**2. Epidemiology of DTC**

The incidence of DTC is rising worldwide [6]. In 2020, 448,915 new cases of thyroid cancer were estimated, with an age-standardised rate of 10.1/100,000 and 3.1/100,000 in

**Citation:** Van Den Heede, K.; Tolley, N.S.; Di Marco, A.N.; Palazzo, F.F. Differentiated Thyroid Cancer: A Health Economic Review. *Cancers* **2021**, *13*, 2253. https://doi.org/ 10.3390/cancers13092253

Academic Editor: Fabio Medas

Received: 18 April 2021 Accepted: 5 May 2021 Published: 7 May 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

women and men, respectively (Global Cancer Observatory, IARC). In the United Kingdom (UK), where thyroid cancer incidence is lower than most other European countries, it has increased by 68% over the last decade with 3700 new thyroid cancers diagnosed a year. The expectation is a further rise to 11 cases per 100,000 by 2035 (Cancer Research UK). In 2019, 52,070 new cases were estimated in the United States (US) [7]. If the rising trend in incidence is maintained, thyroid cancer should become the fourth most common cancer in the United States by 2030 [8]. Despite the progressive increase in incidence, the disease-specific mortality in the US has increased marginally from 0.40 to 0.46 per 100,000 and can be accounted for by the advanced and dedifferentiated cancers that occur most commonly in an ageing population [9]. In 2020, 43,646 patients died from thyroid cancer (27,740 women and 15,906 men) (Global Cancer Observatory, IARC), almost no change from the 40,000 estimated global deaths in 2012 [6]. These trends of incidence and mortality are seen across the developed world, with pockets of extreme increase in incidence in countries where thyroid screening has been adopted, such as in South Korea [5,10,11]. The rate of incidental DTC however has remained stable in autopsy studies since 1970 [12].

The rising incidence of DTC applies primarily in high-income countries where incidence rates are more than two-fold higher than low and middle-income countries [6]. International comparisons can be difficult due to differences in the reporting and treatment of the disease. However, even within the same country different rates of DTC diagnosis exist, usually coinciding with a different medical ethos, healthcare structure, and/or funding strategy as noted in regions of Belgium and Brazil [13–15]. In the US, social-economic group and race are also influential with a higher incidence of thyroid cancer found in white patients with a higher income and health insurance levels [16].

The increasing incidence of thyroid cancer is driven by early-stage DTC without any increase of note in mortality or any increase in the known risk factors [5]. Despite an increase in exposure from medical conditions and their treatments, the overall environmental radiation burden has declined [17–20].

Iodine deficiency [21] predisposes to goitre and thyroid nodularity which are also risk factors for thyroid cancer diagnosis [5]. A meta-analysis reported a PTC/FTC ratio of 3.4–6.5:1 compared to a ratio of 0.19–1.7:1 in iodine-deficient areas [22]. Chronic iodine deficiency may also be a risk factor for anaplastic thyroid cancer [5,23] but overall, there is no epidemiological overlap between the surge in DTC and iodine deficient areas.

In light of the above considerations, whilst the hypothesis of increased population exposure to known or some unrecognised carcinogens is a potential explanation for the thyroid cancer epidemic, this remains somewhat unlikely.
