Burkitt's Lymphoma - a Clinical Perspective

Burkitt's lymphoma (BL) was first recognized in Africa as a tumor of the jaw occurring in high frequency in children. Although it is believed that BL has existed in Africa for thousands of years, the earliest documentation of this tumor can only be traced to the beginning of the twentieth century when its unusual and prominent features were observed and recorded by European missionary doctors. Hospital records from the first missionary hospital in Uganda dating from 1897 to 1956 revealed a high frequency of tumors of the jaw and orbit in children seen there in this period, and analysis of these records suggest strongly that over 50% of the cases of childhood cancer were what we would now call BL - a figure very similar to more recent estimates of the incidence of BL in Uganda.

During the 1950s and '60s, in-depth clinical and pathological descriptions of the features of this tumor were made by Denis Burkitt, Greg O'Conor, Dennis Wright (the author of the accompanying article on page 10) and others. Another of the many contributions made by Burkitt and his colleagues (see also Professor Wright's article) was to delineate the geographical distribution of this tumor in Africa. The findings of their survey suggested that this disease had a high incidence in an area that is approximately 15 degrees north and south of the equator with a prolongation southward in the eastern side of the African continent. This was shown to be a consequence of climatic factors and led to the hypothesis, likely, but still unproven, that malaria predisposes to Burkitt's lymphoma. It also led to the discovery of Epstein Barr virus, based on an earlier and subsequently disproved hypothesis that the disease might be caused by a virus vectored by a mosquito.

Shortly after the descriptions of the African lymphoma were published, pathologists recognized that some childhood lymphomas occurring in the US and Europe at low incidence ("sporadically") were histologically identical to African BL, whose incidence was considered high enough for the disease to be referred to as "endemic." In equatorial African countries, the average annual incidence is four to ten per 100,000 children under the age of 16 years whereas in western countries it accounts for a few percent all childhood cancers and has an annual incidence rate of 0.2 per 100,000.

The clinical distribution of disease, and differences in the frequency of involvement of various sites in different world regions, as well as in HIV-associated BL (particularly with respect to jaw involvement) is described in the accompanying article. Clinical staging is based on the extent of disease, and total tumor volume appears to be a major determinant of prognosis. Patients with central nervous system (CNS) involvement tend to have the worst prognosis in patients outside Africa, where CNS disease is usually associated with extensive disease elsewhere, particularly in the bone marrow. In Africa, however, CNS disease is often isolated, or associated with minimal disease elsewhere, and bone marrow involvement is uncommon (less than 10% of patients, even after relapse).

Many lessons have been learned from the study of African BL, one of the most important being that it was one of the first tumors shown to be curable by chemotherapy alone. The investigation of the efficacy of recently developed chemotherapy agents in the treatment of this disease was a logical approach in the 1960s since traditional approaches to cancer management - radiotherapy and surgery - were not feasible. Radiotherapy was, by and large, not available in Africa, and complete surgical resection of tumor masses, particularly those in the facial region, or large masses in the abdomen, was not possible. Furthermore, rapid recurrence usually occurred in patients who underwent surgical resection of localized disease.

A number of drugs were shown to be active in the treatment of BL, most notably cyclophosphamide (CTX), vincristine (VCR) and methotrexate (MTX). Chemotherapy with CTX alone, even one or two doses, resulted in some cures. However, combination chemotherapy regimens using CTX, VCR and MTX (COM), coupled with intrathecal chemoprophylaxis with MTX, appeared to improve the overall survival rates. Results achieved in studies conducted during the 1970s resulted in the cure of 40 to 50% of patients. The treatment regimens used were not expensive, were relatively simple to administer, and toxicities were manageable in the African setting. Since then, attempts have been made to improve upon the results achieved by employing more complex treatment regimens, for example, based on the French LMB regimens. Although effective, these regimens are more toxic and expensive, and for these reasons cyclophosphamide alone or simple COM or COM-like regimens are still widely used for the treatment of African BL, although there is rather limited documentation of results obtained.

The observation that there was no difference between the histological appearance of African Burkitt's lymphoma and BL observed in the USA and Europe led investigators in the USA to employ the same treatment regimens used in Africa for American patients. From early studies conducted by John Ziegler and colleagues in the USA, it appeared that there was no difference in response or survival rates compared to those achieved in African patients, and a clinical trial conducted by the Children's Cancer Study Group using a "COMP" regimen lasting 18 months, which included prednisone and local radiation, resulted in a survival rate of approximately 50%. Since this time, considerable progress has been made in the treatment of Burkitt's lymphoma in the industrialized nations. The development of newer short duration, more intensive combination chemotherapy regimens along with considerable improvements in supportive care, have made this disease curable in 90% of patients. Unfortunately, current treatment results for children with African BL continue to remain the same as those achieved in the 1970s.

In summary, much was learned and continues to be learned from African BL. This knowledge has resulted in benefits not only to the medical and scientific community, but also to many cancer survivors. It is an important goal of the INCTR to develop strategies to improve the outcome of children with African BL. The INCTR would be pleased to hear from investigators in Africa interesting in participating in studies of BL.

—submitted by Melissa Adde , INCTR