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Non-Hodgkin's Lymphoma

This PatientPlus article is written for healthcare professionals so the language may be more technical than the condition leaflets. You may find the abbreviations list helpful.

Non-Hodgkin's lymphomas (NHLs) are an heterogeneous group of lymphoproliferative malignancies with differing patterns of behaviour and responses to treatment. There is a much greater predilection to disseminate to extranodal sites than in Hodgkin's lymphoma. The prognosis depends on the histological type, stage and treatment. They can be divided into 2 prognostic groups:1

  • Low-grade: relatively good prognosis, with median survival as long as 10 years. However, they are usually not curable in advanced clinical stages.
  • High-grade: shorter natural history, but a significant number of these patients can be cured with intensive combination chemotherapy regimens.

Classification

The World Health Organization (WHO) classification is an update of the Revised European American Lymphoma (REAL) Classification. The classification includes:1

Epidemiology

  • Non-Hodgkin's lymphoma (NHL) is more than 5 times as common as Hodgkin's disease.
  • White people have a higher risk than black and Asian people.1
  • The median age at presentation is older than 50 years, except for patients with high-grade lymphoblastic and small noncleaved lymphomas, which are the most common types of NHL observed in children and young adults. Low-grade lymphomas are very rare in children.1
  • The 2 most common types of NHL are diffuse large B-cell lymphoma (DLBCL) and follicular lymphomas.
  • The annual incidence of DLBCL is 5-6/100,000 (increasing from 0.3/100,000 in those aged 35-39 years to 26.6/100,000 in those aged 80-84 years).2
  • The annual incidence of follicular lymphomas has increased from 2-3/100,000 during the 1950s to 5-7/100,000 recently.3

Risk factors

  • Chromosomal translocations and molecular rearrangements.
  • Some viruses are implicated, including:
    • Epstein-Barr virus: associated with Burkitt's lymphoma, Hodgkin's disease, lymphomas in immunocompromised patients (e.g. from HIV infection, organ transplantation) and sinonasal lymphoma.
    • Human T-cell leukaemia virus type 1 (HTLV-1) causes a latent infection via reverse transcription in activated T-helper cells.
    • Hepatitis C is associated with certain subtypes.
    • Kaposi's sarcoma-associated herpesvirus is associated with lymphomas in patients with HIV infection.
  • Environmental factors: e.g. pesticides, herbicides, solvents organic chemicals, wood preservatives, dusts, hair dye, chemotherapy and radiation exposure.
  • Congenital and acquired immunodeficiency states.
  • Autoimmune disorders, e.g. Sjögren's syndrome and Hashimoto's thyroiditis, promote the development of mucosa-associated lymphoid tissue (MALT) and predispose patients to subsequent lymphoid malignancies.
  • Helicobacter pylori infection is associated with the development of primary gastrointestinal lymphomas, especially gastric MALT lymphomas.1

Presentation

  • Low-grade lymphomas.
    • Painless, slowly progressive peripheral lymphadenopathy is the most common clinical presentation. Spontaneous regression of enlarged lymph nodes may occur.
    • Primary extranodal involvement and systemic symptoms (fatigue, weakness, fever, night sweats, weight loss) are not common at presentation, but are common in patients with advanced or end-stage disease.
    • Bone marrow is frequently involved and may be associated with cytopenia.
    • Splenomegaly.
    • Hepatomegaly.
  • Intermediate and high-grade lymphomas:
    • Most patients present with rapidly growing and bulky lymphadenopathy.
    • Systemic symptoms and extranodal involvement (especially the gastrointestinal tract, skin, bone marrow, sinuses, genitourinary tract, thyroid, and central nervous system (CNS)) are more common.
    • Hepatomegaly, splenomegaly.
    • Obstructive hydronephrosis secondary to bulky retroperitoneal lymphadenopathy obstructing the ureters may occur.
    • Primary CNS lymphomas: account for 1% of all intracranial neoplasms. More commonly observed in patients with immunodeficiency, e.g. Wiskott-Aldrich syndrome, transplantation or HIV infection.
    • Testicular mass.
    • Skin lesions: associated with cutaneous T-cell lymphoma (mycosis fungoides), anaplastic large cell lymphoma, and angioimmunoblastic lymphoma.
    • Lymphoblastic lymphoma: high-grade lymphoma, which often manifests with a mediastinal mass, superior vena cava syndrome, and meningeal disease with cranial nerve palsies.
    • Burkitt's lymphoma: often presents with a large abdominal mass and symptoms of bowel obstruction.

Differential diagnosis

See also other separate articles Assessing Lymphadenopathy, Generalised Lymphadenopathy and Splenomegaly and Hypersplenism.

Investigations

  • Full blood count: anaemia (marrow failure or autoimmune haemolytic anaemia), thrombocytopenia and neutropenia. Thrombocytosis and lymphocytosis may also occur.
  • Renal function and electrolytes: obstructive nephropathy, hypercalcaemia.
  • Liver function tests.
  • Serology: HIV, human T-cell leukaemia virus type 1 (HTLV-1), hepatitis C.
  • Chest X-ray: mediastinal adenopathy, pleural or pericardial effusions and parenchymal involvement.
  • Biopsy: fine needle aspiration samples should not normally be used as the sole tissue for diagnosis. Fresh tissue should be submitted to laboratories where a diagnosis of lymphoma is suspected.4
  • CT scan of the neck, chest, abdomen, and pelvis: to detect enlarged lymph nodes, hepatosplenomegaly. This is the most widely used investigation for initial staging and assessment of treatment response.
  • Bone scans.
  • Other scans used include gallium scan and whole body F-18 2-deoxyglucose (FDG) positron emission tomography (PET) scan.
  • MRI of the brain and spinal cord: if there is suspected primary CNS lymphoma, lymphomatous meningitis, paraspinal lymphoma or vertebral body involvement by lymphoma.
  • Ultrasound of the scrotum.
  • Endoscopy and barium studies for gastrointestinal lesions.
  • Bone marrow aspirate and biopsy.
  • Lumbar puncture.

Staging

The Ann Arbor staging system is the most commonly used staging system for patients with non-Hodgkin's lymphoma (NHL).1

  • Stage I: involves a single lymph node region (I) or localised involvement of a single extralymphatic organ or site (IE).
  • Stage II: 2 or more lymph node regions on the same side of the diaphragm (II) or localised involvement of a single associated extralymphatic organ in addition to criteria for stage II (IIE).
  • Stage III: lymph node regions on both sides of the diaphragm (III) that also may be accompanied by localised involvement of an extralymphatic organ or site (IIIE), spleen (IIIS), or both (IIISE).
  • Stage IV: disseminated or multifocal involvement of one or more extralymphatic sites with or without associated lymph node involvement or isolated extralymphatic organ involvement with distant node involvement.

Subscript letters represent involvement of extralymphatic organs: L - lung, H - liver, P - pleura, O - bone, M - bone marrow, D - skin. E is used when extranodal lymphoid malignancies arise in tissues that are separate from but near to the major lymphatic aggregates.

Stages I-IV can be followed by A or B designations:

  • A - no systemic symptoms.
  • B - any of the following symptoms: unexplained loss of more than 10% of body weight in the preceding 6 months before diagnosis, unexplained fever with temperature above 38° centigrade, and drenching night sweats.

Management

  • Treatment options vary because of the heterogeneous nature of non-Hodgkin's lymphomas (NHLs). Options include watchful waiting, single-agent or multiagent chemotherapy and regional or extended radiotherapy.
  • The role of surgery in treatment is limited but may be useful in certain situations, e.g. localised disease, complications (e.g. gastrointestinal obstruction or perforation) or orchidectomy as part of the initial management of testicular lymphoma.
  • Vaccinations: polyvalent pneumococcal vaccine and influenza vaccine should be given to all patients with NHL.5
  • Meningococcal group C conjugate vaccine and Haemophilus influenzae type b (Hib) vaccine are also recommended, especially for patients receiving treatment and those with asplenia or splenic dysfunction.5
  • 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.5

Diffuse large B-cell non-Hodgkin's lymphoma

  • Rituximab is recommended for use in combination with a regimen of cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Onvovin®), and prednisolone (CHOP) for the first-line treatment of people with CD20-positive diffuse large-B-cell lymphoma at clinical stage II, III or IV. Rituximab is not recommended for use when CHOP is contra-indicated.6
  • Fewer cycles of treatment with rituximab and CHP with additional regional radiotherapy is an alternative.2
  • High-dose chemotherapy with stem-cell transplantation remain experimental in first-line therapy.2
  • Concurrent CNS prophylaxis with intrathecal methotrexate or cytarabine has been recommended for patients at risk of CNS involvement (defined as lymphoma involvement in the bone marrow, testis, nasal or paranasal sinuses, orbits, bone or peripheral blood).7

Mantle cell lymphoma8

  • Mantle cell lymphoma accounts for about 1 in 20 of all cases of NHLs. Mantle cell lymphoma is more common in the over-50s and is three times more common in men than in women.
  • Mantle cell lymphomas are usually responsive to chemotherapy but often relapse after treatment.
  • Treatment options include:
    • Chemotherapy: combinations include rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), fludarabine given in combination with cyclophosphamide and rituximab (FCR).
    • High-dose chemotherapy treatment with stem cell support.
    • Radiotherapy.
    • Temsirolimus is used for the treatment of relapsed or refractory mantle cell lymphoma.

Follicular lymphoma

  • Stages I-II: radiotherapy (involved or extended field) is the preferred treatment but patients with large tumours may be treated with chemotherapy prior to optional radiotherapy.3
  • Stages III-IV:
    • Rituximab (in combination with cyclophosphamide, vincristine and prednisolone) is recommended as an option for the treatment of symptomatic stage III and IV follicular lymphoma in previously untreated patients.9
    • Rituximab, in combination with chemotherapy, is recommended as an option for the induction of remission in people with relapsed stage III or IV follicular NHL.10
    • Rituximab monotherapy as maintenance therapy is recommended as an option for the treatment of people with relapsed stage III or IV follicular NHL in remission induced with chemotherapy with or without rituximab.10
    • Rituximab monotherapy is recommended as an option for the treatment of people with relapsed or refractory stage III or IV follicular NHL (if there is resistance to or intolerance of chemotherapy).10

Primary CNS lymphoma11

  • Chemotherapy (high-dose methotrexate) is first-line treatment.
  • Dexamethasone is the treatment of choice for short-term palliation .
  • Whole brain radiotherapy can provide effective palliation but should not be used as first-line therapy in patients who are sufficiently fit to receive chemotherapy.

Complications

Prognosis

  • Low-grade non-Hodgkin's lymphoma (NHL) types have a relatively good prognosis, with median survival as long as 10 years, but they are usually not curable when advanced.
  • Intermediate-grade and high-grade lymphomas are more aggressive but are more responsive to chemotherapy.
  • The vast majority of relapses occur in the first 2 years after therapy.
  • The risk of late relapse is higher in patients with a histology of both low-grade and high-grade disease.

Document references

  1. National Cancer Institute (US); Adult Non-Hodgkin's Lymphoma
  2. European Society for Medical Oncology; Diffuse large B-cell non-Hodgkin's lymphoma; 2009
  3. European Society for Medical Oncology; Newly diagnosed and relapsed follicular lymphoma; 2009
  4. Best practice in lymphoma diagnosis and reporting, British Committee for Standards in Haematology (2010)
  5. British National Formulary; 59th Edition (March 2010) British Medical Association and Royal Pharmaceutical Society of Great Britain, London.
  6. Non-Hodgkin's lymphoma - rituximab, NICE Technology Appraisal (2003)
  7. Arkenau HT, Chong G, Cunningham D, et al; The role of intrathecal chemotherapy prophylaxis in patients with diffuse large Ann Oncol. 2007 Mar;18(3):541-5. Epub 2006 Dec 12. [abstract]
  8. Macmillan Cancer Support (Cancerbackup); Non-Hodgkin's Lymphoma
  9. Follicular lymphoma - rituximab, NICE Technology Appraisal (2006)
  10. Lymphoma (follicular non-Hodgkin's) - rituximab, NICE Technology Appraisal (January 2008); Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma (review of technology appraisal guidance 37)
  11. Guidelines on the diagnosis and management of adult patients with primary CNS lymphoma (PCNSL) and primary intra-ocularlymphoma (PIOL), British Committee for Standards in Haematology (2007)

Internet and further reading

© EMIS 2011Author: Dr Colin TidyReviewer: Dr John Cox
Document ID: 2517Document Version: 23Last Reviewed: 11 Aug 2010
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