Malignancies have been detected in approximately 40% of all patients with acquired immunodeficiency syndrome (AIDS) sometime during the course of their illness. These cancers have been both a primary cause of death in some patients and also a source of considerable morbidity. In the current era of highly active antiretroviral therapy (HAART), patients infected with the human immunodeficiency virus (HIV) are surviving longer than ever. HAART appears to have substantially reduced the incidence of, and mortality from, Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) and may enhance the efficacy of treatment for those patients who do develop these tumors. Unfortunately, HAART has not shown a similar effect on the development of other types of neoplasms, and caring for patients who develop malignancies in the setting of HIV remains a challenge. Furthermore, HAART is not available universally, with many patients in resource-poor developing countries not having access to antiretroviral drugs.
Kaposi sarcoma (KS) has been the most common tumor associated with HIV infection, but it currently develops in < 10% of homosexual men with AIDS in the United States and in 1% to 2% of other HIV-infected persons. The incidence of KS has declined substantially, from 4.8 per 100 person-years in 1990 to 1.5 per 100 person-years in 1997. In 2003, a European study found that the incidence of KS among HIV-infected individuals was less than 10% of the incidence seen a decade earlier in 1994.
Among AIDS patients in the United States, the incidence of KS is higher in males than in females. There is also a higher incidence of KS in men than in women in Africa (male-female ratio, 2:1), despite the equal prevalence of HIV infection among men and women.
The age distribution of AIDS-related KS follows the distribution of HIV infection. As such, AIDS-related KS can occur in all age groups. In American adult males, the most common age at onset of AIDS-related KS is 30 to 40 years. No peak age has been reported.
No racial or ethnic differences in the incidence of AIDS-related KS have been observed.
In the United States, KS is seen in < 10% of homosexual men with AIDS. The proportion of KS among AIDS-defining diagnoses is lower in parts of Europe, where there are proportionately fewer male homosexual AIDS cases (eg, 6.8% of Italian AIDS patients), and higher in parts of Africa, where KS is endemic in the non–HIV-infected population. Among AIDS cases in the United States, the proportion of patients with KS has declined from the beginning of the AIDS epidemic, possibly as a result of changes in high-risk sexual behavior among homosexual men and the wider use of more effective antiretroviral combination regimens.
In 1994, unique viral DNA sequences were identified in tumor tissues from patients with AIDS-related KS, which led to the identification of a new virus called human herpesvirus type 8 (HHV-8). HHV-8 has been identified in > 90% of AIDS-KS tumors, as well as in classic KS, endemic African KS, and post–organ transplant-related KS. It has also been identified in body cavity–based lymphoma/primary effusion lymphoma, multicentric Castleman's disease, and angio-immunoblastic lymphadenopathy with dysproteinemia in HIV-infected patients.
HHV-8 may be transmitted through sexual contact, blood products, or organ transplantation. The seroprevalence of HHV-8 in AIDS-related KS is nearly 100%. HHV-8 has been found in high concentration in the saliva of patients with KS.
HHV-8 is critical in the pathogenesis of AIDS-related KS. The mechanism by which HHV-8 induces KS in susceptible individuals is the subject of intense current investigations.
Environmental and host factors
Various environmental and host factors, including HIV- and HHV-8–induced cytokines, AIDS-associated infections, the host's hormonal milieu, immunosuppression, and antiretroviral therapy, may induce or suppress the development of KS and alter its growth.
The manifestations of KS in patients with AIDS are variable and range from small, innocuous-looking cutaneous lesions to symptom-producing visceral or oral lesions, which may be troublesome and even life-threatening. Although KS occasionally may involve just about every internal organ, it is rarely seen in the bone marrow or central nervous system (CNS).
KS tumors typically begin as flat or raised lesions that may progress to plaque-like or nodular tumors. Lesions vary in size and shape but are generally nonpruritic and painless. They range in color from light pink to red to deep purple. KS lesions may be cosmetically disfiguring and may result in social stigmatization that far exceeds any actual physical impairment.
Dermal and lymphatic infiltration
Involvement of the skin and lymph glands with tumor can result in edema of the extremities, periorbital areas, and genitals and may be complicated by skin breakdown and bacterial cellulitis. Edema can be marked and may prevent patients from wearing shoes and/or walking.
Lesions on the feet can cause pain and hamper walking.
These are often asymptomatic but can produce pain and swallowing difficulties.
GI tract involvement
KS involves the GI tract in up to 50% of patients. Most lesions are asymptomatic; however, obstruction, bleeding, or enteropathy can occur occasionally.
Lung involvement usually presents as dyspnea without fever and may become severely debilitating and rapidly fatal if untreated.
Currently, there are no screening tests for KS. Although most KS lesions are readily recognized, early lesions may be difficult to diagnose, and the lesions of other diseases (eg, bacillary angiomatosis) may mimic those of KS. Once clinically suspected, the diagnosis of KS is made by biopsy and histologic examination of skin lesions, an excised lymph node, or other tissue or by presumptive diagnosis based on the bronchoscopic or endoscopic appearance of a visceral lesion. Staining for HHV-8 antigen in a biopsy specimen can confirm diagnosis of KS.
Gastrointestinal (GI) KS
These lesions have a typical red, raised appearance and are difficult to diagnose by biopsy because many of them have a submucosal location.
In patients with pulmonary KS, chest radiographs typically demonstrate diffuse, reticular-nodular infiltrates, mediastinal enlargement, and, sometimes, pleural effusion. Bronchoscopy may reveal extensive endobronchial involvement with tumor. Definitive diagnosis requires transbronchial or open-lung biopsy. Transbronchial biopsies, however, often yield negative results. A presumptive diagnosis of pulmonary KS may be made, in the absence of fever, based on typical radiographic and endobronchial findings of KS-appearing lesions and after the exclusion of infections.
Thallium and technetium-99m scanning may help differentiate KS from other pulmonary diseases. Patients with KS have been found to have thallium- and technetium-avid scans, whereas pulmonary lymphomas and infections are more typically gallium-avid.
Cutaneous KS is a lesion of the dermis composed of a proliferation of aberrant vascular structures lined by abnormal-appearing, spindle-shaped endothelial cells and with extravasated erythrocytes and leukocytes within the structures. These spindle cells are generally sparse in early stages but become more numerous and "stack up" between the vascular structures as the tumor advances. Infiltration of mononuclear leukocytes, including plasma cells, T cells, and monocytes, is more prominent in earlier lesions. The histologic appearance of KS in AIDS patients is similar to that seen in non–HIV-infected patients.
Cell of origin
The KS tumor cell is believed to be of mesenchymal, endothelial origin. Several endothelial cell markers are positive in KS, including stains for CD31, CD34, and EN-4. In addition, the tumor stains with factor VIIIa, CD68, and alpha-actin but not with pathologische anatomie leiden endothelium (PAL-E).
Although it is difficult to predict from the initial presentation which patients are most likely to have rapidly progressive tumors, several retrospective studies have shown a correlation of survival with the degree of T-cell immunodeficiency, as reflected in the absolute number of T-helper cells in blood. Prior opportunistic infections or the presence of such symptoms as fevers, night sweats, and weight loss (B symptoms) also portend a poor prognosis. Patients who develop KS or whose tumor growth accelerates after an opportunistic infection often have a more aggressive clinical course. Patients with pulmonary involvement generally have a poor prognosis.
A tumor classification system has been proposed for AIDS-related KS by the oncology committee of the ACTG. This system segregates patients into good or poor prognostic groups based on tumor characteristics, immune system function, and systemic illness (the TIS system; see Table 1). A retrospective analysis of 294 patients with AIDS-related KS has shown that the TIS system is a valid predictor for survival.