the treatment options for graves ' disease consist of antithyroid drugs , radioactive iodine ( rai ) therapy , and surgery .
rai therapy has been used for the treatment of graves ' disease for more than seven decades , and in most studies , it has not been associated with an increased risk of cancer . on the other hand ,
several studies have proposed the potential increase in thyroid malignancies with rai treatment [ 2 - 4 ] . here , we describe a very rare case of anaplastic thyroid carcinoma ( atc ) associated with graves ' disease , following rai treatment .
a 42-year - old woman was referred to our clinic in 1998 , because of palpitations , hand tremor , and laboratory findings of hyperthyroidism ( serum thyrotropin [ thyroid - stimulating hormone , tsh ] 0.05 iu / ml [ reference range , 0.17 to 4.05 ] , free thyroxine 4.01 ng / dl [ reference range , 0.79 to 1.86 ] , and positive tsh receptor antibody at 201.7% [ percent binding inhibition index , radioreceptor assay , reference range ; 15.0% ] ) , and had been diagnosed as graves ' disease .
a technetium-99 m thyroid scan showed enlarged and homogeneously increased uptake , and ultrasonography revealed a diffuse goiter without nodules .
the patient received 200 mg / day of propylthiouracil and -adrenergic blocking agents for 1 year .
however , due to recurrent hyperthyroidism , she received rai therapy twice with an administered dose 370 mbq ( 10 mci ) , 296 mbq ( 8 mci ) , each .
two years later , she received thyroid hormone replacement due to subsequent hypothyroidism at a local clinic . in september 2010 , over 10 years later , she revisited us with complaints of hoarseness , dysphagia , and dyspnea , which had been presented for 2 months .
an anterior neck mass , which was hard and fixed , and some lymph nodes ( lns ) around the mass were palpable .
her chest radiography showed a tracheal narrowing and deviation to the right without active lung lesion . on computed tomography ( ct ) of the neck ,
positron emission tomography - ct , an intense hypermetabolic lesion was noted in the thyroid gland and lns on her left neck without distant metastasis .
a total thyroidectomy with selective neck dissection , tracheal sleeve resection , and end - to - end anastomosis were performed .
subsequently , she had concurrent cisplatin - based chemoradiotherapy for her neck and superior mediastinum ( total 6,600 cgy/33 fractions ) .
after 4 months of follow - up , despite the aggressive treatment , the disease progressed .
on neck ct , a new focal necrotic mass on the left side of her neck was noted , suggesting local recurrence .
the mass extended up to the tracheal lumen and the patient died of sudden uncontrolled bleeding in the airway .
the patient in this case received rai therapy twice for recurrent hyperthyroidism . after more than 10 years , she developed respiratory symptoms and was finally diagnosed with atc .
this case raises questions about the causal relationship between rai therapy for graves ' disease and the subsequent occurrence of thyroid cancer .
although it has been widely accepted that rai is safe , some studies have suggested that rai therapy is possibly associated with a small increased risk of thyroid cancer [ 2 - 4 ] .
degroot   reported that the rai treatment can induce an increase of thyroid antibodies , such as tsh receptor antibody , and it was suggested that thyroid stimulating antibodies play an important role in thyroid carcinogenesis .
these antibodies also can stimulate angiogenesis , which contributes to thyroid tumor cell growth , by activating vascular endothelial growth factor .
sturgis   reported cytomorphologic alterations in thyroid follicular epithelium , which is associated with rai therapy . before treatment , graves ' disease typically lack significant atypia , while after rai therapy , nuclear atypia , and progressive cellular metaplasia could be seen microscopically .
furthermore , it was prominent in those who remain in a hyperthyroid state despite rai treatment .
in addition to our case , two previously reported cases of atc after rai therapy for documented graves ' disease are summarized in table 1 .
baker   reported a 64-year - old woman with atc 12 years after rai therapy . because thyroid toxicity persisted after one course of rai therapy , the patient received a second therapy in 4 months .
gossage et al .   reported a 46-year - old woman who had her first rai therapy , when aged only 23 years .
although she underwent partial thyroidectomy prior to the rai therapy , hyperthyroidism recurred and she received several subsequent doses of radioiodine .
an analysis of these cases is noteworthy , because since the interval to cancer diagnosis was over 10 years in all cases , it supports the importance of long - term vigilance in patients receiving rai therapy .
in addition , these cases had something in common in terms of the occurrence of atc after repetitive , small doses of rai therapy .
the cooperative thyrotoxicosis therapy follow - up study showed that thyroid neoplasms developed in children treated with lower , rather than higher , doses of rai therapy , which is compatible with our finding .
therefore , it can be hypothesized that multiple courses of rai therapy , with small doses , may play a role in carcinogenesis , especially in the poorly differentiated type .
.   demonstrated that i treatment inactivates the tumor suppressor gene that is frequently found in atc rather than in the differentiated type .
however , to discuss the causal relationship between rai therapy and the occurrence of cancer , the number of reports is too small , therefore a population - based study is required and this is a limitation of our report .
in addition to the rai therapy , we can not exclude that graves ' disease itself might also increase the risk of cancer . although our patient had no thyroid nodule by ultrasonography ,
the palpable thyroid nodules found in graves ' patients have a 16.9% malignancy rate , which is higher than that of the general population .
moreover , the finding that thyroid autoantibody stimulates the malignant transformation of the thyroid gland supports this suggestion .
it is not clear that the occurrence of atc reported here was influenced by rai therapy or , alternatively , it may only represent the delayed recognition of a rare change in the natural history of graves ' disease .
nevertheless , this report is worthwhile since it presents a very rare case of atc that occurred 11 years after rai therapy for graves ' disease .
 radioactive iodine ( rai ) therapy has been used as a treatment option for graves ' disease , and it has been widely accepted to be safe . on the other hand , some evidence suggests that rai therapy is possibly associated with a small increased risk of thyroid cancer . 
 herein , we report a rare case of anaplastic thyroid carcinoma ( atc ) associated with graves ' disease , following rai treatment . a 42-year - old woman had been diagnosed with graves ' disease and although she was treated with an antithyroid drug , she remained in a hyperthyroid state , which led to two rai treatments . 
 more than 10 years later , the patient revisited our clinic due to hoarseness , dysphagia , and dyspnea , which had lasted for 2 months . 
 neck computed tomography suggested thyroid carcinoma and a lymph node biopsy showed metastatic papillary carcinoma . 
 the patient underwent total thyroidectomy and was finally diagnosed as having an atc . 
 it is not clear if the occurrence of atc reported here was influenced by the rai therapy or alternatively , it may only represent the delayed recognition of a rare change in the natural history of graves ' disease . 
 nevertheless , this report is worthwhile since it presents a very rare case of atc that occurred eleven years after the rai therapy for graves ' disease . 