In this prospective study of US radiologic technologists, we found that a self-reported history of goiter or benign thyroid adenomas and nodules significantly elevated the risk of thyroid cancer for women and men. A significant increased risk was also observed for women reporting hyperthyroidism, asthma, and benign breast disease. Greater weight and obesity were positively associated, while smoking was inversely associated, with thyroid cancer risk for women. Similar associations were observed among men, although they were based on few incident cases. We did not find significant associations for thyroiditis, hypertension, diabetes, reproductive factors, height, alcohol intake, or physical activity.
Because thyroid cancer is a relatively rare malignancy (1
), most of the epidemiologic studies of nonradiation risk factors for thyroid cancer have used a case-control design. A pooled analysis of 14 thyroid cancer case-control studies, including 2,725 cases and 4,776 controls, investigated a number of factors, including BMI (5
), reproductive and hormonal factors (16
), benign thyroid conditions (18
), diet (19
), smoking (21
), and alcohol consumption (21
) across diverse populations. The strongest and most consistent results from this international pooled case-control analysis were in relation to benign thyroid conditions, particularly goiter, benign nodules/adenomas, and hyperthyroidism, but no association was observed for hypothyroidism (18
); the results did not differ according to histology, and relative risks were generally stronger for men.
A prospective study in San Francisco, California, found no association for hypothyroidism and hyperthyroidism, but, similar to our study, goiter increased the risk more than 3-fold (relative risk = 3.36, 95% CI: 1.82, 6.20) (22
). Goiter and thyroid nodules are strongly and consistently associated with thyroid cancer in epidemiologic studies and may share similar risk factors with thyroid cancer, including diet, smoking, and iodine deficiency (23
). The association we observed for hyperthyroidism may reflect more frequent thyroid examinations among participants with a history of goiter or benign thyroid nodules; in fact, the association was attenuated after excluding participants who also reported a history of goiter (HR = 1.90, 95% CI: 0.94, 3.86) or nodules (HR = 1.73, 95% CI: 0.63, 4.69). Nonetheless, we did not have information on the type of hyperthyroidism or the treatments given for thyroid diseases, and, without diagnostic confirmation, some of these conditions may be subject to misclassification.
We observed a significant increased risk of thyroid cancer for women with a medical history of asthma. However, results from other epidemiologic studies are equivocal. Two case-control studies showed no associations for medical history of asthma (9
) or other allergic conditions (10
). Inverse associations for history of asthma and other allergic disorders were observed in a Swedish case-control study, particularly among women (11
), and a positive association between history of allergies and medullary thyroid cancer risk was shown in the pooled case-control study (8
). A history of allergies has been suggested to reduce cancer risk through a heightened immunologic response, but this hypothesis has received little support and is considered controversial (24
). Although smoking is less common among individuals with asthma (24
), adjustment for smoking did not change the results. Restricting the results to never smokers did attenuate the association for asthma slightly among women (HR = 1.43, 95% CI: 0.73, 2.81), but the number of cases also decreased appreciably (119 to 79). Similar to patients with thyroid disease, asthma patients may be under close medical surveillance and therefore may have a greater chance than the general population of thyroid cancer being diagnosed.
Our finding of an association between benign breast disease and thyroid cancer risk, if not the result of detection bias, may provide further evidence of a common underlying mechanism for breast and thyroid diseases. An increased risk of breast cancer has been observed for individuals with a history of thyroid cancer (25
) and certain types of benign breast disease (26
). Currently, it is unclear whether the association between benign breast disease and thyroid cancer in this study is attributable to a biologic exposure, such as circulating hormone levels (27
), or to greater medical surveillance. Misclassification of benign breast disease was also a concern in this study; benign breast disease encompasses a wide range of conditions (27
), and we did not have detailed information on the specific types of benign breast disease.
While most (10
), but not all (9
), case-control studies of thyroid cancer and cigarette smoking, including the pooled case-control study (21
), support an inverse association, prospective studies have been less consistent (22
). This difference may reflect a greater potential for residual confounding in most prospective studies, which are less likely to have information on thyroid cancer risk factors, including benign thyroid conditions and radiation exposure. In our prospective study, which had detailed covariate information, current smoking was associated with a reduced risk of thyroid cancer, and there was some evidence that the risk decreased with greater intensity, but not duration, of smoking.
The pooled thyroid cancer case-control study found a positive, but small, association for BMI, particularly among women (highest to lowest tertile, odds ratio = 1.2, 95% CI: 1.1, 1.5) (5
). A positive association between BMI and thyroid cancer risk was also observed in several subsequent case-control (28
) and prospective (37
) studies, including those restricted to men (38
). However, no clear association was observed among Swedish male construction workers (≥30 vs. 18.5–24.9 kg/m2
; relative risk = 0.98, 95% CI: 0.49, 1.96; P
-trend = 0.48) (40
). There was also no association between BMI (≥25 vs. <25 kg/m2
) and thyroid cancer risk for men and women in the San Francisco study (relative risk = 1.08, 95% CI: 0.74, 1.56) (22
). Nonetheless, our results are supported by a recent meta-analysis based on prospective observational studies, which found a relative risk of 1.33 (95% CI: 1.04, 1.70) for men and 1.14 (95% CI: 1.06, 1.23) for women for each 5-unit increase in BMI (41
). Assuming a causal relation between obesity and thyroid cancer, we estimate that 6% of thyroid cancer is attributable to obesity in this cohort, based on our results and the 11% prevalence of obesity. In the general US adult population, where the prevalence of obesity was 33% in 2004 (42
), this figure translates to a population attributable risk of 17% (43
). The increasing prevalence of obesity may be one explanation for the increasing incidence of thyroid cancer in the United States over the past 3 decades, but this hypothesis should be explored in future prospective studies.
Some biologic mechanisms have been proposed that may explain the associations we observed in this cohort. In laboratory studies, thyroid-stimulating hormone (TSH) has been shown to regulate the growth and differentiation of thyroid cells (44
). Current smokers may have lower levels of TSH compared with former or never smokers (45
), and TSH levels may be elevated in people who are obese (47
). TSH may also increase during puberty, during pregnancy, or while taking oral contraceptives (23
). Nonetheless, prospective studies examining levels of TSH in relation to thyroid cancer risk for humans are lacking. In addition, prospective studies on the association of TSH with potential thyroid cancer risk factors, particularly obesity (47
), are needed to elucidate whether TSH is a cause or a consequence of these conditions. Estrogen may also play a role in thyroid carcinogenesis given the large sex difference in thyroid cancer incidence; however, epidemiologic evidence linking reproductive or hormonal factors to thyroid cancer has been inconsistent (16
). Although estrogen receptors have been found on thyroid tumors (58
), and estrogen promotes thyroid carcinogenesis in rats (59
), studies of circulating estrogens and thyroid cancer risk have not been conducted to our knowledge. Our study generally does not support a clear role for reproductive or hormonal factors in thyroid carcinogenesis. However, we had limited numbers of thyroid cancer cases to assess the risk for menopausal status and use of hormone therapy.
Despite the relatively large size of this prospective study, the number of male cases was still small. The fairly young age distribution of the cohort also resulted in a limited number of postmenopausal women in this study. A strength of this study compared with several previous prospective studies (33
) is the availability of information on several established and potential thyroid cancer risk factors, including benign thyroid conditions, radiation exposure, cigarette smoking, and BMI, as well as information on thyroid cancer histology. Furthermore, because of their training, radiologic technologists may more accurately report medical history information compared with the general population. For instance, although studies relying primarily on self-report may underestimate the number of incident cases, the accuracy of self-reported thyroid cancers was high in this cohort (positive predictive value = 92.3%) (13
). Misclassification over the follow-up period is a potential limitation given the approximate 10-year interval between questionnaires, but we had updated exposure information for participants who responded to a second questionnaire.
Internal comparisons within this cohort showed that occupational radiation generally did not increase thyroid cancer risk (60
), and personal and occupational radiation exposures were not associated with the nonradiation factors examined in this study. The relative homogeneity of this group with regard to socioeconomic status, occupational exposures, and thyroid cancer screening most likely reduced the potential for bias within the study. However, because radiologic technologists may be monitored more closely for thyroid abnormalities, the generalizability of these findings may be limited.
Some findings from this prospective study warrant further investigation, particularly the positive associations for history of asthma and benign breast disease. Consistent with previous studies, we found that benign thyroid conditions (except thyroiditis) and obesity increase and current smoking reduces the risk of thyroid cancer in men and women. These findings provide additional evidence that obesity may partially contribute to the rising frequency of thyroid cancer.