Our results suggest that sporadic childhood BL in the United States is characterized by early age onset (3–5 years) and by predominance in boys (79%) and in Whites (81%). BL incidence was highest among non-Hispanic Whites and Asians/Pacific Islanders, intermediate in Hispanic Whites, and lowest among Blacks, in agreement with findings from the American Burkitt Lymphoma Registry some 25 years ago [3
]. Incomplete case ascertainment, bias, and small sample size were limitations of that study, but they are unlikely to be important in the current study, which was based on high-quality, unbiased, population-based data from SEER cancer registries.
Our finding of higher risk of sporadic BL among non-Hispanic Whites than Hispanic Whites or Blacks is in accord with earlier studies [3
], but is unexplained. Similar racial patterns have been reported for most lymphoid malignancies, including non-BL NHL subtypes, pediatric Hodgkin lymphoma, and acute lymphocytic leukemia (ALL) [2
],, suggesting they are due to shared risk factors among lymphoid malignancies, such as socioeconomic status, which has been positively associated with ALL in some[19
] but not all studies[21
]. Socioeconomic status is postulated to modulate the risk for lymphoid malignancy by influencing the age of exposure to common childhood infections, including EBV [22
]. Specifically, early age at exposure, such as occurs in socially disadvantaged children, is thought to modulate early immune function, which is considered protective for lymphoid malignancy. Conversely, later age exposure to infections, as may occur in socially advantaged groups[23
], is thought to result in delayed or anomalous immune maturation leads and aberrant immune responses to infections, and is considered a risk factor for lymphoid malignancy. Because children in socially disadvantaged minorities are exposed to and infected by EBV at a younger age than in socially advantaged Whites[22
], the reduced risk for sporadic BL among Blacks and Hispanic-Whites may reflect protective effects of early EBV infection. Our finding of rapidly accelerating BL incidence among very young children, most of them White, challenges the notion, based mostly on studies conducted among African children [6
], that early childhood EBV infection is a risk factor for childhood BL.
The incidence rate of sporadic childhood BL in the United States was 10-fold lower than the incidence of endemic BL that we recently reported in northern Uganda (2.5 vs 25 cases per million)[24
]. Nonetheless, we noted some similarities in the age and clinical presentation patterns of U.S. and Ugandan BL [24
]. In both, the risk peaked rapidly in mid-childhood and then declined, albeit more gradually in sporadic BL. This pattern suggests a fundamental similarity in the acute increase in BL risk in relation to diverse age-specific exposure to cofactors, whose effects wane as children mature. In Africa, EBV and malaria are considered the likely co-factors [25
], but they are not relevant in sporadic BL in the United States, where children with sporadic BL often have not been exposed to EBV, and malaria is not even a theoretical possibility. In both sporadic and endemic BL, face and/or head presentations of BL were especially frequent in males than females. Our finding of male predominance of BL mirrors the reported general pattern of male predominance for lymphoid malignancies and other, but not all, cancers [16
]. The basis for male predominance is unclear, but it prompted us to wonder whether genes on sex chromosomes that modulate developmental milestones [26
] contribute. Some of us have previously speculated[24
] that, possibly, earlier age at and/or faster rate of deciduous teeth, a developmental stage controlled by genes on the Y-chromosome [26
], could explain the male preponderance of face or head BL in Uganda[24
Some contrasts were evident. Sporadic BL arose more often in lymph nodes and bone marrow (leukemic BL), but these sites are rarely involved in endemic BL [24
]. Misclassification of site is possible, but probably would not differ by gender. Thus, anatomic sites involved in BL probably suggest clues about portals of exposure to potential causal infectious agents. While BL is easily identified by histological appearance [27
] and BL leukemia would be readily identified by a routine blood examination, diagnostic misclassification of BL and diffuse large B cell lymphoma is also a concern [28
], but it would be random and would not cause the patterns we observed.
A major strength of our study is our use of population-based, geographically, racially and ethnically diverse high-quality cancer registry data. However, the limitations include possible distortion of incidence rates by the HIV/AIDS epidemic [29
]. Children with HIV/AIDS experience a dramatically elevated risk for BL (some 650-fold increase compared to the incidence in the general population) in the two year-period from AIDS-diagnosis[29
]. However, this result was based on 9 cases linked to 4954 children with AIDS diagnosed from 1978–1996. The absolute contribution of AIDS-BL to sporadic BL is likely small, consistent with the relatively small size of the pediatric AIDS epidemic in the United States [30
]. In support, only 2 (2%) of 97 BL cases diagnosed in Connecticut and Los Angeles cancer registries during 1993 through 2005 were linked to a child with AIDS in the U.S. HIV/AIDS Cancer Match study (unpublished data). Our finding that childhood BL incidence was stable over 14 years and across registries agrees with findings by others that long-term NHL rates in similarly aged children have been stable [31
], and contrasts with the dramatic increase of NHL by calendar-year and in certain registry regions among middle-aged males in the U.S. during the AIDS era [32
]. The higher incidence of sporadic BL in White children mirrors findings from earlier studies [3
] and the general pattern observed in other lymphoid malignancies [2
], and is unlikely to be due to the AIDS epidemic because the majority of children with AIDS in this period were Black[29
]. We lacked access to blood or tumor tissue samples from the children diagnosed with BL and thus could not examine HIV serology, EBV serology, or EBV tumor status. However, such studies, done by race, gender, age and tumor location, might lead to insights as to the role of EBV and HIV in sporadic BL.
To summarize, we have updated the descriptive epidemiology of sporadic childhood BL in the United States, last studied more than 25 years ago. Sporadic BL predominated among males and among non-Hispanic Whites in U.S. children, suggesting that male sex and factors correlated with race may be risk factors for sporadic BL.