Differentiated Thyroid Carcinoma After Iodine-131 Metaiodobenzylguanidine Treatment for Neuroblastoma: Assessment of Causality

Dear Editor:

I read with great interest the cases of differentiated thyroid carcinoma (DTC) after iodine-131-metaiodobenzylguanidine (¹³¹I-MIBG) treatment for neuroblastoma (NBL) and congratulate the authors for their etiological work-up (1). The authors ascribe in the case of the boy, an additional causal or contributory factor to the increased pre-NBL-treatment level of circulating thyrotropin (TSH) in the pathogenesis of DTC. Indeed, the strong relationship between elevated serum TSH and risk of thyroid malignancy is even higher than previously thought, to the extent that the current guideline not to treat prophylactically with L-thyroxine all patients with nodular goiter with the aim of reducing the risk of DTC is currently challenged (2). However, these data are based on many studies of nodular disease in adults, not in children with seemingly normal thyroids, in which setting, the causal role of elevated TSH remains elusive.

Chemotherapy transpires as an additional contributor to the risk of developing a second cancer, although DTC is a much less common occurrence than secondary leukemias, while the sporadic cases of DTC reported in children after having received chemotherapy, but no radiotherapy (3) were cases of retinoblastoma, which is associated with second cancers regardless of radiotherapy (4). The Childhood Cancer Survivor Study (CCSS) study provided evidence of an increased risk of DTC in association with chemotherapy independently of radiation: after adjustment for radiotherapy, a weak association with chemotherapy existed demonstrating that the risk of second primary DTC is typically dominated by the radiation effect, particularly at the highest radiation doses, where cell killing would presumably remove cells from chemotherapy-related cancer risk (5). Nonetheless, a potentially additive rather than multiplicative interaction between chemotherapy and radiation for the risk of developing DTC was concluded based on estimates of excess absolute and relative risk per gray (5). However, the extent to which the absorbed dose of external beam irradiation can be translated to the carcinogenic effects of ¹³¹I-MIBG treatment is uncertain.

As regards the potential genetic predisposition to increased thyroid sensitivity in children with NBL, the argument that the seemingly NBL relatable increased risk of DTC is in fact an age-at-exposure effect and not related to the NBL itself (1,5) may be countered by the findings of the extensive study of developing thyroid tumors in 4096 three-year survivors of childhood cancer treated over decades in France and the United Kingdom (6) in which 5 of 14 thyroid carcinomas developed among 302 patients who received radiotherapy for NBL. Whatever the dose given to the thyroid, patients treated for NBL had a higher risk of developing a DTC than did other patients. When adjustment was made for dose given to the thyroid, age at diagnosis of first cancer, and sex, the relative risk of DTC was still 5.6-fold higher for patients treated for NBL than for other first cancers (6). As to the genomic work-up to detect potential pathogenic imbalances shared by the NBL and DTC, considering that any size of abnormal genomic regions—a spectrum from a single nucleotide to exon(s) to intact gene(s) to many megabases to chromosomal arm(s)—could cause genomic disorders; genome-wide array-comparative genomic hybridization (CGH) chips with a higher resolution than the 4×180 k oligo array could potentially ferret out hitherto occult common genomic denominators between tumorigenesis factors in NBL and in DTC.

I concur with van Santen et al. (1) and conclude that, based on currently available evidence factored into a semiquantitative global introspection scheme of causality assessment, the most probable culprit in the etiology of DTC was ¹³¹I-MIBG, outweighing other possible etiologies of DTC carcinogenesis. An arbiter of whether DTC was induced by ionizing radiation or not may lie in the identification of seven gene signatures in DTC found in a study of quantitative real-time polymerase chain reaction that seem to have completely distinguished between radiation-induced and sporadic forms of DTC (7).