Overview
Hodgkin Lymphoma
1. Clinical Overview
Summary
Hodgkin Lymphoma (HL) is a malignancy of the lymphatic system characterised by the presence of Reed-Sternberg (RS) Cells (Large, Binucleated cells with prominent nucleoli – "Owl's eyes" appearance) within a background of reactive inflammatory cells. It accounts for approximately 10% of all lymphomas but is notable for its excellent prognosis – Cure rates exceed 80-90% for early-stage disease. HL has a bimodal age distribution with peaks at 15-35 years and >55 years. Patients typically present with painless lymphadenopathy (Often cervical or mediastinal), and may have B symptoms (Fever, Night Sweats, Weight loss >10% in 6 months). The disease spreads predictably along contiguous lymph node groups, which influences staging. Treatment is highly effective using chemotherapy (ABVD – Adriamycin, Bleomycin, Vinblastine, Dacarbazine) ± Radiotherapy. Long-term survivors require monitoring for late effects (Secondary malignancies, Cardiac disease, Pulmonary fibrosis). [1,2,3]
Clinical Pearls
"Painless Rubbery Lymphadenopathy": Classic presentation. Often cervical. May have mediastinal mass on CXR.
"Alcohol-Induced Lymph Node Pain": Classic (But rare) symptom – Pain in lymph nodes after drinking alcohol.
"Reed-Sternberg Cells – Owl's Eyes": Diagnostic. Large binucleated cells with prominent "Owl's eye" nucleoli.
"B Symptoms = Worse Prognosis": Fever, Night sweats, Weight loss >10% in 6 months. Included in staging.
2. Epidemiology
Demographics
| Factor | Notes |
|---|---|
| Age | Bimodal: Peak 15-35 years, Second peak >55 years. |
| Sex | Male > Female (Slightly, Especially in childhood). |
| Incidence | ~3 per 100,000 per year. |
| Geography | Higher in developed countries. |
Risk Factors
| Risk Factor | Notes |
|---|---|
| EBV Infection | Association with EBV (Especially Mixed Cellularity subtype). ~40% of cases EBV-positive. |
| Immunosuppression | HIV, Post-transplant. |
| Family History | Slight increased risk in first-degree relatives. |
| Higher Socioeconomic Status | Paradoxically associated (Possibly related to delayed EBV exposure). |
3. Classification (WHO)
Classical Hodgkin Lymphoma (~95%)
| Subtype | Features |
|---|---|
| Nodular Sclerosis | Most common (~70%). Young adults. Mediastinal involvement. Collagen bands. |
| Mixed Cellularity | ~20%. Older patients. EBV-associated. Abundant RS cells. |
| Lymphocyte-Rich | ~5%. Best prognosis among classical subtypes. |
| Lymphocyte-Depleted | Rare (less than 1%). Older patients, HIV. Worst prognosis. |
Nodular Lymphocyte Predominant HL (~5%)
| Feature | Notes |
|---|---|
| Different Entity | Distinct from classical HL. |
| "Popcorn Cells" (LP Cells) | Instead of RS cells. CD20+. |
| Behaviour | Indolent. Excellent prognosis. May transform to Diffuse Large B-Cell Lymphoma. |
4. Pathophysiology
Reed-Sternberg Cells
- Origin: Derived from B lymphocytes (Germinal centre B cells).
- Appearance: Large (20-50 µm), Binucleated (Or multinucleated), Prominent eosinophilic nucleoli → "Owl's eye" appearance.
- Immunophenotype: CD30+, CD15+, PAX5 weak, CD20- (Classical HL).
- Microenvironment: RS cells are rare (less than 1% of tumour). Surrounded by reactive inflammatory cells (T cells, Eosinophils, Histiocytes, Plasma cells). RS cells secrete cytokines that attract and maintain this milieu.
Spread
- HL typically spreads contiguously along lymph node groups.
- This predictable pattern influences staging and treatment fields.
5. Clinical Presentation
Symptoms
| Symptom | Notes |
|---|---|
| Painless Lymphadenopathy | Most common. Cervical (60-80%), Supraclavicular, Axillary, Mediastinal. Rubbery texture. |
| Mediastinal Mass | ~60% have mediastinal involvement. May cause Cough, Dyspnoea, SVC obstruction. |
| B Symptoms | Present in ~25-30%. Fever (>38°C, Pel-Ebstein pattern – Rare), Drenching Night Sweats, Weight loss >10% in 6 months. |
| Pruritus | Generalised itching. May precede diagnosis. |
| Alcohol-Induced Pain | Rare but classic. Pain in affected nodes after alcohol ingestion. |
| Fatigue | Non-specific. |
B Symptoms (Staging Relevant)
| Symptom | Definition |
|---|---|
| Fever | >38°C, Unexplained. |
| Night Sweats | Drenching (Require change of clothes/sheets). |
| Weight Loss | >10% body weight in preceding 6 months. |
Examination Findings
| Finding | Notes |
|---|---|
| Lymphadenopathy | Painless, Rubbery, Non-tender. Cervical most common. |
| Hepatosplenomegaly | May indicate advanced disease. |
| Signs of Mediastinal Mass | SVC obstruction (Facial swelling, Distended neck veins). Stridor. |
6. Investigations
Diagnosis
| Investigation | Notes |
|---|---|
| Excisional Lymph Node Biopsy | Essential. Needed for architecture and RS cell identification. FNA is NOT sufficient. |
| Histology | Reed-Sternberg cells + Inflammatory background. |
| Immunohistochemistry | CD30+, CD15+, PAX5 weak, CD20- (Classical). CD20+, CD45+, CD15-, CD30- (Nodular Lymphocyte Predominant). |
Staging Investigations
| Investigation | Notes |
|---|---|
| PET-CT | Gold Standard for staging. Shows metabolically active disease. |
| CT Neck/Chest/Abdomen/Pelvis | Anatomical staging. |
| Bone Marrow Biopsy | Used to be routine. Now often replaced by PET-CT (If PET negative in marrow, Biopsy often omitted). |
| Bloods | FBC (Eosinophilia, Lymphopenia), LFTs, LDH, ESR, Albumin. |
Staging (Ann Arbor / Cotswolds / Lugano)
| Stage | Definition |
|---|---|
| I | Single lymph node region or single extra-lymphatic organ (IE). |
| II | ≥2 lymph node regions on SAME side of diaphragm. |
| III | Lymph node regions on BOTH sides of diaphragm. |
| IV | Diffuse/Disseminated involvement of extralymphatic organ(s) (e.g., Bone marrow, Liver). |
| A | No B symptoms. |
| B | B symptoms present. |
| X | Bulky disease (Mediastinal mass >1/3 thoracic diameter or >10cm mass). |
7. Management
Management Algorithm
HODGKIN LYMPHOMA DIAGNOSED
(Biopsy-confirmed, PET-CT staged)
↓
ASSESS STAGE AND RISK
- Stage (I-IV)
- B symptoms (A vs B)
- Bulky disease
- Adverse prognostic factors (IPS for advanced stage)
↓
EARLY STAGE (I-II, Non-Bulky, Favourable)
┌──────────────────────────────────────────────────────────┐
│ ABVD x 2-4 cycles │
│ +/- Involved Field Radiotherapy (IFRT) │
│ Response assessed by Interim PET (After 2 cycles) │
│ If PET-negative → May omit RT (Response-adapted) │
└──────────────────────────────────────────────────────────┘
↓
ADVANCED STAGE (III-IV, or Bulky, or Unfavourable Early)
┌──────────────────────────────────────────────────────────┐
│ ABVD x 6 cycles │
│ OR │
│ BEACOPP escalated (More intensive, Higher toxicity) │
│ OR │
│ AVD + Brentuximab Vedotin (BV) (ECHELON-1 trial) │
│ +/- Consolidation RT to bulky sites │
└──────────────────────────────────────────────────────────┘
↓
RESPONSE ASSESSMENT (End of Treatment PET-CT)
┌────────────────┴────────────────┐
COMPLETE RESPONSE REFRACTORY / RELAPSED
↓ ↓
Surveillance Salvage Chemotherapy
(e.g., ICE, DHAP, GDP)
+ Autologous SCT
+/- Brentuximab Vedotin
+/- Checkpoint Inhibitors
(Nivolumab, Pembrolizumab)
Chemotherapy Regimens
| Regimen | Components | Use |
|---|---|---|
| ABVD | Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine | Standard regimen. Less toxic. |
| BEACOPP (Escalated) | Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Oncovin (Vincristine), Procarbazine, Prednisone | More intensive. Higher cure rate. Higher toxicity (Infertility, Secondary leukaemia). |
| AVD + Brentuximab Vedotin | Per ECHELON-1 | Anti-CD30 antibody-drug conjugate. Replaces Bleomycin. Improved PFS in advanced stage. |
Radiotherapy
| Use | Notes |
|---|---|
| Involved Site/Node Radiotherapy | Consolidation after chemotherapy, Especially for bulky disease. Smaller fields than historical "Mantle" radiation. |
| Response-Adapted | May omit RT if interim PET is negative (Reduce late effects). |
Relapsed/Refractory Disease
| Treatment | Notes |
|---|---|
| Salvage Chemotherapy | ICE, DHAP, GDP. |
| Autologous Stem Cell Transplant | Standard for chemosensitive relapse. |
| Brentuximab Vedotin | Anti-CD30 ADC. Post-transplant maintenance or relapsed/refractory. |
| Checkpoint Inhibitors | Nivolumab, Pembrolizumab. PD-1 inhibitors. High response rates in relapsed HL. |
| Allogeneic SCT | For multiply relapsed disease. Graft-vs-lymphoma effect. |
8. Complications
Disease-Related
| Complication | Notes |
|---|---|
| SVC Obstruction | Mediastinal mass. Emergency. |
| Spinal Cord Compression | Rare. |
| Cytopenias | Bone marrow involvement. |
Treatment-Related (Late Effects)
| Complication | Notes |
|---|---|
| Secondary Malignancies | Breast cancer, Lung cancer, AML/MDS. Related to RT and chemotherapy. |
| Cardiac Disease | Anthracycline (Doxorubicin) toxicity, Mediastinal RT. Coronary artery disease, Heart failure. |
| Pulmonary Fibrosis | Bleomycin toxicity. |
| Hypothyroidism | After neck RT. |
| Infertility | Especially with BEACOPP. Sperm/Oocyte cryopreservation offered. |
9. Prognosis and Outcomes
| Factor | Notes |
|---|---|
| Overall Cure Rate | ~80-90%. Excellent. |
| Early Stage (Favourable) | >95% cure rate. |
| Advanced Stage | ~75-85% cure rate. |
| Relapsed Disease | Still curable with salvage + ASCT (~50%). Checkpoint inhibitors improve outcomes. |
| IPS (International Prognostic Score) | For advanced stage. 7 adverse factors. Higher score = Worse prognosis. |
IPS Factors (Advanced HL)
- Age ≥45
- Male sex
- Stage IV
- Hb less than 10.5 g/dL
- Albumin less than 4 g/dL
- WCC ≥15,000/µL
- Lymphocyte count less than 600/µL or less than 8% of WCC
10. Evidence and Guidelines
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Hodgkin Lymphoma | NICE / BSH | ABVD standard. PET-adapted therapy. Fertility preservation. Late effects screening. |
| NCCN Hodgkin Lymphoma | NCCN | Risk-adapted treatment. Brentuximab in advanced stage. |
Landmark Trials
| Trial | Findings |
|---|---|
| RATHL (UK) | PET-adapted therapy. If interim PET negative, Can omit Bleomycin and reduce toxicity. |
| ECHELON-1 | AVD + Brentuximab Vedotin superior to ABVD in advanced HL. |
| GHSG HD10 | 2 cycles ABVD + 20Gy RT = 4 cycles ABVD + 30Gy RT for early favourable HL (Reduced treatment). |
11. Patient and Layperson Explanation
What is Hodgkin Lymphoma?
Hodgkin Lymphoma is a type of cancer that affects your lymphatic system – the network of glands and vessels that help fight infection. It usually starts in lymph nodes.
Who gets it?
It can affect anyone but is most common in young adults (15-35 years) and older adults (>55 years).
What are the symptoms?
- Swollen lymph nodes (Usually painless, In the neck, Armpit, or Groin).
- "B symptoms": Fever, Drenching night sweats, Unexplained weight loss.
- Tiredness, Itching.
- Some people notice pain in lymph nodes after drinking alcohol.
Is it serious?
Hodgkin Lymphoma is a serious diagnosis, BUT it is one of the most curable cancers. With modern treatment, over 8 out of 10 people are cured.
What is the treatment?
- Chemotherapy (Usually ABVD) – Given in cycles over several months.
- Radiotherapy – Sometimes given to affected areas after chemotherapy.
- Newer treatments – Such as antibody therapy (Brentuximab) or immunotherapy for cases that come back.
What about the long term?
Because treatment is so effective, long-term survival is excellent. However, we monitor for late effects of treatment (Heart, Lungs, Second cancers) for many years.
12. References
Primary Sources
- Ansell SM. Hodgkin lymphoma: 2018 update on diagnosis, risk-stratification, and management. Am J Hematol. 2018;93(5):704-715. PMID: 29686478.
- National Institute for Health and Care Excellence. Non-Hodgkin's lymphoma: diagnosis and management (NG52). 2016.
- Connors JM, et al. Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma (ECHELON-1). N Engl J Med. 2018;378(4):331-344. PMID: 29224502.
13. Examination Focus
Common Exam Questions
- Diagnostic Cell: "What is the pathognomonic cell in Hodgkin Lymphoma?"
- Answer: Reed-Sternberg Cell (Large, Binucleated, "Owl's eyes" nucleoli).
- Immunophenotype (Classical HL): "What is the immunophenotype of RS cells?"
- Answer: CD30+, CD15+, PAX5 weak+, CD20-.
- B Symptoms: "What are B symptoms?"
- Answer: Fever >38°C, Drenching Night Sweats, Weight loss >10% in 6 months.
- Standard Chemotherapy: "What is the standard first-line chemotherapy for Hodgkin Lymphoma?"
- Answer: ABVD (Adriamycin/Doxorubicin, Bleomycin, Vinblastine, Dacarbazine).
Viva Points
- Excisional Biopsy Required: FNA is NOT sufficient. Need architecture for diagnosis.
- Contiguous Spread: HL spreads predictably to adjacent lymph node groups.
- Late Effects: Major concern. Cardiac (Anthracyclines, RT), Pulmonary (Bleomycin), Secondary malignancy.
- Fertility Preservation: Offer sperm/oocyte cryopreservation before treatment.
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