Diffuse Large B-Cell Lymphoma (DLBCL)


Diffuse large B-cell lymphoma (DLBCL) is the most common cancer of the lymphatic system, comprising approximately 30% to 40% of cases of non-Hodgkin lymphoma (NHL).1,2 In DLBCL, B cells, a type of white blood cell, become abnormal and infiltrate tissues and organs in a widespread, diffuse pattern.3 Because of its rapid growth rate involving multiple organ systems and tissues, DLBCL can be fatal if left untreated.1

Epidemiology of DLBCL

The estimated incidence rate for DLBCL is 4.68 cases per 100,000 per year.2 

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Classification of DLBCL

Different subtypes of DLBCL develop according to the stage of B-cell differentiation (maturation) at the onset of the genetic alteration and the type of genetic mutation(s).4 

The World Health Organization has identified many different DLBCL histological subtypes, including:5

  • DLBCL, not otherwise specified (DLBCL, NOS)
  • DLBCL subtypes found in specific anatomic sites
    • Primary CNS DLBCL
    • Primary cutaneous DLBCL, leg type
    • Intravascular large B-cell lymphoma
  • T cell/histiocyte rich large B-cell lymphoma (T/HRLBCL)
  • Epstein-Barr virus (EBV)-positive DLBCL
    • DLBCL associated with chronic inflammation
  • Primary mediastinal (thymic) large B-cell lymphoma (PMBL)
  • DLBCLs with plasma cell immunophenotype
    • ALK-positive large B-cell lymphoma
    • Plasmablastic lymphoma (PBL)
    • Primary effusion lymphoma (PEL)
    • DLBCL arising in HHV-8 associated multicentric Castleman Disease (MCD)
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (B-UNC/BL/DLBCL)
    • Double-hit lymphomas
    • Triple-hit lymphomas
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (B-UNC/cHL/DLBCL)

Most DLBCL cases fall into the DLBCL, NOS category. Within this category, researchers have identified 2 main cell-of-origin (COO) molecular subtypes using gene expression profiling: germinal center B-cell (GCB) and activated B-cell (ABC) subtypes.5,6 

These molecular subtypes emerge from the genetic alterations that occur during the B-cell maturation process. Mutations that occur when the B-cell is in the dark zone of the germinal center result in GCB-DLBCLs, while genetic alterations that occur when the B-cell is in the light zone of the germinal center or after it has left the germinal center produce ABC-DLBCLs.7

Over 700 genetic variations and 150 genetic drivers contribute to the development of DLBCL, often involving chromosomal translocations of BCL2, BCL6, and MYC genes.8 Schmitz and colleagues9 created an algorithm that identified 4 genetic subtypes of DLBCL. These 4 subtypes comprised around 46.6% of all DLBCL cases. These 4 genetic subtypes included MCD (MYD88 and CD79B mutations), BN2 (BCL6 fusion and NOTCH2 mutation), N1 (NOTCH1 mutations), and EZB (EZH2 mutations and BCL2 translocations.7,9 

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Signs and Symptoms of DLBCL

Common signs and symptoms include the following1:

  • Lymphadenopathy, especially of the cervical, axillary, and inguinal lymph nodes, which may cause varying pain levels due to size or rate of mass enlargement;
  • Heavy night sweats;
  • Weight loss;
  • Fluctuating pyrexia;
  • Generalized pruritus;
  • Fatigue;
  • Anorexia;
  • Splenomegaly;
  • Pedal edema secondary to extensive pelvic lymphadenopathy; and 
  • Chest discomfort or dyspnea secondary to mediastinal lymphadenopathy. 

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Diagnosis of DLBCL

Imaging

Imaging of the gastrointestinal system, central nervous system (CNS), bones, neck, chest, abdomen, and pelvis can help ascertain the severity of lymphadenopathy and the extent of extranodal spread of disease to the visceral organs.1 

Imaging includes upper and lower gastrointestinal series; computed tomography (CT) with contrast or magnetic resonance imaging (MRI) with gadolinium for CNS imaging; bone scan, gallium-67 scan, and positron emission tomography (PET) with fluorodeoxyglucose for disease staging; and multigated acquisition scan to assess the cardiac ejection fraction before the initiation of chemotherapy.1    

Laboratory Studies

Laboratory studies may include the following1:

  • Complete blood cell count to detect anemia, thrombocytopenia, and/or leukopenia indicative of bone marrow involvement;
  • Serum electrolyte levels to assess for renal involvement;
  • Lactate dehydrogenase and uric acid concentrations, which indicate the tumor burden;
  • Hepatitis B testing for patients receiving chemoimmunotherapy combined with rituximab; and
  • Flow cytometry to assess the clonal cell population and differentiate between DLBCL subtypes of B- or T-cell origin.

Procedures

Bone marrow aspiration and biopsy are completed as a staging procedure. Lymph node biopsy provides confirmation of DLBCL diagnosis. Patients with advanced DLBCL may require a lumbar puncture for cytologic and chemical analysis of the cerebrospinal fluid.

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Prognosis of DLBCL

Since 1993, clinicians have used the International Prognostic Index (IPI) to predict prognosis in patients with DLBCL on the basis of 5 clinical factors, including the following6:

  • Patient age;
  • Stage of disease;
  • Number of extranodal sites of disease;
  • Performance status; and
  • Lactate dehydrogenase (LDH) level.

DLBCL subtype may influence prognosis. ABC subtypes have a worse prognosis than GCB subtypes when treated with standard first-line chemoimmunotherapy. Double- and triple-hit lymphomas also are more resistant to standard treatments.7,10 

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Treatment of DLBCL

Depending on the stage of disease at diagnosis, the primary intent of treatment is to achieve long-lasting, complete remission or to prevent or delay metastasis when disease is more advanced.1,11 In addition to predicting prognosis, the molecular classification of DLBCL subtypes increases the likelihood of successful treatment because it allows the use of customized therapy with novel agents that target specific subtypes.6

The standard, first-line immunochemotherapy for DLBCL is a combination of Rituxan® with cyclophosphamide, hydroxydaunorubicin (sold as Lipodox® or Doxil®), Oncovin®, and prednisone (R-CHOP), which is administered in either a 14- or 21-day cycle. Radiation therapy may be administered subsequently.1,11 R-CHOP results in disease remission in approximately 50% to 60% of patients with DLBCL.6 

Etoposide (sold as Toposar® and Etopophos®) is an alternative for hydroxydaunorubicin in patients with absolute contraindications to treatment with anthracyclines. This can provide an effective substitute regimen of R-CEOP. 11

For patients with relapsed DLBCL or those whose disease fails to respond to standard treatment, options include Xpovio®, Monjuvi® with Revlimid®, high-dose chemotherapy with autologous stem cell rescue with or without subsequent radiation, and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy.1,11

Use of a venous access device may be warranted for the repeated administration of chemotherapy and the collection of blood samples to evaluate possible toxicity due to treatment.11

Patients with consistently low hemoglobin levels due to either chemotherapy or disease progression may require red blood cell transfusions or the administration of hematopoietic growth factor.11 

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References

  1. Gandhi S. Diffuse large B-cell lymphoma (DLBCL): practice essentials. Medscape. Updated May 6, 2021. Accessed August 2, 2022.
  2. Gandhi S. Diffuse large B-cell lymphoma (DLBCL): epidemiology. Medscape. Updated May 6, 2021. Accessed August 2, 2022.
  3. Diffuse large B cell lymphoma. Cancer Research UK. Accessed August 2, 2022.
  4. Gandhi S. Diffuse large B-cell lymphoma (DLBCL): pathophysiology. Medscape. Updated Ma 6, 2021. Accessed August 2, 2022.
  5. Xie Y, Pittaluga S, Jaffe ES. The histological classification of diffuse large B-cell lymphomas. Semin Hematol. 2015;52(2):57-66. 
  6. Liu Y, Barta SK. Diffuse large B-cell lymphoma: 2019 update on diagnosis, risk stratification, and treatment. Am J Hematol. 2019;94(5):604-616. doi:10.1002/ajh.25460
  7. Miao Y, Medeiros LJ, Li J, Young KH. Diffuse large B-cell lymphoma with molecular variations more than ABC and GCB classification. Precision Cancer Medicine. 2018;1(0). doi: 10.21037/pcm.2018.06.03
  8. Bakhshi TJ, Georgel PT. Genetic and epigenetic determinants of diffuse large B-cell lymphoma. Blood Cancer J. 2020;10(12):1-23. doi:10.1038/s41408-020-00389-w
  9. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378(15):1396-1407. doi:10.1056/NEJMoa1801445
  10. Nowakowski GS, Czuczman MS. ABC, GCB, and double-hit diffuse large B-cell lymphoma: does subtype make a difference in therapy selection? Am Soc Clin Oncol Educ Book. Published online 2015:e449-e457. doi:10.14694/EdBook_AM.2015.35.e449
  11. Gandhi S. Diffuse large B-cell lymphoma (DLBCL) treatment and management. Medscape. Updated May 6, 2021. Accessed August 2, 2022.

Reviewed by Harshi Dhingra, on 9/6/2022.

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