Abstract
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 between codons 281 and 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 (3~33 mon, median 12 mon) 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.
Highlights
In the human thyroid, thyroid-stimulating hormone (TSH) activates both the cyclic adenosine monophosphate and the phospholipase C-diacylglycerol regulatory cascades
The TSH receptor (TSHR) mutations were located between codons 281–640
We have investigated the clinical significance and diagnostic utility of TSHR mutations and/or NIS overexpression in thyroid FNB specimens with indeterminate cytology
Summary
Thyroid-stimulating hormone (TSH) activates both the cyclic adenosine monophosphate (cAMP) and the phospholipase C-diacylglycerol regulatory cascades The former cascade positively controls the hormone-producing function and growth of thyrocytes, while the latter cascade contributes to the generation of the intracellular signals myoinositol-1.4.5-triphosphate (1,4,5-PIP3) and diacylglycerol, both of which act on thyrocytes to increase protein iodination and thyroid hormone synthesis [1,2,3,4,5,6]. These fundamental roles of TSH in regulating thyroid growth and function are attained by binding to its receptor, TSH receptor (TSHR), and can be mimicked by activating mutations of the TSHR. NIS function results in a 20- to 40-fold elevation of iodide concentration with respect to the iodide level in circulating blood [7,8,9]
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