Risk of malignancy in cytologically indeterminate thyroid nodules harboring thyroid stimulating hormone receptor mutations.
Dorota Whitmer, John E Phay, Shelby Holt, Benjamin O'Donnell, Jay Nguyen, Dennis Joseph, Anthony Chi, Shuyang Wu, Yangyang Hao, Jing Huang, Joshua P Klopper, Richard T Kloos, Giulia C Kennedy, Joyce Shin
Author Information
Dorota Whitmer: Department of Endocrinology, Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, OH, United States.
John E Phay: Department of Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.
Shelby Holt: Department of Surgery, UT Southwestern Medical Center, Dallas, TX, United States.
Benjamin O'Donnell: Wexner Medical Center, The Ohio State University, Columbus, OH, United States.
Jay Nguyen: Lake Cumberland Regional Hospital, Somerset, KY, United States.
Dennis Joseph: Endocrinology Center of Lake Cumberland, Somerset, KY, United States.
Anthony Chi: Department of Pathology, Mid-Atlantic Permanente Medical Group, Rockville, MD, United States.
Shuyang Wu: 8Department of Research and Development, Veracyte, South San Francisco, CA, United States.
Yangyang Hao: 8Department of Research and Development, Veracyte, South San Francisco, CA, United States.
Jing Huang: 8Department of Research and Development, Veracyte, South San Francisco, CA, United States.
Joshua P Klopper: Department of Medical Affairs, Veracyte, South San Francisco, CA, United States.
Richard T Kloos: Department of Medical Affairs, Veracyte, South San Francisco, CA, United States.
Giulia C Kennedy: 8Department of Research and Development, Veracyte, South San Francisco, CA, United States.
Joyce Shin: Department of Endocrine Surgery, Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, OH, United States.
Objectives: To evaluate the frequency and risk of malignancy of TSHRpI568T mutations discovered in indeterminate thyroid nodules (ITN) within the Veracyte CLIA laboratory undergoing Afirma Genomic Sequencing Classifier (GSC) testing, and to evaluate a broader cohort of TSHR variants and their categorization as Afirma GSC benign (GSC-B) or suspicious (GSC-S). Finally, we seek to assess the risk of malignancy (ROM) of this group of TSHR mutated ITN in the GSC-S category. Methods: ITN submitted to Veracyte for Afirma GSC testing between October 2017 and February 2022 were analyzed for TSHR variants and rates of GSC-B and GSC-S were calculated based upon BIII or IV cytology, by TSHR variant codon amino acid (AA) substitution, age, and gender. For GSC-S samples, surgical pathology reports were requested, and the rate of malignancy was calculated. Results: Five percent of the ITN samples harbored an isolated TSHR variant and 5% of those were classified as GSC-S. Among TSHRpI568T samples, 96% were GSC-B and of the GSC-S samples, 21% were malignant. Among an unselected group of TSHR, absent TSHRpI568T mutations, 16.3% of GSC-S samples were malignant, all but one with codon mutations in the transmembrane subdomains of the TSHR. This prompted a dedicated evaluation of transmembrane codons which revealed a malignancy rate of 10.7% among GSC-S nodules. In total, 13/85 (15.3%) TSHR mutated ITN with Afirma GSC-S results were found to be malignant. Conclusions: TSHR variants are rare in ITN, and most are categorized as benign under Afirma GSC testing which carries a < 4% risk of malignancy. For GSC-S ITN with TSHR mutations, the risk of malignancy is ≥= 15%, which is clinically meaningful and may alter treatment or monitoring recommendations for patients.
