Burkitt lymphoma

Burkitt lymphoma can be divided into three main clinical variants: the endemic, the sporadic, and the immunodeficiency-associated variants. By morphology (i.e., microscopic appearance), immunophenotype, and genetics, the variants of Burkitt lymphoma are alike. Epstein–Barr virus (EBV) infection is found in nearly all patients. The endemic variant of Burkitt lymphoma is in almost all cases associated with EBV infection. The fact that some Burkitt lymphoma cases do not involve EBV allows that many cases of the disease are not caused and/or promoted by EBV, i.e. the virus may be an innocent passenger virus in these cases. However, the almost ubiquitous presence of the virus in the endemic variant of Burkitt lymphoma suggests that it contributes to the development and/or progression of this variant. The mutational landscape in Burkitt lymphoma has recently been found to differ between tumors with and without EBV infection, further strengthening the role of the virus in disease origin. ==Pathophysiology==

Genetics Almost all cases of Burkitt lymphoma are characterized by dysregulation of the c-myc gene by one of three chromosomal translocations which place the myc gene under the control of an immunoglobulin gene enhancer. The MYC gene is found at 8q24. • The most common variant is t(8;14)(q24;q32), which accounts for about 70 to 80% of cases of cases. This involves c-myc oncogene translocation from chromosome 8 to the Ig heavy chain region of chromosome 14. A variant of this, a three-way translocation, t(8;14;18), has also been identified. • Another variant is t(2;8)(p12;q24). This involves the myc oncogene being translocated from chromosome 8 to the Ig kappa locus on chromosome 2. This type of translocation is seen in 15% of cases of Burkitt lymphoma. • A rare variant is t(8;22)(q24;q11). Early in the pathogenesis process, DDX3X mutations limit translation (protein synthesis) allowing lymphoma cells to escape MYC induced proteotoxic stress and apoptosis, then later, DDX3Y mutations restore high level protein synthesis (by producing the translational machinery) and leading to increased proliferation of tumor cells. Due to their ability to bind complementary mRNA sequences and thereby prevent gene expression, BART miRNAs assist EBV-infected cells in avoiding detection by the immune system. BART miRNAs thus contribute to EBV-infected cell survival and proliferation. Malaria has been found to cause genomic instability in endemic Burkitt lymphoma. Malaria can lead to the reactivation of latent EBV and also MYC translocations via activation of the toll-like receptor 9. ==Diagnosis==

Malignant B cell characteristics Normal B cells of a germinal center possess rearranged immunoglobulin heavy and light chain genes, and each isolated B cell possesses a unique IgH gene rearrangement. Since Burkitt lymphoma and other B-cell lymphomas are a clonal proliferative process, all tumor cells from one patient are supposed to possess identical IgH genes. When the DNA of tumor cells is analyzed using electrophoresis, a clonal band can be demonstrated, since identical IgH genes will move to the same position. On the contrary, when a normal or reactive lymph node is analyzed using the same technique, a smear rather than a distinct band will be seen. This technique is useful since sometimes benign reactive processes (e.g. infectious mononucleosis) and malignant lymphoma can be difficult to distinguish. Microscopy The tumor consists of sheets of a monotonous (i.e., similar in size and morphology) population of medium-sized lymphoid cells with high proliferative and apoptotic activity. The "starry sky" appearance seen under low power is due to scattered tingible body-laden macrophages (macrophages containing dead apoptotic tumor cells). The old descriptive term of "small non-cleaved cell" is misleading. The tumor cells are mostly medium in size (i.e., tumor nuclei size similar to that of histiocytes or endothelial cells). "Small non-cleaved cells" are compared to "large non-cleaved cells" of normal germinal center lymphocytes. Tumor cells possess small amounts of basophilic cytoplasm with three to four small nucleoli. The cellular outline usually appears squared off. Immunohistochemistry The tumor cells in Burkitt lymphoma generally strongly express markers of B cell differentiation (CD20, CD22, CD19), as well as CD10 and BCL6. The tumor cells are generally negative for BCL2 and TdT. The high mitotic activity of Burkitt lymphoma is confirmed by nearly 100% of the cells staining positive for Ki67. ==Treatment==

In general, the first line of treatment for Burkitt lymphoma is chemotherapy. A few of these regimens are: the GMALL-B-ALL/NHL2002 protocol, the modified Magrath regimen (R-CODOX-M/IVAC). COPADM, hyper-CVAD, and the Cancer and Leukemia Group B (CALGB) 8811 regimen; In older patients, treatment may be dose-adjusted EPOCH with rituximab. The effects of the chemotherapy, as with all cancers, depend on the time of diagnosis. With faster-growing cancers, such as Burkitt, the cancer actually responds faster than with slower-growing cancers. This rapid response to chemotherapy can be hazardous to the patient, as a phenomenon called "tumor lysis syndrome" could occur. Close monitoring of the patient and adequate hydration is essential during the process. Since Burkitt lymphoma has high propensity to spread to the central nervous system (lymphomatous meningitis), intrathecal chemotherapy with methotrexate and/or ARA-C and/or prednisolone is given along with systemic chemotherapy. Chemotherapy • cyclophosphamide • doxorubicin • vincristine • methotrexate • cytarabine • ifosfamide • etoposide • rituximab Other treatments for Burkitt lymphoma include immunotherapy, bone marrow transplants, stem cell transplant, surgery to remove the tumor, and radiotherapy. ==Prognosis==

Burkitt lymphoma is a very aggressive cancer, which can quickly metastasize and spread throughout the body if the cancer is not treated quickly. If the patient is left untreated, or if treatment is initiated too late, Burkitt lymphoma can be fatal. The overall cure rate for sporadic Burkitt lymphoma in developed countries is about 90%. Burkitt lymphoma is not common in adults, but has worse outcomes than in children. If treatment with an initial chemotherapy regimen of cyclophosphamide, vincristine, prednisolone, and/or other drugs fails to produce meaningful remission or regression, this usually indicates a more severe outcome. Furthermore, failed initial treatment and return of Burkitt lymphoma after a six-month stint of time serve as a poor prognostic indicator. The adequate utilization of therapeutic drugs during initial treatment limits additional treatment options following the return of the disease. Notably, in areas of the world where the initial treatment of Burkitt lymphoma is inadequate further treatment options may remain for cases when the disease returns. Laboratory studies such as lactate dehydrogenase (LDH), CD4 count, and other cytogenetic studies are also prognostic indicators. Unsatisfactory outcomes have been associated with an LDH that is found to be two times above the upper limit of normal. Specifically, there is a poor prognosis associated with a CD4 count that is decreased in the immunodeficiency-associated variant of Burkitt lymphoma. Genetic mutations extending beyond the previously described MYC translocation may also serve as negative prognostic indicators. Some notable genetic findings that may be associated with poor outcomes include: 13q deletion, 7q gain, ID3 and CCND3 double-hit mutations, and 18q21 CN-LOH mutations. The prognosis for Burkitt lymphoma can be better determined following staging utilizing imaging modalities such as positron emission tomography and computed tomography scans where tumor burden and invasion of the central nervous system have been found to indicate a poor prognosis. ==Epidemiology==

As a non-Hodgkin lymphoma (NHL), Burkitt lymphoma makes up 1-5% of cases, and it is more common in males than females with a 3–4 to 1 ratio. The endemic variant mainly impacts areas with an increased prevalence of malaria and EBV in Africa and Papua New Guinea. For children less than 18 years of age from equatorial Africa, the annual incidence of Burkitt lymphoma is 4–5/100,000. EBV is found in virtually all instances of endemic Burkitt lymphoma. ==Research==

Gene targets Unique genetic alterations promote cell survival in Burkitt lymphoma, distinct from other types of lymphoma. These TCF3 and ID3 gene mutations in Burkitt correspond to a cell survival pathway that may be found to be amenable to targeted therapy. ==References==