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Pathogenesis of AIDS-Related Kaposi's Sarcoma

Pathogenesis of AIDS-Related Kaposi's Sarcoma

ABSTRACT: The occurrence of Kaposi's sarcoma (KS) in patients with HIV infection is more than 7,000 times higher than in the non-HIV infected population. The reason for this association is unclear but may involve decreased immune surveillance as a result of the profound cellular immune deficiency caused by HIV, a sexually transmitted KS-inducing virus, whose KS-transforming capabilities may be enhanced by HIV, or a direct or indirect effect of HIV itself in susceptible individuals. Over the last few years, advances have been made in our understanding of the pathogenesis of this tumor, and several models have been proposed for its development in the setting of AIDS. Better characterization of the processes involved in the development of KS will ultimately lead to more effective methods of treating and preventing this unusual tumor. [ONCOLOGY 10(3):335-350, 1996]

Introduction

Kaposi's sarcoma (KS) was first described in 1872 as a rare vascular
tumor characterized by multiple skin nodules of the lower extremity,
which was seen primarily in older men of eastern European or Mediterranean
descent [1]. The tumor rarely involved visceral organs and generally
had an indolent course. A more virulent, endemic form of KS was
subsequently described in sub-Saharan Africa and involved younger
men with cutaneous, lymphatic, and visceral involvement. It ran
a more aggressive clinical course. Yet another group of non-HIV-infected
patients with KS were those who received immunosuppressive therapy
for organ transplantation or an autoimmune disease and in whom
occasional spontaneous regression of lesions had been reported
with withdrawal of immunosuppressive therapy. These various KS-affected
populations suggested possible genetic, infectious, and immunologic
underpinnings to the development of these tumors [2].

AIDS-Related KS

The recognition of KS in US male homosexuals in the early 1980s
heralded the AIDS epidemic [3]. Early descriptions of AIDS suggested
that as many as 50% of gay men with T-cell immune deficiency developed
KS as one of their manifestations of AIDS. The proportion of patients
with KS as the initial manifestation of AIDS has declined to approximately
11% in 1991 [4,5]. Several characteristics of this tumor, including
its more aggressive clinical course; frequent involvement of lymph
nodes, gastrointestinal tract, lung, and other viscera; and its
almost exclusive early occurrence in the gay male AIDS population
with other evidence of immune deficiency suggested that this tumor
was more akin to the African variant of KS and likely was associated
with a sexually transmitted agent.

An additional feature of AIDS-related KS (AIDS/KS) that must be
explained in any model of pathogenesis includes the fact that
approximately 90% of AIDS/KS cases in the United States occur
in homosexual men, and far fewer cases have been seen in women,
intravenous drug users, or heterosexual males. Kaposi's sarcoma
has also been described in homosexual males who are not HIV-infected
[6]. While the number of HIV-infected women is lower than the
number of men, the frequency of KS in women is relatively high
in Africa and in women in western countries who have had sex with
bisexual men, compared to those whose sexual partners are heterosexuals
or intravenous drug users (3% vs 0.7%) [7].

These findings suggest that a sexually transmitted infectious
agent likely is involved in the pathogenesis of KS and that this
agent is more prevalent in US gay men and the general African
population. The findings also suggest that androgens or other
male factors may facilitate the development of this tumor.

Viral Etiology

The declining incidence of KS in the gay male population in the
mid- to late 1980s as a result of increased awareness of HIV and
the more widespread use of safe sex practices led to speculation
that sexually transmitted infections may be associated with the
development of this tumor. Declining incidence of cytomegalovirus
(CMV) seropositivity in association with declining occurrence
of KS led to speculation of a potential role for this virus in
KS pathogenesis [8,9]. Cytomegalovirus was not consistently detected
by in situ hybridization or other methods in KS tissue, however,
and the widespread prevalence of this virus in AIDS patients who
do not have KS argue against the involvement of CMV in KS tumor
development [10].

There also has been speculation about the potential role that
other DNA viruses, such as an Epstein Barr-like virus (EBV) [11]
and the human papilloma virus (HPV), may play in the pathogenesis
of KS [12]. However, the fact these viral sequences have not uniformly
been found in KS tumors suggests that infection with these viruses
may be more coincidental than causative for KS. No clear evidence
of the involvement of CMV, EBV, or HPV in the development of KS
has yet been established.

KS-Associated Herpesvirus

Recently, using representational difference analyses, Chang and
Moore have identified sequences of a unique gamma human herpesvirus,
termed the KS-associated herpesvirus (KSHV), in high frequency
in KS tissues from patients with AIDS [13]. These viral
sequences, somewhat homologous to sequences of the herpes saimiri
virus, which can induce lymphoma in monkeys, have been identified
in more than 90% of KS biopsies from HIV-infected and uninfected
individuals but not in uninvolved tissues from the same patients
or from normal controls [14-16].

Sequences of KSHV also have been found in an unusual variant of
non-Hodgkin's lymphoma in patients with AIDS (ie, body cavity
lymphomas), in association with EBV [17]. However, the recent
finding of KSHV-like sequences in patients with other dermatologic
disorders and the loss of these particles in multiple passaged
KS cell lines raises the possibility that this virus could be
a passenger virus rather than a directly transforming one [18].
Determination of the exact role of KSHV in the pathogenesis of
KS will require viral isolation and further characterization of
the direct and indirect effects of this virus. However, detection
of KSHV sequences in high frequency and specificity in patients
with KS has led to renewed interest in the role of viruses in
the development of tumors in the setting of immunosuppression
and in the possible use of viral inhibitory agents in controlling
tumor development and growth.

Pathology

Lesions of KS vary considerably in their clinical presentation
and, to a lesser degree, in their histologic appearance. These
lesions can involve predominantly the skin and oral mucosa, as
well as a number of visceral organs, and can range in appearance
from pink or red macules to dark blue and purple papules or nodules.

Histologically, KS lesions are characterized by intense neovascularization
and the appearance of spindle cells, which are considered to be
the tumor cells of KS. The spindle cells proliferate among characteristic
slit-like spaces produced by the aberrant vascular structures.
These cells have a low mitotic index and are euploid [19,20].
Fibroblasts, extravasated red blood cells, and inflammatory cells
are mixed in with the spindle cells. The histologic characteristics
of early and advanced KS differ in that the spindle cells in advanced
lesions are more abundant and form more compact masses.

The origin of the spindle cells is somewhat controversial, as
these cells share several histologic features with various other
types of cells [21]. Immunohistochemically, spindle cells are
somewhat similar to endothelial cells in that they stain with
Ulex europaeus and are negative to factor VIII and EN-4
[22]. A mesenchymal origin is suggested by the presence of alpha-actin,
a smooth muscle marker, and shared positivity with the hematopoietic
cell markers CD34 and CD18 [23]. It is currently believed that
KS most likely is of mesenchymal origin, possibly a smooth muscle
progenitor, with multiphenotypic markings reflective of early
differentiation or transformation.

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