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Pathophysiology

Diffuse large B-cell lymphoma (DLBCL) is an aggressive blood cancer characterized by the development of abnormally large B-cells, which typically originate within the lymphatic system (the lymph nodes and bone marrow). DLBCL is the most common type of non-Hodgkin lymphoma (NHL), accounting for one-third of cases globally.¹

Diffuse large B-cell lymphoma is genetically, molecularly, and clinically heterogeneous, affecting various pathways that result in the production of abnormally large, aggressively malignant B-cells at different stages of their development. Most patients with DLBCL have either germinal center B-cell (GCB) DLBCL or activated B-cell (ABC) DLBCL according to gene expression profiling.²

Processes That Contribute to DLBCL Subtyping

Germinal center B-cell DLBCL results from the exposure of B-cells to an antigen that triggers B-cell somatic hypermutation during their stage of development in the dark zone of the germinal center. These cases typically respond to standard chemotherapy treatment.³

Activated B-cell DLBCL results from the exposure of B-cells to an antigen either in the light zone of the germinal center or once the B-cell has already left the germinal center. ABC DLBCL is often refractory to standard chemotherapy treatment.³

Read more about DLBCL types

Exposures and Susceptibilities Triggering DLBCL Development

Exposure to many antigens can trigger the development of DLBCL, including⁴:

Viruses such as Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and human herpesvirus-8 (HHV-8)
Chemicals, certain drugs, pesticides, herbicides, preservatives, dyes, solvents, radiation, and chemotherapy

If exposed to these antigens, patients with weakened immune systems, including all types of immunosuppression, are more at risk of developing DLBCL. Patients with deficient immune systems, such as people with severe combined immunodeficiency, or hyperactive immune systems, such as patients with asthma, are more susceptible to developing NHLs such as DLBCL.⁴ An increased risk of antigen exposure without a sufficient immune response also occurs in patients who have compromised immune systems secondary to immunosuppressant administration following organ or bone marrow transplantation.⁴ Autoimmune disorders such as rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, Hashimoto’s thyroiditis, and celiac disease also increase the risk of developing DLBCL.⁴

Read more about DLBCL etiology

DLBCL-Associated Genetic Mutations and Biomarkers

Most patients with DLBCL present with rearrangements in the heavy and light chains of immunoglobulins. Approximately 80% of DLBCLs express B-cell leukemia or lymphoma 2 (BCL2) protein, while 70% express B-cell lymphoma 6 (BCL6) protein. A minority exhibit MYC gene mutations.²

These expressions are secondary to chromosomal translocations that occur in BCL6, BCL2, and MYC, among other genetic variations. Occasionally, double-hit, triple-hit, or double-expressor lymphomas occur with poor clinical outcomes. Double-hit lymphoma involves both a MYC and BCL2 or BCL6 rearrangement. Triple-hit lymphoma involves MYC, BCL2, and BCL6 rearrangements. Double-expressor lymphoma results in a high coexpression of both MYC and BCL2 proteins.^2,5

Frequently, DLBCL biomarkers such as CD19, CD20, CD22, CD30, CD45, CD79a, and, more rarely, CD5 are expressed, as evidenced by flow cytometry.²

Read more about DLBCL genetics

Alteration of Signaling Pathways in DLBCL

While genetic aberrations and messenger RNA transcription are the root causes of B-cell transformation, protein kinases execute this transformation and alter signal transduction pathways, contributing to tumor pathogenesis. Research has confirmed that germinal center kinase (GCK) signaling is activated in approximately 80% of DLBCL cases, resulting in DLBCL tumor proliferation and survival. It has been further demonstrated that the inhibition of GCK signaling via knockdown resulted in decreased cell proliferation and increased cellular death.⁶

Various signaling pathways may be disrupted in DLBCL, resulting in tumor cell proliferation, survival, and spread, predominantly of the lymph nodes and bone marrow; however, extranodal DLBCL sites of origin are common, occurring in around 40% of DLBCL cases. These extranodal sites include the gastrointestinal tract, bones, brain, adrenal glands, kidneys, and other soft tissues and organs.^1,2

Some of the known pathways that contribute to DLBCL development include the GCK signaling pathway, the nuclear factor kappa B (NF-κB) signaling pathway, the B-cell receptor survival signaling pathway, and deregulation of the BCL6/apoptosis pathway.^6-8

Activated B-cell DLBCL-type tumors require constitutive activation of the NF-κB signaling pathway to support proliferation and survival secondary to this pathway’s role in the regulation of apoptosis and expression of transcription factors such as interferon regulatory factor 4 (IRF4). The NF-κB pathway is not critical for the survival of GCB DLBCL cell lines.^7-9

B-cell receptors on the surface of B-cells regulate downstream cell proliferation and survival signaling.⁸ ABC DLBCL subtypes commonly express an immunoglobulin M B-cell receptor (IgM-BCR), while GCB DLBCL subtypes commonly express an immunoglobulin G B-cell receptor (IgG-BCR). IgM-BCR signals prosurvival and proliferative signals, while IgG-BCR signaling results in plasma cell differentiation.⁷

Variations in altered signaling pathways result in variations in the clinical presentation of DLBCL and differences in patient response to treatment, requiring more precise diagnosis of the DLBCL subtype to improve patient outcomes.

Read more about DLBCL diagnosis

References

Freedman AS, Friedberg JW. Patient education: diffuse large B cell lymphoma in adults (beyond the basics). UpToDate. Updated July 22, 2022. Accessed August 22, 2022.
Padala SA. Diffuse large B cell lymphoma. StatPearls. Updated April 28, 2022. Accessed August 22, 2022.
Miao Y, Medeiros LJ, Li J, Young KH. Diffuse large B-cell lymphoma with molecular variations more than ABC and GCB classification. Precis Cancer Med. 2018;1:4. doi:10.21037/pcm.2018.06.03
Sapkota S, Shaikh H. Non-Hodgkin lymphoma. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated May 1, 2022. Accessed August 22, 2022.
Kawashima I, Inamoto Y, Maeshima AM, et al. Double-expressor lymphoma is associated with poor outcomes after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2018;24(2):294-300. doi:10.1016/j.bbmt.2017.10.013
Matthews JM, Bhatt S, Patricelli MP, et al. Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma. Blood. 2016;128(2):239-248. doi:10.1182/blood-2016-02-696856
Young RM, Shaffer AL III, Phelan JD, Staudt LM. B-cell receptor signaling in diffuse large B-cell lymphoma. Semin Hematol. 2015;52(2):77-85. doi:10.1053/j.seminhematol.2015.01.008
Gandhi S. Diffuse large B-cell lymphoma (DLBCL): pathophysiology. Medscape. Updated May 6, 2021. Accessed August 22, 2022.
Yu L, Li L, Medeiros LJ, Young KH. NF-κB signaling pathway and its potential as a target for therapy in lymphoid neoplasms. Blood Rev. 2017;31(2):77-92. doi:10.1016/j.blre.2016.10.001

Reviewed by Hasan Avcu, MD, on 8/24/2022.

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.

Diffuse Large B-Cell Lymphoma (DLBCL)