Pathogenesis of AIDS-Related Kaposi's Sarcoma

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(Drug information on 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.