The recent series of 28 cases of HIV-negative Kaposi's sarcoma in homo/bisexual men reported by Lanternier et al. , as well as the subsequent editorial comment by Colman and Blackbourn , highlights the strong contribution of cofactors to the development of this malignancy. The primary cause of Kaposi's sarcoma is infection with Kaposi's sarcoma associated herpesvirus (KSHV, also known as human herpesvirus 8), but the vast majority of KSHV-infected people do not develop Kaposi's sarcoma. We estimated that the annual incidence of classic Kaposi's sarcoma (cKS) is about 30/100 000 KSHV-seropositive Mediterranean men over 50 years of age, or approximately 0.3% over 10 years . In contrast, the annual incidence of AIDS Kaposi's sarcoma was about 3/100 in untreated HIV-infected KSHV-seropositive homosexual men, or about 30% over 10 years . This illustrates that HIV is a very potent cofactor, increasing the risk of Kaposi's sarcoma by approximately 100-fold.
There must be cofactors for non-AIDS Kaposi's sarcoma. During 2002–2006, my colleagues and I conducted a case–control study of cKS that encompassed the entire island of Sicily. As in our previous case–control study of cKS , the risk of cKS was three-fold lower among KSHV-seropositive people who had ever smoked at least one cigarette per week . Moreover, the risk was even lower (five-fold) among current smokers and intermediate (two-fold) among former smokers. A significantly reduced risk of AIDS Kaposi's sarcoma with smoking was noted in two cohorts of HIV-infected homosexual men in the United States [7,8]. Neither Lanternier et al.  nor Colman and Blackbourn  mention nonsmoking.
In a study by Lanternier et al. , one of the 28 non-AIDS Kaposi's sarcoma (presumptively cKS) patients was noted to have used corticosteroids for asthma. Systematically collected data on medications would be helpful, as the risk of cKS was increased more than two-fold with asthma in our earlier study  and with corticosteroid use in both studies [5,6].
Diabetes mellitus may also prove to be a cofactor. Four (14%) of the 28 non-AIDS Kaposi's sarcoma patients were noted to have diabetes, although the expected prevalence in this population is unknown . The risk of cKS was increased four-fold with diabetes in our recent study , but this was not seen in the previous study .
Finally, inherited susceptibility surely contributes to the development of Kaposi's sarcoma among people who have been infected with KSHV. In addition to HLA, as mentioned by Colman and Blackbourn , other genes that regulate innate immunity and cytokine balance could be equally important [9,10].
Identification of cofactors can lead to useful interventions to complement drugs directed against KSHV lytic replication . The ultimate goal is not cKS, because the absolute risk is very low , but rather to reduce the very serious morbidity and mortality from Kaposi's sarcoma in Africa [12,13]. Neither I nor anyone would recommend smoking to reduce the risk of Kaposi's sarcoma. Instead, understanding the mechanism that underlies this epidemiologic association could lead to an effective prophylactic or treatment. Nicotine probably will not fulfill this function . Something else will.
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