The non-Hodgkin’s lymphomas occur commonly. There are more than 40,000 new cases of non-Hodgkin’s lymphoma each year in the United States. Recently, it has become clear that there is an increasing incidence of the non-Hodgkin’s lymphomas. There are several components to this increasing incidence. First, non-Hodgkin’s lymphomas occur more frequently in the elderly, and as the elderly population has increased in the United States, so has the incidence of NHL. However, the rates of non-Hodgkin’s lymphomas seem to be going up for all age groups, with the largest increase occurring in the elderly. HIV infections account for a proportion of the increase but in general has added only to the incidence in young single males. The possibility of environmental exposures such as chemicals, pesticides, solvents, and infectious etiologies adding to the increased incidence of lymphoma needs to be considered.

There is no clear etiology of the non-Hodgkin’s lymphomas. However, there are several known factors that increase the risk. Chief among these are immunodeficient states, either acquired, iatrogenic, or genetic. Concomitant Epstein-Barr virus (EBV) infection appears to markedly increase the risk of non-Hodgkin’s lymphoma in immunosuppressed populations. Environmental factors as noted may be involved, and several viruses are closely associated with development of non-Hodgkin’s lymphoma. EBV is strongly associated with the development of Burkitt lymphomas in Africa (but not in the United States). The human T-cell leukemia virus 1 (HTLV-1) has been associated with adult T-cell leukemia-lymphoma. The hepatitis C virus has been linked to a variety of B-cell malignancies, including indolent lymphomas and cryoglobulinemia. Bacterial infections seem to play a role in some non-Hodgkin’s lymphomas. For example, not only is the Helicobacter pylori infection associated with the development of gastric mucosal-associated lymphoid tissue (MALT) lymphoma, but its eradication through antibiotic therapy leads to tumor regression in a majority of cases.

A host of genetic alterations have been reported in the non-Hodgkin’s lymphomas. One example of a translocation seen frequently in follicular lymphomas is the t(14 : 18) translocation. When this occurs, the gene for bcl-2 is juxtaposed to the immunoglobulin heavy chain locus with subsequent overexpression of bcl-2, which is normally involved in control of programmed cell death or apoptosis. The process of planned death of a cell, known as apoptosis, is an important mechanism for maintaining homeostasis in all organisms. Prevention of apoptosis provides a survival advantage to the clone of cells. The increased levels of bcl-2 prevent the programmed death of the cell from occurring. This translocation appears to be present in at least 85% of follicular lymphomas.

Classification
The classification of the non-Hodgkin’s lymphomas can be confusing and has been controversial. Multiple classification systems have been introduced and used over the past 40 to 50 years. The various classification schemes differ in their primary guiding principles of classification from cell morphology, to cell lineage and differentiation, to clinical response to treatment and survival. Over time, as advances in immunophenotyping and molecular genetics have been made, classification based primarily on a single guiding principle has proven inadequate, failing to recognize many distinct, clinically relevant disease entities. This realization led to the introduction of the Revised European-American Classification of Lymphoid Neoplasms (REAL) by the International Lymphoma Study Group in 1994. This classification scheme attempts to include immunophenotype, genetic information, morphology, and clinical features in defining a specific disease entity. Nonetheless, for the purposes of treatment and development of new therapies for the non-Hodgkin’s lymphomas, many clinicians find it useful to distinguish those diseases with a more indolent natural history from those with a more aggressive course.

The indolent lymphomas frequently present with few symptoms but disseminated disease. Survival is quite long, but there is no known curative therapy. Aggressive lymphomas frequently present with more localized disease and can be cured with multiagent chemotherapy, even in advanced stages.

Clinical Manifestations and Treatment
The indolent lymphomas, which make up 20% to 40% of all the non-Hodgkin’s lymphomas, tend to occur with advancing age. The median age is approximately 50 to 60 years. The majority of patients have advanced-stage disease, and bone marrow involvement is common. The t(14 : 18) translocation is seen in most patients with follicular lymphomas. Fevers, sweats, and weight loss (B symptoms) are uncommon.

The staging evaluation of indolent lymphomas is not as critical as in the aggressive lymphomas or in Hodgkin’s disease. Typically, physical examination, routine laboratory tests, chest x-ray, computed tomography (CT) scans, and bone marrow biopsy provide sufficient information to evaluate prognosis and plan of treatment.

Physicians treating indolent lymphomas must recognize that although these diseases are slow to progress and frequently respond to chemotherapy, they are as yet incurable. The median survival approaches 7 to 8 years. However, ultimately the disease progresses and frequently transforms to a more aggressive lymphoma.

The goals of therapy are generally palliative. Rarely, a patient with localized disease can obtain long-term remission with involved field radiation. For the majority of patients who present with advanced-stage disease, there is a wide range of treatment options. Most studies have shown no survival benefit for early treatment, and, in fact, a watch-and-wait approach may be optimal for many patients. However, in these circumstances patients should be monitored closely to prevent complications such as renal failure secondary to ureteral obstruction. In reported series when watchful waiting is applied to a cohort of patients, overall survival is equivalent to those treated at presentation. The median time to instituting therapy is 2 to 3 years. This strategy may be particularly appropriate for older individuals with significant comorbidities that might further adversely affect therapy.

Other treatment strategies, including immediate chemotherapy or aggressive chemotherapy, have also been attempted. Cyclophosphamide and chlorambucil have been used alone, with response rates in the 50% to 80% range. Cyclophosphamide, vincristine, and prednisone frequently have been combined, showing higher response rates. Nonetheless, a continuous relapse pattern is observed. When more aggressive chemotherapy is used, such as the CHOP regimen containing cyclophosphamide, hydroxydaunomycin, Oncovin (vincristine), and prednisone, a higher percentage of responses and complete responses is seen. However, it does not appear to change the rate of recurrence. The purine analogues such as fludarabine have shown activity in indolent lymphomas alone and in combination. Fludarabine, when combined with mitoxantrone, has demonstrated significant response rates.

As an alternative to chemotherapy, the option of monoclonal antibody therapy for indolent, B-cell non-Hodgkin’s lymphoma has become available. The human-mouse chimeric anti-CD20 monoclonal antibody, rituximab, was initially shown to be effective in the setting of recurrent indolent lymphoma, with a response rate of 48% and a favorable toxicity profile. The median time to progression for those responding was approximately 1 year. More recently, rituximab has been studied as initial therapy for indolent lymphoma and has shown high levels of activity, mild toxicity, and excellent progression-free survival. Rituximab’s activity as a single agent, in addition to its favorable toxicity profile and specifically the lack of significant hematologic toxicity, has led to the investigation of its use in combination with conventional chemotherapy. Czuczman et al. have reported an overall response rate of 95% and a complete response rate of 55% in patients with indolent B-cell lymphomas treated with a combination of CHOP and ritux-imab. The study suggests additive activity with the combination without a significant increase in toxicity, which may be particularly pertinent for some elderly patients who have a limited ability to tolerate more toxic therapies. Interestingly, the bcl-2 t(14 : 18) translocation could not be detected in the follicular lymphoma patients who demonstrated a complete response.

The indolent lymphomas tend to be radiosensitive, and frequently symptomatic areas of adenopathy can be treated with palliative radiotherapy. This sensitivity to radiation has also been utilized through radiolabeled monoclonal antibodies. Anti-CD20 monoclonal antibodies radiolabeled with yttrium-90 or iodine-131 have shown superior CR and overall response rates to those of rituximab alone in trials looking at recurrent or refractory indolent lymphomas. Toxicity is greater when compared with rituximab, with the primary toxicity being myelosuppression.

The aggressive lymphomas tend to present with diffuse adenopathy but rarely involve the bone marrow. When the bone marrow is involved, there is a high correlation with involvement of the central nervous system, and this portends a bad prognosis. Extranodal sites such as the gastrointestinal tract are frequent areas of origin of the intermediate-grade lymphomas. They are predominantly B-cell, although as many as 20% of them may be T-cell immunophenotype, which has identical behavior.

The prognosis for patients with aggressive lymphoma has improved markedly with the advent of multiagent chemotherapy, as is detailed here. Nonetheless, many patients do not either obtain or maintain a complete remission (CR). The prognostic factors that predict the likelihood of response have recently been more fully characterized.

Age remains an important prognostic factor. Patients under the age of 60 have a significantly better prognosis than those patients over the age of 60. Serum levels of lactate dehydrogenase (LDH), performance status, and stage of disease, as well as the number of extranodal sites, are also important prognostic factors, as detailed in the international index recently reported. Other important parameters of prognosis include the rapidity of response, usually measured as the time to achieve a CR. Those patients who achieve a CR quickly (fewer than three to four cycles of therapy) have an improved long-term survival compared with those patients who have not achieved a CR by this time. There appears to be a significant dose-response relationship in the treatment of these lymphomas. Patients who receive dose-reduced therapy appear to achieve CR less frequently and relapse from CR more frequently than those who receive full-dose therapy.

The dose intensity of therapy has been studied specifically in the elderly. The Southwest Oncology group studied CHOP chemotherapy in elderly patients. There were several interesting results of this study. The rate of complete response was 65% in those under 40 years of age and 37% in those 65 years and older. The median survival for the younger group was 101 months but only 16 months in the older group. This protocol called for initial dose reduction for patients 60 years of age and older; however, some patients received full doses of chemotherapy in violation of the protocol. When these patients were examined separately, the rates of CR and survival were markedly better than those receiving reduced doses of chemotherapy. This finding suggests that full doses of chemotherapy are important in elderly patients as well as in younger patients. Toxicity, however, remains a major problem.

Other investigators have sought to develop regimens specifically for the elderly. In one prospective, randomized, phase III trial, CHOP was compared to CNOP (cyclophosphamide, mitoxantrone, vincristine, and prednisone) in patients 60 years of age and older with aggressive lymphomas. CHOP was found to be superior in achieving complete responses in 49% versus 31% in the CNOP group. Three-year survival was also superior in the CHOP group, and toxicity was comparable.

Rituximab therapy in elderly patients with aggressive lymphomas has been studied with some promising results. In a recent report, previously untreated patients aged 60 to 80, with aggressive B-cell lymphomas, were treated with a combination of CHOP plus rituximab versus CHOP therapy alone. At 1 year, the combination of CHOP plus rituximab was found to demonstrate superior overall survival and event-free survival as compared with CHOP alone, with comparable toxicity.

In general, it would appear that, for elderly patients with aggressive lymphoma who have good performance status and normal organ function, attempting full-dose chemotherapy with a curative intent seems reasonable. Patients with poor performance status or impaired cardiopulmonary or renal reserves are unlikely to tolerate these aggressive therapies without significant morbidity. There may also be a role for hematopoietic growth factors in mitigating hematologic toxicity for elderly patients. The physician needs to balance the risks and benefits of these aggressive regimens.

For patients who do not achieve a CR or who relapse from CR, the overall prognosis is poor. Several aggressive regimens are available for the treatment of relapsed and refractory lymphoma, and high-dose therapy with bone marrow transplant support has also been used. In general, elderly patients are unlikely to significantly benefit from these aggressive interventions. Continued effort to define optimal initial treatment regimens that may be curative for elderly patients seems warranted.