Clinical Features: AIDS-Related vs Post-Tranplantation Lymphomas
Although the lymphomas that occur in other immunodeficient states
share several common clinical features with AIDS-associated
lymphomas, important differences also exist (Table
2). For example, AIDS-associated peripheral lymphomas are
associated with EBV infection roughly 33% to 66% of the time, but in
the post-transplant setting, lymphomas are related to EBV in
virtually 100% of instances.[24,25] The frequency of c-myc
rearrangements is also substantially greater among AIDS patients than
in organ transplant recipients. In addition, the small noncleaved
cell Burkitts lymphoma comprises roughly 20% of AIDS-related
lymphomas but is rarely seen in other immunosuppressed groups.
Polyclonal lymphoproliferations are more common in the
These various manifestations of NHL in different settings of
immunodeficiency may ultimately provide clues as to how immune
perturbation promotes oncogenesis. This issue has broad implications
that extend beyond the confines of AIDS, post-transplantation
lympho-proliferative disorders, or congenital immune disorders.
The incidence of NHL in the United States has been growing steadily
(at a rate of about 4% per year) for several decades. Lymphomas are
most prevalent among males, in whom a 60% increase has been noted
between 1976 and 1990. This rate coincides with the high
incidence of lymphoma among HIV-infected individuals. Although
malignant lymphomas are the sixth most common cause of death from
cancer in this country, because of the young average age of the
lymphoma population (42 years), lymphomas rank fourth in terms of
lost wages and economic impact.
Why NHL rates are rising remains obscure. However, the rise may be
related to the increased exposure to a variety of environmental
agents, including ionizing radiation, benzenes, hair dyes,
herbicides, and viruses. HumanT-cell leukemia virus type I is the
pathogen most often implicated in lymphomagenesis in southern Japan,
but, with the exception of a few isolated pockets (including
Brooklyn, New York, and the Carolinas), this virus accounts for very
few cases in the United States.
Risk factors for AIDS-associated NHL include male gender, advancing
age, and socioeconomic status. In the United States,
approximately 80% of persons who develop AIDS-associated NHL are
homosexual or bisexual men. Unlike Kaposis sarcoma, which is
seen more frequently among homosexual men than among members of other
AIDS risk groups, NHL occurs broadly among all HIV-infected
groups. This includes children who have been infected
perinatally, hemophiliacs and blood transfusion recipients, and
adults who have acquired HIV infection by heterosexual contact or the
sharing of tainted needles during intravenous drug use.
The clinical and pathologic spectra of lymphoma appear to be similar
among the various HIV transmission groups, with the possible
exception of primary oral and anorectal NHLs, which may occur more
frequently in homosexual and bisexual men than in other AIDS risk
groups. Lymphomas associated with AIDS are most often diagnosed
on the East and West Coasts--a reflection of the bicoastal
distribution of HIV in the United States. Regional and environmental
cofactors are probably less etiologically important in this setting
than in NHL that is not linked to AIDS.
Trends in Incidence
The high incidence of NHL among HIV-infected individuals has been
quantified in several epidemiologic studies. The San Francisco
Linkage Study examined cancer risk among AIDS patients during the
period 1980 to 1987. Based on preepidemic levels of NHL (1973 to
1977), the observed number of cases of lymphoma in the homosexual
AIDS cohort was 97-fold greater than expected. In New York City and
Illinois, the risk has been estimated to be 100 to 150 times greater
than that of the general population.
Secular trends in NHL rates were also noted in a study of a
relatively small cohort of patients with severe HIV infection who
received prolonged antiretroviral therapy. Among long-term survivors
who were treated with zidovudine (Retrovir) or didanosine (Videx) at
the National Cancer Institute (NCI), approximately 8% developed NHL 2
years after starting therapy and 29% after 3 years, with no
significant differences seen between the two antiretrovirals.
Based on their initial observations, Pluda and colleagues speculated
that the incidence of NHL in patients treated with antiretrovirals
was greater than in those who had not received antiretroviral
therapy. With additional follow-up, these authors rejected this supposition.
The potential lymphomagenic properties of zidovudine prompted Levine
and associates to conduct a population-based study in Los Angeles
County comparing AIDS patients with and without lymphoma. They
found no difference in the percentage of patients using zidovudine in
these two groups, or in the mean duration of zidovudine use. They
also failed to detect a relationship between prior zidovudine use and
subsequent NHL development.
In a hemophilia cohort, 14 cases of NHL were reported in a group of
1,295 patients, for an incidence of 0.6 per 100 person-years; this
represents more than a 36-fold increase over the incidence of NHL in
the general population. In an overlapping cohort of hemophiliacs
with transfusion-acquired HIV infection, the incidence of NHL
increased exponentially as the duration of HIV infection was
extended, with the risk doubling every 2.4 years.
This finding is consistent with an NCI study showing that the risk of
peripheral NHL appears to be more intimately related to the duration
of HIV infection than to CD4+ T-helper lymphocyte count. It may also
explain why the risk of Kaposis sarcoma was so quickly linked
to AIDS, while the risk of NHL was not as apparent. In cancers
complicating organ transplantation, Kaposis sarcoma occurs, on
average, 20 months after transplantation, while lymphoma develops 33
The NCI now estimates that between 8% and 27% of the roughly 50,000
cases of NHL diagnosed yearly in the United States are
HIV-related. This contrasts with findings of the CDC, which noted
a 3% incidence of NHL among the first 100,000 patients reported to
have AIDS. This figure underestimates the incidence of NHL because
lymphoma was not an AIDS-defining illness until 1985. Also, CDC
reporting requires only the first AIDS diagnosis; thus, approximately
25% of NHLs occurring at a later AIDS diagnosis are potentially
missed.[27,44] This devastating complication of immunodeficiency
limits survival in at least 10% to 20% of all HIV-infected
individuals destined to develop NHL.
Impact of Highly Active Antiretroviral Therapy
For several years, investigators have speculated that lymphoma rates
would increase as greater numbers of HIV-infected persons survive
with progressive, profound immunodeficiency. Not factored into these
assumptions, however, is the uncertain effect of highly active
antiretroviral therapy, typically consisting of two nucleoside
analogs and a protease inhibitor, on lymphomagenesis. Individuals who
use these potent medications often demonstrate impressive clinical
and immunologic responses; CD4+ T-helper lymphocyte counts may rise
severalfold, and HIV-viral RNA loads may fall to undetectable levels.
Unfortunately, little is known about how complete or how durable
these responses will prove to be. Isolated clinical reports that
describe opportunistic infections occurring in patients whose CD4+
T-helper lymphocytes improved dramatically after beginning highly
active antiretroviral therapy are disturbing, as are immunologic
studies indicating that certain components of the immune system are
only partially restored.
Further complicating the picture is the recent finding that
aggressive antiretroviral therapy fails in as many as 30% to 50% of
patients in a "real world" clinic within a 2-year period;
this may be due to intrinsic properties of HIV or to difficulties
associated with rigid adherence to drug therapies associated with
substantial inconvenience and side effects.[48-50] Although there are
now 11 commercially available antiretroviral drugs, and several other
agents can be obtained via clinical trials or expanded access
channels, once HIV viral isolates develop resistance to initial
protease inhibitor therapy, no clear strategy reliably suppresses
In summary, the incidence of NHL in AIDS patients appears to be 100-
to 200-fold in excess of expected rates. Although this pales in
comparison to the 20,000-fold increase in Kaposis sarcoma seen
among HIV-infected homosexuals, it should be kept in mind that the
background rate of NHL in the general population is much higher.
Overall, the absolute cumulative incidence of lymphoma (in groups
other than homosexual men) is similar to that of Kaposis sarcoma.
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