Clinical Manifestations of Kaposi's Sarcoma

Introduction

The outbreak of Kaposi's sarcoma (KS) and Pneumocystis carinii pneumonia (PCP) among young, previously healthy, homosexual men in early 1981 marked the initial recognition of the acquired immune deficiency syndrome (AIDS) [1,2]. KS was among the first AIDS-defining conditions and has remained one of the major cancers associated with human immunodeficiency virus-type 1 (HIV-1) infection. The sudden increase in the incidence of KS has provided considerable new information. This article summarizes recent developments in research on KS and proposes a coherent model for its pathogenesis.

In 1872, Moritz Kaposi first described this disease as "multiple idiopathic pigmented hemangiosarcoma"[3]. He described the condition as localized, nodular, brown-red to blue-red tumors that appear first on the soles of the feet and then on the hands. He was also aware of the multifocal nature of the disease, the occurrence of visceral involvement, and its vascular nature.

This form of KS, known as classic KS, occurs most commonly in Eastern Europe and North America among older men of Italian or Jewish ancestry [4]. In the 1950s and 1960s, a more aggressive form of KS that occurred in younger individuals was described in central Africa, accounting for 9% of all cancers in Uganda5]. In the mid-1970s, KS was reported among a new group of patients, those receiving immunosuppressive therapy for renal transplantation [6,7].

In early 1980, outbreaks of KS were reported among young homosexual/bisexual men in New York and San Francisco who engaged in promiscuous sexual activity and had signs of cellular immune defects [1,2,8-11].

Epidemiology

Prior to the AIDS epidemic, KS was considered a rare disease [4]. The annual incidence of classic KS in the United States was estimated to be 0.021 to 0.061 per 100,000 people [4,12,13]. Although this form of KS is seen mostly in persons of Italian or Jewish descent, it has been observed in other groups, including three persons of Eskimoan descent [14] and a large group of people in Sweden and Norway, where there is only a small Jewish population [15,16]. A twofold increase in the incidence of classic KS in Sweden during the late 1960s was reported in the late 1980s [15]. Other clusters of classic KS have been reported from the Mediterranean island of Sardinia and on the Peloponnesian peninsula.

The literature indicates a male to female ratio of 15:1 for classic KS, but recent data suggest a ratio of 2:1 to 3:1[4,17]. Classic KS is most common in black African people [12,13,18,19]. It accounts for 1.3% of all cancers in Durban, South Africa, 4% in Tanzania, and 9% to 10% in equatorial countries in Africa, such as Uganda and the Congo [18,19].

Because of the increase in the number of organ transplants and the more frequent use of immunosuppressive therapy for autoimmune disorders, iatrogenically induced KS has been reported with increasing frequency. In organ-transplant recipients, the overall prevalence of KS is 0.52% (1.24% for liver, 0.45% for kidney, and 0.41% for heart) [20].

It has been established that KS occurs primarily in homosexual/bisexual men. To a much lesser degree, it also occurs in female partners of bisexual men and in women from certain regions of the Caribbean and Africa who acquired HIV infection through heterosexual contact [21]. Other groups at risk of AIDS are reported to develop KS, but to a lesser degree. Approximately 95% of all reported cases of AIDS-associated KS in the United States have been in homosexual and bisexual men, representing 26% of all homosexual men with AIDS. In comparison, AIDS-associated KS is reported in 9% of Haitians, 3% of heterosexual intravenous drug abusers, 3% of transfusion recipients, 3% of women with AIDS, 3% of children with AIDS, and 1% of persons with hemophilia. So far, AIDS-associated KS has not been seen in women with AIDS who acquired HIV infection through heterosexual contacts with men with transfusion-acquired AIDS or with iatrogenically infected persons with hemophilia [21].

The incidence of AIDS-associated KS is reported to be quite high among homosexual/bisexual men who meet their partners in places where anonymous sex is common, such as bath houses. Specifically, sexual practices involving rimming (oral/anal contact) and fisting (insertion of a hand or foot into a partner's rectum) were more commonly practiced among homosexual/bisexual men who developed AIDS-associated KS.

There has been a steady decline in the incidence of KS since the mid-1980s ( Table 1). In 1992, it was reported that only 10% of all patients with AIDS had KS. Since the beginning of the epidemic, the overall incidence of AIDS-associated KS is 13%[22]. Recent changes in the definition of AIDS-defining conditions will help reduce the ratio of AIDS-associated KS. This trend has been the subject of several reviews and discussions [21,23]. One explanation may be the decreased use of unlabeled amyl nitrite, an inhalant recreational drug and a possible mitogen [22,24]. Other epidemiologic studies suggest that changes in certain sexual practices may account for the decreasing incidence of KS [25,26].

This steady decline in the incidence of AIDS-associated KS has been paralleled by a decrease in the incidence of seroconversion in homosexual men. Thus, it is believed that changes in the sexual behavior of homosexual/bisexual men and avoidance of high-risk behaviors for contracting HIV have been contributing factors.

AIDS-associated KS has been reported in the pediatric population, mostly in the form of lymphadenopathic KS, which is usually detected at autopsy [27,28]. Mucocutaneous KS has also been reported in children who developed HIV infection via blood transfusions [29,30].

In Africa, AIDS-associated KS appears to be transmitted by heterosexual contact and has an approximately equal incidence among men and women [31]. This is in contrast to the male predominance observed in all other populations, and a male-to-female ratio of approximately 8:1 for AIDS-associated KS in the United States.

Clinical Features

Four different types of KS are recognized: classic, endemic African, iatrogenic, and AIDS-associated. Classic KS usually manifests with reddish-purple macules, papules, plaques, or nodules. Lesions may coalesce to form large plaques and tumors that may produce fungating masses with ulceration. Lesions are frequently located on the lower extremities but may appear anywhere on the skin or mucous membranes. Older lesions become brown and may develop a verrucous and hyperkeratotic surface. The lesions are initially soft and spongy but later become hard and solid. Gastrointestinal lesions are often asymptomatic in classic KS and are usually detected only at autopsy. Nonpitting edema of the lower extremities may precede or follow tumor invasion into the superficial and deep lymphatic system. Lymph nodes and internal organs are rarely involved [18]. Classic KS usually runs a benign, protracted course. Rapid progression with involvement of internal organs is rarely reported.

Clinical forms of African KS have been described as nodular, florid, infiltrative, and lymphadenopathic ( Table 2). This classification is based on the clinicopathologic presentation of the disease. The lymphadenopathic form is usually seen in African children and young adults. It manifests mainly with involvement of the lymph nodes and has a rapidly fatal course.

Among recipients of transplants, KS is the second most common tumor after lymphoma. It has been reported to occur more often in patients who receive cyclosporine (Sandimmune) as part of their immunosuppressive regimen [32]. The mean duration of cyclosporine therapy before the development of KS is 23 months [32,33]. In iatrogenic KS, cutaneous involvement is most common; however, lymphatic and visceral dissemination can occur. The disease runs a clinical course similar to that of classic KS, but, in some cases, the course may be more aggressive. Resolution of the disease has been reported after withdrawal or reduction of immunosuppressive therapy [34].

The clinical presentation of AIDS-associated KS is markedly different from that of other forms of the disease. AIDS-associated KS is characterized by a multifocal, widespread distribution that may involve any location on the skin or mucous membranes, as well as the lymph nodes, gastrointestinal tract, and other visceral organs [35,36]. There is considerable variability in the timing of the initial development of KS in HIV-infected individuals. We have seen patients with AIDS-associated KS who lacked evidence of immune impairment [35-37]. KS may be the first sign of HIV infection, especially in populations where HIV testing is not routinely performed. It can also arise in the later stages of HIV infection, even up until the last week of life, when patients are suffering from severe immune deficiency and various opportunistic infections [37].

Early lesions appear as pink to red macules or tense, purple papules. The lesions appear mostly on the face, especially the nose, eyelids, and ears, and on the trunk. The lower extremities may also be involved. The lesions may progress to form plaques, nodules, and tumors, which may eventually erode and ulcerate. The oral mucosa may be involved, with KS lesions appearing on the palate, gingiva, epipharynx, and larynx. Oral cavity involvement is seen in 10% to 15% of patients with AIDS-associated KS. Considerable discomfort and difficulty in eating and swallowing may be caused by oral KS lesions.

Extracutaneous KS is observed at almost every internal site, including the gastrointestinal tract, lymph nodes, and lungs. Both the gastrointestinal tract and lymph nodes may be the initial and/or exclusive site of KS lesions [38-40]. KS lesions are most commonly found in the stomach and duodenum. The lesions are frequently symptomatic, with patients experiencing nausea, ulcerating, bleeding, and ileus. They are localized mostly in the submucosa and are readily visible by gastroscopy, although they are underdiagnosed by superficial biopsy.

Patients with pulmonary KS often present with symptoms quite similar to those of PCP, such as intractable cough and respiratory insufficiency [41-43]. Accurate diagnosis is achieved by bronchoscopy, bronchoalveolar lavage, and bronchial biopsy. The prognosis of pulmonary KS is poor, even with aggressive systemic chemotherapy and radiation therapy [41-43]. Involvement of bone, subcutaneous tissues and skeletal muscle, bone marrow, peritoneal cavity and omentum, and the heart is rarely reported [44-49].