Other Oncogenic Alterations
Both TP53 and bcl-6 rearrangement mutations have been observed
relatively frequently in AIDS-associated lymphomas. In one study,
TP53 gene mutations were detected in 37% of AIDS-associated NHL.
Mutations in ras have been reported in roughly 15% of AIDS
lymphomas. Alterations in their tumor-suppressor function could
result in increased genomic instability and changes in cell-cycle interactions.
Other investigators have reported that TP53 inactivation appears
exclusively in Burkitts-like tumors and is mostfrequently
present in conjunction with c-myc mutation. The frequent
simultaneous occurrence of TP53 tumor-suppressor gene inactivation
and c-myc oncogene deregulation in the same tumor in vivo and in
lymphoma cell lines in vitro suggests that cells carrying the
activated c-myc oncogene may be under pressure to subsequently
delete a TP53 -dependent pathway. This hypothesis is supported by
preliminary observations showing that the c-Myc protein may be
involved in regulating TP53 gene expression.
In addition to gross rearrangements, bcl-6 may also be affected by
mutations of the gene 5¢ noncoding region. For example,
investigators evaluating NHL tumor specimens collected from 43 AIDS
patients for mutations in the first exon-first intron boundary region
of bcl-6 detected mutations in all categories of
AIDS-associated NHL (at least 25 of 43 cases; 58%), including 12 of
28 AIDS-associated Burkitts lymphomas, 10 of 15 AIDS-associated
diffuse large cell lymphomas, 2 of 3 AIDS-associated anaplastic large
cell lymphomas, and 1 of 5 AIDS-associated body-cavity-based
lymphomas. Mutations of bcl-6 occurred independently of bcl-6
rearrangements and of the presence of other genetic lesions often
associated with AIDS-related lymphoma.
These results indicate that mutations of the 5¢ noncoding
regions of bcl-6 may represent the most common genetic
alteration presently detectable in this setting. The frequency of
these mutations, as well as their location in the proximity of bcl-6
regulatory sequences, suggests that they may play a role in
In San Francisco, Shiramizu and colleagues have emphasized the
existence of a wide histologic and molecular spectrum of
HIV-associated lymphomas. Based on studies of tumor clonality, EBV
genome presence, and c-myc rearrangements, they identified six
distinct molecular subsets of aggressive B-cell lymphomas among 48
AIDS-associated NHL tumor specimens. In 43% of these tumors, no
clonal rearrangements were identified, signifying that polyclonal
lymphoproliferations occur in a significant proportion. Like the
polyclonal lymphoproliferation occurring in the setting of iatrogenic
immunosuppression, HIV-polyclonal lymphomas may be polymorphic and
have an aggressive clinical course (although they may have uniquely
favorable responses to cytotoxic chemotherapy). Unlike their
transplant counterparts, however, AIDS-related lymphomas are notable
for the absence of EBV infection and c-myc gene rearrangements.
Establishing the frequency of polyclonal lymphoproliferations has
been a controversial issue because investigators on the East Coast of
the United States have not been able to reproduce the same high
numbers as those reported in San Francisco; the vast majority are
monoclonal B-cell tumors.[89,90] Could there be intrinsic differences
between the lymphomas reported on the West Coast and those described
in the East? In an attempt to clarify this issue, while expanding on
the morphologic and molecular characteristics of these tumors, Nador
and colleagues analyzed 75 cases of AIDS-related lymphoma, including
27 from the East Coast and 38 from the West Coast. They found
that the majority of cases were monoclonal but that a minority were
truly polyclonal (approximately 3% polyclonal on the East Coast; 8%
polyclonal on the West Coast; see Table 4).
Although the majority of AIDS lymphomas were found to be monoclonal
using a single Joining region sequence of the heavy-chain gene (JH)
probe, these cases required additional techniques (such as an EBV
termini probe) to determine whether they were truly monoclonal.
Various studies on the molecular pathogenesis of AIDS-associated NHL
indicate that distinct clinicopathologic variants are associated with
different patterns of genetic lesions, although the results may be
more heterogeneous than was initially suspected.[28,55] In
particular, AIDS-associated Burkitts lymphomas are
characterized by consistent activation of c-myc and frequent
disruption of TP53, whereas infection by EBV is restricted to a
subset of cases. Diffuse large cell lymphomas associated with AIDS
are more heterogeneous and commonly associated with EBV infection;
arrangements of either c-myc or bcl-6 are found in only a fraction of
these samples. Finally, AIDS-associated body-cavity-based lymphomas
are consistently associated with coinfection by KSHV/HHV-8 and EBV.
The genetic features of AIDS-associated anaplastic large cell
lymphomas have not been studied extensively.
Alterations in B-Cell Regulation
Regulation of B-cells is abnormal in the setting of HIV disease, as
evidenced by the finding of an increased incidence of spontaneously
activated B-cells in the peripheral blood and elevated gamma globulin
in the serum of manypatients with HIV infection. Some
HIV-envelope-inducing T-cell-mediated B-cell effects may contribute
to this perturbation. The nature of the hypergammaglobulinemia
has been characterized as oligoclonal, often with HIV specificity.
In one report, multiple myeloma was seen in an HIV-infected patient
and may have developed from HIV-specific plasma cell clones. The
chronic stimulation of HIV-specific B-cells by oncogenic virus
production may provide the mitogenic impetus for mutagenesis,
resulting in malignancy.
Heightened cytokine production in response to HIV infection (and
perhaps to other viruses) may also contribute to the development of
lymphomas in AIDS. One of the many lymphohematopoietic factors
released under normal and virus-perturbed conditions, interleukin-6
(IL-6) is a potent stimulator of B-cell proliferation and
differentiation. Monocytes obtained from HIV-infected patients
express high levels of IL-6, and IL-6 is also concentrated among
lymphoma-associated macrophages.[94,95] In addition, patients with
symptomatic HIV infection have the highest serum IL-6 levels and,
thus, may be the group most susceptible to developing lymphoma.
In the same manner that IL-6, through paracrine and autocrine loops,
drives B-cell proliferation in multiple myeloma and Castlemans
disease, its interactions with lymphoma-associated IL-6 receptors may
mediate subsets of AIDS-associated lymphoma, including
Recently, investigators from Germany described a series of 15
HIV-infected patients who, over a 4-year period, developed
plasmablastic lymphomas of the oral cavity. The majority of
tumors were negative for bcl-6 protein and KSHV/HHV-8 but were
positive for EBV-related antigens. These tumors displayed morphologic
features of diffuse large-cell lymphomas but differed from them in
that expression of the leukocyte-common antigen, as well as the
B-cell antigen CD20, was minimal or absent. Instead, the tumor cells
stained positive to two new plasma cell reactive antibodies (VS-38c
and CD79a). Given the strong plasma cell immunophenotypic features of
these tumors, it will be interesting to see what role IL-6 plays in
their pathogenesis, and whether they represent a new clinical entity.
In addition to mechanisms that directly stimulate B-cell expansion,
suppression of helper T-cell antiviral or cytotoxic surveillance
activities generally permits the establishment of malignant clones.
Interleukin-10 (IL-10), also known as cytokine synthesis-inhibiting
factor, is a T-cell function suppressor that has been implicated in
the development of AIDS-associated NHL.[97,98] Excess IL-10 may
permit regulation of viruses (particularly EBV and possibly HIV) to
go unchecked and promote a cascade of events culminating in the
establishment of a clonal B-cell malignancy. In addition,
B-lymphocytes produce and also respond to IL-10; hence, the cytokine
may act as an autocrine growth factor in human lymphoid tissues.
Increased levels of IL-10 are present in patients with lymphoma, both
with and without underlying HIV infection, and such increases have
been correlated with poor survival. The addition of neutralizing
antibody to IL-10 inhibits proliferation of tumor-derived B-cell
lines and primary tumors. Thus, IL-10 may have a potential
therapeutic benefit in patients with AIDS-related lymphoma.
The production of various cytokines may also favor the manufacture of
growth factors, which, in turn, may stimulate B-cell proliferation
and differentiation. One study analyzed the expression of parathyroid
hormone-related protein in lymph node tissue from HIV-infected
patients with and without AIDS-related lymphoma.
Immunohistochemical analyses were performed on fixed
paraffin-embedded specimens using antibody directed toward the
immunoterminus of parathyroid hormone-related protein.
In lymph nodes from normal subjects, only rarely did cells stain for
parathyroid hormone-related protein. In lymph nodes from HIV-infected
patients without lymphoma, up to 20% of cells stained for this
protein, while 25% to 50% of cells from B-cell lymphoma tissues/nodes
obtained from HIV-infected and non-HIV-infected individuals stained
for it. The parathyroid hormone-related protein was primarily
localized to the nucleus of large B-cells and to the cytoplasm of
reticular cells. Parathyroid hormone-related protein, since it
induces the expression of bcl-2, may influence B-cell
proliferation in HIV-infected patients.
Individuals infected with HIV are at substantially increased risk for
developing intermediate- and high-gradeB-cell lymphomas. Unlike
Kaposis sarcoma, which is confined primarily to homosexuals and
heterosexuals whoare seropositive for antibodies to KSHV/HHV-8,
AIDS-associated lymphomas frequently occur in all HIV-transmission
groups. Lymphomas associated with AIDS are often EBV-negative and
exhibit unique features that distinguish them from lymphomas arising
in individuals who develop iatrogenic, congenital, or non-HIV immunodeficiencies.
The development of lymphoma in patients with underlying HIV infection
represents an accumulation of multiple factors not yet completely
understood. Nonetheless, the distinctive features of AIDS-associated
NHL suggest that unique pathogenic mechanisms contribute to the
development of malignancy.
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