The thyroid gland was one of the original organs studied using a radionuclide. The uptake and distribution of radioiodine reflect the thyroid metabolism and pathophysiology of both benign and differentiated malignant thyroid tissue. This has enabled imaging and successful therapy of benign and malignant conditions with the same radionuclide [1].

A common presentation of thyroid benign disease is thyrotoxicosis where there is an excess of circulating thyroid hormone. For example, in the UK it has a prevalence of 2% in women and 0.2% in men. In children it is rare with a prevalence of 1–2 per 10,000 [2].

Thyroid cancer has an annual incidence globally of 5.4% in men and 6.5% in women [3] with papillary carcinoma representing about 90% of thyroid carcinomas. In the USA the annual increase of papillary thyroid cancer for regional disease is 4.3% per year [4]. In Europe the incidence of thyroid cancer varies from country to country, the highest being in Lithuania with 15.5 per 100 000 person-years in 2012 followed by Italy (13.5), Austria (12.4), Croatia (11.4), and Luxembourg (11.1) [5]. A meta-analysis of Thyroid Cancer in Europe published in 2023 found a mean incidence (95% CI) per 100,000 person-years of 10.2 (6.3–15.0); for women and men, 15.4 (10.4–21.4) and 5.0 (3.5–6.8), respectively [6]. Furthermore, the standardised incidence ratios for DTC has been found to be raised after 10 years in patients with hyperthyroidism, which was not related to the previous radioiodine treatment in this study [7].

Thus, it is important to be aware of the possibility of co-existing thyroid cancer in thyrotoxic patients presenting for treatment.

In Graves’ disease the incidence of thyroid cancer has been reported to be up to 2% [8] and up to 17% in a selected series of patients who had a thyroidectomy due to failed medical treatment, the presence of a dominant nodule, or refusal of radioiodine treatment [9].

In another series of 243 patients with Graves’ disease who had a total thyroidectomy, 50 patients (almost 20%) had a papillary thyroid carcinoma; 48% were incidental while 52% were suspected. Most of the tumours were small with 72% measuring 1 cm or less [10].

The presence of thyroid cancer is related to the size of the nodule on presentation. In a study of 7348 nodules, 927 (13%) were cancerous; 10.5% of nodules sized between 1.0 and 1.9 cm in diameter were cancerous, while 15% of the nodules over 2.0 cm were cancerous (p < 0.01) [11]. Of the nodules which were malignant, with increasing size follicular cancer became more frequent and papillary less frequent.

Papillary cancer in general responds well to treatment. With appropriate treatment, the survival at 20 years has been reported to be 99% in patients with Graves’ disease who had small < 1 cm coexisting cancers [12]. Disease-free patients after successful treatment for thyroid differentiated cancer can expect a normal residual life span [13].

So, although the incidence may be small, it is important to discover and treat thyroid cancers in patients presenting with thyrotoxicosis. The problem is that the cancers are often small. A routine radioiodine or pertechnetate scan at presentation may discover non-functioning nodules down to 1 cm. These can then be assessed by ultrasound (US) of thyroid and fine needle aspiration (FNA), if appropriate. Extra thyroidal uptake of 99mTc Pertechnetate in a hyperfunctioning histologically proven bone metastases from follicular thyroid carcinoma has also been described as well as an intrathyroidal small non-functioning ‘cold’ lesion in a patient presenting with thyrotoxicosis in presumed Graves’ disease with no palpable thyroid nodule [14].

However, the guidelines do not suggest routine radionuclide imaging in patients presenting with thyrotoxicosis with Graves’ disease. The UK National Institute for Health and Care Excellence (NICE) guidelines [Thyroid disease: assessment and management NG145] only consider 99mTc pertechnetate scanning if the TSH receptor antibodies (TRAbs) are negative and only consider ultrasound in adults with thyrotoxicosis if there is a palpable thyroid nodule [2]. This would potentially exclude the 72% of nodules found in the series by Arosemena et al. [10]. The American Thyroid Association recommends a 123I or 99mTc pertechnetate scan should be obtained only when the clinical presentation suggests a toxic adenoma or multinodular goitre with toxicosis [15].

Similarly, scintigraphy of the thyroid is suggested in the European Thyroid Association guidelines only when thyroid nodularity coexists with hyperthyroidism and prior to therapy [16].

However, radionuclide imaging can help discover non-palpable potentially cancerous nodules which show no uptake of radioiodine or pertechnetate. In a series of 190 patients with thyrotoxicosis and no palpable nodules, aged between 23 and 93 (mean 48 years), 5.3% had Graves’ disease with nodules, 3.2% had Graves’ disease with non-functioning nodules [17], and only 12% had normal images. Furthermore, a significant proportion (20%) of hyperthyroid patients with no suspicion of nodules and clinical ‘Graves’ disease’ had a diagnosis other than solely Graves’ disease and would have received incorrect treatment without the result of the radionuclide scan.

Incidental papillary carcinoma is often indolent so there could be an argument to omit imaging, waiting until a lesion is palpable. This would only happen if there was routine follow-up in a clinic. Importantly, the best chance of successful treatment is when the tumour is small and there are no metastases. In a series of 5897, patients the hazard ratio (HR) for overall survival rose from 1.04, for tumours measuring 2.10 to 4.0 cm, to 2.27 for tumours measuring over 4 cm [18].

It can be argued that radionuclide imaging has a low yield in detecting small cancers, but for those whose thyroid cancer is discovered the survival benefit with early treatment is enormous.

Initial radionuclide imaging in patient with thyrotoxicosis can also assess the size and location of thyroid tissue, ectopic thyroid tissue, discover thyrotoxicosis due to hormone production from differentiated thyroid cancer [19], and struma ovarii [20]. It can also help to discount other causes of thyrotoxicosis such as thyrotoxicosis without hyperthyroidism e.g., transient thyroiditis, subacute/viral thyroiditis, iatrogenic hyperthyroidism, and non-palpable toxic autonomous adenoma [21].

Concomitant thyroid cancer occurring in patients with increased TRAbs is also the possibility. It has been reported that thyroid cancer was identified in 7% of patients undergoing surgery for Graves' disease, of which 3% were significant (not micropapillary > 1 cm) and could be identified by imaging [22]. In general, thyrotoxicosis with concomitant thyroid cancer is poorly recognised. This may result in delayed diagnosis, inappropriate treatment, and even poor prognosis. Functional and anatomic thyroid imaging would aid to more timely diagnosis and change in management [23].

Thus, thyrotoxicosis is no insurance against cancer of thyroid tissue. This should be borne in mind at the first presentation. It is recommended that future revisions of the guidelines for the treatment of thyrotoxicosis should reconsider the value of thyroid scintigraphy at the initial presentation in patients with no palpable nodules and not just in patients with nodular thyroid disease and TRAbs negative disease.