Abstract
Differentiated thyroid cancer in children is a rare disease, accounting for only 1.4% of all pediatric malignancies. The diagnosis, biological behavior and treatment of differentiated thyroid cancer in children is different from that in adults. While there are many unresolved issues regarding approaches to management of differentiated thyroid cancer in the pediatric population, there is near universal consensus that treatment of this disease, which includes total thyroidectomy, central lymph node dissection at the time of initial surgery in those with nodal metastases, and the possible use of iodine-131 radiotherapy, is best performed by specialists including high-volume endocrine surgeons and experts with experience in calculating and administering radioactive iodine in children, when deemed appropriate.
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Introduction
While thyroid cancer represents only 1.4% of all pediatric malignancies, 10% of thyroid cancers occur in those younger than 21 years [1, 2]. The biological behavior of differentiated thyroid cancer is different in children from that in adults. The well-differentiated papillary or follicular subtypes are the most commonly occurring pathological types in children, seen in 95% and 5%, respectively [3], compared to an occurrence rate of 70–80% and 15% in adults [4]. There are other differences, as well. Children typically present with advanced disease at diagnosis [5,6,7,8,9] (Fig. 1). The size of the primary tumor is frequently larger in children than in adults. Extensive regional nodal involvement at diagnosis is present in between 60% and 80% of children with differentiated thyroid cancer [2, 3, 5,6,7,8,9] compared to only 30% to 40% of adults with this disease [4]. Children with differentiated thyroid cancer have a higher rate of distant metastases than adults, typically to the lungs, where metastases are present in 20–25% of children [5,6,7,8,9] compared to less than 7% of adults [4]. Higher rates of both local and distant recurrences occur in children compared to adults with differentiated thyroid cancer. Despite this, children with differentiated thyroid cancer have a rapid response to therapy and an excellent prognosis that is significantly better than their adult counterparts with advanced disease. Overall survival in children with differentiated thyroid cancer is greater than 90%, with survival rates of 98% at 5 years and 15 years compared to 40% at 5 years and 20% at 10 years in adults with distant metastases [2, 4, 10, 11]. Unfortunately, progression-free survival is only between 65% and 70% for children with differentiated thyroid cancer, mandating lifelong surveillance [12,13,14].
Despite extensive investigation and the recent publication of the American Thyroid Association (ATA)’s Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer [15], the treatment of pediatric differentiated thyroid cancer remains controversial for a variety of reasons. Despite its rising incidence [3, 10], pediatric differentiated thyroid cancer remains a rare entity, hence it is difficult to obtain a large single-institution series to evaluate. Moreover, there have been differences in treatment methods at various institutions as well as at the same institution over time, and as a result there has been no large retrospective study of pediatric patients with a well-defined treatment protocol nor the performance of a controlled prospective study in this patient population [8, 16]. Rather, most treatment plans have been derived from experiences in adults with papillary thyroid cancer [16].
The goals of initial treatment of differentiated thyroid cancer in both adults and children are to eradicate disease and extend disease-free survival. Typically, treatment has involved surgery in the form of thyroidectomy with lymph node dissection and the use of radioactive iodine (I-131) either to ablate remnant disease, allowing for surveillance with thyroglobulin levels, or to treat local and distant metastatic disease. But children are not small adults. In general, the complication rates from thyroidectomy are higher in children than in adults [17, 18]. Moreover, children are more sensitive to the effects of ionizing radiation and have a longer life expectancy during which the adverse effects of I-131 radiotherapy might manifest. Although death from differentiated thyroid cancer is low, recent studies reveal an increase in all-cause mortality for childhood survivors of this disease, predominantly from the development of secondary malignancies in those treated with I-131 radiotherapy [11, 19,20,21,22,23,24]. Thus, awareness of the complications of treatment assumes increasing importance, making it imperative to balance risks against potential gains from increasingly aggressive therapies.
This review provides an overview of the current treatment practices and the recent ATA guidelines [15] as well as a discussion of several ongoing challenges in managing this group of patients.
Initial treatment of pediatric differentiated thyroid cancer
Surgery
Current ATA pediatric guidelines [15] suggest that definitive surgical treatment for differentiated thyroid cancer is total or near-total thyroidectomy with central neck dissection at the time of initial surgery in all children with nodal metastases. But is total thyroidectomy necessary in all cases? Performance of central neck dissection — which involves the therapeutic or prophylactic resection of Level VI compartment lymph nodes — is also controversial because it is associated with an increased risk of hypoparathyroidism. Finally, who is best qualified to perform thyroid surgery in children with differentiated thyroid cancer to avoid complications?
In addition to postoperative pain, complications of total thyroidectomy include recurrent laryngeal nerve damage with resultant vocal cord paralysis or dysphagia, and either transient or permanent parathyroid dysfunction. Not only do children undergoing thyroidectomy have higher endocrine-specific complications than adults (9.1% compared to 6.3%), but children ages 0–6 years fare worse than those ages 5–12 years or those age 13–17 years, with surgical complication rates of 22% compared to 15% and 11%, respectively [17]. However when total thyroidectomy in children was performed by a high-volume endocrine surgeon, defined as a surgeon who performs more than 30 cervical endocrine procedures per year, overall outcomes were optimized and the risk of parathyroid dysfunction decreased to less than 2% [18, 25].
In adults, there are data correlating the size of the primary tumor with the risk of advanced disease features as well as with prognosis [26, 27]. Consequently, the 2015 ATA management guidelines for adults with thyroid nodules and differentiated thyroid cancer [28] state that in select cases a hemithyroidectomy is considered sufficient for those without metastases and with primary tumors <4 cm, and further that a lobectomy can be considered for low-risk patients without metastases whose tumors are less than 1 cm. However, for multifocal, bilateral or advanced thyroid cancer (infiltration of surrounding tissues, local or distant metastases), total thyroidectomy is mandated. Unfortunately, studies correlating primary tumor size with risk are not available in children. Rather, limited data in children who underwent less than total thyroidectomy demonstrated that not having a total thyroidectomy was one of the greatest risk factors for developing recurrent disease, increasing the relative risk of relapse by a factor of 10 in some cases [14, 29, 30]. Radical surgery was estimated to be the most significant factor for disease-free survival in this population [14].
Until prospective data on the safety and efficacy of lobectomy for selective use in children with low-risk pediatric differentiated thyroid cancer become available, total thyroidectomy is the recommended treatment in all children with this disease. Not only are children at increased risk of bilateral (30%) and multifocal (65%) disease but, as previously stated, they are at increased risk of recurrence necessitating a second surgery if a total or near-total thyroidectomy was not initially performed [11, 14, 15]. Further, surgical re-intervention for recurrent disease is associated with a higher complication rate in those initially treated with lobectomy compared to those initially treated with total thyroidectomy [31].
The performance of a total thyroidectomy allows for the use of I-123 or I-131 to detect and I-131 to treat remnant thyroid tissue, local and distant metastases. Serum thyroglobulin levels for the detecting residual or recurrent disease are more sensitive when all normal thyroid tissue has been removed or ablated with I-131 [8].
In addition to decreasing the risk of residual or recurrent locoregional disease, the performance of central neck dissection in those with nodal metastases decreases overall disease burden, which might increase the efficacy of subsequent I-131 treatment [16]. On the other hand, performance of central neck dissection increases the risk of developing hypoparathyroidism. While the extent of initial surgery has the greatest effect on improving long-term disease-free survival, it is important to balance the potential benefit of achieving surgical remission against the risks of more aggressive surgical procedures.
Radioiodine therapy: A risk-adaptive approach
The goals of I-131 radiotherapy are two-fold: (1) the ablation of remnant thyroid tissue following total thyroidectomy to facilitate disease surveillance with thyroglobulin levels, imaging or both; and (2) the treatment of residual thyroid cancer or its metastases. But the utility of postoperative I-131 radiotherapy remains controversial. Studies of both adults and children with advanced differentiated thyroid cancer who received postoperative I-131 radiotherapy showed improved survival, decreased disease progression and lower recurrence rates compared to those who did not receive I-131 treatment [30, 32,33,34,35,36,37]. While there is general agreement that I-131 radiotherapy should be used to treat residual disease not amenable to surgical resection as well as iodine-avid metastatic disease [36, 37], I-131 radiotherapy has not been proved to clearly benefit those with low-risk thyroid cancer after a complete surgical resection [38, 39]. Data show that while the use of radioiodine therapy in adults younger than 45 years with low-risk differentiated thyroid cancer increased from 3.3% to 38% between 1973 and 2007, overall survival rates remained constant and there has been an increasing incidence of secondary cancers in those with low-risk disease treated with I-131 radiotherapy [40]. Although one of the most serious sequelae is the development of secondary malignancies [11, 19,20,21,22,23,24,25], it is not the only adverse effect of I-131 radiotherapy. Acute adverse effects occurring at the time of treatment include mild nausea or emesis from radiation gastritis in approximately 50%, acute sialadenitis in as many as 30% and painful swelling of remnant disease or of metastases in 10–20% [33, 37, 41]. Transient, mild leukopenia and thrombocytopenia can occur in up to 66% of patients about 4–6 weeks post-therapy but blood counts typically normalize by 3 months [37, 42]. Secondary malignancies aside, there are numerous other late effects of I-131 radiotherapy (Table 1). These include chronic sialadenitis leading to xerostomia, which can have a negative effect on a person’s quality of life [37, 41, 43]. Females can experience short-term menstrual irregularities and transient amenorrhea, and while permanent infertility has not been reported, birth defects can occur in children conceived in the first 6 months following I-131 treatment [44,45,46]. In males, transient elevation of follicle-stimulating hormone, azoospermia, oligospermia and decreased spermatogenesis without effect on testosterone production have been reported [47, 48]. Therefore, ATA pediatric guidelines [15] recommend that attempts at conception be avoided for at least 4 months following I-131 radiotherapy in males and 12 months in females. Sperm banking should be considered when cumulative I-131 activities are expected to exceed 400 mCi (14.8 GBq). Finally, although rare, radiation pneumonitis and subsequent radiation fibrosis occur in approximately 3%. In people with differentiated thyroid cancer and lung metastases, the risk of pulmonary fibrosis correlates with the intensity of I-131 uptake on whole-body imaging and varies inversely with patient age. As many as 10% of children with lung metastases treated with I-131 radiotherapy develop pulmonary fibrosis compared with only 1% of adults [33, 37, 41]. As a result, dosimetry is recommended to guide I-131 radiotherapy in children with extensive pulmonary metastases.
Both the prevalence and the severity of adverse treatment effects appear to correlate with the cumulative activity of I-131 received [16]. Given the excellent prognosis as well as the life expectancy of children and adolescents with differentiated thyroid cancer, these side effects — particularly the risk of developing a secondary malignancy — must be strongly considered when contemplating treatment with radioactive iodine.
To maintain the low disease-specific mortality currently experienced by children with differentiated thyroid cancer as well as to reduce the potential complications of therapy, the ATA Pediatric Task Force on Thyroid Nodules and Differentiated Thyroid Cancer attempted to prospectively identify children in whom I-131 therapy would be indicated while limiting potential overtreatment in those unlikely to benefit. The task force defined three pediatric risk-stratification groups, based on the use of the tumor–lymph node–metastases (TMN) classification system. These pediatric risk-stratification groups do not define the risk of disease mortality in those with differentiated thyroid cancer but rather identify children at risk for persistent cervical disease; these groups are used to determine who should undergo postoperative staging for distant metastases and potential radioiodine treatment [15]. The ATA pediatric low-risk group [15] includes those in whom disease is confined to the thyroid gland with either no or non-assessed regional lymph node metastases (N0; NX) or children with incidental N1a nodal micro-metastases. Children in this group are at lowest risk for distant metastases (Fig. 2). The ATA pediatric intermediate-risk group [15] includes children with extensive metastases to Level VI nodes (N1a) or minimal metastases to unilateral, bilateral or contralateral levels I, II, III, IV or V cervical or superior mediastinal nodes (N1b). ATA pediatric intermediate-risk group patients are at low risk for distant metastases but at increased risk of incomplete resection and persistent cervical disease. The ATA pediatric high-risk group [15], children with regionally extensive (N1b) or locally invasive T4 tumors, are at highest risk for incomplete resection, persistent disease, and distant metastases. The ATA pediatric guidelines not only define these patient groups but detail initial postoperative staging, suggested thyroid stimulating hormone (TSH) goals, and surveillance management strategies for those with no evidence of disease following initial treatment [15].
Previously, all children with differentiated thyroid cancer underwent post-surgical whole-body staging with either I-131 or, preferably, I-123. The recent ATA pediatric guidelines [15] suggest that the postoperative whole-body staging scan as well as radioiodine therapy be omitted for children in the pediatric low-risk group (Fig. 2). Rather, these children are initially assessed and subsequently monitored for persistent or recurrent disease with neck ultrasound and serial TSH-suppressed thyroglobulin levels following total thyroidectomy. On the other hand, children in either the pediatric intermediate or high-risk groups [15] undergo initial staging with a TSH-stimulated thyroglobulin level and an I-123 whole-body scan, preferably with single-photon emission computed tomography (SPECT)/CT of the neck (Fig. 3) following total thyroidectomy and central node dissection. In those with negative antithyroglobulin antibodies, the decision to administer I-131 therapy in the pediatric intermediate and high-risk groups is based on the results of these two studies, according to an algorithm presented in the ATA pediatric guidelines [15].
According to the ATA pediatric guidelines [15], I-131 radiotherapy is not indicated in children in the pediatric intermediate- or high-risk groups who have no or minimal I-123 uptake in the thyroid bed and a stimulated thyroglobulin level <2 ng/mL unless the child had a T4 tumor or known residual microscopic cervical disease (Fig. 4). In those with no or minimal I-123 uptake in the thyroid bed but with a stimulated thyroglobulin level of 2–10 ng/mL, either I-131 therapy with post-treatment scan, LT4 suppression, or both can be considered (Fig. 5; [49]). I-131 radiotherapy is recommended in those with no or minimal I-123 uptake in the thyroid bed but with a stimulated thyroglobulin level >10 ng/mL as well as in those with distant metastases but no cervical uptake outside the thyroid bed. Finally, if there is cervical uptake outside the thyroid bed, either with or without distant metastases, then anatomical imaging should be obtained to identify residual disease amenable to surgical resection. If no such disease is identified, then I-131 therapy with a post-treatment scan is recommended. Post-treatment scans at 4–10 days following I-131 radiotherapy are highly recommended because there is a dose-related sensitivity of I-131 in disease detection, with new or additional lesions identified in up to 46% of cases [8, 9, 15] (Fig. 6; [50]).
Patient preparation for postoperative staging and potential I-131 radiotherapy
More extensive patient preparation is necessary when performing an I-123 postoperative staging whole-body scan for differentiated thyroid cancer compared to I-123 imaging of benign thyroid disease. Thyrotropin levels above 30 mU/L are considered necessary not only for I-123 postoperative imaging but also when performing I-131 remnant ablation or I-131 therapy, when deemed appropriate. To achieve these high TSH levels, levothyroxine (LT4) should be discontinued for 3–6 weeks prior to planned staging I-123 whole-body imaging or I-131 radiotherapy although supplemental triiodothyronine (T3) can be administered up to 2 weeks prior. Because children are more sensitive to the effects of hypothyroidism than adults, the off-label use of intramuscular administration of recombinant human thyrotropin stimulation (rhTSH) — as opposed to performing thyroid hormone withdrawal as part of the preparative regimen for imaging — results in an unimpaired quality of life [51,52,53,54,55]. While rhTSH results in a lower radiation exposure to the body related to faster peripheral I-131 clearance in the euthyroid peripheral metabolic state [5], limited available data suggest that when used for I-131 radiotherapy in those with persistent local or metastatic disease, rhTSH might not result in an equally high radiation absorbed dose to the tumor compared to the hormone withdrawal method [16].
A low-iodine diet instituted 2 weeks prior to postoperative imaging as well as prior to I-131 radiotherapy has been shown to be effective in lowering the blood concentration of stable iodine, which competes with I-131 uptake [56, 57]. The use of a low-iodine diet increases the effectiveness of I-131 treatment by increasing I-131 uptake in remnant thyroid tissue as well as in metastases and is recommended to maximize therapeutic efficacy [15, 16]. Information regarding low-iodine diets can be found at Thyca.org.
If preoperative staging evaluation has included the use of intravenous iodinated contrast agent, it has been advised to wait 8–12 weeks before performing post-surgical I-123 whole-body staging or administering therapeutic I-131; however, a recent publication presents data that suggest that this interval can be as short as 4 weeks and that current guidelines be revisited [58].
Selection strategies for determining I-131 treatment activities
There are no standard administered activities for radioiodine treatment of children with differentiated thyroid cancer. There are two approaches to dose selection: empirical dosing in which fixed I-131 activities are administered that are sometimes based on patient weight, or the use of dosimetry in which whole-body and blood iodine clearance measures in addition to tumor surveys provide estimates of maximum tolerated doses to critical organs (bone marrow, lungs) [59, 60] or estimates of doses for maximal treatment efficacy [61, 62]. While the ATA pediatric guidelines [15] do not recommend for or against either approach; they do recommend that all I-131 treatment activities be calculated by experts with experience in dosing children.
At our institution, we typically use a risk-adaptive empiric strategy in which fixed I-131 activities, based on adult guidelines and adjusted for patient weight and additional safety factors dependent on patient age, are administered for initial I-131 treatments with some exceptions [8, 9]. We reserve dosimetry for younger children (those younger than 10 years); those who have undergone prior chemotherapy or radiotherapy or in whom thyroid cancer is a secondary malignancy (Fig. 6); those with extensive distant or pulmonary metastases; or when cumulative doses approach 250–500 mCi (9.3–18.5 GBq). Verburg and others [16, 42, 63,64,65], based on a strong body of literature, suggested that the dosimetric approach might be of greater benefit than administering fixed activities in those with advanced disease. However, determination of treatment activities is confounded by highly variable patient-specific factors such as I-131 avidity of tumor tissue, and tumor size and shape, among others, which might be as or more important than the administered activity for effective treatment [65].
Issues such as the management of known or suspected residual or recurrent disease identified 6–12 months after completion of initial treatment based on suppressed thyroglobulin levels, and the management of children with known distant metastatic disease following therapeutic I-131 radiotherapy, or of those with suspected or known non-iodine-avid disease, is beyond the scope of this manuscript. However, when a pediatric patient with known or suspected non-iodine-avid disease is encountered based on post-thyroidectomy I-123 whole-body scans, ultrasound, surgical, pathological, or clinical findings, imaging with fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography (PET)/CT is recommended.
Surveillance and long-term follow-up for each of the ATA pediatric risk groups includes periodic physical examinations, neck ultrasound and laboratory testing of suppressed thyroglobulin levels. TSH-stimulated I-123 or I-131 whole-body imaging is no longer a routine part of these follow-up evaluations, except in very specific situations. The specific recommendations for TSH suppression and surveillance for each of the groups is well delineated in the ATA pediatric-specific guidelines [15].
Conclusion
Despite the aggressive nature of differentiated pediatric thyroid cancer, overall survival is excellent. However no treatment is without risk. It is imperative to be aware of the complications of treatment and balance these risks against potential gains from increasingly aggressive therapies and the very real lifelong possibility of recurrence.
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Parisi, M.T., Khalatbari, H., Parikh, S.R. et al. Initial treatment of pediatric differentiated thyroid cancer: a review of the current risk-adaptive approach. Pediatr Radiol 49, 1391–1403 (2019). https://doi.org/10.1007/s00247-019-04457-7
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DOI: https://doi.org/10.1007/s00247-019-04457-7