Aspects Considered in Differentiated Thyroid Cancer for Radioiodine Therapy

Abstract

Thyroid cancer incidence has rapidly increased in high-income countries for the past 30 years. The increase in thyroid cancer cases may be due to improved diagnostic methods or exposure to unknown risk factors. Even though new thyroid cancer cases have increased, the mortality rate is relatively stable. Most thyroid cancer is differentiated thyroid cancer (DTC). Conventional management of DTC consists of near-total thyroidectomy followed by ablation therapy with radioiodine-131 (RAI). RAI was first used nearly 80 years ago to treat thyroid cancer and still plays a pivotal role in managing DTC. There are three RAI therapy options: remnant ablation, adjuvant therapy, and known disease treatments. After thyroid resection, radioactive Iodine-131 (RAI) is recommended for patients with intermediate to high risk of recurrent disease or distant metastases. Long-term follow-up is needed to detect a persistence or recurrence of the disease after initial RAI administration. RAI effectively improves treatment efficiency and reduces the risk of cancer recurrence and metastasis post-thyroid resection. Clinical outcome prediction is ultimately defined by appropriate management. This article will review some factors to consider when planning RAI therapy for DTC and subsequent surveillance after the therapy.

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, 4, 5, 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⁺/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, 22, 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 provides the tumor with a more aggressive growth initiative. Alternatively, the cancer phenotype may be dictated by the differential nature of the stem cells capable of initiating PTC, FTC, and ATC [24]. The most common thyroid cancer mutations originate from follicular or parafollicular cells [25]. These mutations are the basis for the design of molecular markers and molecular approaches to thyroid cancer.

In some populations, malignant DTC might only occasionally lead to death, including cases of PTC in children and young adults presenting with lymph node metastases (LNMs). Some TC types were recently reclassified from malignant to benign, such as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) [21]. Based on clinical evidence, it is associated with no reports of cancer-related deaths and estimated risk of recurrence of <1% [26]. PTC accounts for 80% of TC with molecular characteristics predominant consisting of BRAF mutation, RAS mutation, and RET rearrangements, nearly 70% as shown in Table 1 [28]. These mutations are associated with radioiodine refractory (RAIR) [10]. BRAF ^V600E mutations are frequently reported in a subgroup of PTCs with more aggressive behavior [23, 26, 28, 29, 30]. The fatal forms of non-anaplastic cancer are generally PTC variants harboring BRAF or RAS mutations plus other genomic alterations such as mutations involving the TERT promoter, POLE, TP53, PI3K/AKT/mTOR pathway, SWI/SNF subunits, and/or histone methyltransferases [10, 30, 31]. BRAF mutations are present in 30%–67% of PTCs and are associated with locoregional metastases and extra-thyroidal extension [32]. A positive test for BRAF mutations means a close to 100% probability of malignancy [27]. This is likely helpful to guide the extent of thyroidectomy.

Classification	Tumor types	Markers
Benign	Follicular adenoma	RAS, PAX8/PPARγ, PI3K/AKT
Borderline/uncertain	Hyalinizing trabecular tumor other encapsulated follicular patterned tumors; Follicular tumor of UMP Well-diffrentiated tumor of UMP NIFT-P	RAS, BRAF
Malignant	PTC; Papillary carcinoma Follicular variant of PTC Encapsulated variant of PTC Papillary micro-carcinoma Columnar cell variant of PTC Oncocytic variant of PT	BRAF (40–50%); RAS (15%); RET/PTC (20–40%); PAX8/PPARγ (rare)
	FTC; Minimally invasive Encapsulated angioinvasive Widely invasive	RAS (20–40%); PAX8/PPARγ (10–66%); PI3K/AKT (rare)
	Hurthle cell carcinoma; Capsular invasion,; Vascular invasion >4 blood	RAS, EIF1AX, TP53, CNA, mtDNA
	Poorly differentiated thyroid; carcinoma	TERT (42%); BRAF (32%); RAS (19%)
	Anaplastic thyroid carcinoma	TP53 (60%); TERT (33%); BRAF (56%)

Table 1.

Classification of thyroid cancer based on World Health Organization (WHO) 2017.

Uncertain Malignant Potential (UMP)

Non-Invasive Follicular Thyroid neoplasm with Papillary-like nuclear features (NIFT-P). References: [10, 22, 32].

Follicular thyroid, accounting for 2%–5% of TC cancer, is considered minimally invasive when capsular penetration is present without vascular involvement (a condition associated with an excellent prognosis) by WHO [10, 11]. The angioinvasive and widely invasive term is when neoplastic emboli involve < 4 or ≥ 4 blood vessels, respectively [11]. FTC type is frequently linked to activation of the PI3K and MAPK pathways through loss of PTEN expression, NRAS mutations, rearrangements such as PPARγ/PAX8, and other events [27, 28, 30]. Hurthle cell carcinomas are no longer classified as follicular tumors. They are generally much less aggressive and less likely to present with lymph node metastases [11]. Hurthle cell carcinomas associated with extensive vascular and/or capsular invasion should be managed like other high-risk carcinomas [11].

Furthermore, once thyroid cancer is highly suspected or diagnosed, a decision must be made regarding the extent of surgery. Risk factors must be considered, such as clinical risk factors associated with aggressive tumor behavior, the patient’s age and sex, the initial tumor size and location, the presence of lymph nodes and/or distant metastases, cytologic and mutational data, and patient preferences. Most DTC can be identified through cytology, and when the result is indeterminate, assessment with malignancy markers (HBME1 or galectin-3) and molecular alterations (BRAF mutations, RET fusions, other novel gene alterations) are reportedly helpful for identifying malignancy [11].

4. Risk stratification

Accurate staging and assessment of DTC risk are essential for its management, which determines the prognosis and guides therapeutic decisions and the intensity of surveillance [4]. Risk stratification in DTC was based on clinic-pathological features after a few weeks of completing thyroidectomy, which previously referred to a static estimate of disease-specific mortality. Nowadays, risk stratification is a dynamic, active process used to predict the appropriateness of minimalistic initial therapy, risk of recurrence, disease-specific mortality, and the most likely response to initial treatment, as shown in Table 2. Moreover, an excellent histopathology report is essential for proper risk stratification [1, 11]. The estimated risk of recurrence ranges from <1% to 55%, and it is classified as low if ≤ 5%, intermediate if 6%–20%, and high if >20%, based on the presence or absence of aggressive features, presence of local or distant metastases, and imaging features on whole-body post-therapy scans [1, 2, 11]

Level of risk	Histology	Definition	RAI therapy (ATA recommendation)	RAI doses (ATA recommendation)
Low; ≤5%	NFTP; PTC; FTC	Noninvasive follicular thyroid tumor with papillary-like nuclear features (‘non-invasive encapsulated follicular-variant PTC)’; With all of the following: Without macroscopic tumor remnants Without loco-regional invasion or local metastases Clinical N0 or pathology N1 (<5 micrometastases, each <0.2 cm) Without distant metastases No RAI uptake shown outside the thyroid bed on post-treatment whole-body RAI scan (if available ) Without vascular invasion Non-aggressive histology BRAF V600E-mutated PTCs can is assigned to the low-risk if the tumor is <1 cm; Intrathyroidal, well-differentiated FTC with capsular invasion and minimal (<4 foci) or without vascular invasion	Remnant ablation is not routinely recommended, unless aggressive histology or vascular invasion.; Other factors may also be considered	1.11 GBq (30 mCi) if given to patients without aggressive histology or vascular invasion
Intermediate; (6%–20%)	PTC; FTC	With at least one of the following: Microscopic invasion of perithyroidal soft tissues Tumor-related symptoms Intra-thyroidal tumor measuring <4cm, BRAFV600E-mutated (if available) Aggressive histology Vascular invasion Multifocal papillary micro carcinoma with extra thyroid extension (ETE) and known BRAFV600E mutation Clinical N1or pathological N1 (>5 involved lymph nodes, each measuring <3 cm) RAI uptake of metastatic foci in the neck on the first post-therapy RAI WBS. With at least one of the following: • Clinical N1 or pathological N1 disease (>5 involved lymph nodes, each measuring <3 cm); • RAI- WBS shown metastatic foci uptake in the neck post RAI therapy	Consider adjuvant therapy with consideration of risk of recurrent disease, especially in tumors >2 cm, histology, vascular invasion and, potentially other factors.; Advancing age (≥ 45 or 55) favors for RAI therapy	>1.11 GBq up to 55.5 GBq (>30 up to 150 mCi)
High; (>20%)	PTC; FTC	With at least one of the following: Gross ETE (macroscopic invasion of peri-thyroidal soft tissues) Pathological N1: one or more nodal metastases measuring>3 cm. Extra nodal extension Concomitant BRAFV600E and TERT mutations Postoperative serum Tg suggestive of distant metastases Incomplete tumor resection Distant metastases With at least one of the following: Widely invasive or extensive vascular invasion(>4foci) Postoperative serum Tg suggestive of distant metastases Incomplete tumor resection Distant metastases	Adjuvant treatment is recommended	>1.11 GBq up to 55.5GBq

Table 2.

Risk stratification and recommendation of radioiodine therapy.

References: [1, 10].

Several systems are designed for risk stratification, considering patients’ age, tumor size, resection completeness, local invasion, and distant metastasis [12]. The DTC risk stratification is applied in the clinical setting despite a validated system’s absence [12, 33]. The original ATA risk category design (low, intermediate, high) is usually applied in clinical practice with promising results [12]. However, the 2015 ATA risk stratification system was built on retrospective studies where nearly all patients were treated with RAI. ATA risk stratification schema for selecting patients for adjuvant treatment is not conclusively validated. However, it prompts the physician to consider the various clinic-pathologic factors in managing low- intermediate-risk patients where the indication for RAI therapy may not be straightforward [1]. The initial risk stratification is revised during follow-up to evaluate the disease and treatment responses (dynamic risk stratification) because the biological behavior of the disease as a response to therapy was not accounted for in initial staging [11, 12].

5. Radioiodine therapy (RAIT)

The ability of thyroid follicular cell to take up and concentrate iodide becomes the basic fundamental of RAI therapy. Selecting the appropriate method for RAI treatment requires careful evaluation of postoperative status. However, no universally accepted recommendations exist to assess postoperative disease status [34]. Consensus in 2019 of the American Thyroid Association (ATA), the European Association of Nuclear Medicine and Molecular Imaging (EANM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), and the European Thyroid Association (ETA) state that the goal of the administration of RAIT in differentiated thyroid cancer is for remnant ablation, adjuvant treatment for irradiation of resumed foci of tumor cells to reduce the recurrence risk, or treat persistent or recurrent disease [1, 11, 12]. Remnant ablation is done after near/total thyroidectomy to destroy presumably benign residual thyroid tissue to eliminate thyroglobulin (Tg) production, facilitating follow-up of remnant ablation [1, 11, 12]. The adjuvant treatment goal is to eliminate potential microscopic foci of thyroid cancer tissue after complete resection of thyroid metastatic (locoregional, distant, or both). The condition can minimize the risk of recurrence, improving disease-specific and progression-free survival. Treatment of persistent or recurrent disease aims to improve progression-free, disease-specific, and overall survival at radioiodine-avid DTC, where the diagnosis is based on anatomical detection or biochemical evidence [1, 11, 12].

A joint of the ATA, the SNMMI, the EANM, and the ETA published a statement acknowledging the absence of high-quality evidence against using RAIT for remnant ablation post-total thyroidectomy for low-risk patients, and RAIT decisions should be taken on an individual basis, depending on tumor features (risk of recurrence), patient-related factors (comorbidities, motivation, emotional concerns), healthcare setting (availability and quality of thyroid surgeons, ultrasonography, RAI scintigraphy, Tg assays), and the local management preferences [11]. The benefit of RAIT should outweigh the risks associated with its administration, which include adverse events and diminished quality of life (QoL) [1, 11]. Application of RAIT activity dose has three broad approaches [4]: (1). Empiric dose (based on convention, experience, and patient-related factors. (2). A maximum permissible dose (determined by the upper bound limit of whole-body blood [bone marrow] dosimetry (WBBD)). (3). Target/lesion dosimetry. ATA guidelines do not endorse RAI dose activity one over the other [2, 12]. The level of risk for persistent/recurrent disease will determine the RAI dose activities. A ¹³¹I-whole-body scan (¹³¹I-WBS) must follow RAI administration to document the RAI avidity and stage of the disease [12]. ¹³¹I-WBS post-therapy scans may show additional metastases in 10–26% of patients compared with pre-therapy scans [35, 36]. Extensive disease noted on ¹³¹I-WBS post-therapy may alter the clinical stage in about 10% and clinical management in 10–15% of DTC patients [2].

The RAI activity consists of low and high doses. A low dose is usually given for remnant ablation at 1.1 GBq (30 mCi) [1, 11]. A high dose for treatment at > 1.1 GBq–5.55 GBq (>30 mCi–150 mCi), is recommended for high-risk recurrence conditions as shown in Table 2 [1, 11, 12, 37]. The RAIT is not recommended for particular low-risk/very low-risk conditions [tumor with a small size nodule (< 1cm intrathyroidal) and without locoregional metastases] [11]. The administered RAI activities higher than 5.55 GBq (150 mCi) are unnecessary in intermediate-risk patients. Limiting RAI dose activities to a maximal 5.55 GBq (150 mCi) mainly considers the risks of side effects [1]. Regarding the treatment of known DTC, the ATA guidelines recommend RAI dose up to 7.40 GBq (200 mCi) and not to exceed 5.55 GBq (150 mCi) in patients ≥70 years old, to avoid the risk of toxicity [12]. In patients with prolonged radioiodine clearance, the RAI dose is reduced by up to 50% [38, 39].

In low-risk DTC patients, RAIT is influenced by any adverse feature that modulates recurrence risk and patient preference. The ATA 2015 guidelines recommend a low RAI dose (1.11 GBq/30 mCi) for remnant ablation of low-risk or intermediate-risk DTC with low-risk features [2, 11, 12]. Radioiodine therapy after total thyroidectomy should be considered in intermediate-risk DTC and is routinely recommended in ATA high-risk DTC. The therapy consideration is to balance treatment efficacy with unwanted side effects [1]. However, patient preference plays a crucial role in decision-making. Therefore, the activity of RAI ought to be specifically prescribed for each patient [12]. Moreover, on the 2015 ATA guidelines, RAI for adjuvant therapy is considered for DTC having a low-to-intermediate risk for recurrence with (1). Tumor with a dimension > 4 cm without nodal or distant metastases (T3a N0 or Nx M0 or Mx) by the AJCC 8^th edition, TNM classification. (2). Any tumor size with microscopic extra-thyroidal extension but without nodal or distant metastasis (3). Tumors (T1–T3a) with nodal but no distant metastasis (T1–T3a N1 M0 or Mx) (4). Tumors (T1–T3a) with vascular invasion and aggressive pathological subtype [1, 11]. A microscopic residual disease increases in intermediate-risk DTC, as evidenced by higher recurrence rates in most intermediate categories compared with low-risk. A study that reported adjuvant RAIT in intermediate-risk patients with the exclusion of aggressive variants and multiple primaries showed a survival benefit in patients <45 years old, and improved overall survival was also shown in patients with aggressive variants of PTC [40, 41, 42]. The adjuvant therapy of RAI in high-risk DTC without distant metastasis shows improved outcome and without controversial decision. RAI adjuvant therapy is recommended in patients with T3b, T4a, and T4b, any N, M0, and high-risk DTC, including cervical nodes (≥3 cm in largest dimension) and/or with extranodal extension [1]. Treatment responses after total thyroidectomy and RAIT are defined as excellent, biochemical incomplete, structural incomplete, or indeterminate based on findings (neck ultrasound and serum Tg and anti-Tg anti- body (TgAb) levels, as shown in Table 3.

Parameters	Excellent	Biochemical incomplete	Structural incomplete	Indeterminate
1. Serum Tg
Non-stimulated	< 0.2 ng/ml	≥ 1 ng/ml	Any	0.2 to < 1ng/ml
Stimulated	<1 ng/ml	≥10ng/ml	Any	1 to < 10ng/ml
2. Anti-Tg antibody	Undetectable	Increasing	Any	Stable or decreasing
3. Imaging results	Negative	Negative	Residual disease positive	Equivocal
4. Prognosis	1%–4% recurrence	Without evidence (spontaneously ≈30%,; after additional treatment ≈20%).	Persistent disease (50%–85%)	Stable or resolves in ≈ 80%; Response is reclassified as structural or biochemical incomplete and may need additional therapy in ≈20%
5. Disease-specific mortality	< 1%	< 1%	Loco-regional metastasis up to 11%; and distant metastasis up to 57%	< 1%
6. Response based on classification
Low	86% to 91%	11% to 19%	2% to 6 %	12% to 29%
Intermediate	57% to 63%	21% to 22%	19% to 28%	8 % to 23%
High	14% to 16%	16% to 18%	67% to 75%	0.5 to 4%

Table 3.

Treatment responses of differentiated thyroid cancer treated with total thyroidectomy and radioiodine therapy.

References: [10, 11].

6. Radioiodine refractory (RAI refractory)

DTC cells can retain functions of follicular cells, such as iodide uptake and iodination, which allows RAI uptake for treating cancer [43]. Most DTC cases have a favorable prognosis after standard therapy, including total thyroidectomy, selective RAI therapy, and TSH suppressive therapy. NIS plays a role in the active transport of iodide into the thyroid follicular cells [9]. Functional NIS expression is regulated at the transcriptional and posttranslational levels, and TSH is primarily involved at the translational level [43]. Concerning posttranslational regulation, abundant NIS expression may mislocalize in the intracellular compartment rather than the cell membrane [43]. This mislocation targeting of NIS disturbs uptake and accumulation of radioiodine, inducing the failure of RAI therapy in DTC [10, 43]. The local recurrence and distant metastasis risk increase to 20% and 10%, respectively [10]. Among these cases, two-thirds show initial or gradual loss of the ability of iodine uptake due to the dysfunction, and even loss, of NIS expression in the basal membrane, indicating a status of dedifferentiation known as radioiodine-refractory (RAIR), which significantly reduces the 10-year survival rate less than 10% [9, 43].

Radioiodine refractory is when progressive dedifferentiation of the tumor cells leads to a loss of ability to accumulate RAI by non-functioning the sodium iodide symporter [43, 44]. The condition included is (a) tumor or metastatic site (one or multiple) that does not ever concentrate radioiodine (no avidity outside the thyroid bed on the initial post-therapy WBS); (b) tumor tissue that initially showed RAI avidity but lost the ability to concentrate on subsequent scans or treatments; (c) radioiodine is concentrated in some, but not all, sites of metastatic; (d) disease progression despite significant concentration of RAI (within 1 year of treatment) [10, 44].

Decreased NIS expression, diminished membrane targeting, or both, which are mainly caused by genetic and epigenetic alterations and dysregulated signaling pathways, are the primary mechanisms underlying RAIR [10]. Genetic alterations in MAPK and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways by point mutations or chromosomal rearrangements are basic molecules in the pathogenesis of thyroid cancers and RAIR. Besides the signaling pathways, epigenetic and genetic alterations of other pathways, such as Wnt/ß-catenin and TGF-ß/Smad signaling pathways, are also related to the silencing of expression of thyroid-specific genes, resulting in RAIR [10, 28].

The evidence has demonstrated a strong association between the BRAF^V600E mutation and RAI-avidity loss in PTC [43]. The BRAF^V600E mutation can upregulate the expression of tumor-promoting genes, such as TGFβ1, mesenchymal-to-epithelial transition factor [MET], vascular endothelial growth factor A [VEGFA], and thrombospondin 1 [TSP1]) [43, 45]. It can downregulate the expression genes of tumor suppressors such as tissue inhibitor of metalloproteinases 3 [TIMP3], death-associated protein kinase 1 [DAPK1]), and solute carrier family five-member 8 [SLC5A8], [46]. BRAF^V600E mutation induces the secretion of TGFβ, which can stimulate SMAD3 and impair PAX8, which cause a decrease in NIS expression [43]. Moreover, telomerase reverse transcriptase (TERT) promoter (TERTp) mutations are particularly prevalent in BRAF^V600E mutation PTC. TERTp mutations were associated with aggressive tumor behavior and poor prognosis in thyroid cancer. They were also observed to be correlated with the reduction of RAI uptake in distant metastatic lesions of PTC [10, 43]. On the other hand, the RET/PTC rearrangement impacts the dedifferentiation of DTC remains limited. In vitro studies reported that alternation of RET/PTC could suppress the expression of thyroid differentiation markers (TPO, TSH receptor, thyroglobulin, and NIS) [47, 48]. Recently, oncogene-activated signaling pathways have also been reported to control histone posttranslational modification affecting thyroid-specific genes’ expression [10, 49]. This finding supports attempts to convert thyroid cancer into redifferentiated thyroid cancer by modulating histone acetylation and deacetylation [10, 43]. BRAF-activated NIS silencing could be influenced by histone deacetylation at critical regulatory regions of the NIS promoter [10].

7. Patient preparation

The effectiveness of RAIT depends on patient preparation. Ideally, serum TSH levels reach ≥30 mU/L to optimize radioiodine uptake [50]. TSH elevation can be reached by waiting at least 3 weeks after thyroidectomy or 4–5 weeks after discontinuing treatment with levothyroxine (LT4). When thyroid hormone is withheld, it should be initiated or resumed 2 days after radioiodine administration [50]. Recombinant human thyrotropin (rhTSH) administration is an acceptable alternative to thyroid hormone withdrawal (TWH) based on ATA guidelines before remnant ablation or adjuvant treatment in low-risk and intermediate-risk DTC without extensive lymph node involvement. In extensive lymph node disease without distant metastasis, the rhTSH stimulation may be considered an alternative to THW before RAIT. The rhTSH is not approved yet by Food and Drug Administration (FDA) to treat distant metastases of DTC. The rhTSH stimulation is recommended for any patient with DTC regardless of the risk level if comorbidities exist that preclude THW [12]. Furthermore, patients should be advised to avoid iodine-containing medications (iodinated contrast agents, antiseptics, eye drops or amiodarone, and iodine-containing foods) for 4–6 weeks prior to RAIT to avoid competition with non-radioactive iodine. Moreover, a low-iodine diet (<50 μg/day), starting 1– 2 weeks prior to RAIT, is recommended optionally [50]. Patients are advised to avoid meals for at least 2 hours before and 2 hours after administering RAI because heavy meals can slow the absorption of RAI [16].

8. Follow-ups

The follow-ups are carried out every 6 months (for the first 5 years after diagnosis), and if no pathological findings since the period, examinations are adequate annually [49, 51]. The follow-up assessment is based on the interview, clinical examination, cervical sonography, and determination of TSH and thyroid hormone levels, Tg, and Tg antibodies. When postoperative hypoparathyroidism occurs, substitution therapy is needed. A diagnostic WBS is obligatory 6–12 months after the initial RAIT, and the next WBS is needed if there is a relapse indication [12, 52]. Metastatic uptake on ¹³¹I-WBS confirms their capacity to concentrate RAI and the potential to respond to RAI in this condition as a permit for RAI activity to treat metastases.

The criteria for a disease-free (6–12 months) after initial therapy of DTC with total thyroidectomy and RAIT are no clinical signs of DTC and without pathological uptake in ¹³¹I-WBS (except the uptake showed after remnant ablation). A serum Tg is below the detection limit, and undetected Tg antibodies [12, 52]. In conditions with elevated/rising Tg serum levels and undetectable radioiodine uptake, F-18-fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET) examination is recommended [49, 50, 53].

9. Conclusions

The RAI administration aims at remnant ablation and adjuvant treatment for irradiating presumed foci of tumor cells to reduce the recurrence risk or treat persistent or recurrent disease. The risk stratification after thyroidectomy becomes pivotal in DTC management to offer an individualized therapy approach. The decisions should be taken depending on tumor features, patient-related factors, healthcare settings, and local team preferences. The local team was considered by interdisciplinary teams in the initial management of DTC patients, focusing on RAIT. Even though RAIT in the low-intermediate risk class is still debatable, RAIT is recommended in high-risk DTC without distant metastasis, showing improved outcomes and without controversial decisions.

Conflict of interest

The author has no possible conflict of interest.