Hodgkin's Lymphoma¶
Chapter 114 | Part 4: Oncology and Hematology
KEY CLINICAL POINTS¶
- HL is a B-cell malignancy with ~10% annual incidence, predominantly classical (cHL) subtype (95% of cases).
- cHL has a 85%+ cure rate with modern therapies, but late toxicities like secondary malignancies and cardiovascular disease are significant challenges.
- Ann Arbor staging system defines disease extent, with PET/CT preferred over bone marrow biopsy for staging.
- PD-L1 overexpression on Reed-Sternberg (RS) cells enables immune evasion, targeted by PD-1/PD-L1 inhibitors.
- Treatment varies by stage: ABVD for early-stage, combination chemo/radiation for intermediate, and novel immunotherapy for relapsed/refractory disease.
1. DEFINITION & OVERVIEW¶
Hodgkin's lymphoma (HL) is a malignancy of mature B lymphocytes characterized by rare neoplastic Reed-Sternberg (RS) cells in a polyclonal inflammatory infiltrate. Classical HL (cHL) accounts for ~95% of cases, while nodular lymphocyte-predominant HL (NLPHL) is a distinct subtype. cHL has a bimodal age distribution (20s and 80s) and is more common in males.
Table 114-1: WHO Classification of Hodgkin’s Lymphoma¶
| Subtype | Description |
|---|---|
| Nodular lymphocyte-predominant HL | Indolent B-cell lymphoma with lymphocyte-predominant features |
| Classical HL | Four subtypes: nodular sclerosis, lymphocyte-rich, mixed cellularity, lymphocyte-depleted |
1.1 Subtypes¶
Classical HL subtypes: nodular sclerosis, lymphocyte-rich, mixed cellularity, lymphocyte-depleted. NLPHL is a separate entity with indolent biology resembling NHL.
1.2 Prognostic Factors¶
B symptoms (weight loss, fever, night sweats), stage, LDH levels, lymph node involvement, and EBV status. International Prognostic Score (IPS) stratifies advanced-stage patients.
2. EPIDEMIOLOGY¶
Incidence: ~8,830 new cases/year in the US (2023). More common in whites/men, bimodal age distribution (20s and 80s). HIV and EBV infections are risk factors. EBV-associated cHL is more common in Asia and Peru.
Table 114-2: Ann Arbor Staging System¶
| Stage | Definition |
|---|---|
| I | Single lymph node region or lymphoid structure |
| II | Two or more lymph node regions on same diaphragm side |
| III | Lymph node regions on both diaphragm sides |
| IV | Extranodal involvement beyond 'E' sites |
2.1 Demographics¶
Median age 60 for cHL; younger age groups (US) predominantly have nodular sclerosis subtype. Elderly, HIV+, and developing countries patients more likely to have mixed-cellularity/lymphocyte-depleted subtypes.
2.2 Geographic Variations¶
EBV-associated cHL is more common in Asia and Peru. HIV-associated cHL has higher EBV prevalence (97% EBV in cHL vs 33% in non-HIV cases).
3. ETIOLOGY & PATHOPHYSIOLOGY¶
HL is B-cell origin with genetic aberrations in PD-L1 (9p24.1 locus). EBV infection (20-40% of cases) contributes to oncogenesis via LMP-1 expression. HIV-associated cHL shows clonal EBV integration. RS cells evade immune destruction via PD-L1/PD-1 axis and cytokine-mediated microenvironment.
3.1 Viral Associations¶
EBV: 20-40% of cHL cases; EBV genomes are clonal in HIV-associated cHL. HIV: 2-3x higher risk for cHL; EBV prevalence 97% vs 33% in non-HIV cases.
3.2 Molecular Mechanisms¶
PD-L1 overexpression (9p24.1 amplification) inhibits T-cell activation. EBV LMP-1 mimics CD40 signaling. RS cells interact with inflammatory microenvironment via cytokines and growth factors.
4. CLINICAL FEATURES¶
Common presentations: painless lymphadenopathy (neck, axilla), B symptoms (weight loss >10%, fever >38°C, night sweats). Subdiaphragmatic involvement (spleen, celiac nodes) is rare. Pel-Ebstein fever (intermittent high fever) occurs in 5-10% of cases. CNS, renal, and hematologic complications possible.
4.1 B Symptoms¶
Unexplained weight loss (>10%), fever (>38°C), night sweats. Present in ~30% of patients, correlates with advanced stage and poor prognosis.
4.2 Complications¶
CNS involvement (paraneoplastic cerebellar degeneration), nephrotic syndrome, immune hemolytic anemia, hypercalcemia, and lymph node pain with alcohol.
5. DIFFERENTIAL DIAGNOSIS¶
Inflammatory processes, mononucleosis, NHL, phenytoin-induced adenopathy, nonlymphomatous malignancies. Key differentiators: presence of RS cells, B symptoms, and specific immunophenotype (CD15/CD30 positivity).
5.1 Key Differentiators¶
RS cells (large, bilobed nuclei with nucleoli), CD15/CD30 positivity, and absence of other B-cell markers (CD19/CD20).
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnostic workup includes: CBC with differential, ESR, liver/kidney function, HIV/hepatitis testing, PET/CT staging (preferred over bone marrow biopsy). Biopsy of lymph node or extranodal site required for diagnosis. EBV load and PD-L1 expression are prognostic markers.
6.1 Imaging¶
PET/CT is more sensitive than bone marrow biopsy for staging. CT for mediastinal assessment. MRI for CNS involvement.
6.2 Biomarkers¶
EBV viral load, PD-L1 expression, and LDH levels. IPS score incorporates albumin, hemoglobin, and lymphocyte counts.
7. MANAGEMENT & TREATMENT¶
Early-stage: ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) ± radiation. Advanced-stage: ABVD or brentuximab-AVD. Relapsed/refractory: PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab), brentuximab vedotin, ICE/GND, or CAR-T. PET/CT-guided treatment decisions.
Table 114-2: Ann Arbor Staging System (continued)¶
| Stage | Definition |
|---|---|
| III1 | Subdiaphragmatic involvement limited to spleen, splenic hilar nodes, celiac nodes, or portal nodes |
| III2 | Subdiaphragmatic involvement includes paraaortic, iliac, or mesenteric nodes plus structures in III1 |
7.1 Early-Stage¶
ABVD (4-6 cycles) with or without involved-field radiation (30 Gy). PET/CT after 2-3 cycles guides treatment duration.
7.2 Advanced-Stage¶
ABVD or brentuximab-AVD for 6 cycles. PET/CT after 2 cycles determines response. Salvage therapy includes ICE/GND with checkpoint inhibitors.
7.3 Maintenance¶
Brentuximab vedotin post-autologous stem cell transplant. CAR-T for multiply relapsed cases.
8. PROGNOSIS & COMPLICATIONS¶
5-year PFS: 88-92% for early-stage, 62-88% for advanced-stage. Late toxicities: secondary malignancies (10-20%), cardiovascular disease, thyroid dysfunction. IPS score predicts outcomes in advanced-stage disease.
8.1 Prognostic Scores¶
IPS: 1 point for male sex, age >45, stage IV, albumin <4 g/dL, hemoglobin <10.5 g/dL, WBC ≥ 15,000/ µ L, lymphocytes <600/ µ L or <8%.
8.2 Long-Term Risks¶
Cardiovascular disease (10-20%), secondary cancers (10-20%), thyroid dysfunction, and metabolic syndrome.
9. SPECIAL CONSIDERATIONS¶
HIV-associated cHL has higher EBV prevalence and poorer outcomes. Pediatric NLPHL is indolent. Elderly patients may require less-intensive regimens. Pregnancy: avoid chemotherapy in first trimester; radiation avoided in first/second trimester.
9.1 HIV-Associated HL¶
EBV prevalence 97% vs 33% in non-HIV cases. Higher risk of treatment failure and mortality.
9.2 Pediatric Considerations¶
NLPHL is indolent; cHL in children responds well to ABVD but requires careful monitoring for late effects.
10. KEY POINTS & CLINICAL PEARLS¶
- PET/CT is the preferred staging modality.
- ABVD is the standard for early-stage cHL.
- PD-L1 expression predicts response to checkpoint inhibitors.
- EBV status and IPS score guide treatment decisions.
- Late toxicities are a major concern in long-term survivors.
- CAR-T and novel immunotherapies improve outcomes in relapsed/refractory disease.