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JAMA Oncol. 2018 Nov 8. doi: 10.1001/jamaoncol.2018.4616. [Epub ahead of print]

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

Author information

Department of Otolaryngology, Head and Neck Surgery, University of Cincinnati Medical Center, Cincinnati, Ohio.
Division of Endocrine Surgery, University of Pittsburgh, Pittsburgh, Pennslyvania.
Division of Endocrine Surgery, University of Wisconsin, Madison.
Endocrinology Division, Department of Medicine, National University Hospital, Singapore, Singapore.
Section of Endocrine Surgery, Department of Surgery, Duke Cancer Institute and Duke Clinical Research Institute, Duke University, Durham, North Carolina.
Department of Surgery, University of California, San Francisco.
Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University School of Medicine, Columbus.
Diabetes & Endocrine Care, St Peter's Health Partners, Rensselaer, New York.
Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora.
Department of Medicine, Endocrinology Section, MedStar Washington Hospital Center, Washington, DC.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison.
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Biostatistics Facility, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.
Departments of Otolaryngology and Immunology, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.
Department of Otolaryngology-Head and Neck Surgery, National University Hospital, Singapore.
Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado.
Department of Pathology, National University Hospital, Singapore.
Department of General Surgery, University Surgical Cluster, National University Hospital, Singapore.
Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin, Madison.
Department Pathology, University of Cincinnati Medical Center, Cincinnati, Ohio.



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.


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.


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.


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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