HAEM4Backup:Burkitt Lymphoma
Primary Author(s)*
Becky Leung, MBBS (Hons), BSc, Pathology Queensland
Cancer Category/Type
Mature B-cell neoplasm
Cancer Sub-Classification/Subtype
Burkitt lymphoma
Definition/Description of Disease
Burkitt lymphoma is a clinically aggressive but curable lymphoma with three aetiologically distinct subtypes, these being endemic, sporadic and immunodeficiency-associated Burkitt lymphoma. Infection with Epstein-Bar virus (EBV), also known as human herpesvirus 4, is seen all three subtypes, but is most strongly associated with endemic Burkitt Lymphoma. Detectable EBV infection is not essential for diagnosis, and may not be the cause in all cases; the frequency of EBV infection varies according to the epidemiological subtype of Burkitt lymphoma. The clinical presentation often involves extra-nodal sites but the disease can also present as an acute leukaemia.
Synonyms/Terminology
Burkitt cell leukaemia
Obsolete terms
- Burkitt tumour
- Malignant lymphoma, undifferentiated, Burkitt type
- Malignant lymphoma, small non-cleaved, Burkitt type
Epidemiology/Prevalence
Endemic Burkitt lymphoma
- Highly associated with Epstein-Barr virus (EBV genome present in >95% of neoplastic cells) and Plasmodium falciparum infection
- Occurs in equatorial Africa and Papua New Guinea, with a distribution that overlaps with regions endemic for malaria
- Demographics: peak incidence among children aged 4-7 years
- The incidence is higher in males than females, at a ratio of 2:1
Sporadic Burkitt lymphoma
- EBV detected in 20-30% of cases, proportion of EBV positive cases appears to be much higher in adults than in children
- Occurs worldwide
- Western Europe and USA: low incidence, accounting for only 1-2% of all lymphomas overall (30-50% of all childhood lymphomas)
- South America and northern Africa: incidence between that of sporadic Burkitt lymphoma in developed countries and endemic Burkitt lymphoma
- Demographics: peak incidence among children and young adults (median age 30 years, with separate incidence peak in elderly patients)
- M:F 2-3:1
Immunodeficiency-associated Burkitt lymphoma
- EBV detected in 25-40% of cases
- Associated with HIV infection (most commonly) and other forms of immunosuppression
- Occurs early in the course of HIV infection, when CD4+ T cell counts are still high
- Increased risk of developing Burkitt lymphoma has persisted across the pre-and post-HAART eras
Clinical Features
Patients often present with bulky disease and high tumour burden, showing rapid clinical progression. The typically involved anatomical sites are different for the three subtypes. At presentation, 30% have localised (stage I or II) disease and 70% have advanced (stage III or IV) disease, according to the revised international paediatric non-Hodgkin lymphoma staging system.
Tumour masses can compress and/or infiltrate adjacent tissues.
Due to the high chemosensitivity of the tumour, treatment of Burkitt Lymphoma with chemotherapy can lead to rapid tumour cell death and an acute tumour lysis syndrome secondary to this.
Sites of Involvement
Extra-nodal sites most often involved:
- Commonly involved sites: jaw and facial bones, ileocaecal region, omentum, gonads, kidneys, long bones, thyroid, salivary glands and breasts
- Jaws and other facial bones are the site of presentation in 50-70% of cases of endemic Burkitt lymphoma
- Central nervous system
- The ileocaecal region is the most frequently involved site in sporadic Burkitt lymphoma
Lymph node and bone marrow involvement less common but:
- Frequent in immunodeficiency-associated Burkitt lymphoma
- Presentation with lymphadenopathy is more common in adults than children
- Waldeyer ring or mediastinal involvement is rare
Burkitt leukaemia variant
- Leukaemic phase can be observed in patients with bulky disease
- Only rare cases present purely as leukaemia with peripheral blood and bone marrow involvement, this more typically seen in males
- Tends to involve the CNS at diagnosis or early in the disease course
- Uncommon in endemic Burkitt lymphoma
Morphologic Features
Tissue specimens
- Diffuse monotonous effacement of normal architecture by sheets of medium-sized lymphoid cells
- At low power, tissue can have interspersed areas of coagulative necrosis or haemorrhage
- High proliferation rate with a high rate of spontaneous apoptosis and many mitotic figures
- A starry sky pattern is usually present, this refers to the presence of numerous tingible body macrophages that have phagocytosed apoptotic tumour cells. These macrophages have abundant clear cytoplasm and are dispersed throughout the basophilic tumour cells.
Nucleus
- Round with finely clumped chromatin and multiple basophilic paracentral nucleoli
Cytoplasm
- Deeply basophillic with lipid vacuoles
Variations
- Some cases have a florid granulomatous reaction, which typically is associated with limited stage disease and good prognosis
- Some cases can exhibit plasmacytoid differentiation with eccentric basophilic cytoplasm and a single central nucleolus (particularly with immundeficiency-associated Burkitt lymphoma)
Immunophenotype
Burkitt lymphoma is a germinal centre B-cell derived malignancy. Aberrant immunophenotypes (CD5 positive, CD10 negative, BCL2 weak) may be seen particularly in the Burkitt lymphoma of older patients. Burkitt leukaemia shows a similar immunophenotype to Burkitt lymphoma, in rare cases TdT and possibly CD34 expression, or loss of CD20 and surface immunoglobulin is seen.
| Finding | Marker |
|---|---|
| Positive (near-universal) | MYC (strong) |
| Positive (typically) | B cell antigens: CD19, CD20, CD22, CD79a, PAX5
Germinal centre markers: CD10, BCL6 surface IgM (moderate-strong) with light chain restriction Ki67 typically high ~100% |
| Positive (frequent) | CD38, CD77, CD43 |
| Positive (paediatric) | TCL1 |
| Negative (usually) | CD5, CD23, CD138, BCL2, TdT |
Chromosomal Rearrangements (Gene Fusions)
The development of Burkitt lymphoma is dependent on the constitutive expression of the MYC proto-oncogene. The MYC encoded protein is a transcriptional regulator, controlling target genes involved in cell cycle regulation, metabolism and apoptosis. Dysregulation of MYC expression occurs due to juxtaposition of regulatory elements of the immunoglobulin loci, usually IGH, but also IGL or IGK. Overexpression of MYC correlates with increased cell survival. The different Burkitt lymphoma subtypes harbour diverse MYC and IGH locus breakpoints. In endemic Burkitt lymphoma, MYC usually breaks several hundred kilobases further upstream and IG usually breaks in the VDJ region. In contrast, most sporadic and immunodeficiency-associated Burkitt lymphoma have chromosomal breakpoints within exon 1 and the first intron of MYC and at the class switch region of IG[1]. Although fluorescence in situ hydribisation (FISH) methods are well established in most pathology laboratories, no single probe set is able to cover all MYC breakpoints. In particular, distant breakpoints, complex rearrangements and cryptic insertions may be overlooked[2]. Hence, multiple FISH probe sets are required for comprehensive detection of clinically relevant MYC gene rearrangements.
A translocation involving MYC cannot be detected by FISH or classical cytogenetics in a small percentage of cases (less than 5%). This may be due to technical issues, such as a very small excision of MYC and insertion of the gene onto the IG loci, or a breakpoint localised outside the regions covered by the utilised FISH probes[3]. Mechanisms other then translocation that similarly lead to MYC overexpression have also been implicated in the development of Burkitt lymphoma[4]. Investigation for these should be considered in the presence of a consistent clinical and laboratory phenotype, where fusions are not detected.
| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Pathogenic Derivative | Prevalence |
|---|---|---|---|
| t(8;14)(q24;q32) | 5'IGH / 3'MYC | der(14) | 85% |
| t(8;22)(q24;q11) | 5'MYC / 3'IGL | der(8) | 10% |
| t(2;8)(p12;q24) | 5'MYC / 3'IGK | der(8) | 5% |
Genomic Gain/Loss/LOH
Most often, Burkitt lymphoma is associated with a simple karyotype. However additional chromosomal abnormalities may also occur and play a role in disease progression, see the table below for the more commonly implicated cytogenetic abnormalities.
In the context of a Burkitt lymphoma-like phenotype and/or Burkitt-like morphological appearance, the diagnosis of 'Burkitt-like lymphoma with 11q aberration' should be considered. This provisional WHO entity lacks a detectable MYC rearrangement, but shows alterations of 11q. These 11q alterations typically include proximal gains (eg 11q23.2-23.3), and telomeric losses (eg 11q24.1-ter). MicroRNA and gene expression profiling patterns are consistent with Burkitt lymphoma. Other common karyotypic features of this condition include a complex karyotype, and lack of the 1q loss typical of Burkitt lymphoma.
| Chromosome Number | Gain/Loss/Amp/LOH | Region |
|---|---|---|
| 1q | Gain | 21-25 |
| 6q | Loss | 11-14 |
| 7 | Gain | |
| 8 | Gain | |
| 12 | Gain | |
| 13q | Loss | 32-34 |
| 17p | Loss | |
| 18 | Gain |
Gene Mutations (SNV/INDEL)
| Gene | Oncogene/Tumor Suppressor/Other | Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) | Prevalence (COSMIC/TCGA/Other) |
|---|---|---|---|
| MYC | Oncogene | GOF | 67% |
| ID3[5] | Tumour suppressor | LOF | 34% |
| DDX3X[6] | Tumour suppressor | LOF | 34% |
| BCL6[7] | Oncogene | GOF | 25% |
| BCL7A[8] | Oncogene | GOF | 24% |
| FBXO11[9] | Tumour suppressor | LOF | 23% |
| FOXO1[10] | Oncogene | GOF | 23% |
| SMARCA4[11] | Tumour suppressor | LOF | 23% |
| ARID1A[12] | Tumour suppressor | LOF | 18% |
| TP53[13] | Tumour suppressor | LOF | 17% |
| CTCF[14] | Tumour suppressor | LOF | 16% |
| CREBBP[15] | Tumour suppressor | LOF | 15% |
| TCL1A[16] | Oncogene | GOF | 15% |
| BCR[17] | Oncogene | GOF | 15% |
| TCF3[18] | Oncogene | GOF | 14% |
| CCND3[19] | Oncogene | GOF | 14% |
Genes and Main Pathways Involved
MYC is the most commonly mutated gene in Burkitt lymphoma, such variants lead to constitutive expression of MYC, which drives cell survival. Aberrant somatic hypermutation is understood to be the major cause of MYC breakpoint formation and the presence of hypermutation in tandem with MYC rearrangement may be detectable if using sequencing methodologies.
Localised TP53 inactivating mutations or chromosomal deletions involving TP53 are also common in Burkitt lymphoma, and cause abrogation of TP53-dependent apoptotic pathways. Loss of TP53 function through the aforementioned means, or dysregulation due to the mutation of TP53 regulatory elements, is believed to be key to the development of Burkitt lymphoma[20].
TCF3 or ID3 mutations are seen in approximately 70% of sporadic Burkitt lymphoma. The normal function of transcription factor E2A (encoded by TCF3) is regulation of the differentiation of B-cells in the germinal centre. Mutations in TCF3 leads to reduced affinity for its negative regulator, ID3, promoting constitutive activity. TCF3 promotes B-cell receptor signaling in Burkitt lymphoma, which enhances survival via the PI3 kinase pathway. TCF3 also transactivates CCND3 which encodes cyclin D3 expression, promoting cell cycle progression and proliferation[21].
Mutations overall, and in particular in TCF3 and ID3, are less common in endemic Burkitt lymphoma when compared to sporadic cases. It is postulated that this additional mutational burden may take the place of EBV in sporadic Burkitt lymphomagenesis, given that either mechanism can lead to the activation of B-cell receptor signaling.
The gene expression and micro-RNA expression profiles of Burkitt lymphoma are different from other lymphomas. The expression profiles of endemic and sporadic BL are also slightly different to each other. There may be grey zones where Burkitt lymphoma is difficult to distinguish from diffuse large B-cell lymphoma based on gene expression, hence expression should not be used as an independent diagnostic tool[22].
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
Deciphering the genomic landscape of Burkitt lymphoma provides additional molecular targets for new treatment regimens. Burkitt lymphoma is often curable using intensive chemotherapy treatments. However, these regimens may not be well tolerated by older individuals and further treatment options are required for those who exhibit refractory or relapsed disease.
Considerations are for inhibitors of PI3K signaling and downstream pathways, and inhibiting cyclin dependent kinase 4/6 to block cyclin D3 mediated cell cycle progression.
Familial Forms
The X-linked lymphoproliferative syndrome 'Duncan disease', is associated with SH2D1A mutations. Individuals with this condition are at greatly increased risk of developing Burkitt lymphoma.
Links
Burkitt-Like Lymphoma with 11q Aberration
References
Arber DA, et al., (2017). Burkitt Lymphoma, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p330-334.
- ↑ Neri, A.; et al. (1988-04-01). "Different regions of the immunoglobulin heavy-chain locus are involved in chromosomal translocations in distinct pathogenetic forms of Burkitt lymphoma". Proceedings of the National Academy of Sciences. 85 (8): 2748–2752. doi:10.1073/pnas.85.8.2748. ISSN 0027-8424.
- ↑ Muñoz-Mármol, Ana M; et al. (2013-09). "MYC status determination in aggressive B-cell lymphoma: the impact of FISH probe selection". Histopathology. 63 (3): 418–424. doi:10.1111/his.12178. Check date values in:
|date=(help) - ↑ De Falco, Giulia; et al. (2015-10-09). "Burkitt lymphoma beyond MYC translocation: N-MYC and DNA methyltransferases dysregulation". BMC Cancer. 15 (1). doi:10.1186/s12885-015-1661-7. ISSN 1471-2407.
- ↑ Leucci, E; et al. (2008-09-18). "MYC translocation‐negative classical Burkitt lymphoma cases: an alternative pathogenetic mechanism involving miRNA deregulation". The Journal of Pathology. 216 (4): 440–450. doi:10.1002/path.2410. ISSN 0022-3417. line feed character in
|title=at position 4 (help) - ↑ Richter, Julia; et al. (2012-12). "Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing". Nature Genetics. 44 (12): 1316–1320. doi:10.1038/ng.2469. ISSN 1546-1718. PMID 23143595. Check date values in:
|date=(help) - ↑ Mo, Jie; et al. (2021-02-24). "DDX3X: structure, physiologic functions and cancer". Molecular Cancer. 20 (1). doi:10.1186/s12943-021-01325-7. ISSN 1476-4598.
- ↑ Kl, Bunting; et al. (2013 Jun). "New effector functions and regulatory mechanisms of BCL6 in normal and malignant lymphocytes". doi:10.1016/j.coi.2013.05.003. PMC 4075446. PMID 23725655. Check date values in:
|date=(help)CS1 maint: PMC format (link) - ↑ Zani, V. J.; et al. (1996-04-15). "Molecular cloning of complex chromosomal translocation t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt lymphoma cell line defines a new gene (BCL7A) with homology to caldesmon". Blood. 87 (8): 3124–3134. ISSN 0006-4971. PMID 8605326.
- ↑ Pighi, Chiara; et al. (2015-12-03). "FBXO11, a Regulator of BCL6 Stability, Is Recurrently Mutated in Burkitt Lymphoma". Blood. 126 (23): 3673–3673. doi:10.1182/blood.v126.23.3673.3673. ISSN 0006-4971.
- ↑ Zhou, Peixun; et al. (2019-07-23). "Sporadic and endemic Burkitt lymphoma have frequent FOXO1 mutations but distinct hotspots in the AKT recognition motif". Blood Advances. 3 (14): 2118–2127. doi:10.1182/bloodadvances.2018029546. ISSN 2473-9537. PMC 6650741. PMID 31300419.
- ↑ Love, Cassandra; et al. (2012-12). "The genetic landscape of mutations in Burkitt lymphoma". Nature Genetics. 44 (12): 1321–1325. doi:10.1038/ng.2468. ISSN 1546-1718. PMC 3674561. PMID 23143597. Check date values in:
|date=(help) - ↑ Love, Cassandra; et al. (2012-12). "The genetic landscape of mutations in Burkitt lymphoma". Nature Genetics. 44 (12): 1321–1325. doi:10.1038/ng.2468. ISSN 1546-1718. PMC 3674561. PMID 23143597. Check date values in:
|date=(help) - ↑ Shannon-Lowe, Claire; et al. (2017-10-19). "Epstein-Barr virus-associated lymphomas". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 372 (1732). doi:10.1098/rstb.2016.0271. ISSN 1471-2970. PMC 5597738. PMID 28893938.
- ↑ Chau, Charles M.; et al. (2006-06-15). "Regulation of Epstein-Barr Virus Latency Type by the Chromatin Boundary Factor CTCF". Journal of Virology. 80 (12): 5723–5732. doi:10.1128/JVI.00025-06. ISSN 0022-538X. PMC 1472585. PMID 16731911.CS1 maint: PMC format (link)
- ↑ Love, Cassandra; et al. (2012-12). "The genetic landscape of mutations in Burkitt lymphoma". Nature Genetics. 44 (12): 1321–1325. doi:10.1038/ng.2468. ISSN 1546-1718. PMC 3674561. PMID 23143597. Check date values in:
|date=(help) - ↑ Aggarwal, Mohit; et al. (2008-09-26). "TCL1A expression delineates biological and clinical variability in B-cell lymphoma". Modern Pathology. 22 (2): 206–215. doi:10.1038/modpathol.2008.148. ISSN 0893-3952.
- ↑ Küppers, Ralf (2005-04). "Mechanisms of B-cell lymphoma pathogenesis". Nature Reviews Cancer. 5 (4): 251–262. doi:10.1038/nrc1589. ISSN 1474-175X. Check date values in:
|date=(help) - ↑ Schmitz, Roland; et al. (2012-10-04). "Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics". Nature. 490 (7418): 116–120. doi:10.1038/nature11378. ISSN 1476-4687. PMC 3609867. PMID 22885699.
- ↑ Schmitz, Roland; et al. (2012-10-04). "Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics". Nature. 490 (7418): 116–120. doi:10.1038/nature11378. ISSN 1476-4687. PMC 3609867. PMID 22885699.
- ↑ Shannon-Lowe, Claire; et al. (2017-10-19). "Epstein-Barr virus-associated lymphomas". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 372 (1732). doi:10.1098/rstb.2016.0271. ISSN 1471-2970. PMC 5597738. PMID 28893938.
- ↑ Schmitz, Roland; et al. (2012-10-04). "Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics". Nature. 490 (7418): 116–120. doi:10.1038/nature11378. ISSN 1476-4687. PMC 3609867. PMID 22885699.
- ↑ Shannon-Lowe, Claire; et al. (2017-10-19). "Epstein-Barr virus-associated lymphomas". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 372 (1732). doi:10.1098/rstb.2016.0271. ISSN 1471-2970. PMC 5597738. PMID 28893938.
Notes
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