Version May 2024
INTRODUCTION — Kaposi sarcoma (KS) is an angioproliferative disorder that requires infection with human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus (KSHV), for its development [1-3]. The disease is named for Moritz Kaposi, a Hungarian dermatologist on the faculty of the University of Vienna, who first described the entity in 1872 as "idiopathic multiple pigmented sarcoma of the skin" [4].
KS is classified into four types based on the clinical circumstances in which it develops: classic (the type originally described by Kaposi, which typically presents in middle or old age), endemic (several forms described in Sub-Saharan African populations prior to the AIDS epidemic), iatrogenic (a type associated with immunosuppressive drug therapy, typically seen in renal allograft recipients), and AIDS associated (epidemic KS). The different epidemiologic and clinical aspects of these four types are summarized in the table (table 1).
This topic review will focus on the epidemiology, risk factors, pathology, and molecular pathogenesis of classic KS. The clinical presentation, diagnosis, staging, and treatment of classic KS is discussed elsewhere, as is AIDS-related KS and iatrogenic KS developing in the setting of immunosuppressive therapy. (See "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment" and "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis" and "AIDS-related Kaposi sarcoma: Staging and treatment" and "Malignancy after solid organ transplantation", section on 'Kaposi sarcoma'.)
EPIDEMIOLOGY — Classic Kaposi sarcoma (CKS) affects males more often than females; the reported male to female ratio is approximately 3:1 [5-7]. Although cases have been described around the world, including in South America [8] and Asia [9], the disease is most often diagnosed in individuals from the Mediterranean basin and Central and Eastern Europe [10-12], or their descendants [5,13-15]. The highest incidence rates in Europe are in two Mediterranean Italian islands, Sardinia and Sicily [16,17].
An analysis of 2667 incident KS cases diagnosed between 1995 and 2002 and registered by 75 population-based European cancer registries that contributed to the RARECARE project ("Surveillance of rare cancer in Europe") estimated that there were 1642 new cases per year in the 27 countries comprising the European Union at that time and approximately 10,500 persons alive in Europe with a past diagnosis of KS as of the beginning of 2008 [18]. The precise proportion of CKS was unknown; in this study, 852 diagnoses were made among individuals 65 years or older (most likely to represent CKS), 1147 among individuals less than 45 years of age (more likely to be HIV associated), and the remaining 572 among individuals 45 to 64 years old [18]. However, older age may be an unreliable surrogate for CKS, given the increasing median age of people living with HIV [19].
CKS, sometimes presenting with advanced cutaneous, lymphatic, and visceral disease, has also been described among Uyghurs [20-22], members of a Turkic/Eurasian ethnic underrepresented group found primarily in the Xinjiang Uyghur Autonomous Region of Northwestern China.
The geographic distribution of CKS corresponds to regional differences in the prevalence of human herpesvirus 8 (HHV-8) infection [11]. A discussion of potential routes of HHV-8 spread is beyond the scope of this review; however, an excellent summary is available that identifies salivary shedding together with unidentified sociocultural practices that promote saliva passage as the likely route of infection in children in endemic, high-prevalence areas [23]. The global, regional, and sex-specific seroprevalence of HHV-8 infection and aspects of viral transmission are discussed in greater detail separately. (See "Human herpesvirus-8 infection".)
CKS typically first presents in males (and females, although less often) in their 60s and 70s but has been described in patients in their teens and 20s [24,25]. Only 4 to 8 percent of cases develop in individuals younger than age 50 [16]. Data suggest that HIV-negative men who have sex with men have a higher risk of developing KS than do males in the general population, they often develop KS at an earlier age, and they have a clinical course that is more typical of CKS than epidemic KS [26-31]. It is not clear whether such patients represent a distinct clinical variant of KS or whether they should simply be considered part of the CKS clinical spectrum. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis".)
RISK FACTORS — Human herpesvirus 8 (HHV-8) infection is required for the development of classic Kaposi sarcoma (CKS), but not all infected persons develop the disease. In the Mediterranean area, for example, CKS develops annually in only 0.03 percent of HHV-8-infected males and only 0.01 to 0.02 percent of HHV-8-infected females over age 50 [32]. This implies the existence of cofactors that influence the risk of CKS after infection with HHV-8.
Interpretation of most studies evaluating potential risk factors for CKS in persons infected with HHV-8 is limited because comparisons were made with control groups whose HHV-8 infection status was unknown. This limitation was overcome by a series of studies performed in Italy in which case patients with CKS were compared with HHV-8-infected persons (ie, those with antibodies to HHV-8) but without KS [33-38]. The following sections describe those factors that have been found to be associated with an elevated risk of CKS among infected persons.
Anti-HHV-8 antibodies and viremia — A comparison of age- and sex-matched HHV-8-infected Italians with and without CKS showed that HHV-8 DNA detection in peripheral blood mononuclear cells (PBMCs) and high HHV-8 lytic and latent antibody titers were significantly associated with the development of CKS [34].
More recently, it has been suggested that a certain subtype of HHV-8, strain A, may be associated with higher blood viral loads and more aggressive disease behavior than strain C, which was associated with slowly progressive disease [39].
Inherited variations in immunomodulating genes — KS lesions are characterized, in part, by the presence of proinflammatory cytokines and growth factors that are thought to regulate HHV-8 replication and possibly CKS pathogenesis. The influence of inherited variations in genes that modulate cytokine expression on the development of CKS was addressed in a study of 28 common genetic variants of 14 immunomodulatory genes using genomic DNA from HHV-8-infected Italians with and without CKS [33]. The risk of CKS was associated with specific haplotypes of the interleukin 8 receptor-beta (IL8RB) and interleukin 13 (IL13) genes. Although it is not clear how these genes cooperate to promote CKS pathogenesis or whether either or both act directly or indirectly to promote CKS pathogenesis, the findings suggest that genetically determined differences in cytokine expression may influence CKS risk. As examples:
●In an analysis of a Finnish family in which five members in two generations developed CKS [40], the gene coding for signal transducer and activator of transcription factor 4 (STAT4), which regulates interferon gamma responses, was identified as a potential CKS predisposition gene [41].
●Another study of a large, consanguineous family in Israel in whom CKS developed in four siblings at a relatively early age (age range 38 to 53) suggested, but did not prove, the contribution of genetic susceptibility to the development of KS, possibly provided by a polymorphism in an interleukin 6 (IL6) GC promoter gene and/or the HLA-DRB1*11 allele [42]. A subsequent genome-wide linkage analysis and whole-genome sequencing of the same Israeli family, as well as a consanguineous Iranian family with multiple cases of CKS, identified several rare KS-associated genetic alterations that were compatible with monogenic recessive inheritance [43].
●Others have found that, among HHV-8-infected Italians without CKS, high HHV-8 lytic antibody titers, which may be a marker of lytic reactivation, were associated with a common promoter variant in IL6 and a specific haplotype of IL4, and a high latent HHV-8 antibody titer was associated with a specific haplotype of the IL12 subunit A (IL12A) [35].
These findings suggest that host genetic factors may affect the risk of CKS at least in part by influencing the ability to develop antibodies to HHV-8 and, ultimately, control HHV-8 infection.
Immunosuppression — Immunosuppression, either iatrogenic (ie, in allograft recipients) or acquired (ie, in the setting of HIV infection), is well described as a risk factor for KS. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis" and "Malignancy after solid organ transplantation", section on 'Kaposi sarcoma'.)
The role of immunosuppression in CKS is less well defined, and there is no evidence for overt immunosuppression in most cases. However, there is evidence that more subtle degrees of immune suppression may be present in people with CKS. The following represents the range of findings:
●In a previously described Italian study, patients with CKS were found to have a significantly lower total lymphocyte count than HHV-8 seropositive individuals without KS, although the mean absolute values for both total lymphocytes and the CD4 and CD8 T-lymphocyte subsets were within the normal range in affected patients [34]. In particular, a lymphocyte count below the median among younger individuals (age <70) was strongly associated with an increased risk of CKS (odds ratio [OR] 8.0).
●Significantly lower total lymphocyte counts and CD4+ T cells were observed in a group of 91 Greek patients with CKS compared with age- and sex-matched controls without CKS (although their HHV-8 infection status was not specified) [44]. As in the previously cited study, mean values for all lymphocyte parameters were within the normal range in patients with CKS.
●A gradual but significant decrease in the number of total and B-lymphocytes has been linked to progression of CKS from its early stages to more advanced disease [45]. A role for B cell depletion is supported by reports of rapid progression of CKS after treatment with rituximab [46-49], which results in depletion of CD20+ B cells.
●An increased risk of CKS has been reported among individuals with a history of topical corticosteroid use (OR 2.73, 95% CI 1.35-5.51) [36], suggesting that local perturbations in cutaneous immune function may be an important predisposing factor for CKS.
●There are conflicting data as to the risk of CKS among patients taking oral corticosteroids, with some studies supporting an association [38] and others not [36].
●The increased incidence of CKS with advancing age, despite likely infection with HHV-8 early in life, may be a result of age-related immunosenescence.
Immune activation — Although immunosuppression has been most consistently associated with the development of CKS, evidence also supports a possible pathogenetic role for immune activation:
●One study found increased levels of the immune activation markers, neopterin and beta-2 microglobulin, in the serum of patients with CKS [9,32]. A link between immune system activation and CKS is also suggested by the association of CKS with a history of asthma and allergy (the latter in males but not in females) [36].
●Another study that compared plasma from 15 CKS cases with plasma from 29 matched controls using a multiplex panel of 70 markers of immunity found a strong and significant association of CKS with elevated levels of four circulating immune mediators, CXCL10, sIL-1RII, sIL-2RA, and CCL3, consistent with a tumor-promoting role for these cytokines [50].
●The occurrence and/or location of CKS lesions may be associated with certain autoimmune diseases [51] and sites of wound healing after surgery [52].
These preliminary findings require confirmation in larger, well-designed studies to assess their etiologic importance in CKS.
Sex — The basis for the higher incidence of CKS among males than females is not well understood, but it appears not to be a consequence of significantly higher HHV-8 seroprevalence among males. It has been hypothesized that CKS risk is related to differences in how males and females manage persistent virus over time [37], possibly due to differential action of sex steroids on the immune system to modify antigen presentation, lymphocyte activation, cytokine and immune cell regulation, and the expression of disease resistance genes, including Fc receptors and the immunoglobulin G (IgG) superfamily. Sex-linked genetic factors that are independent of sex steroids may also lead to more effective immune responses against HHV-8 in females [53].
Association with other malignancies — There are conflicting data on associations with other malignancies, either before or following a diagnosis of CKS, as evidenced by the following observations:
●A strong association between CKS and lymphohematopoietic malignancies was initially suggested by a single-institution United States study that described nine cases (four non-Hodgkin lymphoma, three Hodgkin lymphoma, one multiple myeloma, and one leukemia) diagnosed before, concurrent with, or subsequent to CKS in 72 patients [54]. This corresponded to a 20-fold increase over the number of expected cases in the control population [54].
●Similarly, a study of 68 patients from the United Kingdom also suggested an increased rate of non-Hodgkin lymphoma subsequent to a diagnosis of CKS, but this conclusion was based on only three lymphoma cases [55].
●Another study reported 6 cancer cases, 5 of which involved the lymphohematopoietic system, among 66 CKS patients presenting to a hospital in Athens, Greece [56]. Three of the cancers were diagnosed concurrently with, one preceded, and two were diagnosed subsequent to the diagnosis of CKS; no attempt was made to correlate cancer incidence with that of a control population.
Most of the subsequent, larger, population-based studies from the United States (492 patients), Italy (201 patients), and a Nordic cohort (741 patients) failed to document an excess risk of cancer overall or of lymphomas specifically following the diagnosis of CKS [57-59]. However, an Israeli population-based study that investigated CKS as a second primary malignancy did find an increased incidence following a prior diagnosis of non-Hodgkin lymphoma (OR 5.3), Hodgkin lymphoma (OR 7.5), leukemia (OR 5.3), especially chronic leukemia (OR 10), and breast cancer (OR 2.2) [60]. The risk was particularly high among immigrants to Israel from the former Soviet Union (OR 9.4) and Poland (OR 7) [60]. It is possible that the increased risk of CKS following a prior cancer diagnosis was related to immunosuppression from cancer treatment in a susceptible, HHV-8-infected immigrant population.
Anemia — Two studies have described significantly lower hemoglobin and hematocrit values among patients with CKS as compared with controls without the disease [34,44], although absolute differences were quite modest, and mean values were all within the normal range. The control population in one of the reports consisted of patients with HHV-8 infection without CKS [34]. The biologic significance of lower red blood cell values and their etiologic role in CKS development, if any, are unclear.
Environmental factors — Environmental factors related to skin hygiene or skin disease may influence the development of CKS:
●In one study, infrequent bathing or showering was associated with a moderately increased risk of CKS [36].
●Following up on Ziegler's hypothesis that endemic, African KS is related to localized immune deficiency in the lower extremities that results from chronic exposure of the skin to volcanic soil [61], one study found that the risk of CKS was twofold higher among people born near Mount Vesuvius than among people born in neighboring areas [62].
●Another report has linked Luvisol soils (which are high in iron and aluminosilicates) to the risk of CKS [63].
●Yet another study has suggested that differences in the geographic distribution of certain bloodsucking insects ("promoter arthropods") that cause local inflammatory responses may account for variations in the incidence of CKS and HHV-8 infection [64].
Smoking — A consistent finding is that the risk for CKS is significantly lower among cigarette smokers, particularly those with more intensive (more packs per day) and more cumulative (more pack years) history of tobacco abuse [36,38,65]:
●In a population-based study of 141 Italian patients with CKS and 192 HHV-8 seropositive age-matched controls, CKS risk decreased approximately 20 percent (OR 0.81, 95% CI 0.74-0.89) for each 10 pack years of smoking and was decreased sevenfold (OR 0.14, 95% CI 0.07-0.30) among men with a greater than 40 pack year history [36].
●An even more dramatic protective effect was noted in a later study from these same investigators that included 142 Sicilian CKS cases and 123 HHV-8 seropositive controls [38]. Current cigarette smoking was associated with an 80 percent reduction in CKS among males (OR 0.20, 95% CI 0.06-0.67).
These findings are consistent with other studies in HIV-infected males in the United States, which show a statistically significant reduction in KS risk among smokers [65], and they are supported by reports of a lower risk of other smoking-related diseases, including lung cancer, among people with CKS [13,54,60]. It has been suggested that the protective effect of smoking may be mediated by a decrease in the production of inflammatory cytokines [36,65].
Miscellaneous — Another Italian case-control study documented a 3.65-fold increased risk of CKS among patients with chronic edema of the lower extremities and among those with diabetes mellitus (OR 4.73) [38]. It is postulated that local factors related to vascular insufficiency might predispose to KS and, in particular, to its preferential appearance on the lower extremities.
In contrast, no associations have been found between CKS risk and alcohol consumption, number of lifetime sexual partners, household crowding or birth order, or detection of Epstein-Barr virus (EBV) DNA in PBMCs [34,36].
PATHOLOGY — The microscopic features of all four different types of Kaposi sarcoma (KS) do not differ. All forms show evidence of angiogenesis, inflammation, and spindle cell proliferation.
Three main pathologic stages have been described in the progression of the lesions of KS [66,67]. In the "patch" stage, thin-walled vascular spaces are visible in the upper dermis with a sparse mononuclear cell infiltrate of lymphocytes, plasma cells, and macrophages. In the "plaque" stage, the vascular spaces increase in number, the density of inflammatory infiltrate increases, and spindle cell bundles accumulate around the areas of angioproliferation. In the "nodular" stage, the tumor is more solid, and there are well-defined nodules, which consist of large fascicles of spindle-shaped endothelial cells with fewer and more compact vascular slits. The mononuclear cell infiltrate is no longer prominent, and few extravasated erythrocytes and macrophages are present between spindle cells [66].
The lining cells of the clearly developed vascular structures are positive for vascular markers (such as factor VIII), while the spindle cells consistently stain for CD34 and commonly CD31 but are factor VIII negative.
If needed, polymerase chain reaction can be performed of the skin lesions to detect amplified human herpesvirus 8 (HHV-8) DNA sequences, and immunohistochemical staining of biopsy specimens can also be performed to detect the presence of HHV-8 latent antigen within the spindle cells, thus confirming the diagnosis [68].
MOLECULAR PATHOGENESIS — Human herpesvirus 8 (HHV-8) infects and transforms human endothelial cells, which subsequently form the neoplastic spindle cell component of the Kaposi sarcoma (KS) lesion. (See "Human herpesvirus-8 infection", section on 'Pathogenesis' and "Human herpesvirus-8 infection", section on 'Virology'.)
In brief, several viral gene products of HHV-8 affect both cell cycle regulation and the control of apoptosis, and segments of the HHV-8 genome contain viral oncogenes that are important in the pathogenesis of tumor formation [69]. Most of the spindle cells within the KS lesions show latent infection with HHV-8, although a small proportion of cells express lytic cycle genes. The limited number of viral genes expressed during latency are those that permit the virus to replicate within the host cell as an episome while disrupting the function of tumor-suppressor genes and avoiding recognition by the host immune system. On the other hand, viral genes expressed during the lytic cycle may be particularly important in increased expression of growth factors, such as vascular endothelial growth factor (VEGF) and the tyrosine kinase receptor KIT [70,71], which stimulate angiogenesis and activate growth regulatory pathways, such as the phosphoinositide 3-kinase (PI3K) pathway, that lead to dysregulated cell growth [72,73]. Overexpression of these factors also suggests potential targets for treatment [74]. (See "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment", section on 'Advanced disease'.)
It is not known whether the presence of peripheral vascular disease (with resultant tissue hypoxia and local elaboration of angiogenic factors) accounts for the frequent development of KS lesions on the lower extremities of the older adult patients who are at greatest risk for classic KS.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Kaposi sarcoma (The Basics)")
SUMMARY
●Kaposi sarcoma (KS) is an angioproliferative disorder that requires infection with human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus (KSHV), for its development. (See 'Introduction' above.)
●Several viral gene products of HHV-8 affect both cell cycle regulation and the control of apoptosis, and segments of the HHV-8 genome contain viral oncogenes that are important in the pathogenesis of tumor formation. (See 'Molecular pathogenesis' above.)
●KS is classified into four types based on the clinical circumstances in which it develops: classic, endemic, iatrogenic, and AIDS associated. The different epidemiologic and clinical aspects of these four types are summarized in the table (table 1).
●Classic KS is most often diagnosed in males from the Mediterranean basin and Central and Eastern Europe, or their descendants. (See 'Epidemiology' above.)
●HHV-8 infection is required for the development of classic KS, but not all infected persons develop the disease. Immunosuppression is a well-described risk factor for KS. (See 'Risk factors' above.)
●Three main pathologic stages have been described in the progression of the lesions of KS: the patch stage, plaque stage, and nodular stage. (See 'Pathology' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas F DeLaney, MD, who contributed to an earlier version of this topic review.
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