📋 Key Information Summary
- Hodgkin lymphoma (HL) is a B-cell neoplasm characterised by the presence of Reed-Sternberg cells within an inflammatory microenvironment; accounts for approximately 10% of all lymphomas in Australia.
- Bimodal age distribution with peaks at 15–35 years and >60 years; median age at diagnosis in Australia is approximately 35 years.
- Two major histological subtypes: nodular sclerosis (most common, ~70%) and mixed cellularity (~25%); lymphocyte-rich and lymphocyte-depleted are rare.
- Ann Arbor staging (modified Lugano classification) determines treatment intensity: early-stage favourable (I–II), early-stage unfavourable (I–II with risk factors), and advanced-stage (III–IV).
- Essential investigations: excisional lymph node biopsy, contrast-enhanced CT, PET-CT (with Deauville scoring), bloods (FBC, ESR, LDV, albumin, LFTs), and echocardiography if anthracycline-based therapy planned.
- First-line chemotherapy: ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) remains the standard of care in Australia; escBEACOPP reserved for high-risk advanced disease.
- Early-stage favourable HL: 2 cycles ABVD + 20 Gy involved-site radiotherapy (ISRT) OR 3–4 cycles ABVD alone (PET-guided de-escalation).
- Advanced-stage HL: 6 cycles ABVD; PET-adapted strategy (omit bleomycin if PET-negative after 2 cycles) to reduce pulmonary toxicity.
- Bleomycin pulmonary toxicity (BPT) is the most clinically significant non-haematological ABVD adverse effect; baseline and serial pulmonary function tests (DLCO) are essential.
- Salvage chemotherapy for relapsed/refractory disease: ICE (ifosfamide, carboplatin, etoposide), DHAP, or GDP, followed by autologous stem-cell transplant (ASCT) in chemosensitive disease.
- Brentuximab vedotin (anti-CD30 antibody-drug conjugate) is PBS Authority Required for relapsed/refractory classical HL post-ASCT or post≥2 prior therapies.
- Checkpoint inhibitors (nivolumab, pembrolizumab) are TGA-approved for relapsed/refractory classical HL after ASCT and brentuximab vedotin failure.
- Five-year overall survival exceeds 85% for all stages in Australia; long-term survivors require surveillance for secondary malignancies, cardiovascular disease, and thyroid dysfunction.
- Aboriginal and Torres Strait Islander peoples may present with more advanced disease and have lower survival rates; culturally safe pathways and remote-area telehaematology are essential.
Introduction & Australian Epidemiology
Hodgkin lymphoma (HL) is a unique B-cell malignancy defined by the presence of Reed-Sternberg cells within a characteristic reactive inflammatory microenvironment. Despite its relative rarity—accounting for approximately 10–12% of all lymphomas—HL is one of the most curable haematological malignancies, with five-year overall survival exceeding 85% across all stages in high-income settings including Australia.
In Australia, approximately 700–800 new cases are diagnosed annually (age-standardised incidence ~4.5 per 100,000), with a slight male predominance (M:F ratio 1.3:1). The disease exhibits a distinctive bimodal age distribution with a first peak in adolescents and young adults (15–35 years) and a second, smaller peak in adults over 60 years. The median age at diagnosis in Australia is approximately 35 years, making HL one of the most common cancers in young adults aged 20–34 years.
Established risk factors include immunosuppression (HIV/AIDS, post-transplant), Epstein-Barr virus (EBV) infection (detected in ~40% of classical HL cases in Western populations, higher in mixed cellularity subtype), family history (first-degree relative risk increased 3–9 fold), and prior infectious mononucleosis.
The management of HL in Australia is guided by evidence-based protocols developed through international collaboration (including ANZLG trials) and adapted through Therapeutic Guidelines (eTG) and multidisciplinary team (MDT) consensus at designated cancer centres. PET-CT response-adapted therapy has become central to contemporary treatment algorithms, enabling de-escalation of therapy in good responders and intensification for those with suboptimal response.
Pathology — Reed-Sternberg Cells & Histological Subtypes
The pathological hallmark of Hodgkin lymphoma is the Reed-Sternberg (RS) cell: a large, binucleated or bilobed malignant cell with prominent eosinophilic nucleoli and abundant cytoplasm, giving an "owl-eye" appearance on histology. RS cells are clonally derived from germinal-centre or post-germinal-centre B-cells that have lost most of their B-cell identity gene-expression programme. They typically constitute only 1–5% of the tumour mass, with the remainder comprising a reactive infiltrate of T-lymphocytes, eosinophils, macrophages, neutrophils, plasma cells, and fibroblasts.
| Histological Subtype | Frequency | Key Histological Features | EBV Association |
|---|---|---|---|
| Nodular sclerosis (NS) | ~70% | Broad collagen bands dividing lymph node into nodules; lacunar cells (RS variant with artefactual retraction); prominent fibrosis | ~30–40% |
| Mixed cellularity (MC) | ~20–25% | Classic RS cells in a diffuse inflammatory background; eosinophils, plasma cells, histiocytes; no broad fibrosis | ~70–75% |
| Lymphocyte-rich (LR) | ~5% | Small lymphocyte-predominant background; rare classic RS cells; nodular or diffuse pattern | ~40% |
| Lymphocyte-depleted (LD) | <1–2% | Numerous RS cells; sparse lymphocytes; diffuse fibrosis or reticular pattern; aggressive clinical course | Variable |
Immunophenotype is essential for diagnosis: Classical HL (all subtypes above) is CD15⁺, CD30⁺, PAX5⁺ (weak), CD45⁻, CD20⁻ (weak/variable), OCT2⁻/BOB1⁻. Nodular lymphocyte-predominant HL (NLPHL, a separate entity) is CD20⁺, CD45⁺, CD79a⁺, CD30⁻, CD15⁻, BCL6⁺. Immunohistochemistry panel must be performed on all biopsies.
Nodular lymphocyte-predominant HL (NLPHL) is now classified separately by the WHO (5th edition, 2022). It comprises ~5% of cases, is characterised by CD20⁺ "popcorn" (LP) cells within nodular backgrounds, and generally has an indolent course with different management paradigms (early-stage: radiotherapy alone; advanced-stage: R-CHOP-like regimens).
Clinical Features & Ann Arbor Staging
Clinical Presentation
The most common presentation is painless, progressive lymphadenopathy — typically cervical (60–70%) or supraclavicular. Mediastinal involvement is present in ~60–80% of nodular sclerosis cases and may cause cough, dyspnoea, or superior vena cava obstruction. Systemic "B" symptoms occur in approximately 30–40% of patients at diagnosis:
- Unexplained fever >38°C (Pel-Ebstein fever: cyclical fevers over 1–2 weeks)
- Drenching night sweats
- Unexplained weight loss >10% body weight over 6 months
Other features include generalised pruritus (may be severe), alcohol-induced pain at disease sites (pathognomonic but rare), and fatigue. Extranodal involvement at presentation is uncommon in classical HL (bone marrow ~5%, liver ~3–5%) but occurs more frequently in advanced or relapsed disease.
Ann Arbor Staging (Modified Lugano Classification, 2014)
Stage I
Single Region
Involvement of a single lymph node region or single extranodal site (IE)
Prognosis: Excellent with combined modality
Stage II
Two or More Regions (Same Side of Diaphragm)
Two or more lymph node regions on the same side of the diaphragm; may include contiguous extranodal extension (IIE)
Subclassify: II favourable vs II unfavourable
Stage III
Both Sides of Diaphragm
Lymph node regions on both sides of the diaphragm; may include spleen (IIIS)
Advanced stage — systemic chemotherapy
Stage IV
Diffuse Extranodal Involvement
Diffuse or disseminated involvement of one or more extralymphatic organs (bone marrow, liver, lungs) with or without nodal disease
Advanced stage — systemic chemotherapy
Risk Stratification: Early-Stage Favourable vs Unfavourable
| Risk Category | Criteria (EORTC/GHSG) | Typical Approach |
|---|---|---|
| Early favourable (I–II) | No bulk (<10 cm), no B symptoms, no extranodal sites, ESR <50 (without B symptoms) or <30 (with B symptoms), ≤3 nodal sites, non-mediastinal | 2–4 cycles ABVD + 20 Gy ISRT (or PET-guided chemo-only) |
| Early unfavourable (I–II) | Bulk ≥10 cm, mediastinal bulk (MTR >0.33), B symptoms, ESR ≥50, ≥4 nodal sites, extranodal extension | 4–6 cycles ABVD + 30 Gy ISRT |
| Advanced (III–IV) | Stage III or IV; International Prognostic Score (IPS) for advanced stage | 6 cycles ABVD (PET-adapted) or escBEACOPP for high-risk |
International Prognostic Score (IPS) — Advanced Stage
One point each: albumin <40 g/L, Hb <105 g/L, male sex, stage IV disease, age ≥45 years, WCC ≥15 × 10⁹/L, lymphocytes <0.6 × 10⁹/L or <8% of WCC. Score ≥4 indicates high-risk advanced disease where escBEACOPP may be considered.
Investigations
Essential Baseline Investigations
Essential
Excisional Lymph Node Biopsy
Gold standard. FNA is insufficient for histological subtyping and immunophenotyping. Core biopsy may be acceptable if excisional biopsy not feasible. Must include immunohistochemistry panel (CD15, CD30, CD20, CD45, PAX5, OCT2, BOB1, Ki-67). Available at all public hospitals with pathology services.
Essential
PET-CT (¹⁸F-FDG)
MBS Item 61439. Whole-body PET-CT is the imaging modality of choice for staging and interim/restaging. Baseline PET-CT before treatment initiation; interim PET (iPET) after 2 cycles (Deauville score guides further therapy). Available at major metropolitan centres; regional patients may require travel.
Essential
Contrast-Enhanced CT (Chest, Abdomen, Pelvis)
If PET-CT not immediately available. MBS Item 56800/56803. Provides anatomical detail for radiotherapy planning. Should be performed in conjunction with PET-CT.
Available
Blood Tests
FBC with differential, ESR, LDH, albumin, LFTs, renal function (eGFR, U&E), hepatitis B/C serology, HIV test (recommended for all new HL diagnoses). Baseline TFTs before radiotherapy involving neck/mediastinum.
Essential
Echocardiography (Transthoracic)
MBS Item 55120. Baseline LVEF assessment mandatory before anthracycline (doxorubicin)-based therapy. Repeat if clinically indicated or cumulative doxorubicin dose approaching 300 mg/m². Multigated radionuclide angiography (MUGA) scan an alternative.
Available
Pulmonary Function Tests (PFTs)
Baseline DLCO recommended before bleomycin-containing regimens. Serial PFTs if clinical concern for bleomycin pulmonary toxicity. Available at respiratory laboratories.
Referral
Bone Marrow Biopsy
No longer routinely required if PET-CT available (PET-CT has high sensitivity/specificity for marrow involvement). Consider if PET-CT unavailable or discordant results. Histology + flow cytometry on aspirate.
Deauville 5-Point Scale (Interim PET Response Assessment)
| Score | FDG Uptake | Interpretation |
|---|---|---|
| 1 | No residual uptake above background | Complete metabolic response (CMR) |
| 2 | Uptake ≤ mediastinum | CMR |
| 3 | Uptake > mediastinum but ≤ liver | Likely CMR — PET-negative for treatment purposes |
| 4 | Uptake moderately > liver | PET-positive — consider treatment intensification |
| 5 | Uptake markedly > liver or new lesions | PET-positive — significant residual disease |
Australian practice note: In the RATHL trial and subsequent Australian practice, Deauville scores 1–3 after 2 cycles of ABVD are considered PET-negative, allowing omission of bleomycin (AVD only) for cycles 3–6. Scores 4–5 are PET-positive, prompting escalation to BEACOPP or addition of brentuximab vedotin.
Management — Chemotherapy, Radiotherapy & Salvage
First-Line Chemotherapy Regimens
ABVD Regimen
Standard first-line classical HL · Combination regimen
Drugs & doses
Doxorubicin 25 mg/m² IV D1+15, Bleomycin 10,000 IU/m² IV D1+15, Vinblastine 6 mg/m² IV D1+15, Dacarbazine 375 mg/m² IV D1+15
Cycle
Every 28 days (given days 1 and 15 of each cycle)
Duration
2–6 cycles depending on stage and PET response
PBS status
✔ All components PBS General Benefit
escBEACOPP Regimen
High-risk advanced HL (IPS ≥4 or PET-positive after ABVD) · Escalated-dose
Drugs & doses
Etoposide 200 mg/m² IV D1–3, Doxorubicin 35 mg/m² IV D1, Cyclophosphamide 1250 mg/m² IV D1, Vincristine 1.4 mg/m² IV D8 (cap 2 mg), Bleomycin 10,000 IU/m² IV D8, Procarbazine 100 mg/m² PO D1–7, Prednisone 40 mg/m² PO D1–14
Cycle
Every 21 days with G-CSF support from day 8
Duration
6–8 cycles (PET-adapted)
PBS status
✔ All components PBS General Benefit
AVD (Bleomycin-Omitted ABVD)
PET-negative after 2 cycles ABVD · Reduced pulmonary toxicity
Drugs & doses
Doxorubicin 25 mg/m² IV D1+15, Vinblastine 6 mg/m² IV D1+15, Dacarbazine 375 mg/m² IV D1+15 (bleomycin omitted)
PBS status
✔ PBS General Benefit
Treatment by Stage — PET-Adapted Strategy
1
Early-Stage Favourable (I–II, no risk factors)
- 2 cycles ABVD → iPET at cycle 2
- PET-negative (Deauville 1–3): 2 additional cycles ABVD + 20 Gy ISRT OR 2 additional cycles AVD (omitting radiotherapy — RATHL-based de-escalation)
- PET-positive (Deauville 4–5): Escalate to escBEACOPP × 4 + 30 Gy ISRT
2
Early-Stage Unfavourable (I–II with risk factors)
- 4 cycles ABVD → iPET at cycle 4
- PET-negative: 2 additional cycles ABVD/AVD + 30 Gy ISRT
- PET-positive: Escalate to escBEACOPP × 2–4 + 30 Gy ISRT
3
Advanced Stage (III–IV)
- IPS <4: 6 cycles ABVD with PET-adapted bleomycin omission (iPET after cycle 2; if negative, AVD for cycles 3–6)
- IPS ≥4 or very bulky disease: Consider escBEACOPP × 6 (with PET-adapted de-escalation to ABVD if PET-negative after 2–4 cycles)
- Residual disease at end of treatment (PET-positive): Biopsy confirmation → salvage therapy
- ISRT (20–30 Gy) to residual PET-positive sites or initial bulky sites after chemotherapy
Involved-Site Radiotherapy (ISRT)
ISRT has replaced extended-field radiotherapy as the standard. Doses: 20 Gy (consolidation after complete response) to 30 Gy (residual disease). Modern techniques (3D-CRT, IMRT) minimise exposure to organs at risk (lungs, heart, breast, thyroid). All radiotherapy should be planned at designated radiation oncology centres with lymphoma experience. Cardiovascular and secondary malignancy risk must be discussed, particularly in young women (breast cancer screening commencing 8–10 years post-RT).
Salvage Therapy for Relapsed/Refractory Disease
ICE Regimen
Standard salvage before ASCT · Combination regimen
Doses
Ifosfamide 5 g/m² IV D2 (with Mesna), Carboplatin AUC 5 IV D2, Etoposide 100 mg/m² IV D1–3
Cycle
Every 14 days × 2–3 cycles (with G-CSF)
PBS status
✔ PBS General Benefit
DHAP Regimen
Alternative salvage · Dexamethasone, Cytarabine, Cisplatin
Doses
Dexamethasone 40 mg PO/IV D1–4, Cytarabine 2 g/m² IV D2 (12-hourly × 2 doses), Cisplatin 100 mg/m² IV continuous infusion D1
PBS status
✔ PBS General Benefit
Brentuximab Vedotin
Adcetris® · Anti-CD30 antibody-drug conjugate
Indication
Relapsed/refractory classical HL post-ASCT or post ≥2 prior systemic therapies; also BV+AVD first-line for advanced HL (ECHELON-1)
Dose
1.8 mg/kg IV every 21 days × up to 16 cycles
Key toxicity
Peripheral neuropathy (dose-limiting), neutropenia, tumour lysis
PBS status
Authority Required — Relapsed/refractory classical HL post-ASCT or ≥2 prior lines
Nivolumab
Opdivo® · Anti-PD-1 checkpoint inhibitor
Dose
3 mg/kg IV every 14 days until progression or unacceptable toxicity
Key toxicity
Immune-related adverse events: pneumonitis, hepatitis, thyroiditis, colitis
PBS status
Authority Required — Relapsed/refractory classical HL post-ASCT and brentuximab vedotin
Autologous Stem-Cell Transplant (ASCT)
ASCT is the standard-of-care consolidation for chemosensitive relapsed/refractory HL. Eligibility criteria: age generally <70 years, adequate organ function, chemosensitive disease on salvage chemotherapy (at least partial response). Conditioning regimens: BEAM (carmustine, etoposide, cytarabine, melphalan) is standard in Australia. All ASCT procedures are performed at designated transplant centres (e.g., Royal Adelaide Hospital, Peter MacCallum Cancer Centre, Westmead Hospital).
Bleomycin pulmonary toxicity (BPT): Occurs in 5–10% of patients receiving ABVD. Risk factors: age >60, cumulative dose >300 IU/m², pre-existing lung disease, renal impairment, thoracic radiotherapy. Presents with dry cough, dyspnoea, bilateral infiltrates on CXR, and declining DLCO. Action: Permanently discontinue bleomycin; commence prednisolone 1 mg/kg/day; switch to AVD. Fatal cases reported — maintain high clinical suspicion.
Monitoring During & After Treatment
Every cycle
FBC (day 1), renal function, LFTs; clinical review for toxicity; cumulative anthracycline dose tracking
Cycle 2 (iPET)
Interim PET-CT for response-adapted therapy decisions (Deauville scoring)
End of treatment
PET-CT (restaging), echocardiogram (post-anthracycline), TFTs (if neck/mediastinal RT), PFTs
Years 1–2 post-treatment
Clinical review every 3–4 months; CT chest/abdomen/pelvis every 6 months (if clinically indicated); FBC, ESR, LDH
Years 3–5
Clinical review every 6 months; CT annually or as indicated
Year 5+ (lifelong)
Annual clinical review; secondary malignancy surveillance (breast screening if prior thoracic RT starting age 25 or 8 years post-RT); cardiovascular risk management; thyroid function monitoring; fertility counselling
Special Populations
Pregnancy
Diagnosis: HL diagnosed in ~1:1,000–6,000 pregnancies. Avoid PET-CT during pregnancy; use non-ionising imaging (MRI, ultrasound). Biopsy is safe.
First trimester: Defer treatment if clinically safe. If urgent, ABVD can be given (category D — doxorubicin, vinblastine; avoid dacarbazine if possible).
Second/third trimester: ABVD is considered relatively safe. Avoid bleomycin if possible. Single-agent vinblastine is an alternative for indolent disease.
Radiotherapy: Avoid during pregnancy. Shielding may be considered but is generally avoided.
Multidisciplinary obstetric-oncology team essential. Involve maternal-fetal medicine specialists.
Paediatrics & Adolescents
Children (<18 years): Treated on paediatric protocols (e.g., EuroNet-PHL) emphasising dose reduction of alkylating agents and radiotherapy to minimise late effects.
Adolescents/young adults (15–25): May be treated on adult ABVD protocols or paediatric-derived regimens depending on centre. RATHL-based PET-adapted ABVD increasingly used.
Bleomycin: Use with caution in children; pulmonary function testing challenging in young children.
Refer to paediatric haematology-oncology centres. Fertility preservation (oocyte/embryo cryopreservation, sperm banking) discussed for all pubertal patients.
Elderly (≥60 years)
Challenge: Higher treatment-related mortality, more comorbidities, poorer tolerance of full-dose ABVD.
ABVD: May require dose reduction (especially bleomycin — higher BPT risk in elderly). Consider AVD (without bleomycin) from outset.
escBEACOPP: Generally avoided in patients >60 due to prohibitive toxicity.
Brentuximab vedotin + AVD (BV+AVD): ECHELON-1 showed benefit in patients ≥60 years; increasing use as first-line in elderly.
Comprehensive geriatric assessment; consider reduced-intensity regimens; careful cardiopulmonary monitoring.
Renal Impairment
Dacarbazine: No significant renal adjustment required but use with caution if eGFR <30 mL/min.
Bleomycin: Renally excreted; risk of accumulation. Consider dose reduction or omission if eGFR <30 mL/min; monitor closely.
Ifosfamide (salvage): Nephrotoxic; dose reduce for eGFR <60 mL/min; adequate hydration and Mesna essential.
Monitor renal function every cycle; adjust bleomycin dose based on eGFR.
Hepatic Impairment
Dacarbazine: Hepatically metabolised; reduce dose by 50% for bilirubin >3× ULN.
Doxorubicin: Reduce dose by 50% for bilirubin 1.5–3× ULN; avoid if >3× ULN.
Hepatitis B: Screen all patients. If HBsAg positive, commence antiviral prophylaxis (entecavir/tenofovir) before immunosuppressive therapy — risk of HBV reactivation.
LFTs at baseline and regularly during treatment. Hepatology consultation for significant hepatic disease.
Immunocompromised / HIV
HIV-associated HL: Treat with standard ABVD; concurrent ART essential. EBV positivity near-universal.
Drug interactions: Potential ART–chemotherapy interactions (e.g., azoles, ritonavir boosting). Pharmacy review essential.
PJP prophylaxis: Consider if prolonged steroid use or significant immunosuppression.
Outcomes now approaching those of HIV-negative patients with combination ART + chemotherapy.
Aboriginal and Torres Strait Islander Health Considerations
Aboriginal and Torres Strait Islander Health
Key recommendations for equitable care:
- Engage Aboriginal Health Workers and Liaison Officers at all stages of the cancer pathway.
- Utilise telehaematology consultations to reduce travel burden for remote patients.
- Refer to culturally safe support services (e.g., Cancer Council, Leukaemia Foundation Indigenous support programmes).
- Ensure Yarning-based communication for treatment discussions; allow adequate time for family consultation.
- Partner with ACCHS for long-term follow-up and secondary prevention.
📚 References
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