A role for environmental exposures in cancer etiology can be inferred from changes in cancer incidence after migration from low- to high-risk areas. In a large population-based series of US Asians with lymphoid malignancies, we found that rates were substantially lower in foreign-born than US-born patients for certain lymphoma subtypes, specifically CLL/SLL, FL, and NS HL. Rates of CLL/SLL and NS HL were also significantly lower among Asian women living in ethnic enclaves or lower-SES neighborhoods, compared with rates of Asian women living in lower-enclave or higher-SES neighborhoods, respectively. For HL, the risks associated with higher-SES and lower-enclave neighborhoods were stronger in females than in males. For MM, incidence rates did not differ according to birthplace, ethnic enclave status, or neighborhood SES. We also confirmed that the incidence rates of most subtypes were substantially lower than rates in non-Hispanic white populations; for TCL and DLBCL—the two subtypes for which absolute incidence rates were most similar between Asians and non-Hispanic whites—we did not observe consistent differences in incidence according to birthplace or neighborhood characteristics.
There is little published information regarding the incidence patterns of lymphoid malignancy subtypes among Asians according to detailed ethnicity and birthplace. Our recent analysis based on SEER data documented lower incidence of lymphoid malignancies among six Asian ethnic groups compared with whites(2
), but lacked the data to consider differences by birthplace. In SEER data, an assessment of NHL cases diagnosed in the period 1973–86 and classified according to the Working Formulation scheme also found reduced risk of FL in foreign-born compared with US-born Chinese and Japanese (but not Filipinos), with incidence rates 60–80% lower than rates in their US-born counterparts(22
). However, in that analysis, the authors assumed that the SEER cases without birthplace information had randomly missing data. As we have shown that those with missing data are more likely to be US-born(5
), this earlier analysis may have underestimated rate differences by birthplace, which may explain the difference in findings for CLL/SLL and HL. To our knowledge, ours is the first study to address lymphoid malignancy incidence patterns among US Asians according to neighborhood characteristics, although we did report previously that rates of young-adult HL were lower among Asian women (but not men) living in the lowest terciles of neighborhood SES in California(23
). Our findings of lowered rates of CLL/SLL and NS HL among Asian women living in impoverished or ethnic enclave communities as compared to more affluent and presumably more acculturated communities further support the notion that the causation of these particular lymphoid malignancy subtypes involves environmental exposures more common in westernized environments.
Differences in cancer incidence rates between Asians who immigrate to the US (and their descendents) and those who remain in Asia have long been considered strong evidence of environmental influences on carcinogenesis, although it is possible that there are also genetic differences among persons who are healthy enough to emigrate. For breast cancer, incidence rates among Chinese and Filipina women born in the US are nearly twice those of women living in Asia, and these differences are increasingly thought to relate to reproductive and dietary changes associated with westernized lifestyle(7
). For NS HL, exposures of interest include correlates of the childhood social environment(25
) (e.g., family size, household crowding) and measures of microbial burden or other immunologically relevant environmental exposures (e.g., age at diagnosis with mononucleosis)(26
), particularly in early life (21
). Childhood environment has not been consistently associated with risk of FL or CLL/SLL(34
), although a recent pooled analysis including over 13,500 NHL cases did report for FL significantly positive associations with both birth order and sibship size(36
). However, risk of both FL and CLL/SLL has been inversely associated with atopic disease(37
), which could be associated in turn with early-life microbial exposures. It is uncertain if chronic infection with hepatitis viruses, linked to doubled risks of NHL(38
) and endemic in Asia(40
), are relevant to the observed rate patterns. Although US-born Asians have lower rates of chronic infection with hepatitis B and C viruses than their foreign-born counterparts in the US and Asia(40
), the associations of viral hepatitis with risk of specific NHL subtypes (e.g., DLBCL) do not correspond the observed incidence rate differences by birthplace in our study(43
The stronger effects of birthplace and neighborhood characteristics for CLL/SLL and HL observed in females than males could, in part, reflect socially determined differences in exposure opportunities (such as those involving children) and biologically determined differences in immune response to exposures(23
). For HL, the gender difference in the effect of nativity may result from protection in low-acculturation women afforded by both early exposure to infection and higher parity or lactation, as hormonal exposures through pregnancy and breast-feeding may interact with childhood exposures to affect risk of HL(44
For HL, the varying impact of birthplace by age group is consistent with prior evidence of differing pathogenesis of HL by age (21
). It also is relevant to the differential effect of birthplace on incidence of the NS and MC subtypes, given that young adult HL is predominantly of the NS subtype. Further, subtype differences in birthplace associations may reflect etiologic differences in immune control and age at infection of Epstein-Barr virus (EBV), as EBV is more commonly found in tumors of the MC than NS type (45
) and of Asians than whites (47
Dietary patterns and energy balance/obesity, which also vary by birthplace among US Asians (48
), may also be associated with risk of certain lymphoid malignancies (49
), and therefore represent important areas for future study in Asian immigrant populations. For MM, our observation of substantially lowered rates among Asians as compared to non-Hispanic whites, but no difference according to birthplace or neighborhood characteristics, suggests a more important role for genetic susceptibility and less of an influence of environmental exposures that change with acculturation. In support of this hypothesis, MM risk has been associated with polymorphisms in genes thought to influence innate immunity and immunoregulatory processes (53
By using over 16 years of SEER data from California, we were able to capitalize on the relatively large size of the Asian population in this state and to draw conclusions based on the representativeness of these high-quality, population-based data. We consider the ethnic and birthplace classifications used here to have low probabilities of misclassification or bias. Specific Asian ethnic group was classified directly from registry records or, for those without specific registry information on ethnicity, from applying a validated ethnicity classification algorithm. With this approach, a small proportion (<3%) of patients was excluded from these analyses because of missing ethnic classification. Furthermore, cancer registry classification of specific Asian ethnicity shows good agreement with self-reported information (55
). For cases for whom birthplace information was reported to the registry (the vast majority), we have also demonstrated that this classification shows excellent agreement in comparison with self-reported birthplace (4
); for the remaining cases, we applied a validated birthplace classification algorithm with good sensitivity and specificity.
Despite these important strengths, our results also may be subject to some limitations. First, we had limited statistical power to analyze certain subgroups, such as specific Asian ethnic groups and uncommon lymphoid malignancies. Second, the heterogeneity in the complex pathologic methods required to diagnose and classify lymphoma cases may have resulted in misclassification of some cases by subtype. Our prior comparisons of cancer registry ICD-O-3 classifications to those obtained from uniform re-review of pathologic specimens suggest a high degree of reliability for the diagnosis of overall NHL and HL(56
) and for particular subtype classifications including FL (89%), SLL (79%), DLBCL (90%), and NS HL (95%), but more moderate reliability for rarer subtypes(57
). In addition, cancer registry data lack detail regarding certain histopathologic characterizations (e.g., t(14;18) translocations for FL, and EBV tumor-cell status for HL), as well as information regarding parental race/ethnicity, individual-level education and other measures of SES, medical history, age at immigration, duration of immigration and other risk factors that could be relevant to our observed incidence rate differentials. Lastly, these data cannot speak to the independent or joint influence of genetic factors in modifying risk of FL and CLL/SLL across populations. Recent genomewide association studies found genetic variants that influence risk for FL(59
) and SLL/CLL(60
) and the absolute difference between rates in US-born Asians and whites does not rule out a role for genetic predisposition to FL and CLL/SLL. Regardless, our results suggest that environmental exposures have greater influence than genes on the variation in incidence rates by ethnicity and nativity.
The markedly lowered rates of lymphoid malignancies among Asians relative to other racial/ethnic groups in the US and among foreign-born Asians relative to US-born Asians have suggested some kind of protection from lymphomagenic processes, but it has been unclear whether this protection relates to genetic or environmental differences. Our data suggest a clear pattern of increased risk of FL, CLL/SLL and HL in Asians according to US birthplace and neighborhood acculturation indicators, and thereby point to a strong influence of environmental factors that change with immigration and acculturation to a westernized lifestyle. Future studies of FL, CLL/SLL and HL designed to collect a wide array of environmental exposure information (and implicated genetic variants of risk) are warranted among Asian immigrant populations in the US and other westernized countries, as they may identify heretofore unrecognized and modifiable causes of these malignancies.