Hodgkin's Lymphoma

Hodgkin's lymphoma is a malignant tumour of the lymphatic system that is characterised histologically by the presence of multinucleated giant cells (Reed-Sternberg cells) and associated abnormal and smaller mononuclear cells originating from B lymphocytes in the germinal centres of lymphoid tissue.

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

• Nodular lymphocyte-predominant Hodgkin's lymphoma
• Classical Hodgkin's lymphoma
  • Nodular sclerosis classical Hodgkin's lymphoma
  • Mixed cellularity classical Hodgkin's lymphoma
  • Lymphocyte-rich classical Hodgkin's lymphoma
  • Lymphocyte-depleted classical Hodgkin's lymphoma

• Hodgkin's lymphoma is a rare malignancy, with an incidence of about 2.4 per 100,000 per year.¹
• Most often occurs in those aged 15-30 years and those 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 disease.
• Patients who had developed mononucleosis have an increased risk of developing Hodgkin's disease.
• Other risk factors include HIV, immunosuppression and cigarette smoking.²

• 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 after 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, and night sweats.
• Pruritus and intermittent fevers usually associated with night sweats are classic symptoms of Hodgkin's lymphoma.

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

• Full blood count: exclude leukaemia, mononucleosis and other causes of lymphadenopathy. The degree of any anaemia, leucocytosis and lymphopenia are prognostic indicators.
• Heterophil antibody test may be performed, which is rapid and inexpensive but may not always be accurate.
• ESR: an ESR of greater than 70 carries an unfavourable prognosis.
• Liver function and serum protein tests: the level of any rise in LDH and fall in albumin levels has prognostic significance.
• HIV tests are necessary in patients with suspected Hodgkin's disease.
• Lymph node biopsy: essential; biopsy of peripheral or mediastinal or intra-abdominal nodes may be needed. 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. ³
• Chest X-ray: assess any intrathoracic lymphadenopathy and mediastinal expansion.
• CT scans of the thorax and abdomen are useful in staging Hodgkin's disease.
• Lymphangiography: may be useful if there is subdiaphragmatic presentation of Hodgkin's disease with equivocal abdominal CT findings, or there is subdiaphragmatic presentation of Hodgkin's disease with the intention to treat with radiotherapy alone.
• Gallium scans: can be useful if CT scanning produces equivocal results 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.
• Laparotomy may be needed to stage Hodgkin's disease, but usually only if contemplating supradiaphragmatic radiotherapy, and only in patients who do not have lymphocyte-predominant Hodgkin's disease. Staging laparotomy is not recommended routinely and it should not be done in patients who require combination chemotherapy.
• Bone marrow biopsy is indicated for staging purposes.

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

• Stage 1: Involvement of one lymph-node region or lymphoid structure (e.g. spleen, thymus, Waldeyer's ring)
• Stage 2: Two or more lymph-node regions on the same side of the diaphragm
• Stage 3: Lymph nodes on both sides of the diaphragm
• Stage 3₁: with splenic, hilar, coeliac, or portal nodes
• Stage 3₂: with para-aortic, iliac, or mesenteric nodes
• Stage 4: 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 6 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

• Radiation therapy, chemotherapy, or combined therapies are the treatments used in managing Hodgkin's disease.
• Both chemotherapy and radiation therapy increase the risk of developing secondary solid tumours (e.g. cancers of the lung, breast, and stomach).
• Vaccinations: polyvalent pneumococcal vaccine and other vaccines should be given to all patients before splenectomy or splenic irradiation.
• The choice of treatment will depend on the stage of the disease, the histological subtype and favourable prognostic factors.
  • Stage 1A:
    • Radiation therapy alone can achieve a cure of 90% or more.
    • Favourable prognostic factors include an ESR less than 50, patients aged less than 50 years, lymphocyte-predominant or nodular sclerosing histology, lack of B symptoms, and no bulky adenopathy.
    • Chemotherapy regimens alone or with radiation therapy may prove to be equally effective. The ultimate choice of therapy will then depend on short-term and long-term toxic effects.
  • Stage 1B:
    • These patients with B symptoms must receive combined therapy (radiation + chemotherapy), because those who undergo a laparotomy are upstaged and there is a high risk of relapse in those receiving chemotherapy alone.
  • Stage 2A:
    • Radiation therapy alone can achieve a cure of 80% or more.
    • Patients with early-stage disease and favourable prognostic features can undergo radiation therapy without needing laparotomy after a careful clinical staging.
  • Stage 2B:
    • Combination radiation with chemotherapy.
  • Stage 3A:
    • Combined chemotherapy with or without radiation therapy.
  • Stage 3B:
    • First-choice treatment is combined chemotherapy with or without radiation therapy to site of bulky disease.
    • Chemotherapy used: ABVD, ABV/MOPP hybrid or ABVD alone for 6-8 months; Stanford V regime repeated 3 times can also be used (see below for drug combinations).
    • A meta-analysis of 14 trials found no differences in 10-year survival when comparing chemotherapy alone with chemotherapy plus radiation.
  • Stage 4A and B:
    • Combination therapy is the first choice.
    • Radiation therapy may be used to areas of bulky disease involvement or sites of initial disease.
    • Chemotherapy used: ABVD, ABV/MOPP hybrid or ABVD alone for 6-8 months; Stanford V regime repeated 3 times can also be used.
    • New dose-intensive, time-condensed regimes are under clinical evaluation.
    • Chemotherapy with bone marrow transplantation is under trial.

Chemotherapy

• Effective but carries an increased risk of leukaemia. The peak in risk is seen about 5 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, bleomycin, vinblastine, dacarbazine
  • ABV: same as ABVD but without dacarbazine
  • MOPP: mechlorethamine, vincristine, procarbazine, prednisolone
  • Stanford V: doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, prednisolone
• Granulocyte-colony stimulating factor (G-CSF):
  • A class of drugs that stimulate the production of granulocytic series (G-CSF) and granulocytic and macrophage series (GM-CSF).
  • Both have been used in supportive care of patients with Hodgkin's disease.

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 II disease.
• More extensive radiotherapy reduces the risk of relapse but increases the risk of late mortality from other causes.

• 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.
• Other complications of irradiation include hypothyroidism and cardiovascular disease.
• Other complications of chemotherapy include male infertility and female infertility.

• Commonest causes of death in patients cured of Hodgkin's disease 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 1 and 2 disease, respectively.
• Risk factors in localised disease:
  • Unfavourable prognosis: patients have any of following features: clinical stage 2 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 4 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).