Non-Hodgkin's Lymphoma

Heterogeneous group of lymphoproliferative malignancies with differing patterns of behaviour and responses to treatment. Much greater predilection to disseminate to extranodal sites than in Hodgkin's lymphoma. The prognosis depends on the histologic type, stage, and treatment. They can be divided into 2 prognostic groups: the indolent lymphomas and the aggressive lymphomas.¹

• Indolent types have a relatively good prognosis, with median survival as long as 10 years, but they usually are not curable in advanced clinical stages.
• Aggressive types have a shorter natural history, but a significant number of these patients can be cured with intensive combination chemotherapy regimens.

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

• B-cell neoplasms
  • Precursor B-cell neoplasm: precursor B-acute lymphoblastic leukaemia/lymphoblastic lymphoma (B-ALL, LBL)
  • Peripheral B-cell neoplasm
    • B-cell chronic lymphocytic leukaemia/small lymphocytic lymphoma
    • B-cell prolymphocytic leukaemia
    • Lymphoplasmacytic lymphoma/immunocytoma
    • Mantle cell lymphoma
    • Follicular lymphoma
    • Extranodal marginal zone B-cell lymphoma of MALT type
    • Nodal marginal zone B-cell lymphoma (with or without monocytoid B-cells)
    • Splenic marginal zone lymphoma (with or without villous lymphocytes)
    • Hairy cell leukaemia
    • Plasmacytoma/plasma cell myeloma
    • Diffuse large B-cell lymphoma
    • Burkitt's lymphoma
• T-cell and putative NK-cell neoplasms
  • Precursor T-cell neoplasm: precursor T-acute lymphoblastic leukaemia/lymphoblastic lymphoma (T-ALL, LBL)
  • Peripheral T-cell and NK-cell neoplasms
    • T-cell chronic lymphocytic leukaemia/prolymphocytic leukaemia
    • T-cell granular lymphocytic leukaemia
    • Mycosis fungoides/Sezary syndrome
    • Peripheral T-cell lymphoma, not otherwise characterised
    • Hepatosplenic gamma/delta T-cell lymphoma
    • Subcutaneous panniculitis-like T-cell lymphoma
    • Angioimmunoblastic T-cell lymphoma
    • Extranodal T-/NK-cell lymphoma, nasal type
    • Enteropathy-type intestinal T-cell lymphoma
    • Adult T-cell lymphoma/leukaemia (HTLV 1 )
    • Anaplastic large cell lymphoma, primary systemic type
    • Anaplastic large cell lymphoma, primary cutaneous type
    • Aggressive NK-cell leukaemia
• Hodgkin's lymphoma (Hodgkin's disease)
  • Nodular lymphocyte-predominant Hodgkin's lymphoma
  • Classical Hodgkin's lymphoma
    • Nodular sclerosis Hodgkin's lymphoma
    • Lymphocyte-rich classical Hodgkin's lymphoma
    • Mixed-cellularity Hodgkin's lymphoma
    • Lymphocyte-depleted Hodgkin's lymphoma

• Non-Hodgkin's lymphoma is more than 5 times as common as Hodgkin 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 Non-Hodgkin's lymphoma observed in children and young adults. Low-grade lymphomas are very rare in children.¹

Risk factors

• Chromosomal translocations and molecular rearrangements.
• Some viruses are implicated, including:
  • Epstein-Barr virus: associated with Burkitt lymphoma, Hodgkin 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 sarcoma associated herpes virus 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. Sjogren syndrome and Hashimoto thyroiditis, promote the development of MALT and predisposes patients to subsequent lymphoid malignancies.
• Helicobacter pylori infection is associated with the development of primary gastrointestinal lymphomas, especially gastric MALT lymphomas.¹

• Low-grade lymphomas
  • Peripheral lymphadenopathy that is painless and slowly progressive 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) 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; often manifests with a mediastinal mass, superior vena cava syndrome, and meningeal disease with cranial nerve palsies.
  • Burkitt lymphoma: often present with a large abdominal mass and symptoms of bowel obstruction.

• Metastatic malignant disease.
• Lymphadenopathy secondary to infection or connective tissue diseases.

• Lymph node biopsy ²
• 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, HTLV-1, Hepatitis C
• Chest x-ray: mediastinal adenopathy, pleural or pericardial effusions and parenchymal involvement
• CT scan of the neck, chest, abdomen, and pelvis: to detect enlarged lymph nodes, hepatosplenomegaly. Is the most widely used investigation for initial staging and assessment of treatment response.
• Bone scans
• Other scan 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 suspect 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
• Biopsy of extranodal sites
• Lumbar puncture

The Ann Arbor staging system is the most commonly used staging system for patients with Non-Hodgkin's lymphoma.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 degrees centigrade, and drenching night sweats.

Indolent stage I and contiguous stage II Non-Hodgkin's lymphoma

• Watchful waiting
• Radiotherapy is often be the treatment of choice, especially of the head and neck. Radiotherapy produces a 10-year survival rate of 60-80%.
• The role of adjuvant chemotherapy, in addition to radiation, is not certain but may be given for patients with stage I-II NHL who have unfavourable prognostic factors, e.g. systemic symptoms (B).

Indolent non-contiguous stage II, III, and IV Non-Hodgkin's lymphoma

• Optimal treatment is controversial. For asymptomatic patients, especially older patients and patients with concomitant medical problems, deferred therapy with careful observation is an option. Early intervention does not appear to prolong the survival of asymptomatic patients. The median time to progression is 4-6 years, and overall survival is 6-10 years.
• Treatment for symptomatic patients includes:
  • Purine nucleoside analogues (i.e., fludarabine, 2-CDA), which have significant antitumour activity in low-grade NHL.
  • Oral alkylating agents with or without steroids (i.e. cyclophosphamide, chlorambucil).
  • Combination chemotherapy using cyclophosphamide, vincristine, and prednisone (CVP) or cyclophosphamide, hydroxydaunomycin, oncovin (vincristine), and prednisone (CHOP).
• Intensive therapy with chemotherapy and total body irradiation followed by autologous or allogeneic bone marrow or peripheral stem cell transplantation, especially for younger patients with poor prognostic factors, is under clinical investigation.
• For patients who are unable to tolerate other options, anti-CD20 monoclonal antibody (rituximab) may be considered as the first-line therapy, either alone or with combination chemotherapy.

Aggressive stage I and contiguous stage II (non-bulky or less than 10 cm) Non-Hodgkin's lymphoma

• The preferred treatment option for patients with intermediate-grade Non-Hodgkin's lymphoma is combination chemotherapy (3 cycles of CHOP) plus involved field radiation therapy.
• Patients with high-grade disease should be strongly considered for treatment with more aggressive regimens beyond CHOP.

Aggressive non-contiguous stage II, III, and IV Non-Hodgkin's lymphoma

• The treatment of choice is combination chemotherapy, either alone or supplemented by radiotherapy. Doxorubicin-based combination chemotherapy produces long-term disease-free survival in 35-45% of patients.
• For intermediate-grade lymphomas, CHOP chemotherapy remains the standard of care. However, non-CHOP regimens such as MACOP-B are used as first-line therapies in some subtypes of Non-Hodgkin's lymphoma.
• NICE recommends the monoclonal antibody rituximab (given with cyclophosphamide, vincristine and prednisolone) as a possible treatment for people with symptomatic stage III or IV follicular lymphoma who haven't been treated before.³
• Autologous and allogeneic bone marrow or peripheral stem cell transplantation for patients at high risk of relapse are under clinical investigation.
• CNS prophylaxis, usually with 4-6 injections of intrathecal methotrexate is recommended for patients with paranasal sinus or testicular involvement, diffuse small noncleaved cell or Burkitt lymphoma, or lymphoblastic lymphoma. CNS prophylaxis for bone marrow involvement is controversial.
• Acute lymphoblastic lymphoma: very aggressive form of Non-Hodgkin's lymphoma; intensive combination chemotherapy with CNS prophylaxis is the standard treatment.
• Other subtypes of high-grade lymphomas are usually treated with more aggressive variations of CHOP chemotherapy, such as adding high-dose methotrexate and using higher doses of cyclophosphamide.

Indolent recurrent Non-Hodgkin's lymphoma

Treatment with standard agents rarely produces a cure in patients who have relapsed. For relapse that remains low grade, the following are possible treatment options:

• Single alkylating agents, purine analogues.
• Combination chemotherapy: e.g. CVP, CHOP.
• Rituximab chimeric anti-CD20 monoclonal antibody.⁴
• Radionuclide-conjugated monoclonal antibodies, e.g. Tositumomab (iodine I 131 anti-CD20 monoclonal antibody) and ibritumomab (yttrium Y 90 anti-CD20 monoclonal antibody) are being studied and appear promising for treatment of relapsed or refractory disease.
• Local relapse can be treated with radiotherapy.
• High-dose chemotherapy plus stem cell transplantation is being investigated to determine whether it can produce significantly better survival rates compared with conventional chemotherapy.

Aggressive recurrent adult Non-Hodgkin's lymphoma

• High-dose chemotherapy plus stem cell transplantation is the treatment of choice. Preliminary studies indicate that approximately 20-40% of patients have a long-term disease-free status.
• Patients who are not candidates for transplant can be treated with chemotherapy with or without monoclonal antibodies.

Surgical treatment

• The role of surgery in treatment is limited.
• Surgery is useful in selected situations, especially with localised disease or if there is a risk of gastrointestinal perforation, obstruction, or massive bleeding.
• Orchidectomy is part of the initial management of testicular lymphoma.

• Neutropenia, anaemia, thrombocytopenia: secondary to bone marrow infiltration.
• Bleeding secondary to thrombocytopenia, disseminated intravascular coagulation or direct vascular invasion by the tumour.
• Large pericardial effusion or arrhythmias secondary to cardiac metastases.
• Respiratory problems secondary to pleural effusion and/or parenchymal lesions.
• Superior vena cava obstruction secondary to a large mediastinal tumour.
• Spinal cord compression secondary to vertebral metastases.
• Neurological problems secondary to primary CNS lymphoma or lymphomatous meningitis.
• Gastrointestinal obstruction, perforation, and bleeding in a patient with GI lymphoma (may also be caused by chemotherapy).
• Pain secondary to tumour invasion.
• Chemotherapy-related complications, e.g. cytopenias, nausea and vomiting, fatigue. Tumour lysis syndrome (commonly occurs after treatment of high-grade bulky lymphomas) may lead to hyperuricemia, hyperkalaemia, hyperphosphataemia, hypocalcaemia and renal failure.

• Indolent Non-Hodgkin's lymphoma 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. They are associated with a predicted median survival time of 2-5 years and less than 2 years, respectively. Of those patients with aggressive Non-Hodgkin's lymphoma, 30% to 60% can be cured.⁵
• 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 indolent and aggressive disease.