Risk factors in thyroid cancer: is the obesity pandemic an important factor?

In 2016, the International Agency for Research on Cancer (IARC) supported the evidence that the absence of excess body fat was associated with a reduced risk of several cancers, including thyroid (Figure 1). In this study, the subjects with the highest body mass index (BMI) showed a relative risk of having thyroid cancer of 1.1 (95% CI: 1.0–1.1) [1]. Thyroid cancer, particularly in its differentiated forms (DTC), has been growing worldwide during the last decades [2]. Although several factors that could contribute to this phenomenon cannot be overlooked [3], the routine implementation of the neck ultrasound in clinical practice could be considered a key factor in the increase in early-stage clinically undetectable papillary thyroid cancers (PTCs) [4,5]. Likewise, obesity tripled in men and doubled in women in 200 countries, from 1975 to 2014 [6], and interesting data support the hypothesis that if this trend will continue, by the year 2030, 38% and 20% of the world’s adult population will be overweight or obese, respectively [6]. Obesity is considered to be one of the most common causes of carcinogenesis, along with alcohol and smoking [7,8], and is associated with both increased cancer incidence and progression and could contribute to more than 20% of cancerrelated deaths [9]. Several studies investigated the potential association between BMI and DTC, particularly PTC. Conversely, other indicators of adiposity such as weight circumference and weight gain, although more precise in quantifying visceral adiposity, which could play a key role in carcinogenesis, were less frequently reported in the literature in relation to DTC. Also, the relationship between obesity and other rarer thyroid cancers such as anaplastic, follicular, or medullary thyroid cancer has rarely been evaluated. Therefore, the strengths of evidence regarding obesity and prevalence and aggressiveness of PTC are linked to the evaluation of BMI as a measure of fatness. The pathogenic link between cancers and obesity has been widely studied in recent years [10]. A key role is played by the peculiar function of adipose tissue, an active endocrine organ, which is able to produce not only hormones but also adipokines and growth factors involved in the deregulation of cell growth and survival and in cancer development [9,11]. However, other factors are implicated in thyroid carcinogenesis and could interact with obesity, such as iodine intake, radiation exposure, and endocrine disruptors. To date, the influence of obesity on the increasing rate of PTC is well recognized. Indeed, based on several large prospective cohort or case–control studies, a positive association was observed between BMI, and less frequently also other indicators of adiposity, and the risk of having PTC [12–14]. This is supported by a recent study that estimated that one in six PTC (16.6%), in 2015 in adults (≥60 years) in the USA, was exclusively due to overweight and obesity [15]. The same association was also observed in rarer and more aggressive thyroid cancers such as follicular or anaplastic [12,15]. Conversely, to date, no association between obesity and medullary thyroid cancer was observed [12,16]. Regarding diagnosis, the European Society for Endocrinology (ESE) guidelines on endocrine work-up in obesity [17] stated that no sufficient data are available to recommend systematic assessment by neck ultrasound in subjects with obesity. However, in clinical practice, thyroid glands in subjects with obesity are often difficult to be evaluated by palpation. Accordingly, the results of the available studies in favor or against the routine use of neck ultrasound in subjects with obesity are controversial [18–20]. More controversies were reported about the potential association of obesity with aggressive features of thyroid cancer [21]. A study involving more than 400,000 subjects observed that those with BMI ≥30 kg/m had a risk fivefold greater to have larger PTC (>4 cm) when compared to normal weight [15]. Nevertheless, in this study, an association of larger tumors with disease-specific survival and recurrence was postulated, but not demonstrated. Two recent meta-analysis, partially evaluating the same studies, included 26,196 and 35,237 subjects with PTC [22,23], showed a positive association between higher BMI and minimal extrathyroidal extension (mETE), multifocality, larger tumor size, and lymph node metastases. However, despite this evidence, several limitations were reported by the authors in considering these results: the lack of adjustment for confounding factors, the absence of information about the aggressive variants of PTC, the retrospective observational nature of the studies, and the different