Hodgkin’s lymphoma is a rare haematological malignancy (accounts for<1% of all cancers in the UK) caused by the uncontrolled proliferation of B-lymphocytes. These cells travel through the lymphatic system and build up in the lymph nodes causing lymphadenopathy. They can also spread to other organs such as the spleen or bone marrow. Hodgkin’s lymphoma is differentiated from non-Hodgkin’s lymphoma based on its histological appearance of huge multinucleated lymphocytes called Reed-Sternberg cells. Chemotherapy +/- radiotherapy are the main treatments of Hodgkin's lymphoma, and overall patients have a good prognosis with a 5-year survival rate of 80-90% in the early stages and 40-80% in the advanced stages.


There are two types of Hodgkin’s lymphoma:
  • Classical Hodgkin’s lymphoma (95%)
  • Nodular lymphocyte-predominant Hodgkin’s lymphoma (5%)
    • More commonly affects males (75%)
    • Not associated with EBV
    • Absence of Reed-Sternberg (RS) cells, and is characterised by LP (“popcorn”) cells
    • Presents with peripheral adenopathy, and is the only type of Hodgkin's lymphoma that affects the mesenteric lymph nodes

In classical Hodgkin’s lymphoma, there are four subtypes:

Nodular sclerosingMixed cellularityLymphocyte-richLymphocyte-depleted
Sclerosing fibrotic tissue surrounding lacunar variants of RS cells in a nodular patternMultiple RS cells in a mixed inflammatory background with lymphocytes, plasma cells, eosinophils and histiocytesRS cells are found mainly in the marginal zone, with a background of numerous lymphocytes and a lack of neutrophils and eosinophilsSome of the RS cells are of atypical features, with a background of abundant histiocytes and few lymphocytes
70%, good prognosis20-25%, worse prognosis5%, best prognosis<1%, worst prognosis
Mediastinal lymphadenopathy in 80%, and bulky nodes in 50%Peripheral adenopathy and spleen involvement are commonPeripheral adenopathy. Bulky nodes and mediastinal involvements are uncommonRetroperitoneal and abdominal lymphadenopathy
10-40% associated with EBV75% associated with EBVAffects the older age group75% associated with EBV. This subtype is also more common in HIV patients


  • Incidence: 3.30 cases per 100,000 person-years
  • Peak incidence: 20-30 years
  • Sex ratio: more common in males 1.3:1
Condition Relative
Non-Hodgkin's lymphoma6.36
Hodgkin's lymphoma1
Castleman's disease0.45
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+


The exact aetiology of Hodgkin's lymphoma is still being investigated, but it is thought to be multifactorial:
  • Epstein-Barr virus (EBV) infection (40%) : EBV infection (infectious mononucleosis) often precedes Hodgkin's lymphoma by a median time of 4 years. It is thought that a history of EBV infection greatly increases the risk of Hodgkin's lymphoma.
  • Immunosuppression
    • Organ transplantation
    • Immunosuppressant therapies
    • Patients with HIV
  • Autoimmune conditions e.g. rheumatoid arthritis, systemic lupus erythematosus and sarcoidosis
  • Familial (5%): same-sex siblings of patients with Hodgkin's lymphoma are 10 times more likely to develop the condition


Reed-Sternberg (RS) cells are a distinctive histological feature in Hodgkin's lymphoma. They are post-germinal B lymphocytes that have undergone transformations and are intended for apoptosis. However, several mechanisms are thought to play a role in escaping apoptosis which then leads to unchecked proliferation:
  • Epstein-Barr virus (EBV)-positive Hodgkin's lymphoma takes up around 40% of all Hodgkin's lymphoma. Several EBV-induced proteins e.g. Epstein–Barr nuclear antigen 1 (EBNA1), latent membrane protein 1 (LMP1), and LMP2 are found in EBV-positive RS cells.
    • EBV infects naive B lymphocytes and adapts to their normal B-cell signalling pathway → activated naive B-cells undergo germinal centre reaction → EBV changes between various latency programmes during this reaction (from latency programmes III→II→I→0 with different protein expressions) → ensures the presence of EBV DNA in memory B cells without being detected by cytotoxic T cells. The genes expressed in RS cells during latency II also promote proliferation and survival of the cells.
    • EBNA1 protein is responsible for episome replication and attachment of viral episome to mitotic chromosomes → presence of EBV DNA in RS cells.
    • LMP1 protein increases the turnover of IκBα and activates nuclear factor-κB (NF-κB) → up-regulates >200 genes in the nucleus, including apoptotic regulators and intracellular signalling → promotes the transformation of RS cells.
  • An abundant amount of inflammatory infiltrates is found in Hodgkin's lymphoma, often occupying 99% of the tumour mass. The inflammatory infiltrates consist of various cytokines and chemokines → inhibit T-helper type 1 (Th1) response and promote activation of Th2 phenotypes → immunosuppression and proliferation of B lymphocytes by binding to interleukin-13 and its receptor.
  • Human leukocyte antigen (HLA) class 1 inhibits the antigen presentation to CD8+ cytotoxic T-lymphocytes. In EBV-negative cases, HLA class 1 is down-regulated → escaping cytotoxicity. Whereas in patients with EBV-positive Hodgkin's lymphoma, rarer haplotypes of HLA class 1 are often up-regulated → inhibit the normal anti-EBV immune response.

Clinical features

Hodgkin's lymphoma can affect patients of any age, but it has a bimodal distribution in age groups: 20-30 years and >50 years. 30% of the patients diagnosed with Hodgkin's lymphoma are between the 20-34 age group.

Patients with Hodgkin's lymphoma commonly present with lymphadenopathy which is:
  • Painless
  • Asymmetrical
  • Cervical nodes or mediastinal involvement in 60%
    • If mediastinal lymph nodes are involved, this can compress the airway and lead to dyspnoea, chest pain, and dry cough. It may also cause superior vena cava obstruction.
  • Can also occur in the spleen (27%), and the axillary (14%), abdominal (11-14%), hilar (12%) or inguinal-femoral (1-3%) lymph nodes
  • Alcohol-induced pain at lymph node regions is a non-specific symptom as it can also occur in patients with alcohol intolerance and carcinoid syndrome. There's a lack of research regarding alcohol-induced pain in Hodgkin's lymphoma, but a paper published in 1983 estimated the incidence to be 1.5-5%.

B symptoms are presented in up to 30% of patients:

Other clinical features include
  • Pel-Ebstein fever - cyclical fever followed by periods of being afebrile for 1-2 weeks (rare)
  • Abdominal pain (if abdominal lymphadenopathy is involved)
  • Pruritus (30%)
  • Clinical hepato/splenomegaly is rare (although liver and spleen involvement determined by laparoscopy/laparotomy occurs in up to 30% of the patients)
  • Bone marrow involvement (5-8%)

Referral criteria

NICE cancer referral guidelines for Hodgkin's lymphoma suggest the following:

Hodgkin's lymphoma in adults

Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for Hodgkin's lymphoma in presenting with unexplained lymphadenopathy. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus, weight loss or alcohol‑induced lymph node pain.

Hodgkin's lymphoma in children and young people

Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment for Hodgkin's lymphoma in children and young people presenting with unexplained lymphadenopathy. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss.


The investigations suggested below form part of the workup for patients with suspected Hodgkin's lymphoma:
  • Blood tests
    • Full blood count (FBC): Patients with Hodgkin's lymphoma are often anaemic, lymphopenic and thrombocytopenic, which can be associated with bone marrow involvement. Evidence of neutrophilia and anaemia indicate a poorer prognosis.
    • There is inadequate research on the sensitivity and specificity of FBC in Hodgkin's lymphoma. However studies have shown that an abnormally low absolute lymphocyte count at the point of diagnosis is a negative prognostic factor in patients with Hodgkin's lymphoma.
    • Baseline renal and liver function
    • Erythrocyte sedimentation rate (ESR): Non-specific but tends to be elevated and indicates a poorer prognosis when the ESR level is >50 mm/hour in patients without B symptoms or >30 mm/hour in those with B symptoms.
    • Lactate dehydrogenase (LDH): correlates with disease activity
    • Viral screen e.g. Hepatitis B, C and HIV
  • Lymph node excision biopsy is the definitive diagnosis for Hodgkin's lymphoma.
    • It reveals the characteristic Reed-Sternberg cells (owl's eye appearance), or other distinctive Hodgkin's cells such as lacunar cells or popcorn cells.
    • Core biopsy and fine-needle aspiration can rarely confirm the diagnosis due to inadequate Hodgkin's cells within the specimens
  • PET or PET-CT scans
    • The BMJ Best Practice (Oct 2019) recommends PET scans (93% sensitivity, 87% specificity) for both staging and assessing treatment response post-chemotherapy.
    • Fluorodeoxyglucose (FDG)-PET scans can also be used for detecting bone marrow involvement.
  • Contrast CT chest, abdominal and pelvis, chest x-rays and gallium scans can also help with staging
  • Bone marrow biopsy can be considered in patients with B symptoms or advanced (stage III-IV) Hodgkin's lymphoma

Differential diagnosis

Possible differential diagnoses:

Non-Hodgkin’s lymphoma
Non-Hodgkin's lymphomaHodgkin's lymphoma
Median age 60sBimodal age group - 15-24 and >60
6th commonest type of cancers in adults and accounts for 4% of all cancersMuch rarer, <1% of all cancers diagnosed
Can arise in T or B-lymphocytes or natural killer cellsPresence of Reed-Sternberg cells
Risk factors include patients with autoimmune disorders, HIV or those taking immunosuppressants post organ transplantAffects younger patients, those with a history of Epstein-Barr virus infection or family history of Hodgkin's lymphoma
Lymphadenopathy occurs anywhere in the body but sometimes also in the groin and abdomenLymphadenopathy usually limited to the upper body (neck, chest or axilla)
Lymphadenopathy spreads discontinuouslySpreads continuously from one group to the other
Extra-nodal involvement such as skin (e.g. rash) or the central nervous system is more common

Other carcinomas

Infectious mononucleosis (Epstein-Barr virus)
  • Similarities: cervical or axillary lymphadenopathy
  • Differences: tender lymphadenopathy, sore throat

Reactive lymphadenopathy resulted from other infections
  • Similarities: lymphadenopathy at similar sites
  • Differences: often self-limiting and without B-symptoms


The Cotswolds-modified Ann Arbor staging system helps determine the treatment options and prognosis.
  • Stage I - limited to a single lymph node region.
  • Stage II - two or more lymph node regions involved, on the same side of the diaphragm.
  • Stage III - lymph node regions involved on both sides of the diaphragm.
  • Stage IV - spread to other organs, such as liver, spleen, or bone marrow, with or without nodal involvement.

Each stage is followed by a letter:
  • A - without B symptoms.
  • B - with B symptoms, including fever, weight loss, night sweats.
  • E - an extra-nodal site involved, that is localised to the known lymph node region.
  • X - bulky disease: mediastinal mass exceeds 1/3 of the intrathoracic diameter or nodal mass >10cm in dimension.


Chemotherapy alone or in combination with radiotherapy are the main types of treatment for Hodgkin's lymphoma. This depends on the staging and type of lymphoma.

Stage I/II classical Hodgkin's lymphoma
  • Certain prognostic factors subdivide stage I/ II lymphoma into favourable and unfavourable groups, including the presence of B symptoms, extra-nodal involvement and high erythrocyte sedimentation rate (ESR) levels.
  • Chemotherapy followed by radiotherapy
    • Main treatment regimen: ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) + radiotherapy
    • BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) followed by ABVD and radiotherapy can sometimes be considered in stage I/II unfavourable group . However BEACOPP is found to have a higher risk of secondary leukaemia than ABVD.
    • Chemotherapy alone may be useful in patients with non-bulky Hodgkin's lymphoma (mediastinal mass ratio <1/3).

Stage I/ II nodular lymphocyte-predominant Hodgkin's lymphoma
  • Involved-field radiotherapy alone is the main treatment for this group of patients with excellent clinical benefit.

Stage III/ IV classical Hodgkin's lymphoma
  • Chemotherapy alone
    • A randomized phase 3 trial published on the New England Journal of Medicine in 2017 (updated in 2018) showed that brentuximab vedotin with ABD is shown to have 5% greater 2-year modified progression-free survival rates than ABVD alone (82.1% vs 77.2%).
    • Stanford V chemotherapy (doxorubicin, vinblastine, chlormethine, vincristine, bleomycin, etoposide, prednisolone) may be used to minimise the risk of bleomycin pulmonary toxicity.

Stage III/ IV nodular lymphocyte-predominant Hodgkin's lymphoma
  • Regular monitoring is adequate in asymptomatic patients.
  • R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) is administered in symptomatic patients or those with rapid disease progression .

Relapsed or refractory Hodgkin's lymphoma
  • Management of relapsed or refractory Hodgkin's lymphoma varies between patients based on certain factors including age, past medical history, disease progression and previous treatments.
  • Chemotherapy followed by autologous stem cell transplantation (ASCT) may be useful if chemotherapy and radiotherapy aren't successful.
  • Immunotherapeutic agents can be considered:
    • Brentuximab vedotin is approved for relapsed and refractory Hodgkin's lymphoma. NICE guidelines stated in 2018 that, for patients with CD30-positive Hodgkin's lymphoma, brentuximab vedotin is only recommended if: they have already had ASCT, or they have already had 2 other treatments and can't undergo ASCT or chemotherapy.
    • NICE recommended in 2017 that nivolumab can be used for treating this group of patients after ASCT and brentuximab vedotin treatment
    • In 2018 NICE published further guidelines regarding the use of pembrolizumab in patients with relapsed or refractory Hodgkin's lymphoma: it is recommended in those who have already received brentuximab vedotin and can't undergo ASCT, only if pembrolizumab is taken for less than 2 years if the patient has an ASCT. However, pembrolizumab is not recommended in patients who have received both ASCT and brentuximab vedotin treatments.
  • The use of allogeneic transplantation in relapsed patients following ASCT remains limited and debatable.


Complications of Hodgkin's lymphoma are usually chemotherapy or radiotherapy related.
  • Thyroid disorders
    • Around 50% of the patients who received radiotherapy experience symptoms of hypothyroidism.
    • Other possible thyroid disorders include thyroid cancer and hyperthyroidism.
    • Therefore safe netting and regular monitoring of thyroid function should be done in patients receiving radiotherapy.
  • Chemotherapy drugs, especially alkylating agents are associated with secondary malignancies such as acute myeloid leukaemia and paraneoplastic syndrome. Secondary leukaemia is seen in around 3% of patients receiving the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone). Radiotherapy, on the other hand, is associated with an increased risk of solid tumours especially lung cancer and breast cancer.
  • Cardiac abnormalities
    • Patients receiving anthracyclines e.g. doxorubicin are at a higher risk of developing cardiomyopathy.
    • Patients can develop acute pericarditis shortly after receiving radiotherapy, or valvular heart disease or coronary heart disease in the long-term (around 5-10 years post-radiotherapy).
    • According to BMJ Best Practice (Oct 2019), baseline cardiac function should be established by performing echocardiogram or multi-gated acquisition (MUGA) scans before starting anthracyclines. The article also suggested administrating lower doses of radiotherapy as well as managing cardiovascular risk factors to minimise complications.
  • Pulmonary toxicity
    • About 20% of patients receiving the ABVD regimen (doxorubicin, bleomycin, vinblastine, dacarbazine) develop bleomycin-related pulmonary toxicity.
    • Radiation-induced pneumonitis can also occur post-radiotherapy.
    • BMJ Best Practice (Oct 2019) emphasised on the importance of monitoring pulmonary functions by assessing FEV1 and transfer factor for carbon monoxide (TLCO).
  • Infertility
    • Infertility can occur in over 50% of both male and female patients with Hodgkin's lymphoma, depending on various factors e.g. treatment dose, regimen and age of the patient.
    • The use of chemotherapy in female patients over the age of 30 with advanced Hodgkin's lymphoma is more likely to result in a reduced ovarian function comparing to younger patients.
    • Low doses of radiotherapy (1-2Gy) can lead to infertility in men. In terms of chemotherapy regimen, ABVD has a lower risk of infertility in this gender group.
    • Counselling should be offered to discuss the risk of infertility and explore alternative options.
  • Infections
    • Patients with Hodgkin's lymphoma are often immunocompromised at the point of diagnosis. This can be caused by underlying conditions or certain genetic predispositions (e.g. human leukocyte antigen (HLA)) which impair the immune systems and make the patients more susceptible to Hodgkin's lymphoma.
    • Neutropenia is common in patients taking chemotherapeutic regimens such as ABVD, and almost all patients receiving BEACOPP are neutropenic.


The Ann Arbor staging system helps determine prognosis and the intensity of treatment, with stage I and II patients having a better prognosis.

Stage I and II Hodgkin's lymphoma
  • Certain prognostic factors subdivide stage I and II lymphoma into favourable and unfavourable groups, including the presence of B symptoms, extra-nodal involvement and high erythrocyte sedimentation rate (ESR) levels.
  • Patients in stage I/II favourable group have a prognosis of around 85-90%, and that in the unfavourable group 80-90%, after receiving a combination of chemo- and radiotherapy treatments.

Stage III and IV Hodgkin's lymphoma
  • The prognosis of stage III/IV lymphoma is affected by a set of risk factors that correlate with poorer prognoses: male, age >45, leukocytosis, lymphopenia, low haemoglobin, low albumin and high ESR levels. The 5-year survival rate of patients in this group ranges from 42% (with >5 risk factors) to 84% (without any risk factors).