Diffuse Large B-Cell Lymphoma (DLBCL)

Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of cancer that originates within the lymphatic system. It has the potential to spread easily to multiple organ systems and tissues. Accounting for approximately 30% to 40% of cases of non-Hodgkin lymphoma (NHL), DLBCL is the most common subtype of NHL.¹

DLBCL results from the unregulated proliferation of B cells, a type of white blood cell, at different stages of the maturation process. B cells develop in 3 distinct stages: pre-germinal, germinal, and post-germinal. Most B-cell lymphomas, such as DLBCL, arise during the germinal phase of development. Many cases of DLBCL involve extranodal locations, including the brain, kidneys, bones, adrenal glands, and soft tissues.²

Various factors influence the risk of developing DLBCL, including genetic mutations, a family history of lymphoma, the strength of the immune system, and environmental exposures, such as radiation, or chemical agents, like pesticides or dyes. Individuals who are immunocompromised, such as those who have an autoimmune disease or are medically immunosuppressed, are relatively susceptible to the development of DLBCL.²

The Role of Genetic Mutations in DLBCL Etiology

DLBCL results from mutations in proto-oncogenes and genes involved in tumor suppression.² The environment within the lymph nodes can also promote lymphomagenesis.² Exome sequencing has identified over 150 genetic drivers of DLBCL.³ 

Several proto-oncogenes and tumor suppressor genes that contribute to the development of DLBCL are: B-cell leukemia or lymphoma 2 (BCL2); B-cell lymphoma 6 (BCL6); TP53; and MYC genes.⁴ Most patients with DLBCL exhibit heavy and light chain immunoglobulin gene rearrangements.²

BCL2

BCL2 is an oncogene located on chromosome 18. It encodes an anti-apoptotic protein found in the outer mitochondrial membrane and cytoplasm that blocks the cell death of lymphocytes. In many cases of DLBCL, translocation of the BCL2 gene from chromosome 18 to a promotor region on chromosome 14 results in overexpression of BCL2 protein.^4-6 BCL2 protein overexpression, which is estimated to occur in 15% to 30% of all cases of DLBCL, causes increased lymphocyte proliferation and correlates with a poor prognosis; gene expression profiling has shown it to be associated with chemotherapy resistance and low survival rates.^4-7 A different source has suggested BCL2 protein expression occurs in approximately 80% of cases of DLBCL.²

BCL6

BCL6, a proto-oncogene located on chromosome 3, encodes a protein that blocks genes involved in cell cycle progression and response to DNA damage. BCL6 is typically expressed on normal B cells within the germinal center.⁴ In 30% to 40% of cases of DLBCL, translocation of BCL6 to another chromosome causes sequencing dysfunctions within the DNA promoter region. The faulty sequencing results in the abnormal production of BCL6 protein, which disrupts cellular differentiation and promotes continuous activation of the oncogene and the proliferation of malignant cells.^4,8 A different source suggests that abnormal BCL6 protein expression occurs in approximately 70% of cases of DLBCL.²

TP53

TP53, a tumor suppressor gene located on chromosome 17, encodes a nuclear phosphoprotein, p53, that regulates DNA transcription, cellular proliferation, and apoptosis.⁴ Approximately 30% of B-cell lymphomas involve TP53 mutations, which typically occur on exons 5 and 9. These exons regulate the repair of damaged DNA.⁴ BCL6 mutations may also inactivate p53, facilitating the development of lymphoma.^4,8 The presence of TP53 mutations or complete absence of the gene correlates with relatively aggressive disease progression and a poor prognosis.⁴ Researchers have observed that TP53 mutations may be associated with the evolution of DLBCL from follicular lymphoma.⁹

MYC

The MYC gene, a tumor suppressor gene located on chromosome 8, regulates cell growth, maturation, and apoptosis. Mutations in the MYC gene may occur in exons or introns, leading to recombination of the MYC gene with other genes in a relatively small number of cases of DLBCL (between 2% and 16%). MYC mutations correlate with a decreased likelihood of complete remission of DLBCL and poor survival.^4,8,9

Other Chromosomal Mutations

Using whole-genome sequencing and copy number analysis, Pasqualucci and colleagues identified over 30 genetic alterations per case within the DLBCL coding genome. Some mutations may occur in MLL2, which regulates chromatin methylation, whereas others occur in genes that regulate T-cell immune recognition.^10,11

Double- or Triple-Hit DLBCL

In double-hit DLBCL, disease arises from alterations in the MYC gene along with either the BCL2 or BCL6 gene. In triple-hit DLBCL, alterations in BCL2, BCL6, and MYC are present.²

Double-Expressor DLBCL

Double-expressor DLBCL results from the co-expression of c-MYC and BCL2. The prognosis is often poor, but outcomes are better than those of patients with double- or triple-hit B-cell lymphoma.¹²

DLBCL Biomarkers

DLBCL may exhibit B-cell restricted biomarker expression or activation antigen expression, including CD19, CD20, CD22, CD23, CD45, CD79a, CD30, CD10, and rarely CD5.^2,10

Read more about DLBCL genetics

The Role of Viral Infections in DLBCL Etiology

Infection with a virus, including Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV), may promote the development of DLBCL. Viral DNA is transported into B-cell nuclei, altering the normal growth and maturation of B cells or interfering with the regulation of malignant cells.²

Read more about DLBCL pathophysiology

References

1. Gandhi S. Diffuse large B-cell lymphoma (DLBCL). Epidemiology. Medscape. Updated May 6, 2021. Accessed August 4, 2022.
2. Padala SA, Kallam A. Diffuse large B cell lymphoma. StatPearls [Internet]. Updated April 28, 2022. Accessed August 4, 2022.
3. Reddy A, Zhang J, Davis NS, et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell. 2017;171(2):481-494.e15. doi:10.1016/j.cell.2017.09.027
4. Gouveia GR, Siqueira SAC, Pereira J. Pathophysiology and molecular aspects of diffuse large B-cell lymphoma. Rev Bras Hematol Hemoter. 2012;34(6):447-451. doi:10.5581/1516-8484.20120111
5. Tsuyama N, Sakata S, Baba S, et al. BCL2 expression in DLBCL: reappraisal of immunohistochemistry with new criteria for therapeutic biomarker evaluation. Blood. 2017;130(4):489-500. doi:10.1182/blood-2016-12-759621
6. Abd El-Hameed A. De novo nodal diffuse large B-cell lymphoma: identification of biologic prognostic factors. J Egypt Natl Canc Inst. 2005;17(1):20-28. 
7. Wu G, Keating A. Biomarkers of potential prognostic significance in diffuse large B-cell lymphoma. Cancer. 2006;106(2):247-257. doi:10.1002/cncr.21586
8. Lossos IS. Molecular pathogenesis of diffuse large B-cell lymphoma. J Clin Oncol. 2005;23(26):6351-6357. doi:10.1200/JCO.2005.05.012
9. Ahmadi SE, Rahimi S, Zarandi B, Chegeni R, Safa M. MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies. J Hematol Oncol. 2021;14(1):121. doi:10.1186/s13045-021-01111-4
10. Gandhi S. Diffuse large B-cell lymphoma (DLBCL). Etiology. Medscape. Updated May 6, 2021. Accessed August 4, 2022.
11. Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 2011;43(9):830-837. doi:10.1038/ng.892
12. Hashmi AA, Iftikhar SN, Nargus G, et al. Double-expressor phenotype (BCL-2/c-MYC co-expression) of diffuse large B-cell lymphoma and its clinicopathological correlation. Cureus. 2021;13(2):e13155. doi:10.7759/cureus.13155

Reviewed by Debjyoti Talukdar, MD, on 9/18/2022.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.