History and Clinical Features of Burkitt Lymphoma

In 1958, Dr. Denis P. Burkitt reported on a series of 32 children presenting with large malignant tumors of the jaw at Mulago Hospital in Uganda and six other district hospitals. The syndrome was notable for starting in the mandible and often spreading to other jaw quadrants, as well as to the adrenals, kidneys, and liver. No involvement of spleen or lymph nodes was detected in these initial 38 patients. Of note, in that initial report, the histopathology was described as “strongly resembling lymphocytes... [and] in some cases the tumor [resembled] a lymphosarcoma.” Definitive classification of this as a lymphoma would await O’Conor and Davies’ description of these and other cases in 1960. Of interest, the peculiar distribution of this tumor in the malaria belt of Africa was noted at the outset, with a few cases being reported in North or South Africa, and the bulk of cases coming from tropical areas. To better delineate the regions of endemic tumor, Burkitt and two companions, Drs. Ted Williams and Cliff Nelson, traveled 10,000 miles through ten countries in order to map the tumor endemic areas of Africa. They also took this opportunity to measure the extent of other diseases in different areas. The end result of this “geographical biopsy” was a map that showed tumor prevalence only in areas with mean temperatures consistently over 15°C and rainfall over 20 in. per annum. This map very accurately predicted the areas of endemic “Burkitt lymphoma” (BL), as well as intense endemic malaria. This extensive epidemiologic work linking malaria and BL was confirmed in more detailed examinations of differentially affected areas of Africa, as well as comparing malariaprotected sickle-cell trait children with controls, and in mouse studies of lymphomagenesis. Since Burkitt’s original description in 1958, BL has been described outside of the malaria belt of Africa. Interestingly, there are notable clinicopathologic differences between African (or endemic) BL and the sporadic BL described in the developed world. Sporadic Burkitt lymphoma represents approximately 1–2% of lymphomas in Western Europe and the USA, although in pediatrics it represents 40% of all lymphomas. Sporadic BL typically involves lymphoid tissue in the terminal third of the ileum or Waldeyer’s ring. Although massive abdominal involvement is not rare in sporadic BL, jaw involvement is distinctly rare. Furthermore, advanced cases of the sporadic type present with bone marrow involvement or circulating lymphoma cells. Previously, these were diagnosed as mature B cell acute lymphoblastic leukemia (ALL) or L3-morphology ALL. The FAB classification of L3 ALL is now considered leukemic presentation of BL in the most recent WHO classification. More recently, a third clinical subset of BL has been described in patients with immunodeficiency and is most commonly seen in patients with HIV infection. Immunodeficiency-associated BL is interesting in that unlike other HIV-associated B cell lymphomas it typically occurs in patients with CD4 counts greater than 200 cells per microliter. In fact, because HIV symptoms are often absent at this CD4 count, lymphoma can be the AIDS-defining criterion. Compared to other HIV-associated B cell lymphomas, BL patients are typically younger with higher CD4 counts and with a shorter history of HIV infection. Induction of HAART therapy augments chemotherapy in these cases. Solid organ transplant patients are another population of patients with immunodeficiency-associated BL. These patients typically present with BL four to 5 years after organ transplantation. Again, restoration of immune function by relieving immunosuppression may augment response to therapy. Stem cell transplant patients are less likely to present with immunodeficiency-associated BL, likely reflecting their lower levels of immunosuppression. Immunodeficiency-associated BL is the subtype to most commonly involve lymph nodes. Of interest, these three clinical subtypes – endemic, sporadic and immunodeficiency-associated – all have similar histologic, immunophenotypic, and molecular presentations, although there are unique features to each. 23 The Molecular Pathology of Burkitt Lymphoma