Autonomous thyroid nodule detected by molecular testing with next-generation sequencing
A 35-year-old woman with a medical history significant for anxiety and recurrent episodes of silent or subacute lymphocytic thyroiditis was evaluated in a tertiary care endocrine clinic for symptoms of palpitations.
She was initially evaluated for subclinical hyperthyroidism in February 2013 with a thyroid-stimulating hormone level that ranged from 0.04 mIU/L to 0.14 mIU/L and normal free thyroxine and total triiodothyronine levels that spontaneously evolved through mild hypothyroidism with a TSH of 7.17 mIU/L before normalizing to a TSH of 1.93 mIU/L. Thyroid peroxidase antibody was less than 1 IU/mL (normal < 5 IU/mL) and thyroid-stimulating immunoglobulin titers were negative.
Stephanie L. Lee
The patient reported that her thyroid was never tender. She was diagnosed with painless subacute lymphocytic thyroiditis. At the time of her initial evaluation, she was noted to have a 1.2 cm x 0.8 cm x 1.3 cm (sagittal x anterioposterior x transverse) heterogeneous isoechoic nodule with indistinct margins. Two years later, she had a repeat episode of tachycardia with TSH of 0.04 mIU/L. She returned to the endocrine clinic as a repeat thyroid ultrasound demonstrated growth of the nodule to 2 cm x 1 cm x 1.8 cm (Figure 1).
Imaging, molecular testing
A fine-needle aspiration biopsy showed a Hürthle cell lesion of undetermined significance with a Bethesda III classification. Cells from one of the fine-needle aspiration passes were sent for molecular testing (next-generation sequencing panel for thyroid cancer, ThyroSeq v.2), which revealed a TSH-receptor mutation (M453T) identified at a low level (with allelic frequency of 8%, which corresponds to heterozygous mutation present in 16% of the cells).
Somatic mutations of TSH-receptor gene are known to frequently occur in autonomously functioning thyroid nodules (AFTN). Mutations in this particular hotspot — codon 453 — have been reported primarily in benign thyroid nodules and frequently in AFTN.
Based on this finding, a radioactive-iodine scintigraphy scan was ordered that showed a single area of uptake corresponding with the left lobe nodule (Figure 2). Radioactive iodine uptake in the remainder of the thyroid was suppressed. A large field of view was obtained to exclude ectopic uptake along the thyroglossal duct path or the anterior mediastinum. The measured radioactive iodine uptake was lower than normal at 3.8% at 4 hours (expected, 5%-15%) and 4.7% at 24 hours (expected, 15%-30%). This nuclear scan with a low radioactive iodine uptake was thought to be compatible with a mixed picture of subacute thyroiditis causing the lack of radioactive iodine uptake in the gland surrounding a “hot” or AFTN.
There is evidence of somatic mutations of the TSH receptor in toxic adenomas, and although the incidence of these mutations in the literature varies, it has been reported to be as high as 60% to 80%. The presence of TSH-receptor mutations has also been seen in areas of autonomy in patients with multinodular goiter and been associated with thyroid cancer. The M453T mutation is a replacement of methionine by threonine in amino acid number 453 located in exon 10 of the thyrotropin-receptor gene. The M453T gene mutation has been reported in various case reports and case series to be associated with autonomous toxic adenomas, autonomous nodules in multinodular goiter and congenital non-autoimmune hyperthyroidism, and it also has been seen in papillary thyroid cancer.
This activating mutation of the TSH receptor increases the TSH receptor-cAMP pathway without the binding of the TSH ligand. The sodium-iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates active iodide transport into the thyroid gland. Normally, TSH activation of the TSH receptor increases NIS gene expression. High expression of the sodium-iodate transporter NIS(SLC5A5) gene in this sample provided additional evidence in support of AFTN caused by an activating mutation M453T of the TSH receptor.
Gene sequencing changes practice
Now, with the availability of molecular testing, a mutation found in this patient after fine-needle aspiration prompted a radioiodine scan when her TSH level would not have otherwise indicated performing the imaging at the time. The advantage of knowing this nodule is autonomous will allow future monitoring of hyperthyroidism and avoiding fine-needle aspiration if the nodules grows.
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- Stephanie L. Lee, MD, PhD, ECNU, is an Endocrine Today Editorial Board member. She is associate professor of medicine and director of thyroid health in the Section of Endocrinology, Diabetes and Nutrition at Boston Medical Center. She can be reached at Boston Medical Center, 88 E. Newton St., Boston, MA 02118; email: firstname.lastname@example.org.
- Poorani Goundan, MBBS, is an instructor at Boston Medical Center.
Disclosure: Lee and Goundan report no relevant financial disclosures.