Abstract
Background:
It is well known that the thyroid gland is sensitive to the damaging effects of irradiation (X-radiation or 131I¯). For this reason, during exposure to 131I- metaiodobenzylguanidine (MIBG) in children with neuroblastoma (NBL), the thyroid gland is protected against radiation damage by the administration of either potassium iodide (KI) or a combination of KI, thyroxine, and methimazole. Although hypothyroidism and benign thyroid nodules are frequently encountered during follow-up of these children, differentiated thyroid carcinoma (DTC) has never been reported after treatment with 131I-MIBG in children who have not been given external beam irradiation. Here, we describe the first two cases of DTC after 131I-MIBG-therapy.
Patient Findings:
A 6-year-old boy, treated with 131I-MIBG for NBL at the age of 4 months, and a 13-year-old girl, treated at the age of 9 months, were both diagnosed with DTC at 5 and 12 years after 131I-MIBG treatment, respectively. Both children received thyroid protection during exposure to 131I-MIBG. In each child DTC was discovered in nonpalpable nodules by thyroid ultrasound.
Summary:
The first two pediatric patients with DTC after treatment with 131I-MIBG are reported.
Conclusions:
Both these cases of DTC after 131I-MIBG for childhood NBL underline the importance of adequate thyroid protection against radiation exposure during treatment for NBL. Children who have been treated with 131I-MIBG should be given life-long follow-up, not only with regard to thyroid function, but also with surveillance for the development of thyroid nodules and thyroid cancer.
Introduction
In the past, the thyroid gland was protected against uptake of circulating 131I ¯ by administering potassium iodide (KI) from 1 day before until 14 days after 131I-MIBG treatment. However, uptake of 131I ¯ in the thyroid gland has been reported in 21% of the scintigraphic images taken on day 3 or 7 after the administration of 131I-MIBG (9). Furthermore, after 6 years of follow-up, subclinical hypothyroidism (SH) was observed in 56% of the patients (10). For this reason, the thyroid protective strategy was changed into the combination of KI (dilute), methimazole (block), and thyroxine (T4) (replace), and is also known as “dilute-block-replace (DBR) prophylaxis.” The application of DBR prophylaxis resulted in a decreased occurrence of SH (17%) and a decreased visibility of the thyroid gland on scintigraphy (5%) (11). In addition to SH, thyroid nodules have been described after 131I-MIBG administration (10).
Here, we describe two children who were recently diagnosed with DTC 5 and 12 years after 131I-MIBG treatment. The first patient received DBR prophylaxis, whereas the other received protection with KI.
Written informed consent for publication was obtained from both patients and their parents.
Patients
The first patient, a 6-year-old boy, presented at the age of 4 months with NBL, located in the left adrenal gland, with liver and bone marrow metastases (stage 4). He was treated with four courses of 131I-MIBG (total dose 300 milliCurie [mCi]/11 Gigabequerel [GBq]) and six courses of chemotherapy (4× etoposide and carboplatin, 2× vincristin, etoposide, carboplatin, and ifosfamide). Afterwards his NBL was in complete remission. Before treatment with 131I-MIBG, his plasma thyrotropin (TSH) concentration was mildly elevated (6.0 mIU/L) and his free T4 (FT4) concentration was normal (17.2 pmol/L). During treatment with 131I-MIBG, the thyroid gland was protected with KI (10% solution, thrice daily 0.3 mL), T4 (125 μg/m2 per day), and methimazole (0.25 mg/kg twice daily). The thyroid gland was not visible in the scintigraphic images performed 3 and 7 days after each 131I-MIBG course. During follow-up, the TSH concentration was intermittently elevated (range 3.1–6.7 mU/L), for which he was referred, at age 6, to the department of pediatric endocrinology. Anti-thyroid peroxidase (TPO) antibodies were not measurable. Ultrasonography of the thyroid gland revealed a solitary lesion (1.4×1.4×0.9 cm) in the left thyroid lobe with some calcifications. Fine-needle aspiration cytology (FNAC) was highly suggestive for papillary thyroid carcinoma. There were no distant metastases and no involvement of the cervical lymph nodes. After hemi-thyroidectomy, a histologic examination of the thyroid gland confirmed the diagnosis and, subsequently, he was treated with total thyroidectomy and 131I ¯ ablation therapy (54 mCi/2000 MBq). Due to the presence of thyroglobulin (Tg) after the first ablation therapy, a second 131I ¯ ablation therapy was given (135 mCi/5000 MBq). Postoperatively, there was no hypoparathyroidism or lesion of the recurrent laryngeal nerve. At present, he is feeling well with T4 supplementation.
The second patient was a 13-year-old girl, diagnosed with paravertebral (thoracal) NBL at the age of 9 months. She was treated with two courses of 131I-MIBG (total dose 350 mCi/13 GBq) and two courses of chemotherapy (vincristin, carboplatin, etoposide, and cyclophosphamide), after which she has remained in complete remission. During 131I-MIBG treatment, she received thyroid gland protection with KI (10% solution, thrice daily 0.3 mL). The thyroid gland was not visible in scintigraphic images. During follow-up, thyroid function was normal (TSH<4.5 mU/L, FT4 within the age-specific reference range). Ten years later, the girl was diagnosed with a solitary bone cyst that was punctured and was shown to be benign. However, at the age of 13 years, due to two severe fractures (hip and femur) after only mild trauma, the girl's calcium metabolism was evaluated. Laboratory testing showed hypercalcemia due to primary hyperparathyroidism, (alimentary) vitamin D deficiency and a normal thyroid function (total plasma calcium 3.21 mmol/L [=increased], parathyroid hormone concentration 88.4 pmol/L [=increased], 25 OH Vitamin D 15 nmol/L [=decreased], alkaline phosphatase 404 mU/L [=increased], phosphate 0.72 mmol/L [=decreased], TSH 4.7 mU/L, FT4 12.6 pmol/L, and no measurable anti-TPO antibodies). An ultrasound investigation showed an enlarged parathyroid gland on the right side and a solitary nodule (1.8 cm) in the right thyroid lobe. An MIBI scan showed increased uptake of both parathyroid glands on the right side. FNAC of the solitary thyroid nodule was nondiagnostic. The patient underwent unilateral parathyroidectomy and hemithyroidectomy of the right thyroid lobe. A histological examination showed benign parathyroid adenoma. The thyroid nodule consisted of nodular hyperplasia with a small (0.2 cm) papillary thyroid carcinoma. The postoperative course was complicated by severe hypocalcaemia requiring large amounts of intravenous administration of calcium (hungry bone syndrome). After 6 months, a total thyroidectomy was performed. At present, the girl is clinically well without any calcium supplements. To enable serum Tg as a marker for follow-up, she has been given postoperative radioablation.
Genetic analyses
In the absence of clues for specific tumor predisposition syndromes, array CGH (4×180K oligo array, custom design ID 023363; Agilent Technologies, Inc., Santa Clara, CA) was done in both patients, to exclude constitutional (micro)deletions and/or (micro)duplications. The array CGH did not show any abnormalities in both patients. Karyotyping was done to exclude (balanced) translocations and showed a normal 46,XY and 46,XX karyotype for the boy and the girl, respectively.
In the girl, due to the co-occurrence of primary hyperparathyroidism and the possibility that her NBL might have been a pheochromocytoma (supported by the urinary catecholamine excretion pattern before treatment), analysis for MEN 1 and MEN2A syndrome was done in lymphocytic DNA. A sequence analysis of all MEN1 exons and the selected RET exons 10, 11, 13, 14, 15, and 16 did not show any abnormalities.
Discussion
We report the first two cases of DTC after 131I-MIBG treatment for childhood NBL. Until now, DTC has only been described in children with NBL who have received external beam irradiation.
This article should alert all physicians participating in the care for these children ([pediatric] oncologists, [pediatric] endocrinologists, and nuclear medicine physicians) that children who have been treated with 131I-MIBG for NBL may develop DTC. Second, it implies that adequate thyroid protection during treatment with 131I-MIBG is important.
It is well known that the thyroid gland is highly sensitive to the carcinogenic effects of ionizing radiation (12 –14). The Chernobyl disaster has demonstrated that 131I ¯ exposure increases the risk for children to develop DTC (15).
We could not observe the uptake of 131I ¯ in the thyroid gland in the scintigraphic images. For this reason, we should consider other causes than radiation damage for DTC to occur in these children, such as genetic predisposition. Perhaps children with NBL are inherently at an increased risk for DTC, irrespective of previous radiation exposure. In the girl, it may even be commented that the 0.2 cm focus of PTC was an incidental finding, without clinical significance. In the boy, the TSH levels were already elevated before exposure to 131I-MIBG, and it is unknown whether this may have contributed to the development of DTC.
Since the genetic screening in both our patients for tumor predisposition syndromes was negative, we hypothesize that DTC in these children was caused by 131I ¯ exposure. The absence of a visible uptake of 131I ¯ in the thyroid gland in the scintigraphic images may be explained by a very low uptake of the radiopharmaceutical. What the thyroid irradiation levels have been can, therefore, not be easily speculated. We believe that the dose of 131I ¯ in the thyroid gland must have been very low, but that the iodide must have been taken up in the thyroid gland for a prolonged time, resulting in thyroid damage. The most convincing evidence that the uptake of 131I ¯ in the thyroid gland was the cause for thyroid dysfunction in the children with NBL, despite the missing relationship with uptake in the gland in the scintigraphic images, was that we noted a decrease in the occurrence of hypothyroidism after changing the thyroid protection from KI to the combination of KI with thiamazol and T4 (11). Both these cases of DTC after exposure to 131I-MIBG support our hypothesis that the thyroid gland is exposed to low doses of 131I ¯, which increases the risk for thyroid cancer (16). In addition, the development of DTC in children with NBL may subsequently be the consequence of having a very radiosensitive thyroid gland. Data that support this hypothesis were published by the Childhood Cancer Survival Study (CCSS), in which an increased relative risk for thyroid cancer was described after external radiation for children with NBL compared with children with leukemia or Hodgkin's disease (RR 2.2 vs. 1.0 and 1.1, respectively) (14). It should be commented, though, that in the CCSS cohort, the NBL patients were much younger of age during radiation exposure compared with the leukemia and Hodgkin's disease patients (2 years vs. 7 and 15 years of age respectively). In addition, both our patients were very young at the moment of exposure to 131I-MIBG (4 and 9 months of age respectively).
The prevention of uptake of free circulating 131I ¯ by KI administration alone was earlier described as being insufficient with regard to thyroid function (9). For this reason, thyroid protection during 131I-MIBG treatment was changed into the so-called DBR strategy. The combination of KI (diluting the amount of circulating 131I ¯ and down-regulating the natrium-iodide symporter, thus inhibiting the uptake of 131I ¯ in the thyroid gland), methimazole (inhibiting the organification, and, thus, blocking the binding of 131I ¯ to Tg), and T4 (replacing the thyroid hormone that is decreased due to the administration of methimazole and, thus, preventing the rise in TSH during MIBG administration) resulted in a decrease of occurrence of hypothyroidism (11). However, the patients reported here suggest both methods of thyroid protection may be insufficient with regard to the occurrence of thyroid cancer.
It is important to monitor thyroid function in children after treatment with 131I-MIBG. First, an adequate thyroid function during childhood is essential for adequate growth and development into adulthood. Second, a major role in the pathogenesis of nodules and thyroid cancer has been ascribed to the level of circulating TSH. A prolonged elevated concentration of plasma TSH increases the incidence of thyroid nodules. If TSH is elevated during exposure to irradiation, the susceptibility of the thyroid gland to radiation is increased (17,18). In irradiated rats after hypophysectomy, no thyroid tumors developed at all, suggesting that the complete absence of TSH can even prevent the development of DTC (19). The administration of T4 in irradiated rats resulted in a lower incidence of thyroid tumors (20). Although this has not been confirmed in humans, it may be reasoned that normalization of elevated plasma TSH concentrations after exposure to irradiation will lower the incidence of thyroid nodules and possibly delay the occurrence of thyroid carcinoma.
In the second case presented here the occurrence of primary hyperparathyroidism might be considered a coincidence. However, there has been another similar case report of a young adult with childhood abdominal NBL and benign parathyroid adenoma (21). Hyperparathyroidism may also be caused by exposure to radiation. Whether this is coincidence or is related should be studied in the future.
Conclusions and Advice for Follow-Up of Children After Treatment with 131I-MIBG
Thyroid prophylaxis during exposure to 131I-MIBG for NBL is important and plays a significant role in decreasing, but, potentially not eliminating, the risk of thyroid disease, including hypothyroidism, the development of thyroid nodules and thyroid cancer. Ways to optimize the current thyroid prophylaxis should be looked into.
During childhood and adolescence, annual surveillance of thyroid function (TSH and FT4) should be performed for all children exposed to 131I-MIBG, to enable prompt treatment with T4. Plasma TSH concentrations should be normalized during follow-up.
During childhood and adolescence, there is an increased incidence of developing thyroid nodules and potentially thyroid cancer for patients exposed to 131I-MIBG. Similar to previous reports (12,14), the younger age at the time of exposure and the lower activity of exposure may increase the risk and shorten the latency time to develop thyroid cancer. Since a physical examination may be too insensitive for the early detection of thyroid nodules, surveillance with thyroid ultrasound investigation should be considered. This should be started 2–3 years after exposure and should be conducted on an annual or every-other-year basis. Further cytological and histological analyses are indicated for lesions >1 cm in size.
A prospective evaluation should be done for all children with NBL treated with 131I-MIBG and in those not treated with 131I-MIBG to investigate the possible causal relation between 131I-MIBG and the development of papillary thyroid carcinoma in these children.
Footnotes
Disclosure Statement
The authors declare that no competing financial interests exist.