Up-to-Date Epidemiological Data and Better Treatment for Kaposi's Sarcoma

Kaposi's sarcoma is an angioproliferative disease which is originated from endothelial cells, myofibroblasts and monocyte-macrophage cells. It is characterized by endothelium-lined vascular spaces and spindle-shaped cells. Classical Kaposi's sarcoma affects elderly men of a Mediterranean origin. Endemic Kaposi's sarcoma occurs in younger men from sub-Saharan Africa. Epidemic Kaposi's sarcoma is the form described in AIDS patients. Lastly, posttransplant Kaposi's sarcoma arises in organ recipients. In a recent paper (1), and in the work published in this issue of Transplantation (2), Serraino et al. report a very large epidemiological study in 10,779 HIV or organ-transplant patients, providing new insights into our knowledge of the risk for Kaposi's sarcoma. Epidemiological evidence suggested that Kaposi's sarcoma is caused by HHV8, the virus identified in 1994. HHV8, which is found in all forms of Kaposi's sarcoma, is considered to be its causative agent, albeit not sufficient per se. Serological characterization of HHV8 can be done by recognition of viral antigens either of the latent phase or of the lytic phase using indirect immunofluorescence, or by ELISA methods. Various in-house and commercial assays use synthetic peptides to whole virus lysates. Unfortunately, the lack of standardization may jeopardize results obtained by these serological techniques. DNA-based methods could be preferred, although tedious for epidemiological studies. HHV8 produces a receptor that promotes the proliferation of endothelial cells via the activation of Flk-1/KDR, one of the VEGF receptors. Calcineurin inhibitors increase the production of VEGF, whereas sirolimus impairs VEGF production and reduces the proliferative response of endothelial cells to VEGF. VEGF pathway might be a key target of the differential action of immunosuppressants on Kaposi's sarcoma development. The prevalence of anti-HHV8 antibodies in the general population greatly varies between geographic areas. The prevalence is less than 5% in the United States, most countries in Europe, South America, and Asia. Italy and Israel are two countries with a higher prevalence, around 12%. Very high figures are seen in Africa, between 30% and 50%. Some countries are characterized by a northern-to-southern gradient, such as Italy. Similarly, seroprevalence reported in transplant recipients varies between 6% and 15%. HHV8 prevalence is nearly 100% among HIV-infected patients with Kaposi's sarcoma, over 50% in patients without. In transplant patients, Kaposi's sarcoma is mainly due to reactivation of the virus. Transmission by the allograft has been documented, but seems less frequent. A recent prospective survey conducted in France by C. Frances discovered an HHV8 seroprevalence of 1% among 3,694 donors. These grafts led to Kaposi's sarcoma in 4% of kidney recipients, 33% of heart recipients and 42% of liver recipients. HHV8 primo infection can be severe with fever, pancytopenia, and hemophagocytosis. An early epidemiological study published by A.R. Harwood in 1979 suggested that the incidence of Kaposi's sarcoma was increased 500-fold over a matched controlled population. The prevalence of Kaposi's sarcoma after transplantation was mainly known from the registry hold by I. Penn. After collecting 356 allograft recipients with a Kaposi's sarcoma. in 1997 I. Penn published a higher incidence in kidney recipients than in heart or liver recipients, a vast majority of them being of Arabic, African, Italian, Jewish, or Greek ancestry. On the contrary, no increased risk of Kaposi's sarcoma has been reported in transplant patients from Japan or the Nordic countries. Where the prevalence of posttransplant Kaposi's sarcoma is low, most patients come from abroad, mainly from the Mediterranean, African, and Caribbean countries, where sporadic and endemic Kaposi's sarcoma is common. Prevalence of transplant patients with Kaposi's sarcoma can be classified as low (<0.5%) in United States, Canada, Australia, and most of Europe; but high (between 1.5% and 4%) in Italy, Israel, and Saudi Arabia. Last year, Kasiske et al. reported the rate of malignancies among 35,765 kidney recipients: the age-adjusted rate for Kaposi's sarcoma was higher than in the general population, especially in the first year and in women; and relative risk was ninefold increased compared to patients on the waiting list (3). Serraino et al. (2) conducted a large investigation in 8,074 HIV patients from France and Italy using national databases, and 2,705 organ recipients from northern and central Italy. Incidence rates for Kaposi's sarcoma were 7.22/105 and 1.79/105 in HIV and transplant patients, respectively. With access to population-based cancer registries, they calculated standardized incidence ratios (SIRs). A 451-fold higher SIR was recorded in HIV patients, largely exceeding a 128-fold higher SIR in transplant recipients. Geographical differences were confirmed, such as between French and Italian people, or within Italian people. In contrast with previous reports, the authors found a higher incidence in men and in liver recipients. The level of immunosuppression seemed of importance, as assessed by CD4 cells count and might be extrapolated from HIV to transplant patients. In HIV-infected patients, two different approaches should be used (4). The first one is to give anti-HHV8 agents: alitretinoide gel for topical administration and pegylated liposomal doxorubicin, liposomal daunorubicin, paclitaxel, or interferon-alpha for systemic administration. The concomitant treatment is to give highly active antiretroviral therapy which has been shown to decrease the proportion of new Kaposi's sarcoma cases and to reduce the size and number of existing Kaposi's sarcoma lesions. Of note, Serraino et al. (2) report a drastic reduction of the cumulative probability of developing Kaposi's sarcoma in HIV patients submitted to highly active antiretroviral therapy. Lastly, successes obtained with rituximab in Castleman disease suggest that rituximab could help to control diseases with HHV8 viremia. To what extent data from HIV patients could be extrapolated to transplant recipients remains unknown. Treatment of Kaposi's sarcoma in transplant patients is far from being well established. The consensus is to taper immunosuppressive drugs to the lowest level. This is often sufficient but exposes to a high risk of allograft rejection. Moreover, Kaposi's sarcoma usually recurs after reintroduction of immunosuppressants. Antiviral drugs such as ganciclovir, foscarvir, and cidofovir, have some activity on HHV8 in vitro, but lack sufficient demonstration in vivo. Local treatments such as cryotherapy or radiotherapy could be considered for localized lesions, but they may hamper an appropriate dermatological follow-up. A totally new approach was recently proposed with the use of sirolimus. Campistol (5) and Stallone (6) converted kidney-transplant recipients from cyclosporine to sirolimus in 5 and 15 patients, respectively. This resulted in a complete disappearance of all cutaneous lesions in all patients within 3 months, without provoking acute rejection episodes. Kaposi's sarcoma has revealed some of its mysteries. Knowledge of its causative agent and better epidemiological figures will help managing the disease. Anti-HHV8 topical or systemic agents and conversion to sirolimus might improve its treatment in transplant patients.

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