Kaposi’s Sarcoma: Insights into its Understanding

Kaposis Sarcoma Insights into its UnderstandingAbstractKaposis Sarcoma (KS) is a common vascular neoplasm arising in gentle immunodeficiency computer virus (human immunodeficiency virus) infected patients and is one of the 27 conditions designated by the Centers for Disease Control as an acquired immunodeficiency syndrome (AIDS) defining illness. Human herpes virus virus-8 (HHV-8), now called Kaposis sarcoma-associated herpes virus (KSHV), is a member of herpes virus family and is considered to be the causative agent of KS. This review aims to discuss KS and its necktie with HIV/AIDS with an emphasis on spontaneous features, the role of HHV-8/KSHV in causation of KS, and the current challenges faced in management of the disease.Key words acquired immunodeficiency syndrome, human herpes virus-8, Kaposis sarcoma, Kaposis sarcoma-associated herpes virus mental institutionIn 1869, Helmut Kobner, a German physician, appears to deplete been the first to describe cases of metas ropin essic cutaneous sarcoma. In 1872, the Hungarian physician, Moricz Kaposi, described an idiopathic, multipigmented, tumour-like lesion of the skin that eventually was named Kaposis Sarcoma (KS).1,2 During the 19th century, KS was considered a rargon disease and by the early twentieth century, an increased incidence was suggested.2,3 KS is now a common vascular tumor arising in human immunodeficiency virus (HIV) infected patients, and is one of the 27 conditions designated by the Centers for Disease Control as an acquired immunodeficiency syndrome (AIDS) defining illness.2,4 Human herpes virus-8 (HHV-8), excessively called Kaposis sarcoma-associated herpes virus (KSHV), a member of herpes virus family, is considered to be the causative agent of KS.5Clinical FeaturesBased on epidemiology and demographics, in that location ar four variants of KS 1) Classic KS that is relatively benign and predominantly lapses in elderly men of Mediterranean, Eastern atomic number 63an, or Middle Eastern derivation with a median age of 70 years 2) an Endemic or African form of KS that in addition occurs predominantly in men at a ratio of 31 with a peak median age of 35 to 39 years 3) Iatrogenic or Post-transplant KS that whitethorn occur in HIV-seronegative immunocompromised individuals, long term users of steroids and cytotoxic drugs, and individuals with autoimmune disorders and 4) AIDS-associated KS. Although the four variants of KS ar distinctive, they sh are similar clinical and histologic features, indicative of common pathogenesis.5 In contrast to classic KS, which is often hold to the extremities, AIDS-associated KS a great deal involves the muco-cutaneous regions of the head and neck as primary sites, and visceral involvement is excessively present.6 Muco-cutaneous lesions of the head and neck region, occur in estimated 10% of AIDS patients.7 The spontaneous cavity is frequently involved with the hard and soft palate, gingiva, and tongue being the most co mmon sites.8,9 The prevalence of unwritten KS varies from 0-12% in Africa, and from 0-38% in fall in States and Europe.10,11 A high prevalence of spontaneous KS was demonst calculated in 18.6% of a group of HIV-infected patients in Zimbabwe. Since the advent of AIDS, KS has become more frequent in both the genders, the male to female ratio changing from 191 to 71, particularly in East Africa.12On the basis of clinical appearance, AIDS-associated KS is classified into six major overlapping types patch, plaque, nodular, telangiectatic, infiltrative, and florid.1,3,13,14 Oral lesions appear as red to purple macules, papules, or nodules that may ulcerate and cause topical anaesthetic destruction.9,15 Although the clinical behavior of AIDS-associated oral KS is rather unpredictable, majority of the cases represent rapacious disease and have associated disseminated cutaneous and visceral lesions.16 Slow growing oral tumors are generally associated with patients who have no additional complicating opportunistic infections.17 first derivative DiagnosisEarly lesions of KS may be uncorrectable to distinguish from ecchymoses, nevi, dermatofibroma, and lichen planus.18 noduled or plaque like lesions overlying mucosa should be biopsied to order out bacillary angiomatosis, hemangioma, pyogenic granuloma, angiosarcoma, or lymphangiosarcoma.18,19HistopathologyThe jail cellular origin of KS is difficult to determine as lesions typically exhibit multiple cell types. The tumor is mainly composed of undifferentiated mesenchymal cells and spindle-shaped cells.20-23 The spindle cells, considered the tumor element, are of mesenchymal origin and have features that resemble both endothelial and smooth ponderousness cells.22,23 The tumor cells may be derived from cells of either lymphatic or venous differentiation.17,22 Also, biopsies of KS feature numerous slit like vascular channels and may present extravasation of erythrocytes, hemosiderophages, eosinophilic hyaline inclus ions, and seditious infiltrate.9,20,21The histogenesis of the spindle cell component, believed to be the KS tumor cell, remains controversial although many studies favor an endothelial cell origin.22-24 A nonher highly debatable issue is whether KS is a clonal neoplastic lesion, or whether it is reactive and polyclonal. Most of the evidence suggests that many KS lesions are hyperplastic and polyclonal in nature, and that eitherthese lesions contain a small residual of clonal, neoplastic tumor cells that are difficult to identify and culture, or whatever of these polyclonal lesions may undergo full transformation during disease progression, belike when an actively proliferating cell acquires genetic alterations that provide a selective advantage, leading to the out product of a truly neoplastic clone in the minority of cases of KS.24 role of HHV-8/KSHV HIVMultiple agents, including cytomegalo virus, hepatitis-B virus, human herpes virus-6, HIV, and Mycoplasma penetrans, have be en suspected in the past as causing KS but none of these have been understandably shown to present in most cases and to have a causal affiliation with KS.24 Thus, although an infectious origin has long been suspected, it was only in 1994 that HHV-8/KSHV was first detected in KS specimens.25 KSHV is now considered the causative agent of AIDS-associated, classic, endemic, and iatrogenic KS. In addition, it is overly believed to be the causative agent of primary effusion lymphomas (body cavity found lymphomas),26 multicentric Castlemans disease,26,27 and possibly oral plasmablastic lymphomas.28Serological studies have indicated that unlike other human herpes viruses, KSHV is not ubiquitous.26 The seroprevalence of KSHV is low in the United States and parts of Europe (ranging from 0 to 20%), rising in Mediterranean countries to reach levels greater than 50% in some geographic regions of Africa.12 In North the States and Europe, primary infection with KSHV mainly occurs among adult h omointimate men and is genetical principally via sexual contact the KSHV seroprevalence being associated with the number of sexual partners and sexual practices.12,26 Transmission of KSHV via saliva has also been documented.29 In African populations, KSHV infection seems to occur largely before puberty through casual family and community contacts oral secretions being a potential vehicle of non-sexual horizontal spread plumb transmission of KSHV being insignificant.12,26 A recent study conducted in Malawi, Africa, has also shown that, apparently, healthy people in regions where KSHV is endemic can be infected by multiple strains.30 However, it is still unclear if this reflects a simultaneous co-infection by some(prenominal) KSHV strains, reactivation of latent strains, or super infection.30KSHV is lymphotropic and is more closely colligate to Epstein-Barr virus and herpes virus saimiri than to other herpes viruses.5,27 The KSHV genome contains several genes related to cellular g enes involved in cell proliferation and host responses that probably contribute to viral pathogenesis.26,31The pathogenesis of AIDS-associated KS is multifactorial and involves KSHV, altered expression and response to cytokines, and excitant of KS growth by HIV trans-activation protein (tat).32,33 KSHV is a necessary, but solely not a sufficient cause of KS.34 It encodes protein homologues of interleukin-6, chemokines of the macrophage inflammatory protein family, cell cycle regulators of the cyclin family, and anti-apoptotic genes of the bcl-2 family.26 The HIV tat protein can promote the growth of spindle cells of endothelial origin, but only in battlefront of inflammatory cytokines.32,33 The synergistic relationship amidst inflammatory cytokines and HIV tat protein, when combined with the immunosuppression associated with AIDS, may provide an comment for aggressive nature of AIDS-associated KS compared to relatively non-aggressive, classic Mediterranean form in which the HIV tat protein does not play a role.33 The sequence of events creating the inflammatory angiogenic env pressment has been described by Dezube 33 as follows 1) circulating KS progenitor cells and cells latently infected with KSHV seek sites of pre-existing inflammation in the case of oral KS, pre-existing inflammation may include acute and/or inveterate periodontal disease sites 2) exposure to inflammatory cytokines much(prenominal)(prenominal) as interferon- (IFN-) results in differentiation of latently infected cells into KS-like spindle cells and induces KSHV reactivation 3) reactivation of KSHV leads to expression of potentially pathogenic genes such as viral interleukin-6 that in turn, can activate vascular endothelial growth factor and induce angiogenesis 4) viral lytic replication in the aforementioned(prenominal) cells activates inflammation, which also may play a role in angiogenesis 5) the substructure of inflammatory-angiogenic environment increases the availability of inf ectable cells, i.e. endothelial and KS spindle cells, which are then include in the development of the lesion 6) cells also become responsive to HIV tat protein and 7) the HIV tat protein augments the inflammatory-angiogenic state by the increasing angiogenic activities of basic fibroblast growth factor, IFN-, and vascular endothelial growth factor by mimicking the effects of the outdoor(a) matrix proteins fibronectin and vitronectin and by increasing the expression of matrix metalloproteinases.Prognosis and solicitudeThe prognosis of patients with AIDS-associated KS is often related to factors other than the tumor burden itself. In 1989, the AIDS trial council group devised the TIS staging system, based upon the extent of tumor (T), the status of immune system in terms of CD4+ T-cell count (I), and the presence of other systemic HIV-related illness (S).12At present there is no treatment for AIDS-associated KS. Treatment is thus directed towards the elimination, or at least(preno minal) reduction of cosmetically unacceptable lesions, pain, and oedema, as well as the reprieve of symptoms caused by visceral involvement.33 Local therapy may be effective for limited disease, but systemic therapy is required for disseminated KS.33 Highly active anti-retroviral therapy (highly active antiretroviral therapy) is useful in the management of AIDS-associated KS, as it will reduce the HIV viral commove and raise the CD4+ T-cell count, both of which contribute to the pathogenesis of KS. Recent reports have described a reduced incidence or regression of KS in HIV-infected individuals treated with HAART that includes at least one protease inhibitor. Both in vivo and in vitro studies have demonstrated that protease inhibitors have a direct anti-angiogenic, anti-KS, and anti tumor activity at concentrations likely to be present in the billet of treated individuals. HAART causes fall in KSHV levels in the blood presumably because of a reduction in HIV proliferation, HIV/K SHV-mediated oncogenesis, and HIV-induced immunosuppresion.12 former(a) approaches of managing oral KS have included local irradiation, intralesional injections of vinblastine and 3% atomic number 11 tetradecyl sulphate, laser therapy, surgical excision, cytotoxic therapy with vinca alkaloids (vinblastine, vincristine, and vinorelbine), bleomycin, anthracyclines, paclitaxel, and liposomal anthracyclines. However, only five agents are commonly used for the treatment of KS alitretinoin gel for topical therapy, and liposomal daunorubicin and oloxorubicin, paclitaxel, and IFN- for systemic therapy.12The potent angiogenic component of KS makes it particularly suitable for treatment with drugs that act as anti-angiogenic agents such as thalidomide and newer agents such as matrix metalloproteinases and IM-862. Based upon the apoptotic and anti-proliferative activity of iron chelation on KS cells, it is also suggested that withdrawal strategies may be effective. Several retinoid compounds have also been tested in clinical trials for KS, with a response rate of 23-37%.12Direct antiviral approaches targeting KSHV have been proposed. In vitro studies have shown that KSHV is very sore to cidofovir, moderately sensitive to ganciclovir and foscarnet, but only weakly sensitive to acyclovir. However, the talent of cidofovir in vivo has yet to be proven. IFN- may inhibit infection or reactivation by KSHV. Single agent therapy with IFN-, is associated with significant toxicity, but when in combine with anti retroviral agents it may have some application for disseminated, but non-rapidly industrial KS.12 ConclusionsStudies pertaining to KS suggest epidemiologic patterns that are consistent with a sexually genic agent, before a viral agent HHV-8/KSHV was identified, and that it is strictly not an opportunistic infectious agent related to HIV/AIDS-associated KS. Immune suppression along with genetic and/or environmental factors may interplay in variable combinations in the eventual causation of KS.Currently, a wide array of treatment modalities for KS, are aimed at elimination of cosmetically unacceptable lesions, reduction of unsightly edema and lymphadenopathy, and to alleviate symptoms caused by systemic involvement.