title: A Genomic Alternative to Identify Medullary Thyroid Cancer Preoperatively in Thyroid Nodules with Indeterminate Cytology.
abstract: The use of calcitonin screening for the rare medullary thyroid cancer (MTC) is controversial due to questions of efficacy, accuracy, and cost-effectiveness. This study reports the results of a large prospective validation using a machine-trained algorithm (MTC Classifier) to preoperatively identify MTC in fine-needle aspiration biopsies in lieu of calcitonin measurements.
  
  
  
  Cytology analysis on a prospective consecutive series of 50,430 thyroid nodule biopsies yielded a total of 7815 indeterminate (Bethesda categories III/IV) cases, which were tested with the MTC classifier. A prospective, consecutively submitted series of 2673 Bethesda III-VI cases with cytology determined locally was also evaluated. RNA was isolated and tested for the MTC Classifier using microarrays.
  
  
  
  Forty-three cases were positive by the MTC Classifier among 10,488 tested nodules (0.4%), consistent with the low prevalence of MTC. Of these, all but one was histologically or biochemically confirmed as MTC, yielding a positive predictive value (PPV) of 98%. Of the positive cases, only 19 (44%) had been specifically suspected of MTC by cytology, highlighting the limitations of light microscopy to detect this disease. Three surgically confirmed MTC cases that were detected by the MTC Classifier had low basal serum calcitonin values, indicating these would have been missed by traditional calcitonin screening methods. A pooled analysis of three independent validation sets demonstrates high test sensitivity (97.9%), specificity (99.8%), PPV (97.9%), and negative predictive value (99.8%).
  
  
  
  A clinical paradigm is proposed, whereby cytologically indeterminate thyroid nodules being tested for common malignancies using gene expression can be simultaneously tested for MTC using the same genomic assay at no added cost.
authors.affiliation: 1 Department of Medical Affairs, Veracyte, Inc., South San Francisco, California.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Kloos
authors.affiliation: 2 CLIA, Veracyte, Inc., South San Francisco, California.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Monroe
authors.affiliation: 3 Thyroid Cytopathology Partners , Austin, Texas.
authors.forename: S Thomas
authors.initials: ST
authors.lastname: Traweek
authors.affiliation: 1 Department of Medical Affairs, Veracyte, Inc., South San Francisco, California.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lanman
authors.affiliation: 4 Department of Research and Development , Veracyte, Inc., South San Francisco, California.
authors.forename: Giulia C
authors.initials: GC
authors.lastname: Kennedy
mesh_terms: D000368:Aged; D000465:Algorithms; D044963:Biopsy, Fine-Needle; D002116:Calcitonin / Q000097:blood; D018276:Carcinoma, Medullary / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D003581:Cytodiagnosis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D013964:Thyroid Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D016606:Thyroid Nodule / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000601:surgery
chemical_list: D002116:Calcitonin