Version May 2024
INTRODUCTION — Kaposi sarcoma (KS) is a vascular tumor that is etiologically associated with human herpesvirus 8 (HHV-8), which is also known as the KS-associated herpesvirus (KSHV) [1]. (See "Human herpesvirus-8 infection".)
The clinical manifestations and diagnosis of AIDS-related KS will be reviewed here. The treatment of AIDS-related KS is discussed separately, as is the classic form of KS. (See "AIDS-related Kaposi sarcoma: Staging and treatment" and "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment" and "Classic Kaposi sarcoma: Epidemiology, risk factors, pathology, and molecular pathogenesis".)
EPIDEMIOLOGY AND RISK FACTORS
Epidemiologic forms — There are four epidemiologic forms of KS, all of which have been related to infection with human herpesvirus 8 (HHV-8). These include:
●AIDS-related or epidemic KS – AIDS-related or epidemic KS is the most common tumor arising in persons living with HIV. KS is considered an AIDS-defining illness in the United States Centers for Disease Control and Prevention (CDC) guidelines. In the United States, KS was over 20,000 times more common in persons with AIDS than in the general population prior to the widespread use of potent antiretroviral therapy (ART), although its incidence has declined substantially since that time [2].
●Endemic or African – KS was endemic in all parts of equatorial Africa, particularly in sub-Saharan Africa, prior to the HIV epidemic. Since the onset of the HIV epidemic, the incidence of KS has increased dramatically in those regions [3-5].
●Organ transplant-associated – The incidence of KS is increased after solid organ transplantation, presumably at least partially due to chronic immunosuppression. In addition, the transplant itself may transmit HHV-8 infection. The clinical presentation in this setting is similar to that of classic KS. (See "Malignancy after solid organ transplantation", section on 'Kaposi sarcoma'.)
●Classic – Classic KS is an indolent cutaneous proliferative disease mainly affecting older males of Mediterranean and Jewish origin [6,7]. (See "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment" and "Classic Kaposi sarcoma: Epidemiology, risk factors, pathology, and molecular pathogenesis".)
Epidemiology of AIDS-related KS — Although KS has been reported among all risk groups for HIV infection, it is most common in gay or bisexual males. AIDS-related KS is much less common in heterosexual injection drug users, transfusion recipients, females or children, and hemophiliacs [2].
In patients with AIDS-related KS, the CD4 count appears to be an important factor associated with the development of KS. In a series of 70 patients who presented with a new diagnosis of KS while on treatment with combined ART, the rate ratios for developing KS for patients with CD4 counts <200, 200 to 349, and 350 to 499 cells/mm3 were 18.9, 3.6, and 4.1, compared with those with ≥500 cells/mm3 [8].
However, trends in earlier initiation of ART and improved health care continuity have altered the epidemiology of AIDS-related malignancies. In a study including 466 patients with AIDS-related KS, less than half of KS cases diagnosed between 2007 and 2011 were in patients with CD4 counts <200, with 29 percent having a viral load <500 copies/mL [9]. This reflects the growing proportion of the HIV population that, due to ART, has higher CD4 counts and suppressed viral loads, rather than an increased risk of cancer among such patients. In resource-rich areas, AIDS-related KS is predominantly a disease of males. In contrast, in resource-poor areas such as sub-Saharan Africa, AIDS-related KS is also more frequent in males, although the difference is less pronounced.
Impact of antiretroviral therapy — Since the introduction of combined ART, the incidence of KS has declined markedly in patients living with HIV [10-13]. The dramatic impact of ART on the incidence of KS is illustrated by an analysis of more than 375,000 people with AIDS, in which the incidence of various cancers was analyzed [13]. The standardized incidence ratio (SIR) for KS compared with the general population fell from 22,100 to 3640 with the widespread use of ART. Other large epidemiologic studies have reported a similar decrease in the incidence of KS correlating with the introduction of ART [11,14].
The incidence of KS is particularly high during the first six months following the initiation of ART and then falls dramatically with continued treatment [15]. The high incidence immediately following ART initiation may be attributable to the relatively severe immunosuppression that led to ART or to unmasking of KS by the immune reconstitution inflammatory syndrome.
The declining incidence of KS cannot be attributed to a decreased incidence of HHV-8 infection. In one report, the prevalence of HHV-8 infection remained approximately constant among males in San Francisco from 1978/1979 (26.5 percent) through 1984/1985 (29.6 percent) and 1995/1996 (26.4 percent) [16].
Human herpesvirus-8 — There is a strong relationship between the development of KS, HHV-8 infection, and HIV infection [17-19]. (See "Human herpesvirus-8 infection".)
In a study conducted in San Francisco, HHV-8 seropositivity was observed in 38 percent of 593 gay males compared with none of 195 heterosexual males [17]. Among patients living with HIV who were infected with both HIV and HHV-8 at baseline, the 10-year probability of developing KS was approximately 50 percent. The 10-year risk was about 30 percent in males with HIV infection who were not seropositive for HHV-8 at baseline, while there were no cases of KS among the males without HIV infection. This study was conducted before the widespread use of potent combined ART, and the frequency of progression of HHV-8 infection to KS appears to have decreased since that time.
Steroids and infection — Corticosteroid therapy has been associated with the induction of KS and the exacerbation of preexisting KS in persons living with HIV, as well as in non-AIDS patients receiving corticosteroids for organ transplantation, autoimmune disorders, or lymphoproliferative diseases [20].
The association of corticosteroids with KS is important because of the frequent use of these agents in patients living with HIV and with a variety of disorders including immune thrombocytopenia and Pneumocystis jirovecii pneumonia. In such patients, KS lesions may regress upon reduction or withdrawal of steroids [20,21].
Opportunistic infections have also been associated with the induction of KS and with the exacerbation of preexisting KS similar to that described with corticosteroid therapy. High levels of proinflammatory cytokines, which have been demonstrated in the setting of opportunistic infections, may account for these effects on KS.
CUTANEOUS KS — Although KS can involve virtually any site in the body, cutaneous disease is most common and is the usual initial presentation for KS.
Clinical manifestations — The cutaneous lesions of KS appear most often on the lower extremities, face (especially the nose), oral mucosa, and genitalia (picture 1A-J). The lesions are often elliptical and may be arranged in a linear fashion along skin tension lines; they may be symmetrically distributed. The lesions are not painful or pruritic and usually do not produce necrosis of overlying skin or underlying structures.
The assortment of colors associated with these lesions is due to their vascularity and includes many hues of pink, red, purple, and brown. Yellow perilesional halos may occasionally be seen (picture 2).
Early lesions can easily be mistaken as purpura, hematomas, angiomas, dermatofibromas, or nevi. More commonly, however, KS lesions are papular, ranging in size from several millimeters to several centimeters in diameter. Less commonly, KS lesions may be plaque-like, especially on the soles of the feet and thigh, or exophytic and fungating with breakdown of overlying skin (picture 1I-K).
Lymphedema, particularly in the face, genitalia, and lower extremities may be out of proportion to the extent of the disease and may be related to both vascular obstruction by lymphadenopathy and the cytokines involved in the pathogenesis of KS.
Differential diagnosis — A presumptive diagnosis of cutaneous KS can often be made by a trained observer. However, early lesions can easily be mistaken as purpura, hematomas, angiomas, dermatofibromas, or nevi.
Bacillary angiomatosis is the most important alternative in the differential diagnosis. Bacillary angiomatosis is caused by Bartonella species, a slow-growing, fastidious, gram-negative bacillus, and is readily treated with antibiotic therapy. Skin lesions of bacillary angiomatosis usually appear as numerous small red to purple papules that may gradually expand into large pedunculated lesions or nodules that may become friable. The rash may be associated with symptoms such as fever, chills, malaise, headache, and anorexia. Biopsy is especially important for atypical lesions that are associated with systemic symptoms or appear or progress rapidly, in order to rule out bacillary angiomatosis. (See "Microbiologic diagnosis of Bartonella infections" and "Bartonella infections in people with HIV".)
KS and bacillary angiomatosis can occur simultaneously in the same patient. Furthermore, bacillary angiomatosis lesions can be associated with neovascularization and solid areas of spindle cells that mimic KS. The diagnosis of bacillary angiomatosis is established by the identified of the causative organisms with Warthin-Starry silver staining.
Less commonly, KS can be mimicked by extrapulmonary P. jirovecii, even in the absence of coexisting lung infection [22]. (See "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV".)
Diagnosis — Although a presumptive diagnosis of KS can often be made based upon the characteristic appearance of the lesions, this should be confirmed by a biopsy whenever possible. Biopsy is especially important for atypical lesions that are associated with systemic symptoms or appear or progress rapidly, in order to rule out bacillary angiomatosis.
Pathology — There are three histologic features that are characteristic of KS, both in cutaneous and visceral sites: angiogenesis, inflammation, and proliferation. The lesions generally show two major abnormalities: whorls of spindle-shaped cells with leukocytic infiltration and neovascularization with aberrant proliferation of small vessels.
These small vessels lack a basement membrane and display leaky behavior with microhemorrhages and hemosiderin deposition [23]. As the disease progresses, it evolves from patches to plaques and then to a nodular form. The characteristic histologic pattern of KS does not differ among the affected epidemiologic groups.
VISCERAL DISEASE — KS involvement has been observed in almost all visceral sites, including lymph nodes, liver, pancreas, heart, the testes, bone marrow, bone, and skeletal muscle [24,25]. The most frequent sites of noncutaneous disease are the oral cavity, gastrointestinal tract, and respiratory system. However, visceral involvement as the initial manifestation of KS is relatively uncommon. Furthermore, visceral disease now appears to be much less frequent, given the use of antiretroviral therapy as well as multiple treatment options [26].
Oral cavity — Involvement of the oral cavity occurs in about one-third of patients with KS and is the initial site in about 15 percent. The dental practitioner is often the first to identify these lesions (picture 3A-B). The diagnosis of KS should be confirmed by biopsy whenever possible.
The intraoral site most commonly affected is the palate followed by the gingiva [27]. Intraoral lesions may become easily traumatized during normal chewing, which can result in pain, bleeding, ulceration, or secondary infection. If lesions are advanced, they may interfere with nutrition and speech.
The presence or absence of symptoms from oral lesions is often a major factor in treatment decisions.
Gastrointestinal tract — Prior to the widespread introduction of antiretroviral therapy, the gastrointestinal tract was involved in approximately 40 percent of patients with KS at initial diagnosis and in up to 80 percent at autopsy.
Gastrointestinal involvement can occur in the absence of cutaneous disease. Gastrointestinal lesions may be asymptomatic or may cause weight loss, abdominal pain, nausea and vomiting, upper or lower gastrointestinal bleeding, malabsorption, intestinal obstruction, and/or diarrhea [28,29].
Gastrointestinal KS lesions are easily recognized by the endoscopist (picture 4) [30]. They are typically hemorrhagic nodules that can be either isolated or confluent and may occur in any portion of the gastrointestinal tract (picture 5) [24]. The diagnosis of KS should be confirmed by biopsy whenever possible, although biopsies may not demonstrate KS because the lesions tend to be submucosal. High-grade lesions are more likely to be associated with invasion and dissemination.
Treatment is usually dictated by the presence or absence of symptoms. (See "AIDS-related Kaposi sarcoma: Staging and treatment".)
Respiratory system — Pulmonary involvement is common in AIDS-related KS. The clinical manifestations, diagnosis, and management of pulmonary complications are discussed separately. (See "Pulmonary involvement in AIDS-related Kaposi sarcoma".)
Affected patients can present with shortness of breath, fever, cough, hemoptysis, or chest pain, or pulmonary involvement may be an asymptomatic finding first observed on chest radiograph. Radiographic findings are variable and can include nodular, interstitial and/or alveolar infiltrates, pleural effusion, hilar and/or mediastinal adenopathy, or even an isolated nodule.
The KS lesions have a characteristic appearance of cherry-red, slightly raised lesions seen at bronchoscopy, which can result in a presumptive diagnosis of pulmonary KS. Although bronchoscopic and radiographic findings correlate quite well, patients who have KS documented by bronchoscopy may on occasion have normal chest radiographs.
Treatment decisions are usually guided by the presence of respiratory symptoms, the extent of radiographic and bronchoscopic disease, and exclusion of a concomitant pulmonary infection as the cause of the clinical findings. (See "Pulmonary involvement in AIDS-related Kaposi sarcoma", section on 'Treatment' and "AIDS-related Kaposi sarcoma: Staging and treatment".)
INFLAMMATORY CYTOKINE SYNDROME — Among patients with HIV-associated KS, Kaposi sarcoma herpesvirus (KSHV) has been associated with a syndrome of systemic inflammation. KSHV inflammatory cytokine syndrome (KICS) is marked by clinical symptoms such as fever, edema, neuropathy, and gastrointestinal and respiratory symptoms, which occur in the context of evidence of KSHV viral activity, elevated C-reactive protein, and other laboratory abnormalities [31]. Diagnosis of KICS depends on histopathologic exclusion of multicentric Castleman disease (MCD) if lymphadenopathy is present. While many of the clinical and laboratory findings of KICS exist in patients with KSHV-associated MCD, KICS typically lacks the splenomegaly and widespread lymphadenopathy that characterize MCD and is associated with a higher KSHV-associated tumor burden [31]. (See "HHV-8/KSHV-associated multicentric Castleman disease" and "HHV-8/KSHV-associated multicentric Castleman disease", section on 'Clinical features'.)
In a prospective observational study including 10 patients with KICS, all of whom had HIV-associated KS, most experienced gastrointestinal disturbance, edema, anemia, hypoalbuminemia, and thrombocytopenia [31]. They also had higher levels of interleukin 6 and interleukin 10 compared with HIV and KSHV coinfected controls without KICS. Median survival from time of diagnosis of KICS was 13.6 months, suggesting that development of these inflammatory signs and symptoms portends a poor prognosis among patients with 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 email 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
●Pathogenesis – AIDS-related Kaposi sarcoma (KS) is a vascular tumor associated with infection by the human herpesvirus-8, which is characterized by angiogenesis, inflammation, and cellular proliferation. KS is the most common tumor arising in persons living with HIV. (See 'Human herpesvirus-8' above and "HIV infection and malignancy: Epidemiology and pathogenesis" and "HIV infection and malignancy: Management considerations".)
●Incidence – The incidence of KS rose dramatically with the onset of the AIDS epidemic. However, the introduction and widespread use of potent combination antiretroviral therapy (ART) led to a marked decline in the incidence of KS. AIDS-related KS is seen predominantly among gay males rather than in other groups living with HIV (intravenous drug users, females, transfusion recipients). (See 'Epidemiology and risk factors' above.)
●Clinical presentation and diagnosis – KS typically presents with cutaneous disease (picture 1A-J and picture 2 and picture 1K). (See 'Cutaneous KS' above.)
•Although the diagnosis can often be made based upon the characteristic appearance of the cutaneous lesions, this should be confirmed with a biopsy whenever possible. A biopsy is particularly important in cases with atypical features. (See 'Differential diagnosis' above and 'Diagnosis' above.)
•KS can also involve a wide range of visceral organs, including particularly the oral cavity, gastrointestinal tract, and lungs. Visceral involvement is typically a later manifestation of disease and is unusual as an isolated site for the initial presentation. (See 'Visceral disease' above.)
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