01OverviewDefinition, clinical context and the essential points that orientate the chapter.
Classical Hodgkin lymphoma usually presents with rubbery, painless cervical or supraclavicular nodes and may cause mediastinal widening, pruritus, fatigue or B symptoms: unexplained fever above 38°C, drenching night sweats and loss of more than 10% body weight over 6 months. Examine all nodal regions, liver and spleen and assess mediastinal compression. Nodular sclerosis is common in young adults; mixed cellularity has stronger EBV and immune-dysfunction associations. Nodular lymphocyte-predominant B-cell lymphoma is biologically different, expresses B-cell markers and follows a separate B-cell lymphoma pathway.
Excision biopsy is preferred because architecture and a broad differential matter. If surgery is unsafe, obtain multiple large cores and communicate suspected lymphoma so tissue is allocated for histology, immunohistochemistry, flow where useful and microbiology. Classical Reed–Sternberg cells commonly express CD30 and CD15 with weak PAX5 and lack strong pan-B markers. Their presence alone is not sufficient because Reed–Sternberg-like cells occur in EBV infection and other lymphomas. Review discordant pathology at a specialist haemato-oncology network.
Stage with PET-CT before treatment and calculate baseline metabolic sites for later comparison. Add contrast CT when vascular or radiotherapy anatomy requires it. Check FBC, ESR, renal, liver and bone profile, LDH, HIV, hepatitis B and C, pregnancy, ECG and echocardiogram; document pulmonary symptoms and consider lung function before bleomycin. PET detects marrow involvement accurately, so routine marrow biopsy is unnecessary in most classical cases. Stage I–II is early and III–IV advanced, but bulk, ESR, B symptoms, extranodal sites and early response refine treatment.
Early favourable disease commonly receives abbreviated ABVD plus involved-site radiotherapy, while early unfavourable or bulky disease receives additional cycles and usually 30 Gy according to the BSH pathway. ABVD is doxorubicin 25 mg/m², bleomycin 10,000 IU/m², vinblastine 6 mg/m² and dacarbazine 375 mg/m² IV on days 1 and 15 of a 28-day cycle. Combined treatment gives excellent control but radiotherapy fields and dose must be planned to minimise breast, lung, heart and thyroid exposure. PET-negative chemotherapy-alone strategies trade less radiotherapy for a small increase in relapse in selected groups and require shared protocol decisions.
Advanced classical disease may use ABVD with interim PET adaptation or brentuximab vedotin plus AVD for eligible stage III–IV CD30-positive adults under NICE. A negative PET after two ABVD cycles commonly allows bleomycin omission, completing AVD and reducing lung harm. A positive scan requires specialist escalation rather than simply continuing the same treatment. Do not give routine G-CSF with bleomycin without protocol review because of pulmonary concern; fever or neutropenia does not automatically justify dose delay in curative lymphoma, but sepsis must be treated immediately.
End-of-treatment PET is performed at the protocol interval after chemotherapy. Deauville 1–3 usually represents complete metabolic response; 4–5 needs expert comparison, clinical context and often biopsy because thymic rebound, infection and granulomatous inflammation can be avid. Persistent or relapsed disease should be re-biopsied when feasible. Fit patients commonly receive salvage therapy aiming at PET response followed by high-dose therapy and autologous stem-cell transplant; brentuximab, PD-1 inhibition and later allogeneic approaches depend on CD30, prior therapies, transplant status and NICE commissioning.
Survivorship begins before treatment. Record cumulative anthracycline, bleomycin and radiotherapy exposure. Counsel on smoking, exercise, infection and contraception. Follow cardiovascular risk and symptoms, thyroid function after neck irradiation, lung symptoms after bleomycin and breast screening after qualifying young-age chest radiotherapy. Fertility risk is low with limited ABVD but higher with escalated alkylating regimens and transplant. New nodes years later still require biopsy because relapse, a second cancer and benign inflammation have different management.
Key points
- Painless cervical or supraclavicular lymphadenopathy, mediastinal mass, pruritus and B symptoms are typical; alcohol-induced node pain is memorable but uncommon and non-diagnostic.
- Reference-standard diagnosis is an excision or adequate core biopsy showing architecture, Reed–Sternberg morphology and the appropriate immunophenotype; fine-needle aspiration is inadequate.
- Avoid corticosteroids before biopsy unless life-saving because lymphoma can melt rapidly and leave non-diagnostic tissue.
- Baseline staging uses FDG PET-CT; it usually removes the need for routine bone-marrow biopsy in classical Hodgkin lymphoma.
- Record Ann Arbor stage, bulky disease, B symptoms and early-stage favourable or unfavourable factors; treatment is curative and risk adapted rather than stage number alone.
- Early favourable classical disease often receives two ABVD cycles followed by 20 Gy involved-site radiotherapy; other early groups use more chemotherapy or 30 Gy according to BSH protocol and PET response.
- Advanced disease uses PET-adapted chemotherapy; after a negative interim PET, bleomycin is commonly omitted from later ABVD-derived cycles to reduce pulmonary toxicity.
- NICE supports brentuximab vedotin with doxorubicin, vinblastine and dacarbazine for untreated stage III or IV CD30-positive adult Hodgkin lymphoma.
- Interim PET is interpreted with the Deauville five-point scale and must be timed and acted on through the same protocol; inflammation can produce false positivity.
- Discuss sperm, oocyte or embryo preservation before gonadotoxic treatment whenever delay is safe, and provide long-term cardiac, thyroid, breast, lung and second-cancer follow-up based on exposure.
02AetiologyUnderlying causes, associations and risk factors, with why each one matters.
Germinal-centre B-cell origin
Classical Hodgkin lymphoma arises from a crippled germinal-centre B cell that escapes apoptosis and loses much of its ordinary B-cell phenotype.
EBV-associated subset
Epstein–Barr virus contributes to some cases, particularly mixed-cellularity disease and immunosuppression, but infection is neither necessary nor sufficient for diagnosis.
Host susceptibility
Risk varies with age, family history, HIV and immune dysfunction; nodular lymphocyte-predominant B-cell lymphoma has distinct biology and management.
03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.
- 1Sparse malignant cells
Reed–Sternberg cells form a minority of the mass and recruit abundant lymphocytes, eosinophils, macrophages and fibroblasts through cytokine and chemokine signalling.
- 2Contiguous lymphatic spread
Disease often spreads between adjacent nodal groups before involving spleen, marrow or extranodal organs, creating the characteristic staging pattern.
- 3Immune evasion
Genetic amplification and signalling increase PD-L1 and PD-L2 expression, suppressing antitumour T cells and explaining sensitivity to checkpoint inhibition in relapse.
- 4Systemic inflammatory effects
Cytokines drive fever, drenching sweats, weight loss, pruritus, raised ESR and inflammatory anaemia even when tumour volume is modest.
04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.
Painless cervical, supraclavicular or mediastinal nodes may wax and wane but persist and enlarge without an ordinary infectious explanation.
Measured fever, drenching sweats and substantial unintentional weight loss affect stage suffix and prognosis; vague warmth or mild sweating does not qualify.
Cough, chest pressure, facial swelling, orthopnoea, stridor or inability to lie flat requires urgent anatomical and anaesthetic assessment.
Pruritus, raised ESR, anaemia and hypoalbuminaemia can reflect cytokine burden, while infection and autoimmune causes still require exclusion.
Dry cough or falling oxygen saturation on bleomycin, neuropathy on vinca or brentuximab and exertional cardiac symptoms require prompt drug-specific review.
05InvestigationsWhat to request, why it matters and how to interpret it.
Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.
- 01
Reference standard: excision biopsyFirst stepReference standard - Why
- Preserve nodal architecture and enough tissue for confident subtype and differential diagnosis.
- Interpretation and limitations
- Classical disease shows scarce Reed–Sternberg cells in a rich inflammatory background with CD30, usually CD15 and weak PAX5; specialist review resolves atypical phenotypes.
- 02
First-line staging: FDG PET-CTFirst line - Why
- Map nodal, splenic, marrow and extranodal disease and establish a metabolic baseline.
- Interpretation and limitations
- Use Lugano or Ann Arbor stage and bulk measurements. PET marrow assessment generally replaces routine marrow biopsy but focal uncertainty may need directed evaluation.
- 03
Baseline blood and infection tests - Why
- Assess prognostic features, organ reserve and viral risks before curative treatment.
- Interpretation and limitations
- Obtain FBC, ESR, renal, liver, bone, LDH, HIV, hepatitis B and C and pregnancy testing; screen hepatitis B before any later anti-CD20 exposure in nodular lymphocyte-predominant disease.
- 04
Cardiopulmonary baseline - Why
- Quantify reserve before anthracycline, bleomycin or mediastinal radiotherapy.
- Interpretation and limitations
- Use ECG and echocardiogram and document pulmonary history, oxygen saturation and selected lung function; age, smoking, renal function and prior lung disease increase bleomycin concern.
- 05
Interim and end PET response - Why
- Adapt treatment and confirm metabolic remission.
- Interpretation and limitations
- Apply Deauville score through the protocol at the correct interval; investigate a discordant avid focus and biopsy persistent disease before irreversible salvage when feasible.
06Differential diagnosisRealistic alternatives and the features that help distinguish them.
Reactive or infectious nodes
EBV, CMV, HIV, tuberculosis and bacterial infection can cause constitutional symptoms and PET-avid nodes; architecture, microbiology and clinical course separate them.
Non-Hodgkin lymphoma
Aggressive B- or T-cell lymphoma may grow faster or involve extranodal sites; excision architecture, immunophenotype and genetics establish the correct curative regimen.
Metastatic solid cancer
Head and neck, lung, breast, testicular and other cancers can produce supraclavicular or mediastinal nodes and require cytokeratin and organ-directed pathology.
Sarcoidosis
Symmetrical hilar lymphadenopathy and granulomas can mimic or coexist with lymphoma; adequate tissue must exclude infection and malignant cells before immunosuppression.
07ManagementImmediate care, first-line treatment, alternatives and escalation.
01Persistent nodeObtain architecture before steroidsFirst stepUnexplained lymphadenopathy or mediastinal mass persists or progresses.+
- 1AlternativeAssess compression, infection, HIV and alternative cancer and obtain FBC, ESR, organ and viral baseline.
- 2Arrange excision biopsy or multiple large cores with specialist tissue handling before corticosteroids when safe.
- 3Review integrated pathology, then stage confirmed disease with PET-CT and classify early risk or advanced disease.
02Early classical diseaseBalance cure and late effectsPET-CT shows stage I or II classical Hodgkin lymphoma without an emergency.+
- 1Classify favourable, unfavourable and bulky factors and map heart, lung, breast and thyroid exposure.
- 2Give the current BSH chemotherapy and involved-site radiotherapy protocol, commonly two ABVD plus 20 Gy in favourable disease.
- 3EscalationUse protocol PET response and shared late-effect discussion before omitting radiotherapy or escalating treatment.
03Advanced classical diseaseUse interim-PET-adapted systemic therapyStage III or IV disease or an advanced-treatment strategy is selected.+
- 1Choose ABVD-derived or commissioned brentuximab-AVD treatment from age, pulmonary, neuropathy and disease risk.
- 2EscalationPerform interim PET at the protocol time and omit bleomycin after a qualifying negative ABVD response or escalate a positive response through MDT.
- 3Complete systemic therapy, obtain end PET and enter exposure-based survivorship or biopsy-directed salvage.
04Relapse or refractory diseaseRe-biopsy and aim for transplant responseEnd PET remains suspicious or new disease appears after remission.+
- 1Confirm active lymphoma histologically when feasible and restage metabolic and organ burden.
- 2Select salvage chemotherapy, brentuximab or checkpoint therapy using previous exposure and transplant eligibility.
- 3Proceed to autologous transplant when response and fitness support it, then use risk-directed maintenance or later cellular options.
Key medicines and prescribing safety4 treatments · regimens, roles and cautions+
ABVD
Give doxorubicin 25 mg/m², bleomycin 10,000 IU/m², vinblastine 6 mg/m² and dacarbazine 375 mg/m² intravenously on days 1 and 15 of each 28-day cycle for the protocol-defined number of cycles.Use independent chemotherapy verification, vesicant precautions and cumulative anthracycline assessment. Monitor bleomycin lung injury, neutropenic sepsis, neuropathy, liver toxicity and fertility; stop and investigate bleomycin for new cough or hypoxaemia and avoid pregnancy.
Brentuximab vedotin with AVD
Give brentuximab vedotin 1.2 mg/kg IV, maximum 120 mg, on days 1 and 15 of a 28-day cycle with protocol doxorubicin 25 mg/m², vinblastine 6 mg/m² and dacarbazine 375 mg/m² for six cycles.Give primary G-CSF prophylaxis according to the regimen. Monitor peripheral neuropathy, neutropenia, infection, infusion reaction, pancreatitis and liver toxicity; use dose modifications for neuropathy and severe organ impairment and prevent pregnancy during and after treatment.
Involved-site radiotherapy
Use image-fused specialist planning, commonly 20 Gy after two ABVD cycles for early favourable disease or 30 Gy for selected unfavourable, bulky or residual sites, divided into protocol fractions.Individualise for PET response and anatomy. Document heart, lung, breast, thyroid, salivary and fertility exposure and explain late cardiovascular, endocrine and second-cancer screening; urgent radiotherapy before biopsy can compromise diagnosis.
Salvage and autologous transplant pathway
Give the exact centre salvage regimen for two to three cycles with PET assessment, then high-dose conditioning and autologous stem-cell rescue when chemosensitive disease and physiological fitness are confirmed.Regimen choice depends on prior anthracycline, lung, renal and marrow reserve. Provide infection, transfusion, fertility and mucositis support and consider brentuximab or PD-1 sequencing because pre-transplant exposure can alter toxicity.
08ComplicationsImportant consequences, why they occur and why they matter clinically.
Compressive disease
Bulky mediastinal, spinal, vascular or ureteric disease can impair airway, circulation, cord or renal drainage before systemic treatment takes effect.
Treatment organ toxicity
Bleomycin lung injury, anthracycline cardiomyopathy, neuropathy, gonadal failure and infection vary with regimen, dose and host reserve.
Late second malignancy
Radiotherapy and alkylating chemotherapy increase later solid cancer, myelodysplasia and AML risk, making exposure minimisation and lifelong screening important.
Relapsed or refractory lymphoma
Persistent metabolic disease or later relapse may require biopsy, salvage therapy, autologous transplantation, brentuximab or checkpoint inhibition.
09Monitoring and follow-upTreatment response, safety checks and longer-term review.
- During treatment assess FBC, infection, renal and liver function, neuropathy, pulmonary symptoms, oxygenation and cardiac symptoms before each administration.
- Perform interim PET only at the protocol-defined point and interpret with Deauville scoring in an experienced lymphoma MDT; timing and inflammatory confounding matter.
- Obtain end-of-treatment PET after the recommended interval, biopsy uncertain persistent avidity where feasible and avoid routine surveillance PET in asymptomatic remission.
- Provide exposure-based follow-up for thyroid, cardiac, pulmonary, fertility and second-cancer risk, including breast screening after qualifying young-age chest irradiation.
- Educate about new nodes, B symptoms, infection, neuropathy and cardiopulmonary symptoms and give a named rapid-access route rather than relying on routine scans.
10Special situationsVariants, exceptions and circumstances that change the usual approach.
Reed–Sternberg is contextual
A large CD30-positive cell is not automatically Hodgkin lymphoma. Background architecture, full phenotype and EBV context prevent serious mimic errors.
PET replaces marrow selectively
Baseline PET has high sensitivity for Hodgkin marrow involvement, but it does not replace tissue diagnosis or automatically classify every diffuse marrow signal as lymphoma.
Bleomycin can be removed
A qualifying negative interim scan allows many advanced ABVD patients to complete AVD, preserving control while materially reducing cumulative lung exposure.
Late effects shape first line
A small difference in immediate treatment burden can translate into decades of cardiac, endocrine, fertility and second-cancer consequences in a young survivor.
PET positivity needs proof
Inflammation, infection and sarcoid-like reactions are FDG avid. Biopsy protects a patient from high-dose salvage for a non-malignant scan abnormality.
11Common pitfallsFrequent interpretation and management errors.
- 01
Do not use fine-needle aspiration as the definitive lymphoma biopsy or give corticosteroids before tissue when physiology permits.
- 02
Do not sedate a severely orthopnoeic patient with a mediastinal mass without a position-preserving expert airway plan.
- 03
Do not continue bleomycin through new cough, hypoxaemia or a qualifying negative interim PET without protocol review.
- 04
Do not call every Deauville 4 focus refractory lymphoma without checking timing, pattern and biopsy feasibility.
- 05
Do not apply classical Hodgkin regimens to nodular lymphocyte-predominant B-cell lymphoma without specialist pathological classification.
- 06
Do not end care at remission; cumulative exposure determines screening and cardiovascular, thyroid, fertility and second-cancer follow-up.