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                       KS is an angioproliferative disorder resulting from immune dysregulation.  The early
               lesions of KS are thought to be reactive and, theoretically, reversible.  Most KS lesions are
               polyclonal.  However, the immune system activation, with a TH1 response and cytokine
               production, that continues with KSHV infection, drives the process to true neoplasia, with
               evolution from polyclonal proliferation to monoclonal neoplasm.  Cellular oncogenic alterations
               including mutations in p53, KRAS, or BCL-2 overexpression, or gene amplification, occur only
               in late-stage advanced disease.[544]  The HIV Tat protein also appears to play a role by
               stimulating growth and angiogenesis.[552]
                       In developed nations the HHV-8 agent (KSHV) is seen as a sexually transmissible
               disease that can occur independently of HIV infection, and it accounts for the increased
               incidence of KS in homosexual males.  The prevalence of HHV-8 is 30-40% among homosexual
               males and correlates with the number of sexual partners.  In Africa, KSHV is also spread as a
               congenital infection and in childhood.  Primary infection with KSHV is asymptomatic.[543]
               KSHV can be identified in peripheral blood mononuclear cells with a higher frequency in
               persons with KS than without KS.  It can be detected in saliva and semen.  This agent can still be
               detected despite therapy with anti-herpesvirus drugs.  However, the incidence of KS decreases
               with antiretroviral therapy.[553]
                       Neither cytomegalovirus (CMV) nor human herpesvirus-6 (HHV-6) infection appears to
               be associated with development of KS.[554]  The increased prevalence of KS in men, typical
               those whose risk factor for HIV infection is sexual intercourse with other males, over women is
               explained by the lower prevalence of HHV-8 seropositivity in HIV-infected women.[555]
                       Though the skin is involved in over three fourths of cases and is often the site of initial
               clinical presentation, skin is usually not the sole site of involvement.  Visceral KS (involving one
               or more internal organs sites) is also present in three fourths of cases, but may not be diagnosed
               prior to autopsy.  Visceral involvement frequently includes the lung, lymph nodes, and
               gastrointestinal tract.  In fewer cases, KS appears in the liver or genitourinary system.  Kaposi's
               sarcoma is infrequent in adrenal, heart, and spleen; KS is rare elsewhere (Table 5).  Though
               multifocal, KS appears to be monoclonal in origin, typical of a true neoplasm.[556]
                       Bronchoscopic and gastrointestinal endoscopic biopsy may yield a diagnosis of KS, but
               these methods are hampered by sampling error from the focal nature of KS lesions.  Though it is
               common for KS to become widely disseminated, some patients may have only one site or focus
               of involvement, not necessarily skin.  The natural history of KS, however, is progression over
               time to involve multiple sites in multiple organs.
                       A complete description of gross and microscopic appearances of KS is given in the
               section of organ system pathology on skin.  To summarize, KS lesions grossly are red to red-
               purple.  The lesions range from a flat patch to slightly raised plaques to nodules.  Lesions larger
               than 0.5 cm are usually nodular.  Microscopically, KS is characterized by atypical large spindle
               to fusiform cells that line slit-like vascular spaces.  Red blood cell extravasation, hemosiderin
               pigmentation, and hyaline globules usually accompany the spindle cell proliferation.  The lesions
               have irregular, infiltrating margins.  Sometimes the vascular spaces are dilated and sometimes
               sheets of KS spindle cells have inapparent vascularity.  Kaposi's sarcoma has a propensity to
               infiltrate around large vascular structures, near epithelial or mesothelial surfaces, or near the
               capsules of organs.[545]
                       Small, early KS lesions or KS that is ulcerated or inflamed can be difficult to diagnose.
               Granulation tissue can have a strikingly similar appearance.  Hemangiomas may grossly--and
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