Kaposis sarcoma (KS) is a tumor of
vascular origin that manifests in four different population groups:
(1) classic KS affects mostly elderly men of Mediterranean, East
European, or Ashkenazi Jewish heritage; (2) African-endemic KS is
confined to young adults and children in sub-Saharan Africa; (3)
iatrogenic, immunosuppression-induced KS develops primarily in
transplant recipients; and (4) KS associated with the acquired
immunodeficiency syndrome (AIDS) primarily affects homosexual males.
Kaposis sarcoma is the most common malignancy associated with
AIDS, and arises more frequently in homosexual and bisexual men than
in any other group infected with the human immunodeficiency virus
(HIV).[1,2] Although KS occurred rarely in the United States prior to
1980, its incidence established KS as an AIDS-defining malignancy
during the early years of the AIDS epidemic.[3,4]
Over the past decade, the epidemiology of KS has changed
dramatically, with a significant decline observed in the number of
newly diagnosed AIDS patients presenting with KS. The decline in
the incidence of AIDS-related KS most likely reflects the greater
awareness among the gay community of the need to prevent sexual
transmission of HIV infection, resulting in a trend toward more
consistent safe-sex practices among homosexual males.
To a somewhat lesser extent, the more frequent use of highly active
antiretroviral therapy (HAART) may also have contributed to the
overall decline in the incidence of AIDS-related KS in the developed
world. However, the prolonged effects of HAART on suppressing HIV
infections and thereby influencing the development of AIDS-related KS
remain uncertain because of long-term problems, including multidrug
resistance, treatment-limiting toxicities, and treatment
noncompliance with often complex regimens. Indeed, patients continue
to present with KS despite the use of HAART. Recognition of KS as
a serious manifestation of AIDS has been neglected in recent years,
notwithstanding the extensive morbidity and increasing mortality
associated with KS involvement of the lungs, gastrointestinal tract,
and other visceral organs.
The characteristic, unsightly cutaneous lesions of AIDS-related KS
severely compromise physical appearance and often lead to social
stigmatization because of the association of this disease with HIV
infection. Diverse clinical presentations of AIDS-related KS pose
numerous challenges for the clinician, and treatment approaches must
be individualized, taking into account the patients overall
clinical condition, immune status, psychological status, and other
concurrent medical problems and therapies.
There is no known cure for KS. Traditional treatment options, both
local and systemic, have been palliative in intent. This fact
underscores the need for therapies that not only are safe,
efficacious, and convenient but also minimize the risk of drug
interactions and toxicities when administered concurrently with any
other medications that patients may be taking.
Although the epidemiologic pattern of AIDS-related KS suggests a
virus as the infectious agent, a number of factors are thought to
contribute to the development of this disease. The fact that KS
occurs at a relatively high rate in homosexual males who are HIV
negative,[4,9-11] as well as those who are HIV positive, lends
credibility to the argument for an infectious, sexually transmitted etiology.
Kaposis Sarcoma Herpesvirus
The agent thought to be responsible for KS tumor formation has been
designated Kaposis sarcoma herpesvirus (KSHV) or human
herpesvirus type 8 (HHV-8). This novel human gamma herpesvirus is
transmitted by sexual contact or the blood-borne route.[12-15]
Using representational difference analysis, Chang and colleagues
identified a novel herpesvirus-like viral DNA sequence in patients
with AIDS-related KS, suggesting that a unique virus may be the
underlying cause of this type of KS. In additional studies evaluating
these DNA sequences in both immunocompromised and immunocompetent KS
patients, evidence of HHV-8 was found in 95% of all tissue samples
from patients with AIDS-related KS, in HIV-seronegative homosexual
males with KS, and in patients with classic KS.
Further characterization of HHV-8 isolated from various KS tumors
will be necessary to define more clearly the exact role of this virus
in the pathogenesis of KS.
Role of Cytokines
The role of cytokines in the regulation of growth of KS cells has
received much attention in an attempt to determine the etiology of
KS. Cells infected with HIV and KS cells themselves are known to
actively secrete high levels of angiogenic growth factors and
cytokines, such as tumor necrosis factor-alpha (TNF-alpha),
interleukin (IL)-6, basic fibroblast growth factor (bFGF),
platelet-derived growth factor (PDGF), and oncostatin-M (Onco-M), and
to express receptors with a high affinity for several
cytokines.[17-19] These cytokines have autocrine (ie, supporting
their own growth) and paracrine (supporting the growth of other
cells) characteristics that induce the development of lesions with
features similar to KS.
It appears that multiple cytokines may act in concert to stimulate
the formation and growth of KS cells.[17,21-23] These cytokines
activate the expression of several HIV-1 genes, which, in turn, can
increase the proliferation of KS cells. Various cytokines may enhance
the expression of HIV-tat, the HIV-1 transactivating gene that has
been implicated in KS cell growth.[22,24]
The role played by cytokines in AIDS-related KS is further supported
by the identification of increased production of certain cytokines in
HIV-infected patients. Several cytokines may act locally and over a
long period to stimulate the development of endothelial cells into
tumor cells.[19,25-27] High levels of cytokines (TNF-alpha,
IL-1-alpha, and IL-6) have also been identified in HIV-infected
patients following opportunistic infectionsa fact that may help
explain the development and rapid growth of KS tumors after such infections.
Role of Hormones
Since KS occurs predominantly in men both with and without HIV
infection, and is rare in women, the possibility that hormonal events
may influence the development of KS seems plausible. Findings from
HIV-tat transgenic mice indicate that KS-like vascular tumors develop
in the skin of male mice only. In a human case study, Bouscarat
et al observed proliferative effects of androgen therapy on
cutaneous KS lesions in an HIV-infected male. The lesions stabilized
and regressed following the discontinuation of androgen therapy.
Epidemiologic data collected over a 10-year span during the pre-AIDS
period indicate a male-female incidence ratio of about 4:1 for this
tumor.[3,30] However, further study is necessary to confirm the exact
role of sex hormones in the etiology of AIDS-related KS.
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