**3. Radioiodine therapy**

Radioiodine therapy relies on the unique property of the thyroid follicular cell to transport and incorporate iodide into thyroglobulin, a feature that is maintained in a subgroup of differentiated thyroid carcinomas. Postoperative radioiodine administration can be used to destroy presumably benign residual thyroid tissue (remnant ablation), to destroy suspected but not identified remaining disease (adjuvant treatment), and to destroy known residual or recurrent disease (treatment) [30]. Until recently, most patients with differentiated thyroid carcinoma received postoperative radioiodine therapy, constituting a standard of care. Nowadays, radioiodine therapy has been personalized based on the risk of recurrence stratification and the prognostic indicators obtained during thyroidectomy and also on the findings of postoperative neck ultrasound and serum thyroglobulin levels. Radioiodine therapy is currently exceptionally recommended in patients with low-risk thyroid cancers, which represents the majority of patients with thyroid cancer.

Radioiodine is administered following thyrotropin (TSH) stimulation, the primary regulator of NIS expression in the thyroid follicular cell at both the transcriptional and posttranscriptional levels. TSH stimulation is achieved either by long-term withdrawal of thyroid hormone replacement treatment or after recombinant human TSH treatment. The use of recombinant human TSH avoids symptoms of hypothyroidism,

thereby improving the quality of life of the patients [31]. Restriction of dietary iodine is often recommended, and iodinated radiocontrast agents should be excluded before radioiodine scanning or treatment of differentiated thyroid carcinomas to avoid isotopic dilution, thus possibly improving radioiodine therapy efficacy [32].

Papillary thyroid carcinoma, the most prevalent form of the disease and accounting for approximately 85% of differentiated thyroid carcinomas, includes several tumor subtypes of which ~70% have mutually exclusive mutations of gene-encoding effectors of the mitogen-activated protein kinase (MAPK) signal pathway [33]. The papillary thyroid cancer genome atlas has revealed that the main genomic alterations include point mutations in the proto-oncogenes BRAF and (N, H, or K) RAS and also chromosomal rearrangements involving the proto-oncogenes RET and NTRK [34]. Significantly, BRAFV600E-harboring papillary thyroid carcinomas frequently have a poor response to radioiodine therapy [35]. Related to this, their refractoriness to radioiodine appears to be due to the strong BRAFV600E-triggered MAPK-dependent transcriptional program suppressing (or even abolishing) the expression of genes involved in iodide uptake and metabolism**,** which are hallmarks of the differentiated state of thyroid follicular cells. In contrast, RAS-mutated papillary thyroid carcinomas show a low MAPK-dependent transcriptional program (due to negative feedback regulation), retaining the expression of iodine-metabolism genes, and are usually radioiodine-avid [36]. Low frequency types of differentiated thyroid carcinomas, such as Hürthle-cell carcinomas and poorly differentiated thyroid carcinomas, are particularly refractory to radioiodine therapy.

Since, as mentioned above, BRAFV600E is frequently associated with decreased responsiveness to radioiodine, an emerging clinically relevant question is whether genetic markers can reliably predict the radioiodine refractoriness of thyroid carcinomas [37]. Indeed, recent studies have demonstrated that ~70% of patients with metastatic papillary thyroid cancer carrying the oncogene BRAFV600E do not demonstrate any radioiodine uptake, with this percentage increasing up to 97% when BRAFV600E is associated with mutations in the promoter of the Telomerase Reverse Transcriptase (TERT) [38, 39]. However, a subset of BRAFV600E-carrying papillary thyroid carcinomas does respond to radioiodide therapy [36]. Significantly, the BRAFV600E-containing papillary thyroid tumors that showed better responses to radioiodine therapy also revealed a relatively preserved expression of thyroid differentiation genes, and a higher expression of microRNAs targeting the transforming growth factor β (TGFβ) signaling pathway, which when activated repressed thyroidspecific gene expression [40].
