AUTHOR=Guan Haixia , Matonis Danielle , Toraldo Gianluca , Lee Stephanie L. 

TITLE=Clinical Significance of Thyroid-Stimulating Hormone Receptor Gene Mutations and/or Sodium-Iodine Symporter Gene Overexpression in Indeterminate Thyroid Fine Needle Biopsies

JOURNAL=Frontiers in Endocrinology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2018.00566

DOI=10.3389/fendo.2018.00566

ISSN=1664-2392

ABSTRACT=<p><bold>Objectives:</bold> To examine the prevalence of genetic alterations of thyroid-stimulating hormone receptor (<italic>TSHR</italic>) gene and sodium-iodine symporter (<italic>NIS</italic>) 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.</p><p><bold>Methods:</bold> Between February 2015 and September 2017, 388 consecutive FNBs with indeterminate cytology were evaluated for <italic>TSHR</italic> mutations and <italic>NIS</italic> gene overexpression using ThyroSeqV.2 next-generation sequencing (NGS) panel. Medical records were reviewed for target nodules.</p><p><bold>Results:</bold> Among 388 indeterminate FNBs, <italic>TSHR</italic> mutations and/or <italic>NIS</italic> overexpression were detected in 25 (6.4%) nodules. Ten nodules (2.6%) harbored <italic>TSHR</italic> mutations only, 7 nodules (1.8%) over-expressed <italic>NIS</italic> gene only, and 8 nodules (2.1%) had both alterations. The <italic>TSHR</italic> mutations were located between codons 281 and 640, with codon 453 being the most frequently affected. The allelic frequency of the mutated <italic>TSHR</italic> ranged from 6 to 36%. One nodule with <italic>NIS</italic> overexpression was simultaneously detected <italic>EIF1AX</italic> mutation and <italic>GNAS</italic> mutation. Nodules with <italic>TSHR</italic> mutations and/or <italic>NIS</italic> overexpression presented hyperfunctioning (<italic>n</italic> = 4), hypofunctioning (<italic>n</italic> = 5), and isofunctioning (<italic>n</italic> = 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 (3~33 mon, median 12 mon) showed grow in size.</p><p><bold>Conclusions:</bold><italic>TSHR</italic> mutations and/or <italic>NIS</italic> 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 <italic>TSHR</italic> mutations and/or <italic>NIS</italic> overexpression manifested malignant outcomes. How to use these two molecular markers in thyroid FNBs to guide our clinical practice warrants further investigation.</p>