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Lymphoma

Table of Contents
1 Disease Overview
        1.1 Risk Factors and Prevention
        1.2 History, Symptoms and Signs
        1.3 Diagnosis and Tumour Assessment
        1.4 Staging Investigations
        1.5 Classification
2 Staging
3 Lymphoma - Stage Grouping
4 Hodgkin's Lymphoma
5 Treatment: Hodgkin's Lymphoma
6 Follow-up: Hodgkin's Lymphoma
7 Non-Hodgkin Lymphoma, Classification, Staging and Prognostic Factors
        7.1 B-Cell Neoplasms
        7.2 Prognostic indices for non-Hodgkin Lymphoma
8 Treatment: Non-Hodgkin's Lymphoma
        8.1 Indolent Stage I and II Non-Hodgkin Lymphomas
        8.2 Indolent Stage III and IV Non-Hodgkin Lymphomas
        8.3 Aggressive Non-Hodgkin Lymphomas
        8.4 High Grade or Burkitts Lymphoma
        8.5 Primary CNS Lymphoma
9 Follow-up: Non-Hodgkin's Lymphoma
10 Multiple Myeloma
11 Pivotal Trials

    


Disease Overview

    Lymphomas are among the most diverse and most curable of all human malignancies. Lymphoma is a solid lymphoid tumour that is divided into two main sub-types: Hodgkin Lymphoma, and Non-Hodgkin Lymphoma (NHL). Hodgkin Lymphoma is a potentially curable malignancy, and is more common in males and shows a bimodal age distribution, with peaks in young adults aged 15 to 34 years, and older adults over 55 years of age.

    Although NHL are usually diseases of middle-aged and older people, children and young adults may develop lymphomas. Lymphomas that develop in children and young adults are commonly aggressive subtypes.

Risk Factors and Prevention

    The cause of Hodgkin disease is unknown. No specific risk factors have been identified, and no prevention strategies are available. Several associations have been noted with Epstein Barr Virus infection.

    HIV: HIV-positive individuals have an increased incidence of Hodgkin disease.

    Genetic predisposition: Siblings of individuals with Hodgkin lymphoma have a disease risk three to seven times higher than siblings of unaffected individuals.

    The pathogenesis of NHL involves several chromosomal translocations and molecular rearrangements. Viruses implicated include Epstein-Barr virus (EBV), human T-cell leukemia virus type 1 (HTLV-1), hepatitis C virus (HCV), and Kaposi sarcoma-associated herpes virus (KSHV). Environmental factors associated with NHL include various chemicals, previous chemotherapy, and radiation exposure. Immunodeficiency states and chronic inflammation associated with autoimmune diseases, especially Hashimoto Thyroiditis, also predispose to NHL. Helicobacter pylori is linked to primary gastrointestinal lymphomas, especially gastric mucosa-associated lymphoid tissue (MALT) lymphoma.

History, Symptoms and Signs

    Hodgkin Lymphoma tends to have contiguous lymph node involvement whereas NHL is non contiguous and may involve nodal and extranodal sites. A history of B symptoms (night sweats, fever, weight loss) is present in approximately 40% of patients, with intermittent fever in about one-third of cases. Shortness of breath, cough, or chest pain may be present. Patients may complain of pruritus. A symptom that is specific for Hodgkin disease is pain at nodal disease sites after consuming alcohol; this symptom is seen in fewer than 10% of patients. Central nervous system signs or symptoms may be due to paraneoplastic syndromes .

Diagnosis and Tumour Assessment

    Physical examination may reveal painless, palpable, rubbery lymphadenopathy in the neck (60–80%) or in the axilla or groin (fewer than 20%). Splenomegaly or hepatomegaly may also be present. A variety of laboratory abnormalities may be present, depending on organ involvement. An HIV test should be performed, as antiviral treatment may improve tumour prognosis. HIV positive patients also have more advanced and extranodal disease.

    An excisional biopsy of a lymph node is necessary for histological diagnosis, as changes to lymph node architecture are important to determine the histopathologic tumour classification. Obtaining a good tissue sample is critical for the diagnosis of lymphoma; fine needle aspiration is unacceptable and should never be relied on to make a diagnosis.

    Once the diagnosis of lymphoma is confirmed by microscopy and flow cytometry and fluorescent in-situ hybridization or cytogenetics, the staging workup can proceed.

Staging Investigations

    Laboratory studies in the staging of Lymphomas include complete blood count, measurement of serum lactate dehydrogenase, uric acid and B2 microglobulin and ESR; comprehensive metabolic panel; liver and kidney function tests and a hepatitis panel and HIV testing, Chest x-rays and CT scans of the chest, abdomen, and pelvis are standard, as the CT scans can delineate disease extent.

    Staging with gallium imaging will likely be replaced by Positron emission tomography (PET) scanning in the near future. An echocardiogram or multigated nuclear medicine (MUGA scan) study is done to assess cardiac function, if an anthracycline-based chemotherapy regimen is being considered. All patients with NHL should undergo a bone marrow biopsy. In Hodgkin Lymphoma, a bone marrow biopsy should be pursued in all patients with III or IV disease , B symptoms or unexplained cytopenias.

    In certain circumstances in NHL (for example, in patifollowupents with sinus, bone marrow, testicular, ocular, paravertebral, or parameningeal involvement), a lumbar puncture is indicated to exclude central nervous system involvement requiring additional forms of therapy. There is a higher incidence of central nervous system involvement when large-cell lymphoma is found in any of these sites.

Classification

    The current system for classification of lymphoma is derived by the World Health organization, which currently incorporates immunophenotyping and genetic information into the classification scheme. Lymphoid tumours are classified into three groups: B-cell, T-cell, NK-cell neoplasms, and Hodgkin lymphoma. Canadian Cancer statistics reports incidence of NHL as 7500 and mortality 3200. Hodgkin Lymphoma incidence is 877 and mortality is 137.

Classification criteria

  • Morphology
  • Clinical features
  • Genetic features
  • Immunophenotype

Staging

Ann Arbor Staging

Primary Tumour (T)

No T category exists for Hodgkin and Non-Hodgkin Lymphoma

Regional Lymph Nodes (N)

No N category exists for Hodgkin and Non-Hodgkin Lymphoma

Distant Metastasis (M)

No M category exists for Hodgkin and Non-Hodgkin Lymphoma


Lymphoma - Stage Grouping


Hodgkin's Lymphoma

Types

  • Nodular sclerosis Hodgkin disease (NSHD): 60 to 80% of all cases, most often in adolescents and young adults.
  • Mixed-cellularity Hodgkin disease (MCHD): 15 to 30% of cases, typically diagnosed at an advanced stage with systemic symptoms, most often in patients with human immunodeficiency virus (HIV) infection.
  • Lymphocyte-depleted Hodgkin disease (LDHD): less than 1% of patients, usually presents at an advanced stage, often expresses Epstein-Barr virus (EBV) proteins.
  • Lymphocyte-rich classic Hodgkin disease (LRHD): approximately 5% of cases, typically diagnosed when disease is advanced.
  • Nodular lymphocyte-predominant Hodgkin disease (NLPHD): about 5% of cases

Treatment: Hodgkin's Lymphoma

    Most people who have Hodgkin lymphoma can be cured with chemotherapy, with or without radiation therapy. Chemotherapy is used for all stages of disease. Several combinations may be used. The standard is ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), given every two weeks for 12 treatments. Treatments are usually given on an outpatient basis.

    Prognostic factors for early disease are bulky disease (> 10cm) in the mediastinum, elevated ESR, > 2-3 sites of nodal disease, presence of any extranodal disease.

    For advanced HL prognostic factors age over 45, male, stage IV disease, serum albumin 40g/L, hemoglobin less 105 g/L, white count higher than 15,000/µL, lymphocytes less than 600/µL or a lymphocyte count less than 8% of the WBC.

    Patients with non-bulky stage IA or stage IIA HL are treated with 2-4 cycles of chemotherapy of ABVD chemotherapy followed by involved field radiation therapy, with a cure rate of 90-95%. In stage III disease, cure rate ranges from 70 to 80%. In stage IV disease, while not as high, cure rates are above 50%.


Follow-up: Hodgkin's Lymphoma

    Follow-up of the patient in remission should be performed every three months for the first two years and then every 3 to 6 months for the next 3 to 5 years. Most relapses occur in the first three years. At this point, salvage therapy with autologous bone marrow transplant can be curative in up to 50% of relapsed lymphomas.

    Follow-up includes medical history, physical examination, hematology and chemistry panels, and thyroid-stimulating hormone levels annually, if radiation therapy of the neck was performed. There is no evidence for the use of repeat CT imaging to test for relapse. Screening mammography should be performed in women who received radiation to the chest, starting at 35 years of age, or 5 to 8 years after radiation therapy. Patients with combined modality therapy are at some risk of leukemias. Vaccination against Haemophilus influenzae, pneumococcus, influenza, and meningococcus is important.


Non-Hodgkin Lymphoma, Classification, Staging and Prognostic Factors

    Non-Hodgkin lymphoma (NHL) results from a clonal expansion of B cells (85%) or T cells and/or natural killer (NK) cells (15%).

    NHLs comprise a group of heterogenous diseases that vary in treatment and prognosis. An adequate sized excisional or a large core biopsy sample is mandatory for diagnosis and classification of these diseases by immunophenotyping and by newer molecular and genetic testing. A fine needle aspirate is not adequate for establishing the subtype of NHL. Marked advances have been made in the treatment of these diseases largely due to monoclonal antibodies with and without chemotherapy. The treatments are evolving and the goal is to improve survival and reduce toxicity in this highly treatable disease.

    NHL are grouped into categories of indolent, aggressive, or highly aggressive, based on their biology and natural history. Indolent NHLs are considered incurable (except for the few patients with stage I disease [disease confined to one lymph node group] that can be eradicated by radiotherapy.

    The median survival of patients with indolent NHL (most who present themselves with advanced disease) is 7 to 10 years. Patients with aggressive or highly aggressive NHL are potentially curable with combination chemotherapy. Immunophenotyping of these malignant cells is routinely performed in the diagnosis of NHL. All B-cell-derived NHLs are CD-19* and CD-20*. Characteristic cytogenetic markers may be found in patients with some forms of NHL, and the differential diagnosis of NHL can be narrowed by using a panel of monoclonal antibodies and genetic markers.

B-Cell Neoplasms

  • Low-grade lymphoma: This type is characterized by painless, slowly progressive peripheral lymphadenopathy, which may regress spontaneously. In advanced disease, malignant transformation may occur to intermediate- or high-grade lymphoma.
  • Intermediate- and high-grade lymphoma: This type has a variable clinical presentation but is usually accompanied by lymphadenopathy. In more than one-third of patients, extranodal disease is present, with B symptoms.
  • Diffuse Large B Cell Lymphoma: The most common type of lymphoma, with an increased incidence in HIV positive patients, and higher risk of CNS involvement. [Lumbar puncture is performed when neurologic signs and symptoms are present, in HIV-related lymphoma, primary CNS lymphoma, testicular lymphoma and paranasal sinus involvement.] It is essential that molecular testing is done on tissue specimens to ensure appropriate diagnosis.
  • Burkitt lymphoma: Large abdominal masses may result in presenting signs of and symptoms of bowel obstruction or obstructive hydronephropathy.
  • Primary CNS lymphoma: CNS lymphomas are high-grade B-cell lymphomas, often seen in immunodeficient patients.

    Patients with NHL who have the same stage of disease according to the Ann Arbor staging system, may have very different clinical outcomes. The International Prognostic Index (IPI) was developed as a predictive model of outcome for patients with diffuse large cell lymphoma. The index is based on five pre-treatment characteristics found to be independent predictors of death. The age-adjusted IPI was derived for patients younger than 60 years. For these patients, the age-adjusted factors are performance status, serum lactate dehydrogenase concentration, number of extranodal sites and stage.

    Risk categories and corresponding survival rates are provided below. The IPI was modified to be applied to follicular lymphoma and is referred to as the Follicular Lymphoma IPI (FLIPI). This index also includes five independent factors consisting of a number of extranodal sites, serum lactate dehydrogenase concentration, age, stage, and hemoglbin concentration, which replaces performance status in this scheme:

Prognostic indices for non-Hodgkin Lymphoma

    Patients with high-risk IPI scores are destined to have a poorer prognosis. Aggressive treatment such as high-dose chemotherapy with hematopoietic cell support, as part of front-line therapy to improve the outcome of such patients, is being tested in trials. The National Cancer Center Network guidelines recommend that these patients be considered for clinical trials (preferred) evaluating new approaches, or standard cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP).

    Similarly, patients with follicular lymphoma with a high-risk FLIPI score are candidates for clinical trials, or treatment with standard regimens such as R-CVP (cyclophosphamide, vincristine, prednisone, rituximab) or R-CHOP. There are no data from randomized, prospective trials using these prognostic indices to guide therapeutic decisions. In the future, prognostication will be further refined with the use of DNA micro-array technology, which shows which genes are over- and/or under-expressed in a given tumour.


Treatment: Non-Hodgkin's Lymphoma

    The likelihood of a cure or long-term survival depends on the type of NHL and the stage. Some treatments are standard, while some are being tested in clinical trials. Patients need to be encouraged to go on trials.

Indolent Stage I and II Non-Hodgkin Lymphomas

    People who have very limited disease (stages I and II) are often treated with radiation therapy, limited to the site of the lymphoma and adjacent areas. With this approach, most people do not have a disease recurrence in the irradiated area.

Indolent Stage III and IV Non-Hodgkin Lymphomas

    Closely monitor a patient’s condition without giving any treatment until symptoms appear or change. Treatment may include therapy with monoclonal antibodies (rituximab) alone or chemotherapy with or without rituximab.

Aggressive Non-Hodgkin Lymphomas

    Combination chemotherapy drugs are given promptly. In early stage, it is combined with radiation; and in advanced disease, only 6-8 cycles of combination chemotherapy is given. The most commonly used combination of chemotherapy drugs is known as CHOP (cyclophosphamide, [hydroxy] doxorubicin, vincristine [Oncovin], and prednisone). Therapy is given in the form of CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone), with the addition of Rituximab increasing overall response and survival rates by up to 15% (Coiffier NEJM 2002; 346:235-42).

High Grade or Burkitts Lymphoma

    For high grade NHL aggressive protocols such as CHOMP, MCGRATH, etc, rituximab are used.

Primary CNS Lymphoma

    For treatment of PCNSL, patients receive high-dose systemic methotrexate. Close monitoring and adjustment of intravenous fluids and leucovorin rescue necessitates inpatient administration of this drug.


Follow-up: Non-Hodgkin's Lymphoma

    Low-grade lymphomas have a median survival rate of 6 to 10 years. Little chance of cure exists if the disease results from a chronic relapsing course, post chemotherapy. In low grade lymphomas, early detection, recurrence or upfront treatment of asymptomatic disease does not influence overall survival, and consequently most patients undergo “watchful waiting”. Indications for therapy include progression of B symptoms, cytopenias due to bone marrow infiltration, and progressive lymphadenopathy threatening organ function.

    Follow-up to assess disease and response to treatment with medical history and physical examination at three-month intervals for the first two years, with subsequent follow-up every six months for the next three years. The highest chance of relapse is in the first two years post diagnosis. There is no role for follow-up CT imaging once patients enter remission.

    Goals of follow-up is early recognition and treatment of potentially curable relapses or a second primary.


Multiple Myeloma

    Multiple Myeloma (MM) has the second highest incidence among hematologic malignancies in Canada. Over 2,600 new cases and 1,400 deaths are attributed to MM in Canada.

Symptoms

    MM is a malignancy of plasma cells, characterized by osteolytic bone lesions, anemia, hypercalcemia, and renal failure infection.

Diagnosis

    When MM is suspected, patients should be tested for the presence of monoclonal proteins by serum protein electrophoresis, serum immunofixation, and the serum free light chain assay. Bone imaging studies and a bone marrow biopsy are required if multiple myeloma is suspected.

Prognosis

    Over the last decade median overall survival of patients with MM has improved from 2-3 years to 5-7 years.

    Patients with 17p deletion and translocations at t(14;16) and t(14;20) are considered to have high-risk myeloma. Patients with t(4;14) are considered intermediate-risk. Patients who do not have any of these abnormalities, typically those with trisomies or translocations t(11;14) and t(6;14), are considered to have standard-risk myeloma. The presence of concomitant trisomies ameliorates the adverse prognosis.

The diagnosis of multiple myeloma is made using the WHO criteria:

Multiple (Plasma Cell) Myeloma (all 3 criteria must be met):

  • M-protein in serum or urine
  • Bone marrow clonal plasma cells or plasmacytoma
  • Related end-organ or tissue impairment (CRAB criteria: hyperCalcemia, Renal insufficiency, Anemia, Bone lesions)

Asymptomatic (Smoldering) Myeloma (both criteria must be met):

  • M-protein in serum > 30 g/L AND/OR 10% or more clonal plasma cells in bone marrow
  • No related end-organ or tissue impairment (no CRAB) or myeloma-related symptoms

Monoclonal Gammopathy of Undetermined Significance (MGUS) (all 4 criteria must be met):

  • M-protein in serum < 30 g/L
  • Bone marrow clonal plasma cells < 10% and low level of plasma cell infiltration in biopsy
  • No CRAB
  • No evidence of other B-cell proliferative disorder

    MM is prognosticated with the International Staging system. Patients are staged using the Durie-Salmon Staging system and the International Staging System.

Treatment Modalities

    Improvement in 3-year survival of MM is up from 42% with melphalen and prednisone to over 80%. This improvement reflects the incorporation of novel agents such as thalidomide, bortezomib, and lenalidomide, as well as the integration of autologous stem cell transplant in selected patients and improvements in supportive care, particularly bisphosphonates and RANKL inhibitor.

    Initial therapy for myeloma is determined by eligibility for stem cell transplantation, age (65-75), performance status, and coexisting comorbidities. If a candidate for autologous stem cell transplantation (ASCT), 2-3 cycles of chemotherapy followed by harvest and ASCT is given. If not, patient should continue for 12-18 months. The most commonly used regimens for the treatment of newly diagnosed MM are:

  1. Lenalidomide plus low-dose dexamethasone (Rd)
  2. Bortezomib plus dexamethasone (VD)
  3. Bortezomib plus thalidomide and dexamethasone (VTD)
  4. Lenalidomide plus bortezomib and dexamethasone (RVD)
  5. Cyclophosphamide plus bortezomib and dexamethasone (VCd)
  6. Bortezomib plus melphalan and prednisone (VMP)
  7. Melphalan plus prednisone with thalidomide (MPT)

    Older regimens are vincristine plus doxorubicin and dexamethasone (VAD) or thalidomide plus dexamethasone (TD).

    For more information regarding chemotherapy, go to www.cancercare.on.ca.


Pivotal Trials

Fisher et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced Non-Hodgkin’s Lymphoma. N Engl J Med. 1993;328:1002

Coiffier B et al. ASCO 2003, Abstract #2395: GELA study comparing CHOP and R-CHOP in Elderly Patients with Diffuse Large B-Cell Lymphoma: 3 year median follow-up with an analysis according to co-morbidity factors.