Endemic Kaposi's Sarcoma Research Articles

Detection of human herpesvirus-8 DNA in Kaposi’s sarcomas from iatrogenically immunosuppressed patients

Background: Kaposi’s sarcoma (KS) accounts for more than 5% of malignancies in immunosuppressed organ transplant patients (OKS). A new herpesvirus (HHV-8) was identified with high prevalence in biopsy specimens of AIDS-KS, endemic KS, and classic KS and in OKS. KS has also been associated with other underlying diseases in patients treated with corticosteroids, but this subset of KS has been reported to contain HHV-8 in only a few case reports. Objective: In this larger study, we determined the prevalence of HHV-8 in seven patients of Jewish origin in whom KS developed during immunosuppressive therapy for different primary diseases (ISKS). Methods: The study included HHV-8 DNA detection by polymerase chain reaction (PCR) coupled with Southern blot and sequence analysis as well as by in situ hybridization. Results: HHV-8 sequences were detected by PCR with confirmation by Southern blot and sequence analysis in 100% of the ISKS samples. Direct sequencing revealed several previously unknown base changes within the 208 bp region from open reading frame 26 (ORF26 208 ) of HHV-8 in ISKS. Conclusion: Ours is the largest known study describing the presence of HHV-8 in iatrogenic KS from immunosuppressed nontransplant patients and provides data of previously unknown sequence variations within the ORF26 of HHV-8 DNA. (J Am Acad Dermatol 1998;38:429-37.)

Kaposi sarcoma

Moriz Kaposi was the first who, in 1872, described five patients presenting with "sarcoma idiopathicum multiple hemorrhagicum". In 1912 Sternberg termed this disease Kaposi's sarcoma. Since then various forms of this rare disease have been observed. In 1914 Hallenberg described the first cases of African or endemic Kaposi's sarcoma. In the 1960s the first reports discussing Kaposi's sarcoma following organ transplantation and immunosuppressive therapy were published. After 1981, the epidemic form associated with the acquired immunodeficiency syndrome (AIDS) was described. All these forms, their history, treatment methods and the role of radiation therapy in the management of this rare malignancy are discussed, and the literature is reviewed.

Human herpesvirus 8 and Kaposi's sarcoma.

In the last 2 years, the discovery that the suspected causative agent of Kaposi's sarcoma (KS) is a new gamma-herpesvirus, called human herpesvirus type 8 (HHV8) or Kaposi's sarcoma-associated herpesvirus (KSHV), has been followed by studies showing it to be a sine qua non of all clinical forms of KS and a specific marker for KS in the differential diagnosis of angioproliferative lesions. Reports that the virus is ubiquitous have been based on the polymerase chain reaction and appear to be contradicted by serological studies of blood donors and patients with acquired immunodeficiency syndrome (AIDS)-related and classical KS. Further serological surveys and the application of molecular probes in histological sections should resolve the issue. The recent descriptions of KSHV RNA molecules and several viral mimickers of human cytokines offer the chance to map the viral latent-lytic cycle and will change the direction of cytokine research in KS. These discoveries suggest that the increase of endemic classical KS noted in Nordic countries before the AIDS epidemic was due to spread of KSHV by unknown routes. The aggregate data should force a paradigm shift away from the notion that human immunodeficiency virus infection has a necessary role to play in AIDS-KS other than as a cause of progressive immunodeficiency.

Expression of HHV-8 latency-associated T0.7 RNA in spindle cells and endothelial cells of AIDS-associated, classical and African Kaposi's sarcoma.

Analysis by polymerase chain reaction (PCR) and serological studies have demonstrated a close association between the novel human herpes virus, Kaposi's sarcoma-associated herpes virus (KSHV) or human herpes virus-8 (HHV-8) and the development of Kaposi's sarcoma (KS). To clarify the role of HHV-8 in KS pathogenesis, we investigated at the cellular level by in situ hybridization the expression of a recently described 0.7-kb HHV-8-encoded mRNA (T0.7 mRNA) in KS tissues of different epidemiological origin (AIDS-KS, African endemic KS and classical KS). The T0.7 mRNA likely encodes a small membrane protein, supposedly expressed in latently HHV-8-infected cells. Indeed, we detected T0.7 mRNA in virtually all cells of the cell line BCBL-1 established from a body cavity-based lymphoma (BCBL) and latently infected with HHV-8. In all KS biopsies examined, independent of their epidemiological type, the late-stage (nodular) KS tissues showed a high level of T0.7 mRNA expression in typical KS spindle cells but also in endothelial cells lining blood vessels, indicating latent HHV-8 infection of these cells. The presence of T0.7-expressing cells was restricted to KS tumor tissue and therefore appears to indicate an important role of latent HHV-8 infection in KS pathogenesis.

Expression of HHV‐8 latency‐associated T0.7 RNA in spindle cells and endothelial cells of AIDS‐associated, classical and African Kaposi's sarcoma

Analysis by polymerase chain reaction (PCR) and serological studies have demonstrated a close association between the novel human herpes virus, Kaposi's sarcoma-associated herpes virus (KSHV) or human herpes virus-8 (HHV-8) and the development of Kaposi's sarcoma (KS). To clarify the role of HHV-8 in KS pathogenesis, we investigated at the cellular level by in situ hybridization the expression of a recently described 0.7-kb HHV-8-encoded mRNA (T0.7 mRNA) in KS tissues of different epidemiological origin (AIDS-KS, African endemic KS and classical KS). The T0.7 mRNA likely encodes a small membrane protein, supposedly expressed in latently HHV-8-infected cells. Indeed, we detected T0.7 mRNA in virtually all cells of the cell line BCBL-1 established from a body cavity-based lymphoma (BCBL) and latently infected with HHV-8. In all KS biopsies examined, independent of their epidemiological type, the late-stage (nodular) KS tissues showed a high level of T0.7 mRNA expression in typical KS spindle cells but also in endothelial cells lining blood vessels, indicating latent HHV-8 infection of these cells. The presence of T0.7-expressing cells was restricted to KS tumor tissue and therefore appears to indicate an important role of latent HHV-8 infection in KS pathogenesis. Int. J. Cancer 72:68–71, 1997. © 1997 Wiley-Liss Inc.

Infection with AIDS-related herpesviruses in human immunodeficiency virus-negative infants and endemic childhood Kaposi's sarcoma in Africa.

Novel herpesviruses have been described recently. These include human herpesviruses 6, 7 and 8 (HHV-6, -7, -8). HHV-6 has at least two strain groups, variants A and B. The B strains are predominant in the West and can account for over 97% of infections in infants. In contrast, the A strains are rare and the few well-characterized isolates have been from adult African AIDS patients. It is not clear whether the HHV-6 variant A strains are AIDS-related and/or whether they can also be acquired as childhood infections and may reactivate later during adulthood. What contribution geographical variation plays has yet to be assessed. HHV-8 has been associated with AIDS-related epidemic Kaposi's sarcoma (KS), but has also been identified in endemic KS. In regions of Africa where KS is endemic, the onset of AIDS has led to increased prevalence of KS. In this report, we examine in Zambia, an AIDS epidemic and KS endemic region, infection with these novel herpesviruses during infancy. In blood samples from human immunodeficiency virus-negative infants with first febrile episode, both semi-quantitative PCR and sequence analyses were used to identify HHV-8 in 8% and HHV-6 in 30%, with 44% of these variant A; in childhood endemic KS biopsies HHV-8 was detected in 100% and HHV-6 in none. The high viral-DNA loads in the infant blood samples were consistent with viraemia. This is the first demonstration that HHV-6 variant A and HHV-8 may be acquired as common childhood infections.

HHV8 and Kaposi's sarcoma: a time cohort study.

AIMS: The recent finding that human herpes virus 8 (HHV8) is found in the majority of Kaposi's sarcoma (KS) cases supports the epidemiological observation that the tumour may be caused...

Strain variability among Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genomes: evidence that a large cohort of United States AIDS patients may have been infected by a single common isolate.

Previous analysis of the majority of Kaposi's sarcoma (KS) tumors, in both AIDS and non-AIDS populations, has revealed the consistent presence of two small subsegments (open reading frame 25/26 [ORF25/26] and ORF75) of a novel human gamma class herpesvirus genome referred to as KSHV or HHV-8. We have carried out DNA sequence comparisons with DNAs encompassing a total of 2,500 bp each over three separate PCR-amplified fragments from KS lesions and body cavity-based lymphoma (BCBL) samples from 12 distinct patients, including four African and two classical or endemic non-AIDS KS samples. The results revealed differences at 37 of 2,500 nucleotide positions (i.e., 1.5% overall variation). However, the 12 HHV-8 genomes examined fell into three distinct but very narrow subgroupings (A, B, and C strains). All A strain isolates differed from B strain isolates at 16 positions, but of the eight U.S. samples tested, six were A strains, and these differed at no more than two positions among them. Similarly, three of the four African samples were B strains, which differed from each other at only one position. The two C strain genomes also displayed only one nucleotide variation, but they differed from all A strains at 26 positions and from all B strains at 20 positions. One C strain genome was present in all six independent lesions from an AIDS KS patient with disseminated disease, and the other represented a mosaic A/C recombinant genome from the HBL6 cell line derived from a BCBL tumor. Evaluation of previous data suggests that B and C strains may predominate in Africa and that A strains predominate in classical Mediterranean samples. Although both B and C strains are represented in U.S. AIDS patients, the majority (70 to 80%) of samples from the mid-East Coast region at least appear to be virtually identical, supporting the concept that they may all derive from the spread during the AIDS epidemic of a single recently transmitted infectious agent.

Expression of adhesion molecules in endemic and epidemic Kaposi's sarcoma.

Spindle cells and vascular endothelium in nodular lesions of AIDS associated (epidemic) and endemic Kaposi's sarcoma showed similar immunohistochemical patterns of expression for cell adhesion molecules and extracellular matrix proteins. Spindle cells as well as endothelium also expressed both alpha 5 and alpha V integrin subunits and ICAM-1 suggesting a possible role for inflammatory cytokines in spindle cell formation. The spindle cell compartment was rich in collagen, laminin, fibronectin and tenascin suggesting an important reactive component in the evolution of Kaposi's sarcoma. The lack of thrombospondin expression in the spindle cells favours the contention that they could be transitional, proliferating cells of endothelial origin. Specific expression of tat protein was not seen suggesting minimal if any HIV replication in these lesions. Our findings suggest similar histopathogenetic mechanisms for endemic and epidemic Kaposi's sarcoma. The clinically more malignant features of most AIDS related cases may reflect an important effect of systemic and focal cytokines in HIV patients and possibly other cofactor(s), i.e. tat protein in the induction and growth of the lesions.

Antibodies to human herpesvirus type 8 in the general population and in Kaposi's sarcoma patients

Much of the evidence that human herpesvirus type 8 (HHV-8) is associated with Kaposi's sarcoma (KS) has come from molecular studies of HHV-8 DNA. Seroepidemiological studies have been hampered by the lack of a reliable assay. The serological data reported here were obtained by means of a mouse monoclonal antibody-enhanced immunofluorescence assay for antibodies to lytic and latent HHV-8 antigens. 1435 single samples of serum (or plasma) from many different disease groups and parts of the world were assayed. All patients with African endemic KS and 96% of American patients with AIDS-associated KS were seropositive for lytic antigen, as were 90% of American HIV-infected homosexual men; by contrast only 23% of HIV-seropositive drug users and 21% of HIV-seropositive women were positive for HHV-8 antibody. Factor VIII treatment before 1983 did not increase the risk of HHV-8 infection in patients with haemophilia. In the American general population, about 25% of adults (including volunteer blood donors) and 2-8% of children had antibodies to HHV-8. Our data are consistent with HHV-8 being primarily associated with sexual transmission, but the HHV-8 seropositivity rate in American children suggests that there is a non-sexual route of HHV-8 infection also. On the evidence available so far, the risk of parenteral transmission is low.

Oncogenesis in HIV-infection

The presence of human Kaposi's sarcoma associated herpesvirus-like sequences (KSHV) was examined in different epidemiological variants of Kaposi's sarcoma (KS) and in KS-derived cell cultures by polymerase chain reaction (PCR). KSHV DNA was present in all tumor biopsies of AIDS-associated KS (59 biopsies), endemic KS (26 biopsies; 21 African endemic KS, 5 Greek endemic KS), sporadic/classical KS (28 biopsies) and post-transplant/iatrogenic KS (6 of 7 biopsies). On the contrary, these sequences were only detected rarely in non-involved skin of KS patients (3 positive specimens of 12), in the peripheral blood mononuclear cells of HIV-infected patients (3 positive specimens of 54) and in lymphoma-biopsies (3 positive specimens of 47). Cell cultures derived from KS skin lesions were positive for KSHV DNA only in the first two passages. However, two longer-term positive cultures from a biopsy of a patient affected with sporadic KS and a biopsy of a patient affected with epidemic KS was identified. A strong association of KSHV with KS tissue was observed in all the different epidemiological variants of KS. Long-term positive KS-derived cell cultures will be an important tool to study the herpesvirus-like agent and to investigate its functional role in the initiation and progression of KS.

The importance of clinical features in differentiating HIV related from non-HIV related Kaposi's sarcoma: experience from Dar es Salaam, Tanzania.

HIV-associated Kaposi's sarcoma (KS) is reported to be the most common tumor among people infected with HIV and accounts for significant morbidity and mortality. A study was conducted at Muhimbili Medical Center among consecutive patients presenting at the skin clinic or admitted to the surgical or medical wards during April-December 1992 and suspected to have KS. Patients completed a questionnaire, had venous blood samples and biopsies of the suspicion skin lesion taken, and were tested for infection with HIV. 81 adult patients with histologically proven KS were seen during the study period. Epidemic KS (EKS) was diagnosed in 72 patients of whom 49 were male, while African endemic Kaposi's sarcoma (AEKS) was diagnosed in nine patients of whom seven were male. No patient presented with classical KS. Compared to AEKS, EKS was more aggressive and disseminated in patients. The mean duration of illness for patients with AEKS was 37.3 months compared to 8.3 months for those with EKS. The presenting symptoms and past history of HIV-related illness were most pronounced among patients with EKS. Patients with EKS also demonstrated profound T4 lymphopenia and inverted T4:T8 ratio suggestive of advanced HIV infection.

Diminished delayed hypersensitivity responses in the legs and feet of patients with endemic Kaposi's sarcoma

Diminished delayed hypersensitivity responses in the legs and feet of patients with endemic Kaposi's sarcoma

Long-term follow-up of non-HIV Kaposi's sarcoma treated with low-dose recombinant interferon alfa-2b.

We reviewed the follow-up of 16 patients with Kaposi's sarcoma not related to human immunodeficiency virus (13 with classic Kaposi's sarcoma and three with endemic Kaposi's sarcoma; median age, 58 years) treated by low-dose recombinant interferon alfa-2b (5 million U three times weekly for at least 6 months). One patient had a complete response, nine had a major response, three had stable disease, and one had a minor response. Visceral disease stabilized and symptoms improved in three patients. Limited relapse was noted in four patients after withdrawal of interferon. Our results confirm the efficacy and safety of low-dose recombinant interferon alfa-2b in the long-term treatment of both cutaneous and visceral lesions of Kaposi's sarcoma not related to human immunodeficiency virus.

Kaposi's sarcoma-associated herpesvirus and Kaposi's sarcoma in Africa. Uganda Kaposi's Sarcoma Study Group

Endemic Kaposi's sarcoma (KS) is a clinically and epidemiologically distinct human immunodeficiency virus negative form of KS occurring in Africa. Kaposi's sarcoma is now the most frequently reported cancer in some areas of Africa. To determine if a KS-associated herpesvirus (KSHV) is present in both endemic HIV-seronegative and HIV-seropositive KS lesions from African patients. Paraffin-embedded tissue specimens from Ugandan patients with KS and non-KS tumor control patients attending a university-based oncology clinic were examined in a blinded case-control study. Tissue DNA specimens were examined for detectable KSHV genome by nested polymerase chain reaction performed at two independent laboratories. We identified KSHV in 17 (85%) of 20 KS tissue specimens from HIV-seronegative patients and 22 (92%) of 24 KS tissue specimens from HIV-infected persons. Kaposi's sarcoma lesions from four HIV-infected persons and four HIV-seronegative persons were positive for KSHV. Unlike previous studies in North America and Europe, three (14%) of 22 non-KS cancer control patients' tissue specimens were also positive for KSHV that resulted in an overall odds ratio of 49.2 (95% confidence interval, 9.1 to 335) for detecting KSHV in KS lesions from patients in Uganda. As in North America and Europe, KSHV infection is strongly associated with both HIV-seropositive and HIV-seronegative KS in Africa. However, it is likely that infection with this virus is more highly prevalent in Uganda.

Kaposi's Sarcoma-Associated Herpesvirus and Kaposi's Sarcoma in Africa

Background: Endemic Kaposi's sarcoma (KS) is a clinically and epidemiologically distinct human immunodeficiency virus negative form of KS occurring in Africa. Kaposi's sarcoma is now the most frequently reported cancer in some areas of Africa. Objective: To determine if a KS-associated herpes-virus (KSHV) is present in both endemic HIV-seronegative and HIV-seropositive KS lesions from African patients. Methods: Paraffin-embedded tissue specimens from Ugandan patients with KS and non-KS tumor control patients attending a university-based oncology clinic were examined in a blinded case-control study. Tissue DNA specimens were examined for detectable KSHV genome by nested polymerase chain reaction performed at two independent laboratories. Results: We identified KSHV in 17 (85%) of 20 KS tissue specimens from HIV-seronegative patients and 22 (92%) of 24 KS tissue specimens from HIV-infected persons. Kaposi's sarcoma lesions from four HIV-infected persons and four HIV-seronegative persons were positive for KSHV. Unlike previous studies in North America and Europe, three (14%) of 22 non-KS cancer control patients' tissue specimens were also positive for KSHV that resulted in an overall odds ratio of 49.2 (95% confidence interval, 9.1 to 335) for detecting KSHV in KS lesions from patients in Uganda. Conclusion: As in North America and Europe, KSHV infection is strongly associated with both HIV-seropositive and HIV-seronegative KS in Africa. However, it is likely that infection with this virus is more highly prevalent in Uganda. (Arch Intern Med. 1996;156:202-204)

Herpesvirus-like DNA sequences detected in endemic, classic, iatrogenic and epidemic Kaposi's sarcoma (KS) biopsies

The identification of Kaposi's sarcoma (KS) clusters in sub-equatorial Africa (endemic KS, AKS) and the high frequency of KS in sexually transmitted AIDS (epidemic KS, EKS), have previously suggested a role for infectious agents in the etiopathogenesis of KS. The recent identification of herpesvirus (HHV)-like DNA sequences in one case of EKS and their detection in > 90% of all tested EKS, prompted us to determine the prevalence of these viral sequences in all types of KS, such as AKS, EKS, classic KS (CKS) and iatrogenic KS (IKS). The presence of herpesvirus(HHV)-like DNA sequences has been examined in 61 KS skin tumors obtained from Greece, Italy, USA, Uganda and Kenya. All KS types (100%) were positive by polymerase chain reaction (PCR) and Southern-blot analysis, while 5 out of 6 (83%) and 4 out of 7 (57%) uninvolved autologous skin biopsies from AKS and CKS patients, respectively, were positive for HHV-like sequences. All samples from non-KS patients were negative, i.e. 17 human biopsies from healthy individuals or patients affected by other pathologies, 5 human cell lines and 15 peripheral blood mononuclear cells (PBMC) from HIV-positive subjects. These results suggest that HHV-like sequences play a major role in the pathogenesis of this neoplasm.

Variants of Kaposi's sarcoma in Southern Africa. A retrospective analysis (1980-1992).

All types of Kaposi's sarcoma (KS) are represented in the Southern African region. We present a retrospective analysis of patients with KS, treated and followed up at the Johannesburg General Hospital over a 12-year period (1980-1992). One hundred and nineteen patients with KS, divided into four groups according to their etiology (classical; endemic African; renal transplant recipients; epidemic AIDS-related) were analyzed. Choice of treatment (radiotherapy or chemotherapy) was individualized and based on clinical criteria, extent of disease and severity of symptoms. Kaposi's sarcoma showed a very high response rate to radiation therapy, regardless of variant, radiation modality or schedule. Chemotherapy was also effective in the more aggressive pattern of endemic African KS. Epidemic Kaposi's sarcoma showed the same poor outcome as demonstrated by its Western counterpart. We conclude that radiation therapy can provide excellent palliation with only minimal side-effects in all variants of KS seen in Southern Africa.

The spectrum of African Kaposi's sarcoma: is it consequential upon diverse immunological responses?

Kaposi's sarcoma (KS) is a complex, multicellular growth, the pathogenesis of which remains unclear. Endemic African Kaposi's Sarcoma (KS) is characterized by its epidemiological peculiarities, protean clinical manifestations and an unpredictable natural history. A wide spectrum of clinical manifestations occurs, although the reasons for the heterogeneity remain unclear. Clinical observations in the presentation of human immunodeficiency virus (HIV)-associated epidemic African KS show a considerable overlap with endemic African KS obscuring the conventional binomial concept of African KS which was developed in light of the HIV epidemic. It is probable that once the KS lesions are expressed clinically, the subsequent spectrum and behaviour of all forms of African KS are consequential upon a complex interplay between the nature of the host cell-mediated immune responses and the putative aetiological factor(s).

Frequent presence of a novel herpesvirus genome in lesions of human immunodeficiency virus-negative Kaposi's sarcoma.

While Kaposi's sarcoma (KS) is extremely common in homosexual men infected with human immunodeficiency virus (HIV), it is also found in several clinical settings in which HIV infection is absent. Recently, sequences from the genome of a novel member of the herpesvirus family have been identified within KS biopsies in the AIDS-associated form of the disease. The presence of these sequences was sought in 6 cases of HIV-negative KS, including 4 cases of endemic KS from Africa, and was found in 5 of the 6. These findings strengthen the association between infection with this virus and the development of KS and argue against the notion that this association is simply the result of opportunistic superinfection of profoundly immunodeficient hosts.