Burkitt`s lymphoma C83.7; C91.8;

Denis Parsons Burkitt, British tropical physician and surgeon (1911-1993)

Burkitt's lymphoma (BL), is a highly malignant (aggressive) B-cell non-Hodgkin's lymphoma (NHL) with a very high proliferation rate (Crombie J et al 2021).

The staging of Burkitt's lymphoma (BL) is done according to the Ann Arbor classification. In children and adolescents, it is done using the modified St. Jude classification.

• Endemic Burkitt 's lymphoma: Endemic Burkitt's lymphoma occurs particularly in Africa, Brazil, and Papua New Guinea and usually manifests as a mandibular or facial tumor in childhood. It can spread to the ovaries, testes, kidneys, mamma, and especially bone marrow and meninges. Endemic African BL is 95% EBV-associated.
• Sporadic Burkitt's lymphoma: This occurs worldwide, especially in children and younger adults. It usually manifests abdominally (mainly ileocecal region) with possible involvement of kidneys, testes and/or ovaries. Spread to bone marrow and central nervous system (CNS) is also possible. Sporadic BL is associated with EBV in 20% of cases. See also under primary cutaneous Burkitt's lymphoma.
• Immunodeficiency-associated Burkitt's lymphoma: Burkitt's lymphoma associated with immunodeficiency (see also HIV-associated aggressive B-cell lymphoma) occurs, for example, in association with HIV infection. In most cases there is nodal involvement and bone marrow involvement. Diffuse skin infiltrates may occur (de Masson A et al. 2016).
• Burkitt's leukemia (L3-ALL): When there is extensive involvement of the bone marrow (>25% blasts), BL is called Burkitt's leukemia (L3-ALL). This is one of the acute lymphatic leukemias (ALL). It is a rare clinical picture (only approx. 3-5 % of all acute lymphatic leukaemias, i.e. less than 100 cases per year in the whole of Germany).

Burkitt's lymphoma affects 1-2% of adults with non-Hodgkin's lymphoma (NHL). In children, BL accounts for about 30% of NHL.

The causes of Burkitt's lymphoma are still largely unknown. A connection with viral infections (especially Epstein-Barr virus) and chromosomal damage can be assumed. Burkitt's lymphoma is associated with a translocation of MYC on chromosome 8 (gene location 8q24) in more than 95% of cases. Partners of the translocation are:

• IgH (85 %) on chromosome 14: t(8;14)(q24;q32)
• Kappa light chain (IgK) (5%) on chromosome 2: t(2;8)(p11;q24)
• Lambda light chain (IgL) (15%) on chromosome 22: t(8;22)(q24;q11)

However, other genetic alterations are required for malignant transformation to Burkitt's lymphoma (e.g. mutations in the P53 or retinoblastoma genes).

Common to all BL is the translocation of IG and MYC genes. In this process, the MYC gene moves into the vicinity of immunoglobulin (IG) genes, namely into the region of the immunoglobulin heavy chain on chromosome 14 or the light chains kappa on chromosome 2 or lambda on chromosome 22. The translocation leads to a dysregulation of the MYC gene, which performs a central regulatory function in cell division and influences a large number of other genes. Since the light and heavy chains of immunoglobulins in B cells are read and expressed quasi continuously during antibody production, this also happens for the MYC gene and MYC protein. This results in overexpression of MYC protein and uninhibited cell division. In addition to the dysregulation of the MYC gene, further genetic alterations are necessary for a malignant transformation to a Burkitt lymphoma to occur. Thus, in about 40% of cases of Burkitt's lymphoma, mutations in the p53 gene as well as mutations in the retinoblastoma (Rb) gene (its encoded products are protein 107 (p107) and protein 130 (p130)) are found.

In the endemic form of Burkitt's lymphoma in Africa, infection of B cells by EBV (Epstein-Barr virus) plays an initiating role. This induces polyclonal growth of B lymphocytes (Brady G et al 2007). EBV infestation is about 80% of children in certain areas in equatorial Africa.

Infections with malaria are also thought to play a proliferation-promoting role in this context. Malaria infection leads to a disruption of the T-cell population, which has a proliferation-promoting effect on B-cell clones.

In Europe and North America, EBV infection and childhood malaria are much less common. Sporadic BL show association with EBV in less than 20%.

The age of onset is usually < 35 years. M>w.

Blood tests, including LDH: This value is often elevated in infantile BL and an indicator for a higher risk group. An LDH value > 500 U/L LDH in serum or plasma corresponds to a higher risk group. The co-determination of the LDH in the risk group allocation is mainly used in the therapy optimization studies in German-speaking countries and meanwhile also in Europe.

Imaging procedures: sonography, computer tomography (CT) or magnetic resonance imaging (MRI), PET-CT

Bone marrow puncture with subsequent bone marrow smear

Infiltrate of medium sized cells with round nuclei, multiple nucleoli and a basophilic cytoplasm with vacuoles. The proliferation rate is almost 100 %. Bright macrophages lie between the lymphoid tumor cells, producing the classic "starry sky" pattern. Immunohistochemically, the tumor cells are positive for: CD19, CD20, CD10, BCL6. They are negative for BCL2.

High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 translocations. This category overlaps clinically and biologically with BL and has a poorer prognosis compared to most B-cell lymphomas (Lap CJ et al. 2021)

Treatment should be initiated emergency short and intensive chemotherapy. The cure rate is 90%. Several chemotherapy combination protocols based on high doses of cyclophosphamide exist. Furthermore, prophylactic treatment of the CNS is performed with intrathecal and systemic administration of methotrexate (MTX). With immediate treatment, cure can be expected in 70-80% of patients.

First-line therapy: In adults: GMALL-B-ALL/NHL protocol (rituximab, high-dose MTX + varying use of alkylants, anthracyclines, vinca alkaloids, etoposide and cytarabine).

The addition of rituximab to a short intensive chemotherapy regimen improves EFS in adults with Burkitt's leukemia or lymphoma (Ribrag V et al. 2016).

Radiotherapy and surgical treatments are indicated only in exceptional cases.

Progress or relapse: Autologous stem cell transplantation in question. However, the chances of survival are very limited.

1. Crombie J et al (2021) The treatment of Burkitt lymphoma in adults. Blood 137:743-750.
2. Brady G et al (2007) Epstein-Barr virus and Burkitt lymphoma. J Clin Pathol 60:1397-1402.
3. Burkitt D (1958) A sarcoma involving the jaws in African children. In: British Journal of Surgery 197: 218-223.
4. Bertrand P et al (2007) Mapping of MYC breakpoints in 8q24 rearrangements involving non-immunoglobulin partners in B-cell lymphomas. In: Leukemia 21: 515-523.
5. de Masson A et al. (2016) Disseminated skin involvement in HIV-associated Burkitt lymphoma: a rare clinical feature with poor prognosis. Br J Dermatol174:184-186.
6. Dunleavy K (2018) Approach to the diagnosis and treatment of adult Burkitt's lymphoma. J Oncol Pract14:665-671.
7. Lap CJ et al (2021) Novel Biological Insights and New Developments in Management of Burkitt Lymphoma and High-Grade B-Cell Lymphoma. Curr Treat Options Oncol 22:60.
8. Ng SB et al. (2009) Epstein-Barr virus in lymphoproliferative processes: an update for the diagnostic pathologist. Adv Anat Pathol 16:40-55.
9. Ribrag V et al. (2016) Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet 387:2402-2411.