Epidemiology of Thyroid Cancer

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 destruction of any remaining thyroid cells or tissue. ATCs, poorly differentiated thyroid cancers, and some other uncommon variants are highly aggressive and less amenable to treatment, although individualized medications, kinase inhibitors and others, have been developed (12, 13). During 1974–2013, ATC accounted for only 1% of thyroid cancer diagnoses but 30% of thyroid cancer deaths (14).From the early-1980s to mid-2010s, the incidence of thyroid cancer in the United States nearly tripled, rising at a faster rate than any other cancer type, before stabilizing and then declining during the mid-to-late-2010s (Fig. 2A; refs. 11, 15, 16). The upward trend was driven primarily by PTC, with the greatest rate of increase observed for small, early-stage PTCs (14). Although very modest relative increases in thyroid cancer mortality have been observed during this time (rising, on average, ∼1% per year), in absolute terms, mortality has remained very low and stable over time relative to incidence (14). The rising incidence coincided with the introduction and increasingly widespread use since the 1980s to 1990s of medical imaging techniques, including thyroid ultrasonography, and sensitive diagnostic tools (17, 18), resulting in the incidental detection and diagnosis of cancers that would previously not have been detected. For these reasons, the rising incidence of thyroid cancer has been referred to as an "epidemic of overdiagnosis" (19, 20). Overdiagnosis is defined as the diagnosis of a condition that would not have caused harm to the individual over their lifetime if left undetected. Similar trends in incidence have been observed in nearly every region of the world, including some lower-resource countries, without clear corresponding increases in mortality (17). As an extreme example, thyroid cancer incidence increased 15-fold between 1993 and 2011 in the Republic of Korea following the launch of a national campaign to promote cancer screening, whereas thyroid cancer mortality remained stable (21). Although thyroid cancer incidence subsequently declined after 2014 following major efforts to reverse this trend (22), the country continues to have the highest incidence of thyroid cancer in the world (7).Clinical practice guidelines around the management of thyroid cancer have been modified over the last 15 years, with the goal of reducing the potential for overdiagnosis and resulting overtreatment. For instance, biopsying small nodules is no longer recommended by the American Thyroid Association (ATA; refs. 23, 24). In 2017, the ATA recommended reclassification of noninvasive encapsulated follicular variant subtype of PTCs (NIFTP, noninvasive follicular thyroid neoplasm with papillary-like nuclear features), known for their indolent behavior, from a malignant to an in situ carcinoma (16, 25). These efforts appear to have contributed to the recent reduction in total PTC incidence, driven by declining incidence of small PTCs and the PTC follicular variant (16). On the other hand, the incidence of larger and advanced-stage PTCs continues to increase rapidly (16). Therefore, it is likely that diagnostic practices largely, but not fully, account for the changing trends in thyroid cancer incidence. This raises the question, discussed below, of whether and to what extent lifestyle and environmental risk factors may have played a role (14, 26–28).Thyroid cancer is susceptible to socioeconomic disparities in incidence because it is often detected during routine physical examinations or incidentally during work-up of other conditions. Greater access to and utilization of healthcare increases the likelihood of overdiagnosis and, thus, overdiagnosis and overtreatment. For example, in the United States, PTC patients with private health insurance are more likely to be diagnosed with early-stage disease compared with uninsured patients or those with Medicare or Medicaid (29). They are also more likely to undergo extensive treatment (total thyroidectomy, lymphadenectomy, and/or radioactive iodine). In contrast, those without private insurance may be susceptible to delayed diagnosis and treatment, potentially leading to worse outcomes.Questions have been raised about whether the higher female–male ratio in thyroid cancer incidence is real or artifactual (30). Autopsy studies have suggested a high prevalence (>10%) of subclinical PTC in the population, with no apparent changes in prevalence over time and no evidence of sex differences (30, 31). This contrasts with registry data showing a 4-fold higher incidence of small (≤2 cm), localized PTC in women versus men and two-fold higher incidence of all other types of PTC (30). As mentioned above, no sex disparities are observed for thyroid cancer mortality. Women may have more opportunities for incidental detection of thyroid nodules in clinical settings, via palpation or imaging, and overdiagnosis may be more likely during the reproductive years and around menopause; this may account for the more exaggerated age-at-diagnosis curves in women than men over time (Fig. 2B; ref. 19). On the other hand, the higher incidence in women than in men has been observed for decades and consistently across nearly every region of the world, including regions less affected by overdiagnosis (7). In the United States, a 2-fold higher incidence of thyroid cancer in women than in men was observed in the 1970s, prior to the introduction of thyroid ultrasonography and fine-needle aspiration biopsy (11). Finally, thyroid screening studies in Chernobyl and Fukushima area residents showed a slightly higher prevalence of thyroid nodules and cancer in females than in males, with sex ratios of 1.4 to 1.6 (32–34). Thus, overdiagnosis appears to have inflated the observed sex disparity in thyroid cancer incidence beyond biological reasons for these differences.In the United States, thyroid cancer incidence is highest in non-Hispanic whites and lowest in Blacks and Native American/Alaskan Natives (Fig. 3A; ref. 11). Non-Hispanic whites also have a higher incidence of small, localized PTCs, suggesting more overdiagnosis, whereas no racial/ethnic differences are observed for large or advanced PTCs (35). Five-year relative survival is similar by race/ethnicity, although survival for metastatic thyroid cancer is slightly lower in Black patients versus other race/ethnic groups (Fig. 3B). A study using California Cancer Registry data showed that Black, Hispanic, and Asian/Pacific Islander patients received care at hospitals with lower-quality evaluations for thyroid cancer treatment than white patients after controlling for socioeconomic and insurance status (36). Treatment of thyroid cancer in lower-quality hospitals was associated with worse overall and disease-specific survival (37).Substantial heterogeneity in incidence exists across Asian/Pacific Islander ethnic subgroups. Filipino-Americans have higher rates of PTC than non-Hispanic whites and other Asian/Pacific Islander groups and are more likely to be diagnosed with advanced disease (38), differences that persist after adjustment for sociodemographic factors (39). As higher incidence has been observed in first- versus subsequent-generation Filipinos and not other Asian/Pacific Islander groups (40), environmental exposures are considered to play a role (ref. 38; see "Other environmental exposures" below).Identifying true etiologic (causal) risk factors has been a major challenge in thyroid cancer epidemiologic research. A high proportion of these tumors are indolent and detected incidentally, through thyroid screening, imaging for unrelated reasons, or diagnostic work-up of benign thyroid conditions. Thus, the term "risk factor" in the context of thyroid cancer may mean any characteristic or exposure that increases the likelihood of having a thyroid cancer diagnosis. Where possible, we use the term "causal risk factor" or "etiologic factor" to denote any factor that appears to fulfill most or all of the main criteria for causation: temporality, strength of association, consistency, biological gradient, specificity, biological plausibility, and coherence (41). Modifiable risk factors are those that can, in theory, be changed to increase or lower an individual's risk of the outcome (thyroid cancer). Evidence regarding modifiable (or potentially modifiable) risk factors is summarized in Table 1.Ionizing radiation exposure in childhood is currently the most well-established modifiable risk factor for thyroid cancer. Based on astute clinical observation, Duffy and Fitzgerald were the first to draw attention to the relationship between radiation exposure and thyroid cancer (42). This was confirmed by a groundbreaking study in Rochester, NY, which prospectively followed a cohort of people exposed to thymus-directed radiation treatments as children (43). The third landmark occurred in the 1995 publication of a pooled analysis of seven cohort studies showing that the association between external radiation exposure and thyroid cancer risk follows a linear dose–response pattern, and that the association is much stronger for individuals exposed as young children (44).Perhaps the strongest evidence so far comes from the recent update and expansion of the pooled analysis (45–47). At one time, it was thought that very high radiation exposure to the thyroid, characteristic of cancer therapy, destroys thyroid tissue rendering malignant transformation of cells impossible. However, the updated pooled analysis showed that the risk of thyroid cancer continues to increase until very high doses before curving downward, but never returning to baseline (46). Another long-standing question relates to the existence of a "threshold" effect of radiation exposure on thyroid cancer risk, meaning a level of exposure below which the risk of thyroid cancer is zero. The pooled analysis focused on the dose–response relation at the lowest dose range, finding that 40 mGy is associated with a statistically elevated relative risk, lower than the 100 mGy found in the earlier pooled analysis (47). The data also support a minimum latency period of 5 to 10 years; this is the minimum time after an exposure that its effects on an outcome may be clinically observable. Finally, it showed that the risk increases for 30 to 40 years before decreasing, although not to the baseline. The dose–response estimates from this study can be used as a benchmark for assessing the potential for bias in other epidemiologic studies of radiation-exposed populations (Table 1), particularly in the context of the estimated radiation exposure levels and age and time since exposure (48).There has been long-standing debate about whether thyroid cancer risk is influenced by internal sources of radiation exposure (i.e., from radiopharmaceuticals, such as 131I targeting the thyroid gland) in the same way and to the same degree as with external sources of exposure. 131I and other iodine isotopes are used in the diagnosis and treatment of some thyroid disorders, such as hyperthyroidism. Data from the Chernobyl accident recently confirmed that the association of childhood exposure to 131I and thyroid cancer risk is linear and compatible with findings from populations exposed to external radiation, at least at low to moderate doses (49). However, other factors, especially iodine deficiency in the region of the Chernobyl accident, could affect this comparison. It remains unclear whether 131I treatment for hyperthyroidism influences thyroid cancer risk, although most patients are treated at older ages, and the very high treatment doses (∼100 Gy) used in this therapy may have cell killing effects similar to that of radiotherapy for cancer (45, 50).Whether ionizing radiation exposure may have contributed to population-level trends in thyroid cancer incidence is unclear. Although unique biomarkers of radiation exposure have not yet been identified (to determine with complete certainty that ionizing radiation was the cause of a specific PTC), RET/PTC chromosomal rearrangements are much more prevalent in radiation-exposed cases, and a recent large-scale integrated genomic landscape analysis of PTCs in individuals exposed in utero or in childhood following the Chernobyl accident showed that these carcinogenic events are linearly associated with radiation doses up to 1 Gy (51, 52). Moreover, the DNA-damaging effects of radiation are more apparent for individuals exposed at younger age (52). However, single-institution studies have shown that the proportion of PTC cases with RET/PTC rearrangements appears to decline over time, whereas the proportion of PTCs with BRAF and RAS point mutations remains stable or increase (53, 54). These observations suggest that exposures capable of inducing BRAF or RAS mutations may have had greater influence on population-level trends in PTC incidence than those causing RET/PTC rearrangements. On the other hand, radiation exposure to the general population has increased in recent decades, especially in the United States, owing to a dramatic increase in use of diagnostic imaging, particularly computed tomography (CT; ref. 55). In 2016, CT scans constituted 63% of the total radiation exposure to the U.S. population from all medical sources (56). Between 5% and 15% of all CT scans are conducted in children, and a single head or neck CT scan in children can deliver a dose to the thyroid of about 10 to 20 mGy, although the dose can vary widely depending on the scan type, age of the individual, and other factors (57). Repeated CT scans are common, and each scan contributes to greater cumulative thyroid dose and, thereby, greater risk of thyroid cancer, although it remains uncertain whether the effects of repeated exposures are additive effects or subadditive due to DNA repair mechanisms. From the pooled analysis, cumulative radiation doses between 50 and 100 mGy were estimated to increase thyroid cancer risk by 50% to 100% (46). Consistent with this, a large Australian cohort found that a single head CT scan before age 20 was associated with a 33% to 53% increased risk of thyroid cancer accounting for a one-year exposure lag (58). Thus, it is conceivable that the increased use of CT imaging in children has had at least a small influence on population-level trends in thyroid cancer incidence since the 1980s.Thyroid cancer is often preceded by benign thyroid disease (e.g., thyroid nodules, goiter, hyperthyroidism, hypothyroidism, and thyroiditis), but it remains unclear whether benign thyroid diseases cause the development or progression of thyroid cancer. Diagnostic work-up of benign thyroid conditions may to the incidental detection of thyroid cancer. 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