Increase in Testicular Germ Cell Tumor Incidence among Hispanic Adolescents and Young Adults in the United States

Abstract

Background

While rising incidence rates of testicular germ cell tumors have been well documented in white men, relatively little is known about rates in men of Hispanic origin. In the current study, we compared germ cell tumor trends between men of Hispanic and non-Hispanic origin as a function of age at diagnosis.

Methods

We analyzed testicular germ cell tumor incidence trends in white men by Hispanic ethnicity in two datasets of the National Cancer Institute’s Surveillance, Epidemiology, and End Results program, spanning 1992 to 2010 and 2000 to 2010, and sampling 15% and 28% of the United States population, respectively. Rates were age-adjusted to the year 2000 United States standard population.

Results

Between 1992 and 2010, the annual incidence of testicular germ cell tumors in 15- to 39-year-old Hispanic whites increased 58% from 7.18 cases per 100,000 in 1992 to 11.34 cases per 100,000 by 2010 (p < 1×10⁻⁹). Their incidence rates increased in metropolitan areas for both seminoma and non-seminoma subtypes and for all stages at diagnosis. In the same 19-year interval, incidence among non-Hispanic white young adults increased 7%, from 12.41 to 13.22 per 100,000. During the 2000 to 2010 interval, no significant trends were observed in incidence among non-Hispanic whites.

Conclusion

There has been a recent substantial increase in testicular germ cell tumor incidence among Hispanic adolescents and young adults in the United States. Similar trends were not observed in non-Hispanic whites.

Introduction

Testicular germ cell tumors (TGCT) are the most common solid malignancy among adolescent and young adult (AYA) men, accounting for 21% of all neoplasms in men 15- to 39-years of age according to recent data from the United States Surveillance, Epidemiology, and End Results (SEER) program. TGCTs are one of the most readily treatable tumors, with 98% 10-year survival for seminomas and 91% for non-seminomas (1). From 2005 to 2009, the overall annual incidence was 5.5 per 100,000 American men (2), although incidence varied widely by race. White men are at highest risk for TGCT, with an annual incidence of 6.6 per 100,000 men during 2005–2009, compared to only 1.4 per 100,000 in black men and 1.9 per 100,000 in Asians/Pacific Islanders during the same interval. Annual TGCT incidence in Hispanic men is 4.7 per 100,000. International data parallel incidence by race in the United States, with the highest age-adjusted incidence rates in Europe and Australia where the population is predominately white (3, 4). The incidence is lowest in Asian and African men.

Several reports in the United States have shown increasing TGCT incidence especially in white men during the 1970s to the 1990s (3–10). The incidence in black men began increasing in the early 1990s (7, 10), while the incidence in non-Hispanic whites, Asians and Pacific Islanders, and American Indians and Alaskan Natives appeared to have plateaued at that time (5, 10, 11).

Hispanic Americans are the fastest growing population in the United States with an estimated 50.5 million residents according to the 2010 census (12). A previous report presented limited information on TGCT rates in Hispanic men in the United States from 1992 to 2003, finding an increasing incidence that was not statistically significant (5). To our knowledge, there have been no subsequent reports that describe trends in TGCT incidence in Hispanic Americans in the past decade. The release of the NCI’s Surveillance, Epidemiology, and End Results Program’s largest and most expansive dataset (SEER18), along with incidence data up to 2010 in all SEER registries, allowed a more robust analysis of the trends in TGCT among Hispanic AYAs.

Materials and Methods

Data source

We obtained population-based data on TGCT incidence among white men of Hispanic and non-Hispanic origin from 1992 to 2010 in the United States SEER program of the National Cancer Institute (13, 14). The original nine SEER registries (SEER9), consisting of Connecticut, Iowa, New Mexico, Utah, Hawaii, the metropolitan areas of Detroit, San Francisco-Oakland, and Atlanta, and 13 counties of the Seattle-Puget Sound region have contributed data since 1973–1974. In 1992, four more registries (rural Georgia, Alaskan natives, Los Angeles, and San Jose-Monterey) were added to the SEER program (SEER13), and Hispanic ethnicity became a required data item. For 2000–2008, data from four additional registries are available (the rest of the state of California, Kentucky, New Jersey, and Louisiana) (SEER17). In 2012, the entire state of Georgia was added retrospectively to SEER17 to constitute SEER18. Although SEER9 offers the longest period of incidence data, our analysis began with SEER13 and included SEER18 because these registries classify cases by Hispanic ethnicity, and the goal of this study was to examine TGCT incidence among men of Hispanic origin. SEER classifies persons diagnosed with cancer according to Hispanic origin based on the North American Association of Central Cancer Registries (NAACCR) Hispanic Identification Algorithm (NHIA) (15).

Among 42,532 cases of TGCT in white men from the SEER13 and SEER18 datasets, 823 were younger than 15 years of age and excluded from this study, as they may represent a distinct etiology from TGCT arising later in life. Of the remaining cases, an additional 134 were excluded for being non-malignant, and then another 519 for being non-first primary. 18,545 TGCTs were from SEER13, of which 13,187 cases were diagnosed in the AYA age range. 22,511 cases were from SEER18, of which 15,459 cases were diagnosed in the AYA age range.

Statistical analysis

We compared TGCT incidence from 1992 to 2010 between Hispanic white and non-Hispanic white men using both SEER13 and SEER18 data. Incidence trends were analyzed by 5-year age at diagnosis intervals. We classified AYAs as individuals diagnosed at 15 to 39 years of age, as defined by the National Cancer Institutes (NCI) AYA Oncology progress review group (16). Population data are directly enumerated every tenth year by the United States census bureau, and population estimates were determined for the intervening years. Intercensal estimates for 1991 to 1999 and 2001 to 2009 were updated following the release of the 2000 and 2010 national census, respectively(17). Incidence rates were age-adjusted to the United States year 2000 standard population. Annual percent changes (APC) in incidence were obtained by fitting the natural logarithm of incidence (dependent variable) to a weighted least-square regression model, regressed over calendar year of diagnosis (independent variable). APC is a function of the estimated regression slope parameter. To assess whether any patterns observed were specific to TGCT, we also calculated the 1992 to 2010 APCs for all malignancies as well as all malignancies except TGCT in Hispanic white men 15 to 39 years of age. 95% confidence intervals were constructed from the regression slope standard error. All p-values reported in this study are from tests of the null hypothesis that the corresponding APC=0. P-values were computed from a two-tailed T-distribution of the regression slope; we considered the null hypothesis to be rejected if p<0.05. All APCs and p-values were computed by SEER*Stat.

We analyzed TGCT trends by histology, stage at diagnosis, and population density of the place of residence at diagnosis. We classified TGCT as either seminoma or non-seminoma, with the International Classification of Disease for Oncology (ICD-O-3) morphology codes 9060–9062 and 9064 for seminoma, and 9065 and 9070–9102 for non-seminoma. Stage at diagnosis was determined through SEER’s Historic Stage A recode, with localized disease referring to tumors confined to the testis, regional disease to contiguous and adjacent organ spread, and distant disease to tumors involving remote metastases. Place of residence at diagnosis was categorized as metropolitan or non-metropolitan, based on the SEER Rural-Urban continuum code 2003 developed by the United States Department of Agriculture, with metropolitan counties including metropolitan areas of any population size (codes 1–3), and nonmetropolitan counties referring to urban and completely rural counties of any population size, either adjacent or not adjacent to metropolitan areas (codes 4–9).

To estimate the number of cases of TGCT in Hispanic white AYAs in the United States, the projected number of TGCT diagnoses for men in 5-year age groups was computed for each calendar year between 1992 and 2010. This number was obtained by first calculating the age- and year- specific ratios of the number of Hispanic white Americans in the United States to the number of AYA Hispanic white Americans in SEER13 (for 1992 through 1999) and SEER18 (for 2000 through 2010). This ratio was multiplied by the corresponding observed AYA SEER13 and SEER18 TGCT counts for 1992–1999 and 2000–2010, respectively. National white Hispanic population counts were retrieved from SEER (18).

Results

SEER13, which spans the interval between 1992 and 2010, contains 18,545 first diagnosis, malignant, primary TGCT cases in white men diagnosed at 15 years of age or older, of whom 3,488 were of Hispanic origin and 15,057 of non-Hispanic origin. SEER18 (2000 to 2010) contains 22,511 first, malignant, primary TGCT cases in white men diagnosed at 15 years of age or older, of whom 4,655 were of Hispanic and 17,856 were of non-Hispanic origin, respectively.

Figure 1 shows the incidence of TGCT among white AYAs of Hispanic and non-Hispanic origin over time. TGCT incidence in Hispanic AYAs increased steadily, with an APC of 3.61 (95% CI: 3.02 to 4.21, p<1×10²⁻⁹ in the 1992–2010 interval of SEER13 and 3.81 (95% CI: 2.99 to 4.63, p=2×10⁻⁶) in the more recent 2000–2010 interval of SEER18. In contrast, among non-Hispanic AYAs, a lower APC of 1.04 (95% CI: 0.58 to 1.50, p=0.0002) was observed in SEER13, and in SEER18 there was no evidence of a trend in TGCT incidence. The absolute increase in TGCT incidence over the 19-year interval of SEER13 was only 0.81 cases per 100,000 in non-Hispanic men (a proportional increase of 6.5%), compared with 4.16 cases per 100,000 Hispanic men per year (a proportional increase of 57.9%).

Figure 1.

Age-adjusted testicular germ cell tumor incidence rates among white adolescents and young adults of Hispanic and non-Hispanic origin, SEER13 and SEER18 databases, 1992–2010.

Figure 2 plots SEER13 APCs for testicular cancer incidence by 5-year age intervals among 15- to 49-year-old white men of Hispanic and non-Hispanic origin. (APCs were not calculated for Hispanic men older than 49 years of age due to insufficient sample size.) Among Hispanics, we observed statistically significant increases in APC exceeding 1.5 for all 5-year age cohorts in the AYA age range (15–39). No APC values significantly greater than zero were observed in Hispanic men over 39 years of age. In non-Hispanic men, we observed a statistically significant but much smaller APC increase in the subset of AYAs between 20 to 34 years of age, but not in other age groups. APCs reaching statistical significance (p<0.05) in non-Hispanic white AYA men ranged from 0.9 to 1.6.

Figure 2.

Annual percent change in age-adjusted TGCT incidence for Hispanic (top panel) and non-Hispanic (bottom panel) white men by 5-year age group. Vertical lines depict 95% confidence intervals, SEER13 database, 1992–2010.

Table 1 compares TGCT incidence trends for AYAs and older men of Hispanic and non-Hispanic origin, according to histology, stage at diagnosis, and metropolitan vs. non-metropolitan residency in SEER13 and SEER18. For Hispanic white men, TGCT incidence in AYAs increased for both seminoma and non-seminoma subtypes and for all stages at diagnosis. The APC for seminoma and non-seminoma in Hispanic AYAs in SEER13 were 3.07 (95% CI: 1.94 to 4.21, p=0.00002) and 4.10 (95% CI: 2.91 to 5.32, p=1×10⁻⁶) respectively. Cases of localized disease increased at an APC of 3.50 (p=5×10⁻⁷), regional at 4.49 (p=0.003), and distant disease at 2.26 (p=0.02). The increasing trend in TGCT incidence occurred only in metropolitan counties, where the APC was 3.70 (95%: 3.05 to 4.34, p=1×10⁻⁹) in SEER13. In SEER18, significant and positive APCs were demonstrated among Hispanic AYAs in every histology and stage at diagnosis analyzed, and in both metropolitan and non-metropolitan counties, with a relatively high APC of 6.78 (95% CI: 0.21 to 13.78, p=0.04) observed in non-metropolitan areas. In contrast to Hispanic AYAs, all of the corresponding APCs among older Hispanic white men ranged from strongly negative to strongly positive.

Table 1.

Average annual percent change in testicular germ cell tumors incidence among whites, by Hispanic ethnicity and age, SEER13 and SEER18 databases.

	SEER13 (1992–2010)
	AYA (15–39 years)		Older Men (40+ years)
	N	APC(95% CI)	N	APC(95% CI)
Hispanic White
Seminoma	1,404	3.07(1.94 to 4.21)	380	0.20(−1.72 to 2.15)
Non-Seminoma	1,581	4.10(2.91 to 5.32)	105	−1.01(−5.01 to 3.16)
Local	1,804	3.50(2.68 to 4.32)	324	0.15(−1.79 to 2.13)
Regional	553	4.49(1.77 to 7.28)	100	3.03(−1.26 to 7.50)
Distant	499	2.26(0.36 to 4.20)	57	−2.98(−7.04 to 1.27)
Metropolitan	2,867	3.70(3.05 to 4.34)	466	0.44(−1.40 to 2.31)
Non-Metropolitan	126	1.08(−2.89 to 5.21)	29	~a
Non-Hispanic White
Seminoma	5,350	0.93(0.44 to 1.44)	3,683	1.03(0.41 to 1.66)
Non-Seminoma	4,811	1.14(0.46 to 1.83)	1,083	2.09(0.80 to 3.39)
Local	7,111	1.21(0.64 to 1.80)	3,399	1.65(0.81 to 2.49)
Regional	1,790	−0.13(−0.98 to 0.72)	862	0.71(−0.33 to 1.76)
Distant	1,015	0.68(−1.09 to 2.48)	452	−0.15(−2.29 to 2.05)
Metropolitan	9,257	1.03 (0.54 to 1.53)	4,413	1.36(0.76 to 1.96)
Non-Metropolitan	934	1.01(0.28 to 1.74)	450	0.69(−1.52 to 2.94)
	SEER18 (2000–2010)
	AYA (15–39 years)		Older Men (40+ years)
	N	APC(95% CI)	N	APC(95% CI)
Hispanic White
Seminoma	1,761	3.20(1.22 to 5.21)	527	−0.70(−3.13 to 1.79)
Non-Seminoma	2,207	4.27(2.97 to 5.60)	147	5.17(0.47 to 10.08)
Local	2,343	3.29(1.62 to 4.98)	432	−0.23(−3.19 to 2.82)
Regional	763	5.40(3.29 to 7.55)	139	3.80(−2.68 to 10.71)
Distant	660	2.48(0.26 to 4.75)	88	−4.45(−9.56 to 0.95)
Metropolitan	3,826	3.70(2.77 to 4.64)	662	0.41(−1.18 to 2.04)
Non-Metropolitan	144	6.78(0.21 to 13.78)	23	~a
Non-Hispanic White
Seminoma	5,937	−0.58(−1.28 to 0.12)	4,825	−0.27(−0.88 to 0.36)
Non-Seminoma	5,550	1.11(−0.06 to 2.29)	1,542	1.24(0.20 to 2.28)
Local	7,961	−0.35(−0.98 to 0.29)	4,426	−0.46(−1.39 to 0.48)
Regional	1,985	−0.43(−1.72 to 0.88)	1,128	1.42(−0.06 to 2.93)
Distant	1,150	3.15(0.93 to 5.43)	629	0.70(−2.61 to 4.11)
Metropolitan	10,195	0.26(−0.51 to 1.04)	5,669	0.02(−0.50 to 0.53)
Non-Metropolitan	1,292	0.19(−1.62 to 2.03)	698	0.77(−2.78 to 4.45)

AYA = Adolescent and Young Adult, APC=Annual Percent Change, N=number of TGCT cases, CI=confidence interval

^aAPC could not be calculated due to insufficient sample size

Within the AYA age group, non-Hispanic whites had a consistently lower APC than in Hispanic men. In both SEER datasets, APC in non-Hispanic whites did not exceed 1.5. In SEER18, no APCs from non-Hispanic white AYAs reached statistical significance, except for distant disease at diagnosis, which was observed to be increasing in SEER18 at an APC of 3.15(95% CI: 0.93 to 5.43, p=0.01).

The overall incidence of cancer among AYA Hispanic Americans between 1992 and 2010 did not statistically significantly increase or decrease in SEER13 (data not shown). 10,423 cases of cancer were not of TGCT origin and 2,993 were TGCTs. Non-TGCTs demonstrated a decreasing trend in incidence (APC=−1.62 95% CI: −2.55 to −0.69, p=0.002). We estimate that in 2010, 1,134 Hispanic men in the United States were diagnosed with TGCT, in comparison with 410 in 1992.

Discussion

The incidence of TGCT in the United States has increased among Hispanic white AYAs in the interval between 1992 and 2010, in contrast to a plateau in the incidence for non-Hispanic white men during the same time period. In SEER13, the incidence of TGCT among Hispanic AYAs rose 1.6 fold, from 7.2 per 100,000 Hispanic men in 1992 to 11.3 per 100,000 in 2010. In SEER18, with the larger sample size and representing only the most recent years of diagnosis, we observed a similar rise in TGCT in Hispanic AYAs (1.4-fold) over the course of 11 years. The increase affected every 5-year age group between 15 and 39 years of age, for both seminoma and non-seminoma subtypes, and for every stage at diagnosis. Comparable increases were not observed in non-Hispanic white AYAs or in older men, although the relatively smaller number of older AYA TGCT cases means that the power to detect trends in this group was limited.

The increasing incidence of TGCT among Hispanics could potentially be due to improvements in classification of Hispanics in SEER data over time, as NHIA relies on input data (e.g. place of birth, surname) that may have become more complete or accurate in recent years. For such a phenomena to explain our results, the improvements in classification of Hispanics (and thus increases in incidence) would be expected to affect all cancers as opposed to being specific to TGCT. Yet the incidence rate of all cancers excluding TGCT in Hispanic AYAs, a sample size that outnumbers TGCTs by a factor of 3.5, appears to have decreased, rather than increased, over time.

The Hispanic population is the fastest growing ethnic minority in the United States, accounting for more than half of the total population growth in the United States between 2000 and 2010 (12). This rapid rate of growth is known to have posed challenges to the accuracy of the decennial enumeration of Hispanics as well as to intercensal estimates of the Hispanic population, which in turn may have impacted our analysis of SEER TGCT incidence trends and projections of TGCT cases in United States Hispanics. Census Bureau studies indicate that in the 1990, 2000, and 2010 decennial censuses, Hispanics were undercounted by 5%, 0.7%, and 1.5% (19, 20). Since intercensal estimates are based heavily on the decennial censuses, during our study period (1992–2010) Hispanic denominators are smaller than they should be, and more so in the earlier years than more recent years. This pattern would lead to observed estimated APCs that are weaker than the true APCs, and a projected number of United States Hispanic TGCT cases that is smaller than it would be had Hispanics been accurately counted. Thus, the undercounting of the Hispanic population cannot explain our findings, and if anything, suggests that the true increase in TGCT incidence is larger than we have reported.

Hispanics are a heterogeneous population: the majority of Hispanic Americans in 2010 are of Mexican descent (63.0%) followed by those of Puerto Rican descent (9.2%) (12). The remaining Hispanic Americans are represented by numerous ethnic subgroups from Central and South America. Future research should assess whether the rising TGCT trends are similar across subgroups of Hispanic ethnicities.

The reasons for the increasing TGCT incidence among Hispanic white AYAs, like those that underlie the increasing TGCT rates previously observed in other racial and ethnic groups in the United States, are currently unknown. The four established risk factors for TGCT are height (21–26), cryptorchidism (27, 28), family history of germ cell tumors (27), and prior TGCT (27). Men with undescended testis are at a 2.5–11 fold increased risk for TGCT compared to the general population (28). Whereas there is some evidence that the incidence of cryptorchidism in the United States increased from the late 1960s through the mid-1990s (29), we are not aware of any reports on the trends in this predisposing condition within specific racial or ethnic groups.

Changes in adult height are strongly affected by early life nutrition. Recent increases in TGCT incidence in different race and ethnicity groups over different calendar periods may be reflective of racial and ethnic-specific secular changes in improved access to adequate nutrition. Particularly relevant to our findings, there is evidence that over the thirty-year period in which most TGCT cases in this study were children, the height of Mexican-American boys increased to a much larger extent than for white or black boys (30).

Researchers have recently reported a positive association between marijuana use and TGCT risk, in particular for non-seminomas (31–33). Hispanics are currently more likely than whites or African Americans to use marijuana. In 2011, 50% of Hispanic teens reported marijuana use, in comparison to 40% of African Americans and 35% of Caucasian teens (34). Since the early 1990s, prevalence of lifetime marijuana use among Hispanic12^th graders has increased, from 36.6% in 1994 to 48.7% in 2012 (35). Increases were also noted in non-Hispanic white and black 12^th graders, although since 2008 there has been a disproportionate acceleration in marijuana use in Hispanics (34, 35). Yet because marijuana use has increased in both Hispanic and non-Hispanic whites, and because incidence of both seminoma and non-seminoma TCGT rose among Hispanic whites, marijuana use alone does not adequately explain the observed increase in TCGT among Hispanic AYAs.

In addition to the risk factors for TGCT noted above, several types of environmental exposure have been studied for a potential role in TGCT pathogenesis. These include heat, polyvinylchloride, nonionizing radiation, heavy metals, agricultural work, pesticides and polychlorinated biphenyls (33). For none of these, however, is there evidence clearly supporting associations with TGCT. Similarly, current evidence does not support links between TGCT risk and diet, physical activity, or exposure to ionizing radiation (33). Obesity has increased in the United States over the past several decades (36–38), and trends in Hispanics have mirrored those of other racial groups (39). However, high BMI is associated, if anything, with a reduced risk of TGCT, not an increased risk (40, 41).

In summary, we compared TGCT incidence trends in Hispanic and non-Hispanic white men in the United States. From 1992 to 2010, the incidence of these malignancies has increased among Hispanic whites while among non-Hispanic whites the incidence has plateaued. The observed rising incidence of TGCT, in combination with the increase in the Hispanic American population predicts an increasing clinical importance of TGCT in the United States. Although as of 2010, AYA TGCT incidence remains lower among Hispanic whites than non-Hispanic whites, the rate of TGCT in Hispanic whites may overtake that of non-Hispanic whites if the observed trends persist. Future studies should corroborate these results and investigate the factors responsible for the increase.