What is Burkitt's lymphoma?

Risk Factors

The endemic Burkitt’s lymphoma type usually affects children aged five to ten. A suggested risk factor for the endemic form is chronic infection with malaria, or some other infectious agent carried by mosquitoes, combined with inadequate medical care and late diagnosis and treatment of the disease. Pediatric patients with sporadic Burkitt’s lymphoma are usually slightly older than those with the endemic form. According to the National Center for Biotechnology Information (2012), the incidence for adult diagnosis peaks at age forty and again at age seventy. Burkitt’s lymphoma is one of the most common types of lymphoma seen in AIDS patients. Risk factors for the sporadic or immunodeficiency-associated forms include lifestyle behaviors that increase the risk of HIV infection. As reported by Healthline (2012), all three Burkitt’s lymphoma types are more prevalent in males.

Symptoms

In sporadic cases in children, main symptoms of Burkitt’s lymphoma include abdominal pain and vomiting along with the occurrence of a large abdominal tumor accompanied by fluid (ascites) buildup. Jaw and other facial bones besides abdominal sites are most commonly involved in the endemic form. Other sites of tumor development include the central nervous system and breast. Symptoms may appear as soon as four to six weeks after the lymphoma begins. Lymphoma starting in the blood marrow might induce easy bleeding and anemia. It is essential to see a doctor as soon as symptoms occur because of the aggressive (fast-growing) nature of the tumor.

Screening and Diagnosis

The diagnosis of Burkitt’s lymphoma is usually made by a needle biopsy from a suspected disease site such as the jaw area, abdomen (ascites), bone marrow, or a lymph node. Microscopic analysis of cell morphology is used to determine if the disease is present and, if so, its stage of development. Early clinical and laboratory diagnosis spares the child any life-threatening complications from the rapid tumor growth. Other common diagnostic tests may include a complete blood count (CBC), a platelet count, and a lumbar puncture. Further tests may include specialized radiographic exams such as a computed tomography (CT) scan to look for hidden tumor masses, as well as a gallium scan. This scan requires injection of the radioactive isotope gallium, which concentrates in areas of rapid cell division and allows for visualization of tumor sites by nuclear scan techniques. Gene expression profiling is used to accurately distinguish between Burkitt’s lymphoma and diffuse large B-cell lymphoma, another type of B-cell tumor.

Etiology and Genetics

Burkitt’s lymphoma is a monoclonal proliferation of B-lymphocytes. The common cytogenetic hallmark of all types is the reciprocal translocation of the c-Myc proto-oncogene located on the long arm of chromosome 8 to one of the immunoglobulin (Ig) heavy- or light-chain loci on chromosomes 14 (heavy chain), 22 (lambda light chain), or 2 (kappa light chain).

Proto-oncogenes like c-Myc normally help control the cell cycle by regulating the number of cell divisions. They are especially active when high rates of cell division are needed, as in embryonic development, wound healing, or regeneration. The proto-oncogene might be transformed into a oncogenewhen the chromosomes break and reunite, resulting in a reciprocal translocation. The localization of the chromosomal breakpoints with respect to c-Myc vary between the different forms of Burkitt’s lymphoma, suggesting a different time point of the translocation event at different stages of B-cell development. In endemic cases the chromosomal recombination likely occurs during VDJ rearrangement in early B-cell differentiation, while in the sporadic form the translocation probably takes place during Ig class-switch events. The chromosomal rearrangement in certain translocation events results in deregulation and subsequent continuous overexpression of the c-Myc gene due to the new location that places the gene under control of genetic enhancer elements normally involved in Ig gene regulation. Abnormal activation of the basic helix-loop-helix-leucine zipper-transcription factor MYC leads to a multitude of events, including the regulation of a large number of genes involved in cell proliferation, differentiation, apoptosis, cell cycle control, and immune response. Abnormal activation of MYC is able to trigger most characteristics of Burkitt’s lymphoma cells; however, it is not sufficient by itself. In research reported in 2013 by the American Society of Hematology, associated with MYC activation in more than 40 percent of Burkitt’s lymphoma cases are mutations in TP53, a transcription factor involved in cell cycle arrest, DNA repair, and apoptosis and functioning as a tumor suppressor. The c-Myc gene also frequently accumulates mutations at mutational hotspots, which may lead to an increased transforming activity. Concurrent translocations of MYC and BCL2 were described in a small subset of cases, which were associated with an especially poor prognosis.

The occurrence of Burkitt’s lymphoma in patients from equatorial Africa seems to have a close correlation with the prevalence of EBV. As of 2009, about 95 percent of lymphomas from equatorial Africa carry the EBV genome. By contrast, only 10 to 20 percent of sporadic cases of Burkitt’s lymphoma in Europe and North America are positive for EBV, but 40 to 50 percent of HIV-infected individuals are. EBV has a single, linear, double-stranded DNA genome and was the first herpes virus to be completely sequenced. However, as reported by the National Center for Biotechnology Information (2011), EBV infection is not limited to areas where Burkitt’s lymphoma is found; it infects people worldwide with a prevalence in more than 90 percent of the world population, mostly without producing symptoms. EBV is also the causative agent of infectious mononucleosis, a common disease in which B cells are infected, and is also highly associated with nasopharyngeal carcinoma, a lymphoepithelial tumor with high prevalence in South China. In spite of extensive ongoing research, the contribution of EBV to Burkitt’s lymphoma tumor genesis remains an enigma. In one model, cells infected with EBV accumulate genetic and epigenetic changes, predisposing them to tolerate the consequences of c-Myc translocation events, even long after silencing of EBV gene expression.

The endemic Burkitt’s lymphoma form affects children in equatorial Africa and New Guinea, areas that are characterized by holoendemic malaria. Chronic infection with malaria is believed to impair immune resistance in general and specifically to EBV. The sporadic or non-African form has a similar cellular appearance as the endemic form and is also putatively related to impaired immunity, allowing for development of EBV. The immunodeficiency-associated Burkitt’s lymphoma variant is usually found in HIV-positive patients and can be the first tumor manifestation in AIDS. HIV infection, analogous to malaria, leads to polyclonal B-cell activation and allows poorly controlled proliferation of EBV+ B cells.

Treatment and Therapy

Burkitt’s lymphoma, like all types of non-Hodgkin’s lymphoma, are grouped in four stages according to the Cotswold Modification of the Ann Arbor staging system: stage I, a tumor in one lymph region only; stage II, lymphomas in at least two lymph regions on the same side of the diaphragm; stage III, lymphomas in lymph nodes and/or spleen, and on both sides of the diaphragm; stage IV, extranodal involvement (lung, liver, bone marrow). Non-Hodgkin’s lymphoma in children is most commonly staged according to the system of the St. Jude’s Children’s Research Hospital. Stages I and II are identical to those described for adult patients. Stage III in children is defined by the presence of a large chest or abdominal tumor, whereas in stage IV patients the central nervous system and bone marrow are also involved.

Due to the aggressive nature of the tumor, prompt diagnosis and initiation of appropriate therapy is mandatory. Large chest or abdominal tumors may be removed surgically before starting chemotherapy.

Pediatric Burkitt’s lymphoma patients are treated with chemotherapy and radiation therapy. Endemic Burkitt’s lymphoma is mostly treated with cyclophosphamide (Cytoxan), given either orally or intravenously. This drug acts by suppressing the immune system but also shows severe side effects. Tumors affecting the jaw and other facial bones are also treated with radiation therapy. Sporadic Burkitt’s lymphoma in children is treated with high-dose chemotherapy, usually a combination of cyclophosphamide, methotrexate (MTX), vincristine (Oncovine), prednisone (Medicorten), and doxorubicin (Adriamycin) for a short course. Radiation therapy of the head and spine may be used to prevent infiltration of the tumor into the central nervous system. In addition, intrathecal (direct injection into the patient’s spinal fluid) chemotherapy with the drug methorexate may be applied.

Adult patients with sporadic Burkitt’s lymphoma are treated with a combination of radiation therapy and a high-dose chemotherapy regimen called CODOX-M/IVAC, which seems to render good results. CODOX-M/IVAC is a combination of cyclophosphamide, methotrexate, vincristine, doxorubicin, ifosfamide (Ifex), etoposide (VePesid), and cytarabine (ARA-C).

Adult AIDS patients are treated with low-dose chemotherapy because their immune system is already strongly impaired. Response to treatment is better for non-HIV patients than for HIV-positive individuals.

Other methods of treatment have been applied including bone marrow or stem cell transplantation. Also, as reported by the European Society for Medical Oncology in the Annals of Oncology (2010), treatment with the drug rituximab (Rituxan), a monoclonal antibody, used in combination with standard chemotherapy, has shown promising results in clinical trials, indicating an improvement in the rates of remission and survival in high-risk patients.

Prevention and Outcomes

Prevention of the endemic form of Burkitt’s lymphoma is difficult as a result of the high incidence of malaria in central Africa, concurrent with inadequate medical care. Some risk factors for sporadic Burkitt’s lymphoma can be lowered by a change of lifestyle behaviors that increase the risk of HIV infection.

Because of the good response of Burkitt’s lymphoma to chemotherapy, the National Cancer Institute (2014) reports that the prognosis for children with the disease is generally good: 80 percent of children treated for early-stage Burkitt’s lymphoma remain free from returning tumors five years after treatment. The National Cancer Institute (2013) also reports that more than 90 percent of adult patients given treatment with low-intensity chemotherapy regimens have excellent long-term survival rates. Involvement of bone marrow and the central nervous system in tumor spread generally worsens the prognosis. According to the National Cancer Institute (2014), the survival rate for AIDS patients with Burkitt's lymphoma varies with several key factors including stage, age, and severity of the underlying immunodeficiency. . After chemotherapy, all patients should have regular follow-up examinations because of the possibility of long-term relapse.

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