Performance of a Multigene Genomic Classifier in Thyroid Nodules with Indeterminate Cytology: A Prospective Blinded Multicenter Study


Yuri E. Nikiforov, University of Pittsburgh
David L. Steward, University of Cincinnati Medical Center
Sally E. Carty, University of Pittsburgh
Rebecca S. Sippel, University of Wisconsin-Madison
Samantha Peiling Yang, National University Hospital, Singapore
Julie A. Sosa, Duke Clinical Research Institute
Jennifer A. Sipos, The Ohio State University College of Medicine
James J. Figge, St Peter's Health Partners
Susan Mandel, University of Pennsylvania Perelman School of Medicine
Bryan R. Haugen, University of Colorado School of Medicine
Kenneth D. Burman, Washington Hospital Center
Zubair W. Baloch, University of Pennsylvania Perelman School of Medicine
Ricardo V. Lloyd, University of Wisconsin-Madison
Raja R. Seethala, University of Pittsburgh
William E. Gooding, UPMC Hillman Cancer Center
Simion I. Chiosea, Washington Hospital Center
Cristiane Gomes-Lima, Washington Hospital Center
Robert L. Ferris, UPMC Hillman Cancer Center
Jessica M. Folek, St Peter's Health Partners
Raheela A. Khawaja, The Ohio State University College of Medicine
Priya Kundra, Washington Hospital Center
Kwok Seng Loh, National University Hospital, Singapore
Carrie B. Marshall, University of Colorado School of Medicine
Sarah Mayson, University of Colorado School of Medicine
Kelly L. McCoy, University of Pittsburgh
Min En Nga, Yong Loo Lin School of Medicine
Kee Yuan Ngiam, National University Hospital, Singapore
Marina N. Nikiforova, University of Pittsburgh
Jennifer L. Poehls, University of Wisconsin-Madison
Matthew D. Ringel, The Ohio State University College of Medicine
Huaitao Yang, University of Cincinnati Medical Center
Linwah Yip, University of Pittsburgh

Document Type

Journal Article

Publication Date



JAMA Oncology








© 2019 American Medical Association. All rights reserved. Importance: Approximately 20% of fine-needle aspirations (FNA) of thyroid nodules have indeterminate cytology, most frequently Bethesda category III or IV. Diagnostic surgeries can be avoided for these patients if the nodules are reliably diagnosed as benign without surgery. Objective: To determine the diagnostic accuracy of a multigene classifier (GC) test (ThyroSeq v3) for cytologically indeterminate thyroid nodules. Design, Setting, and Participants: Prospective, blinded cohort study conducted at 10 medical centers, with 782 patients with 1013 nodules enrolled. Eligibility criteria were met in 256 patients with 286 nodules; central pathology review was performed on 274 nodules. Interventions: A total of 286 FNA samples from thyroid nodules underwent molecular analysis using the multigene GC (ThyroSeq v3). Main Outcomes and Measures: The primary outcome was diagnostic accuracy of the test for thyroid nodules with Bethesda III and IV cytology. The secondary outcome was prediction of cancer by specific genetic alterations in Bethesda III to V nodules. Results: Of the 286 cytologically indeterminate nodules, 206 (72%) were benign, 69 (24%) malignant, and 11 (4%) noninvasive follicular thyroid neoplasms with papillary-like nuclei (NIFTP). A total of 257 (90%) nodules (154 Bethesda III, 93 Bethesda IV, and 10 Bethesda V) had informative GC analysis, with 61% classified as negative and 39% as positive. In Bethesda III and IV nodules combined, the test demonstrated a 94% (95% CI, 86%-98%) sensitivity and 82% (95% CI, 75%-87%) specificity. With a cancer/NIFTP prevalence of 28%, the negative predictive value (NPV) was 97% (95% CI, 93%-99%) and the positive predictive value (PPV) was 66% (95% CI, 56%-75%). The observed 3% false-negative rate was similar to that of benign cytology, and the missed cancers were all low-risk tumors. Among nodules testing positive, specific groups of genetic alterations had cancer probabilities varying from 59% to 100%. Conclusions and Relevance: In this prospective, blinded, multicenter study, the multigene GC test demonstrated a high sensitivity/NPV and reasonably high specificity/PPV, which may obviate diagnostic surgery in up to 61% of patients with Bethesda III to IV indeterminate nodules, and up to 82% of all benign nodules with indeterminate cytology. Information on specific genetic alterations obtained from FNA may help inform individualized treatment of patients with a positive test result..

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