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PA19.1-6 | Lymphomas — Hodgkin vs Non-Hodgkin — Part 4

Pathogenesis — Translocations, EBV, and Immunodeficiency

⚑ AI image — pending faculty review (auto-QA score 6/10; best of 3 attempts)

A four-panel diagram summarizing lymphoma pathogenesis through oncogenic translocations, EBV-driven B-cell signalling, and immunodeficiency-related loss of immune surveillance. — **Panel A:** Simplified lymph node, germinal centre B cell, clonal lymphoid proliferation, oncogenic translocation pathway, EBV-driven pathway, immunodeficiency pathway, lymphoma endpoint. **Panel B:** Germinal centre B cell nucleus, immunoglobulin promoter, proto-oncogene activation, t(14;18) BCL2, t(8;14) MYC, t(11;14) Cyclin D1, t(2;5) ALK, follicular lymphoma, Burkitt lymphoma, mantle cell lymphoma, ALCL. **Panel C:** EBV virion, CD21 receptor, infected B cell, LMP1, CD40-like signalling, LMP2A, B-cell receptor-like signalling, antigen-independent proliferation, Reed-Sternberg cell, Hodgkin lymphoma association. **Panel D:** Cytotoxic T cell, impaired immune surveillance, EBV-positive B-cell clone, HIV/AIDS, post-transplant immunosuppression, congenital immunodeficiency, uncontrolled lymphoid expansion.

Three pathogenetic mechanisms account for most lymphomagenesis:

1. Oncogenic Translocations (Immunoglobulin Promoter Hijacking)

B-cell lymphomas exploit the somatic hypermutation and class-switch recombination machinery of the germinal centre. Errors during these physiological processes translocate proto-oncogenes next to constitutively active immunoglobulin gene promoters:

Translocation	Gene deregulated	Lymphoma
t(14;18)(q32;q21)	BCL2 (anti-apoptotic)	Follicular lymphoma
t(8;14)(q24;q32)	MYC (proliferation)	Burkitt lymphoma
t(11;14)(q13;q32)	Cyclin D1 (cell-cycle)	Mantle cell lymphoma
t(2;5)(p23;q35)	ALK (signalling kinase)	ALCL (T-cell)

2. EBV-Driven Oncogenesis

EBV infects B cells via CD21. In immunocompromised hosts, latent EBV proteins (LMP1, LMP2A) mimic CD40 and B-cell receptor signalling respectively, driving B-cell proliferation without normal antigenic stimulus. In HL, EBV infects the RS cell precursor and activates NF-κB, suppressing apoptosis.

3. Immunodeficiency

Normal immune surveillance identifies and eliminates EBV-infected, malignantly transformed B cells. HIV-related CD4 depletion, post-transplant immunosuppression, and congenital immunodeficiencies all remove this surveillance, dramatically increasing lymphoma risk — particularly EBV-driven NHLs (post-transplant lymphoproliferative disorder, primary CNS lymphoma in AIDS).

Diagnosis — Excision Biopsy and Immunohistochemistry

A four-panel medical diagram shows excision biopsy tissue allocation, lymph node architecture on H&E, IHC markers distinguishing Hodgkin from non-Hodgkin lymphoma, and key subtyping markers including CD10, BCL2, and Ki-67. — **Panel A:** Intact excised lymph node, preserved capsule, preserved architecture, fixed sections for H&E morphology, fresh/frozen tissue for flow cytometry, cytogenetics/FISH for translocation detection. **Panel B:** Follicular pattern, diffuse pattern, lymph node capsule, follicle, germinal centre, diffuse lymphoid infiltrate. **Panel C:** Classic Reed-Sternberg cell, CD15+, CD30+, CD45-, NHL cells, CD45+, CD20+ B-NHL, CD3+ T-NHL. **Panel D:** CD10 germinal-centre marker, BCL2 positive within follicles, Ki-67 about 100% in Burkitt lymphoma, Ki-67 below 20% in follicular lymphoma.

The diagnostic pathway for suspected lymphoma is standardised:

Step 1 — Excision Biopsy
The entire lymph node is removed intact. This preserves architecture (follicular vs diffuse pattern) and allows fresh tissue allocation for:
- Fixed sections → H&E morphology
- Frozen/fresh → flow cytometry (immunophenotyping of live cells)
- Cytogenetics/FISH → translocation detection

Step 2 — Immunohistochemistry (IHC) Panel
A minimum panel is applied to distinguish HL from NHL and determine NHL subtype:

Marker	Significance
CD45 (LCA)	Pan-leucocyte; negative in classic RS cells
CD20	B-cell marker; positive in most B-NHL and NLPHL
CD3	T-cell marker
CD15, CD30	Positive in cHL RS cells
CD10	Germinal-centre marker; positive in FL, Burkitt, DLBCL-GCB
BCL2	Anti-apoptotic; positive in FL (within follicles — key diagnostic feature)
Ki-67	Proliferation index; ~100% in Burkitt, <20% in FL

Cross-reference:
- H7 (CLL/SLL overlap): SLL is NHL territory — same clone, different site predominance
- H11 (Myeloma): Multiple myeloma is a plasma cell neoplasm — a post-germinal-centre B-cell malignancy; it is technically an NHL but is classified and managed separately