title: Indeterminate Single Thyroid Nodule: Synergistic Impact of Mutational Markers and Sonographic Features in Triaging Patients to Appropriate Surgery.
abstract: BACKGROUND
  Patients labeled as having indeterminate thyroid nodular disease following fine-needle aspiration cytology are at risk of non-optimal initial surgery: an overly radical total thyroidectomy, or an unnecessary two-stage operation. The objective of this study was to assess the impact of combining mutational markers and ultrasonographic (US) features preoperatively on predicting the risk of malignancy in patients with indeterminate nodules, thereby offering them a tailored initial surgical intervention.
  
  
  METHODS
  The records of 258 patients who underwent conventional total thyroidectomy for single nodules reported as suspicious for a follicular neoplasm (Bethesda category IV) in a four-year period were reviewed. Main issues addressed included: certain US findings (individually and in combination), mutational markers (BRAF and NRAS), and combinations of both. Correlation of these with malignancy was assessed, as was their ability to predict malignancy. The usefulness of combining the absence of suspicious sonographic features and the absence of mutational markers was also evaluated.
  
  
  RESULTS
  Among the 258 patients with an indeterminate diagnosis, only 90 lesions were found to be malignant. The sonographic features that correlated significantly with malignancy were irregular margins, microcalcifications, and a "taller than wide" shape. The presence of irregular margins was the feature with the highest positive predictive value. Combinations of two or more features were always associated with predictivity in excess of 90%, and at times at 100%. NRAS mutation was the most common gene alteration. Both BRAF and NRAS mutations were mutually exclusive and correlated significantly with malignancy. Their predictivity of malignancy was high, particularly when combined with suspicious sonographic features (100%). The major limitation of both suspicious sonographic features and/or mutational markers was their low occurrence in malignancy. The absence of both mutational markers and suspicious sonographic features proved extremely useful in tailoring surgical strategy, as it could have ultimately spared 143/258 patients (55%) an overly radical thyroidectomy.
  
  
  CONCLUSIONS
  The preoperative utility of mutational markers and sonographic features in combination has a synergistic impact. It can predict the risk of malignancy with high accuracy, properly triaging patients to appropriate surgery.
authors.affiliation: 1 Division of Surgery; University Hospital of Pisa , Pisa, Italy .
authors.forename: Luigi
authors.initials: L
authors.lastname: De Napoli
authors.affiliation: 1 Division of Surgery; University Hospital of Pisa , Pisa, Italy .
authors.forename: Sohail
authors.initials: S
authors.lastname: Bakkar
authors.affiliation: 1 Division of Surgery; University Hospital of Pisa , Pisa, Italy .
authors.forename: Carlo Enrico
authors.initials: CE
authors.lastname: Ambrosini
authors.affiliation: 1 Division of Surgery; University Hospital of Pisa , Pisa, Italy .
authors.forename: Gabriele
authors.initials: G
authors.lastname: Materazzi
authors.affiliation: 2 Division of Pathology, Department of Surgical Pathology; University Hospital of Pisa , Pisa, Italy .
authors.forename: Agnese
authors.initials: A
authors.lastname: Proietti
authors.affiliation: 2 Division of Pathology, Department of Surgical Pathology; University Hospital of Pisa , Pisa, Italy .
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Macerola
authors.affiliation: 2 Division of Pathology, Department of Surgical Pathology; University Hospital of Pisa , Pisa, Italy .
authors.forename: Fulvio
authors.initials: F
authors.lastname: Basolo
authors.affiliation: 1 Division of Surgery; University Hospital of Pisa , Pisa, Italy .
authors.forename: Paolo
authors.initials: P
authors.lastname: Miccoli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D018579:Patient Selection; D010641:Phenotype; D011237:Predictive Value of Tests; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015203:Reproducibility of Results; D013964:Thyroid Neoplasms / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics / Q000601:surgery*; D016606:Thyroid Nodule / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics / Q000601:surgery*; D013965:Thyroidectomy; D014218:Triage; D014463:Ultrasonography / Q000379:methods*; D019564:Unnecessary Procedures; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human