Abstract
Background:
Incidence of differentiated thyroid cancer has increased in the United States and globally with disproportionate increases observed among women. Recent data suggest that factors other than increased detection may underlie this increase. To understand incidence and survival patterns in differentiated thyroid cancer during a time period of increasing imaging, we examined data from a contemporary population-based sample of U.S. reproductive-aged women.
Methods:
Women aged 20–49 years (N = 61,552) diagnosed with papillary thyroid cancer (PTC) or follicular thyroid cancer (FTC) during 2000–2016 were identified from the U.S. National Cancer Institute Surveillance, Epidemiology, and End Results 18 registries database. For each age decade (20–29, 30–39, 40–49 years), we estimated age-adjusted average annual percentage changes in incidence using segmented and unsegmented regression models and 15-year survival. Results were stratified by race/ethnicity and cancer stage.
Results:
The estimated incidence of PTC increased during 2000–2016 among women aged 20–29 years and during 2000–2012 among women aged 30–49 years. During 2012–2016, incidence stabilized among women aged 30–39 years and decreased among women aged 40–49 years. For FTC, incidence decreased slightly among women aged 20–29 years and was rather stable among those aged 30–49 years during 2000–2016, although increases were observed among non-Hispanic black women aged 30–49 years. By stage, the percentage increase in PTC incidence was largest for regional disease. Fifteen-year estimated survival was generally high but somewhat lower among women aged 40–49 years than those aged 20–39 years. Survival was similar for PTC and FTC except among women aged 20–29 years, for whom survival was modestly lower with FTC than PTC.
Conclusions:
Our findings confirm increasing incidence of PTC among U.S. women aged 20–29 years, a recent stabilization of PTC incidence in women 30–49 years, and stable to decreasing incidence of FTC. Increased detection based on imaging is unlikely to fully explain the continued increase in PTC incidence, given the increasing incidence of regional disease and routine imaging occurring less often among premenopausal than postmenopausal women. Although survival is generally high, treatment often requires surgery and lifelong medications. Further investigations into contributors to these trends are warranted to reduce future morbidity in reproductive-aged women.
Introduction
Incidence of differentiated thyroid cancer has been increasing since the late 1900s both in the United States and globally (1,2). This increase in incidence has been observed primarily for papillary thyroid cancer (PTC) (1 –3). Multiple reports postulate that increased detection through increased use of imaging resulting in overdiagnosis is the primary contributor to the increased incidence of differentiated thyroid cancer among adults worldwide (1 –5); however, U.S. findings of increasing incidence of larger (>4 cm) and more advanced-stage PTC, as well as mortality from advanced-stage PTC (2,6 –8), challenge this conclusion.
Incidence of differentiated thyroid cancer disproportionately affects women, with data from the U.S. National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) showing a fourfold greater increase in absolute incidence of differentiated thyroid cancer in women than men during 1975–2009 (1). SEER data for 2000–2012 also suggest an increase in overall cancer incidence among adolescents and young adults, with thyroid cancer being the greatest contributor to this increasing incidence, particularly among females (9). Additional data from a state-based surveillance program suggest an increased incidence of PTC in parous versus nulliparous women, with thyroid cancer being the second-most common malignancy following breast cancer that is diagnosed during pregnancy and the postpartum period (10).
Although a sex disparity in incidence of differentiated thyroid cancer has been observed among all age groups, the greatest difference has been reported for those of reproductive age (11). Despite this, contemporary population-based data on incidence and survival of differentiated thyroid cancer in the United States specifically examining reproductive-aged women are sparse. The published data available provide limited insights into incidence and survival patterns by patient and tumor characteristics. To gain increased insights into contemporary population-based incidence and survival patterns for differentiated thyroid cancer among reproductive-aged women, we analyzed population-based data reported from the NCI SEER for women aged 20–49 years diagnosed during 2000–2016. Unlike previous studies, patterns of incidence and survival were examined by age decade, race/ethnicity, tumor stage, and tumor size to better elucidate the burden of this disease in reproductive-aged women.
Materials and Methods
Study design and population
Our protocol for this retrospective cohort study was approved by the University of Iowa Institutional Review Board. We obtained data from the NCI SEER 18 Registries Database (November 2018 submission, 2000–2016). The catchment areas for the 18 population-based cancer registries that provided data for the SEER program comprise ∼28% of the total U.S. population (12). We categorized differentiated thyroid cancer as papillary or follicular; the histologic subtypes in the SEER 18 Registries database were assigned using the International Classification of Diseases for Oncology, third edition (ICD-0-3). Papillary adenocarcinoma was defined as codes 8050, 8260, 8340–8344, 8450, 8452, 8453, and 8460 and follicular carcinoma as codes 8290, 8330–8332, and 8335. Cancer stage was assigned as localized, regional, or distant using Summary Stage 2000 (1998+), which was derived from Extent of Disease for 2000–2003 and Collaborative Stage for 2004–2016 (13). Specifically, localized was defined as a malignancy limited to the organ of origin with no further spread beyond that organ; regional was defined as tumor extension beyond the limits of the organ of origin; and distant was defined as metastases (tumor cells) that have broken away from the primary tumor, traveled to other locations in the body, and begun to grow at one or more of these new locations.
Using the SEER 18 Registries database, we identified 61,629 women whose first invasive primary cancer diagnosis was differentiated thyroid cancer during 2000–2016 and who were aged 20–49 years at time of diagnosis; this age range was selected because these women were likely to be predominantly premenopausal (14). Of these 61,629 women, we excluded 42 whose diagnoses were not microscopically confirmed and 35 whose diagnosis was reported only from an autopsy, leaving 61,552 women in our analytic sample.
Statistical analysis
We grouped age at differentiated thyroid cancer diagnosis into three decades: 20–29, 30–39, and 40–49 years and used SEER definitions to group race/ethnicity into six mutually exclusive groups: non-Hispanic (NH) white, NH black, NH American Indian/Alaska Native, NH Asian/Pacific Islander, Hispanic, and NH unknown race. Due to the sparse number of cases, we did not examine incidence or survival for follicular thyroid cancer (FTC) among NH America Indian/Alaska Native women, nor did we examine incidence or survival for distant FTC among all women in our sample.
We estimated incidence as the number of annual differentiated thyroid cancer diagnoses per 100,000 women, age-adjusted to the 2000 U.S. standard population within each age decade by 5-year age groups using SEER*Stat version 8.3.5 software (15). Average annual percentage changes (AAPCs) in incidence and 95% confidence intervals [CIs] for 2000–2016 were estimated using the Joinpoint Regression Program software, version 4.6.0.0 (16) applying least-squares regression models with the natural logarithm of the age-adjusted rates as the outcome and diagnosis year as the predictor. Segmented regression models were also assessed via a modified Bayesian information criterion model selection method (17) and fit using the Joinpoint software. The locations of breakpoints identified in the segmented regression models for each age decade and histologic subtype were used in subsequent analyses stratified by racial/ethnic groups and cancer stage; models for stratified analyses were fit using R version 3.5.1 (18). Errors in the regression models were assumed to be normally distributed, and model assumptions were evaluated by examining the residuals; no violations were observed.
We estimated 15-year survival for women diagnosed with differentiated thyroid cancer during 2000–2015 (n = 57,038); those diagnosed in 2016 (n = 4384) were excluded due to lack of follow-up time, as were those diagnosed in 2000–2015 with no follow-up time (n = 130). The median follow-up time for our sample was 84 months. We generated Kaplan–Meier estimates and CIs for 15-year survival using SEER*Stat and plotted 15-year Kaplan–Meier curves using R.
Subanalyses
We conducted two subanalyses. To begin to disentangle patterns of diagnosis related to detection/surveillance versus clinical examination, we examined estimated changes in incidence and estimated survival by tumor size among women diagnosed during 2004–2016 (n = 51,206), the time period during which data for tumor size were available. Tumor size was assigned as T1 (most likely diagnosed on imaging) and T2–T4 (most likely diagnosed clinically) using Derived AJCC T, sixth edition (2004–2015) (19) or Derived SEER Combined T (2016+) (20). Due to the possibility of familial nonmedullary thyroid cancer syndromes and secondary malignancies related to treatment (21,22), we conducted a second subanalysis removing women later diagnosed with a second primary malignancy (n = 2678) to assess whether these second primary malignancies impacted our survival estimates.
Results
Our analytic sample included 10,960 women aged 20–29 years, 21,208 women 30–39 years, and 25,309 women 40–49 years with PTC, as well as 851 women 20–29 years, 1460 women 30–39 years, and 1764 women 40–49 years with FTC (Table 1). NH Asian/Pacific Islander and Hispanic women comprised a greater proportion of PTC than FTC diagnoses, with the opposite pattern observed for NH black women. Hispanic women also comprised a smaller proportion of PTC and FTC diagnoses with increasing age; NH white and NH black women tended to comprise a larger proportion of PTC and FTC diagnoses with increasing age. Regarding cancer stage, a larger proportion of PTC than FTC diagnoses were regional rather than localized. The proportion of PTC diagnoses that were regional decreased with increasing age.
Frequencies of Papillary and Follicular Thyroid Cancers by Race/Ethnicity and Cancer Stage Among Women Aged 20–49 Years Stratified by Age Decade, SEER 18 Registries, 2000–2016
Because of rounding, percentages might not total 100.
NH, non-Hispanic; SEER, Surveillance, Epidemiology, and End Results.
Incidence: PTC
During 2000–2016, we observed an increase (AAPC [CI]) in PTC incidence among women aged 20–29 years (3.65 [CI 3.18–4.12]) (Table 2 and Fig. 1). The increase in incidence was larger among women aged 30–39 (6.01 [CI 5.32–6.87]) and 40–49 (6.41 [CI 5.89–6.94]) years during 2000–2012, followed by more stable (30–39: −0.27 [CI −3.46 to 3.02]) or declining (40–49: −1.90 [CI −4.09 to 0.33]) incidence during 2012–2016. Given these patterns, we applied unsegmented regression models for women aged 20–29 years for 2000–2016 and segmented regression models with a breakpoint in 2012 for women aged 30–49 years to estimate incidence stratified by race/ethnicity and cancer stage.
Incidence rates of papillary
Average Annual Percentage Changes in Incidence of Papillary Thyroid Cancer by Race/Ethnicity and Cancer Stage Among Women Aged 20–49 Years Stratified by Age Decade, SEER 18 Registries, 2000–2016
Based on the breakpoint in 2012 for incidence of PTC among all women 30–39 and 40–49, a breakpoint in 2012 was specified a priori for each racial/ethnic group and each cancer stage among women in these age decades.
Women identified by the Alaska Native Registry were excluded from incidence estimations for the Hispanic group, as this registry only collects cases from the Native American and Alaska Native populations within the state.
AAPC, average annual percent change; CI, 95% confidence interval; PTC, papillary thyroid cancer.
Among women aged 20–29 years, the largest increase in PTC incidence during 2000–2016 was for NH white (3.77 [CI 3.14–4.41]) and Hispanic (4.35 [CI 3.32–5.39]) women (Table 2 and Fig. 2). Among women aged 30–39 years, the increase in incidence during 2000–2012 was rather similar among racial/ethnic groups, but among those aged 40–49 years, the largest increases were observed for NH black (8.53 [CI 6.60–10.49]) and NH American Indian/Alaska Native (11.65 [CI 3.94–19.93]) women, although the estimate for these latter women was imprecise. Estimated increases in incidence during 2012–2016, although imprecise, were observed for Hispanic women aged 30–39 (2.13 [CI −1.84 to 6.25]) and 40–49 (2.33 [CI −0.10 to 4.82]) years, NH American Indian/Alaska Native women aged 30–39 years (8.69 [CI −1.22 to 19.59]), and NH black women aged 40–49 years (2.45 [CI −2.69 to 7.86]); stable or decreasing incidence was observed for the remaining racial/ethnic groups. Regarding cancer stage, the percentage increase in PTC incidence among women in each age decade was largest for regional disease (Table 2 and Fig. 3). In addition, during 2012–2016, decreases were observed for localized disease among women aged 30–39 (−1.45 [CI −3.60 to 0.74]) and 40–49 (−3.18 [CI −4.55 to −1.80]) years.
Incidence rates of papillary
Incidence rates of papillary
Incidence: FTC
We examined FTC incidence among women in each age decade using unsegmented regression models. A decrease in incidence was observed among women aged 20–29 years (−1.17 [CI −2.70 to 0.39]), with the largest decrease being for NH Asian/Pacific Islander women (−4.32 [CI −9.87 to 1.57]), although the estimate was imprecise (Table 3 and Figs. 1 and 2). Incidence was rather stable among women aged 30–39 (0.57 [CI −0.45 to 1.61]) and 40–49 (−0.08 [CI −1.24 to 1.09]) years, although increases were observed for NH black women aged 30–39 (2.88 [CI 0.16–5.68]) and 40–49 (2.93 [CI 0.48–5.44]) years, and a decrease was observed for NH Asian/Pacific Islander women aged 30–39 years (−3.43 [CI −6.07 to −0.72]). Incidence by cancer stage was rather stable for localized disease among all women aged 20–49 years (Table 3 and Fig. 3). Regional disease decreased most among women aged 20–29 years (−5.52 [CI −9.71 to −1.13]) and increased among women aged 30–39 years (5.19 [CI 0.32–10.29]), although estimates were imprecise.
Average Annual Percentage Changes in Incidence of Follicular Thyroid Cancer by Race/Ethnicity and Cancer Stage Among Women Aged 20–49 Years Stratified by Age Decade, SEER 18 Registries, 2000–2016
Incidence was not estimated for FTC for NH American Indians/Alaska Natives due to the sparse number of cases.
Incidence was not estimated for distant FTC due to the sparse number of cases.
FTC, follicular thyroid cancer.
Survival: PTC
Fifteen-year estimated survival (% [CI]) for women aged 20–49 years with PTC diagnosed during 2000–2015 was generally high but somewhat lower among women aged 40–49 years (94.8 [CI 94.1–95.3]) compared with those aged 20–29 (98.8 [CI 98.3–99.1]) or 30–39 (97.7 [CI 97.2–98.0]) years (Table 4 and Fig. 4). Survival was lowest for NH black women aged 40–49 years (89.6 [CI 85.2–92.8]) and NH American Indian/Alaska Native women aged 30–39 years (89.7 [CI 73.3–96.3]) within their respective age decades, although estimates for NH American Indian/Alaska Native women were imprecise (Table 4 and Fig. 5). Survival was lower among women aged 30–39 and 40–49 years diagnosed with distant PTC (91.8 [CI 83.6–96.0] and 83.6 [CI 77.0–88.4], respectively) compared with those with localized (97.9 [CI 97.3–98.3] and 95.4 [CI 94.7–96.0], respectively) or regional (97.5 [CI 96.6–98.2] and 93.9 [CI 92.2–95.2], respectively) PTC (Table 4 and Fig. 6).
Fifteen-year survival by age decade for women aged 20–49 years diagnosed with papillary
Fifteen-year survival by age decade and race/ethnicity for women aged 20–49 years diagnosed with papillary
Fifteen-year survival by age decade and cancer stage for women aged 20–49 years diagnosed with papillary
Fifteen-Year Survival for Papillary and Follicular Thyroid Cancers by Race/Ethnicity and Cancer Stage Among Women Aged 20–49 Years Stratified by Age Decade, SEER 18 Registries, 2000–2015
Survival was not estimated for NH American Indians/Alaska Natives with FTC due to the sparse number of cases.
Survival was not estimated for distant FTC due to the sparse number of cases.
Survival: FTC
As with PTC, estimated survival with FTC was generally high but somewhat lower among women aged 40–49 years (93.6 [CI 91.2–95.4]) compared with those aged 20–29 (96.1 [CI 91.9–98.2]) or 30–39 (97.0 [CI 94.9–98.3]) years (Table 4 and Fig. 4). Although FTC survival estimates stratified by race/ethnicity were imprecise, those for NH black and Hispanic women were similar to or higher than those for NH white women, and those for NH Asian/Pacific Islander women aged 20–29 and 40–49 years were lower than those for women of other racial/ethnic groups in the respective age decades (Table 4 and Fig. 5). Estimated survival for regional disease was imprecise but generally similar to localized disease (Table 4 and Fig. 6).
Subanalyses
For the years with available data (2004–2016), we compared patterns of estimated changes in incidence and estimated survival between cancer stage and tumor size (localized relative to T1, regional relative to T2–T4). Patterns of incidence and survival estimates tended to be similar when examining these estimates by either cancer stage or tumor size, except for an estimated decrease in FTC incidence observed for T1 tumors among women aged 20–29 years (data not shown). In our subanalysis excluding women who later developed a second primary malignancy, survival estimates were similar to those from our main analysis, except for women aged 40–49 years with PTC, for whom survival estimates were higher compared with those from our main analysis (data not shown).
Discussion
Our population-based analysis highlights recent trends in differentiated thyroid cancer incidence and survival among U.S. women of reproductive age. Among women aged 20–49 years, we observed that most PTC and FTC cases were localized, but that a larger proportion of PTC than FTC diagnoses were regional among women aged 30–49 years. We also observed increasing incidence of PTC among women aged 20–29 years during 2000–2016; among women 30–49 years, incidence increased during 2000–2012 and was stable or decreasing during 2012–2016. FTC incidence was imprecise but appeared to be either stable or decreasing during 2000–2016 for each age decade. The percentage increase in PTC incidence was greatest for regional PTC in comparison with localized or distant disease among all age groups. Regarding survival, estimates for PTC and FTC were generally high but lower among women aged 40–49 years compared with those aged 20–39 years. Although survival estimates stratified by race/ethnicity were imprecise, survival was lower for NH black women aged 30–49 years with PTC, NH American Indian/Alaska Native women aged 30–39 years with PTC, and NH Asian/Pacific Islander women aged 20–29 and 40–49 years with FTC than women of other racial/ethnic groups within the respective age decades and histologic subtypes. NH blacks and Hispanics, two groups with historically lower survival in cancer (23), experienced similar or higher survival with FTC compared with NH whites.
Our data are consistent with prior reports showing a continued increase in differentiated thyroid cancer in the United States, predominantly due to an increase in PTC (1,3,5 –7,24). Several prior studies used the SEER 9 database and revealed an approximately threefold increase in incidence from the 1970s until the early 2000s (1,5 –7). Another study analyzed SEER 13 data and reported an AAPC of 7.0% during the years 1992–2009 (24). A study that used SEER 9 data for 1974–2013 observed a reduced increase in incidence among women of all ages during 2009–2013 (AAPC = 1.8%) compared with 1997–2012 (AAPC = 6.7%) (7). Regarding previous reports of mortality, comparisons with our findings are difficult due to the younger age of our population and the more recent time frame used in our analyses.
It has been postulated by many that the rise in differentiated thyroid cancer incidence is due to incidental findings on imaging studies secondary to a rise in diagnostic radiology usage (1 –5). An example cited to support this theory has been the rapid increase in thyroid cancer incidence in South Korea following the institution of a national cancer screening program in 1999 (3,25,26). Thyroid cancer screening was not included in the program, although many providers chose to include thyroid ultrasonography (25). During 1999–2008, there was a 6.4-fold increase in thyroid cancer incidence in South Korea, with screen-detected tumors accounting for 66.1% of this total increase. An additional 18.7% of the increase, however, was attributed to clinically detected tumors (26), which raises concern about other risk factors. Both PTC and FTC are differentiated thyroid cancers arising from thyroid follicular epithelial cells (27). Given their similar derivation, one might expect some degree of increase in the incidence of FTC if incidental detection is the predominant causative factor for an increase in PTC. However, FTC incidence was stable to decreasing in the South Korean study and our study. In addition, we observed a larger percentage increase in incidence of regional PTC, which is more likely to be clinically detected than localized PTC.
Use of diagnostic imaging in the United States increased rapidly until the early 2000s, with utilization highest among those aged 65 or older (28,29). However, recent data suggest a stabilization in imaging in more recent years (29,30). Our analysis showed slowing (ages 30–39 years) or reversal (ages 40–49 years) of the increasing PTC incidence in the later years of our study, which may support the theory of increased diagnosis due to increased use of advanced imaging. However, no slowing or reversal was observed for women aged 20–29 years, who are less likely to undergo imaging, and increasing regional but decreasing localized PTC were observed among women aged 30–49 years during 2012–2016. This pattern persisted in our examination of tumor size, with increasing T2–T4 but decreasing T1 tumors among women aged 30–49 years during 2012–2016, further suggesting that factors other than incidental imaging findings underlie this increase.
Our study has several strengths, including the large cohort of reproductive-aged women, the recency of the data, and examination of incidence and survival by race/ethnicity, cancer stage, tumor size, and development of a second primary malignancy. Limitations of our study included lack of information regarding the following: (i) clinically versus radiographically detected tumors, which precluded appropriately accounting for lead-time bias; (ii) systemic treatment; and (iii) reproductive history, which precluded studying the influence of endogenous and exogenous hormone exposure on our incidence and survival estimates.
In summary, our work presents contemporary patterns of incidence and survival of differentiated thyroid cancer in the United States, including an increase in PTC incidence among reproductive-aged women. Notably, PTC incidence may now be stabilizing for all but the youngest women, among whom the increase continues, particularly for regional disease. These findings, together with the necessity of medical intervention through surgery and lifelong medication for many women with differentiated thyroid cancer, impose significant health burdens on this population. Further study of potential etiologic factors will be important to reducing the occurrence of differentiated thyroid cancer and offering effective prevention and screening for this disease.
Footnotes
Author Disclosure Statement
No competing financial interests exist.
Funding Information
This work was supported by grants from the Centers for Disease Control and Prevention (grant nos. U01DD001035 and U01DD001223); the National Cancer Institute (grant no. HHSN2612013000201); and the Nealie Belk Stevens Fund for Breast Cancer Research.