Open access peer-reviewed chapter

Differentiated Thyroid Carcinoma with Elevated Thyroglobulin and Negative Radioiodine Whole-Body Scan Metastases

Written By

Chao Ma

Submitted: 18 November 2015 Reviewed: 23 May 2016 Published: 07 September 2016

DOI: 10.5772/64356

From the Edited Volume

Thyroid Cancer - Advances in Diagnosis and Therapy

Edited by Hojjat Ahmadzadehfar

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Abstract

Serum thyroglobulin (Tg) and Tg antibody (TgAb) levels, together with neck ultrasonography and 131I whole-body scintigraphy (WBS), are diagnostic tools for postoperative follow-up of patients with differentiated thyroid carcinoma (DTC). Generally, good correlation is seen between Tg and WBS in follow-up studies for DTC after thyroid remnant ablation. Undetectable serum Tg with negative WBS results suggests complete remission, whereas detectable, or elevated, serum Tg is associated with radioiodine uptake in local or distant metastases. Patients with thyroid cancer cells lacking radioiodine uptake despite an elevated serum Tg level have been referred to as WBS-negative, Tg-positive patients, who represent 10–15% of cases. 18F-FDG PET (FDG-PET) scanning should be considered in high-risk DTC patients with negative WBS and positive Tg. The preferred therapeutic hierarchy for Tg-positive and WBS-negative metastases is surgical excision of loco-regional disease, 131I therapy for radioiodine-responsive disease, external beam radiation, TSH suppression, and systemic therapy with kinase inhibitors. If FDG-PET diagnostic results are negative, one course of 131I treatment may be considered in high-risk patients and individualized. No further 131I therapy is indicated for patients with a negative post-therapy WBS.

Keywords

  • differentiated thyroid carcinoma
  • thyroglobulin
  • whole-body scan
  • radioiodine

1. Introduction

Serum thyroglobulin (Tg) is a tissue-specific 660 kDa protein that serves as a precursor in thyroid hormone biosynthesis [1]. It is synthesized by both thyroid follicular cells and differentiated cancer cells. Monitoring of serum Tg and Tg antibody (TgAb) levels, together with neck ultrasonography and 131I whole-body scintigraphy (WBS), is used as a diagnostic tool in postoperative follow-up for patients with differentiated thyroid carcinoma (DTC) [2]. Generally, good correlation is seen between Tg and WBS in follow-up studies for DTC after thyroid remnant ablation [3]. Undetectable serum Tg with negative WBS results suggests complete remission, whereas detectable, or elevated, serum Tg is associated with radioiodine uptake in local or distant metastases. Patients with thyroid cancer cells lacking radioiodine uptake despite their elevated serum Tg level have been referred to as WBS-negative, Tg-positive patients [3]. The possible explanations and management for the discordant finding are discussed in this chapter.

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2. Description of DTC with elevated Tg level and negative WBS

Tg is a thyroid tissue-specific antigen produced by thyroid follicular cells. Its measurement is the best sign of detecting thyroid tissue, including metastasis of DTC. After a total thyroidectomy and radioiodine ablation, any detactable Tg is interpreted as recurrent disease. Although it is a highly sensitive and specific marker of recurrence, Tg measurement cannot locate the recurrent DTC [4, 5]. Imaging technologies, including WBS, ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI), play great role in locating the DTC metastases. Tg is a very sensitive marker for thyroid malignancy, and it is not uncommon to encounter patients who show at initial follow-up, detectable Tg levels with negative imaging studies [6]. Patients with thyroid cancer cells lacking radioiodine uptake on WBS despite their elevated serum Tg level have been referred to as WBS-negative, Tg-positive patients; they represent 10–15% of patients with DTC at follow-up. Due to its inferior sensitivity, the routine WBS has been supplanted by serum Tg and neck ultrasonography, CT and/or MRI. The reasons for raised Tg and negative scan results have been summarized previously [7]. The elevated Tg level and negative WBS are classified into “true-negative WBS with false-positive Tg” and “false-negative WBS and true-positive Tg.” Because of the low sensitivity of WBS, cervical ultrasonography plays more important role in the follow-up of DTC patients. Therefore, a new challenging scenario has emerged: the ultrasonography-negative, Tg-positive patient [8].

2.1. True-iodine negative and false-positive Tg

  1. Tg assays interference

    The possibility of a false-positive serum Tg because of assay interference is rare but should be considered. And serum Tg has a lower false-negative rate than WBS after stimulation of thyroid stimulating hormone (TSH) either by thyroid hormone withdrawal or by recombinant human thyroid stimulating hormone (rhTSH) [913]. Optimal follow-up requires remnant ablation, and TSH-stimulated Tg testing [4]. The sensitivities and specificities of various Tg assays vary widely between laboratories, even with the use of an international standard (CRM 457) [14, 15], which have potential to disrupt serial monitoring and prompt inappropriate clinical decisions [9]. Additionally, undetectable serum Tg became detectable in a significant percentage of DTC patients by changing assays [1618]. Therefore, Tg should be dynamically monitored using the same assay performed in the same laboratory. If possible, patient’s serum is frozen and saved for recovery test to assess the reliability of Tg when there is a change in Tg assay [19]. As the sensitivity of commercially available Tg assays improves, TSH-stimulated Tg may not be necessary in patients with low and intermediate risk of recurrence [9].

  2. Circulating TgAb and HAb interferences

    A major problem that hampers accurate Tg measurement is the interference by TgAb and HAb resulting in either an under- or overestimation of the serum Tg concentration [1921]. Depending on the population studied and the assay used, up to 25–30% of patients with DTC have a positive test for TgAb at the time of initial diagnosis [22, 23]. In addition, a small to moderate percentage of patients (in the literature ranging from <1 to >10%) show HAb interference in Tg measurement, an integral tool in the management of DTC patients. These antibodies typically falsely lower the Tg value in immuno-chemiluminometric assays and immuno-radiometric assays, while raising the value in radio-immunoassay.

    Therefore, TgAb should be measured in the same serum sample taken for Tg assay [15, 24]. Although for clinical purposes the measurement of Tg and TgAb before thyroidectomy for a suspected or proven DTC is not recommended, a pre-thyroidectomy Tg and TgAb measurement might be used as an “in vivo” recovery test in order to assess the reliability of Tg for use as a postoperative tumor marker [19, 25]. In DTC patients, the limit of quantitation (LoQ) of a given TgAb assay should be regarded as the upper normal limit for the presence of TgAb [25]. Thyroid laboratories should report two reference ranges for TgAb: one based on the presence of TgAb in a population free of thyroid disease, which should be used for the diagnosis of autoimmune thyroid disorders, and the LoQ which should be used as the upper normal limit in DTC patients. A proposed algorithm for follow-up in TgAb-positive patients with DTC was listed in Figure 1 from Verburg et al. [25].

    Persistence of Tg-Ab for more than 1 year after thyroidectomy and 131I ablation probably indicates the presence of residual thyroid tissue and possibly and/or DTC recurrence [22, 24, 26]. A recent study also showed that TSH receptor mRNA accurately predicted disease status in 68% of DTC patients [27].

  3. Benign sources of Tg secretion

    Apart from their ability to interfere with Tg assays, benign lesions (possibly with foci of thyroiditis) in persistent residual thyroid tissue or non-thyroidal tissue producing Tg may also result in false-positive Tg in DTC patients. However, residual occult disease is usually the source of post-operative Tg elevations [2830]. Rarely, TSH-stimulated thymus may produce Tg [6].

Rarely, ectopic thyroid tissue may persist at the base of the tongue or, more often, at any other position along the thyroglossal tract, with the potential to elevate serum Tg levels. The thyroglossal tract is the most common location for ectopic thyroid tissue. This tissue retains not only the ability to concentrate iodine, but also to produce Tg and release it into the bloodstream [28, 31, 32]. The iodine metabolism-related proteins such as human sodium/iodide symporter (hNIS) [33], TSH receptor at both mRNA and protein level [6] are present in non-thyroidal tissues, including the thymus. Usually, these functions are dormant, but they may be activated by TSH stimulation [34]. Interestingly, these extra-thyroidal foci may be resistant to multiple 131I treatments [28, 31, 32]. In a series of 548 consecutive diagnostic WBS, ectopic thyroid tissue in the tongue or in the upper part of the thyroglossal duct was visualized in five patients (0.9%) [28]. However, in another study of 60 patients, 19/60 (31.7%) had a linear or focal radioactivity at the superior midline of the neck, suggesting thyroglossal duct remnant [29]. The absence of metastases in the thymus despite high Tg levels was confirmed in five cases [33, 35]. Rare cases of thyroid tissue ectopy has been summarized in some locations such as struma ovarii, the heart (struma cordis), the submandibular, parotid and salivary glands, the duodenum, the adrenal glands, the liver and gallbladder, the pancreas, the axilla, and iris of the eye [6].

Figure 1.

The algorithm for treatment and follow-up in Tb-Ab positive differentiated thyroid cancer patients from Verburg et al. [25].

In summary, interference with Tg assays by TgAb and HAb, benign lesions (possibly containing thyroiditis) in persistent residual thyroid tissue or nonthyroidal tissue producing Tg may also result in false-positive Tg in DTC patients.

2.2. False-negative WBS and true-positive Tg

The possible causes of false-negative WBS are mentioned below.

  1. Defect of iodine-trapping mechanism such as acquired inactivation mutation of NIS, TPO gene, pendrin, and TSHR

    Thyroid hormone synthesis starts with the active uptake of iodine from the circulation via NIS. This process, known as iodine trapping, is stimulated directly by TSH and more circuitously by iodine deficiency. Other proteins, including TPO, TSHR, and pendrin, also play an important role in the thyroid metabolism of iodine. Any defect in NIS, TPO, Tg, and TSHR will contribute to false-negative WBS [7].

  2. De-differentiation of tumor such that it can still produce Tg but has lost its iodine-trapping ability

    Various molecular changes within papillary thyroid cancer cells, such as RET/PTC rearrangements, RAS and BRAF mutations [36], β-catenin mutations, PAX8/PPARã, histone acetylation factors involved in angiogenesis including overexpression of vascular endothelial growth factor (VEGF) and EGF receptor (EGFR) underlie the loss of iodide uptake ability [37]. The dedifferentiated DTC cells lost the ability to concentrate iodine but may retain Tg synthesizing capability [3, 7], which underlines the phenomenon of Tg-positive and WBS-negative lesions.

  3. Dispersed microscopic metastases, which are too small to be visualized

  4. Improper patient preparation before WBS

When it is determined that an elevation of Tg is real, if WBS is negative, false-negative scan such as stable iodine contamination and inadequate TSH elevation should be considered [7]. TSH levels should be elevated to at least 30 mIU/L before concluding that a negative WBS is meaningful. This can be achieved either by withdrawal of thyroxine or by rhTSH administration. rhTSH is as effective as thyroid hormone withdrawal on 131I thyroid remnant ablation for DTC patients with significant benefits in decreased whole-body radiation exposure and health-related quality of life [38, 39]. A summary of appropriate patient preparation for WBS in the hypothyroid state is presented in Table 1 from Ma et al. [7].

Withdrawal of L-T4 for 4–6 weeks or of triiodothyronine for 2 weeks.
A strict low-iodine diet (50 g iodine per day) followed for 7–14 days before WBS and continuing throughout period of imaging.
Avoidance of iodine-containing medications (e.g., iodinated contrast medium, amiodarone, betadine), iodine-rich foods (e.g., kelp), and possible additives of iodine in vitamin and electrolyte supplements.
TSH > 30 mIU/L.
A mild laxative sometimes administered on the evening before WBS to simplify image interpretation.
Information relating to patient’s compliance with low-iodine diet, TSH level, history of thyroid hormone withdrawal, measurement of Tg, history of prior administration of contrast medium or iodine-containing drugs (e.g., amiodarone), menstrual history/pregnancy test, nursing/lactation history, etc.
Measurement of urinary iodine in doubtful cases to rule out iodine contamination; repeated WBS 4–6 weeks after iodine depletion regimen such as diuretic program.
Rule out women with pregnancy and breast feeding.

Table 1.

A summary of appropriate patient preparation for WBS from reference by Ma et al.

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3. Management of DTC patients with positive Tg and negative WBS

3.1. Other diagnostic modalities for DTC in this setting

In the clinical setting, the precise location of WBS-negative recurrent DTC is mandatory because surgery is the only curative treatment option and metastases that are unable to concentrate 131I are associated with more aggressive clinical behavior [40]. Cervical ultrasonography, CT and MRI, 124I PET/CT have limited roles in the diagnosis of DTC metastases with positive Tg and negative WBS. Non-iodine imaging agents—such as 201Tl, 99mTc-sestamibi, 99mTc-tetrofosmin, somatostatin receptor (SRS) scan have reasonable accuracy [41]. However, they have been replaced by 18F-FDG in the follow-up algorithm of DTC patients with positive Tg and negative WBS.

  1. Cervical ultrasonography

    Cervical ultrasonography has high sensitivity in detecting recurrence in the thyroid bed and nodal metastases of DTC in the neck [42, 43]. It has been used as first-line diagnostic imaging in DTC follow-up [44, 45]. However, neck ultrasonography has limitations: one is that it does not reveal DTC recurrences in other body sites. It is also difficult for cervical ultrasonography to differentiate scar tissue and locally recurring fibrosis and between nonspecific nodal enlargements and nodal metastases [46]. Therefore, the other limitation of ultrasonography is the low specificity in DTC patients of altered anatomy after thyroid surgery.

  2. CT and MRI

    In patients with elevated or rising Tg or TgAb and no evidence of disease on neck ultrasonography or WBS (if performed), CT imaging of the neck and chest should be considered [47]. Diagnostic CT scan may complement neck ultrasonography for the detection of macrometastases in the central compartment, in the mediastinum and behind the trachea [4850], and is the most sensitive tool for the detection of micro-metastases in the lungs. MRI has also been advocated for imaging the neck and the mediastinum. It is performed without and with injection of gadolinium chelate as contrast medium and does not require any injection of iodine contrast medium. Brain and skeletal MRI and/or CT, or abdominal MRI may be performed in high-risk DTC patients with elevated Tg (generally >10 ng/mL) and negative WBS or ultrasonography, who have systemic symptoms related to those organs, or who will have 131I therapy and may be at risk for complications of tumor swelling [51]. MRI is less sensitive than CT scan for the detection of lung micronodules [47].

  3. 18F-FDG-PET/CT or PET/MRI

    The iodine-negative DTC lesions were found to have increased expression of the glucose transporter-1, and often have FDG uptake [52]. Therefore, 18F-FDG-PET is particularly useful in the detection of recurrent or metastatic DTC in patients with positive Tg and negative WBS, allowing detection of metastases not detected by other imaging modalities [53]. In a recent meta-analysis, the combined sensitivity and specificity for FDG-PET/CT were 93 and 81%, respectively [54].

    Factors influencing PET/CT sensitivity include tumor de-differentiation, larger tumor burden and to a lesser extent, TSH stimulation [47]. PET is more sensitive in patients with an aggressive histological subtype, including poorly differentiated, tall cell, and Hürthle cell thyroid cancer. The sensitivity of PET (ranging from less than 10–30%) is low in patients with a TSH-stimulated Tg < 10 ng/mL. It is therefore recommended to consider 18F-FDG-PET only in DTC patients with a stimulated Tg level ≥10 ng/mL [47]. A meta-analysis of seven prospective controlled clinical trials indicated that FDG-PET under TSH stimulation either by thyroid hormone withdrawal or by rhTSH had slightly improved diagnostic performance in detecting Tg-positive and WBS-negative DTC lesions. FDG-PET/CT is useful in staging, response assessment after chemotherapy, targeted therapies, or radiotherapy and prognostic assessment for patients with cancer [55]. Therefore, PET/CT imaging should be performed as first-line, with empiric 131I treatment being considered only for those patients with no detectable FDG uptake [51]. PET/CT can also identify lesions with high FDG uptake (SUV) that may be more aggressive and should have multi-targeted kinase inhibitors or close monitoring. A study observed that elevated Tg, but normal PET exists as a definitive entity in DTC. Positive Tg with negative PET was regarded as a favorable prognostic indicator to predict symptom-free status during the follow-up period [56].

    However, false positives occur with PET imaging with or without TSH stimulation [50]. The frequency of false-positive lesions varies among series from 0 to 39%, and this high number justifies a fine-needle aspiration (FNA) biopsy with cytology and Tg measurement in the aspirate fluid in cases where surgery is planned, based on PET results.

    FDG-PET/CT is useful in staging, response assessment after chemotherapy, targeted therapies, or radiotherapy and prognostic assessment for patients with cancer [55]. PET/CT imaging is more sensitive and should be performed as first-line, with empiric 131I treatment being considered only for those patients with no detectable FDG uptake [51]. PET/CT can also identify lesions with high FDG uptake (SUV) that may be more aggressive and should have multi-targeted kinase inhibitors or close monitoring. A study observed that elevated Tg, but normal PET exists as a definitive entity in DTC. Positive Tg with negative PET was regarded as a favorable prognostic indicator to predict symptom-free status during the follow-up period [56].

  4. 124I PET/CT

    124I emits positrons, allowing PET/CT imaging in DTC patients. It is used as for dosimetry and also as a diagnostic tool to localize DTC metastases. 124I PET/CT accurately measures the volume, uptake, and half-life of 124I in each DTC lesion, therefore permitting a reliable individual dosimetric assessment for DTC metastases [47]. 124I-PET has higher sensitivity in detecting the residual thyroid tissue and/or DTC metastases than that of WBS (99% vs. 66%) [5761]. The combination of 124I and FDG-PET/CT affords a valuable diagnostic method that can be used to make therapeutic decisions in patients with positive Tg and negative WBS [57, 61]. 124I-PET/CT with thyroid hormone withdrawal was found to detect significantly more foci of metastases of DTC [59]. However, it is unclear whether and to what extent patient preparation with rhTSH rather than thyroid hormone withdrawal affects the diagnostic accuracy of 124I PET/CT [57]. 124I is not yet widely available for clinical use and is primarily a research tool at this time.

  5. Somatostatin receptor scan (SRS)

    Thyroid tumors are known to express SRS, and therefore, 111In-pentetreotide (somatostatin analog) can visualize non-iodine avid DTC metastases with high concentration of SRS. A case of negative WBS recurrent metastatic papillary thyroid carcinoma with positive 111In-pentetreotide scan was reported [62]. Technetium-99m labeled somatostatin analog, 99mTc-Hynic-TOC scintigraphy had a sensitivity of 88.46% (23/26), specificity of 100% (2/2), and an accuracy of 89.2% (25/28) [41]. SRS scintigraphy may be useful both in the staging and monitoring of patients with WBS-negative DTC metastases. 68Gallium-somatostatin analogs PET/CT is currently a promising method to study well-differentiated neuroendocrine tumor which has a better sensitivity and therefore is superior to 99mTc or 111In labeled SRS [63, 64]. SRS scan positive patients are potential candidates for SRS-targeted therapy.

    In addition, 68Gallium-somatostatin analogs PET/CT is currently a promising method to study well-differentiated neuroendocrine tumor which has a better sensitivity and therefore is superior to 99mTc or 111In labeled SRS [63, 64]. 18F-FLT and 11C-MET may also have a diagnostic roles in this clinical setting [65].

  6. Fine-needle aspiration (FNA)

    FNA biopsy for cytology and Tg measurement in the aspirate fluid is performed for suspicious lymph nodes >8–10 mm in their smallest diameter. Non-suspicious and small nodes (<8–10 mm in the smallest diameter) can be monitored with neck ultrasonography [47]. Ultrasonography guidance aspiration may improve the results of FNA biopsy, in particular for small lymph nodes and those located deep in the neck. The measurement of Tg in the FNA biopsy washout fluid (FNAB-Tg) is the more accurate tool to detect DTC recurrences and metastases in the neck [66, 67]. However, the application of FNA biopsy Tg is currently hindered by the absence of methodological standardization, a lack of definite cutoff points, and the ongoing debate regarding its accuracy in nonthyroidectomized patients, those with elevated serum Tg, and those with circulating TgAb [66, 67]. A Tg concentration in the aspirate fluid between 1 and 10 ng/mL is moderately suspicious for malignancy [47]; above 10 ng/mL are highly suspicious of DTC metastases [6870].

In summary, in patients with elevated or rising Tg (>10 ng/mL) or TgAb and no evidence of disease on neck ultrasonography or WBS (if performed), CT imaging of the neck and chest, MRI of the neck and abdomen may be considered. 18F-FDG-PET/CT also plays an important role in the detecting DTC metastases with positive Tg (>10 ng/mL) and negative WBS, and negative conventional imaging. The result of 18F-FDG-PET/CT is helpful in guiding the treatment strategy. FNA biopsy and Tg measurement in washout fluid are helpful in the confirmation of foci detected by 18F-FDG-PET/CT.

3.2. Treatments for Tg-positive and WBS-negative DTC metastases

3.2.1. Empiric 131I treatment

Thyroid hormone withdrawal induces substantial short- and long-term morbidity, decreased quality of life due to associated hypothyroidism.131I therapy may cause early and late sialoadenitis in up to 30% which can lead to xerostomia, dental caries, and stomatitis [71, 72], with a majority of patients suffering from significant changes in physical, psychological, and social well-being [73, 74]. Therefore, the pros and cons of empiric 131I treatment should be well-balanced justified.

The management of elevated serum Tg and radioiodine-negative scans was outlined by Ma et al. [3]. Of 438 patients from 16 studies who were treated empirically with 131I for iodine-negative and Tg-positive DTC disease, 267 (62%) displayed pathological uptakes in the thyroid bed, lungs, bone, mediastinum and lymph nodes. In studies in which data were available for serum Tg levels during TSH suppression therapy or TSH withdrawal, 56% (188/337) patients showed decreased Tg. Of 242 patients from 5 studies who received no specific treatment for iodine-negative and Tg-positive DTC disease, 44% (106/242) showed spontaneous normalization and a significant decrease in serum Tg. Thus, high doses of 131I have therapeutic effects if the Tg level is considered an index of tumor burden, at least in the short term, and could also localize previously undiagnosed recurrences. Therefore, empiric131I treatment may be justified in high-risk patients with serum Tg > 10 ng/mL and a negative WBS and FDG-PET scan results [3, 75, 76]. Pulmonary metastases may be found only on post-therapy WBS [77]. In a study of 283 DTC patients treated with 100mCi (3.7 GBq) of 131I, 6.4% had lung and bone metastases detected after treatment that had been suspected based on high serum Tg alone but had not been detected after 2mCi (74 MBq) 131I WBS [78].

However, most studies in this area have limited reliability as they lacked control groups and an adequate follow-up period [3]. Still missing from our knowledge are long-term survival rates, changes in mass sizes on post-therapy imaging, and radiation-induced side-effects of 131I therapy. Although the tumor burden may be diminished, most patients with negative WBS and positive Tg are not rendered disease free by 131I therapy [79]. Nearly half of patients with Tg-positive and WBS-negative DTC show spontaneous normalization and significant reduction in serum Tg without any specific treatment, 131I therapy should be individualized according to the clinical characteristics and imaging features. A five-year follow-up of 29 patients with elevated Tg (>2 ng/mL) and negative 131I WBS found that 24/29 patients showed Tg decreasing trend without 131I therapy, of whom only one patient recurred; the other 5/29 patients showed a rising trend and all recurred [5].

Therefore, additional diagnostic techniques are strongly recommended for patients with Tg-positive and WBS-negative metastases. If these diagnostic results are positive, treatment options such as surgery, external radiotherapy and tumor embolization can be considered. Empiric 131I therapy is more commonly considered for those with distant metastases or inoperable local disease. If FDG-PET result is negative, one course of 131I treatment may be considered in high-risk patients with. Repeated 131I therapy may be given to patients who had persistent non-resectable DTC metastases and iodine uptake, and there are significant therapeutic benefits until the lesion has been eradicated or the lesion no longer responds to treatment. The risk of repeated therapeutic doses of RAI must be balanced against uncertain long-term benefits. In the case of negative post-therapy WBS, the patient should be considered to have radioiodine-refractory disease and no further 131I therapy should be administered.

3.2.2. Re-differentiation strategies

  1. Retinoic acids (RA) and lithium

    RA are active metabolites of vitamin A able to regulate growth and differentiation of many cell types by binding to specific nuclear receptors, the RA receptors, and the retinoid X receptors (RXR) [80]. Lithium increases the residence time of 131I in the thyroid tissue [37, 81, 82]. RA and lithium [82] were used to redifferentiate metastatic DTC and render them responsive to 131I therapy. However, they only yielded a limited clinical benefit.

  2. Iodine-trapping-related gene transfection

    hNIS protein is a membrane glycoprotein that transports iodide ions into thyroid cells. This process, known as iodine trapping, is stimulated directly by TSH. Other proteins, including thyroperoxidase (TPO) and pendrin, also play an important role in the thyroid metabolism of iodine [83]. Strategies of gene transfection focused on NIS; TPO has been studied to enhance tumor uptake iodine [84, 85]. Co-transfection of the hNIS and hTPO genes can lead to longer retention of radio iodine [85]. Targeted NIS gene transfer, by viral and non-viral vectors, followed by radionuclide 131I, 188Re, 211At therapy, has been recently suggested for the treatment of advanced or WBS-negative DTC metastases. In thyroid cells, TSH stimulates NIS synthesis [86]. Therefore, hTSHR transfection was investigated in FTC-133 thyroid cells, which improved the expression of thyroid-specific molecules including TSHR, NIS, TPO, and Tg and radioiodide uptake [87, 88]. Iodine-trapping-related gene transfection has not been used clinically yet.

  3. MAPK kinase inhibitor

    Mitogen-activated protein kinase (MAPK) signaling inhibits the expression of thyroid hormone biosynthesis genes, including the NIS and TPO, which facilitate iodine uptake and organification, respectively [89, 90]. Inhibition of the MAPK pathway may renew the therapeutic efficacy of 131I by enhancing uptake in patients with thyroid cancer that is refractory to 131I [82]. MAPK1-2 inhibitor selumetinib (AZD6244, ARRY-142886), orally administered at a dose of 75 mg twice daily increased the uptake of 124I in 12 of 20 patients. Selumetinib enhanced 131I uptake in eight patients with advanced DTC. After 131I treatment, partial responses were achieved in 5, stable disease in 3. No severe adverse events were observed [82].

In summary, strategy of re-differentiation of iodine-negative DTC metastases by RA has limited clinical benefit. Iodine-trapping-related protein transfection remains experimental. MAPK kinase inhibitor needs to be confirmed in large population.

3.2.3. Multi-targeted kinase inhibitors

Both sorafenib (BAY 43-9006) and lenvatinib are multi-kinase inhibitors with potent activity against RAF, VEGF receptors, fibroblast growth factor receptors, PDGF receptor, c-KIT and RET kinases [37, 88, 91]. Sorafenib and lenvatinib are both FDA approved for iodine refractory DTC metastases [92]. They achieved clinical benefits in terms of partial response of 12.5–38%, progression-free survival from 9 to 24 months in radioiodine-refractory DTC metastases [37, 91]. The therapeutic effects of other tyrosine kinase inhibitors including sunitinib, imatinib, vandetanib were also summarized [37] and a dozen ongoing trials currently listed in the ClinicalTrials.gov database, evaluating 12 kinase-inhibiting drugs [93].

Adverse effects occurred in 98.6% patients receiving sorafenib: the most frequent were hand-foot skin reactions, diarrhea, alopecia, and rash or desquamation [94].

Selection of a targeted agent should depend on disease trajectory, side effect profile, and goals of therapy. Kinase inhibitor therapy should be considered in radioiodine-refractory DTC metastases, rapidly progressive, symptomatic and/or imminently threatening disease not otherwise amenable to local control using other approaches. Patients who are candidates for kinase inhibitor therapy should be thoroughly counseled on the potential risks and benefits of this therapy as well as alternative therapeutic approaches including best supportive care [47].

3.2.4. Other treatments

  1. TSH suppression

    TSH suppression is considered essential in the treatment of patients with positive Tg and negative WBS, because TSH is a trophic hormone that can stimulate the growth of cells derived from thyroid follicular epithelium [45, 95, 96]. Therefore, the recommended TSH level is below 0.1 mU/L, or slightly below or slightly above the lower reference range [9].

  2. Surgery and stereotactic radiotherapy (SBRT)

    Most recurrent DTCs respond well to surgery and SBRT [45, 97]. The isolated skeletal metastasis of DTC is recommended for surgery or SBRT [9]. Neurosurgery or SBRT is preferred treatments for solitary brain metastases of DTC [98, 99]. SBRT is considered for loco-regional recurrence that is not surgically resectable, or with extra-nodal extension or involvement of soft tissues, in particular in patients with no evidence of distant disease, but has no role in most patients with resectable lymph node metastases [47].

  3. Chemotherapy

    Systematic chemotherapy can be considered for DTC lesions with positive Tg and negative WBS that are not surgically resectable, not responsive to 131I, not amenable to EBRT treatment, or not responsive to multi-targeted kinase inhibitors, and have clinically significant structural disease progression during the last 6–12 months. Two of 49 (3%) patients with DTC metastases had a response to five chemotherapy protocols [100]. In a review by Ahuja et al., 38% of patients with thyroid cancer had reduction in tumor mass to doxorubicin [101]. Combination chemotherapy does not show clear superiority to doxorubicin therapy alone [102]. Therefore, the traditional chemotherapy has limited effects on iodine refractory DTC metastases [9, 103].

  4. Other treatments

    Other treatments include percutaneous ethanol injection (PEI), radiofrequency, or laser ablation.

PEI for patients with metastatic DTC in lymph node is promising as a nonsurgical-directed therapy [104, 105]. Most of the studies limited PEI to patients who had undergone previous neck dissections and 131I treatment, those who had FNA-proven DTC in the lymph node and those with no known distant metastases [106]. A general consensus from studies and reviews is that PEI could be considered in patients who are poor surgical candidates [47]. Radiofrequency ablation has been associated with a mean volume reduction that ranges between approximately 55–95% [107, 108], and 40–60% complete disappearance of the DTC metastases in the treatment of recurrent thyroid cancer [108, 109]. More recently, preliminary findings using ultrasonography-guided laser ablation for treatment of cervical lymph node metastases have been reported [110].

In summary, true-negative WBS with positive Tg may be due to benign thyroid remnants (possibly containing thyroiditis) or, rarely, nonthyroidal tissue producing Tg. False-negative WBS with positive Tg can be caused by a defective of acquired iodine-trapping inactivation; dedifferentiation of tumor which can still produce Tg but has lost its iodine-trapping ability; small dispersed microscopic metastases. Other radioisotopes and additional diagnostic options play an important role in the ascertainment of patients with negative WBS and Tg-positive DTC metastases. FDG-PET/CT should be considered in high-risk DTC patients with negative WBS and positive Tg. If FDG-PET diagnostic results are negative, one course of 131I treatment may be considered in high-risk patients and individualized. No further 131I therapy is indicated for patients with a negative post-therapy WBS. The preferred hierarchy of treatment for Tg-positive and WBS-negative metastases is surgical excision of loco-regional disease in potentially curable patients, 131I therapy for residual radioiodine-responsive disease, external beam radiation or other directed treatment modalities such as thermal ablation, TSH suppression for patients with stable or slowly progressive asymptomatic disease, and systemic therapy with multi-kinase inhibitors, especially for patients with significantly progressive macroscopic refractory disease.

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Written By

Chao Ma

Submitted: 18 November 2015 Reviewed: 23 May 2016 Published: 07 September 2016