Classification

Accurate classification of the type and accurate staging of the disease will determine the most favourable treatment options and prognosis. Hodgkin's lymphoma is classified into two distinct entities:^[1]

• Classical Hodgkin's lymphoma (95% of all cases):
  • Nodular sclerosis
  • Mixed cellularity
  • Lymphocyte-rich
  • Lymphocyte-depleted
• Nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL - 5% of all cases).

Epidemiology

• Hodgkin's lymphoma is a rare malignancy, with an incidence of about 2.2 per 100,000 per year.^[2]
• It most often occurs in those aged 15-30 years and in those aged over 50 years.
• Prevalence in women peaks in the third decade and then falls, but in men it remains fairly constant after the third decade.

Risk factors

• Epstein-Barr virus has been found in the Reed-Sternberg cells of about 50% of patients with Hodgkin's lymphoma.
• Patients who have previously developed mononucleosis have an increased risk of developing Hodgkin's lymphoma.
• Other risk factors include human immunodeficiency virus (HIV), immunosuppression and cigarette smoking.^[3]

Presentation

• Most patients present with an enlarged but otherwise asymptomatic lymph node, typically in the lower neck or supraclavicular region.
• Mediastinal masses are frequent and are sometimes discovered on a routine chest X-ray.
• Patients might complain of chest discomfort with a cough or dyspnoea. About 25% of patients will have systemic symptoms at presentation, typically fatigue, fever, weight loss, pruritus and night sweats.
• Alcohol-induced pain at sites of nodal disease is specific but occurs in fewer than 10% of patients.^[4]
• Findings on examination include lymphadenopathy, hepatomegaly, splenomegaly, and superior vena cava syndrome; there may also be features caused by paraneoplastic syndromes, eg cerebellar degeneration, neuropathy or Guillain-Barré syndrome.^[4]

Differential diagnosis

• Infectious mononucleosis
• AIDS
• Non-Hodgkin's lymphoma
• Tuberculosis
• Leukaemia
• Sarcoidosis
• Myeloma
• Toxoplasmosis
• Cytomegalovirus infection
• Tularaemia

Investigations

• FBC: to exclude leukaemia, mononucleosis and other causes of lymphadenopathy. The degree of any anaemia, leukocytosis and lymphopenia are prognostic indicators.
• Tests for possible differential diagnoses, eg tests for infectious mononucleosis.
• ESR: an ESR of greater than 70 carries an unfavourable prognosis.
• Liver function and serum protein tests: the level of any rise in lactate dehydrogenase (LDH) and fall in albumin levels has prognostic significance.
• HIV tests are necessary in patients with suspected Hodgkin's lymphoma.
• Fine needle aspiration samples should not normally be used as the sole tissue for diagnosis.^[5]
• Lymph node biopsy: pathological diagnosis should be made from a sufficiently large specimen or excisional lymph node biopsy to provide samples for fresh frozen and formalin-fixed samples.^[2] Excisional node biopsy is better than fine needle or core needle biopsy, as it allows the diagnosis of lymphomas based on the morphology of the lymph node, which is not offered by needle biopsy.^[5]
• CXR: assess any intrathoracic lymphadenopathy and mediastinal expansion.
• CT scans of the thorax and abdomen are required for staging Hodgkin's lymphoma.
• Lymphangiography: may be useful if there is subdiaphragmatic presentation of Hodgkin's lymphoma with equivocal abdominal CT findings, or there is subdiaphragmatic presentation of Hodgkin's lymphoma with the intention to treat with radiotherapy alone.
• Gallium scans: can be useful if CT scanning produces equivocal results. They are performed if mediastinal or hilar nodes are involved and as a baseline in patients with bulky disease, for better determination of response during and after therapy.
• Bone marrow biopsy is indicated for staging purposes.

Staging and risk assessment

• Full blood cell count, ESR and blood chemistry including CRP, alkaline phosphatase, LDH, liver enzymes, albumin and thyroid-stimulating hormone.^[2]
• Screening for hepatitis B (HBV), hepatitis C (HCV) and HIV is compulsory.
• CXR, CT scan of the neck, chest and abdomen, and bone marrow aspiration and histology are essential.
• A positron emission tomography (PET) scan may be considered.^[6]
• Staging laparotomy is not recommended.

Staging

Ann Arbor staging system with Cotswold modifications for Hodgkin's lymphoma:^[1]

• Stage I: involvement of one lymph-node region or lymphoid structure (eg spleen, thymus, Waldeyer's ring).
• Stage II: two or more lymph-node regions on the same side of the diaphragm.
• Stage III: lymph nodes on both sides of the diaphragm.
  • Stage III (1): with splenic, hilar, coeliac, or portal nodes.
  • Stage III (2): with para-aortic, iliac, or mesenteric nodes.
• Stage IV: involvement of extranodal site(s) beyond that designated E (see below).
• Modifying features:
  • A: no symptoms.
  • B: fever, drenching night sweats, weight loss greater than 10% in six months.
  • X: bulky disease: greater than a third widening of mediastinum or greater than 10 cm maximum diameter of nodal mass.
  • E: involvement of single, contiguous, or proximal extranodal site.

Disease is further classified into limited, intermediate or advanced:^[2]

• Limited disease: up to IIB with no risk factors.
• Intermediate disease: up to IIB with at least three involved lymph-node areas or high ESR (ESR over 50 mm/h without B symptoms, or over 30 mm/h with B symptoms; B symptoms are defined as fever, night sweat, weight loss.
• Advanced disease:
  • Stage IIB with large mediastinal mass (more than one third of the horizontal chest diameter) or extranodal disease.
  • Any stage III or above.

Management

Before treatment, patients should be assessed for risk of acute and/or long-term complications. Cardiac and pulmonary function tests are mandatory, and consultation with an ear, nose and throat specialist should be considered (particularly for patients with involvement of the head and neck region).^[2]

The patient may also need reproductive counselling if they have not yet started a family, as treatment may compromise fertility.

• Radiation therapy, chemotherapy or combined therapies are the treatments used in managing Hodgkin's lymphoma.
• Both chemotherapy and radiation therapy increase the risk of developing secondary solid tumours, eg cancers of the lung, breast, and stomach.
• Vaccinations: polyvalent pneumococcal vaccine and influenza vaccine should be given to all patients with Hodgkin's lymphoma. Meningococcal group C conjugate vaccine and Haemophilus influenzae type b vaccine are also recommended, especially for patients receiving treatment and those with asplenia or splenic dysfunction.^[7]
• The role of allogeneic hematopoietic stem cell transplantation for Hodgkin's lymphoma is being explored.^[4]

Chemotherapy

• Effective but carries an increased risk of leukaemia. The peak in risk is seen about five years after the initiation of chemotherapy. The risk is higher in patients who undergo splenectomy and who have advanced disease; the risk is unaffected by concomitant radiation therapy.
• Chemotherapy is normally based on certain combinations:
  • ABVD: doxorubicin (used to be called Adriamycin®), bleomycin, vinblastine, dacarbazine. 2-3 cycles of ABVD followed by involved field radiotherapy are standard care for limited-stage disease.
  • ABV: same as ABVD but without dacarbazine.
  • MOPP: mechlorethamine, vincristine (brand name Oncovin®), procarbazine, prednisolone.
  • Stanford V: doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, prednisolone.
• Advanced-stage Hodgkin's lymphoma is treated with chemotherapy alone.
• Any patient with severe neutropenia should be given antibiotic prophylaxis with chemotherapy.
• Recombinant human granulocyte colony-stimulating factor (rhG-CSF) stimulates the production of neutrophils and may reduce the duration of chemotherapy-induced neutropenia and thereby reduce the incidence of associated sepsis.^[7]

Radiotherapy

• Classic pattern is extended radiation field in a supradiaphragmatic mantle involving all nodal areas above the diaphragm in local disease with prophylactic abdominal irradiation in stage I and stage II disease.
• More extensive radiotherapy reduces the risk of relapse but increases the risk of late mortality from other causes.

Treatment regimes

There is some variation between the different guidelines. The following regimes are recommended by the European Society for Medical Oncology (ESMO).^[2] The choice of treatment will depend on the stage of the disease, the histological subtype and favourable prognostic factors:

• Classical Hodgkin's lymphoma, limited stage:
  • 2 cycles of doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD) in combination with regional radiotherapy.
• Classical Hodgkin's lymphoma, intermediate stage:
  • 4 cycles of ABVD in combination with regional radiotherapy.
• Classical Hodgkin's lymphoma, advanced stage:
  • 6-8 cycles of ABVD (8 cycles of bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone are an alternative for patients up to 60 years old) followed by radiotherapy of residual lymphoma larger than 1.5 cm.
• Relapsed classical Hodgkin's lymphoma patients:
  • Nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL), stage IA without risk factors:
    • Regional radiotherapy alone.
  • NLPHL, other stages:
    • NLPHL treatment is identical to classical Hodgkin's lymphoma in all stages except for stage IA without risk factors.
  • Relapsed NLPHL patients:
    • A further biopsy should be obtained in patients with suspected relapse since transformation into aggressive non-Hodgkin's lymphoma (NHL) must be excluded.
    • A localised NLPHL relapse should be treated with rituximab.
    • More advanced relapses require more aggressive salvage therapy in combination with rituximab.

  Follow-up

  After treatment the patient should be seen every three months for the first half year, every six months until the fourth year, and once a year thereafter. At this appointment, history, examination, FBC, ESR and blood chemistry should be performed. In addition TSH should be checked at 1, 2 and 5 years (if the neck has been irradiated) and oestrogen and testosterone monitored in younger patients who have had intensive chemotherapy.
  
  Radiographic tests should be ordered once (to confirm remission) and thereafter, as clinically indicated.

  Complications

  • Leukaemia, especially acute myeloid leukaemia, may occur in patients treated with chemotherapy or combined chemotherapy and radiotherapy.
  • Second solid tumours, especially of the colon, lung, bone, breast, and thyroid, can occur in patients who received radiation therapy with or without chemotherapy.^[8] Cancer screening should be conducted regularly.
  • An increased risk has also been found for melanoma, non-Hodgkin's lymphoma, soft-tissue sarcoma, salivary gland cancers and pancreatic cancers.^[4]
  • Other complications of irradiation include hypothyroidism and cardiovascular disease.
  • Other complications of chemotherapy include male infertility and female infertility.

  Prognosis

  • The most common causes of death in patients cured of Hodgkin's lymphoma are cardiovascular or infectious complications, with 2-3 times the probability than for the general population.
  • Both localised and advanced Hodgkin's lymphoma can be cured in most patients.
  • The European Task Force on Lymphoma reported a 96% complete response rate to primary treatment, with a 99% and 94% 8-year disease-specific survival for stage I and stage II disease respectively.
  • Risk factors in localised disease:
    • Unfavourable prognosis: patients have any of following features: clinical stage II with involvement of at least four nodal areas, age older than 50 years, ESR greater than 50 if asymptomatic and greater than 30 if B symptoms, mediastinal/thoracic ratio greater than 0.35.
  • Hasenclever Index for patients with advanced disease:
    • Unfavourable prognosis: age older than 45 years, male sex, serum albumin less than 40 g/L, haemoglobin concentration less than 10.5 g/dL, stage IV disease, white cell count 15 x 10⁹/L or greater, lymphopenia (less than 0.6 x 10⁹/L or less than 8% of the total white cell count).