**1. Introduction**

Thyroid cancer is a malignant endocrine tumor [1]. Papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) are classified as differentiated thyroid cancer (DTC), which is approximately 95% of all thyroid carcinomas [2, 3]. Over the past 30 years, the incidence of DTC has rapidly increased worldwide [3–6]. The increase in thyroid cancer cases may be due to improved diagnostic methods or exposure to unknown risk factors [1, 5, 6]. Conversely to the increase of new cases, the mortality rates have been steadily declining in most areas of the world [7, 8]. The condition is likely due to improved diagnostic methods, management, and treatment of the disease [7, 8]. DTC is considered a slow-growing malignancy with a generally good prognosis with 5-year survival for the localized disease at 99.9% and for regional metastatic disease at 97.8% [4, 6]. However, distant metastatic DTC is associated with a significantly worse prognosis (5-year survival of 55.3% [4, 6].

After resection of DTC, conventional management is followed by the administration of radioactive Iodine-131 (RAI) in most patients for both thyroid remnant ablation and treatment of expected or proven locoregional or distant metastases [1, 2]. Thyroid follicular cells take up and accumulate radioiodine, the same process as iodine, except for organification [9]. The process utilizes the expression of sodium iodide symporter (NIS), thyroglobulin (Tg), thyroid stimulating hormone receptor (TSHR), thyroperoxidase (TPO), and thyroid-specific transcription factors (bone gene-8 (PAX-8), thyroid transcription factor-1 (TTF-1)) [10]. Even though thyroid cancer cells, including metastases, take up RAI, the efficacy of RAI is limited in large tumor sizes, which need to be treated repeatedly [1, 2, 11, 12]. A study reported a decreased risk of death and risk of recurrence for tumors > 1 cm in a group of 269 patients with PTC treated with extensive initial surgery and then RAI remnant ablation [2]. Moreover, RAI treatment is recommended in high-risk and intermediate-risk patients, where the decision should be on an individual and tumor features basis [1, 2, 11]. This chapter's objective is to discuss the indication of radioiodine therapy in DTC.

### **2. Iodine and radioiodine transport**

Radioiodine is the first radionuclide used for therapy in clinical oncology, including thyroid cancer therapy. It is a beta (β) and gamma (γ) emitter that is used for therapy and also for imaging [9, 13, 14]. RAI is administrated in the form of liquid or a capsule. Once it is ingested, it is quickly absorbed into the bloodstream from the gastrointestinal (GI) tract. Thyroid follicular cells take up RAI through active transport, regulated by thyroid-stimulating hormone (TSH), which requires energy produced by ouabain-sensitive Na+ /K+ -adenosine triphosphatase (Na<sup>+</sup> /K+ -ATPase) using the NIS as co-transport [9, 15, 16]. About 20% of the ingested iodine is converted to iodide (I- ) before being absorbed [17]. In plasma, there is an exchange of iodide with red blood cells and extracellular compartments. The thyroid gland collects as much as 70–90% of I in the body [18]. Besides being captured by the thyroid gland, iodide is collected in the salivary glands, gastric mucosa, choroid plexus, and breast glands and enters the placental circulation. The thyroid gland can collect I as much as 20–40 times compared with plasma under normal physiological conditions [19, 20].

### **3. Pathology and molecular markers of differentiated thyroid cancer**

The main histopathology types of thyroid cancer (TC) consist of papillary and follicular, poorly differentiated (PDTC), anaplastic thyroid cancer (ATC), and medullary thyroid cancer (MTC) from the C cells [21–23]. Papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) are two distinct histological forms of the DTC type [2]. PTC patients are typically younger than 50 and have smaller tumors, a higher incidence of lymph node metastases, multi-centricity, and extra-thyroidal extension. Patients with FTC show a higher incidence of distant metastatic disease and more frequently receive repeated radioiodine [2]. Tumor pathologies show significant variability among the tumors. The variation is particularly notable among types originating from thyroid follicular cells. The progression of DTC to PDTC and ATC is most likely the result of additional genetic mutations developing after the primary oncogenic event, which
