Search

Kaposi sarcoma (KS) is an angioproliferative disorder that is commonly associated with human herpes virus 8 as well as the HIV. In fact, KS is one of the most common AIDS-defining illnesses. KS typically presents with diffuse, violaceous cutaneous nodules, and may have concomitant visceral involvement. However, visceral involvement rarely occurs without skin manifestations. A rare case of localised bronchopulmonary KS without skin involvement is described in a patient with previously undiagnosed HIV. This atypical presentation represents a challenge for modern-day physicians in developed countries where the prevalence of AIDS-related diseases is decreasing., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

In this book chapter, we review the current knowledge of the biology and pathogenesis of Kaposi's sarcomaassociated herpesvirus (KSHV). We describe the lifecycle of KSHV, the cancers associated with this virus, as well as current treatment modalities.

Since the development of combination antiretroviral therapy (cART), the incidence and mortality associated with Kaposi sarcoma (KS) have been reduced, although not eliminated. Clinical presentations of KS range from simple skin involvement to disseminated disease, including involvement of the oral cavity and viscera, which portends a more ominous prognosis. Multiple case reports and data from clinical trials indicate that administration of systemic corticosteroids may aggravate KS. We present a case of disseminated KS following administration of prednisone for presumed immune reconstitution inflammatory syndrome (IRIS) associated with fungal pneumonia in an HIV-infected individual. The discussion that follows outlines the pathophysiology and clinical presentations associated with KS and existing data for the role of corticosteroids in promoting KS progression.

Background: Acquired immune deficiency syndrome related Kaposi's sarcoma (AIDS-KS) remains a significant cause of morbidity and mortality. We describe for the first time a proportion of patients with AIDS-KS who presented with no evidence of cutaneous disease., Patients and Methods: From our cohort of 5932 individuals infected with the human immunodeficiency virus (HIV-1) treated in the HAART era, 319 were identified with KS. Of these, 11 patients (5.4%) were diagnosed with KS without the presence of any cutaneous disease. We compared their survival, clinical, immunological and virological characteristics to other individuals with KS., Results: There were no statistically significant differences in survival, CD4 count or HIV viral load at KS presentation. We observed that tumour-associated oedema (P = 0.046) and non-oral gastrointestinal KS (P = 0.042) were significantly more common in patients with non-cutaneous KS. Only one case of non-cutaneous KS was observed prior to the era of highly active anti-retroviral therapy (HAART)., Conclusions: Non-cutaneous KS is a recognisable condition; patients should be treated with the standard of care as their prognosis is not inferior. This is likely to reflect a strong immune response, in the era of HAART.

AIDS-related Kaposi's sarcoma (AIDS-KS), which is the most prevalent AIDS related cancer, arises in a unique environment characterized by profound immunosuppression in conjunction with sustained immunostimulation. Persistent inflammation and the accompanying increased production of reactive species can promote carcinogenesis by numerous routes including sustained cell proliferation, initiation of nuclear and mitochondrial DNA mutations and induction of a proangiogenic environment. Furthermore, during conditions of continuous inflammation, protein nitration can result in irreversible inactivation of enzymes including the cytoprotective and reactive species degrading enzyme, mitochondrial superoxide dismutase (MnSOD). Because MnSOD serves as a putative tumor suppressor gene in addition to its reactive species inactivating capacities, the loss of MnSOD's cytoprotective functions could markedly facilitate malignant transformation. The purpose of this study was to investigate biochemical and molecular pathways by which reactive species facilitate AIDS-KS pathogenesis. Immunohistochemical studies of AIDS-KS tumors showed intense AIDS-KS lesional cell staining for MnSOD, inducible nitric oxide synthase (NOS 2) and the presence of a cellular 'fingerprint' of nitrative stress, 3-nitrotyrosine. Collectively, these results that imply reactive species stress occurs in situ. Similarly, cultured AIDS-KS cells derived from the AIDS-KS tumors contained both MnSOD protein and the 'high output' isoform, NOS 2. Co-localization studies established that the mitochondria are a primary site for 3-nitrotyrosine localization and immunoprecipitation/immunoblotting experiments confirmed that MnSOD tyrosine nitration occurs in AIDS-KS cells. Functional SOD assays showed that AIDS-KS cells possess significantly lower MnSOD activity relative to matched control cells; findings which correspond with ongoing MnSOD tyrosine nitration and subsequent inactivation within AIDS-KS cells. These results, which show in situ evidence of reactive species stress within AIDS-KS tumors and functional deficits attributable to nitrative stress in tumor-derived AIDS-KS lesional cells, imply that reactive species are intimately associated with AIDS-KS pathogenesis and provide insights for development of novel strategies for AIDS-KS clinical treatments.

The introduction of highly active antiretroviral therapy (HAART) has had a dramatic impact on the morbidity and mortality of individuals living with human immunodeficiency virus (HIV). In addition to contributing to declines in the incidence of several opportunistic infections, HAART is affecting the incidences of several acquired immunodeficiency syndrome (AIDS)-defining malignancies. The incidence of Kaposi's sarcoma (KS) and primary central nervous system lymphoma (PCNSL) has dropped precipitously since the introduction of HAART in 1995. Systemic non-Hodgkin's lymphoma (NHL) appears to be declining in incidence as well, but to a lesser degree than KS and PCNSL. On the contrary, the incidence of invasive cervical carcinoma has not significantly changed in the HAART era. The impact of HAART on the epidemiology of other HIV-associated malignancies, including Hodgkin's disease and anal carcinoma, remains unclear. Data regarding the impact of HAART on the natural history and treatment outcomes of HIV-associated malignancies are limited. The possibility of direct and indirect roles of HIV in HIV-related carcinogenesis suggests that antiretroviral therapy may be an important component of the treatment strategy for several HIV-related malignancies. Patients with HIV-NHL treated with HAART in addition to chemotherapy experience fewer intercurrent opportunistic infections. Furthermore, the simultaneous administration of HAART and chemotherapy does not appear to significantly increase toxicity. Whether the combination of HAART and standard therapy results in improved survival remains uncertain. This two-part article, which will conclude in the May 2002 issue, analyzes the impact of HAARTon the incidence, clinical course, and outcomes of each of the AIDS-related malignancies.

The purpose of this study was to determine whether health-related quality of life (HRQL) would be improved in patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma treated by pegylated-liposomal doxorubicin (PLD) as compared to those treated by a conventional combination of doxorubicin, bleomycin, and vincristine (ABV). One hundred thirty-three patients received PLD and 125 patients received ABV every 2 weeks with a planned total of 6 cycles. Patients completed a 30-item AIDS-related HRQL questionnaire before beginning treatment (baseline), every 2 weeks while on treatment, and about 21 days after the end of treatment. Twenty-two items, involving nine domains, were analyzable. While on treatment, PLD-treated patients with partial clinical responses achieved statistically significant greater improvement (compared to baseline) in general health than did ABV-treated patients with partial clinical responses (rho = 0.008). By the end of treatment, the overall group of patients receiving PLD showed statistically significant greater improvement in pain and energy/fatigue than did the group receiving ABV (rho = 0.01-0.002). In addition, duration of clinically significant improvement in global QL was longer in the PLD arm.

From the perspective of The University of Arizona's innovative Curriculum on Medical (and Other) Ignorance focusing on "what we know we don't know, don't know we don't know, and think we know but don't," the shifting terrain of information-knowledge-ignorance of AIDS (a disorder involving, to various incompletely understood degrees, the four components of the lymphatic system-lymph, lymphatics, lymphocytes, and lymph nodes) and Kaposi sarcoma (a lymphedemogenic lesion thought to arise from trans-differentiated lymphatic endothelium) is surveyed by pinpointing some key unanswered questions that have been raised over the course of the epidemic and pointedly in past International Congresses of Lymphology. These questions are placed in the context of general ignorance about infectious diseases and the relationship of "germ" to "terrain" through the "blood-tissue-lymph loop." A framework is suggested for an "ignorance agenda" encompassing basic biology, clinical management, and societal issues.

Kaposi's sarcoma (KS) is the most common malignancy associated with the acquired immunodeficiency syndrome (AIDS). Recent years have witnessed a decline in the overall incidence of AIDS-related KS, as well as a greater understanding of the pathogenesis of this disease. Despite these occurrences, AIDS-related KS remains an incurable disease that can create many psychosocial problems for patients and can adversely affect their quality of life. Clinical management of AIDS-related KS has proven to be challenging. Traditional treatment approaches for both local and visceral lesions have been palliative in intent. Clinical studies have shown alitretinoin gel (Panretin) to be a useful alternative or adjunct to other treatments for the management of cutaneous KS lesions. Other therapies, such as antiangiogenesis compounds and cytokine inhibitors, are under investigation in clinical trials, and pathogenesis-directed therapies, such as anti-human herpesvirus type 8 agents, show promise for the effective control of this disease. This review highlights the epidemiology and pathogenesis of AIDS-related KS, and describes various local and systemic therapies, with a focus on new and emerging treatments.

The elusive and enigmatic origin of AIDS-associated Kaposi's sarcoma (AIDS-KS) makes it a complex tumor and therefore difficult to treat. Here we demonstrate that AIDS-KS cells express surface interleukin-4 (IL-4) receptors, and that IL-4 toxin (IL-4(38-37)-PE38KDEL) is specifically cytotoxic to these cells. Intratumoral, intraperitoneal and intravenous administration of IL-4 toxin in nude mice with established subcutaneous AIDS-KS tumors caused considerable anti-tumor activity in a dose-dependent manner, with highest dose producing durable complete responses. Metabolic changes, including cachexia and lymphopenia, induced by KS tumors were prevented by IL-4 toxin treatment. This report establishes IL-4(38-37)-PE38KDEL as an experimental therapeutic agent for the treatment of AIDS-KS.

In less than two decades, the disease mechanisms have been elucidated and hypotheses for innovative treatment have been developed. Our understanding of the sarcoma's pathogenesis has led directly to general knowledge of the physiology and pathology of angiogenesis. Hence, it can be expected that new treatments for all cancer patients may someday emerge from clinical intervention trials for the AIDS-related disease.

Kaposi's Sarcoma (KS), the most common AIDS-associated malignancy, occurs with increased frequency in all HIV transmission groups, but at a particularly high rate in homosexual men. Recent studies suggest that KS pathogenesis involves exposure to an infectious agent, altered expression and response to cytokines, and modulation of growth by HIV gene products. KS varies in its clinical presentation from a relatively indolent process to a widely disseminated, aggressive disease. A variety of local and systemic treatments provide effective, but usually temporary, disease palliation. Insights into KS pathogenesis suggest a number of targeted therapeutic approaches that may eventually lead to improved disease management and disease cure.

AIDS-related Kaposi's sarcoma (KS) represents a complex interaction of host and viral factors. There are a number of fundamental questions surrounding the interplay between the disparate factors that can contribute to the pathogenesis and pathophysiology of this disease. Targets such as the enhancement of immune function, inhibition of angiogenic factors or immunostimulatory cytokines, inhibition of viral proteins such as Tat, or hormonal manipulations are now or will in the future become the focus of research to develop innovative anti-KS therapy and prevention measures. Antiviral approaches aimed at HIV or other viruses may potentially target a number of steps in KS pathogenesis. This article reviews diverse modalities--cytotoxic, antiviral, gene-directed, growth factor-targeted, and antiangiogenesis--that singly, or more likely in combination, stand to make an impact on the cure and prevention of AIDS-related KS.

Objective: To describe the presentation and incidence of Kaposi's sarcoma (KS) in a cohort of women infected with HIV and to compare their clinical characteristics with men at the same institution., Design: Retrospective chart and database review., Setting: Adult clinical AIDS program outpatient clinics at a municipal teaching hospital., Results: One hundred and seven people with KS were found of whom twelve (11.2%) were women. The prevalence of KS in women was 3.6% compared with 9.9% among men (P < 0.001). Women born outside the United States were at increased risk of developing KS (P < 0.05). At initial KS presentation, no difference in HIV stage or CD4 count was found between men and women. Women presented with more advanced KS than men, with increased incidence of non-cutaneous disease (P < 0.001), lymphedema (P < 0.0001), lymph-node disease (P < 0.0001) and visceral disease (P = 0.03). Women had decreased survival after KS diagnosis compared to men, although the difference was not significant (P = 0.41)., Conclusions: KS is not a rare diagnosis in HIV-infected women followed at our institution. Although the increased risk of KS in men is most likely to be related to differences in exposure, the sex-related differences in presentation and course may be due in part to delay in diagnosis. KS should be considered in the spectrum of HIV-related complications in women as well as in men.

Human immunodeficiency virus protease inhibitors produce in acquired immune deficiency virus patients a decrease in both existing and new human immunodeficiency virus accompanied by an increase in CD4+ T cells. Yet these inhibitors are not capable of destroying existing human immunodeficiency virus. Thus human immunodeficiency virus cannot explain this 'eighth' mystery, nor can it explain the destruction of five times more CD4+ T cells than the plasma human immunodeficiency virus, either by apoptosis, by reduction in the half-life of human immunodeficiency virus, or by inducing killer cells. It is proposed that the human immunodeficiency virus protease inhibitors (and the reverse transcriptase non-nucleoside inhibitor Nevirapine) inhibit the sperm's proteases which then produces: (1) a reduction in existing human immunodeficiency virus by causing an increase in CD8+ T cells; (2) a reduction in new human immunodeficiency virus by inhibiting the activity of the 'Trojan horse' sperm, and (3) an increase in CD4+ T cells by a reduction in the ability of the sperm's proteases to cause apoptosis. The protection of the human immunodeficiency virus genetic material inside the "Trojan horse' sperm produces a steady-state, rapid turnover of human immunodeficiency virus. Thus the body's immune system, although capable of quickly destroying human immunodeficiency virus, can only dramatically destroy the offspring released into the plasma from sperm-infected T cells and is unable to destroy the source of human immunodeficiency virus, the "Trojan horse' sperm.

Objective: To describe Kaposi's sarcoma (KS) associated with the acquired immunodeficiency syndrome (AIDS)., Design: A review of AIDS-related KS (AIDS-KS), with its associated epidemiologic and etiologic characteristics, pathogenesis, clinical manifestations, histopathologic features, prognosis, and treatment, is presented., Results: KS is the most frequent malignant lesion in patients with AIDS. The incidence of AIDS-KS is high in homosexual and bisexual men who have multiple sexual partners and in children and women with the human immunodeficiency virus (HIV) infection. Anal-oral contact is one of the main routes of the sexually transmitted agents of AIDS-KS. The major pathogenic factors that may possibly induce AIDS-KS are HIV itself or other sexually transmitted agents, HIV tat gene, some oncogenes and cytokines such as interleukin 6, basic fibroblast growth factor, transforming growth factor-beta, oncostatin M, and platelet-derived growth factor. Treatment includes local therapy, radiotherapy, systemic chemotherapy, zidovudine, interferon, granulocyte-macrophage colony-stimulating factor, and other agents., Conclusion: KS may be an early manifestation of AIDS and the most frequent neoplastic complication of AIDS. Growth factors, cytokines, immunosuppression, and interaction with infectious agents seem to have a role in the development of this enigmatic disorder. Treatment of KS should be individualized. Further investigation of the agents and factors of AIDS-KS may help facilitate the treatment and prevention of this neoplasm.

A possible mechanism for explanation of the simultaneous development of acquired immunodeficiency syndrome (AIDS) and malignant tumors may be based on the cell-fusion process with the participation of immunocompetent cells. If the fusion proceeds with a high intensity, i.e. a great number of cells (including immunocompetent cells) are involved in the process, it will cause a rise in multinuclear formations-polykaryocytes. Since polykaryocytes are incapable of proliferation, their formation is equivalent to elimination of immunocompetent cells and may lead to immunodeficiency. If the intensity of fusion is low, the occurrence of binuclear formations- dikaryons-seems more frequent. We have shown (1) a possibility of the transformation of dikaryons into tumor cells under certain conditions and since immunocompetent cells are dominant by their phenotypic properties the malignant cells in AIDS should have mainly macrophage, lymphoid or intermediate morphology. Even low doses of various chemical carcinogens may cause malignancy by the formation of special defects in plasma membrane which promote cell fusion, whereas under high doses of carcinogens (or high intensity of their action) the formation of polykaryocytes and the development of immunodeficiency seem more probable, though it does not exclude the possibility of cancer development.

Kaposi sarcoma (KS) is a complex multicellular neoplasm that is commonly associated with AIDS. The pathogenesis of KS is not well understood. KS tumor cells grow poorly in vitro and require medium conditioned by retrovirus-infected T lymphocytes. We observed that conditioned medium (CM) from type II human T-cell leukemia virus (HTLV-II)-infected T cells (HTLV-II CM) induces conversion of endothelial cells (ECs) to a KS tumor cell-like phenotype. ECs grown in HTLV-II CM acquired a spindle-shaped morphology, the ability to express factor XIIIa and other KS cell markers, and a cytokine production profile similar to that of KS cells. We found that HTLV-II CM contains large quantities of scatter factor (SF), an angiogenic cytokine that stimulates cell motility. SF induced ECs to become spindle-shaped and express factor XIIIa. Moreover, SF was found to be a mitogen for KS cells in vitro and was identified within KS lesions in vivo. SF mRNA was present in KS cells in vitro, and antibodies against SF inhibited the growth of KS cells. The receptor for SF, the c-met protein, was expressed by ECs, dermal dendrocytes, and KS tumor cells in vitro and in vivo. HTLV-II CM was highly angiogenic in vivo, which was blocked by antibodies against SF. Based on these findings, we suggest that SF plays a role in the initiation and maintenance of KS lesions.

Background: Kaposi's sarcoma in HIV antibody positive patients may affect the lungs. This study describes the presentation, chest radiographic appearances, and pulmonary function test abnormalities in patients with AIDS who had tracheobronchial Kaposi's sarcoma., Methods and Results: Twenty nine (8%) of 361 consecutive HIV antibody positive patients undergoing bronchoscopy for respiratory symptoms had tracheobronchial Kaposi's sarcoma. Eight patients had intercurrent infections and one had previously received chemotherapy for cutaneous Kaposi's sarcoma; these patients were excluded. Seven of the remaining 20 patients had localised Kaposi's sarcoma (lesions confined to the trachea or the subsegments of one lobe) and 13 had widespread Kaposi's sarcoma (affecting the trachea and one lobe or the subsegments of more than one lobe); 19 patients also had cutaneous and palatal Kaposi's sarcoma. Seven patients, four with widespread disease, had a normal radiograph. All patients had reduced transfer factor (TLCO) and transfer coefficient (KCO) but only those with widespread disease had reductions in forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF). Follow up pulmonary function testing in seven patients (median three months later) showed further reductions in TLCO. All four patients who received no treatment had progressive radiographic abnormalities; bronchoscopy in two patients showed progressive tracheobronchial disease, and two patients had further reductions in FEV1 and FVC. In three patients treated with chemotherapy palliation of symptoms was achieved but two had further reductions in FEV1 and FVC and the radiograph deteriorated. Bronchoscopy showed regression of disease in only one patient., Conclusion: Pulmonary Kaposi's sarcoma produces abnormalities of TLCO even in patients with localised disease; airflow obstruction may occur in patients with widespread disease. Bronchoscopic reassessment of the extent of disease may not accurately reflect response to chemotherapy.

As previously described, proliferation of Kaposi sarcoma (KS)-derived cells in vitro is dependent on the presence of platelet-derived growth factor (PDGF). To test the hypothesis that PDGF may also be a major growth factor for KS cells in vivo, we performed in situ hybridization and immunohistochemical staining for PDGF and PDGF receptors in tissue sections of AIDS-related KS. The data suggest that KS consists of two types of tumor cells. (i) The main population are spindle-shaped cells with elongated nuclei (KS-s cells). They reveal a strong expression of PDGF beta receptors but do not express the PDGF-A and PDGF-B isoforms. (ii) A minor population of KS cells express PDGF beta receptor as well as PDGF-A and PDGF-B (KS-p cells). These cells are often grouped in whorls and surrounding vascular slits. They reveal spherical nuclei with evenly distributed chromatin and inconspicuous nucleoli. PDGF alpha receptor is not expressed in either form of KS cells. The results suggest that the isoforms of PDGF and the PDGF beta receptor are differentially expressed in two different cell types in KS and that PDGF isoforms may contribute to the pathogenesis of KS.

Kaposi's sarcoma (KS) in general, and acquired immunodeficiency syndrome-related KS (AIDS-KS) in particular, is a highly invasive and intensely angiogenic neoplasm of unknown cellular origin. We have recently established AIDS-KS cells in long term culture and reported the development of KS-like lesions in nude mice inoculated with these cells. Here, we have examined the in vitro invasiveness of basement membrane by AIDS-KS cells, as well as the effect(s) of their supernatants on the migration and invasiveness of human vascular endothelial cells. AIDS-KS cells were highly invasive in the Boyden chamber invasion assay and formed invasive, branching colonies in a 3-dimensional gel (Matrigel). Normal endothelial cells form tube-like structures on Matrigel. AIDS-KS cell-conditioned media induced endothelial cells to form invasive clusters in addition to tubes. KS-cell-conditioned media, when placed in the lower compartment of the Boyden chamber, stimulated the migration of human and bovine vascular endothelial cells across filters coated with either small amounts of collagen IV (chemotaxis) or a Matrigel barrier (invasion). Basic fibroblast growth factor could also induce endothelial cell chemotaxis and invasion in these assays. However, when antibodies to basic fibroblast growth factor were used the invasive activity induced by the AIDS-KS-cell-conditioned media was only marginally inhibited, suggesting that the large quantities of basic fibroblast growth factor-like material released by the AIDS-KS cells are not the main mediators of this effect. Specific inhibitors of laminin and collagenase IV action, which represent critical determinants of basement membrane invasion, blocked the invasiveness of the AIDS-KS cell-activated endothelial cells in these assays. These data indicate that KS cells appear to be of smooth muscle origin but secrete a potent inducer of endothelial cell chemotaxis and invasiveness which could be responsible for angiogenesis and the resulting highly vascularized lesions. These assays appear to be a model to study the invasive spread and angiogenic capacity of human AIDS-related KS and should prove useful in the identification of molecular mediators and potential inhibitors of neoplastic neovascularization.

Prospective evaluation of cardiac function was undertaken in 21 patients with Kaposi's sarcoma (KS) and the acquired immune deficiency syndrome (AIDS) as part of a phase II clinical trial of 4'epirubicin. All patients were homosexual or bisexual males of median age 34 years (range 23-65). All patients had disseminated cutaneous involvement by KS and seven had systemic organ involvement. No patient had a history of cardiac symptoms, and physical examination of the cardiovascular system was within normal limits for all patients. The baseline ECG was normal in only nine patients (45%). Five had non-specific S-T segment and T-wave changes. Two had poor R-wave progression, and one patient each had incomplete right bundle branch block, left axis deviation, and voltage criteria suggestive of left ventricular hypertrophy. Radionuclide angiography was performed on all patients and compared to 12 age-matched, low-likelihood male controls. The mean ejection fraction (EF) at rest was 61.0 +/- 8.4%, and was not significantly different from the normal control value of 62.4 +/- 7.0%. Similarly the EF during exercise was 66.7 +/- 5.0%, again not significantly different from the control value of 67.8 +/- 5.8%. A drop in EF during exercise was seen in five of 15 KS patients compared to three of 12 controls. Chamber size was normal for both ventricles in only 14 patients (67%) with right ventricular dilatation seen in seven patients (33%). Wall motion abnormalities were also seen in nine patients (42.9%), with the right ventricle affected in eight patients (38.1%), chiefly involving the apex. No chamber size or wall motion abnormalities were seen in the control patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Kaposi's Sarcoma (KS) is a tumor of mesenchymal origin of unclear etiology and pathogenesis. The epidemic form of KS (AIDS-associated) occurs in up to 30% of HIV-1 infected individuals with lesions characterized by mixed cellularity, spindle cells proliferation and neoangiogenesis. The establishment of in vitro and in vivo model systems (AIDS-KS cell cultures and nude mouse) have allowed studies toward the understanding of the pathogenesis of KS. The data presented here support the hypothesis that KS is a cytokine mediated disease and that interactions between mesenchymal cell types and HIV-1 gene products might lead to a composite lesion such as KS. In fact, in vitro and in vivo studies indicate that the HIV-1 Tat protein acts as a growth factor for cells derived from AIDS-KS lesions, thus establishing an experimental link between HIV-1 infection and the development of KS in humans. Human immunodeficiency virus (HIV-1) is implicated in various clinical manifestations associated with AIDS, including KS. KS represents the most frequent tumor arising in infected individuals, particularly homosexual and bisexual men. This form of KS (epidemic or AIDS-KS) is aggressive and often results in dissemination and invasion of lymph nodes and viscera. Histologically, KS is characterized by the proliferation of spindle-shaped cells ("KS cells"), considered to be the tumor element of the lesions, associated with endothelial cells, fibroblasts, inflammatory cells and new blood vessel formation (early stage lesions). In a later stage, the spindle cells tend to coalesce in larger tumor masses, although the slit-like spaces, which are characteristic of the lesion, usually remain evident. The histogenesis of the KS spindle cells, however, is still controversial and both types of mesenchymal cells, endothelial and smooth muscle cells, have been proposed as potential cell progenitors. Although KS is clearly associated with HIV-1 infection, little is known about the molecular events underlying its pathogenesis. Recently, however, two experimental advances (the establishment of long-term cell cultures derived from KS lesions of AIDS patients and the development of animal models) have made the study of the pathogenesis of AIDS-KS possible. Here we discuss results obtained from these new systems suggesting that the induction of the AIDS-KS lesions involves a pathway of events mediated by specific cytokines and that the HIV-1 tat gene product may play a crucial role in the development and/or progression of KS in HIV-1 infected individuals.

Viral genes capable of inducing vascular tumors in the skin of transgenic mice are the tat gene of HIV-1 and polyoma virus' middle T antigen gene. Instead of vascular tumors, the tat gene of HTLV-I causes thymic atrophy and mesenchymal tumors in transgenic mice. No proof exists that any of these genes contribute to the induction of KS but HIV-1 tat is a strong suspect. The gene product K-FGF of the oncogene K-fgf/hst (int) uses bFGF receptors, is homologous with bFGF and acts as a mitogen for fibroblasts, endothelial cells and melanocytes. The overexpression of the K-fgf gene in KS is not proven unequivocally; some doubts exist suggesting the activation of this gene during the laboratory procedure of transfection with KS cell heavy DNA. Growth factor(s) not well identified (IL-6?) are released from HTLV-I- or II, or HIV-1- or 2-infected T4 lymphocytes and in particular from HIV-1-infected macrophages. This growth factor(s) promote(s) the continuous proliferation of endothelial cells and KS cells. AIDS-KS cells release other growth factors identical with or closely related to basic FGF, a major inducer of angioneogenesis. In addition, acidic FGF, IL-1 alpha and -beta, GM-CSF, PDGF-B and TGF-beta are released from AIDS-KS cells. The release of GM-CSF is induced by IL-1. GM-CSF promotes granulocytic, monocytic and endothelial cell proliferation. TGF-beta is known to suppress lymphocyte-mediated cytotoxicity and may act as a local immunosuppressive factor together with interferon inactivators. We theorize that when TGF-beta production ceases, TNF-beta (lymphotoxin) production switches on leading to programmed cell death (apoptosis) of KS cells resulting in regression of these lesions. The newly discovered angiogenesis factors VEGF/VPF may emerge as protooncogene-oncogene products analogous to PDGF and c-sis activation. AIDS-KS heavy DNA transfects NIH3T3 cells. NIH3T3 cells carrying this gene induced angiosarcomas when implanted in mice. An as yet unidentified large virus (mycoplasma?) was derived from these cells during passages in culture. No causative relationship between this agent and Kaposi sarcoma has as yet been established. Even though IFN-alpha exerts antiretroviral effects in AIDS, we propose that the therapeutic effect of IFN-alpha in AIDS-KS is based on antiangiogenesis activity by suppressing protooncogenes-oncogenes of the FGF family.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell lines derived from Kaposi sarcoma lesions of patients with AIDS (AIDS-KS cells) produce several cytokines, including an endothelial cell growth factor, interleukin 1 beta, and basic fibroblast growth factor. Since exposure to human immunodeficiency virus increases interleukin 6 (IL-6) production in monocytes and endothelial cells produce IL-6, we examined IL-6 expression and response in AIDS-KS cell lines and IL-6 expression in AIDS Kaposi sarcoma tissue. The AIDS-KS cell lines (N521J and EKS3) secreted large amounts of immunoreactive and biologically active IL-6. We found both IL-6 and IL-6 receptor (IL-6-R) RNA by slot blot hybridization analysis of AIDS-KS cells. The IL-6-R was functional, as [3H]thymidine incorporation by AIDS-KS cells increased significantly after exposure to human recombinant IL-6 (hrIL-6) at greater than 10 units/ml. When AIDS-KS cells (EKS3) were exposed to IL-6 antisense oligonucleotide, cellular proliferation decreased by nearly two-thirds, with a corresponding decrease in the production of IL-6. The decrease from IL-6 antisense in AIDS-KS cell proliferation was reversed by the addition of hrIL-6. We confirmed that AIDS-KS cells produced IL-6 in vivo by preparing RNA and tissue sections from involved and uninvolved skin from a patient with AIDS Kaposi sarcoma. We detected immunoreactive IL-6 in the involved tumor areas and to a lesser extent in the surrounding normal epidermis. Slot blot hybridization showed a great excess of IL-6 and IL-6-R RNA in involved skin compared to uninvolved skin. These results show that both IL-6 and IL-6-R are produced by AIDS-KS cells and that IL-6 is required for optimal AIDS-KS cell proliferation, and they suggest that IL-6 is an autocrine growth factor for AIDS-KS cells.

This article has reviewed the disease process and oral manifestations of AIDS. Specifically, dentists should review the medical history and perform an overall health assessment for all dental patients before treatment is rendered. Attention should be directed to the prodromal signs and symptoms of AIDS. If dental treatment of a patient with AIDS is required, strict infection control guidelines are mandatory.

The epidemic form of Kaposi's sarcoma (KS) that occurs in patients with the acquired immune deficiency syndrome (AIDS) produces lesions that, histopathologically, are indistinguishable from those of classical KS or of the endemic form of the disease seen in children and adults in certain areas of Africa. There are, however, important differences in the pathogenesis of the disease in the different groups affected by the neoplasm. Compared with classical KS in people of eastern European and Mediterranean descent, which commonly takes a protracted, indolent course, the epidemic Kaposi's sarcoma (EKS) is far more aggressive. However, the KS seen in adults in endemic areas of Africa may also become florid and rapidly progressive after years of quiescence. Some degree of immune dysfunction is thought to be a factor in all forms of KS, with immune depression being the hallmark of EKS and the setting in which it occurs. Cytomegalovirus (CMV) is thought to be at least a cofactor in the disease, but it has also been suggested that the etiologic agent of AIDS, human immunodeficiency virus (HIV), may also play a role in EKS.

The role of nutritional factors in the management of acquired immunodeficiency syndrome-related, or epidemic, Kaposi's sarcoma (EKS) is complex, since there are known interactions between malnutrition, immunodeficiency, and cancer. Malnutrition is a well-established cause of immune aberrations, which are seen in deficiencies of both protein and energy, as well as specific nutrients, particularly trace metals. Conversely, malnutrition is a common result of both cancer and immunodeficiency. Cancer patients without an obviously immunological pathogenesis frequently have malnutrition and cachexia, mainly as a result of a decreased dietary intake and poorly defined host-tumor interactions (commonly labeled "hypermetabolic"). Patients with primary immunodeficiency syndromes similarly experience a triad of diarrhea, malabsorption, and weight loss, which are responsible for the development of malnutrition. This triad is common in patients with AIDS, with or without the presence of Kaposi's sarcoma. The specific mechanisms of these interactions in EKS patients are largely unexplored; although some can be explained by the enteropathic effects of opportunistic infections, others can not. Some investigators have advocated careful nutritional evaluation of all AIDS patients, with vigorous nutritional support to be provided where assessment reveals suboptimal nutritional status. Specific nutrient deficiencies have been reported, of which selenium may be the most interesting; preliminary data indicate that it may be responsible for a malnutrition-related immunodepression seen with AIDS. Such supportive measures may significantly improve symptomatic relief, but there is as yet no evidence that they alter the course of the disease.

Pulmonary Kaposi's sarcoma related to the acquired immune deficiency syndrome (AIDS) has not been well characterized. To define the clinical, radiographic, and pathologic features of this entity, 11 autopsy-proved cases of pulmonary Kaposi's sarcoma were reviewed. The most common clinical symptoms were dyspnea and cough, but hemoptysis and stridor were also found. Nodular infiltrates and pleural effusions were the most commonly found radiographic abnormalities. Pulmonary function tests were sensitive in detecting the pulmonary abnormalities due to Kaposi's sarcoma. A low diffusion capacity, lack of arterial desaturation with exercise, and obstruction to airflow were suggestive of pulmonary involvement with this malignancy. Although endobronchial Kaposi's sarcoma was visualized at bronchoscopy as cherry-red, slightly raised lesions, bronchial biopsy specimens always showed no abnormalities. Transbronchial brushings and biopsy specimens and analysis of pleural fluid were also not helpful in establishing a diagnosis. In the seven subjects with extensive parenchymal Kaposi's sarcoma at autopsy, the pleura was always involved. Eight subjects had involvement of the tracheobronchial tree. In all of the subjects, pulmonary Kaposi's sarcoma was a significant cause of morbidity, and in three of 11 subjects (27 percent) it was the direct cause of death.

Interferon alfa-2a (Roferon-A, Hoffmann-La Roche Inc., Nutley, NJ) was used to treat sequential groups of patients with Kaposi's sarcoma associated with the acquired immune deficiency syndrome (AIDS). Major antitumor effects (complete or partial responses) were observed in 38% of the patients treated initially with high-dose interferon alfa-2a and in 17% of patients in whom the dose was increased after low-dose treatment failed. A low dose of interferon alfa-2a was ineffective; one patient (3%) showed a partial response. Patients whose tumors responded to interferon treatment showed a significantly lower rate of opportunistic infection, as well as a longer survival than nonresponders. The status of pretreatment immune function was important in predicting the response to interferon treatment. The implication of these findings with respect to understanding the mechanism of action of interferon and the definition of the most appropriate patients for interferon treatment are discussed.

The Acquired Immunodeficiency Syndrome (AIDS) has stimulated renewed attention toward infectious diseases and dental public health. Currently, AIDS is defined as individuals with Kaposi's sarcoma and/or pneumocystis carinii pneumonia and/or other life-threatening opportunistic infections (e.g., specific forms of tuberculosis or meningitis, candidal esophagitis), and associated immunosuppression that cannot be accounted for by another disease process and/or medications. As of January 1986, the AIDS epidemic has afflicted over 16,000 persons in the United States and has taken over 8,000 lives. All present indications point toward a much more extensive epidemic based on the lack of a vaccine and effective forms of treatment, the large number of carriers in the population, and variable modes of transmission.

The ultrastructural morphology of Kaposi's sarcoma of the oral mucosa in patients with acquired immune deficiency syndrome (AIDS) was examined electron-microscopically. Neoplastic spindle cells and vascular endothelial tumor cells are frequently involved in the phagocytosis of extravasated erythrocytes. Pericytes, fibroblasts, macrophages and other phagocytic cells of the tumor stroma also participate in this process. Erythrocytes are also phagocytized by some of the keratinocytes belonging to the intact surface epithelium covering the Kaposi's sarcoma lesion. Both the phenomenon of erythrophagocytosis and the presence of tubuloreticular structures in the cytoplasm of Kaposi's sarcoma cells in patients with AIDS seem to be prominent ultrastructural markers and thus of diagnostic value.