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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Endocrinol. | doi: 10.3389/fendo.2018.00566

Clinical significance of thyroid-stimulating hormone receptor gene mutations and/or sodium-iodine symporter gene overexpression in indeterminate thyroid fine needle biopsies

 Haixia Guan1, Danielle Matonis2, Gianluca Toraldo2 and  Stephanie Lee2*
  • 1The First Affiliated Hospital of China Medical University, China
  • 2Boston Medical Center, United States

Objectives: To examine the prevalence of genetic alterations of thyroid-stimulating hormone receptor (TSHR) gene and sodium-iodine symporter (NIS) in a series of thyroid fine needle biopsy (FNB) specimens with indeterminate cytology, and to assess the correlation of the type of genetic changes with clinical features and follow-up results in the target thyroid nodule.
Methods: Between February 2015 and September 2017, 388 consecutive FNBs with indeterminate cytology were evaluated for TSHR mutations and NIS gene overexpression using ThyroSeqV.2 next-generation sequencing (NGS) panel. Medical records were reviewed for target nodules.
Results: Among 388 indeterminate FNBs, TSHR mutations and/or NIS overexpression were detected in 25 (6.4%) nodules. Ten nodules (2.6%) harbored TSHR mutations only, 7 nodules (1.8%) over-expressed NIS gene only, and 8 nodules (2.1%) had both alterations. The TSHR mutations were located in codons 281-640, with codon 453 being the most frequently affected. The allelic frequency of the mutated TSHR ranged from 6% to 36%. One nodule with NIS overexpression was simultaneously detected EIF1AX mutation and GNAS mutation. Nodules with TSHR mutations and/or NIS overexpression presented hyperfunctioning (n=4), hypofunctioning (n=5) and isofunctioning (n=3) on the available thyroid scintigraphies. Eight cases accompanied with hyperthyroidism in which only 1 was caused by the target nodule. Evidence of co-existing autoimmune thyroid disease (AITD) and multinodular goiter were found in 52% and 52% of cases, respectively. Seven nodules underwent surgeries and all were benign on final pathology. None of 9 nodules with follow-up by ultrasound (3m~ 33m, median 12m) showed grow in size.
Conclusions: TSHR mutations and/or NIS overexpression can be detected in pre-operative FNB specimens using the NGS approach. These genetic alterations occurred in 6.4% thyroid nodules in this consecutive series with indeterminate cytology. They present not only in hyperfunctioning nodules but also in hypo- or iso-functional nodules, indicating their prevalence may be higher than previously expected. Co-existing AITD was common in cases with these molecular alterations. None of our patients with TSHR mutations and/or NIS overexpression manifested malignant outcomes. How to use these two molecular markers in thyroid FNBs to guide our clinical practice warrants further investigation.

Keywords: Thyroid Nodule, Molecular markers, diagnosis, Fine needle biopsy, TSHR, NIS, genetic alterations

Received: 15 Jun 2018; Accepted: 05 Sep 2018.

Edited by:

Susanne Neumann, National Institutes of Health (NIH), United States

Reviewed by:

Rocco Bruno, Independent researcher
Eijun Nishihara, Kuma Hospital, Japan  

Copyright: © 2018 Guan, Matonis, Toraldo and Lee. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD, PhD. Stephanie Lee, Boston Medical Center, Boston, 02118, Maryland, United States,