Kaposi's sarcoma in HIV-negative men having sex with men
Lanternier, Fannya; Lebbé, Célestec,f; Schartz, Noëlc; Farhi, Davida; Marcelin, Anne–Genevièveb; Kérob, Delphinec; Agbalika, Félixd; Vérola, Oliviere; Gorin, Isabellea; Janier, Michelc; Avril, Marie-Françoisea; Dupin, Nicolasa
From the aDepartment of Dermatology, Cochin Hospital, APHP, Faculté de Médecine René Descartes, France
bDepartment of Virology, Pitié Salpêtrière Hospital, APHP, France
fINSERM U716, Saint-Louis Hospital, APHP, Paris, France.
Received 3 December, 2007
Revised 1 April, 2008
Accepted 2 April, 2008
Correspondence to Professor Nicolas Dupin, Service de Dermatologie et Vénéréologie Pavillon Tarnier Hôpital Cochin, APHP Université René Descartes, Paris V UPRES-EA 1833 89 rue d'Assas, 75006 Paris, France. E-mail: firstname.lastname@example.org
Background: Four epidemiologic forms of Kaposi's sarcoma have been described, all of which are associated with the human herpesvirus-8. In western countries, human herpesvirus-8 is more prevalent in homosexual men than in the general population, and anecdotal cases of Kaposi's sarcoma in HIV-negative homosexual men have been reported.
Patients and methods: We included HIV-negative homosexual and bisexual male patients with histologically proven Kaposi's sarcoma in a retrospective study. Clinical data were collected using a standardized form. Risk factors for human herpesvirus-8 infection and for the development of Kaposi's sarcoma were systematically recorded.
Results: Between 1995 and 2007, 28 men met the defined inclusion criteria. Mean age at first symptoms of Kaposi's sarcoma was 53 years. Clinical presentation resembled classical Kaposi's sarcoma, with limited disease in most patients. No cellular or humoral immunodeficiency was observed. Serologic tests for human herpesvirus-8 (latent immunofluorescence assay) were positive in 88% of patients, and only two patients displayed human herpesvirus-8 viremia at the time of Kaposi's sarcoma diagnosis. Three patients developed lymphoproliferative disorders (Castleman disease, follicular lymphoma and Burkitt lymphoma). In this population, α-interferon was well tolerated and gave a complete response, but most patients require only local treatment, if any.
Conclusion: Kaposi's sarcoma may develop in homosexual or bisexual men without HIV infection. This type of Kaposi's sarcoma has clinical features in common with classical Kaposi's sarcoma but occurs in younger patients. Its prognosis is good, as Kaposi's sarcoma is generally limited, but clinicians should be aware of the association with lymphoproliferative diseases, which may affect prognosis.
Kaposi's sarcoma is a mesenchymal tumor. A virus was identified as the etiologic agent of Kaposi sarcoma in 1994, by Chang et al.  known as human herpesvirus-8 (HHV-8) or Kaposi sarcoma-associated herpes virus (KSHV) . Four clinical forms of Kaposi sarcoma have been described. Classical Kaposi sarcoma mostly occurs in men aged 60 years and over from Mediterranean areas or Central and East European countries and presents as nodules or plaques predominantly located on the lower extremities. Endemic Kaposi sarcoma occurs in Africa and affects men and women aged 35 years and older; it may present as a nodule on the lower extremities, local invasive or visceral disease. In Africa, Kaposi sarcoma may also affect young children, with few skin lesions observed but frequent lymph node and visceral involvement, resulting in a poor prognosis. Iatrogenic Kaposi sarcoma is mostly observed in organ transplant recipients on immunosuppressive treatment. Epidemic Kaposi sarcoma occurs in HIV-positive predominantly homosexual men and presents as multifocal skin lesions with either frequent mucosal or visceral involvement or both.
HHV-8 seroprevalence is strongly correlated with Kaposi sarcoma, and epidemiologic studies have shown that HHV-8 infection precedes Kaposi sarcoma [3,4]. However, HHV-8 seroprevalence is highly heterogeneous worldwide. Prevalence is high in East and Central Africa (>50%), where transmission is mainly horizontal, probably through salivary contact during childhood , with rare cases of vertical transmission from mother-to-child . HHV-8 seroprevalence is intermediate (10 to 20%) in the Mediterranean area (Italy, Greece), where the routes of transmission remain undetermined [7,8]. Finally, seroprevalence (<5%) is low in the general population of Northern Europe and the United States. In countries with a low prevalence of HHV-8, this virus predominantly infects men having sex with men (MSM), through orogenital sexual contact . Independent epidemiologic studies [10,11] carried out in the United States and Europe have shown that HHV-8 infects about 25% of MSM.
Given the high prevalence of HHV-8 in homosexual and bisexual men, and the strong association between Kaposi sarcoma and HHV-8 , immunocompetent MSM could be at risk of developing Kaposi sarcoma. Only anecdotal cases of Kaposi sarcoma in HIV-negative MSM have been reported to date [13–17]. We studied an original cohort of 28 patients of Kaposi sarcoma in HIV-negative MSM from two centers, describing their clinical and epidemiologic characteristics and their HHV-8 status.
Patients and methods
We retrospectively studied all consecutive patients followed between 1995 and 2007 in two dermatology departments (Hôpital Cochin and Hôpital Saint-Louis, Paris, France). HIV-negative MSM with histologically confirmed Kaposi sarcoma were included.
Demographic, epidemiologic and clinical data were collected on a standardized form. The following demographic data were collected – ages at diagnosis and at onset of cutaneous lesions and sexual orientation (homosexual or bisexual). Risk factors for Kaposi sarcoma were also systematically noted – stays in zones of endemic HHV-8 or of classical Kaposi sarcoma zone, geographic origin, past history of sexually transmitted diseases (STD) and known immunodeficiency. Clinical presentation of Kaposi sarcoma (type, number and location of lesions), treatment and outcome were also recorded.
Kaposi sarcoma stage was determined according to the modified Krigel classification . Stage Ia, locally indolent cutaneous lesions on one limb segment; stage Ib, locally indolent cutaneous lesions on at least two limb segments; stage II, locally aggressive cutaneous lesions with or without regional lymph node involvement; stage III, multiple cutaneous lesions or generalized lymph node involvement; stage IV, palatal or visceral Kaposi sarcoma. Morphologic investigations were also recorded 18 patients had a chest radiograph, 18 patients had abdominal ultrasound scans and 8 patients had thoracic and abdominal computed tomography (CT) scans. We also recorded the presence of associated neoplasia and of associated infectious events.
CD4 T-lymphocyte cell count, HHV-8 serologic status and HHV-8 viremia were also recorded. Serologic tests for HHV-8 were performed as previously described, using an indirect immunofluorescence assay (IFA) for latent antigens . HHV-8 viremia was measured on 1 μg of total DNA extracted from peripheral blood mononuclear cells (PBMCs). Quantitative polymerase chain reaction (PCR) detection of HHV-8 was carried out by the Taqman technique, as previously described . The assay was performed on an ABI PRISM 7700 sequence detection system, using components supplied in the Taqman core reagent kit (Perkin Elmer, Foster City, California, USA).
The main characteristics of the patients are shown in Table 1. During the study period, about 300 new cases of Kaposi sarcoma in HIV-negative individuals were seen in the two dermatology referral departments. On the basis of the inclusion criteria, 28 patients were identified as eligible for this study, giving a prevalence of 9% of this type of Kaposi sarcoma in our population. Mean age at first visit was 56 years [interquartile range (IQR): 45–67; range: 35 – 83]. Mean age at first Kaposi sarcoma symptoms was 53 years [IQR: 42–62; range: 35 – 83] and mean age at diagnosis was 55 years [IQR: 43–65; range: 35 – 83]. Eleven patients had traveled in Africa and six patients had traveled in Mediterranean countries. Twenty-six patients were Whites, one was Japanese and one originated from the French West Indies. One of the White patients originated from a Mediterranean country. Twenty-two patients were homosexual and six were bisexual.
Clinical lesions were observed in the form of papules or nodules, mostly located on the lower limbs (89%) (Fig. 1). Some lesions were found on the upper limbs (Fig. 2) (n = 8; 28%), face (n = 4; 14%), trunk (n = 3; 11%) and genitalia (n = 1; 3.5%). Three patients had associated lymphoedema, but none presented visceral involvement, as demonstrated by morphologic investigations (chest radiographs, abdominal ultrasound scans and thoracic and abdominal CT scans). Mucosal involvement in the genital area was observed in only one patient. On the basis of Krigel's classification, 54% of the patients were classified as having stage I Kaposi sarcoma [Ia (n = 12) and Ib (n = 3)], 32% had stage II Kaposi sarcoma and 14% of the patients had stage III Kaposi sarcoma.
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.
Six (21%) patients were treated with systemic drugs α-interferon (n = 5) and/or chemotherapy (n = 3) with bleomycin (n = 2) and/or vinblastine (n = 1). The patient treated with vinblastine documented a partial response. One of the patients treated with bleomycin displayed a partial response, whereas the other achieved a complete response. Three patients treated with α-interferon achieved a partial response, the other two achieving a complete response. One patient who was in complete remission after 6 months of treatment with interferon relapsed 8 months later, with extensive Kaposi sarcoma manifesting as disseminated lesions of the lower limbs, trunk and hands. Nineteen patients had local treatment consisting of radiotherapy (n = 5), surgery (n = 10), cryotherapy (n = 2), imiquimod cream (Aldara) (n = 4) and CO2 laser treatment (n = 1). Six patients received no treatment.
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.
In conclusion, based on our data, this type of Kaposi sarcoma  has the following characteristics occurrence in MSM, particularly in those frequently staying in areas of medium to high HHV-8 seroprevalence; ‘classical Kaposi sarcoma’-like clinical presentation in patients significantly younger than for classical Kaposi sarcoma; and possible association with type 2 diabetes and lymphoproliferative disorders, related or unrelated to HHV-8. As the prevalence of HHV-8 is high in MSM, we recommend serologic testing for HHV-8 in this population when prescribing immunosuppressive molecules, as these patients seem to be at risk of developing Kaposi sarcoma.
We thank Dr Stéphanie Régnier for helping to collect some of the data.
The contributions of the authors are as followed:
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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Castleman; human herpesvirus-8; interferon; Kaposi sarcoma; Kaposi sarcoma-associated herpes virus; lymphoma; men having sex with men
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