What is the pathophysiology of Kaposi sarcoma (KS)?

Updated: Mar 26, 2021
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD  more...
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HIV transactivating (tat) gene, cytokine, and HHV-8 stories in Kaposi sarcoma (KS) are fascinating. Each begins with a classic study. In 1988, the human immunodeficiency virus type 1 (HIV-1) tat gene was introduced into transgenic mice, inducing nodules that resembled Kaposi sarcoma in 33 of 37 males but in none of 15 females. Therefore, it appeared that HIV could play a direct role in causing Kaposi sarcoma. The medication quinine may be a potentially overlooked triggering factor in millions of Africans with Kaposi sarcoma. [10]

The second saga was a result of efforts to grow Kaposi sarcoma cells in culture, requiring a long-term growth factor. Conditioned medium from T cells infected with human T-cell leukemia virus type II (rather than HIV-1 or human T-cell leukemia virus type I) best supported the growth and long-term culture of Kaposi sarcoma cells derived from KS-AIDS lesions. In 1992, this growth factor proved to be a cytokine previously termed oncostatin M, since it had been identified earlier for its inhibitory effects on a variety of cancer cells. Another cytokine scatter factor was found in large quantities in this medium, inducing endothelial cells to demonstrate a Kaposi sarcoma tumor cell-like phenotype. The importance of oncostatin M, scatter factor, and the tat protein has been shown in the pathogenesis of Kaposi sarcoma.

Other cytokines, including interleukin 1 (IL-1), tumor necrosis factor, interleukin 6 (IL-6), and basic fibroblastic growth factor (bFGF), may work synergistically with the HIV tat gene product. Scatter factor may be involved both in initiation and in maintenance of Kaposi sarcoma. Scatter factor stimulates endothelial cells to migrate nearby and become factor XIIIa–positive c-Met- expressing spindle-shaped Kaposi sarcoma cells. The cells further expand neovascularization by producing cytokines and promoting autocrine-mediated and paracrine-mediated growth of Kaposi sarcoma cells. The scatter factor receptor, c-Met proto-oncogene, is expressed by Kaposi sarcoma cells; the oncogene int-2 of the fibroblast growth factor family also may be evident.

Herpes-type viruses have been linked with Kaposi sarcoma for more than 3 decades. A landmark study showed short DNA sequences of a unique human herpesvirus in Kaposi sarcoma tissues via a new molecular biological technique termed representational difference analysis. They resembled herpesvirus saimiri but proved to be a new type of human herpesvirus now termed HHV-8. This virus appears to interact with the HIV tat protein, excess levels of basic fibroblast growth factor, scatter factor, and IL-6. For example, HHV-8–encoded IL-6 has been found to induce endogenous human IL-6 secretion. An HHV-8 oncogene, Kaposin (ORF K12), has been characterized; however, additional factors remain to be found. For example, a 53% prevalence of HHV-8 subtype E in Brazilian Indians does not appear to be linked with the development of Kaposi sarcoma in this population. [11]

Classic Kaposi sarcoma is seen in Italy with hot spots being in the Po River Valley, Sardinia, and southern Italy. It has been suggested that volcanic soil or birthplace/residency in areas abundant with bloodsucking insects may be a risk factor. [12] A survey evaluated the correlation between HHV-8 infection and classic Kaposi sarcoma incidence in northern Sardinia. [13] It revealed that seroprevalence was 35%, within a range of 15.3-46.3% in the five areas. Age was as an important risk factor. Subjects aged older than 50 years had a higher seroprevalence to HHV-8 as compared with younger individuals. A strong direct correlation between HHV-8 prevalence and classic Kaposi sarcoma incidence was also observed.

Kaposi sarcoma–associated herpesvirus (KSHV), or human herpesvirus 8 (HHV-8), is the most frequent cause of malignancy in patients with AIDS. [14] KSHV and related herpesviruses have pirated cellular cDNAs from the host genome. Many of the viral regulatory homologs encode proteins that directly inhibit host adaptive and innate immunity. Other viral proteins may target retinoblastoma protein and p53 control of tumor suppressor pathways, which play key effector roles in intracellular immune responses. The immune evasion strategies used by KSHV in targeting tumor suppressor pathways activated during immune system signaling, may lead to inadvertent cell proliferation and tumorigenesis in susceptible hosts.

HHV-8 variants have been found heterogeneously distributed in diverse geographic regions, but their pathogenicity in Kaposi sarcoma development is unknown. [15] The frequency of KSHV genotypes has been evaluated in numerous settings. [16, 17] The frequency of these genotypes isolated from Kaposi sarcoma lesions among 50 patients from one center in Brazil was evaluated. The most frequently detected viral genotypes were A (50%) and C (48%); the B genotype was isolated only in one case. [18] A genotype was predominant in those HIV-positive, whereas the C genotype was mostly in those in the HIV-negative group. An association between E genotype and Kaposi sarcoma development was observed in Peru.

The origin of the spindle cell, the hallmark cell of Kaposi sarcoma, is unknown. Most research favors a lymphatic endothelial cell or an endothelial-cell precursor evolving into a lymphatic phenotype, both preferentially targeted by KSHV. [19]

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