In the United States, thyroid cancer incidence rates have increased by 211% between 1975 and 2013, with papillary thyroid cancer (PTC), the most common and least-aggressive histologic type, accounting for most of the new cases.¹ Some investigators have suggested that overdiagnosis, or the increased ability to detect and diagnose small indolent tumors that would never otherwise cause symptoms or require treatment, explains a substantial proportion of the increase.^2-5

The prevalence of class III obesity (body mass index [BMI]≥40 kg/m²) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity. In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19–83 y at baseline, classified as obese class III (BMI 40.0–59.9 kg/m²) compared with those classified as normal weight (BMI 18.5–24.9 kg/m²). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976–2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40–44.9, 45–49.9, 50–54.9, and 55–59.9 kg/m² was associated with an estimated 6.5 (95% CI: 5.7–7.3), 8.9 (95% CI: 7.4–10.4), 9.8 (95% CI: 7.4–12.2), and 13.7 (95% CI: 10.5–16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report. Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight. Please see later in the article for the Editors' Summary The number of obese people (individuals with an excessive amount of body fat) is increasing rapidly in many countries. Worldwide, according to the Global Burden of Disease Study 2013, more than a third of all adults are now overweight or obese. Obesity is defined as having a body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) of more than 30 kg/m² (a 183-cm [6-ft] tall man who weighs more than 100 kg [221 lbs] is obese). Compared to people with a healthy weight (a BMI between 18.5 and 24.9 kg/m²), overweight and obese individuals (who have a BMI between 25.0 and 29.9 kg/m² and a BMI of 30 kg/m² or more, respectively) have an increased risk of developing diabetes, heart disease, stroke, and some cancers, and tend to die younger. Because people become unhealthily fat by consuming food and drink that contains more energy (kilocalories) than they need for their daily activities, obesity can be prevented or treated by eating less food and by increasing physical activity. Class III obesity (extreme, or morbid, obesity), which is defined as a BMI of more than 40 kg/m², is emerging as a major public health problem in several high-income countries. In the US, for example, 6% of adults are now morbidly obese. Because extreme obesity used to be relatively uncommon, little is known about the burden of disease, including total and cause-specific mortality (death) rates, among individuals with class III obesity. Before we can prevent and treat class III obesity effectively, we need a better understanding of the health risks associated with this condition. In this pooled analysis of prospective cohort studies, the researchers evaluate the risk of total and cause-specific death and the years of life lost associated with class III obesity. A pooled analysis analyzes the data from several studies as if the data came from one large study; prospective cohort studies record the characteristics of a group of participants at baseline and follow them to see which individuals develop a specific condition. The researchers included 20 prospective (mainly US) cohort studies from the National Cancer Institute Cohort Consortium (a partnership that studies cancer by undertaking large-scale collaborations) in their pooled analysis. After excluding individuals who had ever smoked and people with a history of chronic disease, the analysis included 9,564 adults who were classified as class III obese based on self-reported height and weight at baseline and 304,011 normal-weight adults. Among the participants with class III obesity, mortality rates (deaths per 100,000 persons per year) during the 30-year study period were 856.0 and 663.0 in men and women, respectively, whereas the mortality rates among normal-weight men and women were 346.7 and 280.5, respectively. Heart disease was the major contributor to the excess death rate among individuals with class III obesity, followed by cancer and diabetes. Statistical analyses of the pooled data indicate that the risk of all-cause death and death due to heart disease, cancer, diabetes, and several other diseases increased with increasing BMI. Finally, compared with having a normal weight, having a BMI between 40 and 59 kg/m² resulted in an estimated loss of 6.5 to 13.7 years of life. These findings indicate that class III obesity is associated with a substantially increased rate of death. Notably, this death rate increase is similar to the increase associated with smoking among normal-weight people. The findings also suggest that heart disease, cancer, and diabetes are responsible for most of the excess deaths among people with class III obesity and that having class III obesity results in major reductions in life expectancy. Importantly, the number of years of life lost continues to increase for BMI values above 50 kg/m², and beyond this point, the loss of life expectancy exceeds that associated with smoking among normal-weight people. The accuracy of these findings is limited by the use of self-reported height and weight measurements to calculate BMI and by the use of BMI as the sole measure of obesity. Moreover, these findings may not be generalizable to all populations. Nevertheless, these findings highlight the need to develop more effective interventions to combat the growing public health problem of class III obesity. Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001673.

The incidence of thyroid cancer has risen dramatically in the United States over the past four decades, with similar patterns observed internationally. Thyroid cancer currently ranks as the 13th most common cancer diagnosis overall and the 6th most common among women. Because the greatest increases in incidence have been observed for small and localized tumors having the highest rate of survival, the incidence trends have been primarily attributed to overdiagnosis, resulting from more widespread use of diagnostic imaging and more sensitive diagnostic tools. Increasing incidence of large and advanced thyroid cancers, as well as thyroid cancer mortality, suggests that etiologic factors may have contributed to rising incidence of the disease, albeit to a lesser extent than overdiagnosis. Until recently, childhood exposure to ionizing radiation was considered the only established modifiable risk factor for thyroid cancer. Obesity has emerged as another important risk factor, although the underlying biological mechanisms remain poorly understood. The potential influence of endocrine-disrupting chemicals and thyroid dysfunction on thyroid cancer development has been a focus of recent etiologic studies. Important recent advances in identifying molecular subtypes of thyroid cancer and genetic susceptibility factors provide insights regarding the etiology of this disease.Of the major histologic types, about 90% are papillary thyroid carcinomas (PTC), 4% follicular thyroid carcinomas (FTC), 2% Hürthle cell carcinomas, 2% medullary thyroid carcinomas (MTC), and 1% anaplastic thyroid carcinomas (ATC; ref. 1). MTCs are neuroendocrine tumors arising from calcitonin-producing C cells (parafollicular cells). Other rare thyroid cancers, with some exceptions (e.g., squamous cell, lymphoma, mesenchymal tumors), arise from follicular cells.Thyroid cancers are also classified according to genetic drivers. The 2014 Cancer Genome Atlas Research Network landmark publication reported work that led to the identification of driver mutations in over 95% of nearly 500 PTCs (2). Subsequent work using a similar approach has identified Hürthle cell thyroid cancers as a separate entity from PTCs and FTCs (3). PTCs can now be distinguished according to those with somatic mutations related to the BRAF mutations in the MAPK pathway (BRAF-like) and those related to RAS mutations (RAS-like). BRAFV600E mutation has been associated with disease recurrence and mortality in patients with PTC, particularly when co-occurring with TERT promotor mutations (4, 5). BRAF and RAS mutations appear to play an important role in the development of poorly differentiated and anaplastic thyroid cancers, with BRAFV600E being an early molecular event and TP53 mutations contributing to the progression of PTCs to poorly differentiated and anaplastic types (5). TP53 mutations are present in about 26% of poorly differentiated cancers and 80% of ATCs, but rarely occur in PTCs (5). In general, the TERT promotor mutation and TP53 mutation, especially if co-occurring or co-occurring with other mutations, are strongly linked to higher degrees of dedifferentiation, disease aggressiveness, and poor outcomes (5). RET/PTC rearrangements are another distinct and common molecular event in the development of PTC; these occur more frequently in individuals exposed to radiation in childhood where they act through the MAPK pathway (ref. 6; see the “Ionizing radiation” section). RET mutations are the most common somatic mutations in MTCs, following by H-RAS and K-RAS (5).Thyroid cancer incidence varies substantially by geographic location (Fig. 1A), especially in women (7). In general, the highest incidence is observed in higher-income countries, including the Republic of Korea, Canada, Italy, France, Israel, Croatia, Austria, and the United States, as well as some middle- to upper–middle-income countries, such as Turkey, Brazil, Costa Rica, and China (7, 8). Incidence is also high in some island nations and territories, including Cyprus, Cabo Verde, French Polynesia, New Caledonia, and Puerto Rico (7). This variation is thought to be mainly attributable to geographic differences in access to care and diagnostic practices, although environmental exposures may also play a role (9). Compared with incidence, thyroid cancer mortality rates tend to be much lower and vary much less geographically (Fig. 1B).In the United States, thyroid cancer is estimated to be the 13th most commonly diagnosed cancer, accounting for nearly 44,000 new cancer diagnoses in 2022 (2.3% of the total), and the 6th most commonly diagnosed cancer among women (10). Thyroid cancer incidence is approximately 3-fold higher in women (22.8 per 100,000 per year in 2014–2018) than in men (8.0 per 100,000 per year; Fig. 2A; ref. 1). Thyroid cancer incidence increases from adolescence through middle age, peaking around 55 years in women and 65 years in men, and subsequently declining with older age (Fig. 2B; ref. 11). Currently, one in 55 U.S. women and one in 149 U.S. men are expected to be diagnosed with thyroid cancer during their lifetime (10). Thyroid cancer mortality is very low relative to incidence (approximately 0.5 deaths per 100,000 per year) with less evidence of a sex disparity (7).The prognosis for thyroid cancer is typically excellent, as most cases are PTCs and are localized to the thyroid gland at diagnosis (1). In the United States, the 5-year relative survival rate is 98.6% overall, 99.9% for localized, 98.3% for regional, and 54.9% for distant metastatic disease (1). Relative survival rates are highest for PTC and FTC compared with other histologic types owing to the slow-growing nature of these tumors and effective therapies. Most are effectively managed with total or partial removal of the thyroid or, in some cases, even by prospective observation. In cases that are more advanced, surgery is usually followed by radioactive iodine for the...

Background: Thyroid cancer incidence has risen dramatically in the United States since the early 1980s. Although the prevalence of obesity has doubled during this time period, the relationship between obesity and thyroid cancer is uncertain. Methods: We examined the association between body mass index (BMI) and thyroid cancer risk in a pooled analysis of five prospective U.S. studies, including 413,979 women and 434,953 men. Proportional hazards models with attained age as the time metric were adjusted for education, race, marital status, smoking, alcohol intake, and (where appropriate) cohort and sex. Results: Over follow-up (mean = 10.3 years), 768 women and 388 men were diagnosed with thyroid cancer. The risk of thyroid cancer was greater with increasing BMI [per 5 kg/m²: HR in women, 1.16 (95% CI, 1.08–1.24); HR in men, 1.21 (95% CI, 0.97–1.49)]. There was no significant heterogeneity between studies (both P > 0.05). For women and men combined, the HRs for overweight (25.0–29.9 kg/m²) and obesity (≥30 kg/m²) compared with normal-weight (18.5–24.9 kg/m²) were 1.20 (95% CI, 1.04–1.38) and 1.53 (95% CI, 1.31–1.79), respectively. We found no significant effect modification by other factors, and the results did not differ significantly by histologic type. A significant positive association for BMI in young adulthood (ages 18–20) with thyroid cancer risk was also observed [per 5-kg/m² increase: HR, 1.18 (95% CI, 1.03–1.35)]. Conclusion: BMI was positively associated with thyroid cancer risk in both men and women. Impact: Our study provides strong evidence that obesity is an independent risk factor for thyroid cancer. Cancer Epidemiol Biomarkers Prev; 20(3); 464–72. ©2011 AACR.

Background: Greater height and body mass index (BMI) have been associated with an increased risk of thyroid cancer, particularly papillary carcinoma, the most common and least aggressive subtype. Few studies have evaluated these associations in relation to other, more aggressive histologic types or thyroid cancer-specific mortality. Methods: This large pooled analysis of 22 prospective studies (833,176 men and 1,260,871 women) investigated thyroid cancer incidence associated with greater height, BMI at baseline and young adulthood, and adulthood BMI gain (difference between young-adult and baseline BMI), overall and separately by sex and histological subtype using multivariable Cox proportional hazards regression models. Associations with thyroid cancer mortality were investigated in a subset of cohorts (578,922 men and 774,373 women) that contributed cause of death information. Results: During follow-up, 2996 incident thyroid cancers and 104 thyroid cancer deaths were identified. All anthropometric factors were positively associated with thyroid cancer incidence: hazard ratios (HR) [confidence intervals (CIs)] for height (per 5 cm) = 1.07 [1.04–1.10], BMI (per 5 kg/m ² ) = 1.06 [1.02–1.10], waist circumference (per 5 cm) = 1.03 [1.01–1.05], young-adult BMI (per 5 kg/m ² ) = 1.13 [1.02–1.25], and adulthood BMI gain (per 5 kg/m ² ) = 1.07 [1.00–1.15]. Associations for baseline BMI and waist circumference were attenuated after mutual adjustment. Baseline BMI was more strongly associated with risk in men compared with women ( p = 0.04). Positive associations were observed for papillary, follicular, and anaplastic, but not medullary, thyroid carcinomas. Similar, but stronger, associations were observed for thyroid cancer mortality. Conclusion: The results suggest that greater height and excess adiposity throughout adulthood are associated with higher incidence of most major types of thyroid cancer, including the least common but most aggressive form, anaplastic carcinoma, and higher thyroid cancer mortality. Potential underlying biological mechanisms should be explored in future studies.