TERT Promoter Mutation Spatial Heterogeneity in a Metastatic Follicular Thyroid Carcinoma: Implications for Clinical Work-Up
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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.
KeywordsTERT Thyroid cancer Metastasis Mutation Spatial heterogeneity
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 and anaplastic thyroid carcinoma, but also occur in poor-prognosis cases of well-differentiated thyroid carcinomas (papillary thyroid carcinoma (PTC), and follicular thyroid carcinoma (FTC) . TERT encodes the catalytic subunit of telomerase, an enzyme providing immortalization though the maintenance of telomere length, a fundamental hallmark of malignant tumors. The C228T and C250T promoter mutations alter the transcription output of the TERT gene, thereby thought to confer the tumor with a selective growth advantage.
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. We here present evidence of spatial heterogeneity regarding TERT promoter mutations, and emphasize the clinical implications drawn from the results.
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. 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 . 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. As the TERT promoter mutations were spatially heterogeneous in this FTC, this indicates expansions of specific C228T and C250T clones that could merit further attention regarding the underlying molecular biological mechanisms driving metastatic spread. Indeed, similar observations have been made in meningioma . In our case, the initial finding of dissimilar mutations generated an uncertainty regarding the relation between the thyroid tumor and the pelvic lesion, as the fact that FTCs can harbor both the C228T and C250T mutations was not obvious at the time of diagnosis. The notion that FTCs might display a spatial heterogeneity regarding these mutations is therefore of clinical importance.
In the primary tumor, we observed an association between high proliferation and the C228T mutation. Given the presence of this mutation also in the metastatic lesion, it is likely that the metastasis originated from one of these areas with high Ki-67 proliferation index. As local differences in TERT promoter mutational status could affect the interpretation of the analysis, a multi-regional sampling methodology or sampling of areas with high Ki-67 indexes could in theory increase the accuracy of the method.
We conclude that TERT promoter mutations can exhibit spatial heterogeneity in FTCs, providing insights to molecular underpinnings as well as clinical management of the disease.
The study was supported by grants from the Swedish Cancer Society, the Stockholm County Council and the Cancer Research Funds of Radiumhemmet.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Ethical approval has been approved by the local ethical committee, and informed consent has been obtained.
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