What are EBV (Epstein-Barr Virus)-associated lymphomas?

EBV-Associated Lymphomas: Types, Pathobiology, and Clinical Features

EBV-associated lymphomas are a heterogeneous group of malignancies characterized by the presence of Epstein-Barr virus in lymphoid cells, primarily affecting B-cells but also T/NK-cells, with distinct clinical and pathological features depending on the specific lymphoma subtype and host immune status. These lymphomas represent serious complications with significant morbidity and mortality, requiring prompt diagnosis and specialized treatment.

Types of EBV-Associated Lymphomas

B-Cell Lymphomas

• Burkitt Lymphoma: Classically associated with EBV, especially endemic variant 1, 2
• Diffuse Large B-Cell Lymphoma (DLBCL): EBV-positive DLBCL not otherwise specified is recognized as a provisional entity in the 2016 WHO classification 3
• Hodgkin Lymphoma: EBV is found in Reed-Sternberg cells in approximately 40% of cases 4
• Post-Transplant Lymphoproliferative Disorders (PTLD): Almost exclusively EBV-related after hematopoietic stem cell transplantation 5

T/NK-Cell Lymphomas

• Extranodal NK/T-cell lymphoma, nasal type: Strongly associated with EBV 2
• Angioimmunoblastic T-cell lymphoma: Frequently contains EBV-infected B cells 6
• Other rare T-cell lymphoma subtypes 6

Pathobiology of EBV-Associated Lymphomas

Viral Mechanisms

• Latent Infection Patterns: Different patterns of viral gene expression (latency I, II, III) are associated with specific lymphoma types 5
  • Latency I (EBNA-1 and EBERs only): Typically seen in Burkitt lymphoma 5
  • Latency II (EBNA-1, EBERs, and LMPs): Common in Hodgkin lymphoma, T-cell lymphomas, and NK-cell lymphomas 5
  • Latency III (All EBNAs, LMPs, and EBERs): Seen in immunodeficiency-associated lymphoproliferative disorders 5

Host Factors

• Immune Dysregulation: Critical factor in development of EBV-associated lymphomas 6
• Age-Related Immunosenescence: Associated with EBV-positive DLBCL in elderly patients 3
• Iatrogenic Immunosuppression: Predisposes to PTLD and other EBV-driven lymphoproliferative disorders 5, 3

Clinical Features and Diagnosis

Clinical Presentation

• Lymphadenopathy: Often prominent and may be localized or generalized 7
• B Symptoms: Fever, night sweats, weight loss 7
• Organ-Specific Symptoms: Depends on site of involvement (e.g., CNS, GI tract, bone marrow) 7
• Rapid Disease Progression: Particularly in immunocompromised hosts 5

Diagnostic Approach

• Histopathology: Essential for definitive diagnosis

  • EBER-ISH (EBV-encoded RNA in situ hybridization): Gold standard for detecting EBV in tissue specimens 5
  • Immunohistochemistry: For viral proteins, though less sensitive than EBER-ISH 5

• Molecular Testing:

  • Quantitative PCR: For EBV DNA in peripheral blood 7
  • Clonality Assessment: To determine monoclonal or oligoclonal cell populations 5

Classification Criteria

• WHO Classification: Recognizes four morphological types of PTLD 5:
  1. Polyclonal early lesions
  2. Polymorphic PTLD
  3. Monomorphic PTLD (B-cell or T/NK-cell)
  4. Classical Hodgkin lymphoma-type PTLD

Special Considerations

Post-Transplant Setting

• HSCT Recipients: At particularly high risk for EBV-PTLD 5
• Monitoring: Regular EBV viral load monitoring recommended after high-risk allogeneic HSCT 7
• Pre-emptive Therapy: Consideration of rituximab for significant EBV DNA-emia without clinical symptoms 7

Immunocompetent vs. Immunocompromised Hosts

• Immunocompetent Hosts: Typically develop specific subtypes (e.g., endemic Burkitt lymphoma, some Hodgkin lymphoma cases) 1
• Immunocompromised Hosts: Higher risk for aggressive lymphoproliferative disorders with poorer outcomes 5, 3

Treatment Approaches

First-Line Therapy for EBV-PTLD

• Reduction of Immunosuppression: When applicable 7
• Rituximab: Anti-CD20 monoclonal antibody therapy 7

Advanced or Refractory Disease

• Cellular Therapy: EBV-specific cytotoxic T lymphocytes or donor lymphocyte infusion 7
• Novel Approaches:
  • Activation of lytic viral infection combined with antiviral drugs 6
  • Inhibition of EBV-induced oncogenic cellular signaling pathways 6
  • EBV vaccines (investigational) 6

Prognosis and Monitoring

• Variable Outcomes: Depending on lymphoma subtype, host factors, and treatment response 2
• Monitoring: EBV viral load can be used to monitor disease response 2
• Mortality: Despite improvements in therapy, mortality remains significant, with approximately one-third of PTLD patients dying from the disease 5

EBV-associated lymphomas represent a complex group of malignancies with distinct biological and clinical features. Early diagnosis, appropriate classification, and targeted therapy are essential for improving outcomes in affected patients.