Haematological malignancies - Hodgkin lymphoma
Description
- Germinal-centre B-cell malignancy in which the malignant cells are <1% of the tumour mass - the rest is a reactive inflammatory infiltrate
- This is why it is chemo- and radiosensitive, and why checkpoint blockade works
Classical Hodgkin lymphoma (~90%)
| Subtype | Frequency | Notes |
|---|---|---|
| Nodular sclerosis | ~70% | Young adults, mediastinal mass, F=M |
| Mixed cellularity | ~20% | Older, EBV-associated, HIV |
| Lymphocyte-rich | ~5% | Best prognosis |
| Lymphocyte-depleted | <1% | Elderly, HIV, advanced at presentation, worst |
Nodular lymphocyte-predominant (~10%)
- Renamed nodular lymphocyte-predominant B-cell lymphoma (WHO 5th ed) - no longer classified as Hodgkin lymphoma
- LP ("popcorn") cells: CD20+, CD45+, EMA+, CD15-, CD30-
- Indolent, late relapses, transforms to DLBCL in ~5-10%
Immunophenotype - the exam point
| Classical HL | NLPHL | |
|---|---|---|
| CD30 | + | - |
| CD15 | + (~80%) | - |
| CD20 | - / weak | + |
| CD45 | - | + |
| PAX5 | Weak + | Strong + |
Epidemiology
- ~700 new cases/yr in Australia; ~10% of all lymphoma
- Bimodal age distribution: 20-34 years and >55-60 years
- M slightly > F overall (F>M in nodular sclerosis)
- EBV genome in Reed-Sternberg cells in ~40% - higher in mixed cellularity, children in low-income countries, and HIV
- Risk: prior infectious mononucleosis (~3x), HIV, immunosuppression, family history (~3-9x in siblings)
Aetiopathogenesis
- Origin: "crippled" germinal centre B cell with non-functional immunoglobulin genes that should have undergone apoptosis but did not
- Loss of B-cell programme (dec CD20, dec CD79, dec immunoglobulin) - explains the aberrant phenotype
- Constitutive NF-kB activation - the central survival pathway
- JAK/STAT activation; 9p24.1 amplification -> PD-L1/PD-L2 overexpression
- *This is why PD-1 blockade has such high response rates in Hodgkin lymphoma*
- Reed-Sternberg cells secrete cytokines (IL-5, IL-10, IL-13, TGF-beta, TARC) -> the eosinophil-, plasma cell- and T-cell-rich infiltrate and the B symptoms
- Contiguous spread along nodal chains - unlike the haematogenous scatter of non-Hodgkin lymphoma
Diagnosis
Presentation
- Painless cervical or supraclavicular lymphadenopathy (~70%), rubbery, non-tender
- Mediastinal mass - cough, SVC obstruction; often asymptomatic on CXR
- B symptoms: fever >38, drenching night sweats, weight loss >10% in 6 months
- Pel-Ebstein cyclical fever - classic, rare
- Pruritus and alcohol-induced nodal pain - characteristic, non-staging
- Splenomegaly; bone and marrow involvement uncommon at diagnosis
Biopsy
- *Excisional lymph node biopsy - FNA is inadequate* (architecture and the reactive background are the diagnosis)
- Reed-Sternberg cell: binucleate "owl's eye", CD15+/CD30+
Staging (Lugano, modified Ann Arbor)
| Stage | |
|---|---|
| I | One nodal region or lymphoid structure |
| II | >=2 regions same side of diaphragm |
| III | Both sides of the diaphragm |
| IV | Diffuse extranodal (marrow, liver, lung) |
- Suffix A/B (B symptoms), E (contiguous extranodal), X (bulk)
- PET-CT is the staging modality - routine bone marrow biopsy is no longer required if PET is done
- Bulky disease: mediastinal mass >1/3 thoracic diameter, or nodal mass >10 cm
Response assessment
- Deauville 5-point score on interim and end-of-treatment PET
- 1-3 = negative (uptake <= liver); 4-5 = positive
- Interim PET after 2 cycles drives treatment de-escalation or escalation - the central principle of modern therapy
Baseline before treatment
- FBE, ESR, LDH, albumin, UEC, LFT, HIV/HBV/HCV
- Lung function (bleomycin), echo (anthracycline)
- *Fertility preservation discussion before cycle 1*
Management
Axis: stage and interim PET response. Cure is the expectation - the modern problem is minimising late toxicity in people who will live 50 more years.
A. Early stage (I-II)
- ABVD x2 -> interim PET
- Deauville 1-3: continue AVD (bleomycin omitted) +/- involved-site radiotherapy
- Deauville 4-5: escalate (BEACOPP-type) +/- radiotherapy
- Favourable: 2-4 cycles total; unfavourable (bulk, B symptoms, >=3 sites, high ESR): 4-6 cycles
- Radiotherapy increasingly omitted in PET-negative patients - trades a small PFS gain for decades of second-cancer and cardiac risk
- Cure ~90-95%
B. Advanced stage (III-IV, and IIB/bulky)
- *Nivolumab + AVD (N-AVD) is the new standard* - SWOG S1826: superior PFS to brentuximab-AVD (2-yr PFS ~92% vs ~83%), better tolerated, less neuropathy, and a larger advantage in patients >60
- Brentuximab vedotin + AVD (A+AVD) - ECHELON-1, the first regimen to show an overall survival benefit over ABVD; bleomycin removed
- ABVD x6 remains acceptable (cure ~60-75%)
- Escalated BEACOPP / BrECADD - higher cure rate, much higher toxicity and infertility; used in European protocols, generally avoided over age 45-60
- The direction of travel is away from bleomycin and away from radiotherapy
C. Relapsed / refractory
- Salvage chemotherapy (DHAP, ICE, IGEV) -> autologous stem cell transplant - cures ~50%
- Brentuximab vedotin maintenance post-ASCT for high-risk relapse (AETHERA)
- PD-1 blockade (nivolumab, pembrolizumab) - very high response rates; used pre-transplant and in post-transplant failure
- Allogeneic SCT for those failing autograft
D. NLPHL
- Stage IA non-bulky: radiotherapy alone, or watchful waiting
- Advanced: rituximab-containing chemotherapy (CD20+, unlike classical HL)
E. Drug toxicities
| Agent | Watch for |
|---|---|
| Bleomycin | Pulmonary fibrosis - cease on any DLCO fall or symptoms; avoid high FiO2 lifelong |
| Doxorubicin | Cardiomyopathy - cumulative dose |
| Vinblastine/vincristine | Neuropathy, constipation, ileus |
| Dacarbazine | Emesis, infusional pain |
| Brentuximab vedotin | Peripheral neuropathy (dose-limiting), neutropenia, PML; fatal with bleomycin - never combine |
| Checkpoint inhibitors | Immune-related adverse events - thyroid, colitis, hepatitis, pneumonitis, hypophysitis; worse GVHD if later transplanted |
F. Supportive
- PJP and antifungal prophylaxis with BEACOPP; G-CSF as protocol requires (not with bleomycin-containing ABVD - pulmonary toxicity)
- Vaccination; irradiated blood products if treated with purine analogues or transplanted
- Fertility: semen cryopreservation, oocyte/embryo storage, GnRH agonist
Associations
- EBV - Reed-Sternberg cells in ~40%; prior infectious mononucleosis
- HIV - more mixed cellularity/lymphocyte-depleted, advanced stage, extranodal and marrow disease
- Immunosuppression - post-transplant, methotrexate, TNF inhibitors
- Autoimmune disease - RA, SLE, sarcoidosis (and "sarcoid-like" reactions in draining nodes)
- Paraneoplastic: nephrotic syndrome (minimal change disease), cerebellar degeneration, autoimmune haemolytic anaemia, ITP
- Familial clustering, HLA associations
- NLPHL - transformation to DLBCL; progressive transformation of germinal centres
Natural history & complications
- The most curable adult malignancy - overall cure ~80-90%
- Relapses are mostly within the first 3 years; late relapse suggests NLPHL
International Prognostic Score (advanced disease) - one point each
- Albumin <40 g/L
- Hb <105 g/L
- Male sex
- Stage IV
- Age >=45
- WCC >=15 x10^9/L
- Lymphocytes <0.6 x10^9/L or <8% of WCC
- 0-1 points -> ~90% 5-yr freedom from progression; >=5 -> ~60%
Late effects - the dominant long-term issue
*More survivors eventually die of treatment sequelae than of Hodgkin lymphoma*
Second malignancy
- Breast cancer - RR ~75x after chest/mantle radiotherapy in young women
- Annual MRI +/- mammography from 8 years post-radiotherapy or age 30, whichever is later
- AML/MDS 2-10% at 10 years - alkylating agents, etoposide, combined modality, splenectomy
- NHL 1-5% at 10 years
- Thyroid ~30x, lung ~4x (multiplicative with smoking - cessation is a cancer intervention here), bone/GI 5-20x, brain ~10x
- Solid tumours emerge after a 7-10 year latency in the radiation field
Non-malignant
- Premature ischaemic heart disease and valvular disease - radiation and anthracycline
- Pulmonary fibrosis (bleomycin, radiation)
- Hypothyroidism after neck irradiation - lifelong TFT monitoring
- Infertility - mainly BEACOPP; ABVD largely spares gonadal function
- Functional asplenia after splenic irradiation - vaccination and antibiotic advice
- Fatigue, psychosocial and employment effects
🔒
6 more sections, plus exam facts
Premium unlocks every note across every specialty, and the full exam fact library behind it.
Get premium access