Hodgkin lymphoma (HL) is an uncommon B-cell malignancy with marked epidemiologic heterogeneity across histologic subtypes and patient age, sex, and race/ethnicity. Studies have long supported socioeconomic influences on disease etiology for children and young adults [1–11]; risk factors include characteristics describing intensity and timing of childhood social exposure, and management of infection [12], notably Epstein–Barr virus (EBV), which is present in monoclonal form in tumor cells of an epidemiologically distinctive proportion of cases [13–16]. Yet, racial/ethnic differences in HL occurrence persist regardless of socioeconomic status (SES) [4, 17], with higher rates [18] and lower tumor EBV prevalence [13, 16] in whites. This variation suggests additional environmental [17, 19] and/or genetic influences [20–23].

These contributions to HL etiology could be explored efficiently through migrant studies, but the paucity of large immigrant cohorts for evaluating this rare and complex disease has limited such research [11, 17, 19–21]. US Hispanics represent an ideal study population: This is a large group with a substantial foreign-born subset, and US- and foreign-born Hispanics likely differ in relevant childhood infectious exposures and other immune system influences [22]. However, migrant studies of HL in US Hispanics have been impeded by methodologic challenges, including cultural and genetic heterogeneity [23–28], which can dilute study findings, and missing cancer registry information on birthplace for a sizeable, non-random segment of cases, which may introduce bias into estimated rates [29–34].

To advance understanding of how environment affects HL incidence variation, we examined the effect of nativity on HL rates in US Hispanics in comparison with non-Hispanic whites, addressing the aforementioned challenges using California Cancer Registry (CCR) data, and nativity-specific numerators and denominators [35, 36] associated with the California Neighborhoods Data System [37]. This approach provided access to a Hispanic population that is large, relatively homogeneous culturally and ethnically (approximately 80 % of Mexican origin in 2001 [38]), and for which missing registry birthplace information for cases was imputed by a validated method [36, 39, 40]. In addition, as the association of tumor cell EBV with HL is strong in Hispanics [13, 41, 42] but not well studied by birthplace, we examined variation in its prevalence across a subset of study cases [16].

This study is the first to examine HL incidence rates using a case series of US Hispanics whose large size, relative ethnic homogeneity, fully characterized birthplace, and tumor cell EBV status for a subset, permitted detailed insights into immigration-related differences in occurrence. Overall, the lower HL rates in Hispanics than in whites among AYAs, but higher rates in children and older adults (notably males), varied by nativity. Ethnic differences were quite marked in foreign-born Hispanics, particularly younger children, but attenuated for US-born Hispanics, especially for women and for the NS subtype. EBV prevalence in HL tumors declined from foreign-born Hispanics to US-born Hispanics to whites, more dramatically in AYA women than in other age–sex groups. Together, these patterns extend evidence for strong socioeconomically associated environmental influences on HL incidence and on its EBV-defined subtypes. They also support the hypothesis that HL results from age-differing challenges to immune function [12], with higher risk in children exposed to intense, early infection, consistent with their larger family sizes [50]; higher risk in AYAs with delayed exposures to infection related to fewer childhood social contacts (e.g., fewer older siblings [51], less nursery school attendance [52]); and higher risk in older adults linked with more social contacts, likely because control of infection, especially with chronic herpesviruses, diminishes with immunosenescence. Beyond that, HL rate differences between US-born Hispanics and whites raise questions about the timing, duration, and/or extent of environmental change required to reduce ethnic variation in rates. Differences in nativity-specific variation for NS and MC underscore distinct etiologies. The markedly larger nativity effect on NS rates in AYA females than in males, but the lesser effect on rates for girls than for boys, illustrates the strong, age-varying influence of gender on NS HL occurrence.

Previous studies reported lower overall HL rates in US Hispanics, especially in AYAs, but higher rates for children and older adults, although most studies did not have adequate sample sizes to calculate rates simultaneously by age, sex, and histologic subtype [3, 4, 11, 17, 19, 53–55]. The three prior studies evaluating the effect of nativity on HL in Hispanics [11, 17, 19] lacked either the numbers of cases to stratify data by age, sex, and histologic subtype [17, 19], or nativity for all cases [11]; none included EBV information. In our study, nativity results generally resembled the prior findings. However, whereas Cozen et al. [17] showed higher NS rates in foreign- than in US-born Latinos under age 14 in Los Angeles County in 1972–1985, we observed no significant nativity differences at these ages, suggesting possible temporal or cohort changes in NS incidence. In SEER-wide data (2,067 Hispanic cases from 1992–2007), Evens et al. [11] reported lower proportions of MC in the US- than in the foreign-born; in our study, the lack of difference in MC rates by nativity, likely reflecting adjustment for age differences between groups, indicates little impact of birthplace on overall incidence of this histologic subtype. Numerous studies of EBV-related HL have described higher tumor EBV prevalence in Hispanics than in whites [16, 41, 42, 56–59]. Although none considered nativity, prevalences in our foreign-born cases were similar to those reported from Mexico and Costa Rica [42, 58].

As HL rates vary with economic conditions [1, 2, 4, 5, 7, 10, 17], some of the ethnic and nativity variation in rates reported here likely reflects socioeconomic differences. In 2001, California Hispanics differed from whites in having less education (74 vs. 31 % completing high school or less), more poverty (35 vs. 6 % living at or below the federal poverty level), and larger households (86 vs. 56 % with 3 or more persons) [60]—all characteristics associated with lower HL risk [1–11]. Similarly, foreign-born Hispanics differed from US-born Hispanics in reporting less education (84 vs. 57 % completing high school or less) and more poverty (42 vs. 28 % living at or below the federal poverty level) [60]. These socioeconomic conditions likely reflect aspects of the timing and intensity of exposure to infection linked to HL risk [12]. In several studies, Mexican-Americans had higher seroprevalence and overall burdens of common, latent infections even after control for social class [61, 62], and earlier age at infection [63, 64] than whites, and foreign birthplace was an independent predictor of these associations [61–66]. For children, these findings may describe the early and intense infections assumed to predict higher HL risk and may help explain the higher HL rates in foreign-born Hispanic children. For AYAs, they may speak to a well-primed childhood immune system, particularly in the foreign-born, consistent with their much lower young adult HL rates [67]. For older adults, greater infectious disease burdens among Mexican-Americans, particularly the foreign-born [68], may relate to the increased HL rates in Hispanics compared with whites; specifically, higher antibody titers against latent herpesviruses in Hispanics [69] may reflect diminished immune function and poorer control of latent infection due to stress [68, 70–72], lower SES [61, 69, 72, 73], or related aspects of immigration [74, 75] that could be related to HL development.

EBV-positive HL tumors appear to result from an aberrant immune response to EBV infection due to abnormal immune function [25, 76, 77]. The higher EBV prevalence in tumors of foreign-born than US-born Hispanics than whites in our study, which recalls the higher EBV prevalence in HL in populations from developing than developed economies [13, 42, 57, 78–80], and in some but not other European populations [13], suggests that foreign-born Hispanics have poorer immune control of EBV than US-born Hispanics and whites, particularly among children and older adults. For Hispanics, some data indirectly support this conjecture. In children and teenagers, adjusted PRs for EBV seroprevalence [81] and absolute antibody titers [81, 82] were higher in Mexican-Americans than whites, foreign- than US-born individuals, girls than boys, and children from lower versus the highest quartiles of household income [81]. In adults ages 24–32, EBV antibody titers were increased for Hispanics, females, and having lower SES during adolescence, suggesting long-lasting impacts of early environment on immune control of EBV [71]. EBV seroprevalence and antibody titers against lytic and latent antigens were higher in Mexicans than in Italians, Dutch, Israelis, Columbians, or Papua New Guineans [83], although a Texas community study found lower antibody titers against EBV lytic antigens in Hispanics than in whites [72]. Our finding of a lower EBV prevalence in HL tumors among US-than foreign-born Hispanics thus may reflect improved immune function as related to EBV control. However, given their higher HL rates, it also may reflect increased exposure to, or greater prevalence of, other environmental causes.

The deficit of AYA HL rates even in US-born Hispanics compared with whites in these data may diminish with increasing acculturation. In 2001, the California Hispanic population was still relatively recently immigrated (46 % foreign-born, 30 % residing in the US for under 10 years [60]). Nevertheless, to date, no study of HL incidence has observed an equivalence of rates in immigrants to those in the host country or of rates in young adult non-whites with those in whites over time [10, 11, 20, 21, 84]. For His-panics, young adult HL rates did not change over the 1990s and 2000s in either the US- or foreign-born [11]. Thus, persistent differences in HL rates between US-born Hispanics and whites may in part also reflect less modifiable aspects of HL etiology, such as HLA genotype [85–88], which manifests racial/ethnic variation in its association with HL overall [89] and by tumor cell EBV status [87]. Prevalence of the HLA-A2 allele, protective against EBV-positive HL [87, 90], varies across racial/ethnic groups, including Hispanics [87, 91, 92], and Mexican-Americans have specific HLA region determinants of immune response to EBV infection, including SNPs associated with HL [93].

The greater rate stability with immigration for the MC than for the NS subtypes in our data and the stronger association of EBV with MC irrespective of ethnicity and nativity support separate histology-specific etiologies [94] and, for MC, a larger component of invariable etiologic pathways across populations. Nevertheless, the nativity variation in MC rates also reveals environmental sensitivity in MC etiology, possibly through changes in immune function: Barros et al. [59] hypothesized that, as in HIV-related HL, EBV infection in children with poorer immune responses due to challenging environments may promote development of MC, while those with stronger immune function associated with healthier environments would develop NS. For NS, the higher rates in US- than in foreign-born AYAs, together with the lower EBV prevalences, confirm the view that EBV is not a dominant etiologic factor for this HL subtype [47]. However, as infectious mononucleosis, a strong risk factor for young adult EBV-associated HL [95, 96], seems less likely in US-born Hispanic AYAs than in whites in California, given their socioeconomic profiles [60], other pathways may lead to the observed higher EBV prevalences in HL in AYA US-born Hispanic males.

The larger immigration-related variation in HL rates in females than in males may reflect acculturation-related exposures together with biologic differences. If hormonal exposures related to reproduction interact with exposures to children to affect HL risk in women [97], the greater HL rate variation by ethnicity and nativity among AYA females than males may reflect protection to Hispanic women from earlier and more intense household exposure to infection. Among California women ages 15–39 in 2001, 41 % of foreign-born Hispanics, 17 % of US-born Hispanics, and 12 % of whites had had three or more children [60]. Among older men, the high HL rates in foreign-born than in US-born Hispanics might result in part from chronic inflammation from higher lifetime infection burdens [75].

Our findings are subject to some limitations. First, our inability to account for duration of US residence among foreign-born Hispanics, or degree of acculturation among US-born Hispanics, limits the precision of estimated rates and may bias our nativity-specific findings [17]. Second, although SES is a predictor of racial/ethnic differences in HL incidence [4, 13, 16], we lacked the denominators to calculate nativity- and neighborhood-level SES-specific rates. Third, tumor cell EBV status was available only on a small proportion of cases, limiting statistical power. HL tumors not retrievable for EBV testing were more likely to be from cases that were non-white, male, and from southern California [16], potentially resulting in selection bias. However, for 704 Hispanic cases in that study, birthplace distributions (US, foreign, unknown) did not differ significantly between those with and without available specimens (data not shown). Fourth, estimated nativity via imputation could underestimate rates for the foreign-born to the extent that they were undocumented, and thus be counted in the cancer registry but not in the census. Fifth, registry-recorded Hispanic ethnicity is subject to some misclassification [32] and may undercount Hispanics, enhancing ethnic rate differentials [24].

Our study also has several notable strengths. First, the case series is both large enough for evaluating HL rates simultaneously by age group, sex, and histologic subtype and for allowing evaluation of the joint effects of race and nativity on HL by tumor cell EBV status [16]. Second, as cancer registry cases without recorded birthplace are younger, better educated, and more likely to be US-born [29–34], our imputation of nativity where missing, rather than exclusion or proportional assignment of such cases, eliminates underestimation of rates in US-born Hispanics and subsequent attenuation of nativity comparisons [11]. Third, use of population-based cancer registry and census data for a relatively ethnically homogeneous population of Hispanics assures more precise study findings, given genetic admixture among Hispanics [27, 28] and enhances representativeness and generalizability of study findings. Fourth, by calculating rates with annual nativity-specific denominators based on statistical modeling, we avoided the likely biases associated with applying single-year census estimates to a longer time period.