Burkitt lymphoma (BL)

Cytomorphology and histology are directional for guiding downstream diagnosis in Burkitt lymphoma. Assessment of the bone marrow smear provides initial landmark information as to whether lymphoma infiltration exists. Cytomorphology and histology are also useful in assessing the degree of lymphoma maturity.

Cytomorphology often reveals a characteristic phenotype with medium-sized blastic forms that are notable for a deeply basophilic cytoplasm with characteristic vacuolization.

The nuclei are round and multiple basophilic nucleoli can be observed (WHO 2022).

In immunophenotyping, the mostly medium-sized malignant cells are often found in the extended blast gate (medium SSC, CD45+-low). Characteristic for BL is the expression of CD19, CD20, CD10, CD38, CD43, CD81, FMC-7 and MYC. Here, the expression of CD38 and CD81 is particularly pronounced. It is also typical that BL tumor cells express little CD45. BCL2, CD44 and TdT are not expressed (WHO 2022). Differentiation from another B-lymphoblastic neoplasia is made by the lack of expression of immature markers (CD34, TdT) and by the presence of light chain expression.

Characteristic of Burkitt lymphoma are chromosomal alterations affecting the MYC gene on chromosome 8. The most common is the translocation t(8;14)(q24;q32), which is associated with an IGH::MYC rearrangement. In rarer cases, rearrangements may also occur with the immunoglobulin light chain lambda locus on chromosome 22 (IGL::MYC/t(8;22)(q24;q11)) or kappa on chromosome 2 (IGK::MYC/t(2;8)(p11;q24)). Other characteristic aberrations include gain of the long arm of chromosome 1 (+1q), trisomy 7, and trisomy 12.

When MYC breakpoints on chromosome 8 are considered, they are increasingly located above MYC in EBV-positive BL and increasingly within the MYC region in EBV-negative BL (Thomas et al. 2023).

MYC rearrangements are characteristic but not specific for BL. They are also found in other mature B-cell neoplasms such as diffuse large B-cell lymphoma (DLBCL) or high grade B-cell lymphoma with MYC and BCL6 rearrangement (HGBL). Compared to other lymphomas with MYC rearrangement, the karyotypes in Burkitt lymphoma are less complex.

Fluorescence in situ hybridization (FISH) plays a central role in the detection of the MYC rearrangement (8q24) typical for BL. For this purpose, both the translocation probe IGH::MYC or a partner gene-independent probe against MYC are used as standard. In the absence of a MYC rearrangement, an 11q23/11q24 probe can be used to detect 11q23 gains or an 11q24 deletion, respectively, which serve to detect a HGBL-11q. The use of FISH probes to detect a BCL6 and BCL2 rearrangement allows the differential diagnosis of a DLBCL/HGBL-MYC/BCL2, a HGBL, NOS or DLBCL, NOS. Furthermore, in addition to the classical chromosome analysis, chromosome painting with 1-3 colors or 24-color FISH can be used to clarify or validate chromosome aberrations typical for BL (e.g. trisomy 12) as well as complicated chromosomal aberrations.

In BL, mutations may be present in genes that control cell proliferation, cell growth, and cell survival. However, among the recurrently mutated genes, no specific oncogene is known to be characteristic of BL. A high frequency of mutations in the TCF3 gene (E2A) and its negative regulator ID3 can be detected in BL. They are among the predominant coding mutations in EBV-negative BL, but are also common in EBV-positive cases (WHO 2022). In a study by Richter et al. the following mutations, among others, occurred in at least 20% of the total cohort (Richter et al. 2022):

• ID3 (63%)

• MYC (60%)

• TP53 (56%)

• FOXO1 (23%)

In a study by Sureda-Gómez et al., it was also shown that EBV-negative cases expressing SOX11 have higher frequencies of mutations in ID3 and TP53 compared to EBV-negative/SOX11-negative cases (Sureda-Gómez et al. 2024).

According to Thomas et al. 2023, BL can be further subdivided into three subgroups. These subgroups are each associated with certain molecular genetic changes (e.g. FOXO1, ID3 and TP53) and show an influence on the course of the disease (Thomas et al. 2023). In a further analysis, Thomas et al. also describe two epigenetic subtypes of Burkitt lymphoma (HyperBL, HypoBL) that differ in terms of EBV status, mutation burden, cell-of-origin signatures (HyperBL more closely associated with germinal centers, HypoBL more closely associated with memory B cells), and clinical course (Thomas et al. 2025).