Burkitt lymphoma (BL) is defined in the WHO classification as a highly aggressive lymphoma, often extranodal, composed of monomorphic, medium-sized B cells with basophilic cytoplasm and numerous mitotic figures (1). Chromosomal translocations involving myc (previously known as c-myc) are virtually always present, and Epstein-Barr virus (EBV) is present in a subset of cases. The percentage of EBV+ neoplasms shows geographic variation.

Undifferentiated, Burkitt’s type (Rappaport classification); small noncleaved cell lymphoma, Burkitt type (Working Formulation); acute lymphoblastic leukemia, L3 type (French-American-British classification).

In earlier classifications, a group of tumors was recognized that had histologic features somewhat similar to BL and yet were not classic. These tumors were designated as small noncleaved cell, non-Burkitt type in the Working Formulation and, provisionally, as high-grade B-cell lymphoma Burkitt-like in the Revised European American Lymphoma (REAL) classification. It was recognized that this group was heterogeneous and probably included some cases of true BL as well as cases of DLBCL with high-grade features.

In the WHO classification, the term atypical Burkitt lymphoma/Burkitt-like is used for highly aggressive lymphomas that have immunophenotypic and genetic features that meet the criteria for BL and yet have atypical histologic features (1). In particular, myc translocation or “presumptive evidence” of myc translocation is required to establish the diagnosis of atypical BL (1). The remaining tumors that used to be designated as Burkitt-like lymphoma or small noncleaved cell, non-Burkitt type in the REAL classification or Working Formulation, respectively, are now classified as either high-grade B-cell lymphoma unclassified or as diffuse large B-cell lymphoma (DLBCL).

Three types of BL are histologically identical but differ in epidemiologic, geographic, and molecular findings. These types are referred to as endemic, sporadic, and immunodeficiency-associated.

Chromosomal translocations involving myc are the key molecular event involved in the pathogenesis of all types of BL (1,11). The most common translocation, occurring in 80% of cases, is the t(8;14)(q24;q32) in which myc is translocated to the derivative chromosome 14. In the so-called variant translocations, either the t(2;8)(p12;q24) or the t(8;22)(q24;q11), the κ or λ light chain gene is translocated to the derivative chromosome 8. Immunoglobulin (Ig) enhancer elements upregulate myc transcription, and MYC protein is involved in many cell processes including cell cycle progression, apoptosis, growth, differentiation, metabolism, and adhesion.

Other cofactors are involved in the pathogenesis of BL and these differ according to the type. Virtually all cases of eBL occur in childhood and are associated with EBV infection, which most Africans in the lymphoma belt are exposed to at a very early age. In Uganda, where the prevalence of eBL is very high, most children have high titers of antibodies to EBV by their first birthday (11). This, of course, is circumstantial evidence. More direct evidence for an etiologic relationship between EBV and BL is provided by the detection of virus within the tumor cells in most cases and the ability of EBV to transform human B lymphocytes in vitro (12). In addition, EBV injected into marmosets produces an undifferentiated lymphoma resembling BL (13). As mentioned earlier, the geographic distribution of patients with eBL suggests that malarial infection is involved in pathogenesis. Children with malaria have up to a 100 times greater risk of developing eBL compared with children not infected by malaria.

Klein was one of the first to propose a multistep pathogenesis for eBL (14). Epstein-Barr virus infection is suggested as the initial step, immortalizing B cells and inducing some degree of immune tolerance. Malarial infection is the next step, serving as a potentiator by stimulating expansion of B cells and thereby increasing the number of cells at risk for a genetic event. Malarial infection also might suppress T cells involved in controlling EBV infection. Eventually, a chromosomal translocation involving myc occurs, giving the affected cell a dramatic growth advantage and leading to the development of eBL.

Although malaria and EBV are clearly involved in pathogenesis, these cofactors do not explain the occasional clustering of cases eBL, or the time intervals when the frequency of eBL increases in epidemic fashion (3). Arbovirus infection has been suggested as another possible cofactor. Arboviruses are RNA viruses transmitted by insect vectors, and some of these viruses have been shown to have oncogenic properties. Arbovirus epidemics occur periodically, every 3 to 20 years, and could therefore explain clustering of eBL cases in certain geographic regions or time periods. Mosquitos carry arboviruses, as they carry malaria, and attempts at reducing eBL by reducing malarial infection would also reduce arbovirus infection as well. Van den Bosch (3) also has suggested that ingestion of a plant, Euphorbia tirucalli, which is a household herbal remedy, may also be involved in the pathogenesis of eBL. This plant has been shown to grow near the homes of patients with eBL more frequently than those of persons without this neoplasm (3,15). E. tirucalli contains a substance similar to a tumor promoter, TPA (12–0–tetradecanoylphorbol-13–acetate), that can promote EBV infection and induce chromosomal translocations in B cells (3,15).

The cofactors involved in the pathogenesis of sBL and immunodeficiency-associated BL are less well understood. Epstein-Barr virus is detected in the neoplastic cells of approximately 15% to 20% of sBL and 25% to 40% of immunodeficiency-associated BL (1). In the latter group, HIV infection may serve as a potentiator (similar to the role of malarial infection in eBL). In addition, T-cell suppression in immunodeficient patients is likely to be involved in the pathogenesis of immunodeficiency-associated BL.

Endemic BL affects predominantly children in equatorial Africa and Papua, New Guinea. These children are best known for presenting with tumors involving the jaw or other facial bones, in approximately 50% to 60% of patients, but they also can present with tumors involving the breast and abdomen (1,4,11,16). Abdominal presentations include tumors involving the gastrointestinal tract, kidneys, ovaries, and retroperitoneal or extradural tumors that can compress the spinal cord and cause paraplegia (1,4,11,16). The bone marrow is involved in less than 10% of patients (16). Peripheral lymph nodes, mediastinum, and spleen are rare primary sites of involvement by eBL (1,16).

In contrast, the abdomen is the most common anatomic location of disease in patients with sBL (1,17,18). The gastrointestinal tract (Fig. 69.1), liver, kidneys, and retroperitoneum can be involved, and disease is often bulky. Patients often present with abdominal pain, nausea, vomiting, gastrointestinal bleeding or obstruction, or symptoms mimicking acute appendicitis (17). Patients can present with spinal cord compression. The jaw or other facial bones can be involved in patients with sBL, in approximately 25% of patients (Fig. 69.2). Peripheral lymph nodes also can be involved, usually cervical and more commonly in adults than children. Lymphadenopathy is often localized to one area; generalized lymphadenopathy is very rare. The bone marrow is involved in approximately one-third of patients, and the central nervous system is involved in approximately 15% of patients (17).

A subset of patients with sBL can present in leukemic phase. These patients have extensive involvement of the bone marrow and involvement of peripheral blood. These neoplasms were designated as acute lymphoblastic leukemia, L3 type, by the French-American-British group (19), but it is now recognized
that these neoplasms are the leukemic equivalent of BL and they are designated as such in the WHO classification (1). Many patients who present with leukemic involvement also have bulky abdominal disease shown by radiologic imaging studies.

The clinical presentation of patients with immunodeficiency-associated BL is dominated by the cause of immunosuppression, whether it be secondary to HIV infection, congenital immunodeficiency, or acquired immunodeficiency most often secondary to organ transplantation. Nodal and bone marrow involvement are relatively more common in the immunodeficiency setting relative to eBL and sBL (1). Central nervous system involvement by BL is more common in AIDS patients (20).

Burkitt lymphoma of all types is a rapidly growing tumor with a very high growth fraction. The doubling time is very short, approximately 25 hours. As a result, patients with BL have rapidly growing disease that can quickly become bulky. Serum lactate dehydrogenase (LDH), β-2–microglobulin, and uric acid levels can be high (5). Burkitt lymphoma cells, in part because of their doubling time, are very sensitive to cytotoxic chemotherapy, and the rapid release of intracellular contents following cell death can result in tumor lysis syndrome (17).

In the absence of treatment, the prognosis of patients with BL is very poor. However, the prognosis of patients with BL is good with therapy, and this has been shown most clearly for patients in nations with high-quality health care. The overall therapeutic approach also has changed over the years, from aggressive surgical resection with relatively less intensive chemotherapy to conservative surgery or biopsy with intensive chemotherapy regimens (17,21). High-dose, short-duration chemotherapy regimens have evolved to minimize the risk of chemotherapy resistance in patients with BL because the neoplasm has such a fast doubling time. Any delays between chemotherapy cycles allow residual viable cells to quickly re-enter the cell cycle and potentially mutate and acquire resistance. As discussed by Blum and colleagues (17), a number of chemotherapy regimens have been employed for the treatment of patients with BL. In general, children have a better prognosis than adults. For children, most patients respond to therapy and overall 2–year disease-free survival rates ranging from 75% to 89% have been reported (17). In adults, 47% to 86% of patients go into clinical remission, with lower 2–year disease-free survival rates (17). Patients with localized BL have better responses to therapy. The treatment of patients with immunodeficiency-associated BL is complicated by the compromised immune status of these patients. However, patients with AIDS-associated BL have been successfully treated with high-dose chemotherapy in the era of HAART therapy. Modifications of chemotherapy doses are often required, and antibiotic therapy and transfusion support are necessary (22,23).