Four of the 28 (14%) patients were being followed for type 2 diabetes mellitus at the time of Kaposi sarcoma diagnosis. One patient was treated with steroids for asthma. One patient was treated with methotrexate for rheumatoid arthritis, but this treatment was introduced after the diagnosis of Kaposi sarcoma.
Two patients had tuberculosis, at the same time as Kaposi sarcoma in one patient, and 31 years before the diagnosis of Kaposi sarcoma. The patient with concurrent tuberculosis and Kaposi sarcoma also had a spondylodiscitis and osteitis, with Staphylococcus aureus isolated from bone cultures. Two patients had a history of acute hepatitis A, and four other patients had a history of acute syphilis. Four patients developed neoplasia after Kaposi sarcoma diagnosis. One patient developed Castleman disease 7 years after the onset of the first Kaposi sarcoma symptoms. One patient developed Burkitt lymphoma 4 years after Kaposi sarcoma. Another developed follicular lymphoma 2 years after the onset of the first symptoms of Kaposi sarcoma and one patient had six basal cell carcinomas during the follow-up period after Kaposi sarcoma diagnosis.
None of our patients had CD4 lymphopenia; mean CD4 cell count was 920 [IQR: 649–1057; range: 485 – 1548]. Mean CD8 cell count was 498 [IQR: 348–624] and CD4/CD8 ratio was 2.1 [IQR: 1.4–2.7]. Mean lymphocyte B cell count was 261 [IQR: 153–292] and mean natural killers count was 241 [IQR: 111–276]. Serum γ-globulin concentrations were in the normal range in all patients evaluated (n = 25).
Serologic tests for HHV-8 were positive in 22 patients (88%), negative in three patients (12%) and not carried out in three patients. HHV-8 peripheral blood viremia was not determined for six patients. Twenty patients had no HHV-8 in the bloodstream at Kaposi sarcoma diagnosis (91%). Only two patients had HHV-8 viremia at the time of Kaposi sarcoma diagnosis. One of these patients had a single nodule on one leg, whereas the other patient had multiple nodules on both legs, associated with lymphoedema. HHV-8 viremia was determined for only two of the three patients who developed lymphoproliferative disorders after Kaposi sarcoma diagnosis. Neither presented HHV-8 viremia at Kaposi sarcoma diagnosis, but HHV-8 viremia was observed at the time of diagnosis of Castleman disease in one patient (3039 copies/150 000 cells) and at the time of follicular lymphoma diagnosis in the other (12 500 copies/150 000 cells).
We describe here a new epidemiologic form of Kaposi sarcoma in HIV-negative MSM displaying no signs of cellular or humoral immunodeficiency. Epidemiologic studies have shown that Kaposi sarcoma is associated with homosexuality or bisexuality in HIV-infected patients, this condition rarely being reported in heterosexuals or in patients infected through the blood, such as hemophilic patients and intravenous drug users. Kaposi sarcoma has been reported in HIV-negative homosexual men [13–17], with most of the known cases described between 1986 and 1990.
HHV-8 seroprevalence has been estimated up to 2% in the French general population . In a study  on patients consulting at a French STD clinic, HHV-8 prevalence was lower in heterosexual white men (4%) than in homosexual white men (24%). HHV-8 seroprevalence among homosexual men in the United States remained steady between 1984 and 1995 , at around 25%, suggesting that HHV-8 was already present in the homosexual and bisexual community at the beginning of the HIV epidemic, and that measures for preventing HIV have little or no impact on HHV-8 transmission. Homo/bisexuality has been shown to be associated with HHV-8 infection in western countries [22,24]. Epidemiologic studies  have suggested that HHV-8 in MSM may be sexually transmitted, mainly through orogenital contact , based on the high frequency of HHV-8 oral shedding . As HHV-8 prevalence is higher in homosexual and bisexual men than in heterosexual men and women, regardless of HIV status, MSM seem to be at a higher risk of developing Kaposi sarcoma as shown by previous epidemiologic studies  carried out long before the discovery of HHV-8. All the patients in our series presented risk factors for HHV-8 infection, as they were all MSM, but none presented classical risk factors associated with Kaposi sarcoma development. All were HIV negative, none displayed a quantitative CD4 T-lymphocyte or γ-globulin deficiency, and only one patient was treated occasionally with steroids, which are known to favor the progression of Kaposi sarcoma. Further studies will be necessary to analyze the risk factors associated with Kaposi sarcoma in this setting, such as the association between this type of Kaposi sarcoma and HLA class II DRB1 polymorphism as it has been linked to Kaposi sarcoma development in HIV-infected patients .
An effect of aging has been proposed as a possible explanation for the development of Kaposi sarcoma in older patients with the classic form of Kaposi sarcoma. The age at onset of the disease was 53 in our series. Interestingly, this age is similar to the mean age of 51 reported for a cluster of HIV-infected patients who developed Kaposi sarcoma despite having a high CD4 cell count and low-viral load . Disease onset seems to have occurred earlier in our patients than in patients with classic Kaposi sarcoma, for whom estimated age at onset is between 64 and 72 years [30–34]. Endemic Kaposi sarcoma begins much earlier and may affect young children, below the age of 6 years . These differences illustrate the probable involvement of other cofactors in triggering Kaposi sarcoma, as recently suggested .
We found that 14% of our patients had type 2 diabetes mellitus – prevalence similar to the one found in 16–22% previously reported patients with classical Kaposi sarcoma [30,31,33]. It is possible that diabetes favors immunodepression, thereby promoting Kaposi sarcoma development in HHV-8 infected individuals.
A second neoplasia was detected in 14% of our patients, mostly in the form of lymphoproliferative disorders. Questions have been raised concerning the possible association between Kaposi sarcoma and neoplasia, with the prevalence of neoplasia in Kaposi sarcoma patients ranging from 15 to 17%, with a high proportion of lymphoproliferative disorders [30,32,36]. In our series, three patients developed lymphoproliferative disorders. HHV-8 PCR gave negative results on Kaposi sarcoma diagnosis but positive results at the time of diagnosis of Castleman disease or follicular lymphoma in these patients. This illustrates the value of determining HHV-8 load in the peripheral blood of patients with Kaposi sarcoma for the diagnosis of lymphoproliferative diseases potentially associated with HHV-8 infection .
Three patients (12%) were seronegative for HHV-8. This proportion is higher than that for cohort studies, in which 96–100% of American patients with Kaposi sarcoma are seropositive for HHV-8. This difference in results may be due to the use of a latent immunofluorescence assay, which is probably less sensitive than lytic assays or other tests such as enzyme-linked immunosorbent assay. However, in the three seronegative cases, the diagnosis of Kaposi sarcoma was confirmed histologically and by immunohistochemistry with a specific monoclonal anti-HHV-8 antibody (not shown). HHV-8 PCR on PBMCs was positive for only 9% of our patients at the time of the initial evaluation. One patient testing positive for HHV-8 DNA in peripheral blood had a single cutaneous nodule, whereas the other had disseminated cutaneous lesions. This reflects the limited nature of Kaposi sarcoma in most of our patients and the absence of major immunosuppression, as HHV-8 viremia has been shown to reflect both tumor burden and level of immunosuppression [37–38].
Systemic treatments including interferon were generally well tolerated. Interferon controlled disease progression in a sustained manner in five patients, with complete responses observed in two of these patients. No firm conclusions can be drawn from such a small sample, but these results do suggest that interferon is a possible first-line treatment for this type of Kaposi sarcoma.
We thank Dr Stéphanie Régnier for helping to collect some of the data.
N. Dupin and C. Lebbé designed the study
F. Lanternier, C. Lebbé, M. Janier and N. Dupin wrote the draft
F. Lanternier, I. Gorin, D. Kerob and N. Schartz collected the data
D. Farhi did the statistics and contribute to the draft
F. Agbalika and A.G. Marcelin did the virological experiments
O. Verola did the pathological analysis of the skin biopsies
I. Gorin, M. Janier, N. Dupin, D. Kerob and C. Lebbé took care of the patients
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