Case 3: Discussion

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Background and Causative Agent

Kaposi's sarcoma is a vascular tumor that manifests as nodular lesions primarily on the skin and, to a lesser extent, visceral organs. It is the most common neoplasm encountered in patients infected with HIV, and disproportionately occurs more frequently among HIV-infected men who have sex with men. Although Kaposi's sarcoma was first described prior to the AIDS epidemic among Mediterranean and African persons, current cases almost always involve HIV-infected individuals [1]. Development of Kaposi's sarcoma is an AIDS-defining condition [2]. In 1994, investigators identified a novel herpesvirus in Kaposi's sarcoma tumors from HIV-infected individuals; this virus was named human herpesvirus type 8 (HHV-8) and is now known also as Kaposi's sarcoma-associated herpesvirus (KSHV) [3]. Further research revealed infection with HHV-8 precedes the development of Kaposi's sarcoma lesions [4]. Rarely, Kaposi's sarcoma can be seen in individuals infected with HHV-8 but not with HIV, further supporting the hypothesis that HHV-8 causes Kaposi's sarcoma. In addition, HHV-8 has been associated with two rare malignancies that can occur in HIV-infected individuals: primary-effusion lymphoma [5] and multicentric Castleman's Disease [6].

Transmission

The exact mechanism regarding HHV-8 transmission remains unclear. Early epidemiologic work suggested a sexual mode for HHV-8 transmission. Recently, however, investigators reported more frequent isolation (and at higher titers) of HHV-8 from saliva than from anal or genital secretions in men who had sex with other men [7]. Specifically, the study found that among men seropositive for HHV-8, 30% had an oropharyngeal mucosal sample positive for HHV-8, compared with only 1% positive from anal and genital samples. The same authors identified deep kissing with an HIV-infected partner and use of amyl nitrite capsules as risk factors for transmission.

Pathogenesis

The development of Kaposi's sarcoma lesions involves HHV-8-induced hyperproliferation of spindle cells and local vasculature [8]. The exact manner by which HIV infection allows for HHV-8 induced tumorigenesis remains unclear, though an HIV gene product, the tat protein, has been implicated as modulating Kaposi's sarcoma growth. Similarly, the exact mechanism by which oncogenic transformation of spindle cells occurs is not entirely clear and appears to involve multiple factors, including oncogene activation and/or increased secretion of cytokines and chemokines by infected cells (Figure 1) [1]. In addition, it appears that these chemokines enhance angiogenesis and inhibit the immune type 1 helper T response resulting in vascular hyperproliferation [1].

Clinical Manifestations

Kaposi's sarcoma may present in several forms and the clinical course of Kaposi's sarcoma is variable, ranging from isolated indolent, asymptomatic cutaneous lesions to rapidly progressive, fatal systemic involvement. The initial manifestation typically consists of violaceous skin lesions, but visceral forms, such as nodal, gastrointestinal, or pulmonary Kaposi's sarcoma, may precede cutaneous lesions. Cutaneous Kaposi's sarcoma lesions are often multifocal at the time of initial diagnosis, and commonly involve the head and neck region (Figure 2), trunk (Figure 3), and mucous membranes, such as the palate (Figure 4). The lesions are typically poorly demarcated, flat or slightly raised, red or purple papules that can progress to form more clearly circumscribed plaques or nodules. Skin biopsy is recommended to distinguish suspected Kaposi's sarcoma from other cutaneous lesions that can have a similar appearance, such as bacillary angiomatosis, atypical mycobacterial infection, fungal infection, or dermatofibromas. The lymphatic system, the gastrointestinal tract, and the lungs are the most common sites of visceral Kaposi's sarcoma involvement. Pulmonary disease can result in pleural effusions, often bilateral and sometimes bloody. Symptoms associated with visceral involvement may include dyspnea from pulmonary lesions, whereas gastrointestinal involvement can result in cramping pain, diarrhea, or gastrointestinal bleeding [9]. Lymphatic involvement can result in localized obstruction and edema of the affected region, including the edema of the extremities (Figure 5), genitalia (Figure 6), or periorbital region. The lymphatic obstruction may lead to recurrent cellulitis.

Therapy

Treatment of Kaposi's sarcoma is highly individualized and depends on many factors, including the extent and nature of the lesions, co-morbidities, the patient's ability to take antiretroviral therapy for HIV, and their overall AIDS-related prognosis. In general, treatment is indicated for symptomatic or cosmetically bothersome lesions. The goals of therapy for Kaposi's sarcoma are improvement of cosmetic appearance, pain relief, and diminution of symptomatic lesions. Although most patients with only cutaneous Kaposi's sarcoma can be effectively treated with local therapy, systemic treatment is sometimes indicated, especially with concomitant visceral involvement. For patients who present with cutaneous lesions, some experts recommend performing a staging CT of the chest and abdomen to look for occult visceral involvement. If symptoms or CT findings suggest pulmonary or gastrointestinal involvement, bronchoscopy and/or endoscopy are warranted to confirm the diagnosis. Effective antiretroviral therapy can often improve both systemic and localized Kaposi's sarcoma, apparently via immune reconstitution [10-12]. Thus, for most patients diagnosed with Kaposi's sarcoma who are not already on antiretroviral therapy and do not have obvious systemic involvement, it is reasonable to initiate HAART and observe for regression of lesions before beginning Kaposi's sarcoma-specific treatment.

Cutaneous Kaposi's sarcoma lesions can be treated by liquid nitrogen cryotherapy, intralesional chemotherapy, radiation therapy, or a combination of these modalities. The choice of therapeutic options depends on the pattern of involvement in individual patients. Electron beam therapy, for example, can be a useful modality for treating Kaposi's sarcoma associated with periorbital edema, but is less useful for oral lesions due to the possibility of radiation-induced mucositis [13]. Cryotherapy with liquid nitrogen can be used successfully for most localized cutaneous lesions, with a complete and partial response rate of approximately 85% [14]. The cosmetic effect is usually very good, though Kaposi's sarcoma may persist in the dermis beneath the site of treatment. For nodular lesions greater than one centimeter in diameter and for symptomatic oral lesions, intralesional chemotherapy with vinblastine (Velban) is generally more effective than cryotherapy [15]. Incremental dosages are used according to the size of the lesion. The FDA has recently approved a topical retinoic acid preparation, alitretinoin (Panretin), for treatment of cutaneous Kaposi's sarcoma [16]. Large tumor masses, especially in the setting of palliative care, generally warrant radiation therapy [17,18]. Patients with widespread cutaneous lesions and/or visceral involvement generally require systemic chemotherapy and this should be performed by or in conjunction with an oncologist. Systemic therapies include interferon-alpha (Roferon or Intron-A), doxorubicin (Adriamycin), liposomal doxorubicin (Caelyx; Myocet), and paclitaxel (Taxol) [1,19,20].

Newer therapies for Kaposi's sarcoma include (1) oral and topical bexarotene (Targretin), a retinoid that is a selective retinoid X receptor that has been FDA-approved to treat cutaneous T-cell lymphoma and (2) COL-3, a tetracycline derivative that has properties as an angiogenesis inhibitor and specifically inhibits matrix metalloproteinases [21]. Multiple antiviral compounds, including foscarnet (Foscavir), ganciclovir (Cytovene), and cidofovir (Vistide), have activity against HHV-8 and one study suggested persons with cytomegalovirus retinitis who received ganciclovir therapy had a decreased likelihood of developing Kaposi's sarcoma [22]. Use of antiviral compounds to treat HHV-8 in patients with active Kaposi's sarcoma, however, is not likely to be effective.

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