The interplay of the immune system and cancer was recognized prior to the acquired immunodeficiency syndrome (AIDS) epidemic. In the setting of immunosuppression (either congenital or acquired), there is an increased risk of several malignancies, including non-Hodgkin’s lymphoma (NHL), Kaposi’s sarcoma (KS), nonmelanoma skin cancers, and anogenital neoplasia (see Table 1).[1-10] The relationship between immunosuppression and malignancy is not entirely understood. Putative mechanisms of tumorigenesis in immunosuppressed patients implicate impaired immune surveillance and uncontrolled viral replication in a permissive environment. The clinical course of immunodeficiency-related malignancies is variable. In some cases of transplantation-related malignancy, reducing the level of immunosuppression results in restoration of antigen-specific cytotoxic lymphocyte responses with subsequent regression of the tumors.
Though AIDS-related malignancies share some features with malignancies arising in the setting of congenital or iatrogenic immune deficiencies, they are distinct in several ways. The AIDS-defining malignancies include KS, systemic NHL, central nervous system NHL (CNS-NHL), and cervical cancer. As is the case with congenital or iatrogenic immunodeficiency-related malignancies, the pathogenesis of AIDS-related malignancies remains unclear. AIDS-related neoplasms are associated, to varying degrees, with specific viruses, such as Epstein-Barr virus, human herpesvirus 8 (HHV-8), and human papillomavirus (see Table 2, Table 3, and Table 4).[1,5,11-16] Unique to AIDS-related malignancies is the direct role that HIV may play in tumorigenesis.
Malignancies that arise in the setting of HIV infection follow an aggressive clinical course. Historically, therapies effective against these malignancies were difficult to use in individuals with already-impaired immune function and poor bone marrow reserve. Until recently, the possibility of restoring the immune system of HIV-infected individuals proved elusive. The phenomenon of immune reconstitution has been observed in many individuals treated with highly active antiretroviral therapy (HAART). Whether such patients truly recover normal immune function is questionable. In fact, qualitative studies of immune function suggest that the T-cell repertoire may not be completely restored once significant damage has occurred. Similarly, there are limited data regarding the function of antigen-presenting cells and natural killer cells following HAART. As such, the impact of HAART on the incidence, clinical course, and outcomes of each of the AIDS-related malignancies is variable. This two-part article, which will conclude in next month’s issue, will attempt to describe the changes in the epidemiology, treatment, and outcomes of individuals with HIV and cancer in the HAART era.
Epidemiology and Pathogenesis
The epidemic form of KS was first observed in the late 1970s in homosexual men, heralding the AIDS epidemic.[1,17] Between 1981 and 1983, KS was the initial AIDS diagnosis in 50% of non-injectional drug-using homosexual men in New York. Kaposi’s sarcoma remains the most common AIDS-associated malignancy. From the early 1980s through the 1990s, the lifetime risk of developing KS for an HIV-infected homosexual male was approximately 40% to 50%. HIV-infected homosexual men have the highest risk of developing KS. The relative risk (RR) of developing KS in HIV-infected men with a history of sex with men is 106,000, compared to a relative risk of 13,000 in men who deny a history of sex with men. The relative risk in HIV-infected women is unknown, but the rare cases of KS in women are usually in those who have had a bisexual male partner.[1,19]
The impact of HAART on the epidemiology and clinical course of KS is best understood in the context of the pathogenesis of KS. An interaction between HHV-8, immunosuppression, and HIV appears to be necessary for the development of AIDS-associated KS. The observed epidemiology of KS suggested a sexually transmissable etiology. Since its identification in 1994, HHV-8 has been found in nearly all KS tissue specimens of both HIV-infected and HIV-uninfected individuals.[1,20] Its sexual transmission is strongly suggested by its association with number of homosexual partners. Aside from this sexual risk factor, no specific sexual practices are associated with HHV-8 infection. While HHV-8 DNA has been detected in saliva, mucous membranes, semen, and gastrointestinal mucosa from HIV-infected individuals and from organ allografts, its exact mode of transmission is unclear.[18,22-24] Recently, saliva has been identified as a likely mode of transmission, with the oropharynx as a portal of entry.
HHV-8, a gamma-2 DNA herpesvirus, shares some homology with Epstein-Barr virus and herpesvirus saimiri. It is lymphotrophic and has been documented in the lymph nodes and peripheral B cells of seropositive individuals.[1,18] A potential etiologic role of HHV-8 in the pathogenesis of KS is inferred from epidemiologic observations. The seroprevalence rates of HHV-8 correlate with incidence rates for KS in various subpopulations (see Table 5).[1,5,18,26,27] Furthermore, infection with HHV-8 precedes and predicts development of KS. The Multicenter AIDS Cohort Study (MACS) reported of 40 men with a history of sex with men who developed KS, 80% were seropositive for HHV-8 prior to the development of KS, compared to 18% of men with a history of sex with men who were HIV-positive but did not develop KS within the study period.
The latent form of HHV-8 predominates in KS. Interestingly, HHV-8 encodes many latent and lytic genes that are homologs of human cellular genes involved in inflammation, cell cycle regulation, and angiogenesis. An example is the viral homolog of cellular D-type cyclin that can activate kinases, resulting in phosphorylation and inactivation of the retinoblastoma tumor suppressor gene. A viral homolog of the human bcl-2 gene product inhibits apoptosis. Expression of vbcl-2 has been shown to increase with advancing stages of KS.[18,28,29] HHV-8 also encodes a G protein-coupled receptor (vGPCR) that is homologous to the human interleukin (IL)-8 receptors CXCR1 and CXCR2. This vGPCR is capable of inducing angiogenesis in vitro. Viral homologs of IL-6, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) may be important autocrine and paracrine growth factors for KS tumor cells.
HIV may act both directly and indirectly as a cofactor in the development of KS. The HIV-1-encoded tat protein has been shown to cause interferon (IFN)-gamma-primed endothelial cells to proliferate and form tubelike structures that can secrete angiogenic and growth factors. Innoculation of the tat gene and bFGF into nude mice results in the development of tumors similar to KS.[30-32]
A potential unifying pathogenic model explaining the interplay of HIV infection and HHV-8 postulates that individuals at risk for KS have activated endothelial and inflammatory cells caused by chronic antigenic stimulation (ie, HIV infection). These cells are then infected by Kaposi’s sarcoma herpesvirus (known as KSHV or HHV-8) via circulating mononuclear cells harboring HHV-8. A milieu of inflammatory proteins allows for the development of spindle cells, which, in turn, secrete growth factors (FGF and VEGF) leading to angiogenesis, edema, and KS lesions. The expression of KSHV gene products further stimulates angiogenesis and growth, resulting in the development of a clonal tumor.[18,30,34]
Some degree of immune deficiency appears to be necessary for KS development. Individuals infected with HHV-8 with intact immune systems are at very low risk for developing KS. In parts of Italy with seroprevalence rates of 20%, the annual risk of classic KS is less than 0.1%. Up to 20% to 30% of transplantation-related KS cases show spontaneous regression with discontinuation of immunosuppressive therapies. Although KS can occur at any CD4 count, the risk of KS increases as the CD4 count falls and more advanced disease is common with lower CD4 counts.