Category: Thyroid

Monitor: 23


Thursday, Apr 25
1:00 PM – 1:30 PM

Objective :

In thyroid, NTRK fusions involving the NTRK1 or NTRK3 genes are found in papillary thyroid carcinomas (PTC) and poorly differentiated thyroid carcinomas. Recently, a selective pan-TRK inhibitor, Larotrectinib, was approved by the FDA for treatment of patients with TRK fusion-positive cancers based on an overall high response rate. In addition to diagnostic utility of NTRK detection in thyroid fine needle aspiration (FNA) samples, testing for NTRK fusion may be used to select patients for targeted therapy. In this study, we evaluated the frequency of detection of NTRK fusions in FNA samples and their potential therapeutic utility.


Methods :

ThyroSeq v3 GC test detects all types of NTRK1 and NTRK3 fusions by targeted sequencing of known fusion types and detecting novel fusions by differential expression of NTRK mRNA. Retrospective analysis was performed to determine the frequency of NTRK fusions in consecutive FNA samples tested from November 2017 until December 2018 and in selected surgically removed thyroid tumors.

Results :

Out of14,759 tested FNA samples, NTRK fusions were detected in 98  cases, including 90/13,832 (0.7%) Bethesda III-V, 2/624 (0.3%) Bethesda II, and 6/303 (2%) Bethesda VI cytology. Among resected tumors, 15 PTC were positive for NTRK fusions. Overall, 90% of all detected fusions were NTRK3 and 10% NTRK1. These included 96% of known fusion types and 4% of novel fusions with high expression of the tyrosine-kinase domain. Among surgically removed tumors, 7 patients had distant metastasis. One patient with iodine-resistant PTC with multiple soft tissue, pulmonary, and bone metastases diagnosed 4 years after initial surgery received treatment with Larotrectinib and had a partial response.

Discussion :

NTRK fusions are well-established oncogenic drivers in thyroid cancer, although their frequency in thyroid nodules remained unknown. Our analysis of a large cohort of thyroid nodules allowed us to establish the prevalence of these fusions in various cytological groups of FNA samples. The study of surgically removed tumors showed that many tumors driven by NTRK fusions had hematogenous spread, raising a possibility that these fusions may serve as an unfavorable prognostic marker for thyroid cancer.

Conclusion :

NTRK fusions were detected by ThyroSeq in 0.7% of consecutive FNA samples with indeterminate cytology. NTRK3 fusions were significantly more common than NTRK1, and 4% of all detected fusion types were novel functional fusions. In surgically removed cancer samples, these fusions were frequently found in cases with distant metastasis and serve as a promising therapeutic target.



Linwah Yip

University of Pittsburgh Medical Center


Rajeev Dhupar

Assistant Professor
University of Pittsburgh Medical Center

Assistant Professor of Cardiothoracic Surgery
Chief, Thoracic Surgery, VAMC of Pittsburgh
Department of Cardiothoracic Surgery

Steven Hodak

NYU Langone Health

Professor, Department of Medicine
Chief, Endocrinology at Tisch Hospital
Director, Glycemic Control at Tisch Hos
Director, Medicine Faculty Group Practice
Assoc Dir of Clinical Aff, Div of Endocrinology

Laura Favazza

Molecular and Genomic Pathology Fellow
University of Pittsburgh Medical Center

Molecular and Genomic Pathology Fellow

Seza Gulec

Surgical Oncologist
Aventura Hospital and Medical Center

Dr. Seza Gulec is a Surgical Oncologist and a Nuclear Medicine physician. He is board certified in surgery and nuclear medicine and fellowship trained in surgical oncology. Dr. Gulec received his medical degree at Ankara University College of Medicine, Ankara, Turkey. He was trained in surgery at Louisiana State University Health Sciences Center, New Orleans, LA, in nuclear medicine and nuclear oncology at the Memorial Sloan-Kettering Cancer Center, New York, NY, and in surgical oncology and endocrinology at the John Wayne Cancer Institute, Santa Monica, CA. Dr. Seza Gulec is a Professor of Surgery, Nuclear Medicine, and Radiology. He is Chief of Surgical Oncology and Endocrinology at Florida International University - Herbert Wertheim College of Medicine. He is also the Chairman of Department of Surgery at Aventura Hospital and Medical Center. Dr. Gulec's areas of clinical expertise include treatment of thyroid and parathyroid diseases, carcinoid and neuroendocrine tumors, primary and metastatic liver cancers, pancreatic cancer, melanoma, and breast cancer. He currently leads the Thyroid Center of Excellence Program at the Aventura Hospital and Medical Center.

Sally Carty

University of Pittsburgh Medical Center


Yuri E. Nikiforov

Vice Chair, Dept of Pathology.
UPMC, Pennsylvania

Dr. Nikiforov is Professor of Pathology and Vice Chair at the Department of Pathology, University of Pittsburgh where he also serves as Director of the Division of Molecular & Genomic Pathology. He has published over 170 peer-reviewed articles and over 15 book chapters, and is a senior editor of the textbook “Diagnostic Pathology and Molecular Genetics of the Thyroid.” His research program is funded by the National Institute of Health and focused on molecular genetics of thyroid cancer, thyroid cancer diagnostics, and molecular mechanisms of chromosomal rearrangements. He is an elected member of the American Society for Clinical Investigation and a recipient of the 2007 Van Meter Award from the American Thyroid Association, 2014 Light of Light Foundation Honorary Award, 2016 Aldo Pinchera Award from the Italian Thyroid Carcinoma Observatory, and 2017 Sidney H. Ingbar Distinguished Lectureship Award the American Thyroid Association.

Marina N. Nikiforova

Director, Molecular and Genomic Pathology Lab
University of Pittsburgh

Dr. Nikiforova is a Professor of Pathology and Director of the Molecular & Genomic Pathology Laboratory at UPMC where she also serves as the Director of Molecular Oncology Services. She has published 159 peer reviewed articles and serves on multiple committees in the field of Molecular Genomics, including the Association of Molecular Pathology, the College of American Pathologists, and the American Thyroid Association.