What are the risk factors and causes of non‑Hodgkin lymphoma?

Risk Factors and Causes of Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma arises from malignant transformation of B-lymphocytes, T-lymphocytes, or natural killer cells, with immune dysfunction—including immunosuppression, chronic antigenic stimulation, and autoimmune conditions—representing the most strongly established risk factors. 1, 2

Immunologic Risk Factors

Immunodeficiency States

• Severe immunodeficiency confers the highest risk, with relative risks of 10-100 or greater in patients with HIV/AIDS, those receiving immunosuppressive therapy after organ transplantation, and individuals with congenital immunodeficiency syndromes. 2
• The mechanism involves loss of immune surveillance that normally prevents malignant lymphocyte proliferation, creating a permissive environment for lymphomagenesis. 2

Autoimmune Diseases

• Autoimmune conditions are associated with moderately increased NHL risk, including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, psoriasis, and celiac disease. 2
• The underlying mechanism likely involves chronic antigenic stimulation leading to sustained B-cell proliferation, which increases the probability of random replication errors and malignant transformation. 3
• However, GWAS studies show that shared genetic variation between autoimmune diseases and NHL subtypes explains little of the total risk, suggesting the association is primarily mediated through inflammatory pathways rather than common inherited genetic factors. 4

Allergic and Atopic Conditions

• Allergic conditions and early birth order appear protective against NHL, suggesting that immune system modulation in early life may reduce lymphoma risk. 2

Infectious Agents

Virus-Associated Lymphomas

• Specific viral infections are causally linked to distinct NHL subtypes:
  • Epstein-Barr virus causes immunodeficiency-associated central nervous system NHL 2
  • Human T-lymphotrophic virus type 1 causes adult T-cell leukemia/lymphoma 2
  • Human herpesvirus 8 causes body cavity-based lymphoma 2
  • Hepatitis C virus is associated with increased NHL risk 3

Bacterial Infections

• Helicobacter pylori infection causes gastric mucosa-associated lymphoid tissue (MALT) lymphoma through chronic antigenic stimulation of gastric lymphoid tissue. 2

Important caveat: While these specific infections are well-established causes of particular NHL subtypes, they account for only a small proportion of total NHL incidence. 2

Environmental and Occupational Exposures

Chemical Exposures

• Occupational exposures to pesticides, herbicides, and organic solvents show weak to moderate associations with NHL risk, though the evidence is less consistent than for immunologic factors. 2
• Agricultural workers exposed to these chemicals demonstrate elevated NHL rates in multiple epidemiologic studies. 2

Ultraviolet Radiation

• Sun exposure appears protective against NHL, with two studies reporting decreased risk associated with higher UV exposure. 2
• This finding is paradoxical given UV radiation's known immunosuppressive effects, and the mechanism remains unclear. 3

Lifestyle Factors

Tobacco and Alcohol

• Smoking shows weak positive association specifically with follicular NHL subtype, but not with NHL overall. 2
• Alcohol consumption is associated with decreased NHL risk across multiple studies. 2

Blood Transfusions

• Blood transfusions have been implicated as a potential risk factor, possibly through immunomodulatory effects or transmission of oncogenic agents. 3

Genetic Factors

• Inherited genetic variation identified through GWAS studies has shown limited reproducibility and explains little of NHL risk, despite extensive investigation. 5, 6
• A study of 118 genes controlling lymphocyte development, immunity, DNA repair, and apoptosis found no replicable associations after correction for multiple testing. 6
• The lack of strong inherited genetic signals suggests that somatic mutations, gene-environment interactions, and epigenetic factors likely play more important roles than common germline variants. 5

Epidemiologic Context

• NHL represents approximately 4% of all new cancer cases in the United States, with B-cell lymphomas accounting for 80-85% of cases and T-cell lymphomas representing 15-20%. 1, 7
• NHL incidence doubled over the past two decades in westernized countries, with only about 50% of this increase explained by improved cancer reporting, classification changes, and AIDS-associated lymphomas. 3

Critical clinical pitfall: The heterogeneity of NHL subtypes means that risk factors may differ substantially between diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and other subtypes—clinicians should not assume uniform risk profiles across all NHL types. 1, 5