Prior to 1980, Pneumocystis carinii pneumonia was a distinctly uncommon infection most often diagnosed in persons with impaired immunity due to malnutrition, neoplasia, or organ transplantation. In 1981, Gottlieb and associates described profound defects in cell-mediated and humoral immunity in several young homosexual men and intravenous drug users who had developed oral candidiasis, Kaposis sarcoma, or life-threatening P carinii pneumonia.
Opportunistic infections or Kaposis sarcoma in the setting of unexplained acquired immunodeficiency became the initial criteria used in 1981 by the Centers for Disease Control and Prevention (CDC) to define the acquired immunodeficiency syndrome (AIDS). Just one year later, the CDC took notice of the remarkable increase in the number of primary central nervous system non-Hodgkins lymphomas (NHLs) that were occurring in persons under 60 years of age without a known cause of immunosuppression and included this as an additional diagnostic criterion for AIDS.
Over the next several years, investigators described high-grade B-cell lymphomas with aggressive growth patterns occurring in unusual extranodal locations in immunologically impaired homosexuals and intravenous drug users.[4-7] These observations provided the impetus for including specific types of peripheral high-grade NHL in the 1985 CDC revised case definition of AIDS.
That same year, serologic tests to diagnose human immunodeficiency virus (HIV) infection became commercially available. As the number of cases of lymphoma in HIV-infected persons continued to accumulate, the CDC again amended its case definition of AIDS to include HIV-seropositive individuals with intermediate- or high-grade NHL of B-cell or indeterminate phenotype, even in the absence of opportunistic infections or Kaposis sarcoma. Now, nearly 2 decades into the AIDS epidemic, these tumors are recognized as the second most common malignancy to afflict HIV-infected women and homosexuals and the most frequently diagnosed cancer in other HIV-transmission groups.
Lymphomas associated with HIV share several important features with NHLs observed in other acquired or congenital immunodeficiency states. These include the propensity for rapid tumor growth, intermediate- or high-grade histologies, and B-cell phenotype. More unique are the roles that Epstein-Barr virus (EBV), Kaposis sarcoma-associated herpesvirus/human herpesvirus-8 (KSHV/HHV-8), and, to a lesser extent, HIV, may play in the pathogenesis of at least a subset of these malignancies.
Studies of HIV-associated NHL provide insights into the mechanisms that promote neoplastic transformation in states of altered immunity. As our understanding of the pathogenesis of AIDS is refined and our appreciation of the complex molecular interactions taking place expands, so too will our ability to harness novel agents capable of reconstituting a compromised immune system, regulating oncogene-gene expression, or altering complex tumor-promoting cytokine pathways. Such therapies, some of which are now in clinical development, represent state-of-the-art treatments that will hopefully prolong life for the increasing number of HIV-infected individuals who develop this devastating complication of immunodeficiency.
The emergence of NHL as one of the two most common malignancies of AIDS was not surprising because it has long been linked with diseases of acquired and inherited immunodeficiencies, as well as autoimmune diseases (Table 1). For example, the incidence of NHL in organ transplant recipients receiving long-term immunosuppressive therapy to prevent graft rejection is more than 100 times than that in age-matched populations.
The precise incidence of lymphoma after organ transplantation correlates with the type of organ transplanted. In one study, lymphomas occurred in 1% of renal transplant recipients, 1.8% of cardiac transplant recipients, 2.2% of liver transplant recipients, and 4.5% of recipients of heart-lung allografts. B-cell lymphoproliferations have been reported in 0.23% to 0.45% of recipients of human leukocyte antigen (HLA)-identical bone marrow. Among patients who have non-HLA-matched transplants, this risk increases to 5% to 25%.
Although multiple factors contribute to lymphomagenesis, patients who experience repeated episodes of rejection following organ transplantation and require immunosuppressive treatment with high-dose steroids, antithymocyte globulin, and, especially, monoclonal antibodies are most likely to develop B-cell lymphoproliferations. Among cardiac transplant recipients, the incidence of lymphoproliferative disorders increased markedly when a new, potent immunosuppressive agent was introduced, the monoclonal antibody muromonab-CD2 (Orthoclone OKT3).
The intensity of the immunosuppressive regimen is also an important variable. In a recent multicenter study of 45,114 patients receiving kidney and 7,634 heart transplants between 1983 and 1991, the risk of NHL was 15 times greater after intensive immunosuppressive therapy than after a less aggressive regimen.
The interval between transplantation and the development of a lymphoproliferative disorder may only be a few months, especially if cyclosporine (Neoral, Sandimmune) or antithymocyte globulin is used to modulate graft rejection. Furthermore, if such immunosuppression is reversed (eg, by discontinuing immunosuppressive agents following organ transplantation), a small percentage of these lymphomas regress spontaneously.
On the basis of molecular, immunologic, and pathologic studies, Knowles and colleagues have described three types of post-transplantation lympho-proliferative disorders . The first type, plasmacytic hyperplasia, arises in the oropharynx or lymph nodes and is polyclonal, as indicated by the detection of EBV infection in multiple genomic sites without immunoglobulingene rearrangements or mutations and without oncogenes or tumor-suppressor genes. The second type, polymorphic post-transplantation lymphoproliferative disorder, presents at nodal and extranodal sites, and is usually characterized by monoclonal EBV infection. The third type, which includes immunoblastic lymphoma and multiple myeloma, is characterized by disseminated monoclonal neoplasms that may be associated with alterations in oncogenes and tumor-suppressor genes.
Attempting to stratify such post-transplantation lymphoproliferative disorders based on histologic morphology may be beneficial in predicting clinical course and response to treatment. For example, B-cell lymphoproliferations in immunologically compromised patients may be polyclonal, oligoclonal, or monoclonal. Polyclonal tumors can behave aggressively but are most likely to respond favorably to cytotoxic chemotherapy, acyclovir, interferon-alfa (Intron A, Roferon-A), or immune disinhibition. Histologically, they are comprised of a polymorphous infiltrate of B-cells, including lymphocytes, plasma cells, and large transformed cells, or a monomorphous infiltrate resembling high-grade lymphoma in nonimmunocompromised persons. Monomorphic lymphoid proliferations tend to occur at somewhat longer intervals after transplantation; Southern blot testing reveals EBV DNA in tumor cells.
Lymphomas in Patients With Rheumatologic Diseases
Whether patients with rheumatologic diseases are at increased risk for lymphoma remains unclear. The underlying immunosuppressive therapy--most notably, azathioprine(Drug information on azathioprine) and cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar), and less frequently, methotrexate(Drug information on methotrexate) and cyclosporine--may contribute to lymphomagenesis in these cohorts of patients. Some authors report increased risk independent of immunosuppressive therapy, implying that immune activation plays a contributing role. Other epidemiologic studies have not been able to demonstrate increased risk of NHL among these patients, regardless of whether immunosuppressive therapy is given.
Mechanisms of Lymphoma in Immunosuppressed Patients
Studies of lymphoma epidemiology lead to an important question: Why are certain immunosuppressed individuals particularly prone to develop NHL? Specific mechanisms that may lead to the emergence of malignancy in the setting of disordered immunity include an inadequate or inappropriate host response to transforming infectious pathogens, such as EBV. In the normal host, EBV-driven lymphoproliferation is primarily controlled by EBV-specific cytotoxic T-cells, with a lesser role being played by humoral responses, antibody-dependent cellular cytotoxicity, natural killer cell activity, and, possibly, gamma-interferon.
In the immunodeficient host, the proliferation of EBV-infected B-cells can continue unchecked. When regulatory systems go awry, such as in the rare X-linked lymphoproliferative syndrome (a congenital disorder characterized by uncontrolled B-cell proliferation following initial exposure to EBV), afflicted male infants have roughly a 50% risk of developing fulminant NHL before the age of 3 years.