Lymphoma Symptoms, Prognosis, Diagnosis and Treatment

Friday, September 18th 2015. | Disease


Lymphomas are a heterogenous group of malignancies that arise from immune cells residing predominantly in lymphoid tissues. Differences in histology have led to classification as Hodgkin’s and non-Hodgkin’s lymphoma, which are ad- dressed separately in this chapter.




  • Current hypotheses indicate that B-cell transcriptional processes are disrupted, which prevent expression of B-cell surface markers and production of immunoglobulin mRNA. Alterations in the normal apoptotic pathways favor cell survival and proliferation.
  • Malignant Reed-Sternberg cells overexpress nuclear factor-κ B, which is associated with cell proliferation and anti-apoptotic signals. Infections with viral and bacterial pathogens upregulate nuclear factor-κ B. Epstein-Barr virus (EBV) is found in many, but not all, Hodgkin’s lymphoma tumors.


  • Most patients with lymphomas present with adenopathy, which waxes and wanes and which is painless and rubbery. Adenopathy is usually localized to the cervical region but can also occur in the mediastinal, hilar, and retroperitoneal regions.
  • Up to 40% of patients with Hodgkin’s disease present with constitutional, or “B,” symptoms (e.g., fever, night sweats, weight loss, and pruritus).
  • Diagnosis requires the presence of Reed-Sternberg cells.
  • Staging is performed to provide prognostic information and to guide therapy. Staging has evolved from previous classifications, and it continues to evolve.
  • Approximately half of the patients have early-stage disease (stages I, II, and IIE). The other half have advanced disease, of which 10% to 15% is stage IV.
  • Clinical staging is based on noninvasive procedures such as history, physical examination, laboratory tests, and radiography. Pathologic staging is based on biopsy findings of strategic sites (e.g., muscle, bone, skin, spleen, abdominal nodes) using an invasive procedure (e.g., laparoscopy).
  • Prognostic factors that predict poor treatment outcome include advanced stage, advanced age, male gender, B symptoms, high number of involved nodal regions, large mediastinal mass, extranodal disease, elevated erythrocyte sedimentation rate (ESR), anemia, leukocytosis, lymphocytopenia, and low serum albumin.

The treatment goal for Hodgkin’s disease is to maximize curability while minimizing treatment-related complications.


  • Treatment options include radiation therapy, chemotherapy, or both (combined-modality therapy). The choice depends on the stage of disease and presence of risk factors ( 62-1).
  • Studies are being conducted to identify how to maximize efficacy and minimize toxicity such as by limiting the volume of radiation therapy or the number of chemotherapy cycles.
  • Surgery is rarely indicated unless pathologic staging would affect treatment. The use of laparotomy and splenectomy is diminishing because of associated morbidity and mortality.

Radiation Therapy

  • Radiation therapy is an integral part of treatment and can be used alone for selected patients with early-stage disease. Involved-field radiation therapy targets a single field of Hodgkin’s lymphoma. Extended-field or subtotal nodal radiation targets the involved field and an uninvolved area. Total nodal radiation therapy targets all areas.
  • Low-dose consolidative radiation therapy can be beneficial for advanced-stage Hodgkin’s disease if chemotherapy induces a partial response.
  • The major concern with radiation therapy is long-term effects such as cardiovascular disease and secondary solid malignancies.

Salvage Chemotherapy

  • Response to salvage therapy depends on the extent and site of recurrence, previous therapy, and duration of first remission. Choice of salvage therapy should be guided by response to initial therapy and patient’s ability to tolerate therapy.
  • Patients who relapse after an initial complete response can be treated with the same regimen, a non–cross-resistant regimen, radiation therapy, or high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT).
  • Lack of complete remission after initial therapy or relapse within a year after completing initial therapy is associated with poor prognosis. Patients with these prognostic factors are candidates for high-dose chemotherapy and HSCT.

Complications of Chemotherapy

  • Myelosuppression is the major dose-limiting toxicity of most combination regimens. Hematopoietic growth factors can decrease neutropenia and allow delivery of optimal doses on schedule.
  • Nausea and vomiting are frequently seen with dacarbazine, doxorubicin, and mechlorethamine. The severity has diminished with the use of the 5-HT3 antagonists.
  • Neurotoxicity is frequently seen with vincristine.
  • Other acute toxic effects include alopecia, dermatitis, mucositis, phlebitis, malaise and fatigue, pulmonary reactions, and renal dysfunction.
  • Long-term complications include gonadal dysfunction, secondary malignancies, and cardiac disease. The risk of developing acute leukemia is highest after chemotherapy, with or without radiation therapy. The risk is higher with MOPP than with ABVD.




  • Chromosomal translocations have become a hallmark of many lymphomas.
  • Non-Hodgkin’s lymphomas are derived from monoclonal proliferation of B or, less commonly, T lymphocytes and their precursors.
  • There are many histologic subtypes of non-Hodgkin’s lymphoma, and new entities are still being recognized.



  • Chromosomal translocations have become a hallmark of many lymphomas.
  • Non-Hodgkin’s lymphomas are derived from monoclonal proliferation of B or, less commonly, T lymphocytes and their precursors.
  • There are many histologic subtypes of non-Hodgkin’s lymphoma, and new entities are still being recognized.


  • Patients present with a variety of symptoms, which depend on the site of involvement and whether it is nodal or extranodal.
  • Adenopathy can be localized or generalized. Involved nodes are painless, rubbery, and discrete and are usually located in the cervical and supraclavicular regions. Mesenteric or gastrointestinal involvement can cause nausea, vomiting, obstruction, abdominal pain, palpable abdominal mass, or gastrointestinal bleeding. Bone marrow involvement can cause symptoms related to anemia, neutropenia, or thrombocytopenia.
  • Lymphomas can be classified by degree of aggressiveness. Slow-growing or indolent lymphomas are favorable (untreated survival measured in years), whereas rapid-growing or aggressive lymphomas are unfavorable (untreated survival measured in months).
  • Indolent lymphomas usually arise in middle-aged or older adults (median age 55 years). Most patients present with advanced disease, often the result of bone marrow involvement. These lymphomas have an indolent course with adenopathy waxing and waning for months to years before diagnosis.
  • Aggressive lymphomas occur over a broader age range. Patients present at various stages of disease. Lymphoma tends to disseminate rapidly and often involves extranodal and privileged sites.
  • Only 20% of patients with non-Hodgkin’s lymphoma have constitutional, or B, symptoms.


  • Diagnosis is established by biopsy of an involved lymph node.
  • Diagnostic workup of non-Hodgkin’s lymphoma is generally similar to that of Hodgkin’s disease.
  • There are many systems for classifying non-Hodgkin’s lymphomas, which continue to evolve.
  • Prognosis depends on histologic subtype and clinical risk factors (e.g., age more than 60 years, performance status of 2 or more, elevated lactic dehydrogenase, extranodal involvement, and stage III or IV disease). These risk factors are used to calculate the International Prognostic Index (IPI). A newer prognostic index uses similar risk factors except that low performance status is replaced with low hemoglobin (less than 12 g/dL).

The primary treatment goals for non-Hodgkin’s lymphoma are to relieve symptoms and, whenever possible, cure the patient of disease without causing unaccep toxicity.


  • General Principles
  • Appropriate therapy for non-Hodgkin’s lymphoma depends on many factors including patient age; disease type, stage, and site; and patient preference.
  • Treatment options include radiation therapy, chemotherapy, and biologic agents.
  • Radiation therapy is rarely sui for remission induction because non-Hodgkin’s lymphoma is rarely localized at diagnosis. Radiation therapy is used more commonly in advanced disease, mainly as a palliative measure.
  • Effective chemotherapy ranges from single-agent therapy for indolent lymphomas to aggressive, complex combination regimens for aggressive lymphomas. Paradoxically, indolent or favorable lymphomas are rarely curable, whereas aggressive or unfavorable lymphomas are potentially curable.
  • Treatment strategies are summarized for the most common non-Hodgkin’s lymphomas as examples of how to treat indolent (i.e., follicular) and aggressive (i.e., diffuse large B-cell) lymphomas. Strategies are also summarized for AIDS-related lymphoma.

Follicular Lymphoma, an Indolent Lymphoma
Localized Follicular Lymphoma
Options for stage I and II follicular lymphoma include locoregional radiation therapy, chemotherapy followed by radiation therapy, and extended-field radiation therapy.
Radiation therapy is the standard treatment and is usually curative. Chemotherapy is not recommended, unless the patient has high-risk stage II disease.

Advanced Follicular Lymphoma

  • Management of stages III and IV indolent lymphoma is controversial because standard approaches are not curative. Complete response can be induced in 50% to 80% of patients, but the median duration of remission is only 18 to 36 months. After relapse, response can be re-induced; however, response rates and durations decrease with each retreatment.
  • Therapeutic options are diverse and include watchful waiting, single-agent therapy, combination chemotherapy, biologic therapy, and combined-modality therapy. Immediate aggressive therapy does not improve survival compared with conservative therapy (i.e., watchful waiting followed, only when needed, by single-agent chemotherapy).
  • Oral alkylating agents, chlorambucil, 0.1 to 0.2 mg/kg, or cyclophosphamide, 1.5 to 2.5 mg/kg (adjusted to white blood cell and platelet counts), are the mainstay of treatment. These single agents are as effective as combination regimens and produce minimal toxicity, but secondary acute myelogenous leukemia (AML) is a concern. Fludarabine and cladribine produce high response rates without secondary AML, but they are more myelosuppressive.
  • Rituximab, a chimeric monoclonal antibody directed at the CD20 molecule on B cells, has become one of the most widely used therapies for follicular lymphoma. Rituximab was initially used as salvage therapy and is also being used as first-line therapy, either alone or combined with CHOP (cyclophosphamide, doxorubicin [hydroxydaunomycin], vincristine (Oncovin), prednisone). Rituximab has the advantage of being sui for retreatment therapy and, interestingly, produces a longer duration of remission after the second course than after the first course.
  • The rituximab dosage is 375 mg/m2 weekly for 4 weeks. Other dosages are being studied. For example, maintenance therapy every 6 months appears to improve the initial response rate and to prolong the duration of response.
  • Adverse effects are usually infusion related, especially after the first infusion of rituximab. Adverse effects include fever, chills, respiratory symptoms, fatigue, headache, pruritus, and angioedema. Patients should receive acetaminophen, 650 mg, and diphenhydramine, 50 mg, 30 minutes before the infusion.
  • Anti-CD20 radioimmunoconjugates are mouse antibodies linked to radioisotopes (e.g., 131I-tositumomab and 90Y-ibritumomab tiuxetan). They have the advantage of delivering radiation to tumor cells expressing the CD20 antigen and to adjacent tumor cells that do not express it. They have the disadvantage of damaging adjacent normal tissue (e.g., bone marrow).
  • Radioimmunotherapy was initially used as salvage therapy and is being evaluated as first-line therapy in combination with CHOP.
  • Radioimmunotherapy is generally well tolerated. Toxicities include infusion-related reactions, myelosuppression, and possibly myelodysplactic syndrome or AML. 131I-tositumomab can cause thyroid dysfunction.
  • The decision to use radioimmunotherapy requires consideration of the complexity, risks, and cost. The ideal candidate has limited bone marrow involvement and adequate blood cell counts.
  • High-dose chemotherapy followed by HSCT is an option for relapsed follicular lymphoma. The recurrence rate is lower after allogeneic than after autologous HSCT, but the benefit is offset by increased treatment-related mortality. The ideal candidate is young and does not have serious comorbidities.


Diffuse Large B-Cell Lymphoma, an Aggressive Lymphoma

Early-Stage Diffuse Large B-Cell Lymphoma
Stage I and nonbulky stage II should be treated with 3 cycles of CHOP ( 62-3) followed by locoregional radiation therapy.
If a poor prognostic factor is present, the patient should receive additional cycles of CHOP (e.g., total of six to eight cycles).

Advanced Diffuse Large B-Cell Lymphoma Disease

  • Bulky stage II and stages III and IV lymphoma should be treated with intensive combination chemotherapy and continued for 2 cycles after inducing complete response. Maintenance therapy does not improve survival.
  • Rapid response (i.e., complete response in first three treatment cycles) produces a more durable remission than responses requiring more prolonged treatment.
  • CHOP remains the treatment of choice, but it is not ideal. Only half of patients have complete remissions, and only one-third are cured. Many institutions recommend adding rituximab to CHOP (R-CHOP) for treatment of all aggressive lymphomas.
  • Elderly adults have lower complete response and survival rates than do younger patients, possibly because elderly adults do not tolerate intensive chemotherapy and therefore receive less aggressive chemotherapy.
  • R-CHOP is becoming the standard for elderly adults with aggressive non-Hodgkin’s lymphomas. Full-dose CHOP should be used whenever possible.
  • Attempts to improve on CHOP include adding single agents, such as bleomycin (CHOP-Bleo, BACOP) or methotrexate (M-BACOD), and administering as many agents as possible. These strategies do not significantly affect treatment outcome and are more difficult to administer, more toxic, and more expensive.
  • Patients with high-intermediate- or high-risk IPI scores are candidates for more aggressive regimens such as high-dose chemotherapy with autologous HSCT. A study is being conducted to determine whether high-dose chemotherapy with autologous HSCT should be administered early (as consolidation after first complete remission) or late (after relapse).

Salvage Therapy for Aggressive Lymphoma

  • Salvage therapy is more likely to induce response if the response to initial chemotherapy was complete (chemosensitivity) than if it was less than complete (chemoresistance).
  • High-dose chemotherapy with autologous HSCT is the therapy of choice for younger patients with chemosensitive relapse.
  • Salvage regimens incorporate drugs not used as initial therapy. Commonly used regimens include DHAP (dexamethasone, high-dose cytarabine [Ara-C], and cisplatin [Platinol]), ESHAP (etoposide, methylprednisolone [Solumedrol], high-dose cytarabine [Ara-C], and cisplatin [Platinol]), and MINE (mesna, ifosfamide, mitoxantrone [Novantrone], and etoposide). None is clearly superior to the others.
  • ICE (ifosfamide, carboplatin, and etoposide) appears to be better tolerated than cisplatin-containing regimens, especially in elderly adults.
  • Rituximab is being evaluated in combination with many salvage regimens.


Non-Hodgkin’s Lymphoma in AIDS

  • Patients with AIDS have a 150- to 250-fold increased risk of developing non-Hodgkin’s lymphoma, which is usually aggressive.
  • Treatment of AIDS-related lymphoma is difficult because underlying immu- nodeficiency increases the risk of treatment-related myelosuppression.
  • Standard combination regimens (e.g., CHOP) yield disappointing results. The new approach, dose-adjusted EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, and doxorubicin [hydroxydaunomycin]), is promising.
  • Antiretroviral therapy and prophylactic antibiotics should be continued during chemotherapy.


  • The primary outcome to be identified is tumor response, which is based on physical examination, radiologic evidence, and other baseline findings. Complete response is desirable because it yields the only chance for cure.
    Patients are evaluated for response at the end of 4 cycles or, if treatment is shorter, at the end of treatment.
    Optimal outcomes for most types of lymphoma require delivery of full doses on time. Hematopoietic growth factors and other supportive care measures are often needed to achieve this goal.
    To optimize chemotherapy administration, the clinician must identify, monitor, treat, and prevent or minimize treatment-related toxicity. Pertinent laboratory data and other procedures should be reviewed to establish a baseline for mo- nitoring purposes. Major organ and system toxicities to be monitored include hematologic, neurologic, skin, pulmonary, gastrointestinal, renal, and cardiac.
    Myelosuppression and neutropenic fever with infection are constant concerns with aggressive chemotherapy. Appropriate patient education and monitoring are critical.

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