Epidemiology and Pathogenesis of AIDS-Related Lymphomas
Epidemiology and Pathogenesis of AIDS-Related Lymphomas
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
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 and cyclophosphamide (Cytoxan,
Neosar), and less frequently, 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.