Lymphoma: Etiology, Pathogenesis, and Mechanistic Insights

Introduction

Lymphomas are malignant neoplasms of lymphocytes (and rarely histiocytes) arising in lymph nodes or extranodal lymphoid tissues. They reflect disruption of normal B‑cell, T‑cell, or NK‑cell differentiation and survival pathways. Because lymphoid tissue is widely distributed and lymphocytes recirculate, lymphoma can present in virtually any anatomical site. Incidence has risen globally, influenced by aging populations, immunosuppression, and improved diagnostics.

Major Categories

• Hodgkin Lymphoma (HL): Defined by the presence of Reed–Sternberg cells in an inflammatory background; classical subtypes vs nodular lymphocyte‑predominant HL.
• Non‑Hodgkin Lymphoma (NHL): Diverse group subdivided by cell of origin (B‑cell ≈85–90%, T‑/NK‑cell ≈10–15%) and clinical behavior (indolent vs aggressive vs highly aggressive).

Etiologic Factors

1. Oncogenic Viruses

| Virus | Associated Lymphoma(s) | Mechanism Highlights |
|—|—|—|
| Epstein–Barr virus (EBV) | Endemic Burkitt, subset of Hodgkin (mixed cellularity, nodular sclerosis), extranodal NK/T‑cell lymphoma, immunodeficiency‑associated diffuse large B‑cell lymphoma (DLBCL) | Latency programs (EBNA, LMP proteins) drive B‑cell proliferation, inhibit apoptosis, induce genomic instability |
| Human T‑cell lymphotropic virus type 1 (HTLV‑1) | Adult T‑cell leukemia/lymphoma (ATLL) | Tax and HBZ dysregulate NF‑κB and cell cycle; chronic proliferation predisposes to transformation |
| Kaposi sarcoma–associated herpesvirus (HHV‑8) | Primary effusion lymphoma, multicentric Castleman disease‑associated plasmablastic proliferations | Viral IL‑6, vCyclin, and LANA promote survival and proliferation |
| Hepatitis C virus (HCV) | Marginal zone lymphoma, DLBCL (subset) | Chronic antigenic stimulation; potential regression after antiviral therapy |
| HIV (indirect) | High‑grade B‑cell lymphomas (DLBCL, Burkitt), primary CNS lymphoma | Profound immunosuppression allows unchecked EBV‑driven B‑cell proliferation |

2. Immune Dysregulation

• Iatrogenic immunosuppression (post‑transplant lymphoproliferative disorders, PTLD) from calcineurin inhibitors or biologics.
• Primary immunodeficiencies (e.g., CVID, Wiskott–Aldrich) and acquired (HIV/AIDS).
• Autoimmune disease (e.g., Sjögren syndrome → MALT lymphoma; celiac disease → enteropathy‑associated T‑cell lymphoma; Hashimoto thyroiditis → thyroid MALT lymphoma).

3. Chronic Antigenic Stimulation

• Helicobacter pylori (gastric MALT lymphoma); Chlamydia psittaci (ocular adnexal MALT); Borrelia burgdorferi (cutaneous MALT); Campylobacter jejuni (immunoproliferative small intestinal disease).
• Persistent antigen drives lymphoid proliferation and somatic hypermutation, increasing chance of oncogenic hits.

4. Genetic and Epigenetic Lesions

• Translocations activating oncogenes (e.g., t(14;18) BCL2 in follicular lymphoma; MYC rearrangements in Burkitt; BCL6 alterations in DLBCL; CCND1 t(11;14) in mantle cell lymphoma).
• Mutations in epigenetic modifiers (EZH2, KMT2D, CREBBP) and signaling pathways (MYD88 L265P, CARD11, NOTCH1/2, STAT3) alter differentiation, survival, and NF‑κB/JAK‑STAT signaling.

5. Environmental and Other Factors

• Ionizing radiation, occupational pesticide exposure (epidemiologic associations), obesity, and aging (accumulation of genomic mutations, immunosenescence).

Pathogenesis Themes

1. Dysregulated Survival: Overexpression of anti‑apoptotic proteins (BCL2, MCL1) or loss of pro‑apoptotic controls.
2. Constitutive Signaling: Chronic activation of B‑cell receptor (BCR), JAK‑STAT, NF‑κB, or NOTCH pathways sustains proliferation.
3. Genomic Instability: Somatic hypermutation and class switch recombination create double‑strand breaks that facilitate translocations.
4. Immune Evasion: PD‑L1/PD‑L2 amplification (e.g., 9p24.1 in classical HL) and reduced antigen presentation (β2‑microglobulin loss) enable persistence.
5. Microenvironment Dependence: Stromal cells, follicular dendritic cells, and cytokine milieu provide survival signals (e.g., CXCL12/CXCR4, IL‑6, BAFF).

Illustrative Entities

• Endemic Burkitt Lymphoma: EBV‑associated; MYC translocation t(8;14) drives unchecked proliferation; high Ki‑67 index (~100%).
• Follicular Lymphoma: Germinal center B‑cell origin; t(14;18) → BCL2 overexpression; indolent but incurable; risk of transformation to aggressive lymphoma.
• Diffuse Large B‑Cell Lymphoma (DLBCL): Molecular subtypes (GCB vs ABC) with prognostic and therapeutic significance; ABC subtype often has NF‑κB pathway activation.
• Mantle Cell Lymphoma: t(11;14) → Cyclin D1 overexpression; SOX11 expression in classic subtype; typically aggressive.
• Hodgkin Lymphoma: R–S cells secrete cytokines shaping an immunosuppressive microenvironment; frequent 9p24.1 alterations upregulate PD‑L1/PD‑L2.

Clinical Implications

• Etiologic clues (e.g., chronic H. pylori gastritis) may allow disease regression with targeted antimicrobial therapy (gastric MALT).
• Viral association (EBV, HTLV‑1, HHV‑8) influences prognosis and potential therapeutic targets (e.g., antiviral or immunomodulatory strategies).
• Genetic profiling refines classification and guides targeted therapy (e.g., BTK inhibitors in BCR pathway–activated lymphomas, EZH2 inhibitors in EZH2‑mutant follicular lymphoma, lenalidomide in ABC DLBCL).

Prevention and Risk Reduction

• Control chronic infections (eradicate H. pylori; treat HCV with direct‑acting antivirals).
• Optimize HIV management with effective antiretroviral therapy.
• Judicious immunosuppression in transplant recipients; monitor EBV load in high‑risk PTLD settings.

Key Takeaways

• Lymphoma pathogenesis is multifactorial: viral infection, antigenic drive, immune dysregulation, and hallmark genetic lesions converge on survival and proliferation pathways.
• Recognition of specific infectious or immune triggers can enable non‑cytotoxic interventions in select entities.
• Molecular subclassification increasingly directs precision therapies and prognostication.