Abstract
Background
The incidence of testicular germ cell tumors (TGCT) in the United States (US) is notably higher among white men than other men. Previously, however, our group reported that rates were rising among Hispanics in certain areas. To determine whether this finding was evident in a wider area of the US, data from 39 US cancer registries were examined.
Methods
Racial/ethnic-specific incidence rates per 100,000 man-years were calculated overall and by census region for the period 1998–2011. Annual percent changes (APCs) were estimated and joinpoint models were fit. Differences in incidence by region were examined using the Wald test.
Results
During the time period 1998–2011, 88,993 TGCTs were recorded. TGCT incidence was highest among non-Hispanic whites (NHWs) (6.57/100,000), followed by Hispanics (3.88), American Indian/Alaska Natives (2.88), Asian/Pacific Islanders (A/PIs) (1.60), and non-Hispanic blacks (NHBs) (1.20). Incidence significantly increased among Hispanics (APC: 2.31, p<0.0001), with rates rising in all regions except the South. Rates rose slightly among NHWs (APC: 0.51, p=0.0076). Significant differences in rates by region were seen for Hispanics (p=0.0001), NHWs (p<0.0001) and A/PIs (p<0.0001) with the highest rates among Hispanics in the West, and highest rates among NHWs and A/PIs in the Northeast.
Conclusions
While TGCT incidence remained highest among NHWs between 1998 and 2011, the greatest increase was experienced by Hispanics. Rising rates of TGCT among Hispanics in the US suggest that future attention is warranted. Reasons for the increase may include variability in birthplace, changing exposures, genetic susceptibility, and/or length of US residence.
Keywords: testicular cancer, TGCT, trends, NAACCR, incidence, ethnic groups
INTRODUCTION
Testicular germ cell tumors (TGCT) are rare cancers in the general population, but are the most common malignancy among men between ages 15 and 44 years in the United States (US).1 TGCTs can be classified by histologic subtype into three groups: seminoma, nonseminoma, and spermatocytic seminoma. Nonseminomas and seminomas together comprise 98–99% of all TGCTs and have peak incidence at approximately ages 25 years and 35 years, respectively. Spermatocytic seminomas are very rare at all ages, accounting for only 1–2% of TGCTs, and have peak incidence at age 55 years.2
The incidence of TGCT has been rising in the US and many other countries since the mid-20th century.1, 3 While the incidence is highest among white men, recent data suggest that incidence rates are increasing among other racial/ethnic groups, especially among Hispanics.1, 4 A prior study by our group examining data from the Surveillance, Epidemiology, and End Results (SEER) 13 registries found that between 1992 and 2011, TGCT incidence increased significantly among non-Hispanic white, Hispanic white, black, and Asian/Pacific Islander (A/PI) men. Incidence rates also increased among American Indian/Alaskan Native (AI/AN) men, although not significantly so.1 Hispanic men had the greatest annual percent change (APC) in TGCT incidence among all racial/ethnic groups. A limitation of our prior study, however, was that the SEER 13 registries only include approximately 14% of the US population and the coverage of Hispanic populations is limited. Thus, the current study sought to examine whether the trends noted in our prior publication remained evident in the broader US population and to determine whether regional differences existed.
MATERIALS AND METHODS
Data for the current study were drawn from the Cancer Incidence in North America (CiNA) analytic file provided by the North American Association of Central Cancer Registries (NAACCR). Population-based cancer incidence data were obtained from NAACCR member registries that are funded by NCI’s SEER program and/or the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR).5 Participating registries met NAACCR’s data quality criteria for the December 2013 submission cycle. Data from thirty-nine registries were included for the years 1998 through 2011. These registries cover approximately 84% of the US population. The CiNA analytic file dates back to 1995, but due to missing data from many of the registries, we restricted all analyses to the year 1998 forward. Two data files were provided: (1) the CiNA analytic file for expanded races and (2) the CiNA analytic file for NAACCR Hispanic Identification Algorithm (version 2) Origin. The first data file was used to obtain data on A/PI and AI/AN populations. The second data file was used to obtain data on non-Hispanic white, Hispanic (all races), and non-Hispanic black populations. Identification of Hispanic ethnicity was based on the file for NAACCR Hispanic Identification Algorithm Origin.6 The NAACCR Hispanic/Latino Identification Algorithm, version 2.2.1 (NHIA v2.2.1) uses a combination of NAACCR variables to directly or indirectly classify cases as Hispanic/Latino for analytic purposes.7 The algorithm uses the following NAACCR standard variables: Spanish/Hispanic origin (item 190), name-last (item 2230), name-maiden (item 2390), birthplace (item 250), race 1 (item 160), sex (item 220), and Indian Health Service (IHS) link (item 192).8
TGCT was defined using the International Classification of Diseases for Oncology (3rd ed.) topography (C62) and morphology codes (seminoma: 9060–9062, 9064; nonseminoma: 9065–9102; spermatocytic seminoma: 9063).9 Data on race, Hispanic ethnicity, histology, and year of diagnosis were available for each TGCT case. Incidence rates per 100,000 man-years, age-adjusted to the US 2000 standard population, and their 95% confidence intervals were calculated. TGCT incidence rates were calculated for non-Hispanic white, Hispanic (all races), non-Hispanic black, A/PI, and AI/AN men. Estimates of annual percent change (APC) were calculated for the 1998–2011 time period using the annual rates and weighted least squares regression.10 For temporal analysis, years of diagnosis were grouped into five periods: 1998–2000, 2001–2003, 2004–2006, 2007–2009, and 2010–2011. For geographical analyses, states were grouped into the four US census regions: West (Alaska, Arizona, California, Colorado, Hawaii, Idaho, Montana, Nevada, New Mexico, Oregon, Utah, Washington, Wyoming), South (Alabama, Georgia (Atlanta only), Delaware, Florida, Kentucky, Louisiana, Oklahoma, South Carolina, Texas, West Virginia), Midwest (Illinois, Indiana, Iowa, Michigan, Missouri, Nebraska, North Dakota, Ohio, Wisconsin), and Northeast (Connecticut, Maine, Massachusetts, New Jersey, New York, Pennsylvania, Rhode Island) (Figure 1). Due to missing data from one registry in the West census region for the year 2011, a sensitivity analysis that excluded data from this registry was conducted. The Wald test was used to examine differences in rates by geographic area among the different racial/ethnic groups. Statistical significance was based on a two-sided p-value less than or equal to 0.05. The Wald test was performed using SAS (version 9.3, Cary, NC). APCs were estimated using the Joinpoint Regression Program (version 4.1.1.3). All other statistical analyses were performed using the SEER*Stat statistical package (version 8.1.5).
Figure 1.
Census Regions of the United States
RESULTS
During the time period 1998–2011, 88,993 TGCTs (51,647 seminomas; 36,650 nonseminomas; 696 spermatocytic seminomas) were recorded in the 39 SEER/NPCR registries included in the current analysis (Table 1). The incidence of TGCT was highest among non-Hispanic white men (6.57 per 100,000 man-years), followed in order by Hispanic (3.88), AI/AN (2.88), A/PI (1.60), and non-Hispanic black men (1.20) (Table 1). Rates for both seminomas and nonseminomas followed the same ranking. Among all men, temporal analysis showed that the incidence of TGCT modestly increased during the interval (APC: 0.41, p=0.0038). Rates of nonseminoma increased significantly (APC: 1.33, p<0.0001) while rates of seminoma showed little change (APC: −0.19, p=0.0941). Spermatocytic seminoma rates decreased (APC: −1.05, p=0.1288), however this decrease was not statistically significant and was based on small case counts.
Table 1.
Incidence of testicular germ cell tumors by histologic subtype, 1998–2011, SEER/NPCR Registries
| Testicular germ cell tumors | Seminoma | Nonseminoma | Spermatocytic Seminoma | |||||
|---|---|---|---|---|---|---|---|---|
| Count1 | Rate (95% CI)2 | Count1 | Rate (95% CI)2 | Count1 | Rate (95% CI)2 | Count1 | Rate (95% CI)2 | |
|
|
||||||||
| All Races | 88,993 | 5.31 (5.28–5.35) | 51,647 | 3.12 (3.10–3.15) | 36,650 | 2.15 (2.13–2.17) | 696 | 0.04 (0.04–0.05) |
| APC 3 | 0.414 | −0.19 | 1.334 | −1.05 | ||||
| Non-Hispanic White | 70,869 | 6.57 (6.52–6.62) | 42,229 | 3.88 (3.84–3.92) | 28,044 | 2.64 (2.61–2.67) | 596 | 0.05 (0.05–0.05) |
| Hispanic (All Races) | 12,575 | 3.88 (3.81–3.95) | 6,192 | 2.07 (2.01–2.12) | 6,327 | 1.78 (1.74–1.83) | 56 | 0.03 (0.02–0.04) |
| Non-Hispanic Black | 2,138 | 1.20 (1.15–1.26) | 1,333 | 0.77 (0.73–0.81) | 780 | 0.42 (0.39–0.45) | 25 | 0.02 (0.01–0.03) |
| Asian/Pacific Islander | 1,546 | 1.60 (1.52–1.68) | 858 | 0.91 (0.85–0.98) | 682 | 0.68 (0.63–0.73) | 5 | 5 |
| American Indian/Alaska Native | 656 | 2.88 (2.67–3.12) | 347 | 1.62 (1.45–1.81) | 305 | 1.24 (1.10–1.39) | 5 | 5 |
May not sum to total because of missing race
Rates are per 100,000 and age-adjusted to the 2000 US Standard Population (19 age groups - Census P25-1130)
APC = Annual Percent Change
The APC is significantly different from zero (p<0.05)
Case counts less than 16 (rate not calculated)
TGCT incidence trends by race/ethnicity are shown in Table 2 and Figure 2. While rates increased only slightly, but significantly, among non-Hispanic white men (APC: 0.51, p=0.0076), the largest increase in rates was experienced by Hispanic men (APC: 2.31, p<0.0001). Incidence rates also increased among A/PI men (APC: 1.46, p=0.0827), however this increase was not statistically significant. Rates remained relatively stable among both non-Hispanic black (APC: 0.12, p=0.8194) and AI/AN (APC: 0.60, p=0.6188) men.
Table 2.
Incidence of testicular germ cell tumors by race/ethnicity and year of diagnosis, 1998–2011, SEER/NPCR Registries
| Testicular germ cell tumors | Seminoma | Nonseminoma | ||||
|---|---|---|---|---|---|---|
| Count | Rate (95% CI)1 | Count | Rate (95% CI)1 | Count | Rate (95% CI)1 | |
|
|
||||||
| Non-Hispanic White | ||||||
| 1998–2000 | 15,176 | 6.31 (6.21–6.42) | 9,350 | 3.84 (3.77–3.92) | 5,701 | 2.42 (2.36–2.48) |
| 2001–2003 | 15,227 | 6.47 (6.36–6.57) | 9,227 | 3.87 (3.79–3.95) | 5,869 | 2.55 (2.48–2.61) |
| 2004–2006 | 15,256 | 6.73 (6.62–6.84) | 8,957 | 3.91 (3.83–4.00) | 6,165 | 2.76 (2.70–2.83) |
| 2007–2009 | 15,264 | 6.70 (6.60–6.81) | 8,909 | 3.89 (3.80–3.97) | 6,237 | 2.77 (2.71–2.84) |
| 2010–2011 | 9,946 | 6.64 (6.51–6.78) | 5,786 | 3.85 (3.75–3.95) | 4,072 | 2.74 (2.66–2.83) |
| Hispanic (All Races) | ||||||
| 1998–2000 | 1,936 | 3.34 (3.19–3.51) | 1,002 | 1.89 (1.77–2.02) | 928 | 1.43 (1.33–1.53) |
| 2001–2003 | 2,381 | 3.66 (3.50–3.82) | 1,213 | 2.02 (1.90–2.14) | 1,156 | 1.61 (1.51–1.71) |
| 2004–2006 | 2,657 | 3.83 (3.68–3.99) | 1,299 | 2.03 (1.92–2.15) | 1,348 | 1.78 (1.68–1.88) |
| 2007–2009 | 3,303 | 4.28 (4.13–4.43) | 1,593 | 2.22 (2.10–2.33) | 1,691 | 2.03 (1.93–2.13) |
| 2010–2011 | 2,298 | 4.26 (4.08–4.45) | 1,085 | 2.16 (2.03–2.29) | 1,204 | 2.07 (1.95–2.20) |
| Non-Hispanic Black | ||||||
| 1998–2000 | 435 | 1.20 (1.09–1.32) | 281 | 0.79 (0.70–0.89) | 146 | 0.38 (0.32–0.45) |
| 2001–2003 | 468 | 1.25 (1.14–1.37) | 296 | 0.81 (0.72–0.91) | 168 | 0.42 (0.36–0.49) |
| 2004–2006 | 425 | 1.14 (1.03–1.25) | 251 | 0.69 (0.61–0.78) | 168 | 0.43 (0.37–0.50) |
| 2007–2009 | 473 | 1.19 (1.09–1.31) | 299 | 0.78 (0.69–0.87) | 171 | 0.41 (0.35–0.48) |
| 2010–2011 | 337 | 1.25 (1.12–1.40) | 206 | 0.79 (0.68–0.90) | 127 | 0.45 (0.38–0.54) |
| Asian/Pacific Islander | ||||||
| 1998–2000 | 276 | 1.63 (1.44–1.84) | 166 | 1.02 (0.87–1.19) | 109 | 0.60 (0.49–0.73) |
| 2001–2003 | 261 | 1.33 (1.17–1.50) | 150 | 0.78 (0.66–0.92) | 111 | 0.55 (0.45–0.66) |
| 2004–2006 | 333 | 1.61 (1.43–1.79) | 184 | 0.91 (0.78–1.06) | 149 | 0.69 (0.58–0.81) |
| 2007–2009 | 378 | 1.64 (1.47–1.81) | 208 | 0.92 (0.80–1.05) | 167 | 0.70 (0.59–0.81) |
| 2010–2011 | 298 | 1.82 (1.62–2.05) | 150 | 0.94 (0.79–1.10) | 146 | 0.88 (0.74–1.03) |
| American Indian/Alaska Native | ||||||
| 1998–2000 | 103 | 2.66 (2.16–3.26) | 56 | 1.52 (1.14–2.01) | 45 | 1.07 (0.78–1.48) |
| 2001–2003 | 130 | 2.88 (2.40–3.46) | 65 | 1.57 (1.20–2.04) | 65 | 1.31 (1.01–1.70) |
| 2004–2006 | 150 | 3.04 (2.55–3.60) | 82 | 1.77 (1.39–2.24) | 67 | 1.24 (0.96–1.60) |
| 2007–2009 | 159 | 2.95 (2.50–3.47) | 79 | 1.54 (1.21–1.93) | 79 | 1.39 (1.10–1.76) |
| 2010–2011 | 114 | 2.86 (2.35–3.46) | 65 | 1.75 (1.35–2.26) | 49 | 1.11 (0.82–1.49) |
Rates are per 100,000 and age-adjusted to the 2000 US Standard Population (19 age groups - Census P25-1130)
Figure 2.
Age-adjusted incidence rates of testicular germ cell tumors among non-Hispanic white, Hispanic (All Races), non-Hispanic Black, Asian/Pacific Islander (A/PI), and American Indian/Alaska Native (AI/AN) men, SEER/NPCR Registries, 1998–2011
Incidence trends by histologic subtype are also presented in Table 2 and Figure 2. Seminoma rates increased significantly only among Hispanic men (APC: 1.36, p=0.0009). Seminoma incidence also increased, but not significantly so, among AI/AN men (APC: 1.20, p=0.4103). Seminoma rates remained relatively stable among non-Hispanic white (APC: 0.04, p=0.7626), non-Hispanic black (APC: −0.15, p=0.8575), and A/PI (APC: −0.32, p=0.7602) men. Nonseminoma rates increased significantly among Hispanic (APC: 3.46, p<0.0001), A/PI (APC: 3.69, p=0.0015), and non-Hispanic white (APC: 1.23, p=0.0004) men, and non-significantly among non-Hispanic black men (APC: 1.02, p=0.3139). In comparison, nonseminoma rates did not change substantively among AI/AN men (APC: 0.14, p= 0.9413). Among all racial/ethnic groups, the increases in rates were greater for nonseminoma than seminoma. Joinpoint analysis revealed only one significant finding; a joinpoint was observed in the nonseminoma rates of non-Hispanic white men (APC 1998–2005: 2.47, p=0.0005; APC 2005–2011: −0.28, p=0.6393).
TGCT rates for the most recent time period (2010–2011) by census region are presented in Table 3. There was a statistically significant difference in rates by region among non-Hispanic white (p<0.0001), Hispanic (p=0.0001), and A/PI (p<0.0001) men, but not among non-Hispanic black men (p=0.6266). Similar findings were observed for both seminomas and nonseminomas. Among seminomas, there was a statistically significant difference in rates by region among non-Hispanic white (p<0.0001) and Hispanic (p=0.0024) men, but not among non-Hispanic black men (p=0.9289). Among nonseminomas, there was a statistically significant difference in rates by region among non-Hispanic white (p=0.0014) and Hispanic (p=0.0064) men, but not among non-Hispanic black men (p=0.2137). Rates among AI/AN men by census region were not calculated due to small numbers. Seminoma and nonseminoma rates among A/PI men by census region were also not calculated due to small numbers. TGCT rates among Hispanic (4.74 per 100,000 man-years) and non-Hispanic black (1.40) men were highest in the West while rates among non-Hispanic white (7.65) and A/PI (2.14) men were highest in the Northeast.
Table 3.
Incidence of testicular germ cell tumors by census region, 2010–2011, SEER/NPCR Registries
| Population | Testicular germ cell tumors | Seminoma | Nonseminoma | |||||
|---|---|---|---|---|---|---|---|---|
| Count | Rate (95% CI)1 | Count | Rate (95% CI)1 | Count | Rate (95% CI)1 | |||
|
|
||||||||
| Non-Hispanic White | ||||||||
| West | 38,200,425 | 2,593 | 7.07 (6.79–7.35) | 1,509 | 4.11 (3.90–4.33) | 1,059 | 2.90 (2.72–3.08) | |
| South | 41,261,464 | 2,122 | 5.58 (5.34–5.83) | 1,192 | 3.12 (2.95–3.31) | 916 | 2.43 (2.28–2.60) | |
| Midwest | 44,476,522 | 2,686 | 6.45 (6.20–6.70) | 1,546 | 3.72 (3.53–3.91) | 1,112 | 2.67 (2.51–2.83) | |
| Northeast | 35,670,423 | 2,545 | 7.65 (7.35–7.96) | 1,539 | 4.58 (4.35–4.82) | 985 | 3.02 (2.84–3.22) | |
| p-value2 | p<0.0001 | p<0.0001 | p=0.0014 | |||||
| Hispanic (All Races) | ||||||||
| West | 20,768,092 | 1,099 | 4.74 (4.45–5.04) | 522 | 2.45 (2.24–2.69) | 576 | 2.28 (2.09–2.49) | |
| South | 15,736,006 | 687 | 3.85 (3.56–4.16) | 318 | 1.88 (1.67–2.10) | 364 | 1.92 (1.73–2.14) | |
| Midwest | 4,302,377 | 203 | 4.19 (3.60–4.88) | 98 | 2.12 (1.71–2.64) | 105 | 2.07 (1.66–2.58) | |
| Northeast | 7,039,198 | 309 | 3.86 (3.42–4.35) | 147 | 1.97 (1.64–2.34) | 159 | 1.82 (1.55–2.15) | |
| p-value2 | p=0.0001 | p=0.0024 | p=0.0064 | |||||
| Non-Hispanic Black | ||||||||
| West | 3,564,887 | 52 | 1.40 (1.04–1.85) | 27 | 0.75 (0.49–1.11) | 25 | 0.64 (0.41–0.97) | |
| South | 11,763,598 | 141 | 1.26 (1.06–1.49) | 91 | 0.82 (0.66–1.01) | 48 | 0.42 (0.31–0.56) | |
| Midwest | 6,449,817 | 68 | 1.11 (0.86–1.42) | 43 | 0.73 (0.53–0.99) | 23 | 0.35 (0.22–0.53) | |
| Northeast | 6,023,214 | 76 | 1.30 (1.02–1.64) | 45 | 0.79 (0.57–1.06) | 31 | 0.51 (0.35–0.74) | |
| p-value2 | p=0.6266 | p=0.9289 | p=0.2137 | |||||
| Asian/Pacific Islander | ||||||||
| West | 7,745,768 | 158 | 1.94 (1.64–2.27) | 80 | 0.99 (0.78–1.24) | 78 | 0.95 (0.75–1.18) | |
| South | 2,237,642 | 24 | 0.90 (0.58–1.39) | 3 | 3 | 3 | 3 | |
| Midwest | 1,590,481 | 39 | 1.97 (1.39–2.77) | 17 | 0.88 (0.51–1.49) | 21 | 1.02 (0.63–1.65) | |
| Northeast | 3,258,301 | 77 | 2.14 (1.68–2.70) | 42 | 1.20 (0.85–1.65) | 34 | 0.91 (0.63–1.29) | |
| p-value2 | p<0.0001 | 4 | 4 | |||||
| American Indian/Alaska Native | ||||||||
| West | 1,976,014 | 71 | 3.34 (2.59–4.27) | 39 | 2.04 (1.44–2.84) | 32 | 1.30 (0.88–1.90) | |
| South | 931,094 | 26 | 2.66 (1.72–4.01) | 18 | 1.87 (1.10–3.07) | 3 | 3 | |
| Midwest | 431,562 | 3 | 3 | 3 | 3 | 3 | 3 | |
| Northeast | 401,496 | 3 | 3 | 3 | 3 | 3 | 3 | |
| p-value2 | 4 | 4 | 4 | |||||
Rates are per 100,000 and age-adjusted to the 2000 US Std Population (19 age groups - Census P25-1130)
Global p-value (calculated from the Wald test)
Case counts less than 16 (rate not calculated)
p-value not calculated
TGCT incidence trends between 1998 and 2011 by census region among non-Hispanic white, Hispanic, and non-Hispanic black men are shown in Figure 3a. Incidence among non-Hispanic white men was stable in the West (APC: 0.12, p=0.5332), and the South (APC: 0.22, p=0.4036), but increased significantly in the Northeast (APC: 1.19, p<0.0001) and, to a lesser extent, in the Midwest (APC: 0.55, p=0.0480). Among Hispanic men, incidence increased significantly in the West (APC: 3.01, p<0.0001), the Midwest (APC: 2.95, p=0.0028), and the Northeast (APC: 3.43, p=0.0003), but remained stable in the South (APC: 0.71, p=0.1042). Among non-Hispanic black men, there were no significant trends in any region.
Figure 3.
Age-adjusted incidence rates of testicular germ cell tumors by census region, SEER/NPCR Registries, 1998–2011
a. Testicular Germ Cell Tumors
b. Seminoma
c. Nonseminoma
Seminoma incidence trends are displayed in Figure 3b. Among non-Hispanic white men, the only significant increase in the incidence of seminoma was seen in the Northeast (APC: 0.87, p<0.0001). Among Hispanic men, there were significant increases in both the West (APC: 1.96, p=0.0018) and the Midwest (APC: 1.78, p=0.0443), while among non-Hispanic black men there were no significant changes in the incidence in any region. Nonseminoma incidence trends are shown in Figure 3c. Among non-Hispanic white men, there were significant increases in the South (APC: 1.17, p=0.0181), Midwest (APC: 1.31, p=0.0095), and the Northeast (APC: 1.75, p=0.0001). Among Hispanic men, there were significant increases in all four regions: West (APC: 4.36, p<0.0001), South (APC: 1.48, p=0.0007), Midwest (APC: 4.63, p=0.0015), Northeast (APC: 4.51, p=0.0019). There were no significant changes among non-Hispanic black men during the study period.
In all census regions, Hispanic men had the greatest APC for all histologic subtypes and overall TGCT. APCs could not be calculated for A/PI and AI/AN men by census region due to small numbers. Results remained essentially unchanged when the sensitivity analysis that excluded one registry in the West census region was conducted (data not shown).
DISCUSSION
The current study found that while non-Hispanic white men had the highest incidence of TGCT between 1998 and 2011, the greatest increase in incidence was experienced by Hispanic men. Further, Hispanic men were the only racial/ethnic group to experience significant increases in both seminoma and nonseminoma and were the only group to experience significant increases in incidence in 3 out of 4 census regions.
The reasons for the differences in TGCT risk among different racial/ethnic groups in the US remains unknown. Environmental risk factors for TGCT have not been well identified, although TGCT is known to be associated with other male reproductive disorders (cryptorchidism, hypospadias, impaired spermatogenesis), the group of which is collectively known as the Testicular Dysgenesis Syndrome (TDS).11 TDS disorders have been suggested to share a common in utero etiology, suggesting that environmental risk factors would have to be operative during the pre- or perinatal period of life. One such factor that has been widely hypothesized to be related to risk is maternal exposure to endocrine-disrupting chemicals (EDCs).12 While evidence suggests that EDCs such as p,p′-dichlorodiphenyldichloroethylene (DDE) and chlordane-related compounds cis- and trans-nonachlor may be associated with TGCT risk, there is currently less evidence of their association with other TDS disorders.13
Genetic susceptibility to TGCT certainly exists, as evidenced by the increased risk among 1st degree relatives of affected men14 and by findings of genome wide association studies (GWAS). To date, GWAS have identified at least 21 loci associated with TGCT susceptibility.15–21 It is unlikely, however, that risk is determined by the risk loci alone as the incidence of TGCT has increased steadily over the last five or six decades. Rather, increases in one or more environmental risk factors or decreases in protective factors are likely leading to the increasing incidence among genetically susceptible men.
Similar to findings from earlier reports,1, 4 the current study found that the most pronounced increase in TGCT incidence was among Hispanic men. The 2010 US census reported that the majority of Hispanics in the US are of Mexican ancestry (63.0%), followed by Puerto Rican (9.2%), Cuban (3.5%), Salvadoran (3.3%), Dominican (2.8%), and Guatemalan ancestries (2.1%).22 Estimated TGCT incidence rates in Mexico (2.8 per 100,000 man-years), Puerto Rico (3.1), Cuba (1.4), El Salvador (0.4), Dominican Republic (0.4), and Guatemala (0.6)23 are variable, but are all lower than the rate among US Hispanics of all races (3.9). A possible explanation for the higher rates seen in US Hispanics is that rates among Hispanics rise with migration to the US. Previous 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 rather, among subsequent generations.24, 25 This suggests that rates could be rising in some regions of the US due to a greater proportion of Hispanic men being of second or higher generation. Although it is not certain why rates rise among second generation migrants to higher rate countries, the finding is consistent with the evidence suggesting that the in utero environment is critical to determining risk. Maternal exposures are likely to change among subsequent generations and socioeconomic status (SES) may also increase. Some studies have reported that risk of TGCT increases with increasing SES.26, 27 Whatever the exposure or exposures may be, they are likely to affect a genetically susceptible population. In this regard, an examination of the allele distribution of the TGCT risk loci finds that the distribution among Hispanic men is more similar to the distribution among European men than among men of low risk, such as Africans.28 In particular, the allele distribution of the major TGCT GWAS locus at KITLG, is very similar among Hispanics (A: 17%, G: 83%) and Europeans (A: 20%, G: 80%), in contrast to the opposite distribution among Africans (A: 75%, G: 25%).28
In the most recent time period, Hispanic men had the highest incidence of TGCT in the West (4.74 per 100,000 man-years), followed by the Midwest (4.19), while rates in the Northeast (3.85) and the South (3.86) were very similar. The proportion of men of Mexican ancestry also varies by region with greater percentages in the West (79.9%) and the Midwest (74.5%),22 suggesting that men of Mexican ancestry might be more genetically susceptible that other Hispanic men. In opposition to this hypothesis, however, is that the proportion of men of Mexican ancestry in South (60.0%) varies greatly from that in the Northeast (13.1%), but the regions have nearly identical TGCT rates. In addition, the region with the greatest APC for 1998–2011, the Northeast, was the region with the smallest percentage of men of Mexican ancestry.
A strength of the current study was the use of population-based cancer registry data from 39 registries, which captured a larger sample of the US population than did previous SEER studies.1, 4 Additionally, this is the first study to our knowledge to examine TGCT rates by US census region. Limitations included the inability to restrict AI/AN populations to Contract Health Services Delivery Area (CHSDA) regions, which better represent true AI/AN status, and the lack of information on place of birth and country-specific ancestry, which may be useful in examining hypotheses concerning environmental and genetic risk factors of TGCT. An additional limitation was the use of the NAACCR NHIA algorithm, or any algorithm, for the identification of Hispanic ethnicity, as this could result in misclassification. As the current study included only men, however, such misclassification is less likely than if the study had also included women.
The current study indicates that TGCT incidence is increasing most rapidly among US Hispanic men, with increases observed in all geographic areas except the South. Reasons for the geographical variation in rates and trends are unclear, but could be related to as yet unidentified varying exposures, place of birth, country of ancestry and/or length of residence in the US. The increasing rates among Hispanic men suggest an area where both etiologic research and public health efforts are warranted.
Acknowledgments
FUNDING SUPPORT: This work was supported by the Intramural Research Program of the National Cancer Institute.
Footnotes
The authors declare no conflicts of interest or financial disclosures
CONFLICT OF INTEREST DISCLOSURES
The authors declare no competing interests and have no financial disclosures.
References
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