Increasing incidence of testicular germ cell tumors among racial/ethnic minorities in the United States

Abstract

Background

The incidence of TGCT has been rising in the US and is notably higher among white men. Previously, our group reported that rates were rising among Hispanic men in certain areas. The present study sought to determine whether the patterns noted in our prior publication remained evident in more recent years and to determine whether any new patterns have emerged.

Methods

Data from 51 US cancer registries were examined. Racial/ethnic-specific incidence rates per 100,000 man-years were calculated overall and by census region. Annual percent changes (APC) were estimated and joinpoint models were fit. Differences in regional incidence were examined using the Wald test.

Results

During the time period 2001–2016, 126,575 TGCTs were recorded. TGCT incidence was highest among non-Hispanic whites (NHW) (6.63/100,000), followed by Hispanics (4.20), American Indian/Alaska Natives (AI/AN) (3.27), Asian/Pacific Islanders (A/PI) (1.72), and non-Hispanic blacks (NHB) (1.27). TGCT incidence increased significantly among all men; the greatest increase was experienced by A/PIs (APC: 2.47), followed in order by Hispanics (2.10), AI/ANs (1.71), NHBs (1.28), and NHWs (0.41). Significant differences in rates by region were seen for all men except NHBs with the highest rates among Hispanics (5.38/100,000), AI/ANs (4.47), and A/PIs (2.37) found in the West, and among NHWs (7.60) and NHBs (1.51) found in the Northeast.

Conclusions

While TGCT incidence remained highest among NHWs between 2001 and 2016, the greatest increase was experienced by A/PI men.

Impact

Rising rates of TGCT among men of all racial/ethnic backgrounds in the US suggest that future attention is warranted.

INTRODUCTION

Testicular germ cell tumors (TGCT) are rare in the general population, but are the most commonly occurring malignancy among men aged 15–44 years in the United States (US) (1). TGCTs are classified by histologic subtype as seminomas, nonseminomas, and spermatocytic tumors. Seminomas and nonseminomas comprise the majority of TGCTs (98–99%) and have a peak incidence at 35 and 25 years of age, respectively. Spermatocytic tumors account for only 1–2% of TGCTs, and have a peak incidence at 55 years of age (2).

Incidence rates of TGCT have been rising in the US since the mid-20th century (1,3). While rates are notably higher among non-Hispanic white (NHW) men than men of other ancestries, recent studies have reported that incidence rates have been rising in other racial/ethnic groups, especially Hispanics (1,4,5). A prior study by our group found that between 1998 and 2011, the largest increase in TGCT incidence was experienced by Hispanics, followed by only a slight increase in rates among NHWs (4). Incidence rates also increased, but not significantly, among Asian/Pacific Islander (A/PI) men. Reasons for the reported increases are unclear as there are few well-identified risk factors for TGCT.

The availability of more recent data on incidence in the US prompted further examination of TGCT incidence trends by race/ethnicity. As such, the purpose of the current study was to examine whether the patterns noted in our prior publication remained evident in more recent years and to determine whether any new patterns have been emerging.

MATERIALS AND METHODS

Data for the current study were drawn from the US Cancer Statistics (USCS) public use databases maintained by the Centers for Disease Control and Prevention (CDC) (6). High-quality, population-based cancer incidence data reported to the CDC’s National Program of Cancer Registries (NPCR) and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) programs are combined by the USCS. Registries included in the current analysis met USCS’s data quality criteria for the November 2018 submission cycle. Data from 51 registries, including the 50 states and the District of Columbia, were included for the years 2001–2016, covering approximately 99% of the US population.

TGCT was defined using the International Classification of Diseases for Oncology (3^rd ed.) topography (C62) and morphology codes (seminoma: 9060–9062, 9064; nonseminoma: 9065–9102; spermatocytic tumors: 9063) (7). Data on race, Hispanic ethnicity, histology, and year of diagnosis were available for each case. Identification of Hispanic ethnicity was based on the North American Association of Central Cancer Registries (NAACCR) Hispanic/Latino Identification Algorithm (NHIA) (8). Incidence rates per 100,000 man-years, age-adjusted to the US 2000 standard population, and their 95% confidence intervals were calculated. Estimates of annual percent change (APC) were calculated for the 2001–2016 time period using the annual rates and weighted least squares regression (9). For temporal analysis, years of diagnosis were grouped into four periods: 2001–2004, 2005–2008, 2009–2012, and 2013–2016. For geographical analyses, states were grouped into the four census regions (Northeast, Midwest, South, and West) based on the US Census Bureau’s system of State groupings (10). Statistics were suppressed where there were fewer than 16 cases, for purposes of confidentiality. The Wald-test was used to examine differences in rates by geographic region. Statistical significance was based on a two-sided p-value < 0.05. The Wald-test was calculated using SAS (version 9.4, Cary, NC). APCs were estimated using the Joinpoint Regression Program (version 4.7.0.0). All other statistical analyses were performed using the SEER*Stat statistical package (version 8.3.6).

RESULTS

During the years 2001–2016, 126,575 TGCTs (72,171 seminomas; 53,476 nonseminomas; 928 spermatocytic tumors) were recorded by the USCS registries (Table 1). TGCT incidence rates were highest among NHW men (6.63 per 100,000 man-years), followed by Hispanic (4.20), AI/AN (3.27), A/PI (1.72), and NHB men (1.27) (Table 1). Rates of both seminomas and nonseminomas followed the same ranking. Among all men, temporal analysis showed that TGCT incidence modestly increased (APC: 0.41, p<0.01), though the increase was due to a significant increase only in nonseminoma (APC: 0.97, p<0.01) as rates of seminoma showed little change (APC: 0.05, p=0.62). Spermatocytic tumor rates decreased significantly (APC: −1.57, p=0.02). The majority of tumors were diagnosed at localized stages in all men (68.8%) (Table 2); however non-Hispanic white men had the highest percentage of localized disease (70.1%) while non-Hispanic black men had the lowest percentage (61.9%).

Table 1.

Incidence of testicular germ cell tumors by race/ethnicity and histologic subtype, USCS Registries, 2001–2016

	Testicular germ cell tumors		Seminoma		Nonseminoma		Spermatocytic Tumors
	Count 1	Rate (95% CI) 2	Count 1	Rate (95% CI) 2	Count 1	Rate (95% CI) 2	Count 1	Rate (95% CI) 2
All Races	126,575	5.34 (5.31–5.37)	72,171	3.09 (3.07–3.11)	53,476	2.21 (2.19–2.23)	928	0.04 (0.04–0.04)
APC		0.41		0.05		0.97		−1.57
p-value		p<0.01		p=0.62		p<0.01		p=0.02
NHW	99,062	6.63 (6.59–6.67)	57,973	3.86 (3.83–3.89)	40,282	2.73 (2.70–2.75)	807	0.05 (0.04–0.05)
Hispanic	18,801	4.20 (4.14–4.27)	9,122	2.19 (2.14–2.23)	9,612	1.99 (1.95–2.03)	67	0.03 (0.02–0.03)
NHB	3,628	1.27 (1.22–1.31)	2,254	0.81 (0.78–0.84)	1,342	0.44 (0.42–0.47)	32	0.01 (0.01–0.02)
A/PI	2,421	1.72 (1.65–1.79)	1,315	0.95 (0.90–1.01)	1,095	0.75 (0.71–0.80)	†	†
AI/AN	1,102	3.27 (3.08–3.48)	578	1.83 (1.68–1.99)	521	1.43 (1.30–1.56)	†	†

¹May not sum to total because of missing race

²Rates are per 100,000 and age-adjusted to the 2000 US Standard Population (19 age groups - Census P25-1130)

^†Case counts less than 16 (rate not calculated)

Abbreviations: A/PI (Asian/Pacific Islander), AI/AN (American Indian/Alaska Native), APC (Annual Percent Change), CI (Confidence Interval), NHW (Non-Hispanic White), NHB (Non-Hispanic Black), US (United States), USCS (United States Cancer Statistics)

Table 2.

Incidence of testicular germ cell tumors by stage at diagnosis, USCS Registries, 2001–2016

	Localized			Regional			Distant			Unstaged/Unknown
	Count 1	Percent	Rate (95% CI) 2	Count 1	Percent	Rate (95% CI) 2	Count 1	Percent	Rate (95% CI) 2	Count 1	Percent	Rate (95% CI) 2
All Races	87,078	68.8%	3.69 (3.66–3.71)	22,982	18.2%	0.97 (0.95–0.98)	14,150	11.2%	0.59 (0.58–0.60)	2,365	1.9%	0.10 (0.10–0.10)
NHW	69,475	70.1%	4.67 (4.63–4.70)	17,941	18.1%	1.20 (1.18–1.21)	9,959	10.1%	0.66 (0.65–0.67)	1,687	1.7%	0.11 (0.11–0.12)
Hispanic	11,757	62.5%	2.65 (2.60–2.70)	3,533	18.8%	0.79 (0.76–0.82)	3,104	16.5%	0.67 (0.65–0.70)	407	2.2%	0.09 (0.08–0.10)
NHB	2,246	61.9%	0.79 (0.75–0.82)	723	19.9%	0.25 (0.23–0.27)	575	15.8%	0.20 (0.18–0.21)	84	2.3%	0.03 (0.02–0.04)
A/PI	1,666	68.8%	1.19 (1.13–1.25)	400	16.5%	0.28 (0.25–0.31)	310	12.8%	0.22 (0.20–0.25)	45	1.9%	0.03 (0.02–0.04)
AI/AN	704	63.9%	2.09 (1.94–2.26)	209	19.0%	0.64 (0.55–0.74)	170	15.4%	0.49 (0.41–0.57)	19	1.7%	0.06 (0.03–0.09)

¹May not sum to total because of missing race

²Rates are per 100,000 and age-adjusted to the 2000 US Standard Population (19 age groups - Census P25-1130)

Abbreviations: A/PI (Asian/Pacific Islander), AI/AN (American Indian/Alaska Native), CI (Confidence Interval), NHW (Non-Hispanic White), NHB (Non-Hispanic Black), US (United States), USCS (United States Cancer Statistics)

Trends in TGCT incidence by race/ethnicity are shown in Table 3 and Figure 1. While rates increased only slightly, but significantly, among NHW men (APC: 0.41, p<0.01), larger increases were seen in all other groups. The largest increase was experienced by A/PI men (APC: 2.47, p<0.01), then Hispanics (APC: 2.10, p<0.01), AI/ANs (APC: 1.71, p=0.03), and NHBs (APC: 1.28, p<0.01). Incidence trends by histologic subtype are also presented in Table 3 and Figure 1. Seminoma rates increased significantly among AI/AN (APC: 2.25, p=0.02), A/PI (APC: 1.81, p=0.03), Hispanic (APC: 1.40, p<0.01), and NHB (APC: 1.37, p=0.01) men but not among NHW men (APC: 0.14, p=0.22). Nonseminoma rates increased significantly among almost all racial/ethnic groups: A/PI (APC: 3.34, p<0.01), Hispanic (APC: 2.98, p<0.01), NHB (APC: 1.28, p=0.03), and NHW (APC: 0.82, p<0.01) men. Nonseminoma rates also increased among AI/AN men (APC: 1.04, p=0.29), but not significantly so. Joinpoint analyses revealed no significant joinpoints for any of the histological subtype and racial/ethnic group combinations.

Table 3.

Incidence of testicular germ cell tumors by race/ethnicity and year of diagnosis, USCS Registries, 2001–2016

	Testicular germ cell tumors		Seminoma		Nonseminoma
	Count	Rate (95% CI) †	Count	Rate (95% CI) †	Count	Rate (95% CI) †
NHW
2001–2004	24,516	6.43 (6.35–6.52)	14,697	3.81 (3.75–3.87)	9,619	2.57 (2.52–2.63)
2005–2008	24,882	6.63 (6.55–6.71)	14,649	3.87 (3.81–3.94)	10,043	2.71 (2.66–2.77)
2009–2012	24,623	6.65 (6.57–6.74)	14,271	3.85 (3.78–3.91)	10,137	2.76 (2.70–2.81)
2013–2016	25,041	6.79 (6.70–6.87)	14,356	3.89 (3.83–3.96)	10,483	2.85 (2.80–2.91)
APC		0.41		0.14		0.82
p-value		p<0.01		p=0.22		p<0.01
Hispanic
2001–2004	3,429	3.63 (3.50–3.76)	1,746	2.01 (1.91–2.12)	1,669	1.59 (1.51–1.67)
2005–2008	4,371	4.06 (3.93–4.19)	2,102	2.10 (2.01–2.20)	2,247	1.92 (1.84–2.00)
2009–2012	5,019	4.24 (4.12–4.36)	2,425	2.19 (2.10–2.28)	2,574	2.02 (1.94–2.11)
2013–2016	5,982	4.74 (4.62–4.87)	2,849	2.39 (2.30–2.48)	3,122	2.34 (2.26–2.42)
APC		2.10		1.40		2.98
p-value		p<0.01		p<0.01		p<0.01
NHB
2001–2004	771	1.15 (1.07–1.24)	482	0.73 (0.67–0.80)	281	0.40 (0.35–0.45)
2005–2008	874	1.25 (1.16–1.33)	542	0.80 (0.73–0.87)	323	0.44 (0.39–0.49)
2009–2012	947	1.30 (1.21–1.38)	587	0.83 (0.76–0.90)	353	0.46 (0.41–0.51)
2013–2016	1,036	1.36 (1.27–1.44)	643	0.87 (0.80–0.94)	385	0.47 (0.43–0.52)
APC		1.28		1.37		1.28
p-value		p<0.01		p=0.01		p=0.03
A/PI
2001–2004	408	1.39 (1.25–1.53)	227	0.79 (0.69–0.90)	181	0.60 (0.51–0.69)
2005–2008	538	1.66 (1.52–1.81)	306	0.97 (0.86–1.08)	228	0.67 (0.58–0.77)
2009–2012	656	1.77 (1.63–1.91)	342	0.94 (0.85–1.05)	311	0.81 (0.73–0.91)
2013–2016	819	1.96 (1.83–2.10)	440	1.07 (0.97–1.18)	375	0.88 (0.79–0.97)
APC		2.47		1.81		3.34
p-value		p<0.01		p=0.03		p<0.01
AI/AN
2001–2004	208	3.00 (2.59–3.45)	106	1.64 (1.34–2.00)	101	1.34 (1.09–1.65)
2005–2008	245	3.05 (2.67–3.48)	122	1.60 (1.32–1.93)	122	1.44 (1.19–1.74)
2009–2012	288	3.15 (2.79–3.55)	159	1.85 (1.57–2.18)	129	1.30 (1.08–1.55)
2013–2016	361	3.76 (3.37–4.18)	191	2.14 (1.84–2.48)	169	1.61 (1.37–1.88)
APC		1.71		2.25		1.04
p-value		p=0.03		p=0.02		p=0.29

^†Rates are per 100,000 and age-adjusted to the 2000 US Standard Population (19 age groups - Census P25-1130)

Abbreviations: A/PI (Asian/Pacific Islander), AI/AN (American Indian/Alaska Native), APC (Annual Percent Change), CI (Confidence Interval), NHW (Non-Hispanic White), NHB (Non-Hispanic Black), US (United States), USCS (United States Cancer Statistics)

Figure 1.

Age-adjusted incidence rates of testicular germ cell tumors among non-Hispanic white (NHW), Hispanic (all races), non-Hispanic black (NHB), Asian/Pacific Islander (A/PI), and American Indian/Alaska Native (AI/AN) men, United States Cancer Statistics registries, 2001–2004 to 2013–2016. The annual percent change (APC) is displayed. An asterisk represents that the annual percent change is significantly different from zero (p<0.05).

TGCT rates for the most recent time period (2013–2016) by census region are presented in Table 4. TGCT rates among Hispanic (5.38), AI/AN (4.47), and A/PI (2.37) men were highest in the West while rates among NHW (7.60) and NHB (1.51) men were highest in the Northeast. There was a statistically significant difference in rates by region among NHW (p<0.01), Hispanic (p<0.01), A/PI (p<0.01), and AI/AN (p<0.01) men, but not among NHB men (p=0.28). Similar findings were observed for seminomas and nonseminomas, where statistically significant regional rates were observed for all groups except NHBs. Seminoma and nonseminoma rates among AI/AN men were not calculated for all census regions due to small numbers.

Table 4.

Incidence of testicular germ cell tumors by census region, USCS Registries, 2013–2016

		Testicular germ cell tumors		Seminoma		Nonseminoma
	Population	Count	Rate (95% CI)1	Count	Rate (95% CI)1	Count	Rate (95% CI)1
NHW
Northeast	73,926,005	5,198	7.60 (7.39–7.81)	3,045	4.45 (4.29–4.61)	2,100	3.09 (2.96–3.23)
Midwest	103,504,180	6,761	7.03 (6.86–7.21)	3,870	4.04 (3.91–4.17)	2,841	2.95 (2.84–3.06)
South	139,582,823	7,689	5.97 (5.83–6.11)	4,332	3.36 (3.26–3.46)	3,299	2.57 (2.49–2.66)
West	79,049,162	5,393	7.15 (6.95–7.34)	3,109	4.11 (3.96–4.26)	2,243	3.00 (2.87–3.13)
p-value2			p<0.01		p<0.01		p<0.01
Hispanic
Northeast	15,595,327	708	4.05 (3.76–4.37)	366	2.20 (1.97–2.44)	339	1.83 (1.64–2.05)
Midwest	10,573,177	564	4.79 (4.40–5.22)	276	2.51 (2.21–2.84)	288	2.28 (2.03–2.58)
South	41,879,161	2,002	4.30 (4.11–4.5)	936	2.08 (1.95–2.23)	1,062	2.20 (2.07–2.34)
West	44,999,136	2,708	5.38 (5.18–5.6)	1,271	2.71 (2.56–2.87)	1,433	2.65 (2.51–2.80)
p-value2			p<0.01		p<0.01		p<0.01
NHB
Northeast	12,530,550	188	1.51 (1.30–1.75)	120	0.99 (0.82–1.19)	67	0.51 (0.39–0.65)
Midwest	14,356,704	181	1.35 (1.16–1.57)	110	0.85 (0.70–1.03)	71	0.50 (0.39–0.64)
South	44,802,533	548	1.29 (1.19–1.41)	350	0.85 (0.76–0.95)	191	0.43 (0.37–0.49)
West	7,785,827	119	1.48 (1.22–1.79)	63	0.85 (0.65–1.09)	56	0.64 (0.48–0.84)
p-value2			p=0.28		p=0.56		p=0.10
A/PI
Northeast	7,441,532	155	1.84 (1.56–2.16)	82	0.99 (0.79–1.24)	71	0.82 (0.64–1.04)
Midwest	4,464,157	97	1.90 (1.53–2.34)	49	1.00 (0.73–1.35)	46	0.86 (0.63–1.17)
South	8,577,925	126	1.32 (1.1–1.58)	65	0.69 (0.53–0.89)	61	0.63 (0.48–0.82)
West	17,342,731	441	2.37 (2.15–2.6)	244	1.33 (1.17–1.51)	197	1.04 (0.90–1.19)
p-value2			p<0.01		p<0.01		p<0.01
AI/AN
Northeast	864,515	18	1.86 (1.09–3.04)	†	†	†	†
Midwest	1,326,177	57	4.25 (3.19–5.60)	21	1.88 (1.15–2.93)	36	2.37 (1.65–3.37)
South	2,731,767	89	3.09 (2.47–3.82)	49	1.75 (1.29–2.33)	40	1.34 (0.95–1.85)
West	4,195,866	197	4.47 (3.86–5.17)	113	2.76 (2.27–3.35)	83	1.68 (1.33–2.11)
p-value2			p<0.01		††		††

¹Rates are per 100,000 and age-adjusted to the 2000 US Standard Population (19 age groups - Census P25-1130)

²Global p-value (calculated from the Wald test)

^†Case counts less than 16 (rate not calculated)

^††p-value not calculated

Abbreviations: A/PI (Asian/Pacific Islander), AI/AN (American Indian/Alaska Native), APC (Annual Percent Change), CI (Confidence Interval), NHW (Non-Hispanic White), NHB (Non-Hispanic Black), US (United States), USCS (United States Cancer Statistics)

Trends in TGCT incidence by census region among NHW, Hispanic, NHB, and A/PI men are shown in Figure 2a. Incidence among NHW men was stable in the West (APC: 0.10, p=0.51), and the South (APC: 0.33, p=0.05), but modestly increased in the Northeast (APC: 0.71, p<0.01) and the Midwest (APC: 0.62, p<0.01). Among Hispanic men, incidence increased significantly in all four regions: Midwest (APC: 3.89, p<0.01), West (APC: 2.79, p<0.01), Northeast (APC: 1.84, p<0.01), South (APC: 0.97, p=0.02). Among NHB men, incidence increased significantly in the South (APC: 1.74, p<0.01), but remained stable in the Northeast (APC: 0.34, p=0.73), and the Midwest (APC: 0.69, p=0.43). While rates increased in the West (APC: 1.70, p=0.16), the increase was not statistically significant. Among A/PI men, rates increased significantly in the West (APC 3.03, p<0.01).

Figure 2.

Age-adjusted incidence rates of testicular germ cell tumors by histologic subtype and census region among non-Hispanic white (NHW), Hispanic (all races), non-Hispanic black (NHB), and Asian/Pacific Islander (A/PI) men, United States Cancer Statistics registries, 2001–2004 to 2013–2016. A) Testicular germ cell tumors; B) seminoma; C) nonseminoma. The annual percent change (APC) is displayed. An asterisk represents that the annual percent change is significantly different from zero (p<0.05). A dagger represents that the annual percent change could not be calculated. A double dagger represents that the annual percent change is reported for the years 2002–2016.

Trends in the incidence of seminoma by census region are shown in Figure 2b. Among NHWs, the only significant increase was seen in the Northeast (APC: 0.47, p=0.01). Among Hispanics, there were significant increases in both the Midwest (APC: 3.16, p<0.01) and the West (APC: 2.18, p<0.01), while among NHBs, the only significant increase was in the South (APC: 1.99, p=0.02). Among A/PIs, rates increased significantly in the West (APC 2.30, p=0.04). Trends in the incidence of nonseminoma by census region are shown in Figure 2c. Among NHWs, there were significant increases in the Northeast (APC: 1.03, p<0.01), Midwest (APC: 1.00, p<0.01), and South (APC: 0.80, p<0.01). Among Hispanic men, there were significant increases in all four regions: Midwest (APC: 4.76, p<0.01), West (APC: 3.51, p<0.01), Northeast (APC: 2.46, p<0.01), South (APC: 2.11, p<0.01). Among NHB men, rates increased significantly in the South (APC: 1.50, p=0.04) while among A/PI men, rates increased significantly in the West (APC 4.14, p<0.01).

Hispanic men had the greatest APC for TGCT and both histologic subtypes in the Northeast and Midwest and the same was true for A/PI men in the West (Figures 2a, 2b, 2c). Hispanic men also had the greatest APC in nonseminoma rates in the South. NHB men had the greatest APC for TGCT and seminoma in the South. Joinpoint analyses revealed two significant findings; a joinpoint was observed among NHW men in the Northeast for TGCT (APC 2001–2012: 1.24, p<0.01; APC 2012–2016: −1.57, p=0.11) and seminoma (APC 2001–2011: 1.05, p<0.01; APC 2011–2016: −1.15, p=0.11). APCs among A/PI men could not be calculated in any census region, except the West, due to small numbers. Similarly, APCs could not be calculated for AI/AN men by census region.

State-level data on TGCT incidence are presented in Figure 3 and by histologic subtype in Supplementary Table 1. The states with the highest rates of TGCT were New Hampshire (7.07 per 100,000 man-years) and Utah (6.92). The states that experienced the greatest increase in rates were Hawaii (APC: 2.07, p=0.03) and Kansas (APC: 1.94, p=0.01). TGCT rates were lowest in Mississippi (3.59 per 100,000 man-years) and Georgia (4.00).

Figure 3.

Age-adjusted incidence rates of testicular germ cell tumors by state, United States Cancer Statistics registries, 2001–2016 W (Non-Hispanic White), NHB (Non-Hispanic Black), US (United States), USCS (United States Cancer Statistics)

DISCUSSION

The current study found that while NHW men had the highest incidence of TGCT between 2001 and 2016, the greatest increase in incidence occurred among A/PI men. By histologic type, A/PI men experienced the greatest increase in nonseminoma rates, while AI/AN men experienced the greatest increase in seminoma rates. Geographic analyses revealed that Hispanic men were the only racial/ethnic group to experience significant increases in TGCT incidence in all four US census regions.

As in our prior report (4), the current analysis found a significant increase in TGCT incidence among Hispanic men and a modest, yet significant, increase among NHW men. In contrast, however, the present study found significant increases in TGCT incidence among men of all other racial/ethnic ancestries, including NHB, A/PI, and AI/AN men. Furthermore, our previous study reported that Hispanic men were the only racial/ethnic group to experience increases in rates for both seminomas and nonseminomas. The present study, however, found significant increases in seminoma and nonseminoma rates among not only Hispanic men, but to a greater degree among A/PI men, and among NHB men.

Asians are the fastest growing population group in the US, with a growth rate between 2000 and 2010 more than four times that of the total US population (11). The main driving force for this rapid growth has been attributed to international migration (12). A comparison of rates among A/PI men in the US (1.7 per 100,000) to rates among men in Asia finds that rates are somewhat higher in Japan (2.1), but lower in China (1.5), the Philippines (0.8), Thailand (0.5), and India (0.6). It is possible that rates among US A/PIs have risen with migration. Prior studies of migrants from lower to higher rate countries have reported that changes in TGCT incidence do not occur among the first generation of migrants, but in subsequent generations (13,14). Thus, it is possible that the increase in TGCT rates among A/PIs could be a result of exposures that are more prevalent in the US. In the current study, this could not be examined as migration status was not available. A previous study examining TGCT rates in the SEER-13 registries (1992–2004) found that TGCTs were 1.4-fold more likely to develop in A/PIs than in NHWs (15). This study, however, only examined rates among boys of ages 0–14 years. The authors hypothesized that the rate difference might reflect a difference in tumorigenesis related to early-life endocrine disrupting chemical exposure.

The significant increase in TGCT rates among NHB and AI/AN men is a noteworthy finding. A previous study examining trends in TGCT incidence among black men found that rates increased between 1988–1992 (16). In studying the subsequent time period, 1992–2011, our group found that incidence rates among black men continued to increase significantly (17). These studies, however, did not distinguish NHB men from Hispanic black men. Two other studies conducted by our group examined TGCT rates among NHB men and found no significant increase in TGCT incidence rates (1,4). The present study, however, found that rates among NHB men increased for both histologic subtypes and for overall TGCT, mainly in the South. While the rates of TGCT among NHB men remain notably lower than the rates of other racial/ethnic groups, the current study’s significant finding suggests that TGCT among NHB men should not be disregarded. Similarly, this is the first study to demonstrate a statistically significant increase in TGCT rates among AI/AN men. While previous studies have noted an increase in rates among AI/AN men, those increases have never reached a level of statistical significance, possibly due to the misidentification of AI/AN status.

It remains unclear why there are differences in the risk of TGCT among racial/ethnic groups in the US, or in other countries. The only established risk factors for TGCT include family history of TGCT (18,19), cryptorchidism (20), hypospadias (21), and impaired spermatogenesis (22). The collection of these male reproductive disorders, collectively known as the Testicular Dysgenesis Syndrome (TDS), has been suggested to have an in-utero etiology (23). Whether the prevalence of each of the TDS conditions varies by racial/ethnic group, however, remains unclear.

Genetic susceptibility to TGCT has been evidenced by the increased risk among 1^st degree relatives of men with TGCT (19,24–26) and by the results of genome-wide association studies (GWAS). Approximately 40–50 loci, thus far, have been found by GWAS to be associated with TGCT susceptibility (27–34). Among these loci, genetic variation in the KIT ligand (KITLG) gene has been found to have the strongest association (33) with some single nucleotide polymorphisms (SNPs) varying by ancestry. For example, the KITLG rs3782181 SNP has an allele frequency that varies greatly between men of African ancestry (A:70%, G:30%) and men of other ancestries, such as European (A: 20%, G: 80%), Hispanic/Latino (A:17%, G: 83%), and east Asian (A: 23%, G: 77%). Thus, it is possible that variation in genes which are associated with TGCT risk, combined with the presence of an environmental risk factor, can lead to an additive or multiplicative increase in TGCT risk as a gene-environment interaction (35).

While genetic susceptibility to TGCT may be related to some of the difference in incidence by race/ethnicity, it is unlikely to explain the decades long continuing increase in rates. Such increases are consistent with environmental risk factors playing an important role in the TGCT etiology (36). Prenatal exposures such as maternal nutrition and exposure to endocrine disrupting chemicals (EDC), as well as other factors, have been suggested to be related to risk (37). An assessment of prenatal exposures, however, is difficult as the exposure and the outcome are among different persons (mothers and sons). Meta-analyses, however, have found that TGCT is significantly associated with cryptorchidism, inguinal hernia, twinning, low birthweight, short gestational age, maternal bleeding, birth order, sibship size, and possibly caesarean section (20,38). Postnatal exposures that have been associated with TGCT include occupational exposures such as firefighting (39–44) and aircraft maintenance (45–49), age at puberty (50), adult stature (51), cannabis use (52–56), and exposure to particular EDCs (57,58). The prevalence of cannabis use in the US has recently increased in the general population, possibly due to the changing cannabis laws (59). While it is possible that cannabis use could explain some of the increase in TGCT rates, most published studies on cannabis and TGCT are limited by being based on self-reported data from retrospective studies.

In the current study, the increase in TGCT incidence was driven by an increase in nonseminoma rates. The peak age at diagnosis of nonseminoma is 25 years, while the peak age at diagnosis of seminoma is 10 years older, at age 35 years. The younger age at presentation of nonseminoma may explain why it is the most common TGCT among Hispanic men, as the Hispanic population is younger than other populations in the US. Why nonseminoma rate increases would be statistically significant, while seminoma increases were not, is unclear as risk factors that differ between the two types, other than marijuana smoking, have yet to be identified. It is important to note, however, that while nonseminoma rates are propelling the increase in TGCT rates, nonseminomas are less common than seminomas among all groups, with nonseminoma to seminoma ratios of NHWs = 0.71, Hispanics =0.91, NHBs = 0.54, APIs = 0.79, and AI/ANs = 0.78.

While based on small numbers, a notable finding of the current study is the significant decrease in the rates of spermatocytic tumor. Spermatocytic tumors are not clinically aggressive tumors and rarely warrant treatment other than orchiectomy (60). Even though the median age at diagnosis of spermatocytic tumor is age 50 years, the incidence is always lower than that of seminoma. While previous studies have found modest, non-significant, increases (61) and decreases (4) in the rates of spermatocytic tumor, the finding a statistically significant decrease in incidence is novel.

In the most recent time period, A/PI men had the highest incidence of TGCT in the West (2.37 per 100,000 man-years), followed in order by the Midwest (1.90), the Northeast (1.84), and the South (1.32). The highest APC was also observed in the West. It is conceivable that the ancestral make-up of the A/PI population in various parts of the country contributed to the regional difference in rates, as cancer statistics are heterogenous among the various A/PI populations (62–64). The data used in the current analysis, however, did not permit the disambiguation of the A/PI population into its constituent components. Thus, further study of may provide insight into whether particular A/PI groups have greater susceptibility to TGCT.

A strength of the current study was the use of population-based cancer registry data from 51 registries, which included virtually the entire US population (99%). Additionally, this study was able to use state-level TGCT data. Limitations included the inability to restrict AI/AN populations to PRCSDA, which better captures AI/AN status. In addition, it was not possible to disaggregate the A/PI population, thus the study could have failed to detect any differences that might exist within the component API groups. Another limitation was the use of the NAACCR NHIA algorithm to categorize Hispanic ethnicity. The current study was restricted to men, however, and as such, there was less chance for misclassification. The algorithm is based partially on surname and, as women are more likely to change their surnames, there is greater chance of misclassifying women than men. Finally, the current study lacked information on birthplace and country-specific ancestry, as well as information on A/PI and Hispanic subpopulations, which could provide further insight into whether subpopulations may have greater genetic susceptibility to TGCT.

In summary, the current study suggests that TGCT incidence is increasing among men of all racial/ethnic backgrounds in the US, with the most notable increases in A/PI and Hispanic men in the West. Rising rates of TGCT among men of non-European ancestry suggests that both etiologic research and public health efforts among these populations are warranted. Reasons for the increase in rates could be related to as yet unidentified environmental exposures and/or genetic susceptibility to TGCT.