Definition and characteristics of Burkitt’s lymphoma

Burkitt's lymphoma (BL) is a highly aggressive lymphoma and is characterized by an extraordinarily high cell division rate of B cells.

Burkitt's lymphoma - Classification

According to the WHO, 3 clinical variants of Burkitt’s lymphoma (BL) are recognized: the endemic Burkitt's lymphoma is occurs in tropical regions, e.g. in Africa, and is associated with a tumour-inducing effect of EBV. There it is one of the most frequent tumor diseases in children between the ages of 4-7 years. The sporadic Burkitt's lymphoma occurs in temperate climate zones (mainly USA and Western Europe), accounting for 1-2% of all lymphomas. The median age of the adults is 30 years, with men being affected twice as often as women. Immunodeficiency-associated Burkitt's lymphoma is more common in the setting of HIV Infection than in other forms of immunosuppression. A leukemic form of Burkitt's lymphoma is characterized by a bone marrow infiltration of more than 25% lymphocytic blasts in the bone marrow and is called Burkitt's leukemia (formerly "mature B-ALL").

A new provisional entity described in the WHO 2017 includes "Burkitt-like" lymphoma with 11q aberration. Burkitt-like lymphoma with 11q aberration is similar to Burkitt's lymphoma in morphology and gene expression profile, but differs from it cytogenetically, clinically (often nodal involvement) and molecularly.

Diagnostics of Burkitt's lymphoma

Since there is no method that represents the sole gold standard in the diagnosis of Burkitt's lymphoma or Burkitt's leukemia, an integrated diagnostic approach taking into account morphology/histology, immunophenotype and genetics is central. Due to the frequent involvement of the CNS an additional cerebrospinal fluid (CSF) examination should be performed.

Cytomorphology

Unilateral bone marrow biopsy and cytomorphology is highly recommended. The evaluation of the bone marrow smear allows to assess whether lymphoma infiltration exists or is possible. Cytomorphology and histology are also useful for evaluating the degree of lymphoma maturity.

Cytomorphology often shows a characteristic phenotype with medium-sized blast forms, which are conspicuous by a deep basophilic cytoplasm with characteristic vacuolisation.

Immunophenotyping

In immunophenotyping, the mostly medium-sized malignant cells are often found in the extended blastocyst gate (medium SSC, CD45+-low). Typical is an expression of CD19, CD20, CD79b and FMC7 with simultaneous expression of CD10 and often CD38 and IgM. CD23 and CD5 are negative. Differentiation from another B-lymphoblastic neoplasia is possible by lacking expression of immature markers (CD34, TdT) and by the presence of light chain expression.

Chromosome analysis

Burkitt's lymphoma is characterized by chromosomal changes affecting the MYC gene on chromosome 8. The most frequent translocation here is t(8;14)(q24;q32), which is associated with an IGH-MYC rearrangement. In rare cases, rearrangements with the locus of the immunoglobulin light chain lambda on chromosome 22 (IGL-MYC/t(8;22)(q24;q11)) or kappa on chromosome 2 (IGK-MYC/ t(2;8)(p12;q24)) may also occur. Other characteristic aberrations include the gain of the long arm of chromosome 1 (+1q), trisomy 7 and trisomy 12.

Although MYC rearrangements are characteristic for Burkitt's Lymphoma, they are not specific for this entity. They are also found in other mature B-cell neoplasms such as diffuse large B-cell lymphoma (DLBCL) or highly malignant B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement (HGBL). The latter category (formerly known as "double hit lymphoma" or "triple hit lymphoma") show a variable morphology similar to DLBCL, Burkitt's lymphoma and rarely follicular lymphoma. HGBL are mostly aggressive lymphomas with an unfavorable prognosis (see also further information on HGBL). Compared to other lymphomas with MYC rearrangement, the karyotypes in Burkitt's lymphoma are less complex.

Instead of MYC rearrangement, Burkitt-like lymphoma shows proximal gains and losses of the telomere region of the long arm of chromosome 11. The smallest deleted region was described as region 11q24.1-ter and the smallest amplified region was described as region 11q23.2- 23.3. The 1q gains typical for Burkitt's lymphoma (BL) have not been observed in this new provisional entity, but an association with more complex karyotypes has been observed (Aukema et al. 2015, Salaverria et al. 2014).

FISH

Fluorescence in situ hybridization (FISH) plays a central role in the detection (Burkitt's lymphoma) or exclusion (Burkitt-like) of a MYC rearrangement (8q24). The use of FISH probes for the detection of a BCL6 and BCL2 rearrangement makes it possible to check whether a highly malignant B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement is present. In addition, in addition to the classical chromosome analysis, "chromosome painting" with 1-3 colours or 24-colour FISH can be used to clarify or validate Burkitt's lymphoma typical (e.g. trisomy 12) as well as complicated chromosomal aberrations.

Molecular genetics

While t(8;14) causes dysregulation of the MYC gene, mutations in TCF3, ID3 and CCND3 activate the TCF3 signaling pathway. The combination of both events plays an important role in the development of Burkitt's lymphoma and leads to both increased proliferation and prolonged survival of Burkitt's lymphoma (BL) cells. 70% of sporadic BLs show mutations in the TCF3 (also known as E2A) genes. In addition, mutations in the genes TP53 (60%), MYC (49%) and ID3 (36%) were found (Haberl et al. 2016). Further recurrent mutations were described in the genes CCND3, RHOA, SMARCA4 and ARID1A.

In contrast, Burkitt-like lymphoma with 11q change shows no mutations in the genes of the ID3-TCF3 pathway, TP53 or SMARCA4 (Wagener et al. 2019, Gonzalez-Farre et al. 2019). Instead, a GNA13 mutation is often found, which is otherwise associated with "germinal center B-cell (GCB) like" lymphomas.

Prognosis of Burkitt's lymphoma

Since Burkitt's lymphoma is an aggressively growing tumor with a proliferation rate of often 100%, early therapy is necessary. Intensive combination chemotherapy leads to a 5-year survival of 90% for adolescents, 84% for adults and 62% for elderly patients (Hölzer et al. 2014).

References

Aukema SM et al. Sequential karyotyping in Burkitt lymphoma reveals a linear clonal evolution with increase in karyotype complexity and a high frequency of recurrent secondary aberrations. Br J Haematol 2015;170(6):814-825.

Gonzalez-Farre B. et al., Burkitt-like lymphoma with 11q aberration: a germinal center-derived lymphoma genetically unrelated to Burkitt lymphoma. Haematologica 2019; 104(9):1822-1829.

Guikema JE et al. IGH switch breakpoints in Burkitt lymphoma: exclusive involvement of noncanonical class switch recombination. Genes Chromosomes. Cancer 2006;45(9):808-819.

Haberl S et al. MYC rearranged B-cell neoplasms: Impact of genetics on classification. Cancer Genet 2016;209(10):431-439.

Hölzer D et al., Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial. Blood. 2014;124(26):3870-3879.

Patte C et al. Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 2007;109(7):2773-2780.

Salaverria I et al. A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma. Blood 2014;123(8):1187-1198.

Shiramizu B et al. Patterns of chromosomal breakpoint locations in Burkitt's lymphoma: relevance to geography and Epstein-Barr virus association. Blood 1991;77(7):1516-1526.

Swerdlow SH et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer (IARC) 2008.

Swerdlow SH et al. WHO classification of tumors of haematopoietic and lymphoid tissues. International Agency of Research on Cancer 2017. Revised 4th Edition.

Wagener R. et al., The mutational landscape of Burkitt-like lymphoma with 11q aberration is distinct from that of Burkitt lymphoma. Blood 2019;133(9):962-966.