The transformation from thyroid papillary carcinoma to anaplastic carcinoma point of view

Papillary thyroid carcinoma (PTC) is the most common type of thyroid neoplasm and generally well-behaved with favorable survival rates. However, a small subset of these well-differentiated tumors can unfortunately transform into anaplastic thyroid carcinoma (ATC) with highly aggressive behavior and dismal prognosis (1-4). As widespread adoption of next generation sequencing (NGS), a number of molecular alterations involved in this transition had been delineated. Previous studies supported the hypothesis that ATC might arise from dedifferentiation of preexisting PTC tumor stepwise (2,5,6). In consideration of their totally different outcomes, it is of utmost importance to recognize the rare aggressive PTC. In addition, more precise sub-classification and prognostic evaluation system of thyroid carcinoma need be established.

Much progress has been made in uncovering molecular alterations that were responsible for thyroid carcinogenesis and progression (5-8). Comprehensive molecular studies have shed lights on several genetic mutations or chromosomal abnormalities in both ATC and PTC based on NGS techniques (9-11). By comparing with their genome characteristics, mRNA and protein expressions, the results showed greatly overlapping between ATCs and PTCs (5,6,12). However, in spite of the homogeneity, ATCs present impaired gene regulations according to cell cycle control and proliferation rate (5,6). A number of genetic alterations have been investigated to play a role in anaplastic transformation, including derangement of the E-cadherin/catenin complex, additional mutation of TP53, bcl-2, cyclin D1, β-catenin, c-myc and genetic alterations in BRAF, RAS and PIK3CA genes (1,3,10). To date, the timing or sequence of the genetic alterations that occur during PTC progression is still obscure. Some previous studies described BRAF and PI3KCA mutation as beneficial events for ATC formation, and TERT promotor mutation was not involved (2,10,13,14). In another research, by studying concomitant ATC and PTC samples, BRAF and PI3KCA mutations were found more prevalent than in de novo ATC (8).

In order to uncover the risk factors for anaplasia transformation, Oishi et al. investigated genetic alterations of PTC and ATC components in 27 tumors in which anaplastic carcinoma coexisted with antecedent papillary carcinoma. In accordance with many other studies (10,13), Oishi et al. present that expression of p53, loss of TTF-1 and SWI/SNF mutations are associated with transforming to ATC, which might be late events for tumor progression (15). Besides, the present study holds quite a different view about the role of TERT promotor mutation. The researchers demonstrate that PTCs harboring TERT promotor mutation have aggressive behaviors and are more likely to transform into ATC (15). It’s the first time to place TERT mutation as a high risk for anaplastic formation.

Clinicians are badly in need of a reliable biomarker to predict prognosis and offer intervention at early stage for those aggressive PTC patients. BRAF mutation, as the most common genetic alteration in PTCs, is existing in more than 60% PTCs and also prevalent in ATCs (4,9). Although it has a high specificity for thyroid cancer, the diagnostic and prognostic value is still controversial (9,16). TERT promotor has a much lower mutation detection rate than BRAF, reported about 9% (9). But it has been well documented as an aggressive clinicopathological characteristic for thyroid cancer (4,9,12,17-19). Current reports have established a vital role of TERT promoter mutation in the tumorigenesis of human thyroid carcinoma (16,17,20). Combined with this finding, the prognostic value of TERT promotor mutation will be of more clinical significance. It is not only indicative of aggressive behavior but also a risky factor of anaplasia transformation. In this way, detecting the mutation status of TERT promoter has the potential to enable treatment personalization and monitoring across the course of the disease for those particular PTC patients.

The present work truly presents an inspiring finding; however, sample selection bias and studying retrospectively may reduce its reliability and limit its application in clinic. As many other studies preciously demonstrated that BRAF mutation was associated with anaplasia transformation (2,10,13,14), and TERT mutations frequently occurred together with BRAFV600E mutations (20), combined detecting of TERT with BRAF mutation may be more significant and complementary. Besides, more multicenter large-scale clinic trails including comprehensive tumor samples are wanted.

Overall, although controversial, the study by Oishi et al. presents a challenging result that PTCs with TERT promotor mutation have aggressive behaviors and are more likely to transform into ATCs. This research illustrates a promising biomarker and will inspire more researchers applying themselves to uncover profound mechanism in thyroid carcinogenesis.

Acknowledgments

Funding: This study is partially supported by Grants from the National Natural Science Foundation of China (No. 81772853), and the Natural Science Foundation of Zhejiang Province (No. LY18H160012).

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by Section Editor Dr. Jie Li (Department of Pathology, Chinese PLA general Hospital, Beijing, China).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aot.2017.11.04). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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