title: Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: a prospective analysis of 1056 FNA samples.
abstract: BACKGROUND
  Thyroid nodules are common in adults, but only a small fraction of them is malignant. Fine-needle aspiration (FNA) cytology provides a definitive diagnosis of benign or malignant disease in many cases, whereas about 25% of nodules are indeterminate, hindering most appropriate management.
  
  
  OBJECTIVE
  The objective of the investigation was to study the clinical utility of molecular testing of thyroid FNA samples with indeterminate cytology.
  
  
  METHODS
  Residual material from 1056 consecutive thyroid FNA samples with indeterminate cytology was used for prospective molecular analysis that included the assessment of cell adequacy by a newly developed PCR assay and testing for a panel of mutations consisted of BRAF V600E, NRAS codon 61, HRAS codon 61, and KRAS codons 12/13 point mutations and RET/PTC1, RET/PTC3, and PAX8/PPARγ rearrangements.
  
  
  RESULTS
  The collected material was adequate for molecular analysis in 967 samples (92%), which yielded 87 mutations including 19 BRAF, 62 RAS, 1 RET/PTC, and five PAX8/PPARγ. Four hundred seventy-nine patients who contributed 513 samples underwent surgery. In specific categories of indeterminate cytology, i.e. atypia of undetermined significance/follicular lesion of undetermined significance, follicular neoplasm/suspicious for a follicular neoplasm, and suspicious for malignant cells, the detection of any mutation conferred the risk of histologic malignancy of 88, 87, and 95%, respectively. The risk of cancer in mutation-negative nodules was 6, 14, and 28%, respectively. Of 6% of cancers in mutation-negative nodules with atypia of undetermined significance/follicular lesion of undetermined significance cytology, only 2.3% were invasive and 0.5% had extrathyroidal extension.
  
  
  CONCLUSIONS
  Molecular analysis for a panel of mutations has significant diagnostic value for all categories of indeterminate cytology and can be helpful for more effective clinical management of these patients.
authors: Department of Pathology and Laboratory Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. nikiforovye@upmc.edu
authors: Yuri E
authors: YE
authors: Nikiforov
authors: N Paul
authors: NP
authors: Ohori
authors: Steven P
authors: SP
authors: Hodak
authors: Sally E
authors: SE
authors: Carty
authors: Shane O
authors: SO
authors: LeBeau
authors: Robert L
authors: RL
authors: Ferris
authors: Linwah
authors: L
authors: Yip
authors: Raja R
authors: RR
authors: Seethala
authors: Mitchell E
authors: ME
authors: Tublin
authors: Michael T
authors: MT
authors: Stang
authors: Christopher
authors: C
authors: Coyne
authors: Jonas T
authors: JT
authors: Johnson
authors: Andrew F
authors: AF
authors: Stewart
authors: Marina N
authors: MN
authors: Nikiforova
mesh_terms: D000328:Adult; D044963:Biopsy, Fine-Needle; D004252:DNA Mutational Analysis; D006801:Humans; D011446:Prospective Studies; D013961:Thyroid Gland / Q000473:pathology*; D016606:Thyroid Nodule / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology