Introduction
Kaposi’s 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.
Kaposi’s 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.[2] 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.[5]
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.[6] 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.[6] 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.[7]
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 patient’s 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.
Etiology and Pathogenesis
Although the epidemiologic pattern of AIDS-related KS suggests a virus as the infectious agent,[8] 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.
Kaposi’s Sarcoma Herpesvirus
The agent thought to be responsible for KS tumor formation has been designated Kaposi’s 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[12] 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.[16]
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.[20]
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 infections—a fact that may help explain the development and rapid growth of KS tumors after such infections.[20]
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.[28] In a human case study, Bouscarat et al[29] 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.
