Preoperative Identification of Medullary Thyroid Carcinoma (MTC): Clinical Validation of the Afirma MTC RNA-Sequencing Classifier

Gregory W. Randolph, Julie Ann Sosa, Yangyang Hao, Trevor E. Angell, David C. Shonka, Virginia A. LiVolsi, Paul W. Ladenson, Thomas C. Blevins, Quan Yang Duh, Ronald Ghossein, Mack Harrell, Kepal Narendra Patel, Michael H. Shanik, S. Thomas Traweek, P. Sean Walsh, Michael W. Yeh, Amr H. Abdelhamid Ahmed, Allen S. Ho, Richard J. Wong, Joshua P. KlopperJing Huang, Giulia C. Kennedy, Richard T. Kloos, Peter M. Sadow

Research output: Contribution to journalArticlepeer-review


Background: Cytopathological evaluation of thyroid fine-needle aspiration biopsy (FNAB) specimens can fail to raise preoperative suspicion of medullary thyroid carcinoma (MTC). The Afirma RNA-sequencing MTC classifier identifies MTC among FNA samples that are cytologically indeterminate, suspicious, or malignant (Bethesda categories III–VI). In this study we report the development and clinical performance of this MTC classifier. Methods: Algorithm training was performed with a set of 483 FNAB specimens (21 MTC and 462 non-MTC). A support vector machine classifier was developed using 108 differentially expressed genes, which includes the 5 genes in the prior Afirma microarray-based MTC cassette. Results: The final MTC classifier was blindly tested on 211 preoperative FNAB specimens with subsequent surgical pathology, including 21 MTC and 190 non-MTC specimens from benign and malignant thyroid nodules independent from those used in training. The classifier had 100% sensitivity (21/21 MTC FNAB specimens correctly called positive; 95% confidence interval [CI] = 83.9–100%) and 100% specificity (190/190 non-MTC FNAs correctly called negative; CI = 98.1–100%). All positive samples had pathological confirmation of MTC, while all negative samples were negative for MTC on surgical pathology. Conclusions: The RNA-sequencing MTC classifier accurately identified MTC from preoperative thyroid nodule FNAB specimens in an independent validation cohort. This identification may facilitate an MTC-specific preoperative evaluation and resulting treatment.

Original languageEnglish (US)
Pages (from-to)1069-1076
Number of pages8
Issue number9
StatePublished - Sep 1 2022


  • indeterminate cytology
  • machine learning
  • medullary thyroid cancer
  • molecular diagnostics
  • molecular testing
  • thyroid nodule

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism


Dive into the research topics of 'Preoperative Identification of Medullary Thyroid Carcinoma (MTC): Clinical Validation of the Afirma MTC RNA-Sequencing Classifier'. Together they form a unique fingerprint.

Cite this