Epidemiological evidence for the role of falciparum malaria in the pathogenesis of Burkitt's lymphoma.

Nearly all epidemiological characteristics of Burkitt's lymphoma (BL) can be explained on the basis of relationships of BL to the intensity of the host response to Plasmodium falciparum. The major epidemiological associations are: the high degree of geographic correlation between the incidence rate of BL and the intensity of P. falciparum transmission, both at a global level and within individual countries; the close correlation between the age incidence of BL and the age of acquiring maximum levels of antimalarial immunoglobulin; the relative protection from BL by residence in urban areas, where levels of malaria transmission are lower, compared with rural areas; the decline in BL incidence in areas where death rates due to malaria have declined and, within such areas, a differential decline in BL incidence in people making better use of health facilities; the older age of onset in patients who have migrated from low-intensity to high-intensity malaria areas as compared with patients born in the high-intensity areas - the higher absolute age-specific incidence rate in those above age ten in this immigrant group being consistent with the hypothesis that intense malaria infection and consequent host defence response serve as the major triggering event in the pathogenesis of the lymphoma; the inverse geographic correlation between the average age of onset of BL and the intensity of falciparum malaria infection. An inverse association of BL with sickle-cell trait (AS haemoglobin) would provide strong evidence for the role of intense falciparum malaria, but most studies to date have not achieved statistical significance. Time-space clustering and reports of seasonal variation in BL incidence would indicate that a precipitating factor operates over a relatively short time-span, at least in some areas. Combining the evidence concerning cytogenetics, Epstein-Barr virus (EBV) and falciparum malaria, the following three-phase model for the oncogenesis of BL could account for virtually all the currently known facts and be tested by further laboratory and field studies: Primary infection with EBV, perhaps early and intense, leads to the immortalization of large numbers of B lymphocytes. Severe falciparum malaria then leads to an intense host response with particular proliferation of the EBV-infected B lymphocytes. Finally, the great increase in the B lymphocytes provides a much higher statistical opportunity for the emergence of the cytogenetically abnormal BL cell.