What is the pathophysiology of Kaposi sarcoma (KS)?

Updated: Apr 11, 2019
  • Author: Jessica Katz, MD, PhD, FACP; Chief Editor: Edwin Choy, MD, PhD  more...
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Answer

The discovery of Kaposi sarcoma human herpes virus (KSHV) in 1994 led to rapid progress in understanding the disease’s pathophysiology. Different epidemiologic and clinical presentations of the disease may be related to modifiable risk factors, such as uncontrolled HIV and immunosuppressive medications used in transplantation. This knowledge has helped spur individualized therapeutic approaches to the disease.

Kaposi sarcoma is caused by an excessive proliferation of spindle cells that are thought to have an endothelial cell origin. Despite their heterogeneity, the tumors are predominantly composed of KSHV genomic material with immunohistochemical markers of both lymphoid, spindle, and endothelial cells. [40]  

Although the cell of origin is still unknown, increased endothelial factor VIIIa antigen, spindle cell markers such as smooth muscle alpha-actin, and macrophage markers such as PAM-1, CD68, and CD14 expressed by these spindlecells have been observed. [41] This suggests a pluripotent mesenchymal progenitor. The spindle cells proliferate in a background of reticular fibers, collagen, and mononuclear cells including macrophages, lymphocytes and plasma cells. They tend to be vascular, involving either the reticular dermis (patch stage) or the entire thickness of the dermis (plaque or nodular stage). [31]

KSHV contains a large genome with greater than 85 antigenically competent genes. Immunofluorescent assays in KSHV-infected primary effusion lymphoma and an enzyme-linked immunoassay (ELISA) to major antigens have been developed to measure antibodies to KSHV. [42, 43] Seropositivity varies and is more than 50% in sub-Saharan Africa, 20-30% in Mediterranean countries, and less than 10% in most of Europe, Asia, and the United States. Prevalence is higher in men who have sex with men, Amerindians in South America, and certain ethnic groups in China. [44, 45]

Molecular studies previously suggested that Kaposi sarcoma originates from a single cell clone rather than a multifocal origin. However, more recent data in a study of 98 patients with Kaposi sarcoma with primarily cutaneous disease analyzed by molecular diagnostic techniques comparing viral HHV8 DNA of the tumors showed that nearly 80% of the tumors arose independently from multiple cells. [46] The conclusion reached was that few Kaposi sarcoma tumors originate from a single cell and that Kaposi sarcoma may not be metastatic in its advanced form but multifocal and independently occurring at multiple sites. These data are primarily applicable to initially less aggressive cutaneous Kaposi sarcoma. They may not apply to de novo more aggressive visceral Kaposi sarcoma, which may be less likely to respond to therapy.

Human herpes virus 8 (HHV-8) genomic sequences have been identified by polymerase chain reaction in more than 90% of all types of Kaposi sarcoma lesions (including epidemic and endemic forms), suggesting a causative role for this DNA virus. The current working hypothesis is that HHV-8 must be present for the disease to develop. It is transmitted in saliva. Blood-borne transmission has yet to be proved. HIV significantly increases the risk of immune suppression.

These viral sequences additionally have been associated with body cavity–based lymphomas, Castleman disease, and leiomyosarcomas that occur in individuals infected with HIV. Other diseases may yet be found to be associated with KSHV, particularly in HIV-positive individuals. Factors that are thought to contribute to the development of Kaposi sarcoma in individuals infected with HHV-8 and HIV include an abnormal cytokine milieu associated with HIV infection, and involving the following angiogenic cytokines:

  • Interleukin-1 (IL-1) beta
  • Basic fibroblast growth factor (bFGF)
  • Acidic fibroblast growth factor
  • Endothelial growth factor
  • Vascular endothelial growth factor (VEGF)

Other cytokines include IL-6, granulocyte-monocyte colony stimulating factor (GM-CSF), transforming growth factor beta (TGF-beta), tumor necrosis factor (TNF), and platelet-derived growth factor alpha (PDGF-alpha) from interstitial and mononuclear cells.

Oncostatin M, IL-1, IL-6, fibroblast growth factor, tumor necrosis factor (TNF), and the HIV-tat protein—all of which originate from HIV-infected T cells—act as costimulants for Kaposi sarcoma cells. [31] Indeed, theTAT gene may be a key component responsible for conversion of the Kaposi sarcoma cell to a malignant phenotype. A specific viral gene, ORF74, encodes for a G-protein coupled receptor that causes production of VEGF and other angiogenic mediators. [47, 48]

In a comparison of plasma from 15 HIV-negative classic Kaposi sarcoma cases to plasma from 29 matched controls, Aka and collegues reported elevated plasma levels of CXCL10, sIL-1RII, sIL-2RA, and CCL3 in classic Kaposi sarcoma cases. However, the researchers caution that larger, prospective studies are needed to assess for possible diagnostic, prognostic, or etiologic importance for Kaposi sarcoma. in larger, prospective studies, including those involving HIV-infected patients with AIDS-related disease. [49]  

Thus, Kaposi sarcoma may be caused by HHV-8 (KSHV) with stimulation by autocrine and paracrine growth factors secreted by the spindle cells themselves as well as the supporting network of mononuclear and endothelial cells. Coinfection with HIV may create a more aggressive course, which is mitigated by effective antiretroviral therapies. Indeed, the risk of Kaposi sarcoma development is amplified 500-10,000 times in patients coinfected with KSHV and HIV. The use of technologies such as comprehensive genetic profiling with gene expression arrays may further elucidate the very complicated viral gene-host interaction and facilitate identification of molecular targets for both prevention and treatment. [50]

In summary, complex immune dysregulation is the center theme for the pathogenesis of Kaposi sarcoma. This includes cellular immunity defects, [51, 52] humoral immunity defects [53, 54] and abnormalities of vascular endothelial growth factor. Apparent overlapping mechanisms for upregulation of multiple pathways produce the malignant phenotype.


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