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

Abstract

ObjectivesTo evaluate the frequency and risk of malignancy of TSHRpI568T mutations discovered in indeterminate thyroid nodules (ITN) within the Veracyte CLIA laboratory undergoing Afirma® Genomic Sequencing Classifier (GSC) testing, and to evaluate a broader cohort of TSHR variants and their categorization as Afirma GSC benign (GSC-B) or suspicious (GSC-S). Finally, we seek to assess the risk of malignancy (ROM) of this group of TSHR mutated ITN in the GSC-S category.MethodsITN submitted to Veracyte for Afirma GSC testing between October 2017 and February 2022 were analyzed for TSHR variants and rates of GSC-B and GSC-S were calculated based upon BIII or IV cytology, by TSHR variant codon amino acid (AA) substitution, age, and gender. For GSC-S samples, surgical pathology reports were requested, and the rate of malignancy was calculated.ResultsFive percent of the ITN samples harbored an isolated TSHR variant and 5% of those were classified as GSC-S. Among TSHRpI568T samples, 96% were GSC-B and of the GSC-S samples, 21% were malignant. Among an unselected group of TSHR, absent TSHRpI568T mutations, 16.3% of GSC-S samples were malignant, all but one with codon mutations in the transmembrane subdomains of the TSHR. This prompted a dedicated evaluation of transmembrane codons which revealed a malignancy rate of 10.7% among GSC-S nodules. In total, 13/85 (15.3%) TSHR mutated ITN with Afirma GSC-S results were found to be malignant.ConclusionsTSHR variants are rare in ITN, and most are categorized as benign under Afirma GSC testing which carries a < 4% risk of malignancy. For GSC-S ITN with TSHR mutations, the risk of malignancy is ≥= 15%, which is clinically meaningful and may alter treatment or monitoring recommendations for patients.

Combined Afirma Genomic Sequencing Classifier and TERT promoter mutation detection in molecular assessment of Bethesda III–VI thyroid nodules

“…Recently, both original research and literature review have demonstrated that certain molecular variants lessen the ROM in GSC-S ITN samples from a standard ROM of 50% with a GSC-S result by the GSC ensemble classifier. For example, Whitmer et al 23 have reported Afirma will classify 95% of indeterminate thyroid nodules harboring thyroid stimulating hormone receptor (TSHR) variants as GSC-B, which represents an enhancement beyond solely reporting the presence or absence of these variants. In contrast, when the GSC ensemble classifier reports them as GSC-S, the risk of malignancy is ≥15%.…”

“…In contrast, when the GSC ensemble classifier reports them as GSC-S, the risk of malignancy is ≥15%. 23,24 Such personalized and nuanced information may reassure clinicians and patients who prefer an active surveillance plan for ITN with a low (although not benign) molecular risk of malignancy. Given Afirma XA findings may alter clinical decisions beyond the GSC-B and GSC-S call, as well as the prognostic information that may be gleaned from the presence of specific molecular variants and fusions, the Afirma report automatically includes XA information for all GSC-S and, as will be described, nodules with BV and BVI cytology as of April 2023.…”

“…have reported Afirma will classify 95% of indeterminate thyroid nodules harboring thyroid stimulating hormone receptor ( TSHR ) variants as GSC‐B, which represents an enhancement beyond solely reporting the presence or absence of these variants. In contrast, when the GSC ensemble classifier reports them as GSC‐S, the risk of malignancy is ≥15% 23,24 . Such personalized and nuanced information may reassure clinicians and patients who prefer an active surveillance plan for ITN with a low (although not benign) molecular risk of malignancy.…”

Оптимізація Алгоритму Доопераційної Діагностики Вузлових Утворень При Хворобі Грейвса

“…На сьогодні хвороба Грейвса (ХГ) розглядається як класичне автоімунне захворювання, в якому головну патогенетичну роль відіграють стимулюючі антитіла (АТ) до рецептора тиреотропного гормону (рТТГ), які здатні стимулювати ріст і функцію тиреоцитів [1]. Оскільки більшість вузлів щитоподібної залози (ЩЗ), включно зі злоякісними, зберігають експресію рТТГ [2,3], існує ймовірність того, що стимулюючий ефект може бути результатом зв'язування АТ з рТТГ вузлових утворень (ВУ). Цей процес може відбуватись у тиреоцитах, що мають соматичні генетичні/епігенетичні зміни, які спричиняють зростання ВУ.…”