There is compelling evidence that KS is caused by the KS herpesvirus (KSHV), also called human herpesvirus 8 (HHV8). Exactly how KSHV infection leads to KS is still unclear. Like other herpesviruses, KSHV establishes latent infection, during which several proteins are produced with potential roles in stimulating spindle cell proliferation and preventing apoptosis. These include a viral homologue of the cell cycle regulator cyclin D (an oncogene) and several inhibitors of p53 (a key tumor suppressor gene), both of which have been implicated in tumor development (Chapter 6). The spindle cells produce proinflammatory and angiogenic factors, which recruit the inflammatory and neovascular components of the lesion, and the latter components supply signals that aid in spindle cell survival and growth. However, KSHV infection, while necessary for KS development, is not sufficient, and additional cofactors are needed. In the AIDS-related form, that cofactor is clearly HIV. HIV-mediated immune suppression may aid in widespread dissemination of KSHV in the host.
Clinically, AIDS-associated KS is quite different from the sporadic form (Chapter 10). In HIV-infected individuals, the tumor is usually widespread, affecting the skin, mucous membranes, gastrointestinal tract, lymph nodes, and lungs. These tumors also tend to be more aggressive than sporadic KS.
Lymphomas. Lymphoma occurs at a markedly increased rate in individuals with AIDS, making it another AIDS-defining tumor. Roughly 5% of AIDS patients present with lymphoma, and approximately another 5% develop lymphoma during their subsequent course. Even in the era of anti-retroviral therapy, lymphoma continues to occur in HIV-infected individuals at an incidence that is at least 10-fold greater than the population average. Based on molecular characterization of HIV-associated lymphomas and the epidemiologic considerations above, at least two mechanisms appear to underlie the increased risk for B-cell tumors in HIV-infected individuals.
Tumors Induced by Oncogenic Viruses. T-cell immunity is required to restrain the proliferation of B cells latently infected with oncogenic viruses such as EBV and KSHV. With the appearance of severe T-cell depletion in the course of HIV infection, this control is lost, and the infected B cells undergo unchecked proliferation that predispose to mutations and the development of B-cell tumors. As a result, AIDS patients are at high risk for developing aggressive B-cell lymphomas composed of tumor cells infected by oncogenic viruses, particularly EBV. The tumors often occur in extranodal sites, such as the CNS, gut, orbit, and lungs, and elsewhere. AIDS patients also are prone to rare lymphomas that present as malignant effusions (so-called “primary effusion lymphoma”), which are remarkable in that the tumor cells are usually coinfected by both EBV and KSHV, a highly unusual example of cooperativity between two oncogenic viruses.