The BRAF V600E mutation is usually associated with higher malignancy and aggressiveness in papillary thyroid carcinomas  and in most cases with typical ultrasound features of thyroid malignancy . However, due to the unifocality of the lesion and the fact that the papillary carcinoma in our patient measured less than 10 mm, according to the 2009 consensus of the American Thyroid Association no radioiodine therapy was performed . Therefore, postsurgical thyroglobulin (TG) levels are still detectable in our patient (Table 1) and only of limited use in postsurgical follow up.
It is commonly believed that papillary microcarcinomas only rarely collocate within toxic thyroid adenomas, although several case reports are found in the literature [9–16]. A selection of retrospective studies estimate the risk of concurrent papillary carcinomas in functioning nodules ranging from 0.34% up to 5% [5, 17, 18]. In a cohort of US children with toxic adenoma the malignancy rate was yet higher (about 11%) . Thus, despite the relatively low risk of malignant transformation of functioning nodules, these lesions need careful clinical follow up with ultrasound and possibly fine needle aspiration biopsy especially when patients are young.
Furthermore, it is still subject of debate whether the frequency of thyroid cancer is higher in patients with Graves’ disease, mostly because the studies are typically retrospective and extend over a long period of time, where diagnostic capabilities and tools might have changed significantly (extensively reviewed in ). However, it seems that the prevalence of palpable nodules is about 3-fold higher in Graves’ patients (15.8%)  compared to the general population living in a non-endemic region (5%) . Studies relying on ultrasound imaging also find a higher prevalence for thyroid nodules in patients suffering form Graves’ disease (33.6%)  compared to the general population (about 26%) although to a lesser extent [24, 25]. Of note, in the former study more than half the patients suffering from Graves’ disease developed thyroid nodules during the 2-year follow up, which suggests that Graves’ disease promotes de novo thyroid nodule formation . Furthermore, the mean malignancy rate of palpable nodules in Graves’ patients is about 16% versus a 5% malignancy rate in the general population (reviewed in ). Thus, in conjunction with the above-mentioned prevalence rates of thyroid nodules, it can be estimated that Graves’ patients have an almost 10-fold higher chance of developing thyroid cancer. In a retrospective multicenter study with more than 500 Graves’ patients thyroid carcinomas were found in 3.8% (20 out of 21 were papillary carcinomas) . Another study matched these results and found a malignancy rate of 3.3% in their collective of Graves’ patients , whereas the incidence of thyroid cancer in the general US population was estimated at about 14.4 per 100,000 . Of note, in the former study all papillary carcinomas were detected within thyroid nodules embedded into a Graves’ goiter. In total 15% of the patients suffering from both, nodules and Graves’ disease, also had thyroid carcinomas . In another study the risk for malignancy of a thyroid nodule within a toxic diffuse goiter even reached 22% , therefore any nodule within a Graves’ goiter should be carefully examined to rule out a thyroid carcinoma.
There is evidence that thyroid cancer in Graves’ patients is more aggressive. Therefore, an important question is, whether the presence of Graves’ disease in thyroid cancer patients affects their clinical outcome. Studies have found that in Graves’ patients thyroid carcinomas grow more invasively and develop lymph node and distant metastases more frequently compared to euthyroid controls [31–33], although a more recent study was not able to confirm these data . Yet, given the possibility that Graves’ disease increases nodule formation and their respective risk for malignant transformation, it is conceivable that Graves’ disease may constitute an additional risk factor when managing thyroid cancer patients lowering the threshold for surgical intervention.
Color flow Doppler sonography has proven a useful tool in the differential diagnosis of toxic multinodular goiter. Boi et al. have indicated that hyperthyroid patients with multinodular goiter can be subdivided into two distinct groups using color flow Doppler patterns: 1) Nodules with normal vascularization surrounded by hypervascularized hypoechoic thyroid tissue showing a similar picture as in Graves’ patients. Notably, in 44% of these patients TSH receptor antibodies were elevated; and 2) heterogenous hypervascularized nodules embedded into normoechoic-normovascular thyroid parenchyma. None of these patients were tested positive for TSH receptor antibodies . The first group constitutes a group of patients, who probably developed Graves’ disease in a non-toxic multinodular goiter. Our patient on the other hand showed features of both groups. His prominent nodule was heterogeneous and clearly more vascularized compared to the surrounding thyroid parenchyma matching the ultrasound criteria of group 2). However, his TSH receptor antibody titers were also elevated, indicating that both thyroid autonomy and Graves’ disease are concurrent.
Finally, hyperthyroid patients have a disproportionate increase in T3 compared to T4 levels . Laurberg et al. have found that this probably results from a relative increase in type 1 iodothyronine deiodinase activity in hyperthyroid patients compared to healthy subjects, where type 2 iodothyronine deiodinase accounts for the majority of T3 production [37, 38]. Our patient with Marine-Lenhart syndrome also presented with an increased T3 to T4 ratio of 1.9%. This matches what Laurberg et al. have found in their collective of multinodular toxic goiter. Their patients with thyroid autonomy had a lower T3/T4 ratio compared to those with Graves’ disease (2.0 versus 2.7%) , suggesting that in our patient the autonomous adenoma was the more prominent component of disease, which is also supported by the relatively low levels of circulating TSH-RAb and thyroid uptake in the region outside of the adenoma.