Hodgkin's Lymphoma¶
Oncology and Hematology · Part 4 – Oncology: Hematologic Malignancies · Part 4 – Oncology: Hematologic Malignancies · Chapter 114
Key Clinical Points¶
- Hodgkin's lymphoma (HL) is a malignancy of mature B lymphocytes, representing ~10% of all lymphomas.
- Classical Hodgkin's lymphoma (cHL) is the majority subtype; Nodular lymphocyte-predominant HL (NLPHL) is biologically related to indolent B-cell NHLs.
- HL has a bimodal age distribution with peaks in the 20s and 80s.
- Reed-Sternberg (RS) cells are diagnostic, large with bilobed nuclei, expressing CD15 and CD30 (<1% of tumor cellularity).
- 97% have PD-1L locus aberrations leading to immune suppression.
- B symptoms (fever >38°C, night sweats, weight loss >10%) are prognostic factors in staging.
- Pain in lymph nodes on alcohol ingestion is a characteristic finding in HL.
- Early-stage disease (Stage I-II) treated with ABVD chemotherapy (4-6 cycles) ± radiation; 5-year OS ~97-100%.
- Advanced-stage disease (Stage III-IV) treated with ABVD or AVD ± radiation.
- Relapsed disease treated with salvage chemotherapy (ICE, GND) + autologous stem cell transplantation and immune checkpoint inhibitors (nivolumab, pembrolizumab).
- International Prognostic Score (IPS) predicts survival based on 7 risk factors in advanced-stage disease.
- EBV is detected in nearly all cases of HIV-associated cHL.
1. DEFINITION & OVERVIEW¶
• Definition: Hodgkin's lymphoma (HL) is a malignancy of mature B lymphocytes, representing ~10% of all lymphomas. • Subtypes: ◦ Classical Hodgkin's lymphoma (cHL): The majority subtype; cure rates >85% due to advances in chemotherapy and radiation therapy. ◦ Nodular lymphocyte-predominant HL (NLPHL): Biologically related to indolent B-cell NHLs.
1.1 Subtypes of Hodgkin's Lymphoma¶
• WHO Classification (Table 114-1): ◦ Nodular lymphocyte-predominant Hodgkin's lymphoma ◦ Classical Hodgkin's lymphoma (cHL): ◦ Nodular sclerosis (common in younger patients) ◦ Lymphocyte-rich ◦ Mixed cellularity (more common in elderly, HIV+, and developing countries) ◦ Lymphocyte-depleted ◦ Note: Nodular sclerosis and mixed-cellularity account for ~95% of cases.
2. EPIDEMIOLOGY¶
• Incidence: Stable; ~8830 new cases in the US (2023). • Demographics: More common in whites and males. • Age Distribution: Bimodal distribution with peaks in the 20s and 80s. • Presentation: Over two-thirds present with localized disease.
2.1 Risk Factors¶
• HIV Infection: Increases HL risk. • EBV Association: EBV is detected in ~100% of HIV-associated cHL vs. ~33% of non-HIV cases.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Reed-Sternberg (RS) Cells: ◦ Diagnostic hallmark; large cells with bilobed nuclei and abundant cytoplasm. ◦ Markers: CD15+ and CD30+. ◦ Prevalence: <1% of tumor cellularity. • Immune Evasion: ◦ RS cells interact with the microenvironment via cytokines to evade immune destruction. ◦ 97% have PD-L1 locus aberrations leading to immune suppression.
3.1 EBV and HIV Association¶
• EBV Role: Implicated in HL pathogenesis, particularly in HIV-associated cases. ◦ EBV genomes are episomal and clonal in HIV-related cHL, suggesting a direct oncogenic role. ◦ RS cells in these cases express LMP-1 (EBV-transforming protein).
4. CLINICAL FEATURES¶
• Primary Presentation: Palpable lymphadenopathy (neck, supraclavicular, axilla) and mediastinal adenopathy. • B Symptoms: Occur in ~1/3 of cases; used as prognostic factors. ◦ Fever >38°C ◦ Night sweats ◦ Weight loss >10% • Other Manifestations: ◦ Pel-Ebstein fever (intermittent fevers). ◦ Severe itching. ◦ Cutaneous disorders (erythema nodosum, ichthyosiform atrophy). ◦ Paraneoplastic cerebellar degeneration. ◦ Nephrotic syndrome. ◦ Immune hemolytic anemia/thrombocytopenia. ◦ Hypercalcemia. ◦ Alcohol-induced lymph node pain (characteristic finding).
5. DIFFERENTIAL DIAGNOSIS¶
• Mimickers: ◦ Inflammatory processes. ◦ Mononucleosis. ◦ Non-Hodgkin's lymphoma (NHL). ◦ Phenytoin-induced adenopathy. ◦ Nonlymphomatous malignancies.
6. INVESTIGATIONS & DIAGNOSIS¶
- Histopathology: Expert hematopathologist review of biopsy specimens to identify RS cells (bilobed nuclei, CD15+, CD30+; <1% tumor cellularity).
- Staging: PET/CT is preferred for staging over bone marrow biopsy due to patchy marrow involvement.
- Ann Arbor Staging System (Table 114-2): ◦ Stage I: Involvement of a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer's ring). ◦ Stage II: Involvement of ≥2 regions on same diaphragm side. ◦ Stage III: Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm. ◦ Stage III1: Subdiaphragmatic involvement limited to spleen, splenic hilar nodes, celiac nodes, or portal nodes. ◦ Stage III2: Subdiaphragmatic involvement includes paraaortic, iliac, or mesenteric nodes plus structures in III1. ◦ E: Localized, solitary involvement of extralymphatic tissue, excluding liver and bone marrow.
6.1 Diagnostic Criteria¶
• RS Cells: Bilobed nuclei, CD15+, CD30+ (<1% tumor cellularity). • Imaging: PET/CT preferred for bone marrow assessment.
7. MANAGEMENT & TREATMENT¶
- Early-Stage Disease (I-II): • Treatment: ABVD chemotherapy (4-6 cycles) ± radiation. • 5-year OS: ~97-100%. • Risk Stratification (Table 7.1): ◦ Low-risk/Favorable → ABVD, No radiation (or IFRT 30 Gy), 4-6 cycles. ◦ Good-risk → ABVD, Low-dose radiation (20 Gy), 2 cycles. ◦ Bulky Disease → ABVD, Involved Field radiation, 6+ cycles. • Monitoring: PET/CT after 2-3 cycles may guide treatment duration.
- Advanced-Stage Disease (III-IV): • Treatment: ABVD or AVD (Brentuximab vedotin + doxorubicin, vinblastine, dacarbazine) for 6 cycles. • Brentuximab: CD30-targeting ADC; provides benefit in advanced disease.
- Relapsed/Refractory Disease: • Salvage Chemotherapy: ICE or GND. • Consolidation: Autologous stem cell transplantation. • Advanced Options: Immune checkpoint inhibitors (nivolumab, pembrolizumab) and CAR T-cell therapy for multiply relapsed cHL.
7.1 Early-Stage Treatment Options¶
See Table 7.1 for risk-stratified treatment pathways.
7.2 Advanced-Stage Treatment Options¶
See Table 7.2 for advanced-stage regimens.
8. PROGNOSIS & COMPLICATIONS¶
• Prognostic Factors: B symptoms, bulky disease, ESR, and age. • International Prognostic Score (IPS) for Advanced Stage (Table 8.1): ◦ Risk Factors (each = 1 point): ◦ Male sex ◦ Age >45 years ◦ Stage IV ◦ Albumin <4 g/dL ◦ Hemoglobin <10.5 g/dL ◦ WBC ≥ 15,000/μL ◦ Lymphocytes <600/μL or <8% ◦ Outcome: 5-year PFS 88% (no risk factors) to 62% (≥ 4 factors). • Late Toxicity: ◦ Secondary malignancies. ◦ Cardiovascular disease (premature CAD, stroke). ◦ Thyroid dysfunction.
8.1 International Prognostic Score (IPS) Criteria¶
See Table 8.1 for specific criteria.
9. SPECIAL CONSIDERATIONS¶
• HIV-Associated HL: ◦ Risk: Increased risk of HL in HIV patients. ◦ EBV Status: Detected in nearly all cases (~100%). ◦ Molecular: RS cells express LMP-1; EBV genomes are episomal and clonal.
10. KEY PEARLS & CLINICAL TRAPS¶
• High Cure Rates: >85% with modern therapy. • Diagnostic Hallmark: RS cells (bilobed, CD15+, CD30+; <1% cellularity). • Staging Preference: PET/CT is superior to bone marrow biopsy for assessing marrow involvement. • Clinical Clue: Alcohol-induced lymph node pain is highly characteristic of HL. • Prognostic Value: B symptoms are key indicators for staging and prognosis. • Advanced Therapy: Immune checkpoint inhibitors show high response rates in relapsed disease.
Board Exam Favorites¶
• Bimodal age distribution (20s and 80s). • RS cells: CD15+/CD30+ (<1% tumor cellularity). • IPS criteria for advanced-stage prognosis. • ABVD as standard regimen for early-stage disease.
Reference Tables¶
TABLE 114-1 World Health Organization Classification of Hodgkin’s Lymphoma Nodular lymphocyte-predominant Hodgkin’s…¶
Harrison's 22e, p.868
- Nodular lymphocyte-predominant Hodgkin’s lymphoma
- Classical Hodgkin’s lymphoma
- Nodular sclerosis
- Lymphocyte-rich
- Mixed cellularity
- Lymphocyte-depleted
TABLE 114-2 The Ann Arbor Staging System for Hodgkin’s Lymphoma STAGE I II¶
Harrison's 22e, p.869
| STAGE | DEFINITION |
|---|---|
| I | Involvement of a single lymph node region or lymphoid structure (e.g., spleen, thymus, Waldeyer’s ring) |
| III | Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm |
| III 1 |
Subdiaphragmatic involvement limited to spleen, splenic hilar nodes, celiac nodes, or portal nodes |
| III 2 |
Subdiaphragmatic involvement includes paraaortic, iliac, or mesenteric nodes plus structures in III 1 |
| A | No symptoms |
| E | Localized, solitary involvement of extralymphatic tissue, excluding liver and bone marrow |