Hodgkin’s disease

01Definition and overview

Hodgkin lymphoma (HL), formerly Hodgkin's disease, is a cancer of B lymphocytes that starts in a lymph node, usually in the neck or mediastinum, and spreads from one group of nodes to the next. Unlike almost any other cancer, its malignant cells are a small minority: large Hodgkin and Reed–Sternberg cells (HRS cells), around 1 per cent of the cells in the node or fewer, sit in a dense background of reactive T and B cells, eosinophils, histiocytes, plasma cells and fibrous tissue. The classic Reed–Sternberg cell has two mirror-image nuclei or lobes, each with a large eosinophilic nucleolus ("owl's eyes"); its single-nucleus variants are Hodgkin cells.

HL is one of the two great groups of lymphoma; all the others are the non-Hodgkin lymphomas. The WHO classification (5th edition, 2022) and the International Consensus Classification (ICC, 2022) divide HL into two diseases:

The subtypes of cHL share the same HRS cell and, with modern treatment, have lost most of their bearing on outcome, so they are treated alike. NLPHL behaves more like an indolent B-cell lymphoma: the ICC has renamed it nodular lymphocyte-predominant B-cell lymphoma, while the WHO 5th edition keeps the name NLPHL, so as not to disturb running trials, and accepts the B-cell name as an alternative.

1. 1832

   Thomas Hodgkin

   At Guy's Hospital in London, Hodgkin describes seven patients who died with enlarged lymph glands and spleen; in 1865 Samuel Wilks names the disease after him.

2. 1898 and 1902

   The giant cell

   Carl Sternberg and Dorothy Reed describe the giant cells, and Reed shows that the disease is not a form of tuberculosis.

3. 1960s and 1975

   The first cures

   Henry Kaplan cures localised disease with high-energy radiotherapy, Vincent DeVita's team cures advanced disease with MOPP, and in 1975 Gianni Bonadonna's team in Milan introduces ABVD, far less damaging to fertility, which later becomes the standard.

4. 1994 to 1996

   A B cell after all

   Single Reed–Sternberg cells picked from tissue prove to be clonal B cells from the germinal centre. In 2001 the WHO adopts the name Hodgkin lymphoma.

02Etiology and pathophysiology

Who is at risk

The cause is unknown in most patients, but some factors raise the risk:

• Epstein–Barr virus (EBV) is in the HRS cells of about a third of cHL in Europe (20 to 40 per cent), mostly mixed cellularity, children and older adults, and almost every case in people with HIV. After infectious mononucleosis, the risk of EBV-positive HL is about four times higher (a median of about four years between the two); that of EBV-negative HL is not raised.
• Immunodeficiency: HIV raises the risk several-fold, even with effective antiretroviral treatment; so do organ transplantation and immunosuppressive drugs.
• Family: first-degree relatives have a risk a few times higher, an identical twin a far higher one.
• Autoimmune diseases, such as rheumatoid arthritis, lupus and sarcoidosis, carry a modestly higher risk.
• Upbringing: young adult nodular sclerosis HL is commoner in people from smaller, wealthier families, which suggests that meeting a common infection late rather than in early childhood plays a part. The evidence is indirect.

How it develops

1. 1

   A germinal centre B cell

   In the germinal centre, B cells mutate their immunoglobulin genes to make better antibodies; a cell whose mutations wreck its B-cell receptor normally dies by apoptosis.
2. 2

   Rescue

   The HRS precursor survives anyway, its receptor genes visibly crippled in about a quarter of cases. EBV rescues it (its LMP1 mimics CD40 signalling, its LMP2A the B-cell receptor), or, in EBV-negative cases, mutations keep the NF-κB and JAK–STAT pathways switched on.
3. 3

   Loss of B-cell identity

   The cell loses most of its B-cell programme (no receptor, little or no CD20, weak PAX5), turns on CD30 and CD15, and grows large, often with several nuclei.
4. 4

   Building a niche

   HRS cells release cytokines and chemokines: CCL17 (TARC) recruits helper and regulatory T cells, IL-5 and eotaxin bring eosinophils, TGF-β lays down collagen. The background feeds the HRS cells in return.
5. 5

   Hiding from T cells

   Almost all cHL have extra copies of chromosome 9p24.1, which raise PD-L1 and PD-L2 on the HRS cells and switch off the T cells around them. This is why PD-1 inhibitors work so well in HL.

How it spreads and why it causes symptoms

• cHL spreads in order, from one group of nodes to the next, so at diagnosis it is often confined to nodes above the diaphragm, which is why radiotherapy to the involved sites can cure early disease. Spread through the blood to the spleen, liver, lungs and marrow comes later.
• The cytokines cause the B symptoms, itch, fatigue, eosinophilia and the anaemia of inflammation.
• Cell-mediated immunity is impaired, before treatment and for years after it: herpes zoster, tuberculosis and fungal infections are commoner, and skin tests to recall antigens are negative (anergy).

03Clinical features

Symptoms and signs

• A painless, enlarging lymph node, most often in the neck or above the clavicle, less often in the axilla; rubbery rather than hard, and it may wax and wane. Disease only below the diaphragm is unusual.
• A mediastinal mass, typical of young women with nodular sclerosis: found on a chest film, or causing cough, chest discomfort, breathlessness and, rarely, superior vena cava obstruction.
• B symptoms, in about a third of patients, more often in advanced disease: unexplained fever above 38 °C, drenching night sweats, and loss of more than 10 per cent of body weight in the previous 6 months. A cyclical fever, high for a week or two then normal for as long (Pel–Ebstein fever), is classic but rare.
• Pruritus, generalised and sometimes severe, in around 1 in 10 patients.
• Pain in the involved nodes within minutes of drinking alcohol: uncommon, but very suggestive of HL.
• Fatigue; splenomegaly and hepatomegaly in advanced disease; bone pain.

The blood count is often normal in early disease. There may be a normocytic anaemia of inflammation, neutrophilia, eosinophilia, lymphopenia (an adverse sign), a raised ESR (a risk factor that sets treatment), low albumin and a raised alkaline phosphatase. Rarer associations are minimal change nephrotic syndrome, hypercalcaemia from calcitriol made in the tumour, paraneoplastic cerebellar degeneration, and autoimmune haemolytic anaemia or immune thrombocytopenia.

Hodgkin or non-Hodgkin?

The table simplifies: the non-Hodgkin lymphomas are a family of very different diseases.

Differential diagnosis

• Infection: infectious mononucleosis (its nodes can hold cells that look like Reed–Sternberg cells), cytomegalovirus, toxoplasmosis, HIV, tuberculosis, cat-scratch disease.
• Other lymphoid cancers: non-Hodgkin lymphomas, including primary mediastinal large B-cell lymphoma in young women, and chronic lymphocytic leukaemia.
• Sarcoidosis, drug reactions; metastatic cancer (head and neck squamous carcinoma in the neck, lung, breast or abdominal cancer above the left clavicle).
• In the anterior mediastinum: thymoma, germ cell tumours, lymphoma and a retrosternal thyroid.

04Diagnosis and management

Making the diagnosis

1. An excision biopsy of a whole node, or a core biopsy if excision is not possible, read by a haematopathologist. A fine-needle aspirate can neither make nor exclude the diagnosis: the architecture and enough HRS cells are needed.
2. Immunohistochemistry: HRS cells are CD30-positive, usually CD15-positive, CD45-negative, weakly PAX5-positive, and CD20-negative or weakly positive; EBV can be shown in them (EBER). The LP cells of NLPHL are CD20-, CD45- and BCL6-positive and lack CD15 and CD30.

Staging and work-up

• PET-CT with contrast-enhanced CT. HL takes up FDG avidly, and PET-CT finds disease in spleen, bone and marrow that CT misses, so a marrow biopsy is no longer needed.
• History (B symptoms), examination, performance status; full count, ESR, kidney and liver tests, albumin, LDH; HIV, hepatitis B and C serology; a pregnancy test where relevant.
• ECG and echocardiography before doxorubicin, lung function with gas transfer before bleomycin.
• Fertility counselling, and preservation for anyone who may want children, before treatment starts: sperm banking for men, and egg, embryo or ovarian tissue freezing for women as time allows.

The stage follows the Lugano classification (2014), a modification of Ann Arbor:

The spleen, thymus and Waldeyer's ring count as lymphoid tissue. In HL only, A means no B symptoms and B at least one. Bulk is a nodal mass of 10 cm or more, or a mediastinal mass wider than a third of the chest.

Risk groups

Early stages are divided by clinical risk factors. The German Hodgkin Study Group (GHSG) uses four; the European EORTC group's set differs slightly (it counts an age of 50 or more and four or more nodal areas).

In advanced disease, the International Prognostic Score (IPS, the Hasenclever score) gives a point each for albumin below 40 g/L, haemoglobin below 105 g/L, male sex, age 45 or more, stage IV, white cells of 15 × 10⁹/L or more, and lymphocytes below 0.6 × 10⁹/L (or below 8 per cent). In the 1980s and early 1990s, freedom from progression at 5 years fell from 84 per cent with no factors to 42 per cent with five or more; modern treatment has narrowed the gap.

Response is read on the 5-point Deauville scale, comparing uptake in the lymphoma with the mediastinal blood pool and the liver: 1 to 3 (no more than the liver) is a complete metabolic response, a negative PET-CT, in most pathways; 4 or 5 (above the liver, or new lesions) is positive. The PET-CT after two cycles (interim PET) steps treatment up or down, and the one at the end decides whether a residual mass needs radiotherapy. Surveillance scans in remission are not advised.

Treatment of classic HL

Treatment is chemotherapy, with involved-site radiotherapy (ISRT) in early stages or to masses still PET-positive at the end; ISRT treats only the nodes involved at diagnosis, sparing the heart and breasts, and has replaced the large mantle fields of the past. The regimens:

• ABVD: doxorubicin, bleomycin, vinblastine and dacarbazine, on days 1 and 15 of a 4-week cycle; AVD leaves out bleomycin.
• Escalated BEACOPP (eBEACOPP): bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone, every 3 weeks; eBEACOPDac swaps procarbazine for dacarbazine and is less toxic.
• BrECADD: brentuximab vedotin (an anti-CD30 antibody carrying a microtubule poison into the HRS cell), etoposide, cyclophosphamide, doxorubicin, dacarbazine and dexamethasone, every 3 weeks.
• N-AVD: the PD-1 inhibitor nivolumab with AVD, for six 4-week cycles. A-AVD is brentuximab vedotin with AVD; in the ECHELON-1 trial it raised 6-year survival in stage III and IV disease from 89 per cent with ABVD to 94 per cent, at the cost of more neuropathy and neutropenia.

The European recommendations of 2026, by group:

to the involved sites after two cycles of ABVD, in early favourable disease

20Gyto the involved sites after two cycles of ABVD, in early favourable disease

of BrECADD, by the PET-CT after two

4 or 6cyclesof BrECADD, by the PET-CT after two

a negative PET-CT

3or less on Deauvillea negative PET-CT

Leaving out radiotherapy is weighed with a radiation oncologist, since modern radiotherapy may carry less late risk than the extra chemotherapy that replaces it. Over 60, bleomycin is limited to two cycles, and over 70 leaving it out altogether is considered. In the RATHL trial, dropping it after a negative interim PET-CT spared the lungs at little cost in disease control: 84 against 86 per cent were free of progression at 3 years, just short of the trial's margin for proving the two equal.

Supportive care and toxicity

• G-CSF and co-trimoxazole are given from the start with BrECADD, eBEACOPP and A-AVD, which cause deep neutropenia. Fever during chemotherapy is neutropenic sepsis until proven otherwise and needs intravenous antibiotics within the hour (febrile neutropenia).
• ABVD seldom causes lasting infertility; eBEACOPP often does, above all in men and in women over 30, and BrECADD less so.
• In the UK, everyone with HL receives irradiated red cells and platelets for life, because their impaired T-cell immunity cannot reject donor lymphocytes, which can cause fatal transfusion-associated graft-versus-host disease.

Relapsed and refractory classic HL

1. 1

   Confirm it

   A biopsy confirms relapse where possible, as infection and other cancers can mimic it on PET-CT. Progression during first-line treatment or within 3 months is refractory disease; relapse within 12 months is early.
2. 2

   Salvage

   The aim is a complete metabolic response. Where funded, a PD-1 inhibitor with chemotherapy (pembrolizumab with GVD, nivolumab with ICE) achieves one in about 9 in 10; otherwise brentuximab vedotin with chemotherapy, or chemotherapy alone (DHAP, ICE, GVD).
3. 3

   Autologous transplant

   High-dose chemotherapy (BEAM) with an autologous stem cell transplant is the standard for those fit for it; age alone does not rule it out. With a complete metabolic response beforehand, about 3 in 4 are free of progression at 5 years, against a quarter to under a third with a positive PET-CT.
4. 4

   Consolidation

   At high risk (primary refractory disease, early relapse, extranodal relapse), brentuximab vedotin maintenance for up to 16 doses after the transplant raised 5-year progression-free survival from 41 to 59 per cent in the AETHERA trial.
5. 5

   Later relapse

   After a transplant, a PD-1 inhibitor for up to 2 years, with an allogeneic transplant discussed with fit patients. When no transplant is possible, a PD-1 inhibitor alone is preferred, or brentuximab vedotin.

Nodular lymphocyte-predominant HL

• Stage IA without risk factors: 30 Gy ISRT alone (about 92 per cent free of progression and 99 per cent alive at 8 years).
• Other early stages: as for cHL, with or without an anti-CD20 antibody such as rituximab.
• Advanced disease: from watchful waiting to chemotherapy with rituximab (R-CHOP, R-CVP, bendamustine-rituximab). The LP-IPS (age 45 or more, stage III or IV, haemoglobin below 105 g/L, spleen involvement) separates risk groups.
• A suspected relapse is biopsied, because about 1 in 10 transform into an aggressive B-cell lymphoma within 10 years; many relapses respond to rituximab alone or radiotherapy.
• Brentuximab vedotin (LP cells lack CD30) and PD-1 inhibitors have no place.

Particular groups

Older patients have more comorbidity, toxicity and EBV-positive disease, and worse results; a geriatric assessment guides treatment. People with HIV receive the same curative regimens, with antiretroviral therapy continued (watching for interactions) and infection prophylaxis. Children and adolescents are treated on paediatric protocols, which aim to limit radiotherapy to those whose disease responds slowly on PET-CT.

05Epidemiology

• Europe has about 2 to 4 new cases per 100,000 people a year, depending on the region and the estimate, and 0.3 to 0.6 deaths. GLOBOCAN estimates about 19,400 new cases and 4,000 deaths in Europe in 2024, and 84,500 new cases and 19,500 deaths worldwide. HL is roughly 1 in 10 lymphomas.
• Two age peaks: adolescents and young adults, mostly nodular sclerosis, and after 55, with more mixed cellularity and EBV-positive disease. Men are affected slightly more often (about 1.3 to 1).
• In lower-income countries the first peak falls in childhood, mostly in boys, with mixed cellularity and EBV.
• Incidence has been fairly stable for decades, while mortality has fallen steeply since the 1970s, leaving a large and growing population of young survivors.

06Prognosis

Most patients are cured. In trials of adults up to 60:

Trial patients are fitter than most, and results are worse after 60: even with N-AVD, about 82 per cent of fit older patients were free of progression at 3 years. The interim PET-CT is now the strongest guide to outcome; stage, risk factors, age and comorbidity add to it. After relapse, the response to salvage matters most.

Late effects

The treatment that cures causes most of the long-term harm, and the risks last for decades:

• Second cancers: in a Dutch cohort of 3,905 five-year survivors treated between 1965 and 2000 at ages 15 to 50, second cancers were 4.6 times commoner than expected, and 48.5 per cent had had one by 40 years; mostly breast, lung and gut cancers, and leukaemia after alkylating drugs.
• Breast cancer is the main risk for women irradiated to the chest when young, from about 8 years after radiotherapy; doxorubicin adds to it.
• Heart disease: in a Dutch cohort of 2,524 patients, half had cardiovascular disease by 40 years, and coronary disease and heart failure were 4 to 6 times commoner than in the general population even 35 years on. Mediastinal radiotherapy raised the risk of coronary and valve disease and of heart failure, and anthracyclines that of cardiomyopathy with heart failure, and of valve disease.
• Hypothyroidism after neck radiotherapy; lung damage; infertility and early menopause; fatigue, anxiety and depression.

These cohorts had radiotherapy fields and drugs (MOPP) no longer used; today's patients should fare better, but by how much will not be known for decades.

Follow-up after remission is clinical, without routine scans, and turns from relapse to late effects:

• TSH every year if the neck was irradiated; blood pressure and lipids every year; sex hormones in younger patients after intensive chemotherapy;
• women irradiated to the breasts before the age of 36 need a mammogram or breast MRI every year from 8 years after radiotherapy, but not before 25;
• no smoking, control of cardiovascular risk factors, and the usual cancer screening;
• questions about breathlessness, chest pain, fatigue, mood, sexual function, fertility, work and money.