Abstract

Introduction

In the United States, thyroid cancer incidence rates have more than tripled between 1975 and 2013, with papillary thyroid cancer (PTC), the most common and least aggressive histologic type, accounting for most of the new cases¹. Some investigators have suggested that over-diagnosis, 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.

However, there is growing evidence in support of a true increase in the occurrence of thyroid cancer. An analysis of Surveillance, Epidemiology and End Results (SEER) cancer registry data from 1980–2005 revealed substantial increases in the incidence of advanced-stage PTCs and PTCs >5 cm in diameter; these tumors are generally large enough to be detected via palpation or to cause symptoms⁶. The rates of increase for the largest (>5 cm) and the smallest PTCs (≤1 cm) were nearly equal among white women, a group considered to be particularly susceptible to over-diagnosis⁶. While thyroid cancer mortality rates are much lower relative to incidence, providing the impression of stability over time^2–5, thyroid cancer mortality rates have increased significantly since the late 1980s (0.7% per year, P<0.001)¹. These trends are consistent with temporal changes in the prevalence of some risk factors, including obesity and non-current smoking⁷.

As advanced-stage PTC is less amenable to treatment than localized PTC, the rising mortality rates may be a direct consequence of the trends in advanced-stage PTC. To address this question, the current analysis used SEER data during 1974–2013 to systematically compare thyroid cancer incidence and mortality trends by demographic and tumor characteristics at the time of diagnosis.

Methods

Results

Of the 79,409 thyroid cancer cases diagnosed among residents of the SEER-9 areas during 1974–2013, 77,276 (97%) met the case definition and were included in the incidence analysis (Table 1). Women (75%) and whites (82%) comprised the majority of the cases. Mean age at diagnosis was 48 (standard deviation=16) years. The most common histologic types were PTC (84%) and FTC (11%). Of the eligible cases, 2,371 died of thyroid cancer during 1994–2013 and were included in the incidence-based mortality analysis. Of the deaths, 57% occurred in women and 81% in whites. Compared with all cases, patients who died of thyroid cancer were more likely to have been diagnosed at older ages, with non-PTC histologies, and advanced-stage and/or larger tumors. Among those who died of thyroid cancer, the median time between thyroid cancer diagnosis and death was 25 months; 19% survived >10 years after diagnosis. Among PTC patients who died of thyroid cancer, 27% survived >10 years after diagnosis.

Table 1.

Thyroid cancer incidence (1974–2013) and incidence-based mortality (1994–2013): the SEER-9 Registry Database

	Incidence								Incidence based mortality
Characteristic at diagnosis	Thyroid cancer				Papillary thyroid cancer				Thyroid cancer				Papillary thyroid cancer
	No. of cases a	%	Rateb	95% CI	No. of casesa	%	Rateb	95% CI	No. of deathsc	%	Rateb	95% CI	No. of deathsc	%	Rateb	95% CI
Overall	77,276	100	7.98	7.93, 8.04	64,625	100.0	6.66	6.61, 6.71	2,371	100	0.44	0.42, 0.46	1063	100	0.20	0.19, 0.21
Gender
Male	19,063	24.7	4.20	4.14, 4.26	15,074	23.3	3.28	3.23, 3.33	1,017	42.9	0.44	0.41, 0.47	464	43.7	0.20	0.18, 0.22
Female	58,213	75.3	11.63	11.53, 11.72	49,551	76.7	9.92	9.83, 10.01	1,354	57.1	0.44	0.41, 0.46	599	56.3	0.19	0.18, 0.21
Race
White	63,479	82.1	8.18	8.12, 8.24	53,219	82.4	6.85	6.80, 6.91	1,914	80.7	0.43	0.41, 0.45	841	79.1	0.19	0.18, 0.20
Black	4,582	5.9	4.88	4.73, 5.03	3,473	5.4	3.64	3.52, 3.77	143	6	0.32	0.27, 0.38	48	4.5	0.11	0.08, 0.15
Othersd	8,442	10.9	9.14	8.95, 9.34	7,305	11.3	7.85	7.66, 8.03	312	13.2	0.59	0.52, 0.66	173	16.3	0.33	0.28, 0.38
Age (years)
<20	1,794	2.3	0.62	0.59, 0.65	1,512	2.30	0.52	0.49, 0.55	-	-	-	-	-	-	-	-
20–39	23,877	30.9	8.00	7.89, 8.09	21,106	32.7	7.06	6.97, 7.16	102	4.3	0.02	0.02, 0.02	47	4.4	0.01	0.01, 0.01
40–59	32,188	41.7	13.28	13.14, 13.43	27,727	42.9	11.45	11.32, 11.59	631	26.6	0.11	0.10, 0.12	314	29.5	0.06	0.05, 0.06
60–79	16,877	21.8	13.15	12.95, 13.35	12,825	19.8	9.92	9.75, 10.10	1,148	48.4	0.22	0.21, 0.24	515	48.4	0.10	0.09, 0.11
≥80	2,540	3.3	8.81	8.47, 9.16	1,455	2.3	5.05	4.79, 5.31	479	20.2	0.09	0.08, 0.10	184	17.3	0.03	0.03, 0.04
Histologic type
Papillary	64,625	83.6	6.66	6.61, 6.71					1,063	44.8	0.20	0.19, 0.21
Follicular	8,359	10.8	0.87	0.85, 0.89					404	17	0.08	0.07, 0.08
Medullary	1,685	2.2	0.18	0.17, 0.18					189	8	0.04	0.03, 0.04
Anaplastic	975	1.3	0.11	0.10, 0.11					471	19.9	0.09	0.08, 0.10
Othere	1,632	2.1	0.17	0.17, 0.18					244	10.3	0.05	0.04, 0.05
SEER Historic Stage A
Localized	45,919	59.4	4.75	4.71, 4.79	39,971	61.9	4.13	4.09, 4.17	280	11.8	0.05	0.05, 0.06	143	13.5	0.03	0.02, 0.03
Regional	25,835	33.4	2.66	2.62, 2.69	21,435	33.2	2.20	2.17, 2.23	1,045	44.1	0.19	0.18, 0.21	566	53.2	0.11	0.10, 0.11
Distant	3,658	4.7	0.39	0.37, 0.40	2,045	3.2	0.21	0.20, 0.22	922	38.9	0.17	0.16, 0.18	308	29.0	0.06	0.05, 0.06
Unknown	1,864	2.4	0.19	0.18, 0.20	1,174	1.8	0.12	0.11, 0.13	124	5.2	0.02	0.02, 0.03	46	4.3	0.01	0.01, 0.01
AJCC/TNM stagef
Stage I	25,580	67.4	8.91	8.80, 9.02	23,974	71.5	8.34	8.24, 8.45	17	0.7	0.01	0.003, 0.01	-	-	-	-
Stage II	2,870	7.6	0.92	0.89, 0.96	2,091	6.20	0.67	0.64, 0.70	-	-	-	-	-	-	-	-
Stage III	4,562	12.0	1.46	1.42, 1.50	3,821	11.4	1.22	1.18, 1.25	45	1.9	0.02	0.01, 0.02	24	8.7	0.01	0.01, 0.01
Stage IV	3,045	8.0	1.01	0.97, 1.04	2,111	6.3	0.69	0.66, 0.72	680	28.7	0.23	0.21, 0.25	218	77.6	0.07	0.06, 0.08
Unknown	1,881	5.0	0.62	0.59, 0.65	1,541	4.6	0.51	0.48, 0.53	49	68.1	0.02	0.01, 0.02	19	6.9	0.01	0.00, 0.01
Tumor size (cm)g
≤1	19,943	28.6	2.50	2.47, 2.54	19,257	32.5	2.42	2.38, 2.45	71	3.1	0.01	0.01, 0.02	53	5.2	0.01	0.01, 0.01
>1-≤2	18,113	26.0	2.26	2.23, 2.29	16,477	27.8	2.05	2.02, 2.09	188	8.2	0.04	0.03, 0.04	130	12.9	0.02	0.02, 0.03
>2-≤4	16,031	23.0	2.00	1.97, 2.03	12,772	21.6	1.59	1.56, 1.61	483	21.1	0.09	0.08, 0.10	274	27.2	0.05	0.05, 0.06
>4	6,713	9.6	0.85	0.83, 0.87	3,973	6.7	0.50	0.48, 0.51	852	37.1	0.16	0.15, 0.17	278	27.5	0.05	0.05, 0.06
Unknown	8,879	13.0	1.12	1.10, 1.14	6,721	11.4	0.84	0.82, 0.86	700	30.5	0.13	0.12, 0.14	276	27.3	0.05	0.05, 0.06

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Abbreviations: AJCC/TNM, American Joint Committee on Cancer/Tumor-Node-Metastasis; APC, annual percent change; CI, confidence interval

- Statistic suppressed due to <16 cases/deaths in the time interval

^aCases included first primary tumors that matched the selection criteria, were microscopically confirmed, were not identified only from autopsy records or death certificates.

^bRates were calculated as number of cases or deaths per 100,000 person-years and age-adjusted to the 2000 U.S. standard population.

^cBased on cases diagnosed during 1974–2013.

^dIncludes American Indian/Alaskan Native and Asian/Pacific Islander.

^eIncludes other specified, poorly differentiated, and other types.

^fBased on cases diagnosed during 2004–2013 and deaths during 2004–2013.

^gBased on cases diagnosed during 1983–2013 and deaths during 1994–2013.

Of the 77,276 cases occurring during 1974–2013, 10% were diagnosed in years prior to the availability of tumor size data starting in 1983, and 51% were diagnosed prior to the availability of AJCC/TNM stage information starting in 2004 (Table 1). Of the 2,371 incidence-based mortality deaths occurring during 1994–2013, 3% had been diagnosed in years prior to the availability of tumor size data and 66% were diagnosed prior to the availability of AJCC/TNM stage information. During the years in which specific tumor characteristics were reported to the registries, SEER stage (1974–2013) was unknown for 2% of cases and 5% of deaths, tumor size (1983–2013) was unknown for 13% of cases and 31% of deaths, and AJCNN/TNM stage (2004–2013) was unknown for 5% of cases and 6% of deaths.

A comparison of the agreement between SEER Historic Stage A, tumor size, and AJCC/TNM stage among PTC cases diagnosed between 2004 and 2013 by age (<45 and ≥45 years) is shown in eTable 1. In general, more advanced stage was associated with larger tumor size. There was greater agreement of SEER stage with size and AJCC/TNM stage for patients aged ≥45 years compared with younger patients, reflecting the differences in AJCC/TNM staging guidelines for PTC patients diagnosed before and after age 45 ¹⁴.

Trends in thyroid cancer incidence by demographic and tumor characteristics are described in Table 2, with joinpoints denoted as Trends 1–5. Trends by selected tumor characteristics are shown graphically in Figures 1a-​-1c.1c. Thyroid cancer incidence rates increased over the study period (from 4.56 [95% CI 4.40–4.73] per 100,000 in 1974–77 to 14.42 [95% CI 14.20–14.64] per 100,000 in 2010–13), rising 3.6% (95% CI 3.2–3.9%) per year, on average. Rates increased 6.7% (95% CI 6.1–7.2%) per year during 1997–2009, but did not increase during 2009–2013 (APC=1.8%, 95% CI −0.7–4.4%). Thyroid cancer incidence rates increased for all sex, race, and age groups. Significant increases were observed for PTC (APC=4.4%, 95% CI 4.0–4.7%), FTC (APC=0.6%, 95% CI 0.2–0.8%), and MTC (APC=0.7%, 95% CI 0.2–1.1%). PTC incidence increased significantly for every stage and tumor size category. During 2009–2013, incidence rates did not increase significantly for overall, localized, Stage I, or small (≤2 cm) PTCs, while there was no evidence of a reduction in the increase for regional, distant, or large PTCs.

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Figure 1.

Trends in annual thyroid cancer incidence rates (cases per 100,000 person-years). (A) Thyroid cancer incidence, overall and by histologic type (1974–2013) (B) Papillary thyroid cancer incidence by SEER Historic Stage A at diagnosis (1974–2013) (C) Papillary thyroid cancer incidence by tumor size at diagnosis (1983–2013). Tumor size was not recorded for cases diagnosed 1974–1982. Rates are age-adjusted to the 2000 U.S. standard population. Each line represents the annual percent change (APC).

Table 2.

Trends in thyroid cancer incidence rates ^a (1974–2013): the SEER-9 Registry Database

	Overall			Trend 1			Trend 2			Trend 3			Trend 4			Trend 5
Characteristic at diagnosis	APC (95% CI)	P value	Year	APC (95% CI)	P value	Year	APC (95% CI)	P value	Year	APC (95% CI)	P value	Year	APC (95% CI)	P value	Year	APC (95% CI)	P value
Total	3.6 (3.2, 3.9)			<0.001			1974–77			5.5 (1.4, 9.8)			0.01			1977–80		−5.9 (−13.1, 1.9)	0.10	1980–97	2.6 (2.3, 2.9)	<0.001	1997–09	6.7 (6.1, 7.2)	<0.001	2009–13	1.8 (−0.7, 4.4)	0.20
Gender
Male	3.1 (2.7, 3.5)	<0.001	1974–80	−2.9 (−5.9, 0.2)	0.07	1980–98	2.5 (1.8, 3.2)	<0.001	1998–13	5.6 (4.7, 6.4)	<0.001
Female	3.7 (3.3, 4.1)	<0.001	1974–77	5.8 (0.7, 11.2)	0.03	1977–80	−5.3 (−14.2, 4.6)	0.30	1980–96	2.6 (2.2, 3.0)	<0.001	1996–09	6.7 (6.1, 7.4)	<0.001	2009–13	1.6 (−1.5, 4.8)	0.30
Race
White	3.8 (3.4, 4.2)	<0.001	1974–77	6.2 (2.2, 10.4)	<0.001	1977–80	−5.9 (−12.9, 1.6)	0.10	1980–97	2.9 (2.6, 3.2)	<0.001	1997–09	7.0 (6.5, 7.6)	<0.001	2009–13	1.4 (−1.1, 3.9)	0.30
Black	3.4 (2.8, 4.0)	<0.001	1974–88	−1.3 (−2.8, 0.3)	0.10	1988–13	5.4 (4.7, 6.1)	<0.001
Othersb	1.5 (1.1, 1.9)	<0.001	1974–96	−0.2 (−0.9, 0.4)	0.50	1996–13	3.9 (2.9, 5.0)	<0.001
Age (years)
<20	1.9 (1.3, 2.4)	<0.001	1974–06	1.1 (0.5, 1.7)	<0.001	2006–13	9.8 (3.4, 16.7)	0.003
20–39	3.0 (2.6, 3.3)	<0.001	1974–82	−1.4 (−3.1, 0.3)	0.10	1982–93	1.8 (0.6, 3.1)	0.005	1993–13	4.7 (4.3, 5.2)	<0.001
40–59	3.9 (3.5, 4.3)	<0.001	1974–81	−1.2 (−3.9, 1.5)	0.40	1981–95	2.8 (1.7, 3.9)	<0.001	1995–13	6.2 (5.5, 6.9)	<0.001
60–79	4.2 (3.8, 4.6)	<0.001	1974–96	2.2 (1.8, 2.7)	<0.001	1996–09	7.7 (6.5, 8.9)	<0.001	2009–13	0.8 (−5.2, 7.2)	0.80
≥80	2.3 (1.8, 2.7)	0.002	1974–96	1.0 (0.1, 2.0)	0.03	1996–13	4.1 (2.7, 5.5)	<0.001
Histologic type
Papillary	4.4 (4.0, 4.7)	<0.001	1974–77	6.9 (1.5, 12.6)	0.01	1977–80	−5.9 (−15.2, 4.4)	0.20	1980–97	3.6 (3.2, 4.0)	<0.001	1997–09	7.3 (6.6, 8.1)	<0.001	2009–13	2.6 (−0.7, 6.1)	0.10
Follicular	0.6 (0.2, 0.8)	<0.001	1974–00	−0.2 (−0.7, 0.2)	0.30	2000–06	6.0 (0.8, 11.4)	0.03	2006–13	−3.0 (−5.9, −0.1)	0.05
Medullary	0.7 (0.2, 1.1)	0.005
Anaplastic	−0.1 (−0.7, 0.6)	0.80
Otherc	−0.6 (−1.3, 0.0)	0.06	1974–94	−3.0 (−4.6, −1.7)	<0.001	1994–13	1.9 (0.2, 3.7)	0.03
Papillary
SEER Historic Stage A
Localized	4.6 (4.1, 5.1)	<0.001	1974–77	8.2 (0.0, 17.2)	0.05	1977–80	−7.3 (−20.9, 8.7)	0.30	1980–93	2.6 (1.6, 3.5)	<0.001	1993–09	7.8 (7.1, 8.5)	<0.001	2009–13	1.1 (−3.8, 6.3)	0.70
Regional	4.3 (4.0, 4.6)	<0.001	1974–77	8.4 (1.4, 15.9)	0.02	1977–81	−3.3 (−9.5, 3.4)	0.30	1981–84	11.7 (−2.2, 27.5)	0.10	1984–99	2.8 (2.1, 3.4)	<0.001	1999–13	6.7 (6.0, 7.4)	<0.001
Distant	2.4 (1.7, 3.2)	<0.001	1974–81	−7.7 (−15.0, 0.3)	0.06	1981–13	3.5 (2.6, 4.4)	<0.001
Unknown	1.8 (0.9, 2.7)	<0.001	1974–78	−18.2 (−33.2, 0.1)	0.05	1978–95	7.7 (5.1, 10.4)	<0.001	1995–01	−11.8 (−23.6, 1.7)	0.08	2001–13	5.6 (1.7, 9.6)	<0.001
AJCC/TNM staged
Stage I	5.8 (4.5, 7.1)	<0.001	2004–09	8.2 (5.7, 10.7)	<0.001	2009–13	2.6 (−0.7, 6.1)	0.10
Stage II	3.9 (0.6, 7.3)	0.03
Stage III	9.2 (6.6, 11.9)	<0.001	2004–06	26.0 (7.8, 47.3)	0.01	2006–13	6.5 (4.3, 8.7)	<0.001
Stage IV	5.2 (3.3, 7.2)	<0.001
Unknown	−3.9 (−6.4, −1.3)	0.009
Tumor size (cm)e
≤1	9.3 (8.8, 9.8)	<0.001	1983–88	2.6 (−1.0, 6.3)	0.15	1988–98	9.0 (7.4, 10.6)	<0.001	1998–08	12.2 (10.6, 13.8)	<0.001	2008–13	3.1 (−0.5, 6.9)	0.09
>1-≤2	5.4 (4.9, 5.9)	<0.001	1983–99	3.1 (2.6, 3.7)	<0.001	1999–09	9.1 (7.6, 10.6)	<0.001	2009–13	2.2 (−2.5, 7.2)	0.40
>2-≤4	4.5 (4.2, 4.9)	<0.001	1983–95	2.5 (1.4, 3.6)	<0.001	1995–13	5.7 (5.1, 6.3)	<0.001
>4	6.1 (5.4, 6.7)	<0.001	1983–88	−2.8 (−9.7, 4.6)	0.40	1988–13	6.9 (6.2, 7.6)	<0.001
Unknown	−1.8 (−2.6, −1.0)	<0.001	1983–00	1.4 (0.4, 2.4)	0.005	2000–13	−6.4 (−7.7, −5.1)	<0.001

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Abbreviations: AJCC/TNM, American Joint Committee on Cancer/Tumor-Node-Metastasis; APC, annual percent change; CI, confidence interval.

^aRates were calculated as number of cases per 100,000 person-years and age-adjusted to the 2000 U.S. standard population.

^bIncludes American Indian/Alaskan Native and Asian/Pacific Islander.

^cIncludes other specified, poorly differentiated, and other types.

^dBased on cases diagnosed during 2004–2013.

^eBased on cases diagnosed during 1983–2013.

Thyroid cancer incidence-based mortality rates were underestimated in the earliest calendar years, but consistent with observed nationwide and SEER-9 thyroid cancer mortality rates during 1994–2013 (Figure 2a, eTable 2). Thyroid cancer incidence-based mortality increased, on average, 1.1% (95% CI 0.6–1.6%) annually during 1994–2013 (Table 3; Figure 2a), from 0.40 (95% CI 0.36–0.44) per 100,000 in 1994–97 to 0.46 (95% CI 0.43–0.50) per 100,000 in 2010–13. Positive APCs were observed for most demographic subgroups and statistically significant for females, whites, blacks, and patients diagnosed after age 79. By histologic type, the annual increase in incidence-based mortality rates was restricted to patients diagnosed with PTC (1.7%, 95% CI 0.6–2.9%). Positive APCs were observed for PTCs of all known stages at diagnosis, but were statistically significant only for patients with distant (2.9%, 95% CI 1.1–4.7%) and/or Stage IV (APC=12.9%, 95% CI 7.2–19.0%) disease (Table 3; Figure 2b). Positive APCs occurred for PTCs of all known sizes, with significant increases for tumors ≤2 and >2-≤4 cm (Table 3; Figure 2c).

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Figure 2.

Trends in annual thyroid cancer mortality rates (deaths per 100,000 person-years). (A) Observed total U.S. thyroid cancer mortality (1974–2013), observed SEER-9 thyroid cancer mortality (1974–2013), thyroid cancer incidence–based mortality, overall (1974–2013) and by histologic type (1994–2013), based on cases diagnosed during 1974–2013 (B) Thyroid cancer incidence-based mortality by SEER Historic Stage A at diagnosis (1994–2013), based on papillary thyroid cancer cases diagnosed during 1974–2013 C) Thyroid cancer incidence-based mortality by tumor size at diagnosis (1994–2013), based on papillary thyroid cancer cases diagnosed during 1983–2013. Tumor size was not recorded for cases diagnosed 1974–1982. Rates are age-adjusted to the 2000 U.S. standard population. Each line represents the annual percent change (APC). *APCs were not calculated if 0 deaths occurred in one or more years.

Table 3.

Trends in observed thyroid cancer mortality rates ^a (total U.S. and SEER-9) and thyroid cancer incidence-based mortality rates ^a (1994–2013): the SEER-9 Registry Database

Characteristic at diagnosis	Overall
	APC (95% CI)	P value
Observed
Total U.S	0.9 (0.7, 1.5)	<0.001
SEER-9	1.0 (0.4, 1.5)	<0.001
Incidence-based b
Total	1.1 (0.6, 1.6)	<0.001
Gender
Male	1.0 (−0.1, 2.1)	0.10
Female	1.2 (0.4, 2.0)	0.01
Race
White	0.9 (0.3, 1.6)	0.01
Black	3.8 (0.2, 7.6)	0.04
Others c	−0.2 (−2.4, 2.2)	0.90
Age (years)
<20	-	-
20–39	-	-
40–59	1.4 (0.0, 2.8)	0.05
60–79	0.8 (−0.2, 1.8)	0.10
≥80	1.3 (0.5, 2.1)	0.002
Histologic type
Papillary	1.7 (0.6, 2.9)	0.01
Follicular	−0.2 (−1.6, 1.2)	0.80
Medullary	−0.7 (−3.2, 1.9)	0.60
Anaplastic	0.9 (−0.4, 2.2)	0.20
Other d	2.4 (−0.1, 5.1)	0.06
Papillary (incidence-based)
SEER Historic Stage A b
Localized	2.1 (−0.1, 4.2)	0.06
Regional	1.7 (−0.3, 3.6)	0.09
Distant	2.9 (1.1, 4.7)	0.003
Unknown	-	-
AJCC/TNM stage e
Stage I	-	-
Stage II	-	-
Stage III f	14.5 (−6.1, 39.7)	0.20
Stage IV f	12.9 (7.2, 19.0)	<0.001
Unknown f	16.5 (−3.4, 40.4)	0.09
Tumor size (cm) g
≤2	6.8 (2.4, 11.4)	0.004
>2-≤4	4.3 (1.3, 7.3)	0.01
>4	2.8 (−0.1, 5.9)	0.06
Unknown	−0.6 (−2.7, 1.5)	0.50

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Abbreviations: AJCC/TNM, American Joint Committee on Cancer/Tumor-Node-Metastasis; APC, annual percent change; CI, confidence interval.

^- APC could not be calculated due to 0 deaths in at least one year.

^aRates were calculated as number of deaths per 100,000 person-years and age-adjusted to the 2000 U.S. standard population.

^bBased on deaths during 1994–2013 and cases diagnosed during 1974–2013.

^cIncludes American Indian/Alaskan Native and Asian/Pacific Islander.

^dIncludes other specified, poorly specified, and other types.

^eBased on deaths during 2004–2013 and cases diagnosed during 2004–2013.

^fAPCs were calculated during 2005–2013 due to 0 deaths in 2004.

^gBased on deaths during 1994–2013 and cases diagnosed during 1983–2013.

Rate differences were calculated for PTCs by known/unknown values of SEER stage and tumor size (eTables 3 and 4). The incidence rate for unstaged PTC increased by 0.07 (95% CI 0.04–0.10) from 1974–77 to 2010–13, indicating that the observed increase in PTC with known SEER stage was underestimated by this amount. PTC with unknown tumor size declined by 0.57 (95% CI 0.49–0.65) from 1994–97 to 2010–13, which may have overestimated the observed increase in PTC with known tumor size by this amount; however, apart from PTCs >4 cm, the observed increases for PTCs with known tumor sizes were much larger. The unstaged PTC mortality rate declined by −0.01 (95% CI [−0.01–0.01]) from 1994–97 to 2010–13, indicating that the increase in mortality for PTCs with known SEER stage was overestimated by this amount. The mortality rate for PTCs with unknown tumor size decreased by 0.02 (95% CI 0.00–0.04) since 1998–2001, which may have overestimated mortality rates for PTC with known tumor size by this amount.

The annual numbers of cases or deaths and incidence and incidence-based mortality rates used in this analysis are provided in eTables 5-16.

Discussion

To our knowledge, the current study is the first to describe U.S. trends in thyroid cancer mortality by demographic and tumor characteristics at diagnosis and to systematically compare trends in thyroid cancer incidence and mortality rates by these characteristics. The main finding from this study was the significant increase in thyroid cancer incidence-based mortality from 1994 to 2013 (about 1.1% per year, on average) for thyroid cancer patients overall and those who were diagnosed with advanced-stage PTC (2.9% per year). This finding appears to be associated with the increasing incidence of advanced-stage PTC (3.5% per year since 1981).

The results of this study challenge the prevailing notion that all of the increase in PTC incidence in the United States is related to over-diagnosis^2,4,19, resulting from the introduction and increasing widespread use of diagnostic ultrasound and other imaging modalities and fine-needle aspiration biopsies that have allowed for incidental detection and diagnosis of localized and/or small (<2 cm) cancers that are mostly indolent²⁰. Such changes could account for the rapid increases in the incidence rates for localized and/or small PTCs, which have been previously observed^2,4,6,19,21. Likewise, the deceleration in rates for localized, but not advanced, PTC incidence rates since 2009, as observed previously^19,21, may be explained by less aggressive diagnostic work-up of small thyroid tumors in recent years due to a rising awareness of the problems associated with over-treatment of low-risk thyroid cancers^15,19,22. However, the significant, albeit less rapid, increase in advanced-stage and larger PTC incidence rates and increasing thyroid cancer mortality rates among patients diagnosed with advanced-stage PTC is incompatible with the notion that over-diagnosis is solely responsible for the changing trends in PTC incidence. Thus, trends in PTC incidence may be explained by two underlying processes, the dominant one being over-diagnosis, and the other being a small but actual increase in PTC incidence, possibly resulting from changes in exposure to environmental risk factors⁷.

Additional epidemiologic research is needed to identify the specific environmental factors that have contributed to increasing rates of PTC, namely those with greater aggressive potential. Ionizing radiation exposure in childhood is the most established risk factor for PTC²³, and exposure has increased in the U.S. general population in recent decades, due primarily to more widespread use of diagnostic medical exams²⁴. However, studies of changes in radiation-related somatic mutations have shown declines in the proportion of PTCs with radiation signatures, such as RET/PTC rearrangements, over time, whereas point mutations, such as BRAF or RAS that are more likely to have a non-radiation etiology, have increased^25–28. There is growing evidence suggesting that changes in obesity and smoking prevalence have contributed to rising thyroid cancer rates⁷. Paralleling trends in thyroid cancer incidence, obesity prevalence has increased threefold among U.S. adults between 1960 and 2012, with the fastest rate of increase between 1980 and 2010²⁹. In contrast, the prevalence of daily cigarette smoking has significantly decreased in the United States since 1980³⁰. Epidemiologic studies have consistently found positive associations between excess adiposity in childhood and adulthood and subsequent risk of thyroid cancer, including PTC^31,32, while current smoking consistently has been associated with a 30–40% reduction in thyroid cancer risk, independent of obesity and other risk factors³³. Obesity and smoking could influence thyroid cancer development via insulin resistance, thyroid hormone, and estrogen-related pathways^34,35. Together, these factors have been estimated to be related to >40% of all new cases of thyroid cancer annually in the United States ⁷. Endocrine-disrupting chemicals (e.g., pesticides, bisphenol A) also have been suspected to contribute to thyroid cancer incidence trends through their effects on thyroid hormone metabolism³⁶. However, evidence in support of a causal association between environmental chemicals and thyroid cancer risk is currently lacking, largely due to the challenges in studying exposures that are ubiquitous and for which long-term exposure is extremely difficult to measure accurately.

The increasing mortality rates among patients with advanced-stage PTC suggest that for patients with these high-risk tumors, there should be renewed focus on aggressive transdisciplinary management that includes surgery, adjuvant radioactive iodine, and, when indicated for the 5–10% of patients who develop progressive disease, systemic therapy. While there is continued debate about the appropriate extent of surgery for low-risk tumors, total thyroidectomy and adjuvant radioactive iodine are indicated for high-risk disease¹⁵. Thorough preoperative imaging should be used to evaluate the neck for nodal metastases to inform whether simultaneous lymphadenectomy is necessary, and prophylactic central neck dissection should be considered for large and advanced tumors. Sorafenib and lenvatinib are approved for the management of advanced, iodine-resistant differentiated thyroid cancer including PTC, but unfortunately neither has been shown yet to afford a survival advantage, likely due to the indolent natural history of the disease^37,38. Clinical trials to optimize the development and use of novel systemic therapies are necessary.

This study has several important limitations. Due to the descriptive nature of this study, it is only possible to speculate about potential explanations for the observed thyroid cancer trends. Individual-level environmental exposures and lifestyle-related factors were not captured by registries, nor were methods of thyroid cancer detection. While changes in mortality and incidence-based mortality rates capture secular trends in detection, diagnosis, and case ascertainment, as well as treatment and associated survival, the current study did not evaluate the influence of treatment on these trends. Analyses relying on tumor size and AJCC/TNM stage data were restricted to the years in which the information was reported to the registries. APC estimates for incidence-based mortality by tumor size and AJCC/TNM stage may be artificially inflated as this information was only available for cases diagnosed during 1983–2013 and 2004–2013, respectively, leaving a shorter latency period between diagnosis and death; however, the results generally agree with estimates by SEER stage. The results of an analysis evaluating the effect of unknown stage and size data during the study period suggest that the increasing incidence rates of PTC with unknown SEER stage information underestimated, rather than overestimated, the true increase in PTC incidence for known SEER stages. Unknown SEER stage data could only explain, at most, about one-third of the observed increase in mortality due to advanced-stage PTC. As specimens have been cut more finely and smaller tumors that are incidental findings have become better documented, the reduction in unknown size data over time most likely overestimated the observed trends for the smallest, rather than largest, PTCs. Finally, some results were based on small numbers of cases or deaths. It will be important to continue monitoring thyroid cancer incidence and mortality rates over time to see if the observed trends persist.

Conclusion

Among U.S. patients diagnosed with thyroid cancer from 1974–2013, the overall incidence of thyroid cancer increased 3% annually, with increases in the incidence rate and thyroid cancer mortality rate for advanced-stage PTC. These findings are consistent with a true increase in the occurrence of thyroid cancer in the United States.

Supplementary Material

Acknowledgments

Footnotes

References