TERT promoter mutational screening as a tool to predict malignant behaviour in follicular thyroid tumours—three examples from the clinical routine

Abstract

Follicular thyroid adenomas (FTAs) and carcinomas (FTCs), collectively the most common thyroid neoplasms, constitute a significant clinical challenge since histological evidence of invasive behaviour is required for a malignant diagnosis. Small subsets of FTAs relapse as manifest malignant FTCs, indicating that histology is not always adequate to predict malignant potential. Lately, recurrent mutations in the promoter of the Telomerase reverse transcriptase (TERT) gene have been coupled to FTCs, whereas FTAs usually lack this aberrancy. We describe three patients with follicular thyroid tumours in which TERT promoter mutational screening was employed as part of the clinical work-up to pinpoint malignant potential. In two retrospective analyses of seemingly benign lesions, the detected mutations predicted future skeletal metastases, and in one prospective case, the mutational screening led to a different clinical management of the afflicted patient. We therefore consider TERT promoter mutational screening an adjunct tool of value in equivocal cases.

TERT Promoter Mutation Spatial Heterogeneity in a Metastatic Follicular Thyroid Carcinoma: Implications for Clinical Work-Up

“…Moreover, as TERT immunohistochemistry displays poor correlation to overall mRNA expression in FTCs, mutational screening remains the most clinically consistent method to detect cases with aberrancies in the TERT axis [8]. In all, TERT promoter mutational screening should be considered as a reliable complimentary diagnostic marker in equivocal FT-UMP cases as well as a prognostication tool for FTCs in general [2,4]. Until now, TERT promoter mutations have not been considered as subclonal events in thyroid cancer, and no clear guidelines as to how extensive the mutational testing should be in terms of numbers of tissue blocks submitted for analysis exist.…”

“…TERT promoter mutational screening has been shown to reveal malignant potential of follicular tumors of uncertain malignant potential (FT-UMPs) and identify patients with PTC and FTC at risk for recurrence [1][2][3][4][5][6][7], suggesting that the implementation of this analysis is an effective method complementing routine analyses when diagnosing thyroid tumors. Even so, little is known regarding spatial distribution of these mutations within a unique lesion, and if multi-regional sampling affects the sensitivity of the method.…”

Metastatic Anaplastic Thyroid Carcinoma in Complete Remission: Morphological, Molecular, and Clinical Work-Up of a Rare Case

“…For TERT, bi-directional Sanger sequencing of the promoter region interrogating the two mutational hotspots C228T and C250T was performed using the Genetic Analyzer 3500, Applied Biosystems, CA, USA [9], and a conventional protocol in a clinically accredited setting. The same Sanger methodology was used for exons 4 to 8 of the TP53 gene, to verify the mutation found through NGS.…”

Spatial Distribution Patterns of Clinically Relevant TERT Promoter Mutations in Follicular Thyroid Tumors of Uncertain Malignant Potential

“…[2][3][4][5][6][7][8][9] In contrast, TERT promoter mutational sequencing has been suggested to be a simple yet reliable method to identify follicular thyroid tumors at risk of disseminated disease. [10][11][12][13][14][15][16][17][18][19][20][21] In general, two recurrently observed mutations of the TERT promoter (denoted C228T and C250T) are reported in various forms of thyroid malignancies, with frequencies around 15-20% in well-differentiated thyroid carcinomas (FTCs and papillary thyroid carcinomas; PTCs) and much higher occurrence (50-90%) in poorly differentiated thyroid carcinomas (PDTCs) and undifferentiated (anaplastic) thyroid carcinomas (ATCs). 10,15,[17][18][19]22 Moreover, FTCs and PTCs with TERT promoter mutations usually exhibit worse prognosis compared to wildtype cases, and are often found in older patients with tumors displaying extrathyroidal extension and more advanced tumor stages.…”