title: Molecular genotyping of follicular variant of papillary thyroid carcinoma correlates with diagnostic category of fine-needle aspiration cytology: values of RAS mutation testing.
abstract: BACKGROUND
  The follicular variant of papillary thyroid carcinoma (FVPTC) presents distinct histologic subtypes and molecular genotyping. The preoperative diagnosis of FVPTC through fine-needle aspiration cytology (FNAC) is challenging.
  
  
  METHODS
  We reviewed 59 archival thyroid FNAC specimens of surgically confirmed FVPTC according to histologic subtype: encapsulated FVPTC (n = 30) and infiltrative FVPTC (n = 29). Galectin-3 immunostaining and molecular analyses for BRAF and three RAS genes (NRAS, HRAS, and KRAS) were performed.
  
  
  RESULTS
  FNAC diagnoses of FVPTC included benign (5%), atypia of undetermined significance (19%), follicular neoplasm/suspicious for follicular neoplasm (14%), suspicious for PTC (29%), and PTC (34%). Galectin-3 immunostaining was positive in 50% of FNAC specimens. A BRAF mutation was found only in 14 (24%) tumors with the FNAC diagnosis of PTC or suspicious for PTC: 13 cases with the usual c.1799T>A (p.V600E) mutation and 1 case with a 3 base-pair deletion (c.1799_1801delTGA), resulting in a deletion of lysine at codon 601 and a deletion c.1799_1801delTGA that results in a valine-to-glutamate substitution at codon 600 (p.V600_K601>E) while preserving the reading frame. A BRAF K601E mutation was not found. RAS mutations were observed in 18 (33%) tumors (NRAS, 22%; HRAS, 6%; KRAS, 6%). Mutations of the three RAS genes were detected in codon 61 but not in codons 12 and 13. There was a decreasing trend of RAS mutation rates associated with an increasing risk of malignancy in the FNAC diagnostic categories. The triage efficacy of FNAC to make a recommendation for surgery was 73% for encapsulated tumors and 79% for infiltrative tumors. Addition of galectin-3 or the BRAF test to FNAC showed no significant improvement in the triage efficacy. However, RAS mutations significantly improved the triage efficacy of FNAC. There was no significant difference in the triage efficacy of FNAC, galectin-3 expression, and the prevalence of somatic mutations between encapsulated and infiltrative tumors.
  
  
  CONCLUSIONS
  Thyroid FNAC has a low sensitivity for the detection of FVPTC regardless of histologic subtype. Encapsulated FVPTC and infiltrative FVPTC have similar molecular profiles and rates of galectin-3 expression. RAS mutational analysis is more useful than BRAF testing to improve the triage efficacy of FNAC for FVPTC.
authors.affiliation: 1 Department of Hospital Pathology, College of Medicine, The Catholic University of Korea , Seoul, Republic of Korea.
authors.forename: Sang Ryung
authors.initials: SR
authors.lastname: Lee
authors.forename: Chan Kwon
authors.initials: CK
authors.lastname: Jung
authors.forename: Tae Eun
authors.initials: TE
authors.lastname: Kim
authors.forename: Ja Seong
authors.initials: JS
authors.lastname: Bae
authors.forename: So Lyung
authors.initials: SL
authors.lastname: Jung
authors.forename: Yeong Jin
authors.initials: YJ
authors.lastname: Choi
authors.forename: Chang Suk
authors.initials: CS
authors.lastname: Kang
mesh_terms: D000328:Adult; D000368:Aged; D044963:Biopsy, Fine-Needle; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics*; D002291:Carcinoma, Papillary; D018265:Carcinoma, Papillary, Follicular / Q000175:diagnosis* / Q000235:genetics*; D003062:Codon; D004252:DNA Mutational Analysis; D005260:Female; D037502:Galectin 3 / Q000378:metabolism; D017353:Gene Deletion; D011905:Genes, ras; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D008239:Lysine / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D055815:Young Adult
chemical_list: D003062:Codon; D037502:Galectin 3; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D008239:Lysine