uncommon BRAF mutations in the follicular variant of thyroid papillary carcinoma: New insights.
abstract: BACKGROUND
  Mutational analysis is reshaping the practice of fine-needle aspiration cytology for the diagnosis of thyroid nodules. The v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) valine (V) to glutamic acid (E) substitution at codon 600 (BRAF(V600E)) is the most effective diagnostic/prognostic marker and is used mainly for papillary thyroid carcinomas (PTCs). Although BRAF(V600E) represents 95% of all BRAF mutations, uncommon BRAF mutations have been identified in thyroid carcinomas. For the current study, the authors evaluated morphologic (plump pink cells and sickle-shaped nuclei) anti-BRAF(V600E) antibody (VE1) immunocytochemical and molecular findings of BRAF mutations in PTCs and in the follicular variant of PTC (FVPC).
  
  
  METHODS
  Between January 2013 and June 2014, there were 150 cytologic samples with surgical follow-up at the authors' institution. BRAF mutations, which were identified using liquid-based cytology, were classified into wild-type BRAF, BRAF(V600E), and uncommon BRAF mutations. All clinicopathologic correlations between BRAF and FVPCs were analyzed.
  
  
  RESULTS
  Forty-four of 150 samples were identified as benign histologic lesions, and the authors focused on the 106 cytologic samples from patients who had malignant outcomes (60 PTCs and 46 FVPCs). The series included 16 follicular neoplasms, 36 samples diagnosed as suspicious of malignancy, and 54 samples diagnosed as positive for malignancy. The BRAF(V600E) mutation was detected in 17.4% of FVPCs and in 66.6% of PTCs, whereas uncommon BRAF mutations were detected only in FVPCs. Plump pink cells and VE1 expression were not identified in samples that had uncommon BRAF mutations. VE1 immunocytochemistry yielded positive results in all 36 samples that had the BRAF(V600E) mutation.
  
  
  CONCLUSIONS
  Uncommon BRAF mutations were observed only in FVPCs and were linked to less aggressive behavior. Negative/weak VE1 expression was observed in both wild-type and uncommon BRAF mutations. The current investigation did not reveal any plump cells or morphologic BRAF findings in samples that had uncommon BRAF mutations. In the authors' experience, BRAF mutations detected by DNA methods were more accurate in identifying FVPCs.
authors.affiliation: Division of Anatomic Pathology and Histology, "Agostino Gemelli" School of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Esther Diana
authors.initials: ED
authors.lastname: Rossi
authors.affiliation: Division of Anatomic Pathology and Histology, "Agostino Gemelli" School of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Martini
authors.affiliation: Division of Anatomic Pathology and Histology, "Agostino Gemelli" School of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Bizzarro
authors.affiliation: Division of Anatomic Pathology and Histology, "Agostino Gemelli" School of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Capodimonti
authors.affiliation: Division of Anatomic Pathology and Histology, "Agostino Gemelli" School of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Tonia
authors.initials: T
authors.lastname: Cenci
authors.affiliation: Division of Endocrine Surgery, "Agostino Gemelli" School of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Celestino Pio
authors.initials: CP
authors.lastname: Lombardi
authors.affiliation: Division of Endocrinology, "Agostino Gemelli" School of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Pontecorvi
authors.affiliation: Division of Anatomic Pathology and Histology, "Agostino Gemelli" School of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Fadda
authors.affiliation: Division of Anatomic Pathology and Histology, "Agostino Gemelli" School of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Luigi Maria
authors.initials: LM
authors.lastname: Larocca
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D044963:Biopsy, Fine-Needle; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D016022:Case-Control Studies; D003581:Cytodiagnosis; D004247:DNA / Q000032:analysis / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016606:Thyroid Nodule / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D004247:DNA; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF mutations; follicular neoplasms; follicular variant of papillary thyroid carcinoma; liquid-based cytology; papillary thyroid carcinoma