African Kaposi's Sarcoma Research Articles

Kaposi's sarcoma in a hospital setting in Lomé (Togo): a study of 93 cases

To define the epidemiologic and clinical profile and course of the disease in African Kaposi's sarcoma (KS) and acquired immunodeficiency syndrome (AIDS)-associated KS in Togo. This was a retrospective study performed on the medical records of patients seen at the Department of Dermatology, University Hospital of Lomé, Togo from January 1994 to December 2004. The medical records of all patients with KS, who had undergone human immunodeficiency virus (HIV) serology, were included in the study. Ninety-three files on 98 patients with KS, who had undergone HIV serology, were included in the study. The annual incidence during the study period was 8.5. HIV serology was positive in 73 patients (78.5%) and negative in 20 patients (21.5%). The mean age of the patients with AIDS-associated KS was 33.8 +/- 8.2 years, and 49.5 +/- 15.8 years for African KS. The male to female ratio for AIDS-associated KS was 1.4, and 9 for African KS. The mortality rate at 2 years for African KS was 5%, and 45% for AIDS-associated KS. The low level of access to antiretroviral drugs in HIV-infected patients explains the morbidity and mortality from AIDS-associated KS in Togo.

Disseminated classic Kaposi's sarcoma

Kaposi's sarcoma (KS) is characterised by proliferation of vascular endothelial and lymphoreticular cells, frequently with a multicentric expression developed from a single node and evolving to multiple cutaneous lumps or plaque-like appearance. Four types of KS with similar histological patterns have been described in terms of their clinical and epidemiological features: classic KS, endemic (African) KS, iatrogenic KS and epidemic (AIDS-related) KS. The differences in clinical features are quite relevant: classic KS is usually limited to the lower extremities; whereas immunodeficiency-related diseases frequently involve several organs. A case of a 67-year-old woman with metastatic KS and unproven immunodeficiency is presented.

Kaposi sarcoma of the musculoskeletal system

Kaposi sarcoma (KS) of bone and skeletal muscle is unusual. In this report, the authors review 66 published patients with KS who had involvement of the musculoskeletal system reported from 1925 to 2006. In only 3 patients was acquired immunodeficiency syndrome (AIDS)-related KS identified within skeletal muscle. Osseous KS lesions were more frequent and occurred with African, classic, and AIDS-related KS and occurred rarely in transplantation-associated KS. Patients seldom were asymptomatic. They usually had bone pain with limited mobility or infrequently developed serious sequelae like spinal cord compression. Locally aggressive African and classic KS lesions typically involved the peripheral skeleton; whereas, in patients with AIDS, the axial (vertebrae, ribs, sternum, and pelvis) and/or maxillofacial bones more commonly were involved. Almost all patients had concomitant nonosseous KS lesions. Joint involvement was exceptional, and pathologic fractures were not observed. Computed tomography scans and magnetic resonance images were better at detecting osseous KS lesions, which frequently went undetected on plain x-ray films or bone scans. Pathologic diagnosis was important to exclude similar lesions like bacillary angiomatosis. Treatment options, including surgery and, in more recent patients, radiation and/or chemotherapy, had limited success.

Imaging Manifestations of Kaposi Sarcoma

Kaposi sarcoma (KS) is a low-grade vascular tumor that typically manifests as one of four variants: classic KS, endemic (African) KS, iatrogenic (organ transplant-related) KS, or acquired immunodeficiency syndrome (AIDS)-related KS. Several clinical and epidemiologic differences have been noted among these variants. Classic KS and endemic KS rarely require radiologic evaluation due to their usually chronic course and stability of skin compromise. However, iatrogenic KS and AIDS-related KS, the most common forms of the disease, are frequently disseminated or symptomatic and may thus require imaging studies for both diagnosis and staging. KS is the most common tumor among AIDS patients, affecting a high percentage of these individuals, and is considered to be an AIDS-defining illness. Multiple organs can be involved by AIDS-related KS. KS has been linked with human herpes virus type 8 infection and other cofactors. Although pulmonary, gastrointestinal, and skin involvement by KS has previously been described, this tumor can affect multiple organs, generating a wide spectrum of imaging findings and pathologic correlates. It is important for the radiologist to be familiar with this spectrum of imaging manifestations and corresponding pathologic findings.

The clonality of tumor-infiltrating lymphocytes in African Kaposi's sarcoma.

African Kaposi's sarcoma (KS) lesions contain human herpesvirus-8 (HHV-8) and Epstein-Barr virus (EBV), both of which are associated with various types of non-Hodgkin's lymphomas and are known to produce several factors suspected of lymphomagenic potential. The aim of this study was to evaluate tumor-infiltrating lymphocytes for the evidence of clonal expansion in African KS. We used polymerase chain reaction (PCR)-based assays to determine the clonality of tumor-infiltrating lymphocytes in African KS lesions and compared the results to similar studies of patient-matched uninvolved skin and peripheral blood. T cells were polyclonal in all samples tested. Peripheral blood B cells were also polyclonal; however, a minority of lesional and uninvolved skin samples exhibited evidence of restricted B-cell clonality. Correlation with immunohistological analysis revealed that this clonal B-cell restriction was secondary to the sparse nature of lesional B cells rather than their clonal overgrowth. We conclude that, despite the putative lymphomagenic potential of HHV-8 and EBV and their co-existence in African KS lesions, tumor-infiltrating lymphocytes in these cases do not show evidence of clonal expansion that might be an early manifestation of lymphoma. Nevertheless, these studies are a case in point that sparse lymphoid subpopulations in lesional and uninvolved extranodal tissues can give rise to restricted clonal patterns that must be interpreted carefully to avoid the misdiagnosis of occult lymphoma.

Author reply

Viral agents have been implicated in the development of Kaposi sarcoma (KS) and lymphoproliferative diseases; a relation between KS and human herpesvirus type 8 (HHV-8)1 has been ascertained, and Hodgkin's disease often is found in association with Epstein–Barr virus (EBV).2 The two viruses may be concomitant in some B-cell lymphomas (body cavity-based lymphomas).3 Both of these viruses belong to the gamma-herpesviridae family and have lymphotropic and oncogenic activity.4 The stimuli activating their oncogenic potential vary and often are unknown. An important factor in the case of KS is an impaired immune defense due to the aging of the immune system (Mediterranean KS),5 the onset of chronic malnutrition-induced infectious diseases (African KS), iatrogenic immunosuppression (KS in organ transplantation), or immunosuppression during the course of the acquired immunodeficiency syndrome. The triggering factors in the case of EBV remain unknown. It is unlikely that the simultaneous onset of the two pathologies is a matter of chance, although to our knowledge the stimuli activating both herpesviruses at the same time are not known.6 The genetic substrate may be of fundamental importance.7 Quantitative HHV-8 antibody serology may provide information regarding the course of KS, but not regarding the possibly associated lymphoproliferative disease6 because to our knowledge HHV-8 has never been found in the latter type of pathology other than body cavity-based lymphomas and Castleman disease. Lucia Brambilla M.D.*, Vinicio Boneschi M.D.*, Silvia Ferrucci M.D.*, Silvia Fossati M.D.*, * Institute of Dermatology, State University, IRCCS Ospedale Policlinico, Milan, Italy

Author reply

Viral agents have been implicated in the development of Kaposi sarcoma (KS) and lymphoproliferative diseases; a relation between KS and human herpesvirus type 8 (HHV-8)1 has been ascertained, and Hodgkin's disease often is found in association with Epstein–Barr virus (EBV).2 The two viruses may be concomitant in some B-cell lymphomas (body cavity-based lymphomas).3 Both of these viruses belong to the gamma-herpesviridae family and have lymphotropic and oncogenic activity.4 The stimuli activating their oncogenic potential vary and often are unknown. An important factor in the case of KS is an impaired immune defense due to the aging of the immune system (Mediterranean KS),5 the onset of chronic malnutrition-induced infectious diseases (African KS), iatrogenic immunosuppression (KS in organ transplantation), or immunosuppression during the course of the acquired immunodeficiency syndrome. The triggering factors in the case of EBV remain unknown. It is unlikely that the simultaneous onset of the two pathologies is a matter of chance, although to our knowledge the stimuli activating both herpesviruses at the same time are not known.6 The genetic substrate may be of fundamental importance.7 Quantitative HHV-8 antibody serology may provide information regarding the course of KS, but not regarding the possibly associated lymphoproliferative disease6 because to our knowledge HHV-8 has never been found in the latter type of pathology other than body cavity-based lymphomas and Castleman disease. Lucia Brambilla M.D.*, Vinicio Boneschi M.D.*, Silvia Ferrucci M.D.*, Silvia Fossati M.D.*, * Institute of Dermatology, State University, IRCCS Ospedale Policlinico, Milan, Italy

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.

Cell-homologous genes in the Kaposi's sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its pathogenicity?

The epidemiology of Kaposi’s sarcoma (KS) among patients with AIDS has suggested that a sexually transmitted infectious agent other than human immunodeficiency virus (HIV) must be involved in its pathogenesis. KS is about 20,000 times more common in patients with AIDS than in the general population of the United States, and other immunosuppressed groups develop KS approximately 600 times more frequently than the healthy population. During the first decade of the AIDS epidemic, about 20% of homosexual and bisexual patients developed KS, in contrast to about 1% of men with hemophilia. Women were more likely to have KS if their partners were bisexual rather than parenterally infected men (4). This led to a broad search by PCR in patients with KS for the presence of viruses known to affect humans, such as cytomegalovirus (53, 57), human herpesvirus 6 (HHV-6) (29), and BK virus (43). Some of these viruses were found frequently in KS biopsy specimens, but none of them was consistently present (25, 30). A new era of KS research began when Y. Chang, P. S. Moore, and their colleagues (14) detected by representational difference analysis (35) two short DNA fragments from a herpesvirus that was distinct from all previously known herpesviruses. Remarkably, more than 90% of KS tissues obtained from patients with AIDS contained the virus. The viral sequences were not present in biopsy specimens from patients without AIDS but were found in 15% of non-KS tissue DNA from patients with AIDS. The new virus, tentatively termed KS-associated herpesvirus or HHV-8, was soon found to be common in all epidemiological forms of KS (24). Viral DNA is consistently present in AIDS-associated KS lesions (1, 36) and in the vast majority of classical European-Mediterranean KS lesions (1, 18), while it is far less frequent in uninvolved skin of patients with KS and in the various biopsy specimens from Caucasian patients without KS and HIV. AIDS-associated African KS specimens (92%) and non-AIDS-associated KS lesions in Uganda (85%) had the virus (16). Based on PCR, the prevalence of HHV-8 appeared to be high in the general population in Uganda, while searches in non-KS tumors and in normal tissues showed that the virus is rarely detectable in Caucasians. While some lymphomas carry other herpesviruses, such as Epstein-Barr virus (EBV) and HHV-6 (22), those specimens did not contain HHV-8 DNA. However, one type of lymphoid tumor, the AIDS-associated body cavity-based lymphoma (BCBL), was positive for HHV-8 DNA by PCR and Southern

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).

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.

Chemotherapy for AIDS-related and endemic African Kaposi's sarcoma in southern Africa.

Kaposi's sarcoma (KS), either in its endemic (African) form or its AIDS-related variant, is a common neoplastic disorder seen in Southern Africa. Chemotherapy has been proven to be very effective in advanced or relapsed African Kaposi's sarcoma, but much less so in AIDS-related, endemic KS. The study consists of a retrospective analysis of the results of chemotherapy alone in 17 patients with African KS (AKS) and in 32 patients with epidemic AIDS-related KS (EKS), treated at the Johannesburg General Hospital between 1982 and 1992. Single agents included vinblastine, actinomycin D, bleomycin, and vincristine; combined regimens were largely doxorubicin/vincristine/bleomycin or etoposide/methotrexate. Outcome classifications were: complete remission (CR), partial remission (PR), and treatment failure (TF). Four of the 17 patients with AKS had CR, 10 a PR, and three were TF and died rapidly from their disease. The combined chemotherapeutic regimens produced marked symptomatic relief and even long-term remission in AKS. In patients with EKS, the response rate to chemotherapy was very low and of brief duration. No patient had a CR and debilitating side effects were common. The African type of AKS is a chemo-sensitive tumor, whereas the endemic type EKS, like its Western counterpart, has a dismal prognosis.

The appearance of kaposi sarcoma during corticosteroid therapy

Four epidemiologic types of Kaposi sarcoma (KS) are known: classic KS, endemic African KS, epidemic or acquired immunodeficiency syndrome-related KS, and KS associated with immunosuppressive therapy. In most of the latter patients, KS was reported to have developed after organ transplantation, particularly renal transplantation. Thirty-nine patients who have not had a transplant have been reported to have KS associated with corticosteroid therapy. The authors studied 10 patients with the appearance of KS during corticosteroid therapy (6 men, 4 women; age range, 42-79 years) who were treated with corticosteroids for autoimmune disorders (5 patients), lymphoproliferative disorders (2 patients), and diseases unrelated to the immune system (3 patients). Genetically programmed susceptibility to corticosteroid-related KS was suggested by the descent of the study patients as well as most of those reported previously. The prognosis was guarded in all the study patients. Corticosteroids should be withdrawn to achieve clinical remission.

Radiation therapy in endemic (african) Kaposi's sarcoma (EKS) — a retrospective study

Radiation therapy in endemic (african) Kaposi's sarcoma (EKS) — a retrospective study

Spindle cell ploidy and proliferation in endemic and epidemic African Kaposi's sarcoma

Comparative studies of ploidy and proliferative activity of spindle cells in sections of 20 (skin, 17; lymph node, 3) biopsy specimens from African patients, 10 with endemic Kaposi's sarcoma (EKS) and 10 with AIDS-associated Kaposi's sarcoma (AKS) were performed by histopathology, feulgen-based DNA measurement and proliferating cell nuclear antigen (PCNA)/cyclin immunohistochemistry, respectively. All specimens were classified as nodular lesions with basically the same histology. In 17 cases immunostained for cyclin/PCNA, the percentage of proliferating spindle cells range between 2–18, with a higher mean rate in AKS although this was not statistically significant. In situ measurement of DNA showed no significant values greater than the diploid level of control cells indicating that spindle cells in both EKS and AKS have euploid DNA content. Our findings indicate that both EKS and AKS represent the same type of euploid low rate cell proliferations. This corroborates previous suggestions that KS could represent a reactive process to yet undefined stimulus rather than a clonal proliferation, of transformed malignant cells.

African endemic-type Kaposi's sarcoma. A histopathologic study and flow cytometric DNA analysis of nine cases.

Flow cytometric DNA analysis using formalin-fixed, paraffin-embedded tissues were performed on nine cases of African endemic-type Kaposi's sarcoma (KS). Histologically, these cases were classified into the following three types; granulation tissuelike (one case), angioma/angiosarcoma-like (four cases) and spindle cell (four cases). Although these three types showed a variety of cellularity and cellular atypism, there were no fundamental differences in the view point of proliferation of spindle cell. Mitotic figures were not prominent. All cases were exclusively diploid and lacked an aneuploid population by flow cytometric measurement of DNA content. These results suggest that African endemic-type KS is a less aggressive disease rather than a malignant neoplasm.

Cytomegalovirus infection in classic, endemic and epidemic Kaposi's sarcoma analyzed by in situ hybridization

In order to evaluate the association between cytomegalovirus (CMV) infection and Kaposi's sarcoma (KS) at the cellular level, four classic KS, five endemic (African) KS and 55 epidemic KS from 12 patients with AIDS were analyzed by in situ hybridization with a biotinylated specific CMV-DNA probe. CMV-DNA was sparsely demonstrated in the sarcomas in 10 of the patients with AIDS but in none of the classic or endemic sarcomas. The distribution and localization of the CMV-infected cells did not suggest CMV as a major pathogenic stimulus for the development of KS but rather as an opportunistic infection in severely immunosuppressed patients.

The Epidemiology of Classic, African, and Immunosuppressed Kaposi's Sarcoma

The etiology of Kaposi's sarcoma remains somewhat obscure. While lesions of classic Kaposi's sarcoma, African Kaposi's sarcoma, and immunosuppressed Kaposi's sarcoma have been found to be indistinguishable from one another, the reasons for the variations in type and severity have not been established. The origin of the spindle cell is yet to be agreed on. Geographic variation does not seem as important as ethnic variation. The very young and the very old, perhaps two ages of weakened immunity, tend to have a higher incidence of Kaposi's sarcoma. Children and AIDS patients tend to develop more virulent disease. Males tend to get Kaposi's sarcoma at higher rates than do females. Jewish and Mediterranean males have the highest incidence of classic Kaposi's sarcoma, and African Bantu have the highest incidence of African Kaposi's sarcoma, classifications which do not apply to the Kaposi's sarcoma population in the United States. Male homosexuals have much higher incidence of Kaposi's sarcoma than do male heterosexuals, but since the early 1980s, its incidence as the presenting manifestation of AIDS has decreased dramatically. There is no unequivocal association with HLA haplotype (though DR5 carriers may be at especially high risk) or evidence of family clustering. There is an impressive but not always consistent association between Kaposi's sarcoma development and immunodeficiency. Environmental factors, such as nitrite use, immunosuppression, and repeated cytomegalovirus infection, are associated with Kaposi's sarcoma, but the exact mechanism is unclear and the associations remain inconsistent. Finally, it is still unclear if there is a causative infectious agent for Kaposi's sarcoma. While cytomegalovirus has been linked to Kaposi's sarcoma, there are weaknesses in its hypothetical role as an etiologic agent as is the case for HIV itself.(ABSTRACT TRUNCATED AT 400 WORDS)

Non-AIDS-Associated Kaposi's Sarcoma (Classical and Endemic African Types): Treatment with Low Doses of Recombinant Interferon-Alpha

In the treatment of the classical and endemic African forms of Kaposi's sarcoma (KS), radiation therapy and chemotherapy have been widely used with varying degrees of success and morbidity. We here report our preliminary experiences with low doses of recombinant interferon alfa-2b (rIFN alpha-2b) in the treatment of these types of KS, non-linked to the acquired immunodeficiency syndrome (AIDS). Ten consecutive patients (eight patients with classical and two with endemic KS) with a median age of 62 years were treated long-term with 5 × 106 units of rIFN alpha-2b (Introna) given subcutaneously three times weekly for at least 6 months. Of the 10 patients, six presented with cutaneous disease only, and four had additional visceral involvement. After 6 months of treatment, seven of the 10 patients had a major response of the cutaneous lesions, and three patients showed stable skin diseases. Of the four patients with additional visceral disease, one patient showed a complete regression of an intramyocardial tumor involving the right atrium and ventricle, whereas in the three other patients stabilization of the visceral lesions with marked symptomatic improvement occurred. On the whole, the long-term results over a median duration of 12 months (range, 7 to 30) are also satisfactory: IFN-alpha continued to control KS in all patients. The treatment was generally well tolerated; no serious side effects were observed. Our preliminary data suggest that low-dose rIFN alpha-2b regimens are effective in classical and endemic African KS. However, further studies are needed to establish the exact role for IFN-alpha as alternative to radiation and chemotherapy.