Locally invasive classical papillary thyroid carcinoma with TSH receptor I568T mutation: case report

Abstract

Summary Autonomous thyroid adenomas are caused by activating mutations in the genes encoding the thyroid-stimulating hormone receptor (TSHR) or mutations in the Gas subunit of the TSHR. Nodules with suspicious sonographic features should be submitted to fine-needle aspiration. Additional molecular testing may be performed to characterize the thyroid nodule’s malignant potential further. We present a patient who underwent whole-transcriptome RNA-sequencing that indicated a TSHR I568T mutation after an ultrasound showed suspicious sonographic features and fine-needle aspiration was ‘suspicious for malignancy’. The patient underwent thyroid resection and was found to have a locally invasive classical papillary thyroid carcinoma. Most reports of TSHR I568T mutation have been seen in patients with benign thyroid conditions. While there is insufficient data to suggest that the TSHR I568T mutation causes aggressive thyroid malignancy, we believe clinicians who identify the presence of this mutation on genome sequencing should be cautious about the possibility of locally invasive thyroid malignancy, especially when associated with Bethesda V cytopathology. Learning points Germline and somatic activating mutations in the genes coding for the thyroid-stimulating hormone receptor (TSHR) have been frequently reported in familial and sporadic autonomous thyroid adenomas and non-autoimmune hyperthyroidism. Most reports of TSHR I568T mutation have been detected in patients with benign thyroid conditions. We present a patient who underwent whole-transcriptome RNA-sequencing that indicated a TSHR I568T mutation and subsequently underwent thyroid resection and was found to have a locally invasive classical papillary thyroid carcinoma. Clinicians who identify the presence of TSHR I568T mutation on genome sequencing should be cautious about the possibility of locally invasive thyroid malignancy, especially when associated with Bethesda V cytopathology.

Recombinant Human TSH Fails to Induce the Proliferation and Migration of Papillary Thyroid Carcinoma Cell Lines

“…Therefore, to eliminate the problem of low TSHR levels, we generated clones of K1 and TPC-1 cells with controllable wt-TSHR expression, using the Lenti-X Tet-on Advanced system. The wild-type receptor was selected due to its prevalence in PTC patients and its increased constitutive activity compared to many mutations [34,35]. Plasmids were constructed containing the wild-type TSHR gene, and the successful construction was verified with DNA agarose gel electrophoresis ( Figure A2a ).…”

“…To multiply the TSH signal reception, cell clones were created to overexpress the TSHR receptor in a controllable manner. Instead of using mutant types of the TSHR gene (many of which have been reported), the wild type allele was selected since most TSHR mutations are associated with follicular thyroid carcinoma (FTC) much more often compared to PTC, where mutations are relatively rare [34]. Additionally, wild-type TSHR ( wt-TSHR ) has been reported to possess a high level of constitutive activity in the wild-type form [35]; thus, overexpressing would significantly multiply signal reception and transduction.…”

Risk of malignancy in cytologically indeterminate thyroid nodules harboring thyroid stimulating hormone receptor mutations

“…This study was inspired by a query after the management of an aggressive case of PTC where the index lesion was positive for a TSHRpI568T mutation ( 12 ). We showed that this variant is extremely rare, representing only ~0.7% of all molecular findings in the Afirma database.…”

“…The current study was influenced by an interesting case report of an aggressive thyroid malignancy with a TSHRpI568T mutation ( 12 ). Briefly, a 53-year-old female underwent a fine needle aspiration biopsy (FNAB) of a thyroid nodule with resultant Bethesda V cytology and Afirma ® Xpression Atlas (XA) testing that revealed a TSHRpI568T mutation ( 13 ).…”