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Etiology and Pathology

Burkitt's tumor can be distinguished histologically and cytologically from other forms of malignant lymphoma. Sections show an undifferentiated type of B-cell lymphoma. Immature cells 10-25 µm in diameter proliferate and have several prominent nucleoli within rounded nuclei. The cytoplasm has a high RNA content and stains deeply. The sheets of tumor cells are interspersed with large pale macrophages, providing the "starry-sky" appearance, which is typical of but not unique to Burkitt's tumor. The cause of this tumor has been hotly debated and its relationship to the Epstein-Barr virus is not clear. (The EB virus causes infectious mononucleosis.) It has been suggested that EBV is essential to the process of chromosomal translocation and the molecular changes in Burkitt's lymphoma have been extensively investigated. The tumor generates antibodies against EBV; raised anti-EBV titers have also been found in nasopharyngeal carcinoma and in Hodgkin's disease, as well as in Burkitt's lymphoma.

Four separate antigenic complexes have been found in cultures of Burkitt's tumor cells. These are:

1. The EBV capsid antigen

2. The EBV associated membrane antigen

3. The "early" EBV antigen

4. The soluble antigen which evokes precipitins

The capsid antigen is demonstrated by indirect immunofluorescence, as is the membrane antigen, the one on a fixed target cell and the other on living cells. Similar antibodies have been detected in monkeys in Africa, but not in the Americas; some herpes viruses have produced malignant lymphoma in monkeys.

There are at least two distinct variations of Burkitt's lymphoma: the "endemic African" and the "sporadic" non-African patterns. There are differences in the incidence, clinical characteristics and epidemiology, and although all varieties have similar chromosomal translocations, there are molecular differences. There is no doubt that the immunological status is significant. The EBV effect in Burkitt's lymphoma may be influenced by the patient's age at the time the EBV infection occurs: the younger the child the more likely the lymphoma will develop. Other infections may affect the predominant stage of immature B cell differentiation and it has been postulated that there is multi-step carcinogenesis. First, the EBV infects the B cells, causing proliferation: then malaria (or some other infection or toxin) causes further proliferation and, in this large pool of cells, there is then chromosomal translocation and a cancer-causing gene (c-myc) which results in cells with the capability of unlimited growth, the nucleus of the B cell lymphoma. Clearly, this is an oversimplified description of a very complex process, a sequence which is still controversial. It cannot, however, be the virus alone that causes the Burkitt tumor; the EBV occurs worldwide and there must be some other etiological factor associated with it in tropical areas. If there is an altered immunological background of the host, it is more subtle than in AIDS. The relationship with parasitic infections, such as stable Plasmodium falciparum malaria, is still debated. In patients with Burkitt's tumor, the frequency of the sickle-cell trait is less than would be expected. The sickle-cell trait is known to offer protection against heavy infections of P. falciparum malaria and this may explain why such patients are less likely to develop Burkitt's tumor. It can be shown experimentally in animals that there is a synergistic action between a potentially oncogenic virus and a plasmodium.

Also, malarial parasites have an immunosuppressive effect on mice, and these mice, after repeated infection with malaria (P. berghei), have developed a lymphoma resembling Burkitt's tumor.

The livers of children who live in areas of stable malaria show tremendous hypertrophy and phagocytosis of pigment by Kupffer cells. For all these reasons, it is tempting to suggest that malaria is in some way incriminated in the etiology of Burkitt's tumor in Africa and other malarial areas. The remarkable decrease in its incidence in New Guinea following the eradication of the malarial parasite, together with the late arrival and comparative absence of the tumor in Zanzibar while the island was free of malaria, lends credence to this theory, even if the exact mechanism is not yet understood.

But there is still more to the complex immunological story of Burkitt's tumor. Spontaneous remissions have been noted, and fulminating lymphomatous breast tumors developing during pregnancy have undergone spontaneous reversion after parturition. There is also a difference in the hypersensitivity reactions of Burkitt's lymphoma patients. When the disease is localized, the patient will probably have a delayed hypersensitivity reaction to autologous tumor extract, but when the disease is widespread before treatment there will be no such delayed reaction. However, if a positive hypersensitivity response is obtained following treatment, when the disease is clinically in remission, such patients may be cured. While the skin test is positive, relapse is unlikely; when a positive skin test does not develop during treatment, recurrence may be expected. Clearly there is a cell-mediated immunity which is of importance in the prognosis of this disease. Where such immunity is deficient, the outlook is poor. There is even histological correlation: the degree of lymphocytic infiltration around the tumor before and during treatment can be correlated with the prognosis.

The distribution of Burkitt's tumors in the body is unlike any of the more common malignant lymphomas in nontropical countries. Jaw tumors as the presenting site are more common in younger children, become less common in older children, and are rare over the age of 15 years and in adults. If there are deposits of tumor elsewhere in the body, however, then tumors in the jaw may occur also, even if at first not clinically obvious. Massive bilateral involvement of the ovaries is common, and tumors may develop in any of the other abdominal organs, especially the liver, spleen and kidneys. There may be Burkitt's lymphoma in the abdominal and mediastinal lymph nodes, but there is a remarkable rarity of superficial lymph node involvement. The cervical lymph nodes may be affected, but these are the only superficial lymph nodes in which Burkitt's lymphoma is common in patients in the tropics.

Any organ of the body can be affected, including the central nervous system. The lungs are probably the least frequently involved, although microscopic involvement is found more often than is recognized grossly.

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Copyright: Palmer and Reeder