Abstract
Follicular thyroid carcinoma (FTC) is not routinely diagnosed by a preoperative fine needle aspiration biopsy (FNAB), and the final diagnosis relies on histopathological criteria visible upon microscopic examination of the excised tumor. Several markers have been proposed as helpful in the identification of follicular thyroid tumors with malignant potential and worse prognosis, of which the specific point mutations C250T and C228T in the Telomerase Reverse Transcriptase (TERT) promoter region seem to be particularly promising. We describe a patient presenting with a large pelvic mass, in which a core needle biopsy was consistent with follicular-patterned thyroid tissue positive for a Q61R NRAS mutation and the C228T TERT promoter mutation. Upon clinical investigation, a 60-mm lesion was detected in the right thyroid lobe. The ensuing FNAB was consistent with a follicular thyroid tumor, Bethesda IV, positive for the same NRAS mutation and both the C228T and C250T TERT promoter mutations. A total thyroidectomy was performed, and a widely invasive FTC was diagnosed. Tumor tissue samples from various parts of the primary lesion were investigated for TERT promoter mutations, displaying C228T in three samples and C250T in one. Interestingly, the C228T mutations showed a coupling to areas with high Ki-67 proliferation indexes. Our data indicate that TERT promoter mutations can exhibit spatial heterogeneity in FTCs, with implications for clinical management as well as providing insights into the molecular biology underlying the tumoral etiology.
Highlights
Two somatic transversions of the Telomerase reverse transcriptase (TERT) gene promoter are recurrently demonstrated in poorly differentiated thyroid carcinomaElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.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 Follicular thyroid carcinoma (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
Molecular genetic analyses using the targeted exome-sequencing platform Oncomine Solid Tumor Panel (Ion Torrent S5, Thermo Scientific, MA, USA) and DNA extracted from formalin-fixated paraffin-embedded core-needle biopsy material revealed a Q61R NRAS mutation, and separate Sanger sequencing of the TERT promoter region revealed the C228T mutation, strengthening the suspicion of metastatic FTC
TERT promoter mutational screening is rapidly gaining ground as a confident rule-in marker of malignant properties in follicular thyroid tumors, as the occurrence of a mutation is a strong predictor of future recurrences and worse patient outcome
Summary
Two somatic transversions of the Telomerase reverse transcriptase (TERT) gene promoter (chr 5:1,295,228 C>T; termed C228T and chr5:1,295,250 C>T; C250T) are recurrently demonstrated in poorly differentiated thyroid carcinoma. 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. Little is known regarding spatial distribution of these mutations within a unique lesion, and if multi-regional sampling affects the sensitivity of the method. We here present evidence of spatial heterogeneity regarding TERT promoter mutations, and emphasize the clinical implications drawn from the results
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