Molecular Testing Has Limited Utility in the Surgical Evaluation of Bethesda III Thyroid Nodules

William H. Scola, Samantha M. Linhares, Rachel S. Handelsman, Omar Picado, Zahra F. Khan, Josefina C. Farrá, John I. Lew

Research output: Contribution to journalArticlepeer-review


Background: The Bethesda System for Reporting Thyroid Cytopathology has 6 diagnostic categories, each with an implied cancer risk of malignancy (ROM). Bethesda III, defined as atypia or follicular lesions of undetermined significance (AUS/FLUS) on fine needle aspiration (FNA), has an indeterminate ROM. This study investigates the utility of Afirma Gene Expression Classifier (GEC) and Thyroid Sequencing (ThyroSeq) molecular testing to predict malignancy in AUS/FLUS thyroid nodules. Methods: A retrospective review of prospectively collected data of 1457 patients with index thyroid nodules who underwent FNA and thyroidectomy at a single academic institution was performed. Use of GEC or ThyroSeq for AUS/FLUS thyroid nodules was examined. GEC testing was reported benign or suspicious for malignancy whereas ThyroSeq testing was reported on a spectrum of low, intermediate or high ROM. Descriptive statistics were utilized to compare the ROM among AUS/FLUS thyroid nodules. Results: Of 1457 patients with FNA thyroid cytology, 359 (25%) corresponded to AUS/FLUS results. There were 132 (37%) patients with GEC testing and 88 (24%) had ThyroSeq testing. ROM without GEC or ThyroSeq testing was 49%, whereas ROM with suspicious GEC was 55%. ROM with positive ThyroSeq was 73%. Among ThyroSeq patients, 43 had intermediate-risk mutations with 60% malignancy, and 23 had high-risk mutations with 96% malignancy (P < 0.01). Conclusion: Surgical patients with AUS/FLUS thyroid nodules have a high ROM. High-risk ThyroSeq testing may have some utility in predicting malignancy, but GEC and intermediate-risk TGC results have limited value. Surgeons should carefully consider the utility of molecular tests to determine surgical resection.

Original languageEnglish (US)
Pages (from-to)209-213
Number of pages5
JournalJournal of Surgical Research
StatePublished - Dec 2021


  • Bethesda system
  • FNA
  • Molecular testing
  • Risk of malignancy
  • Thyroid nodules

ASJC Scopus subject areas

  • Surgery


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