What is the etiology of Hodgkin lymphoma?

Etiology of Hodgkin Lymphoma

Hodgkin lymphoma (HL) is strongly associated with Epstein-Barr virus (EBV) infection, which plays a key role in the malignant transformation of germinal center B-lymphocytes into Hodgkin-Reed-Sternberg cells through activation of pro-proliferative and antiapoptotic pathways. 1

Epidemiology and Risk Factors

Hodgkin lymphoma has a distinctive bimodal age distribution:

• First peak: Young adults in their third decade of life
• Second peak: Adults aged 55 years or older 2

The incidence of HL in Western countries is approximately 2-3 cases per 100,000 people annually, resulting in about 9,050 new cases in the United States each year 2

Key risk factors include:

• EBV infection (particularly for mixed cellularity and lymphocyte-depleted subtypes)
• Family history (siblings of patients have increased risk)
• Immunodeficiency states (HIV infection, post-transplant)
• Prior chemotherapy or radiation therapy

Pathogenesis

The pathogenesis of Hodgkin lymphoma involves several mechanisms:

1. Viral-mediated transformation: EBV infection of B cells leads to expression of viral proteins that activate NF-κB and other signaling pathways 1, 3

2. Genetic alterations: Chromosomal abnormalities and mutations affecting:

   • Cell cycle regulation
   • Apoptotic pathways
   • Cytokine signaling

3. Immune evasion: Hodgkin-Reed-Sternberg cells:

   • Lack functional B-cell receptors that would normally trigger apoptosis
   • Express immunosuppressive cytokines
   • Create an immunosuppressive microenvironment 3

4. Microenvironmental interactions: The characteristic inflammatory background consists of:

   • T lymphocytes
   • Histiocytes
   • Eosinophils
   • Plasma cells
   • Fibroblasts

   These cells are recruited by cytokines secreted by the malignant cells and contribute to tumor growth and immune evasion 2

Histopathological Classification

Hodgkin lymphoma is divided into two main types:

1. Classical Hodgkin Lymphoma (CHL) - 95% of cases 4

   • Characterized by Reed-Sternberg cells with CD15+/CD30+/CD20- immunophenotype
   • Subtypes:
     • Nodular sclerosis (most common)
     • Mixed cellularity
     • Lymphocyte-rich
     • Lymphocyte-depleted
     • Unclassifiable

2. Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL) - 5% of cases

   • Characterized by "popcorn cells" (lymphocyte-predominant cells)
   • Different immunophenotype: CD15-/CD30-/CD20+ 2, 4

Molecular Mechanisms

The malignant transformation in HL involves:

1. Constitutive activation of NF-κB pathway: Promotes cell survival and proliferation

2. Dysregulation of JAK/STAT signaling: Leads to increased cytokine production and cell growth

3. Aberrant expression of transcription factors: Alters normal B-cell development programs

4. Defective apoptotic mechanisms: Allows cells that would normally undergo apoptosis (due to lack of B-cell receptor) to survive 3

Clinical Presentation

Most patients (>60%) present with painless, enlarged cervical or supraclavicular lymph nodes. Mediastinal involvement is common, while sub-diaphragmatic presentations are less frequent. Approximately 35% of patients exhibit systemic "B symptoms" (fever, night sweats, weight loss) 2, 1.

Diagnostic Approach

Diagnosis requires a lymph node biopsy showing the characteristic histopathological features and immunophenotype of Hodgkin lymphoma. The disease typically spreads contiguously through the lymphatic system before involving distant organs 2.

Prognosis

With modern treatment approaches, HL is curable in at least 80% of patients. The 5-year survival rate is approximately 81%, with early-stage disease having even better outcomes (>95% 5-year overall survival) 2, 1.

Understanding the etiology of Hodgkin lymphoma has led to improved risk stratification and targeted therapies, including antibody-drug conjugates like brentuximab vedotin for CD30+ disease and immune checkpoint inhibitors for relapsed/refractory cases 5, 6, 7.