Which viruses may lead to the development of non-Hodgkin's lymphoma?

Viruses Associated with Non-Hodgkin's Lymphoma Development

Hepatitis C virus (HCV) is strongly associated with the development of non-Hodgkin's lymphoma (NHL), particularly B-cell lymphomas, with multiple case-control studies demonstrating this relationship. 1

Evidence for Viral Associations with NHL

Hepatitis C Virus (HCV)

• Strong association between HCV seropositivity and development of NHL, particularly B-cell lymphomas, demonstrated in multiple case-control studies 1
• Prevalence of HCV seropositivity is consistently increased among patients with B-cell histologies, including diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphomas 1
• A retrospective study showed significantly higher cumulative incidence of developing malignant lymphomas in patients with persistent HCV infection compared to those who achieved sustained virologic response (15-year incidence rate: 2.6% vs. 0%) 1
• The pathogenic role of HCV is further supported by evidence that antiviral treatment can lead to regression of NHL in HCV-positive patients 1
• The fraction of NHL attributable to HCV is geographically variable and may reach 10% in highly endemic areas 1

Epstein-Barr Virus (EBV)

• EBV has been identified as an etiologic agent for NHL, particularly Burkitt's lymphoma 2
• EBV is linked to NHLs in immunosuppressed individuals and extranodal natural killer/T-cell NHL 3
• EBV directly transforms lymphocytes, which is one mechanism for lymphomagenesis 3, 4

Human Immunodeficiency Virus (HIV)

• HIV causes profound depletion of CD4+ T lymphocytes, leading to acquired immunodeficiency syndrome and an associated high risk for some NHL subtypes 3
• HIV-related immunosuppression is strongly correlated with increasing incidence of NHL 5

Other Viruses

• Human T-cell lymphotropic virus type I (HTLV-I) is associated with adult T-cell leukemia/lymphoma 2, 3
• Human herpesvirus 8 (HHV8) is linked to primary effusion lymphoma 3, 5

Mechanisms of Viral Lymphomagenesis

• Viruses can contribute to NHL development through three main mechanisms:

  1. Direct transformation of lymphocytes (EBV, HHV8, HTLV-I) 3
  2. Profound immunosuppression (HIV) 3
  3. Chronic immune stimulation (HCV) 3

• For HCV specifically, three general mechanisms have been proposed:

  1. Continuous stimulation of lymphocyte B-cell receptors by viral antigens 1
  2. Oncogenic effect mediated by intracellular viral proteins during HCV replication in B-cells 1
  3. B-cell damage from mutation of tumor suppressor genes ("hit and run" theory) 1

Clinical Implications

• HCV-positive patients with indolent NHL may benefit from antiviral treatment as initial therapy 1
• Antiviral therapy (interferon with or without ribavirin) has shown to induce lymphoma regression in HCV-positive patients with indolent NHL 1
• In HCV-positive patients who achieve remission with antitumor therapy, subsequent antiviral treatment may be associated with lower risk of disease relapse 1
• Achievement of sustained virologic response with antiviral therapy may reduce the incidence of malignant lymphoma in patients with HCV infection 1

Diagnostic Considerations

• In subjects with HCV infection, diagnosis of lymphoma should be suspected based on clinical symptoms and confirmed by histological examination of involved tissue 1
• Specific histotype must be defined according to WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 1
• Marginal zone lymphoma, lymphoplasmacytic lymphoma, and diffuse large B-cell lymphoma are the histotypes most frequently associated with HCV infection 1