Thyroid Cancer in Patients with Hyperthyroidism

Key words

Graves’ disease - toxic multinodular goiter - hot nodules - hyperthyroidism - thyroid cancer

Introduction

In 1937 Means [1] suggested that hyperthyroidism might be protective against thyroid cancer and this initially gained some support, but was soon abandoned due to findings in the following decades. Supportive of that are reports performed in the 1950’s that indicated a low incidence of thyroid cancer in patients with Graves’ disease in the range of 0.15–0.5% [2] [3] or even a slightly higher incidence of 2.5% [4]. All the above data were based on patients treated with sub­total thyroidectomy. However, later studies by Shapiro et al. on patients with Graves’ disease demonstrated an unsuspected thyroid cancer in 8.7% of them [5]. This increase was probably observed due to the fact that the patients were treated with total thyroidectomy; a more intense histological examination of the surgical specimen further increased the chances of diagnosing thyroid cancer [6] [7].

To further complicate the matter, discrepancies appear not only in reports on the incidence but also on the aggressiveness of thyroid cancer associated with hyperthyroidism. For instance, while some reports describe the cancer as very aggressive [8] [9], often invasive, and metastatic to regional lymph nodes, even when the primary tumor is small [10] and possibly fatal [11] [12]; in other series the clinical course was not different from euthyroid patients [13]. Up to date the reasons for these discrepancies have not been solved and the incidence and aggressiveness of thyroid cancer remain controversial.

This review attempts to shed some light on the reasons behind these discrepancies in order to gain a better understanding in the association and the evolution of thyroid cancer in patients with hyperthyroidism, particularly with respect to the type of hyperthyroidism found in some patients and whether this co-existence affected the outcome of the patients.

Methods

This is a literature review based on articles found in PubMed up to August 2011. An electronic search of Pubmed/Medline database using the MeSH (Medical Subjected Headings) was performed, using combinations of the following keywords/phrases: thyroid cancer, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, anaplastic thyroid cancer, hyperthyroidism, Graves’ disease, autonomous adenoma, toxic thyroid nodule, and toxic multinodular goiter. Original research papers, case reports, and review articles were included in the present review.

Findings

Thyroid cancer in patients with hyperthyroidism

The prevalence of thyroid carcinomas found during surgery in hyperthyroid patients, is reported to vary widely, ranging up to 21.1% [8] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] ([Table 1]). This is probably due to multiple factors, including the cause of hyperthyroidism, the different criteria for choosing surgery as the treatment modality of hyperthyroidism, the extent of thyroidectomy (lobectomy or total thyroidectomy), but most likely due to the extent of histological examination of the removed thyroid tissue and possibly also the geographical variation in incidence of thyroid cancer in general [27] [28]. All histological types of thyroid cancers can be associated with all types of hyperthyroidism, although the most frequently reported type is papillary thyroid carcinoma, followed by follicular thyroid carcinoma, and rarely by anaplastic carcinoma and medullary thyroid carcinoma [11] [12] [29] [30], in keeping with the lower incidence of these cancers in general.

Table 1 Incidence of thyroid carcinoma in hyperthyroid patients (Graves’, autonomous adenoma, toxic multinodular goiter).

Author	Hyperthyroid patients (n)	Thyroid cancer n	Thyroid cancer %
Taneri [15]	120	10	8.3
Cappelli C [8]	691	32	4.7
Terzioglou [19]	138	8	5.8
Gabriele [22]	425	7	1.6
Cakir [18]	375	26	6.9
Vaiana [21]	512	24	4.7
Linos [20]	400	27	7.0
Pacini [14]	179	11	6.1
Lin [24]	45	6	13.3
Lian [94]	394	12	3.0
Senyurek Giles [17]	817	53	6.5
Calò [26]	71	15	21.1
Sahin [16]	333	13	3.9
Zanella [25]	202	12	5.9

It has been reported that thyroid cancer is diagnosed more frequently in patients with Graves’ disease than in patients with uninodular toxic goiter or toxic multinodular goiter (TMG) [8] whereas other studies presented the same results for Graves’, but slightly higher carcinoma prevalence within hot nodules and TMG [17] [18]. In Graves’ patients, carcinomas are found to be larger, more often multifocal, locally invasive and more often metastatic to distant sites than in patients with hot thyroid nodules [31].

Most carcinomas are small in size [10] [13] [32] and the majority are microcarcinomas ([Table 2]). In many cases thyroid cancer is not known preoperatively, but is found incidentally during postoperative histologic examination of the thyroid [33]. We previously reported a study of 60 hyperthyroid patients diagnosed with thyroid cancer [11]. Among those patients, only 12 were operated for suspicion of thyroid cancer preoperatively, whereas in the remaining 48, in whom the indication for thyroidectomy was treatment for thyrotoxicosis, thyroid cancer was incidentally found after surgery. No significant differences were found in clinical characteristics at presentation between coincidentally discovered thyroid cancers and preoperatively known clinical cancers. The time of diagnosis of hyperthyroidism to thyroidectomy was not different. However, Miccoli et al. reported that, the diagnosis of incidental thyroid carcinoma in patients who were operated on for a benign disease was more frequent in euthyroid patients than in patients with hyperthyroidism [23].

Table 2 Percentage incidence of microcarcinomas in patients with both thyroid cancer and hyperthyroidism.

Author	Thyroid Cancer patients (n)	Type of hyperthyroidism	Tumor size n	≤10 mm  %
Farbota [34]	6	Graves’ disease	3	50.0
Belfiore [31]	22	Graves’ disease, hot nodule	11	50.0
Ahuja [72]	20	All types	7	35.0
Vini [102]	23	All types	12	51.2
Ozaki [10]	19	Graves’ disease	9	47.4
Cakir [18]	26	All types	9	34.6
Cerci [92]	11	Multinodular goiter	8	72.7
Taneri [15]	10	All types	7	70.0
Chao [49]	61	Graves’ disease	49	80.3
Pazaitou-Panayiotou [11]	60	All types	39	65.0
Pellegriti [32]	36	Graves’ disease	15	41.7
Lian [94]	12	All types	7	58.3
Omur [96]	76	All types	50	65.7
Gerenova [37]	8	Graves’	7	88.0
Erbil [38]	18	Graves’	15	83.3
Hales [13]	16	Graves’	14	87.0

Thyroid cancer in patients with Graves’ disease

Prevalence

The prevalence of thyroid carcinoma in Graves’ hyperthyroidism has been examined over many years but the issue still remains controversial. There are significant differences in the reported incidence of thyroid cancer in patients operated for Graves’ disease, ranging between 0.5 and 15.0%, [2] [3] [4] [5] [8] [10] [14] [16] [17] [18] [19] [20] [21] [23] [31] [34] [35] [36] [37] [38] [39], ([Table 3]). Some studies suggest an association between Graves’ disease and thyroid cancer [8] [14] [18] [34] [40] as the annual incidence of clinical thyroid cancer in patients with Graves’ disease was reported as 175/100 000 [32], well above the incidence of 0.5–8.0/100 000 reported for the general euthyroid population [41].

Table 3 Prevalence of thyroid carcinoma in Graves’ disease.

Author	Graves’ diseasen	Thyroid cancer	n    %
Beahrs [3]	3022	14	0.5
Sokal [2]	13868	21	0.15
Olen [4]	2114	53	2.5
Pacini [14]	86	6	6.9
Shapiro [5]	172	15	8.7
Farbota [34]	117	6	5.1
Belfiore [31]	132	13	9.8
Sahin M [16]	144	5	3.5
Terzioglou [19]	33	4	6.0
Vaiana [21]	108	7	6.4
Cappelli [8]	145	9	6.5
Ozaki [10]	743	19	2.6
Cakir [18]	67	4	6.0
Pellegriti [32]	450	21	4.7
Gerenova [37]	103	8	7.8
Kraimps [39]	557	21	15.0
Erbil [38]	150	18	12.0
Lee [35]	779	58	7.4
Senyurek Giles [17]	342	13	3.8

Aggressiveness

It has been reported that, thyroid carcinoma concurrent to Graves’ disease is usually aggressive [40] and metastatic to regional lymph nodes [8], even when the primary tumor is small [10] and that it has a worse clinical outcome compared to euthyroid patients with differentiated thyroid cancer [8] [31] [32] [42] [43]. Lymph nodes involvement was found in up to 61.5% of the patients [8] [31] and the incidence of locally advanced cancers was significantly higher in older patients [44].

However, some studies report discordant results or do not highlight the aggressive characteristics of thyroid carcinomas in Graves’ disease [13] [37] [45] [46] [47]. Hales et al. compared 16 patients with Graves’ disease with concomitant thyroid cancer with a group of euthyroid patients with thyroid cancer who underwent surgery during the same time period and were matched for sex and age to the patients with Graves’ disease [13]. The authors did not find increased aggressiveness of thyroid cancer in patients with Graves’ disease when compared to euthyroid subjects. In this study the mean tumor diameter in the Graves’ group was 1.0 cm and in the control group 2.5 cm and this is an obvious disadvantage of the study. The outcome may suggest that small carcinomas in Graves’ patients have the same prognosis as larger carcinomas in euthyroid patients. Yano et al. compared the features of 154 cases of papillary thyroid cancers diagnosed in patients with Graves’ disease to a euthyroid group with thyroid cancer [46] and did not find significant differences in multifocality, lymph node metastases, or distant metastases between the Graves’ disease and the euthyroid group. Edmonds et al., in their study with 502 patients with thyroid cancer, reported similar mortality rates when comparing patients with Graves’ disease and with multinodular goiter to that of euthyroid patients matched for age [45].

All the above mentioned studies are retrospective and explore different clinical or histological parameters and therefore are not totally comparable. Prospective studies with a large number of patients could give clear answer about the aggressiveness of thyroid cancer in GD.

Microcarcinomas – Clinically important cancers

Most carcinomas associated with Graves disease are small [10] [13] [32] and are found incidentally during postoperative histological examination of the thyroid [33] [48]. Incidental cancers of ≤10 mm were found up to 88.0% of all cancers detected in Graves’ disease [10] [13] [32] [34] [37] [38] [49]. The clinical significance of these microcarcinomas is uncertain. In a recent report, patients with microcarcinomas and concomitant Graves’ disease were compared with euthyroid patients with cancers of equal size and were found to have an excellent prognosis and longer disease-free survival [42].

Pellegriti et al. evaluated the frequency and the evolution of incidentally found vs. clinically important thyroid carcinomas in 450 Graves’ patients who underwent thyroidectomy, in 2 different studies in the periods 1982–1987 and 1988–1994 [32]. The overall frequency of incidentally found carcinomas in Graves’ patients undergoing surgery was 3.33% (15/450) and that of clinically important thyroid carcinomas was 4.7% (21/450). All patients with microcarcinoma were disease-free except for one case that developed a local recurrence. On the contrary, patients with clinically important disease presented lymph nodes metastases, distant metastases and deaths (odd ratios=3.14 as compared with euthyroid patients). In the study of Lee et al. clinically overt thyroid carcinomas were diagnosed in 3.3% and incidental carcinoma in 4.2% of patients with Graves’ disease [35]. In this study comparison of clinical findings of incidental and clinical carcinoma patients revealed no difference between the 2 groups in terms of duration of thyrotoxic symptoms, serum levels of thyroid hormones before the administration of antithyroid drugs, and postoperative serum concentration of thyroglobulin. Local recurrence was identified in 4 patients (6.9%), all of whom belonged to the clinical carcinoma group. This finding supports the conclusion that thyroid microcarcinomas in Grave’s disease seldom cause metastasis.

Nodular Graves’ disease

It appears that thyroid nodules in Graves’ goiters have a greater risk of malignancy. Thyroid carcinoma occurs in 3–10% of palpable nodules in general, whereas the numbers for incidentally found nonpalpable nodules vary very widely, according to different studies, mostly due to differences in iodine availability [50] [51] [52]. Kraimps et al. in their multicentric study with 557 patients who underwent thyroidectomy for Graves’ disease found that the incidence of thyroid carcinoma associated with Graves’ disease was 3.8% [39]. This incidence was higher and – actually – 15%, if patients with a nodule were considered. Pacini et al. reported that when a thyroid nodule was present in a toxic diffuse goiter the possibility to find a carcinoma reached 22.2% of the cases, while only 2.9% with diffuse toxic goiter, without a nodule, had thyroid cancer [14]. Due to this finding the authors conclude that in patients with Graves’ disease any nodule must be screened carefully to rule out malignancy. Belfiore et al. reviewed previously published data on the incidence of thyroid cancer in Graves’ patients with or without thyroid nodules and found that the incidence of thyroid cancer in patients with nodules was up to 45.8% of the cases in contrast to those without nodules in whom thyroid cancer did not exceed 9.8% [53]. Thyroid scintigraphy is an important test in the evaluation of patients with Graves’ disease and nodules, and the prevalence of thyroid cancer in a cold nodule provides justification for further diagnostic evaluation [54]. In the recently published medical guidelines for clinical practice for the diagnosis and management of thyroid nodules it is recommended that nodules in Graves’ disease should be managed in the same way as any other thyroid nodule including follow-up and consideration of a second FNAB to reduce the number of false negative results [55].

Fine-needle aspiration cytology from nodules, which are found in patients with Graves’ disease, can cause diagnostic difficulties because the cytomorphologic changes in this disease as a consequence of antithyroid drug treatment may mimic features of papillary thyroid carcinoma. Furthermore, atypia produced by the administration of radioactive iodine (RAI) may be severe, leading to an erroneous diagnosis of malignancy [56]. Provision of the appropriate clinical history of Graves’ disease treated with RAI may prevent this pitfall. In a recent study nuclear elongation, pale powdery chromatin, intranuclear grooves, and small eccentric nucleoli were found to be significant for the diagnosis of PTC arising in GD [57].

Diagnosis of thyroid cancer according to Graves’ initial treatment

Thyroid cancer associated with Graves’ disease is found more commonly in surgically treated patients than in patients after radioactive iodine therapy. Ozaki et al. reported a 0.17% thyroid cancer incidence in Graves’ patients treated with radioactive iodine vs. 2.5% in Graves’ patients treated with surgery [58]. In a study by Behar et al., 303 patients received RAI therapy for Graves’ disease and only one (0.3%) subsequently developed thyroid carcinoma [40]. Of course, one could claim that patients undergoing surgery have a higher chance of a cancer being recognized, when compared to radioiodine treated patients.

Pathogenesis

The possible reasons that could explain the increased frequency and aggressiveness of clinical thyroid cancer reported by some studies for patients with Graves’ disease are not clear. Thyroid stimulating hormone (TSH), by binding to the thyroid-stimulating hormone receptor (TSHR), and probably multiple other factors, affect the evolution of thyroid cancer. Neoplastic cells of differentiated thyroid cancer, like normal thyroid cells, express functional receptors for TSH.

Graves’ disease is characterized by a marked decrease in TSH [59]. In Graves’, antibodies (TSAbs) are produced that have strong agonistic activity to the TSHR, and this results in antibody-mediated stimulation of the receptor. Stimulation of TSHR by antibodies leads to secretion of thyroid hormone and hyperthyroidism independently of the hypothalamic-pituitary-thyroid axis. Moreover, TSAbs might play a role in stimulating thyroid cancer growth, invasiveness [9] [60] and angiogenesis by upregulating vascular endothelial growth factor, placenta growth factor, and their receptors. TSAbs use the same signaling pathways that are used by TSH for cell activation and growth [61]. Taking into consideration that chronic TSH stimulation affects the prognosis of thyroid cancer it could be postulated that the TSH mimicking effect of TSAbs could explain the increased aggressiveness of thyroid cancer in Graves’ patients. Apart from that, different growth factors that probably are produced by the over stimulated, by TSAbs, and hypervascularized thyroid [31] could also affect the growth and metastases of thyroid cancer in Graves’ patients.

Extent of surgery

The extent of surgery for thyroid carcinoma concomitant with Graves’s disease has rarely been discussed. As clinically important thyroid cancers associated with Graves’s disease seems to behave more aggressively, with a tendency to lymph node metastases, total or near-total thyroidectomy plus central neck dissection are recommended [32]. In these cases surgical treatment for thyroid carcinoma is the goal and this surpasses the surgical treatment for hyperthyroidism.

Carcinomas smaller than 10 mm concomitant with Graves disease could be treated by subtotal thyroidectomy with excellent outcomes [62]. 2 guidelines for the management of thyroid cancer have been published by European and American thyroid associations. Both agree that if papillary thyroid microcarcinoma (PTM) is diagnosed preoperatively, total or near-total thyroidectomy is the treatment of choice, because it eliminates multifocal disease and decreases the recurrence rate. If PTM is found after total or near-total thyroidectomy for multinodular goiter or Graves’ disease both guidelines state that no further treatment is indicated when the PTM is unifocal, well-differentiated, without lymph node metastases or extrathyroidal invasion [63] [64]. Recently, the revised guideline of the American thyroid association suggests that lobectomy alone is a sufficient treatment for small (<1 cm), low-risk, unifocal, intrathyroidal papillary carcinomas in the absence of head and neck irradiation or cervical lymph nodes metastases [65]. Obviously this recommendation would not be applicable for patients with Graves’ hyperthyroidism, as lobectomy is no sufficient treatment for relapsing Graves’ disease. Evidence-based criteria support total thyroidectomy as the surgical technique of choice when surgery is considered for definitive management for Graves’ disease [66].

Thyroid cancer in patients with autonomous adenoma

Most autonomously functioning thyroid nodules (AFTN) are benign follicular neoplasms but rarely patients with toxic adenoma may harbor thyroid cancer in the autonomously functioning nodule. These mainly involve papillary and less often follicular or Hurthle histological types. The published data regarding the association of thyroid cancer and hot nodules are few, and are mostly limited to case reports or series with a small numbers of patients [67] [68] [69] [70] [71]. The reported probability of a hot nodule being associated with malignancy (i. e., a thyroid carcinoma in or outside the hot nodule) ranges between 1–10.3% [8] [18] [49] [72] [73] [74] [75] [76] [77] ([Table 4]). An exception to that is one small series where the incidence of cancer in hot nodules was 44% [64]. Schröder and Marthaler reviewed 30 reports of warm or hot thyroid carcinomas published between 1989 and 1996 and found that only in 10 of these 30 cases the carcinoma was clearly described as located inside the hot nodule [78]. Similar findings were reported in many other studies [8] [11] [17] [22] [73] [79]. However, hot nodules in children seem to carry a higher risk of malignancy of up to 29% of thyroid carcinomas within the hot nodules [80] [81].

Table 4 Incidence of thyroid carcinoma in patients with autonomous adenoma (inside or outside the hot nodule).

Author	Toxic adenoma n	Thyroid cancer n	Thyroid cancer %
Senyurek Giles [17]	176	21	12.0
Vaiana [21]	153	8	5.2
Cappelli [8]	207	10	4.8
Gabriele [22]	120	3	2.5
Cakir [18]	63	4	6.3
Foppiani [36]	16	2	2.5
Harach [76]	73	6	8.2
Smith [77]	30	2	6.6
Hamburger [74]	29	3	10.3
Sahin [6]	77	6	7.8

The true incidence of thyroid cancer in patients with auto­nomous adenomas may be underestimated because occasionally large doses of radioiodine are used to treat such cases if they do not undergo surgery, which may be sufficient not only to cure the thyrotoxicosis but also the cancer. However, in a recent report by Als et al. in 5 of 19 patients, one or more courses of ¹³¹I were preoperatively administered to the autonomously functioning thyroid nodule that initially had been mistaken for benign and after thyroidectomy proved to be thyroid cancer [82]. The same is reported by other authors [68].

There are reports of malignant hot nodules, in which activating mutations of the thyrotropin receptor (TSHR) gene were identified [83] [84] [85] [86] [87] [88] [89] [90]. Among these the I486F, T620I, F631I, D633Y, T632A, and T632I activating TSHR gene mutations were identified in 5 follicular carcinomas, the D633H mutation in one insular, the M453T and L512R mutations in 2 papillary (one per one) and the L677V in one Hürthle cell carcinoma. However, functional reanalysis of these reported TSH receptor mutations revealed that only the hot thyroid carcinomas with the TSHR mutations M453T, I486F, L512R, F631I, T632A, T632I, D633H and D633Y were associated with constitutively activating TSHR mutations [91], ([Table 5]).

Table 5 All patients reported up to date with a differentiated hot thyroid carcinoma.

Activating TSHR mutations	Cell surface expression percent of wt	cAMP accumulation (according to SSFA of GPHRs) Basal (wt=100%)	IP accumulation (according to SSFA of GPHRs) Basal (wt=100%)	RAS, RAF, p53, and MAPK activation	Histopathology of the tumor	Age/Sex
The cell surface expression determined by TSH binding
The expression levels of the respective constructs were evaluated by FACS analysis. LRA has only been reported for TSHR mutation M453T (LRA: 5.2)
TSHR: thyroid stimulating hormone receptor; GPHR: glycoprotein hormone receptor; wt: wild type; LRA: linear regression analyses; FACS: Fluorescence-activated cell sorting
T632I	40 50	420 330	n.d. n.d.	Not studied	Follicular carcinoma	50/M
D633H	84	620	221	No mutations	Insular thyroid carcinoma	60/F
I486F	17 20 35	550 400 820	327 n.d. 97	Not studied	Follicular carci-noma (capsular invasion)	49/F
M453T	n.d. 66	700 570	n.d. 103	Not studied	Papillary carcinoma	11/F
D633Y	60*	405	127	PAX8-PPARγ	Follicular carcinoma	59/M
F631I	n.d.	n.d.	n.d.
L512R	56	325	100	Not studied	Papillary carcinoma	52/F

Thyroid cancer in patients with toxic multinodular goiter

Whereas carcinomas, largely of the papillary type, occur in nontoxic nodular goiters with a reported frequency of 4–17% of cases, the reported incidence of thyroid cancer in patients with hyperfunctioning multinodular goiter ranges between 1.8–8.8% [8] [16] [17] [18] [21] [22] [92] [93] [94] [95], ([Table 6]). However, the data avail­able in the literature regarding the incidence and the evolution of the disease are controversial. Cerci et al. found no significant difference for the incidence of thyroid cancer between toxic and nontoxic multinodular goiter [92]. In another study, lymph node involvement was found in 23% of the cases with toxic multi­nodular goiter and cancer [17]. In a third one, 43 toxic multi­nodular goiters were associated with differentiated thyroid cancer. No lymph node metastases were detected in this latter study although distant metastases were found in 3 cases [96]. The variable findings in these 3 studies are difficult to explain and to understand.

Table 6 Incidence of thyroid carcinoma in patients with toxic multinodular goiter n=number of patients.

Author	Toxic multinodular goiter n	Thyroid cancer n	Thyroid cancer %
Cerci [99]	124	11	8.8
Senyurek Giles [17]	299	19	6.4
Vaiana [21]	251	10	3.9
Cappelli [8]	339	13	3.9
Gabriele [22]	241	4	1.6
Cakir [18]	245	18	7.3
Sahin [16]	112	2	1.8

Incidence of hyperthyroidism in cancer patients

Most of the reports examined the incidence of thyroid cancer in patients with hyperthyroidism and there are only few reports looking for the incidence of hyperthyroidism in patients operated on for thyroid cancer which is reported to be up to 14% [11] [17] [26] [45] [72] [94] [96] [97] [98] [99] [100] [101] [102] [103] [104], ([Table 7]). It would be very interesting to compare the evolution of thyroid cancer in both euthyroid and hyperthyroid patients in these studies in order to really understand if thyroid cancer progresses in a different way, depending on the metabolic condition of the thyroid gland.

Table 7 Incidence of all types of hyperthyroidism in patients with thyroid cancer.

Author	Thyroid carcinoma n	Hyperthyroidism (all types)
		n	%
Kilpatrick [97]	100	7	7.0
Hancock [98]	120	10	8.3
Mazzaferri [99]	576	19	3.3
Hall [100]	79	3	3.8
Wahl [101]	554	23	4.2
Edmonds [45]	502	22	4.2
Ahuja [72]	251	22	8.8
Vini [102]	986	23	2.3
Bolko [103]	217	20	9.1
Pazaitou-Panayiotou [11]	720	60	8.3
Gulcelik [104]	422	12	2.8
Lian [94]	245	12	4.9
Omur [96]	1800	76	4.2
Calò [26]	110	15	13.6

Conclusions

Hyperthyroidism is a benign disease. Some patients with Graves’ disease are treated with antithyroid drugs for many years. This often leads to underestimation of the risk of thyroid cancer and to a delay in performing thyroidectomy, which should be the choice of treatment in patients with Graves’ disease and suspicious nodules [40]. Evaluation of the malignancy risk of a nodule in patients with Graves’ disease appears to be crucial. Creation of rodent models of thyroid cancers and hyperthyroidism could elucidate molecular genetic changes underlying cancer development and progression [105].

Patients with a toxic nodule or toxic multinodular goiter usually undergo thyroid ablation soon after the diagnosis of hyperthyroidism and therefore rarely receive prolonged antithyroid treatment. These patients are at low risk for developing thyroid carcinoma in the toxic nodules based on the data reported above. It is important to perform thyroid and neck US and US-guided FNAC prior to radioiodine therapy or thyroidectomy [16], in order to detect thyroid cancer. US-FNAC should be focused on lesions, which appear suspicious by US features as stated by the Consensus of Society of Radiologists in Ultrasound [55] [106], and not on larger or clinical dominant nodules. In cases of nodules that show suspicious features and when it is not possible to exclude the possibility of malignancy by fine needle aspiration cytology, the preferred choice of treatment should be surgery. The detection of the rare truly hot thyroid carcinomas remains a clinical challenge.

Unfortunately all the reported series in the present review are retrospective. Therefore, it is impossible to know the selection criteria, which have led to choose surgery: treatment of hyperthyroidism or because a nodule was suspicious? Prospective multicenter studies based on such selection could answer if the incidence and progression of thyroid cancer is different or not.

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