Relation between demographic status and clinical characteristics of Kaposi sarcoma: a single centre study

Kaposi sarcoma (KS) is a vascular tumor of the skin, subcutaneous tissues, or gastrointestinal tract arising from endothelial cells in immunocompromised, human herpesvirus-8 (HHV8)-positive patients. In addition to human immunodeficiency virus (HIV) infection, immunosuppressive medication, for example, after solid-organ transplantation, may lead to reactivation of a latent HHV8 infection and KS formation. Although a regular dermatological check up is mandatory for solid-organ transplant recipients to exclude frequent epithelial tumors (1), diagnosis of posttransplant KS may be delayed because of less awareness for this entity in nonendemic areas such as Germany. Differences in host defense and complex subcellular regulations may sign responsible for a great variation in KS incidence (2, 3). Mammalian target of rapamycin inhibitors such as everolimus or sirolimus are the mainstay of KS therapy through its vascular endothelial growth factor inhibitory action (4, 5). Evidence from registry studies with HIV-positive and AIDS patients showed that 23% of HIV/AIDS patients with incident deep venous thrombosis (DVT) had KS as exclusive tumor comorbidity (6). For posttransplant KS, it is unclear whether DVT risk is increased. In a case report, posttransplant KS developed at a skin site where DVT occurred before suggesting the possibility of KS being promoted by DVT through a yet unclear mechanism (7). Alternatively, KS lesions may impede venous blood flow directly or by KS-associated lymphedema (8), thereby promoting DVT in the absence of classic DVT risk factors. At a kidney transplant unit of a University clinic in Germany, a case-control study was conducted to determine the incidence of DVT in kidney transplant recipients with and without histologically proven posttransplant KS. Four HHV8-positive kidney transplant recipients or 0.4% of all kidney transplant recipients were diagnosed with posttransplant KS at the Hospital of the Johann-Wolfgang-Goethe University, Frankfurt am Main, Germany, between 1991 and 2006. As case-control study, each kidney transplant recipient with posttransplant KS matched by a control. Control patients received a kidney transplant 3 months before or after kidney transplantation of the index patient. They had the same transplant modality (living-donor or deceased-donor kidney transplantation), the same gender, and a comparable allograft survival. If more than one patient fulfilled these criteria, the patient with the closest age match was chosen. Based on hospital and outpatient-care records, the incidence of DVT was determined for both posttransplant KS and control patients between 1991 and 2006. Time from transplantation to occurrence of posttransplant KS was 1112±990 days. KS patients and control patients had similar immunosuppression regimens. DVT was not reported before kidney transplant in neither group (Table 1). However, DVT occurred in three of four KS patients at 889±713 days after kidney transplantation, whereas none of the control patients developed DVT after kidney transplant (P=0.02). DVT diagnosis preceded KS diagnosis by 851 and 578 days in two posttransplant KS patients or occurred 674 days after KS diagnosis in one patient.TABLE 1: Patient characteristics of kidney transplant recipients with (cases) or without (controls) incident posttransplant Kaposi sarcoma between 1991 and 2006In all KS patients, calcineurin inhibitor was switched to mammalian target of rapamycin inhibitor therapy, while steroid and mycophenolate mofetil therapy was maintained. One posttransplant KS patient received an empiric interferon therapy. Because of side effects, two patients had to be switched back to a low-dose calcineurin inhibitor regimen. No KS patient lost kidney transplant function or died by the end of the observation period. However, one KS patient unexpectedly died from acute aortoiliac thrombosis, acute Leriche syndrome, 593 days after DVT or 1.5 year after the end of the study period. Control patients had no change of immunosuppression drug class by the end of the study period. One control patient lost kidney transplant function 14.9 years after transplantation and had to resume intermittent hemodialysis therapy. No control patient died during the study period or during a 2-year follow-up period. Taken together, this single-center, case-control study found a significantly increased occurrence of DVT in kidney transplant recipients with KS when compared with age-matched KS-free counterparts. However, because of the small number of KS cases and the relatively long time elapsed between DVT and KS diagnosis of up to 2.4 years, the occurrence of both KS and DVT may be a coincidental finding. However, from the data of this small case-control study, a further investigation for a possible association between KS and DVT seems to be justified. Rainer U. Pliquett1,2 Helmut Schöfer3 Aida Asbe-Vollkopf1 Ingeborg A. Hauser1 Ernst H. Scheuermann4 Heinz-Georg Kachel4 1 Department of Nephrology University Hospital Johann Wolfgang Goethe University Frankfurt/Main, Germany 2 Currently, Department of Nephrology University of Halle Halle/S, Germany 3 Clinic for Dermatology, Venereology, and Allergology University Hospital Johann Wolfgang Goethe—University Frankfurt am Main, Germany 4 KFH Nierenzentrum/Renal Unit Frankfurt am Main, Germany

In order to investigate the seroprevalence of human herpesvirus 8 (HHV-8) infection in central and southern Italy, sera from human immunodeficiency virus (HIV)-seronegative subjects, with and without Kaposi's sarcoma (KS), were analyzed by immunofluorescence assay, using BC-3, a cell line latently infected with HHV-8. High titers of antibody against HHV-8 lytic and latent antigens were detected in all 50 KS patients studied, while in 50 HIV-seronegative subjects without KS, 32 (64%) were found positive for HHV-8 antibodies. Titers in the sera of these patients were lower than those for KS patients. This data suggests that HHV-8 infection is not restricted to KS patients and that the prevalence of HHV-8 infection in the general population may be correlated with differing rates of prevalence of KS in different parts of the world. In view of these findings, possible nonsexual transmission routes were evaluated. Nested PCR was used to test for the presence of HHV-8 DNA in saliva, urine, and tonsillar swabs from KS and non-KS patients. In KS patients, 14 out of 32 tonsillar swabs (43.7%), 11 out of 24 saliva samples (45.8%), and just 2 out of 24 urine samples (8.3%) tested positive for HHV-8 DNA. In the control group, on the contrary, none of the 20 saliva and 20 urine specimens was positive for HHV-8 DNA; only 1 out of 22 tonsillar swabs gave a positive result. This data supports the hypothesis that HHV-8 infects the general population in a latent form. The reactivation of viral infection may result in salivary shedding of HHV-8, contributing to viral spread by nonsexual transmission routes.

Kaposi Sarcoma (KS) is a vascular tumor originating from endothelial cells and is associated with human herpesvirus 8 (KSHV) infection. It disproportionately affects populations facing health disparities. Although antiretroviral therapy (ART) has improved KS control in people with HIV (PWH), treatment options for advanced KS remain limited. This study investigates the tumor microenvironment (TME) of KS through whole-transcriptomic profiling, analyzing changes over time and differences based on HIV status. The TME was categorized into four subtypes: immune-enriched (IE), non-fibrotic, immune-enriched/fibrotic (IE/F), fibrotic (F) and immune-depleted (D). Nine KS patients (four HIV-negative and five HIV-positive) were enrolled in the study. Longitudinally collected KS samples from three patients (one HIV-negative and two HIV-positive) allowed for the investigation of dynamic TME changes within individual patients. The immune cellular composition was determined using deconvolution and compared to a cohort of non-KS patients. Our findings revealed that all KS samples, regardless of HIV status, were enriched in endothelial cells. Compared to non-KS tissues, the KS samples contained a higher percentage of NK and CD8+ T cells. HIV-negative KS samples displayed the IE and IE/F TME subtypes, while HIV-positive samples exhibited IE, IE/F, and F subtypes. Over the course of the disease, a decrease in angiogenic signatures was observed in two HIV-positive KS patients. Notably, HIV-negative KS samples showed alterations in NK cell-mediated immunity and cytotoxic response pathways, whereas HIV-positive samples exhibited changes in growth regulation and protein kinase activity pathways at the time of initial diagnosis. The gene expression of immune checkpoints, including CD274 (PD-L1) and PDCD1LC2 (PD-L2), was comparable between HIV-positive and HIV-negative KS samples at diagnosis. Furthermore, sequencing identified a shared TCRβ chain in all patients analyzed, indicating a T-cell immune response to a common antigen. This study demonstrates unique transcriptomic features and TME subtypes in KS that differ based on HIV status. Additionally, it illustrates longitudinal dynamic changes in the gene signatures and TME subtypes in individual patients. The identification of a shared TCRβ chain suggests that immune T cells in KS patients may target a common antigen. Future studies should further explore the immune microenvironment and unique T cell clonotypes, which could pave the way for the development of novel therapeutic strategies for KS patients.

Since the discovery of Kaposi's sarcoma-associated herpesvirus, also known as human herpesvirus 8 (HHV-8), several studies have been conducted to identify the body fluids into which the virus is shed, with consequent potential virus transmission (7, 10). Although saliva has been pointed out as the main route of virus transmission, mostly in populations in areas where the virus is endemic, semen, blood, urine, and stool have also been suggested as vehicles of virus transmission-acquisition in populations at risk of infection, such as homosexual males and human immunodeficiency virus (HIV)-AIDS patients (4, 5, 11). Unfortunately, all specimens analyzed up to now have yielded controversial results except saliva, which tested positive for HHV-8 DNA for several asymptomatic carriers and for Kaposi's sarcoma (KS) patients (3, 4, 9, 11, 12). In the last years, a group of researchers published interesting studies conducted on Malawian people. First, they investigated the molecular epidemiology of HHV-8 and the routes of virus transmission (1, 8). Then, using PCR, sequencing, and other molecular approaches, they evaluated blood and several oral samples from KS patients and their relatives and identified the HHV-8 subtypes named B1, A2, and A5 that circulate in Malawi. They also detected infection with multiple HHV-8 subtypes in a single individual and mixed patterns of HHV-8 transmission (sexual and nonsexual transmission via intra- and extrafamilial routes), confirming HHV-8 shedding in oral fluids (1, 8). In recent issues of the Journal of Clinical Microbiology, Beyari et al. presented the results obtained for urine and oral rinse from the same Malawian people. Using PCR and sequencing of open reading frame (ORF) 26 and K1/V1, they detected HHV-8 DNA in 6.4% of urine samples (5 of 78 samples), identified monotypic virus in urine and multitypic virus in saliva, and pointed out urine as another site of virus shedding (2). To add some information concerning this matter, we present the results obtained with a group of KS patients and HIV-infected patients in Sao Paulo, Brazil, whose urine was analyzed for the presence of HHV-8 DNA by PCR of ORF 26 and K1/V1, as previously described (1). The results obtained revealed HHV-8 DNA positivity in 6 out of 55 (11%) KS patients and in 5 out of 18 (28%) HIV-1-infected patients without clinical evidence of KS. Interestingly, the group without KS presented the higher prevalence rate of HHV-8 infection. On the basis of clinical and epidemiological data, we may speculate that these patients were recently infected with HHV-8 or had KS at sites not yet identified. In agreement with this hypothesis, two out of five HHV-8-infected patients were found to be HHV-8 seropositive in immunofluorescence assays (6). In contrast, the relatively low rate of HHV-8 infection detected in the urine of KS patients may be the result of highly active antiretroviral therapy and/or ABV treatment to which these patients were submitted, which can contribute to virus clearance in blood and urine. We do not know the exact significance of HHV-8 DNA in urine, but we can hypothesize that when virions are present in urine, this specimen could be of importance for virus transmission-acquisition, mainly in populations of countries with poor socioeconomic and sanitary conditions where the virus is endemic and also in individuals with promiscuous behaviors. Additional investigations, including the determination of viral load using real-time PCR and primers for different regions of the HHV-8 genome, are needed to solve this question. If urine is confirmed to be another vehicle of virus transmission, it will be necessary to formulate recommendations to block the spread of the virus.

BackgroundThe association of the human herpesvirus-8/Kaposi's sarcoma (KS)-associated herpesvirus (HHV-8/KSHV) serology with various malignancies in Tanzania is not currently well established while previous studies were based on either PCR or immunofluorescence assays [IFA] but not with a sensitive enzyme-linked immunosorbent assay (ELISA). Selected archival diagnostic biopsies (n = 184) and sera from indigenous patients with KS (n = 120), non-KS tumors (n = 24) and non-neoplastic lesions (n = 40) at Muhimbili National Hospital (MNH), Tanzania, were evaluated by diagnostic histopathology, immunohistology [anti-HHV-8 latency-associated nuclear antigen (LANA)] and serology for HIV (ELISA) and HHV-8 (IFA and ELISA).ResultsAbout 66.3% (n = 122) cases including AIDS-associated Kaposi's sarcoma (AKS) (n = 93), reactive conditions (n = 28) and only one non-KS tumour were HIV positive. Endemic KS (EKS) patients were mostly males (96.3%, 26/27) who were less (69.9%, 65/93) predominant in AIDS-associated (AKS). A high (89%) percentage of patients with anti-HHV-8 antibodies was found in the cohort including the HIV positive (92%) cases, males (81.2%), KS patients (93%), non-KS tumors (92%), and reactive conditions (75%). All HHV-8 seronegative KS cases were nodular stage whereas both sera and corresponding biopsies from early stage KS were HHV-8+. Assay sensitivity, positive predictive value (PPV) and specificity were 98.6%, 93.5% and 16.7% for IFA and 93.5%, 98.6% and 50.0% for ELISA respectively.ConclusionHHV-8 seroprevalence at MNH appears high as expected among AKS cases and males but also in non-KS patients. ELISA showed a combination of high HHV-8 sensitivity as well as higher PPV and specificity than IFA which however, showed higher sensitivity. The apparent stage-dependent, inverted serum HHV-8 immunoreactivity supports a notion of viral immune-segregation during KS development. Routine HHV-8 screening should be considered particularly in patients at risk of KS and for selection of blood/organ donations.

Human herpes virus 8 (HHV-8) is associated with all clinical forms of Kaposi's sarcoma. HHV-8 DNA is present in Kaposi's sarcoma biopsies and is observed regularly in saliva and less consistently in blood of Kaposi's sarcoma patients. The expression pattern of latent (ORF 73) and lytic (vGCR, vBcl-2, and vIL-6) HHV-8 mRNA was studied in peripheral blood mononuclear cell (PBMC) samples and Kaposi's sarcoma skin biopsies from 11 AIDS Kaposi's sarcoma patients with four different nucleic acid sequence-based amplification (NASBA) assays. Patients were divided into groups according to the clinical stage of Kaposi's sarcoma (stage I-IV). All biopsies were positive for two or more of the mRNA measured. No clear difference could be seen in the expression pattern in the lesions of the different clinical stages. In the corresponding PBMC samples, very little or no mRNA was measurable in the patients with Kaposi's sarcoma stage I or II, whereas patients with more advanced Kaposi's sarcoma (stage III or IV) had more detectable mRNA in the PBMCs. Thus, the HHV-8 DNA load in the PBMCs increases in more advanced Kaposi's sarcoma, as does the frequency of mRNA detection in PBMCs.

This study investigates the association between human herpesvirus eight (HHV8) and Kaposi's sarcoma (KS), the most common cancer occurring in renal transplant recipients in Saudi Arabia. A cross-sectional study of seroreactivity to HHV8 antigens in posttransplant KS patients from a tertiary care hospital in Riyadh, Saudi Arabia, and in control subjects without KS was conducted. Seroreactivity rates were determined using immunoblotting assays to detect antibodies to two lytic cycle HHV8 antigens: p40, an antigen found in infected cells, and sVCA, an HHV8-encoded small viral capsid antigen expressed in Escherichia coli. Antibodies to HHV8 p40 and sVCA were present in a significantly higher proportion of renal transplant patients with KS (13 of 14 patients) compared to renal transplant patients without KS (5 of 18; P<0.001) and compared to other control individuals (6 of 44; P<0.001). HHV8 seroreactivity was more common among patients with renal failure (28%) than among other control groups (7%). The serologic results provide evidence of a strong association between HHV8 and posttransplant KS in Saudi Arabia.

Background and aim: Patients under immunosuppressive treatment are in risk of developing malignant tumours. Primary infection or reactivation of Human herpes virus 8 (HHV-8) may predispose to Kaposi sarcoma (KS) after solid organ transplantation. KS in pediatric liver transplant recipients has a low incidence and poor prognosis. We report the clinical presentation of a KS in lymph node following HHV-8 primary infection in a pediatric liver transplant recipient. Case: Boy who received living donor liver transplant for acute liver failure with hepatitis A at 4 years age. 4 months after transplant he started with abdominal pain, distention, fever and was admitted 5 days later with ascitis and polyadenomegalies. He was under usual immunosuppressant with Meprednisone + Tacrolimus (previous level 8.9 ng/ml). Pretransplant CMV and EBV +.With initial diagnosis of peritonitis, we started antibiotic and continued studies. Tacrolimus was discontinued. Within 3 days he showed general improvement but he still had ascitis and polyadenomegalies. We performed a biopsy of one axilar adenomegaly. Usual bacterias, mycobacterium and fungi were negative. Histology: morphologic characteristics of Kaposi disease. We searched HHV-8 in receptor saliva, blood and lymph node; and in donor saliva and blood. HHV-8 PCR was + in lymphocytes, saliva and lymph node and antibodies against HHV-8 were detected by immuofluorescense (IF titer >1:640). Serum before transplant was negative by IF (< 1:40). The liver donor had IF titers > 1:640 and was PCR+ for HHV-8 in blood and saliva. HHV-8 PCR was always positive in donor blood and saliva. The patient blood and saliva were negative 2 months after the diagnosis. These results remained unchanged during 2 years. He had a good outcome, ascitis and polyadenomegalies disappeared without Tacrolimus. A month after diagnosis, he presented liver enzymes 6 folds above normal values. A liver biopsy was performed and with diagnosis of mild acute rejection, he started treatment with Sirolimus (1 mg/m2/day, levels between 5 and 8 ng/ml). Currently, he is 11 year-old, with normal liver results, and he is under Sirolimus monotherapy. Discussion: We report this case as HHV-8 primary infection with Kaposi sarcoma in a patient with liver transplant and it is a remainder that KS should be taken into consideration in the differential diagnosis of posttransplant complications.

In a case-control study, we studied the effect of a single nucleotide polymorphism in the IL-8 promoter on the risk of the development of AIDS-related Kaposi's sarcoma (KS). KS developed in 46% of individuals with the TT genotype and in 66% of AA/AT genotypes (P=0.038). Patients with TT genotype were rarely affected with visceral KS (7% versus 36%; P=0.06), which suggests that carriers of the TT genotype are protected from (severe) KS development.

British HIV Association guidelines for HIV‐associated malignancies 2008

Kaposi's sarcoma in Malawi: a continued problem for HIV-positive and HIV-negative individuals.

In the general population, the incidence of the most common types of cancer (i.e., carcinomas of the lung, breast, colon, stomach, prostate and bladder) increases with age among both males and females and in different geographic areas.1,2 This pattern is explained by the multistage model for carcinogenesis, which posits that cancer arises as a consequence of multiple genetic hits acquired with aging.3 Alternatively, it has been hypothesized that this age-related increase in incidence can be attributed, at least in part, to the diminishing immunologic function associated with aging. However, among persons with severe immunosuppression, such as those who are iatrogenically immunosuppressed after organ transplantation or persons infected with the human immunodeficiency virus (HIV), the incidence of the most common types of cancer is no higher than that among immunocompetent persons. By contrast, the incidence of both non-Hodgkin’s lymphoma (NHL) and Kaposi’s sarcoma (KS), which are rare in immunocompetent persons younger than 40 years of age, has been reported to be quite high among persons with severe immunosuppression.4,5 KS is a mesenchymal tumor that, until the appearance of the HIV epidemic, was rare in the general population of industrialized countries; it was generally found in elderly men of Mediterranean or Eastern European origin.6 With regard to the pathogenesis of KS, an infectious agent – the human herpesvirus 8 (HHV-8)—has been isolated in all forms of the disease,7,8 and epidemiologic, serologic and molecular evidence has proved that infection with HHV-8 is necessary for the development of KS. Nonetheless, it has been difficult to determine the magnitude of the association between KS and HHV-8 infection because the currently used serologic assays are limited in terms of their sensitivity and specificity9 and because other, as yet unknown, cofactors exist that are likely to play a role in the development of KS.10,11 Given that HIV-infected individuals have been shown to live longer since highly active antiretroviral therapy (HAART) was introduced,12 it is now possible to study thoroughly the relationship among immunosuppression, aging and cancer. In a study13 that investigated whether or not aging affects the risk of developing HIV-associated KS and lung cancer, using data from the AIDS-Cancer Registry Match Study, the incidence of KS appeared to increase through 39 years of age and to decline thereafter. However, no information was available from this study on the duration of HIV infection, the level of immunosuppression or the prevalence of HHV-8 infection (i.e., the main determinant of KS8). We investigated the relationship among HIV-induced immunosuppression, aging and KS, taking into account the duration of HIV infection, the level of immunosuppression and, for a subgroup of the study population, the prevalence of HHV-8 infection. This study used data from the Italian HIV-Seroconversion Study. The Seroconversion Study, which was begun in 1987, is a prospective incident cohort study of HIV seroconverters who belong to different HIV exposure categories and for whom it is possible to estimate the date of seroconversion with a certain degree of accuracy, specifically, persons for whom the results of a negative HIV test followed by a positive test within 24 months are available; the date of seroconversion is estimated as the midpoint in time between the most recent negative HIV test result and the first positive result. A detailed description of the Seroconversion Study has been published elsewhere.14,15 Residual sera samples for detection of antibodies against HHV-8 were available for some of the individuals enrolled as of June 1996 in the Seroconversion Study. A single HHV-8 serologic measurement was performed: the median time that had elapsed from the date of HIV seroconversion to the date of HHV-8 testing was 0.7 years (interquartile range: 0.4–1.6 years). HHV-8 seropositivity was determined by HHV-8 lytic antigens, using an immunofluoroscence assay with a body cavity B-cell lymphoma cell line. A detailed description of the methodology used has been reported elsewhere.16 For the present analysis, we applied the Kaplan-Meier method and the Cox proportional hazards model.17 The date of HIV seroconversion was considered time-zero of the analyses, and KS was considered the end point. In particular, we estimated the KS-free survival time as the time that had elapsed from the date of HIV seroconversion to the date of diagnosis of KS (independently of whether or not it was the first AIDS-defining disease), or the date of death or the end of the study (i.e., December 2000). The

Successful secondary prophylaxis for primary effusion lymphoma with human herpesvirus 8 therapy

Salivary Lactoferrin Is Recognized by the Human Herpesvirus-8

Valproic acid induces human herpesvirus 8 lytic gene expression in BCBL-1 cells.