What are the causes of Diffuse Large B-Cell Lymphoma (DLBCL)?

Causes of Diffuse Large B-Cell Lymphoma (DLBCL)

Diffuse Large B-Cell Lymphoma (DLBCL) is primarily caused by a combination of genetic alterations, immune dysregulation, and environmental factors, with specific risk factors including family history of lymphoma, autoimmune disease, HIV infection, hepatitis C virus seropositivity, high body mass as a young adult, and certain occupational exposures. 1

Epidemiology and Incidence

DLBCL is the most common type of aggressive non-Hodgkin lymphoma, accounting for:

• 30-58% of all non-Hodgkin lymphomas 1, 2
• Crude incidence in Europe of 3.8/100,000/year 1
• Incidence increases with age 1, 3

Established Risk Factors

Several well-documented risk factors have been identified:

• Genetic predisposition:

  • Family history of lymphoma 1
  • Genetic alterations involving MYC, BCL2, and BCL6 genes 2

• Immune system disorders:

  • Autoimmune diseases 1
  • Human Immunodeficiency Virus (HIV) infection 1
  • Hepatitis C Virus (HCV) seropositivity 1

• Lifestyle and environmental factors:

  • High body mass as a young adult 1
  • Certain occupational exposures 1

Molecular and Pathophysiological Mechanisms

DLBCL arises from the germinal center and represents a heterogeneous disease with different molecular subtypes:

1. Cell of Origin Classification 3, 4:

   • Germinal center B-cell-like (GCB) subtype
   • Activated B-cell-like (ABC) subtype
   • Unclassifiable cases

2. Genetic Alterations 2, 5:

   • MYC rearrangements
   • BCL2 and/or BCL6 rearrangements
   • Double-hit or triple-hit lymphomas (concurrent rearrangements)
   • TP53 mutations
   • CDKN2A loss

3. Molecular Pathogenesis 6, 5:

   • Chronic replication stress
   • DNA repair pathway dysfunction
   • Genomic instability
   • Alterations in cell cycle regulation

Specific Subtypes Based on Molecular Features

Recent molecular studies have identified distinct DLBCL subtypes with different pathogenic mechanisms 5:

• Low-risk ABC-DLBCLs of extrafollicular/marginal zone origin
• Two distinct subsets of GCB-DLBCLs with different outcomes
• ABC/GCB-independent group with biallelic inactivation of TP53 and CDKN2A loss

Clinical Implications of Causal Factors

Understanding the causes of DLBCL has important clinical implications:

• Prognosis: Different molecular subtypes have varying outcomes (GCB generally has better prognosis than ABC) 2, 4
• Treatment response: Non-GCB subtypes respond more poorly to standard chemoimmunotherapy 4
• Targeted therapies: Identification of specific genetic alterations may guide targeted treatment approaches 6, 5

Diagnostic Considerations

The diagnosis of DLBCL requires:

• Excisional biopsy of suspicious lymph node 1, 4
• Immunohistochemistry to determine cell of origin 1, 4
• Fluorescent in situ hybridization (FISH) to detect genetic rearrangements 2, 4
• Advanced molecular techniques for comprehensive genetic profiling 3, 5

Understanding these causal factors is essential for risk stratification, prognostication, and development of targeted therapeutic approaches for patients with DLBCL.