Background and Causative Agent
Kaposi's sarcoma is a vascular tumor that manifests as nodular lesions on the skin and, to a lesser extent, visceral organs. Kaposi's sarcoma is the most common neoplasm encountered in HIV-infected patients, and disproportionately involves men who have sex with men.[,] Development of Kaposi's sarcoma is an AIDS-defining condition. Prior to the AIDS epidemic, reports existed of Kaposi's sarcoma occurring in elderly Mediterranean men and African children, but modern cases almost always involve HIV-infected individuals. In 1994, researchers discovered a novel herpesvirus in Kaposi's sarcoma biopsy tissues taken from patients with AIDS and named this Kaposi's sarcoma-associated herpesvirus (KSHV). This newly identified pathogen was subsequently classified as a gammaherpesvirus and thereafter commonly referred to as human herpesvirus type 8 (HHV-8). Additional epidemiologic studies strengthened the link between HHV-8 and Kaposi's sarcoma and further work established that HHV-8 infection precedes the development of Kaposi's sarcoma lesions.[,] Investigators also later identified HHV-8 as the cause of two uncommon lymphoproliferative disorders: primary-effusion lymphoma and multicentric Castleman's Disease.
The exact mechanism regarding HHV-8 transmission remains unclear and various lines of data indicate possible sexual, horizontal, and parenteral transmission. Studies involving men who have sex with men reported more frequent isolation (and at higher titers) of HHV-8 from saliva than from anal or genital secretions. Specifically, 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. Other investigators have isolated HHV-8 in oral epithelial cells in HIV-infected persons and found that HHV-8 shedding occurred independent of the patient's immune status.
The term Kaposi's sarcoma is somewhat of a misnomer since this term implies similarity with traditional mesenchymal tumors, but Kaposi's sarcoma differs from classical cancers in many respects. Most notably, Kaposi's sarcoma displays a diversity of cell types that contrast sharply with the uniform and monotonous outgrowth of a solitary cell type seen in most cancers. In addition, early lesions generate profound angiogenesis prior to the development of a mass lesion, whereas classic cancers stimulate angiogenesis after tumor proliferation has caused outgrowth of the tissue vascular supply. Further, the dominant cell in the Kaposi's lesions, the spindle cell, has several characteristic that differ from most cancer cells, including lack of full transformation, inability to maintain autonomous growth, lack of clonality, and dependence on exogenous cytokines for in vitro growth.[,] Overall, the development of Kaposi's sarcoma is highly complex and involves the combination of three parallel processes: proliferation (primarily of spindle cells), inflammation, and angiogenesis. The virus HHV-8 encodes multiple proteins that play a role in the pathogenic process, including viral cyclin, viral interferon regulatory factor, latency-associated nuclear antigen, viral Bcl-2, viral FLICE inhibitory protein, and viral interleukin-6 (Figure 1). These factors can inhibit normal checks on cell proliferation and apoptosis, and stimulate secretion of multiple human factors that can impact cell growth, including vascular endothelial growth factor, platelet derived growth factor, angiopoietin 2, interleukin-6, and interleukin-8.[,] The coinfection with HHV-8 and HIV has synergistic impact on the development of Kaposi's sarcoma lesions. The exact manner by which HIV infection facilitates HHV-8-induced tumorigenesis remains unclear, but may relate to enhanced growth stimulated by the HIV tat protein or to increased secretion of local levels of cytokines and interferons induced by HIV-infected cells.
Clinical Cutaneous Manifestations
Dermal Kaposi's sarcoma has a highly variable clinical course, ranging from isolated indolent, asymptomatic lesions to explosive growth of lesions that may cause major morbidity. Dermal Kaposi sarcoma characteristically develops in three stages: patch, plaque, and nodular. The initial patch stage lesions appear as flat, red dermal lesions that have abundant inflammatory cells evident on histology. The lesions typically progress to the second phase, the plaque stage, and appear indurated, with an erythematous or violaceous color. Progression to the third stage, the nodular stage, is characterized by visible masses that show a dominance of spindle cells on histology. Patients with cutaneous Kaposi's sarcoma lesions unfortunately often have multifocal lesions at the time of initial clinical diagnosis. Dermal Kaposi's sarcoma can appear anywhere on the body, but often involves the head and neck region (Figure 2), trunk (Figure 3), and oral cavity (Figure 4). 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.
Although Kaposi's sarcoma most often involves the dermis or oral cavity, some patients can have extracutaneous involvement, either in conjunction with cutaneous lesions, or, less commonly, without any obvious cutaneous involvement. Extracutaneous lesions most often occur as gastrointestinal, pulmonary, or lymphatic Kaposi's sarcoma. For patients who initially present with dermal Kaposi's sarcoma, some experts recommend performing a staging computed tomography (CT) of the chest and abdomen to look for occult visceral involvement. If symptoms or CT findings suggest pulmonary or gastrointestinal involvement, bronchoscopy or endoscopy is warranted to confirm the diagnosis. Pulmonary disease can manifest as obstructive endobronchial lesions, parenchymal lesions, and pleural effusions (often bilateral and sometimes bloody), whereas gastrointestinal complications most often involve invasion of the intestinal mucosa with potential bleeding. Lymphatic Kaposi's sarcoma can result in localized obstruction and edema of the affected region, including the extremities (Figure 5), genitalia (Figure 6), or periorbital region. The lymphatic obstruction increases the patient's risk of developing cellulitis in the involved region.
Staging of Disease
In 1989, the ACTG Oncology Committee proposed a Kaposi's sarcoma staging system that incorporated extent of tumor involvement, the patient's immune status, and the patient's overall clinical status (based on performance status and presence of other AIDS-related diseases). This ACTG system stratifies patients based on good risk (0) or poor risk (1) for three categories: tumor (T), immune system (I), and systemic illness (S). A prospective assessment of this staging system in the HAART era found poor predictive value in the immune system category, but the tumor and systemic illness categories had prognostic value. Specifically, the combination of poor tumor stage and poor systemic illness risk (T1S1) correlated with an unfavorable prognosis: patients with T1S1 had a 3-year survival rate of only 53%, compared with a survival rate of 81% with T0S1, 81% for T1S0, and 88% for T0S0. In addition to staging the patient's Kaposi's sarcoma, it is important to determine the patient's past and current antiretroviral therapy history.
General Approach to Treatment
The specific treatment for Kaposi's sarcoma is highly dependent on the nature and extent of lesions and areas of body involvement. In general, all patients with Kaposi's sarcoma should receive potent, fully suppressive antiretroviral therapy. For most patients diagnosed with Kaposi's sarcoma who are not already taking antiretroviral therapy and do not have obvious systemic involvement, it is reasonable to initiate potent antiretroviral therapy and observe for regression of lesions before beginning Kaposi's sarcoma-specific treatment. Although potent antiretroviral therapy (with or without local therapy) often adequately treats patients with localized cutaneous Kaposi's sarcoma, systemic treatment may be indicated, especially with extensive cutaneous involvement or cutaneous involvement associated with significant localized edema. In addition, patients who have visceral or lymphatic involvement generally require prompt initiation of systemic therapy. Uncomplicated, limited dermal Kaposi's sarcoma that does not improve after 3 to 4 months of antiretroviral therapy typically requires local treatment, particularly for symptomatic or cosmetically bothersome lesions. The goals of treatment for dermal Kaposi's are to improve cosmetic appearance, provide relief of pain, and diminish the number and size of symptomatic lesions.
The widespread use of potent antiretroviral therapy has led to a marked reduction in the incidence of Kaposi's sarcoma.[,,,] In addition, multiple groups have reported improvement or regression of Kaposi's sarcoma lesions following the use of potent antiretroviral therapy.[,,] Patients with Kaposi's sarcoma who have tumor regression with antiretroviral therapy appear to have a long-term response. The favorable impact of antiretroviral therapy on Kaposi's sarcoma likely results from multiple factors, including inhibition of HIV replication, decreased production of HIV-1 transactivating protein, and enhancement of the immune response against HHV-8. In addition, in vitro data suggest that HIV protease inhibitors have a direct anti-angiogenic effect on HHV-8, but studies comparing the use of protease inhibitor-based regimens with non-nucleoside reverse transcriptase inhibitor-based regimen have not shown differences in prevention[,] or treatment responses for Kaposi' sarcoma.[,] Although antiretroviral therapy benefits most patients with Kaposi's sarcoma, a subset of patients have a significant flare in the Kaposi's sarcoma after starting antiretroviral therapy, as a result of immune reconstitution inflammatory syndrome (IRIS). The onset of IRIS may occur as early three weeks after starting antiretroviral therapy and usually develops within 2 months. In some instances this can lead to a dramatic clinical deterioration and deaths have been reported, particularly with flares of pulmonary Kaposi's sarcoma. The treatment of patients with severe Kaposi's sarcoma IRIS usually requires initiating systemic cytotoxic chemotherapy and ideally continuing antiretroviral therapy, but given that the management of patients is highly complex, expert consultation should be obtained.
Kaposi's sarcoma local therapy treatment options include excisional surgery, liquid nitrogen cryotherapy, topically-applied therapy, intralesional chemotherapy, photodynamic therapy, 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. Cryotherapy with liquid nitrogen can be used successfully for most localized cutaneous lesions, with a complete response rate of 80% and a duration of response of longer than 6 weeks. 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. Incremental dosages are used according to the size of the lesion. The topical retinoic acid preparation alitretinoin 0.1% gel (Panretin) is the only self-administered FDA-approved treatment for cutaneous Kaposi's sarcoma. Large tumor masses are generally better managed by radiation therapy than localized therapy.[,] Photodynamic therapy is an experimental approach that involves light activation of a photosensitive drug that accumulates at a high concentration in the Kaposi's lesions. Patients with widespread cutaneous lesion, but without visceral or lymphatic involvement, often require systemic chemotherapy, but, in some instances, topical alitretinoin gel can be considered as an alternative.
Systemic Cytotoxic Chemotherapy
Systemic cytotoxic chemotherapy is warranted in patients with visceral involvement, extensive lymphatic involvement, widespread dermal disease (more than 20 lesions), and with rapidly advancing disease. Cytotoxic chemotherapy should only be administered by a medical provider qualified and experienced in prescribing chemotherapy. For patients with advanced Kaposi's sarcoma, the liposomal anthracyclines—pegylated liposomal doxorubicin(Doxil, Dox-SL, Evacet, and LipoDox) or liposomal doxorubicin (Caelyx, Myocet)—are now established as the preferred therapy. Randomized trials have shown pegylated liposomal doxorubicin has better response rates than the more toxic three drug regimen of doxorubicin (Adriamycin), bleomycin (Blenoxane), and vincristine (Oncovin) or the two-drug regimen consisting of bleomycin and vincristine. The liposomal doxorubicin and pegylated doxorubicin preparations have a much lower incidence of cardiomyopathy than the older non-liposomal anthracyclines. The taxane drug paclitaxel (Taxol) has produced high clinical response rates in patients with Kaposi's sarcoma[,], but is hampered by multiple side effects, including allergic reactions, alopecia, myalgias, and bone marrow suppression. Similarly, docetaxel (Taxotere) has shown promise as effective therapy, even in patients who have failed paclitaxel, but severe neutropenia frequently occurred. The predominant role of the taxanes in the treatment of Kaposi's sarcoma is for patients who have progressive disease despite receiving antiretroviral therapy and liposomal anthracycline therapy.
In the early years of the AIDS epidemic interferon alfa (Roferon or Intron-A) was commonly used to treat advanced Kaposi's sarcoma. Responses to interferon preparations are better in patients who have a CD4 count greater than 200 cells/mm3 and those with asymptomatic HIV disease. An AIDS Clinical Trials Group study that investigated didanosine (Videx) combined with either low dose (1 million units/day) or high dose (10 million units/day) interferon alpha, reported that patients in the low-dose group had a response rate of 40% versus 56% in the high-dose group. In a similar study involving zidovudine (Retrovir) combined with either 1 or 8 million units/day of interferon alfa, patients in the high dose group had a significantly better response rate than those in the low dose group (31% versus 8%). In a subsequent study, investigators compared pegylated liposomal doxorubicin with interferon alfa and patients who received pegylated liposomal doxorubicin clearly had better response rates and lower adverse effects.
Antiviral Medications and Molecular Targeted Agents
Several antiviral compounds, including foscarnet (Foscavir), ganciclovir (Cytovene), and cidofovir (Vistide), have in vitro activity against HHV-8; these antiviral agents, however, are unlikely to provide clinical activity for Kaposi's sarcoma since they inhibit lytic rather than latent viral replication (most spindle cells are latently infected with HHV-8. Theoretically, antiviral agents are more likely to have benefit as preventive therapy, but this strategy has not been widely used, primarily because of medication toxicity. Specific molecular targeted agents under investigation for Kaposi's sarcoma include angiogenesis inhibitors[,] tyrosine kinase inhibitors, and matrix metalloproteinase inhibitors. These molecular targeted therapies are considered investigational for the use of treatment of Kaposi's sarcoma.