Abstract
The close association between pre-existing Hashimoto’s thyroiditis and thyroid cancer is well established. The simultaneous occurrence of multiple neoplastic foci within the same organ suggests a common genotoxic effect potentially contributing to carcinogenesis, the nature of which is still not clear. Next-generation sequencing (NGS) provides a potent tool to demonstrate and compare the mutational profile of the independent neoplastic foci. Our collection of 47 cases with thyroid carcinoma and Hashimoto’s thyroiditis included 14 with at least two tumorous foci. Detailed histological analysis highlighted differences in histomorphology, immunoprofile, and biological characteristics. Further, a 67-gene NGS panel was applied to demonstrate the mutational diversity of the synchronic tumors. Significant differences could be detected with a wide spectrum of pathogenic gene variants involved (ranging between 5 and 18, cutoff >5.0 variant allele frequencies (VAF)). Identical gene variants represented in both synchronous tumors of the same thyroid gland were found in only two cases (BRAF and JAK3 genes). An additional set of major driver mutations was identified at variable allele frequencies in a highly individual setup suggesting a clear clonal independence. The different BRAF statuses in coincident thyroid carcinoma foci within the same organ outline a special challenge for molecular follow-up and therapeutic decision-making.
Highlights
Thyroid carcinoma is the most frequent endocrine neoplasia, the incidence of which is increasing worldwide [1,2]
Parenchymal hypofunction, on the other hand, triggers a constant proliferative stimulus by thyroid-stimulating hormone (TSH), enabling increased survival and adaptive selection, which are both important factors in the process of carcinogenesis
thyroid cancer (TC) was confirmed by classical histological criteria in hematoxylin-eosin-stained conventional sections
Summary
Thyroid carcinoma is the most frequent endocrine neoplasia, the incidence of which is increasing worldwide [1,2]. While the immunological background and pathological consequences of autoimmune lymphocytic thyroiditis and, more recently, IgG4-related chronic inflammation have been gradually elucidated, the exact mechanisms of subsequent carcinogenesis are mostly unknown. According to the current view, has the association between HT and especially papillary-type thyroid carcinoma (PTC) been established, but the frequent multifocality of PTC can be explained by HT-related injury and consequent stimulatory mechanisms [6,9]. Following the histopathological evaluation of multifocal thyroid lesions provided in our single-center cohort, we performed an NGS-based 67 multigene analysis in a selected set of HT-related TC cases to highlight the mutational pattern and potential common features of this special and complex form of carcinogenesis
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