Kaposi Sarcoma

Practice Essentials

Kaposi sarcoma (KS) is an indolent angio-proliferative spindle-cell tumor derived from endothelial and immune cells infected with human herpes virus type 8 (HHV-8; also known as Kaposi sarcoma herpes virus [KSHV]). HHV-8 is identified as the causative agent of KS; it is present in 95-98% of all cases.^[1] KS is categorized into the following 4 types^[2] :

• Epidemic (AIDS related)
• Iatrogenic (immunosuppressant therapy related)
• Classic, or sporadic
• Endemic (African)

Increasing reports describe cases of KS in men who have sex with men but who have no evidence of HIV infection or immunodeficiency. These cases present in an indolent cutaneous form that resembles classic KS, and have been regarded as a fifth type of KS, termed nonepidemic KS.^{[3, 4, 5]}

Although all types of KS have in common infection with HHV-8, each has a distinct clinical course. Therefore, it is likely that other factors, such as extent and type of immune suppression, influence the disease.^[6] The presentation of KS ranges from minimal mucocutaneous disease to extensive organ involvement.

The epidemiology of KS has changed dramatically from 1872, when it was first described as a rare disease in Eastern European men. In the 1950s, an endemic form of KS was reported to be one of the most common neoplasms observed in central Africa, affecting men, women, and children. The cases in children are due to maternal-child transmission of HHV-8 through saliva.^[6]  

A surge in KS cases was noted just prior to the identification of the AIDS epidemic in the early 1980s. AIDS-related KS is the most common KS presentation in the United States. Estimates indicate that the risk of KS in people living with HIV from 2009-2012 was 500-fold higher than for the US general population. KS accounts for 12% of cancers in people living with HIV, with 765 to 910 new cases per year in the US.^{[7, 8, 9]}

Notably, following the AIDS epidemic, the incidence of KS in Africa increased markedly. From 1968 to 1970, KS accounted for 6.6% of all cancers occurring in men; however, from 1989 to 1991, KS became the most commonly reported cancer in men.^{[10, 11]}

Iatrogenic KS cases have also increased, due to greater use of immunosuppression in medical practice. These include the post-transplant setting and treatment of autoimmune disease.^[9]

Signs and symptoms

Lesions in KS may involve the skin, oral mucosa, lymph nodes, and visceral organs. Most patients present with cutaneous disease (see the image below). Visceral disease may occasionally precede cutaneous manifestations.

View Image

Epidemic Kaposi sarcoma (KS). Large violaceous truncal nodules with typical linear and symmetric distribution pattern.

See Clues in the Oral Cavity: Are You Missing the Diagnosis?, a Critical Images slideshow, to help identify the causes of abnormalities of the oral cavity.

Cutaneous lesions in KS are characterized as follows:

• Cutaneous lesions may occur at any location but typically are concentrated on the lower extremities and the head and neck region
• Lesions may have macular, papular, nodular, or plaquelike appearances
• Nearly all lesions are palpable and nonpruritic
• Lesions may range in size from several millimeters to several centimeters in diameter
• Lesions may assume a brown, pink, red, or violaceous color and may be difficult to distinguish in dark-skinned individuals
• Lesions may be discrete or confluent and typically appear in a linear, symmetrical distribution, following Langer lines
• Mucous membrane involvement is common (palate, gingiva, conjunctiva)

Gastrointestinal lesions can occur anywhere in the gastrointestinal tract. Lesions are often asymptomatic and clinically indolent, but signs and symptoms can include the following:

• Odynophagia, dysphagia
• Nausea, vomiting, abdominal pain
• Hematemesis, hematochezia, melena
• Bowel obstruction

Pulmonary lesions may be an asymptomatic radiographic finding, but signs and symptoms can include the following:

• Cough
• Dyspnea
• Hemoptysis
• Chest pain

Classic Kaposi sarcoma

This form of the disease has a more indolent course than AIDS-related KS, progressing over 10-15 years or more, with very gradual enlargement of cutaneous lesions and development over years of new ones.

See Presentation for more detail.

Diagnosis

Laboratory studies

CD4 lymphocyte counts and plasma HIV viral-load studies should be performed for patients with HIV infection.

Imaging studies

Chest radiographic findings in patients with KS are variable and nonspecific. They may include any of the following:

• Diffuse reticulonodular infiltrates
• Interstitial infiltrates
• Pleural effusions
• Hilar or mediastinal lymphadenopathy
• An isolated pulmonary nodule

Thallium and gallium scans may help differentiate pulmonary KS from infection. Pulmonary KS lesions typically demonstrate intense thallium uptake and no gallium uptake, whereas infection is often gallium avid and thallium negative.

Procedures

• Punch biopsy
• Bronchoscopy
• Esophagogastroduodenoscopy (EGD) or colonoscopy

Typical histologic findings in KS include the following:

• Proliferation of spindle cells
• Prominent, slitlike vascular spaces
• Extravasated red blood cells.

See Workup for more detail.

Management

Antiretroviral therapy

Optimal control of HIV infection using highly active antiretroviral therapy (HAART) is an integral part of successful KS therapy. HAART may be tried as the sole modality in nonvisceral disease. For visceral disease, chemotherapy may be added.

Local therapy

The following local therapies can be used for palliation of locally advanced symptomatic disease or in individuals who have cosmetically unacceptable lesions:

• Radiation therapy
• Cryotherapy
• Laser therapy
• Surgical excision
• Intralesional vinca alkaloid therapy
• Topical retinoids

Immunomodulation

Immunomodulation with interferon-alfa has clinical activity in KS that may be mediated by its antiangiogenic, antiviral, and immunomodulatory properties.

Combination therapy

Combination therapy with regimens such as ABV (actinomycin D, bleomycin, vincristine) produces higher response rates than does single-agent therapy (such as doxorubicin), but time to progression and overall survival rates are similar.

Cytotoxic agents

Several single cytotoxic agents have been approved by the Food and Drug Administration (FDA) for AIDS-related KS; they include the following:

• Liposomal doxorubicin (Doxil)
• Liposomal daunorubicin (DaunoXome)
• Paclitaxel (Taxol) or oral etoposide (VePesid)

Liposomal technology has resulted in higher response rates with less cardiac toxicity and myelotoxicity for liposomal doxorubicin and liposomal daunorubicin.^{[12, 13, 14]}

See Treatment and Medication for more detail.

• References

Background

Kaposi sarcoma (KS) was described initially in 1872 by a Hungarian dermatologist, Moritz Kaposi. The lesions are characterized by proliferation of spindle cells of endothelial origin, with varying degrees of abnormal vascularity, inflammatory infiltrates, and fibrosis. Red cells and hemosiderin deposits give lesions their characteristic purplish color. Spindle cells are infected with HHV-8. HHV-8 encodes a number of genes that induce proliferation, cytokine production, and angiogenesis and thereby contribute to pathogenesis.

Kaposi sarcoma follows a variable clinical course, ranging from minimal mucocutaneous disease to extensive organ involvement. See the table below.^[1]

Types of Kaposi sarcoma

View Table

See Table

Adapted from Antman K, Chang Y. Kaposi's sarcoma. N Engl J Med. 2000 Apr 6. 342 (14):1027-38.

The common theme of immune dysregulation is associated with all 4 types of Kaposi sarcoma. Diminished responsiveness of cytotoxic T-lymphocytes is associated with Kaposi sarcoma pathogenesis.^[15]  Restoration of natural killer cell cytoxic effect may explain regression of Kaposi sarcoma in AIDS patients treated with antiretrovirla therapy.^[16] Immune activation may also be a factor in Kaposi sarcoma, with a role for inflammatory cytokines such as gamma interferon and the initiation of HHV-8 infected cell proliferation by HIV-tat protein.^{[17, 18]} This complex interaction of HIV, HHV-8, environmental factors, and the immune system requires further investigation to attempt to decipher the true pathogenesis of Kaposi sarcoma.

Epidemic (AIDS-related) Kaposi sarcoma

This entity occurs in patients with advanced HIV infection and is the most common presentation of Kaposi sarcoma. It is an AIDS-defining cancer, and is approximately 500 times more common in HIV-infected patients than the general US population. Kaposi sarcoma accounts for 12% of cancers in people living with HIV, with 765 to 910 new cases per year in the US.^{[7, 8, 9]}

Decreased CD4 counts and increased HIV-1 viral loads are independent prognostic factors in the development of epidemic Kaposi sarcoma.  The disease usually develops in HIV-infected patients with severe immunodeficiency; less than one sixth of HIV-infected patients with Kaposi sarcoma have CD4 counts of over 500 cells per microliter. Immune reconstitution during the first 3 months of HAART may contribute to the risk for AIDS-defining Kaposi sarcoma.^[19]

Kaposi sarcoma is a frequent complication of AIDS in men who have sex with men (MSM). A cross-sectional analysis of factors affecting risk in 99 cases among 503 HHV-8 seropositive MSM with AIDS found that Kaposi sarcoma was^[20] :

• Significantly less common in blacks than in whites (risk ratio [RR] = 0.4; 95% confidence index [CI] = 0.2-0.8).
• More common in subjects who had completed college (RR = 1.7; 95% CI = 1.1-2.7) or had annual income greater than $30,000 (RR = 1.5; 95% CI = 1.1-2.2).
• Less common in cigarette smokers (RR = 0.6; 95% CI = 0.5-0.9) and users of crack cocaine (RR = 0.4; 95% CI = 0.1-0.8).
• Less common in bisexual men than in men who were exclusively homosexual (estimated RR = 0.6; 95% CI = 0.4-0.9) and inversely associated with the number of female partners.
• Less common in men who had received pay for sex (RR = 0.6; 95% CI = 0.4-1.0). 

Cigarette smoking may be protective for Kaposi sarcoma risk in HHV-8–seropositive patients infected with HIV, and relative affluence may increase the risk of Kaposi sarcoma in HIV-positive patients.The incidence of HHV-8 infection is higher in homosexual men than in drug users.^{[21, 20]}

The presence of HHV-8 antibodies in HIV-infected persons increases the risk of Kaposi sarcoma. Among HIV-infected persons, those who subsequently seroconvert for HHV-8 are at highest risk. A comparison of 69 men who became infected with HHV-8 after acquiring HIV-1 with 182 men who were HHV-8 seropositive before their HIV-1 infection found that the risk of developing Kaposi sarcoma was higher in those whose HHV-8 seroconversion followed acquisiiton of  HIV-1 infection (risk ratio, 2.55; 95% confidence interval, 1.06–6.10).^{[21, 22]}

Risk for Kaposi sarcoma in HHV-8-infected men increased by 60% (P< 0.001) for each year of HIV-1 infection. Faster CD4 cell loss and higher HIV-1 RNA levels significantly predicted Kaposi sarcoma. The quicker development of KS in men acquiring HHV-8 after HIV-1 and its association with CD4 slope argues that Kaposi sarcoma is more likely if HHV-8 infection occurs in an immunocompromised person.^{[21, 22]}

Iatrogenic (immunosuppression-related) Kaposi sarcoma

This entity can occur following solid-organ transplantation or in patients receiving immunosuppressive therapy for other indications. The incidence of Kaposi sarcoma is increased 100-fold in transplant patients^{[23, 24]} However, individuals with congenital immunodeficient states are not at increased risk for developing Kaposi sarcoma. Iatrogenic Kaposi sarcoma is rare,^[1] but is more common in patients at risk for the classic form of  the disease.^[25]

The average time to development of Kaposi sarcoma following transplantation is 15-30 months. This subtype is usually aggressive and commonly presents as lymph node, mucosa, and visceral involvement. Disease regression is frequently seen with reduction or withdrawal of immunosuppressive therapy.^[26] This is further evidence for the important role that immune suppression may play in the development of Kaposi sarcoma. Immune activation and suppression affect the natural history of HHV-8 in a very complex manner.^[27]

One drug used for preventing transplant rejection, sirolimus (Rapamune), appears to have an anti–Kaposi sarcoma effect independent of its immunosuppressive action.^{[28, 29]}  In a study of 15 kidney transplant patients with biopsy-proven Kaposi sarcoma who were switched from cyclosporine to sirolimus, all cutaneous lesions in all patients resolved.^[30]

Sirolimus may have a therapeutic effect in Kaposi sarcoma due to its antiangiogenesis effect, with reduction of vascular endothelial growth factor (VEGF) and the Flk-1/KDR receptor on tumor cells, as well as its inhibition of the mammalian target of rapamycin (mTOR) pathway by blocking of Akt. Notably, mTor can activate various mediators of proliferation and affect control points of translation in the cell cycle. 

Classic (sporadic) Kaposi sarcoma

This entity typically occurs primarily in elderly men of Mediterranean and Eastern European background. It has a male predominance with a male-to-female ratio of 10-15:1. The age of onset is between 50 and 70 years.

Classic Kaposi sarcoma usually follows a protracted and indolent course. Common complications include venous stasis and lymphedema. This form of the disease rarely includes lymph node, mucous membrane, or visceral involvement.^[31]

As many as 30% of patients with classic Kaposi sarcoma subsequently develop a second malignancy, typically a non-Hodgkin lymphoma.^[31] These second malignancies may be due to immune suppression from age, host genetics, history of other neoplasm, and possible concurrent infections such as malaria.^{[32, 33, 34]}

Contradictory evidence suggests that immune activation is requisite for the development of classic Kaposi sarcoma. Indeed both hypotheses may be correct,^{[17, 18]} indicating a complicated mechanism of immune dysregulation.

Infrequent bathing; a history of asthma; and, in men, a history of allergy have been linked to classic Kaposi sarcoma in Italian patients.^[35]  Long-term use of topical steroids is associated with increased risk, either indicating an effect of chronic dermatitis or of the steroids themselves. As in epidemic AIDS-related Kaposi sarcoma, a protective effect of cigarette smoking has also been noted.

Endemic African Kaposi sarcoma

This entity occurs primarily in men but also in women and children who are HIV seronegative and may have an indolent or aggressive course. It was relatively common before the AIDS epidemic. Since the advent of AIDS, its incidence has increased about 20-fold in the African countries of Malawi, Swaziland, Uganda, Zambia, and Zimbabwe.^{[36, 1]}

In central Africa, Kaposi sarcoma has become the most prevalent form of cancer in men and the second most prevalent in women.^[37] It represents about 9% of all cancers seen in Ugandan males. This form of the disease involves lymph nodes more commonly than the classic variant. Factors associated with risk in HHV-8 seropositive patients are not as well characterized.

Rarely or never wearing shoes is associated with an increase of endemic Kaposi sarcoma in rural areas with volcanic clay soils, possibly related to chronic lymphatic obstruction in the feet and legs from fine soil particles.^{[38, 39]} Relative affluence in Ugandan patients is associated with increased risk for endemic Kaposi sarcoma, a finding similar to that of Kaposi sarcoma in AIDS patients.^[35]

A lymphadenopathic form of Kaposi sarcoma is also seen in Africa, chiefly in HIV-seronegative children before the age of puberty. Generalized lymphadenopathy is seen with visceral involvement and carries a dismal prognosis, with a 100% fatality rate at 3 years.

• References

Pathophysiology

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.

Cofactors

The fact that Kaposi sarcoma develops in only a small percentage of HHV-8–seropositive individuals points to the importance of other factors. Some of these may be genetic: For example, individuals with certain polymorphisms in the MDM2 gene, which is involved in the function of the tumor suppressor protein p53, may be at increased risk for Kaposi sarcoma.^[39]

It is possible that some agents may either stimulate or inhibit the development of Kaposi sarcoma, depending on the presence of influences such as genetic predisposition, environmental factors, drug intake, or lymphatic system disorders. The high prevalence of Kaposi sarcoma in areas where quinine and its derivatives are widely used for treatment of malaria may be partly attributable to the immunosuppressant effect of those drugs; however, quinolones also have several effects that could inhibit Kaposi sarcoma development. Likewise, angiotensin-converting enzyme (ACE) inhibitors have been described as inducing Kaposi sarcoma, in some reports, and inhibiting it, in others.^[39]  

Transmission

KSHV is now thought to be largely transmitted via saliva. Although associated with sexual risk factors, these may just be a surrogate for close contact.^[55] Heterosexual risk factors largely do not play a role here. Transmission by blood or blood products can occur but use of leukopoor stored blood is likely to significant reduce this risk.^[56] Transmission of KSHV may occur during solid organ donation, but it does not appear to affect clinical outcome in terms of survival or graft loss. In solid organ transplant recipients, the incidence of Kaposi sarcoma may be higher in those who are seropositive than in those who are seronegative.^[57]

• References

Epidemiology

Frequency

United States

Before the AIDS epidemic, Kaposi sarcoma was rare. Between 1975 and 1980, only 19 cases occurred in men aged 20-54 years, according to Surveillance, Epidemiology, and End Results (SEER) data (0.1 cases per 100,000). In 1981, an aggressive form of Kaposi sarcoma began to appear among men who have sex with men (MSM) as one of the harbingers of the AIDS epidemic.^[37] At the beginning of the AIDS epidemic, just before 1980, 40-50% of MSM with AIDS developed Kaposi sarcoma. This phenomenon spurred research into the possibility of an infectious etiology.^[58]  

The rate in all SEER areas increased from in the late 1970s to 17.5 per 100,000 in the late 1980s and then decreased to 2.2 per 100,000 as of 1999-2000.^[59] In the United States, the risk of Kaposi sarcoma in sexually active MSM is much greater than in others infected with HIV.^[60] The incidence of Kaposi sarcoma reached its zenith in 1989 among white men aged 20-54 years when it was the most common AIDS-associated neoplasm. Its incidence has dramatically declined since then.

In the mid 1990s, approximately 1 in 4 MSM contracted the disease. This number has decreased precipitously with the advent of safer sexual practices in the early 1990s and accelerated with the introduction of highly active antiretroviral therapy (HAART) in the mid 1990s.^{[60, 61]} The dramatic decrease supports the hypothesis of the need for severe immunosuppression for the presumed sexual transmission of an infective agent such as Kaposi sarcoma–associated herpesvirus/human herpes virus 8(KSHV/HHV-8).^[31]  

The decrease in HIV-related Kaposi sarcoma was most profound in men in the San Francisco area, from 7.9 to 1.6 cases per 100,000.^[59] The incidence in other HIV risk groups initially was 10% in intravenous drug abusers, 4% in hemophiliacs, and 3% in children with AIDS.^[62] It has decreased in these groups as well to a relatively steady rate of 2%, which is now the same rate for MSM. The disease may be contracted by other groups with HIV, such as women and heterosexual men, through unprotected sex. Overall, there has been a historic tendency to underreport Kaposi sarcoma in the AIDS population.^[63]

The other major group in the United States in whom Kaposi sarcoma occurs is the posttransplant population, in whom the incidence is about 1 in 200.^[64]

Currently, approximately 2,000 cases of Kaposi sarcoma, or about 6 cases per million population, occur yearly in the United States.^[64] Historically, the incidence in African-American men peaked somewhat later than in white men, in 1991-1999. It was first noted in Hispanic men in 1992 when its incidence was transiently higher than in African Americans or whites. The dramatic drop in incidence has been seen in all major ethnic groups from 1992-2001, with stabilization since then. Currently, the highest rate is seen in African-American men, with a rate of 3 per 100,000, as opposed to rates less than 3 per 100,000 in decreasing incidence for Hispanics, whites, and Asians/Pacific Islanders, respectively.

As noted above, the incidence and severity of Kaposi sarcoma has lessened following the introduction of HAART. This reduction has been attributed to restoration of the immune system caused by these drugs. The regression occurs in parallel with increases in CD4 counts, usually within no more than 9-12 months. Conversely, progression occurs with increasing viral load, low CD4 counts, and opportunistic infection .^[65]

Maurer et al, however, reported a cluster of cutaneous, refractory HIV-associated Kaposi sarcoma in patients in the San Francisco area with CD4 counts above 300 cells/μL and suppressed viral loads below 300 copies for at least 2 years.^[66] All patients presented between November, 2004 and November, 2006 and were being treated with a protease inhibitor (PI) or non–nucleoside reverse transcriptase inhibitors (NNRTIs). None had a history of opportunistic infection. All the courses were indolent. These authors proposed that these cases are the result of aging in persons infected with both HIV and HHV8.

In a cohort study of 86,620 HIV-infected and 196,987 uninfected adults from 1996–2009, the cumulative incidence by age 75 for Kaposi sarcoma was 4.4% but dropped to 4.1% in the most recent period analyzed (2005–2009).^[67]  

The specific HAART regimen may be important, as the drugs may also act as antitumor or antiangiogenic agents; for example, PIs may inhibit Kaposi sarcoma.^[68]  However, a systematic review found that HAART significantly reduced the risk of incident Kaposi sarcoma regardless of the antiretroviral drug class used, even after adjusting for CD4 count. The CD4-adjusted incidence of Kaposi sarcoma decreased by approximately 50%, with either NNRTI-based- or PI-based HAART.^[69]

International

Prior to the advent of HIV, Kaposi sarcoma was common in central Africa and prevalent in Mediterranean countries and the Middle East. It rarely occurred elsewhere. In Africa, the annual incidence of Kaposi sarcoma is very high at 37.7 per 100,000 in men and 20.5 per 100,000 in women. In Europe, the highest rates of classic Kaposi sarcoma are in Sicily (Ragusa, 30.1 cases per million in men/5.4 cases per million in women) and Sardinia (24.3 cases per million in men/7.7 cases per million in women).

A meta-analysis of the worldwide epidemiology of Kaposi sarcoma found the following incidence rates (per 100,000 person-years)^[70] :

• General population: 1.53 (95% confidence interval [CI] 0.33-7.08) 
• HIV-infected persons: 481.54 (95% CI 342.36-677.32) 
• HIV-infected MSM:1397.11 (95% CI 870.55-2242.18)
• HIV-infected children: 52.94 (95% CI 39.90-70.20) 
• Transplant recipients: 68.59 (95% CI 31.39-149.86) 

Mortality/Morbidity

AIDS-related Kaposi sarcoma, unlike other forms of Kaposi sarcoma, tends to have an aggressive clinical course. Morbidity may occur from extensive cutaneous, mucosal, or visceral involvement. In patients receiving HAART, the disease often has a more indolent clinical course or may regress spontaneously. The most common causes of morbidity include cosmetically disfiguring cutaneous lesions, lymphedema, gastrointestinal involvement, or pulmonary involvement (see Presentation). Pulmonary involvement is the most common cause of mortality with uncontrolled pulmonary hemorrhage.

Race

See the list below:

• In Africa and developing regions, epidemic AIDS-related Kaposi sarcoma is common in heterosexual adults and occurs less often in children.
• Classic Kaposi sarcoma typically occurs in elderly men of Mediterranean and Eastern European background.
• Endemic African Kaposi sarcoma occurs in HIV-seronegative men, women, and children in Africa.

Sex

See the list below:

• AIDS-related Kaposi sarcoma: In the United States, this condition occurs primarily in homosexual and bisexual men, and in the female sexual partners of bisexual men.
• African Kaposi sarcoma occurs in heterosexual men and women with equal frequency.
• Classic Kaposi sarcoma occurs primarily in men, with a male-to-female ratio of 10-15:1.

Age

See the list below:

• AIDS-related Kaposi sarcoma generally occurs in young to middle-aged adults age 20-54 years
• Classic Kaposi sarcoma typically occurs in patients age 50-70 years.
• African Kaposi sarcoma occurs in people of a younger age (35-40 y).

• References

History

AIDS-related Kaposi sarcoma (KS) has a variable clinical course ranging from minimal mucocutaneous disease to widespread organ involvement. The lesions may involve the skin, oral mucosa, lymph nodes, and visceral organs. Most patients present with cutaneous disease. Visceral disease may occasionally precede cutaneous manifestations. Lesions involving virtually every organ have been reported in autopsy series. The brain is spared, however.

Cutaneous lesions occur in virtually all patients. Note the following:

• Multiple skin lesions - See Physical for description.
• Usually multicentric in a continuum of development
• Tumor-associated lymphedema - Typically manifested by lower extremity or facial involvement, thought to occur secondary to obstruction of lymphatic channels
• Pain associated with ambulation - Due to lesions involving the soles of the feet

Gastrointestinal lesions can occur anywhere within the gastrointestinal tract. Lesions are often asymptomatic and clinically indolent. Gastrointestinal disease is usually an indicator of more advanced HIV infection. Symptoms include the following:

• Odynophagia, dysphagia
• Nausea, vomiting, abdominal pain
• Hematemesis, hematochezia, melena
• Bowel obstruction

Pulmonary involvement may be difficult to distinguish from opportunistic infections. Symptoms include the following:

• Cough
• Dyspnea
• Hemoptysis
• Chest pain
• Pulmonary lesions may be an asymptomatic radiographic finding.
• Pleural effusions are often exudative and bloody.

Lymphadenopathy may be the only site of disease requiring a lymph node biopsy. It may lead to significant lymphedema.

Classic Kaposi sarcoma has a more indolent course of 10-15 years or more with very gradual enlargement of cutaneous lesions and development of new ones. These lesions result in venous stasis and lymphedema of the lower extremities. Visceral lesions occur in the GI tract, lymph nodes, and other organs but are usually incidental findings at autopsy. As many as one third of patients develop a second neoplasm, most often a non-Hodgkin lymphoma.

• References

Physical

See the list below:

• Cutaneous lesions may occur at any location but typically are concentrated on the lower extremities and the head and neck region.
• Lesions may have macular, papular, nodular, or plaquelike appearances.
• Nearly all lesions are palpable and nonpruritic.
• Lesions may range in size from several millimeters to several centimeters in diameter.
• Lesions may assume a brown, pink, red, or violaceous color and may be difficult to distinguish in dark-skinned individuals.
• Lesions may be discrete or confluent and typically appear in a linear, symmetric distribution, following Langer lines.
• Mucous membrane involvement is common (palate, gingiva, conjunctiva). Ulcerated or bulky tumor involvement may interfere with speech or mastication.

• References

Causes

Etiologic factors include the following:

• Coinfection with HIV and HHV-8 (Kaposi sarcoma-associated herpesvirus [KSHV])
• Iatrogenic immunosuppression (including corticosteroids)
• Elevated degree of expression of numerous cytokines and angiogenic growth factors, including tumor necrosis factor alpha, interleukin-6, basic fibroblast growth factor, HIV-tat protein, and oncostatin M

• References

Laboratory Studies

All patients who present with Kaposi sarcoma should be evaluated for underlying immunodeficiency and undergo HIV screening. CD4 lymphocyte counts and plasma HIV viral-load studies should be performed for patients with known HIV infection. Patients with AIDS-associated Kaposi sarcoma should also have fecal occult blood testing to screen for possible gastrointestinal involvement.^[71]  ). This usually is not necessary for patients with less aggressive forms of Kaposi sarcoma, in which visceral involvement is uncommon.

Patients with Kaposi sarcoma who present with unexplained fevers should undergo additional workup to assess for other human herpes virus 8 (HHV-8)–associated disease, including multicentric Castleman disease or Kaposi sarcoma herpes virus (KSHV)–associated inflammatory cytokine syndrome.

Recommended laboratory tests include the following^[72] ;

• C-reactive protein
• KSHV/HHV-8 viral load
• Serum protein electrophoresis (SPEP)
• Interleukin-6 (IL-6) or IL-10

• References

Imaging Studies

Chest radiographs

Chest x-ray is recommended in all patients with AIDS-associated Kaposi sarcoma to assess for pulmonary involvement. Radiographic findings in Kaposi sarcoma are variable and nonspecific and may include any of the following:

• Diffuse reticulonodular infiltrates
• Interstitial infiltrates
• Pleural effusions
• Hilar or mediastinal lymphadenopathy
• An isolated pulmonary nodule

Thallium or gallium scans

These studies may help to differentiate pulmonary Kaposi sarcoma from infection. Pulmonary Kaposi sarcoma lesions typically demonstrate intense thallium uptake and no gallium uptake, whereas infection is often gallium avid and thallium negative.

This differentiation has become less of an issue in the era of highly active antiretroviral therapy (HAART). Prior to that, with the decreasing incidence of Pneumocystis jirovecii pneumonia (PCP), there had been an increased incidence of tuberculosis (TB), Mycobacterium avium-intracellulare (MAI), Kaposi sarcoma, and malignant lymphoma.

In a study performed in the mid 1990s, thallium-positive and gallium-negative pattern of scanning had a sensitivity of 63%, specificity of 95%, positive predictive value of 92%, and negative predictive value of 75%.^[73] Presently, this type of scanning has little clinical relevance, and diagnosis must be suspected on more clinical grounds.

Other imaging studies

Additional imaging studies may be warranted, in patients with signs or symptoms that suggest visceral or bone involvement. Computed tomography (CT) scans of the chest, abdomen, pelvis; magnetic resonance imaging with contrast of the spine, and/or positron emission tomography (PET)/CT are helpful to identify lymphadenopathy, visceral masses, splenomegaly, effusions, or bone lesions.

• References

Procedures

See the list below:

• Punch biopsy: A punch biopsy of the skin or an endoscopic, pleural, or transbronchial biopsy is necessary to establish a definitive diagnosis.
• Bronchoscopy: Pulmonary involvement is typically characterized by a slightly raised (submucosal) cherry-red lesion. Biopsy is generally avoided due to the risk of bleeding.
• Esophagogastroduodenoscopy (EGD) or colonoscopy: Gastrointestinal lesions are frequently observed. The yield of endoscopic biopsy may be low secondary to the submucosal location of many lesions.

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Histologic Findings

Typical histologic findings include proliferation of spindle cells, prominent slitlike vascular spaces, and extravasated red blood cells.

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Staging

Kaposi sarcoma does not lend itself to conventional tumor, node, metastases (TNM) classification. It should be individualized and customized for the type of Kaposi sarcoma. Patients with classic (sporadic) Kaposi sarcoma tend to have indolent disease and should not be subjected to extensive evaluation by imaging. A good physical examination, routine laboratories, and confirmatory biopsy may be all that is needed. If there is clinical suspicion for systemic disease, then appropriate imaging and even bronchoscopic or endoscopic procedures may be indicated.

Although no staging system has been accepted, several have been proposed. Some have included laboratory parameters as well as clinical features. One must remember that most patients with epidemic Kaposi sarcoma, the most common form of the disease in the United States, do not die of the disease. Therefore, factors other than tumor burden may have a role to play in survival. Because of this, the AIDS Clinical Trials Group (ACTG) has proposed a system based on immune status, extent of tumor involvement, and presence of systemic illnesses. The staging system has not been evaluated prospectively; however, some evidence suggests that it may have prognostic significance.

• ACTG Kaposi sarcoma staging classification^{[74, 40, 75]}

  • Good risk
    • Tumor (T) - Confined to skin and/or lymph nodes and/or minimal nonnodular oral disease limited to the palate
    • Immune system (I) - CD4 greater than 150/mm³
    • Systemic illness (S) - No history of opportunistic infection, thrush, unexplained fevers, more than 10% involuntary weight loss, or diarrhea persisting more than 2 weeks
    • Karnofsky performance status greater than 70
  • Poor risk
    • Tumor (T) - Tumor-associated edema or ulceration, extensive oral Kaposi sarcoma, gastrointestinal Kaposi sarcoma, Kaposi sarcoma in other non-nodal viscera
    • Immune system (I) - CD4 less than 150/mm³
    • Systemic illness (S) - History of opportunistic infection, thrush, unexplained fever, night sweats, more than 10% involuntary weight loss, or other HIV-related illness (ie, lymphoma, neurologic disease)
    • Karnofsky performance status less than 70
    • Other HIV-related illness (concurrent malignancy such as lymphoma or neurologic disease)
  • Good risk is shown with a 0 subscript and poor risk with a 1 subscript. For example, T₀, S₀, and I₀ are good risk, and T₁, S₁, and I₁ are poor risk. In the pre-HAART era, any category with poor risk designated the patient as an overall poor risk. One must remember that previous studies were conducted in the pre-HAART era. HAART has had a clear impact on survival by pushing many patients into the good risk category. Now it appears as though CD4 levels do not carry the same prognostic significance. Two broad categories have been defined, good risk (T₀ S₀, T₁ S₀, and T₀ S₁) and poor risk (T₁ S₁) in HAART responders. The original TIS classification may instead be more applicable to multidrug-resistant HIV.
  • Pre-HAART date, confirm the use of the original TIS staging system. Analysis of 294 patients placed on ACTG clinical trials for Kaposi sarcoma in the period from 1989 to 1995 confirmed that each of the variables of tumor, immune system, and systemic illness were independently associated with survival.^[76] Immune system impairment is the single most important predictor of survival by multivariate analysis. Three adverse prognostic factors for survival include prior or coexistent opportunistic infection (OI), the presence of B symptoms (weight loss, fever, and night sweats), and an absolute CD4 count of less than 300/μ L. The most important appears to be opportunistic infection (OI), with a survival of only 7 months versus 20 months without an OI.^[77]
  • An accurate assessment of response to treatment for Kaposi sarcoma is often difficult because the lesions may not be amenable to conventional bidimensional tumor measurements.

   

  

   
• Standard response evaluation criteria in solid tumors (RECIST) are not very useful for evaluating treatment effect in Kaposi sarcoma. New Kaposi sarcoma response criteria, using an assessment of the impact of treatment on tumor-related symptoms, are currently being evaluated prospectively.
• ACTG response criteria establish a cutaneous lesion response as a 50% decrease in total body lesion count and a flattening of 50% of previously raised lesions. Evaluation of visceral and oral Kaposi sarcoma is more difficult because lesions in this type do not lend themselves to measurement by either imaging or physical assessment.

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Approach Considerations

Currently, no treatment is available to eradicate HHV-8 infection. Therefore, there is no cure for Kaposi sarcoma (KS). Instead, the purpose of therapy in all forms of KS is directed at alleviating symptoms and slowing disease progression. Treatment decisions vary depending on KS form, presence of symptoms, and extent of disease.

Classic KS is usually limited to the skin and has an indolent course. A retrospective analysis of 123 patients with classic KS found that the median time to progression with observation alone was 4 months. However, multivariate analysis determined that immunosuppression was the only significant independent factor that predicted disease progression. Therefore, observation alone may be sufficient for immunocompetent asymptomatic patients.^[78]  

Lower extremity edema can be managed with compression stockings. Local therapies, including surgical resection, radiotherapy, cryotherapy, and intralesional chemotherapy, can be used to treat symptomatic or cosmetically unacceptable lesions. Systemic chemotherapy should be reserved for patients in whom local therapy fails or who have extensive disease.^[78]

Therapy for epidemic Kaposi sarcoma centers on the use of highly active antiretroviral therapy (HAART), which has decreased the incidence and severity of this disease. Most good-risk patients show tumor regression with HAART alone. Local therapies can also be implemented for symptomatic or cosmetically disfiguring cutaneous lesions.The least invasive and toxic modality should be used due to high risk for infectious complications in this population. Poor-risk patients usually require a combination of chemotherapy with HAART.  Treatment is typically continued until response plateau or unacceptable toxicity. 

Iatrogenic or post-transplantation Kaposi sarcoma commonly responds to reduction or discontinuation of immunosuppression. In one study, tapering of immunosuppressive therapy alone led to complete or partial KS regression in 9 of 20 patients.^[79]  However, this approach may not always be feasible and can place patients at risk for graft rejection.

Several retrospective and prospective studies have shown a benefit of switching from calcineurin inhibitors (eg, cyclosporine, tacrolimus) to a mammalian target of rapamycin (mTOR) inhibitor, specifically sirolimus. Although the exact mechanism is not fully understood, sirolimus is thought to have a direct cytotoxic effect on KS tumor cells due to inhibition of vascular endothelial growth factor, Flk-1/KDR and phosphorylated Akt which are commonly upregulated in Kaposi sarcoma.^[80]  As in other forms of KS, chemotherapy is commonly reserved for limited disease refractory to local therapy or in patients with disseminated disease.

Of note, the role for antiviral agents against herpes viruses (eg, foscarnet, ganciclovir,valganciclovir) is unclear. These agents usually are ineffective in Kaposi sarcoma, likely because the neoplastic spindle cells harbor a latent HHV-8 infection. However, a study in patients with AIDS and cytomegalovirus (CMV) retinitis found that oral or intravenous ganciclovir (which is approved for use in CMV infection) reduced the risk of Kaposi sarcoma.^[81] Further studies are needed in this area.^[31]  Activation of drugs by Kaposi sarcoma herpes virus (KSHV) kinases is an approach that needs further investigation. Also, the c-kit oncogene is up-regulated by KSHV and would be a rational target for blockade.

 A course of antiviral therapy with cidofovir or foscarnet may be considered if there is suspicion for other coexisting HHV-8–related diseases (eg, multicentric Castleman disease, primary effusion lymphoma).^[82]

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Medical Care

Antiretroviral therapy for AIDS-related Kaposi sarcoma

Optimal control of HIV infection using HAART is an integral part of therapy for AIDS-related Kaposi sarcoma, and should be the first step in therapy. Response to HAART can range from 20-80%, depending on the stage of disease and the amount of pretreatment.^[83]  Since its inception, HAART has changed the therapeutic goal in Kaposi sarcoma from short-term palliation to long-term remission and control.

Effective combination antiretroviral therapy usually comprises a combination of either a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) with 2 nucleoside reverse transcriptase inhibitos (NRTIs). Some evidence suggests a direct antitumor effect on angioproliferative Kaposi sarcoma–type lesions, but to date no level 1 evidence supports this clinically.^[84]  No difference is apparent between PI-based and NNRTI-based antiretroviral regimens in terms of response of Kaposi sarcoma.^[69] ​

HAART may be tried as the sole modality in nonvisceral disease. For visceral disease, chemotherapy may be added. For locally symptomatic disease, radiation therapy may be introduced.^[31]

However, patients with poor-risk Kaposi sarcoma rarely respond to HAART alone. In addition, approximately 6-39% of patients with AIDS-related Kaposi sarcoma develop immune reconstitution inflammatory syndrome (IRIS) with worsening of Kaposi sarcoma within 3 to 6 months after re-initiating ART.^[85]  This occurs in association with increase in CD4 counts and control of HIV viremia.^{[85, 76]} The criteria for Kaposi sarcoma IRIS per the AIDS Clinical Trial Group are as follows:

• Onset after starting, restarting, or altering of the HAART regimen
• Increase of CD4 count by ≥50 cells/μL or a 2-fold increase in CD4 count, and decrease in HIV-1 viral load of greater than 0.5 log
• More-than-expected progression of Kaposi sarcoma within 12 weeks of initiating HAART

Risk factors for Kaposi sarcoma–associated IRIS include pulmonary involvement, concurrent or recent use of glucocorticoids, and advanced immunosuppression. Glucocorticoids are generally contraindicated in Kaposi sarcoma due to their stimulatory effect on Kaposi sarcoma spindle cells.^[86]  In this clinical situation, chemotherapy may be necessary to ameliorate and reverse the disease progression.

The choice of therapy beyond HAART must be individualized and depends on the extent of disease, the presence and nature of the symptoms, the rate of disease progression, and the overall therapeutic goals. 

Palliative systemic therapy is indicated for symptomatic or life-threatening visceral disease, rapidly progressive mucocutaneous disease with pain or ulceration, and symptomatic lymphedema. In this setting, few reliable estimates of response rate with HAART alone compared with combined HAART and chemotherapy are available. One trial from South Africa reported response rates of 39% to HAART alone versus 66% to HAART plus chemotherapy; in addition,, 35% of patients in the HAART arm crossed over to require palliative chemotherapy or radiation within 12 months of randomization. These results support the use of chemotherapy combined with HAART in patients with high tumor volume (T1).^[87]

Systemic therapy for epidemic Kaposi sarcoma

Chemotherapy is the preferred first-line therapy for refractory/relapsed limited cutaneous disease and advanced disease. It  is indicated for symptomatic visceral or rapidly progressive mucocutaneous disease for which a rapid response is desirable. It is used in disseminated disease not amenable to local modalities.

Cytotoxic agents are approved by the Food and Drug Administration (FDA) for AIDS-related Kaposi sarcoma and include the following:

• Liposomal doxorubicin (Doxil)
• Liposomal daunorubicin (DaunoXome)
• Paclitaxel (Taxol)
• Oral etoposide (Vepesid)

Current National Comprehensive Cancer Network (NCCN) guidelines recommend liposomal doxorubicin (or liposomal daunorubicin) or paclitaxel in the first-line setting.^[71] The liposomal technology has resulted in higher response rates with less cardiac and myelotoxicity for both liposomal doxorubicin and liposomal daunorubicin because of their more targeted nature.^{[12, 13, 14]} Response rates of up to 80% can be seen with either of these drugs.

The same is true for paclitaxel, which can be safely administered to severely immunocompromised patients whose diseaserefractory to other chemotherapeutic agents.^[75] Response rates of 50-71% were reported in two phase II trials.^{[88, 89]}

Several trials have compared pegylated-liposomal doxorubicin with combination chemotherapy and have found it to be as effective as or superior to conventional combination chemotherapy, with higher response rates and lower toxicity. In a randomized phase III trial of 258 patients receiving pegylated-liposomal doxorubicin or doxorubicin/bleomycin/vincristine (ABV) the overall response rate was 46% in the liposomal doxorubicin arm versus 25% in the ABV arm. The median time to treatment failure was similar to both arms, with decreased grade 3-4 adverse events in the liposomal doxorubicin arm. Therefore, single-agent regimens are commonly preferred.

In AIDS-associated Kaposi sarcoma, the problem has been balancing the immunosuppressive effects of chemotherapy with its potential benefit. This has required a great deal of finesse in the era of HAART, which can itself cause regression of Kaposi sarcoma. Treatment duration should be to a response plateau with lengthening of the treatment interval to approximately 6 weeks, a period in which Kaposi sarcoma will progress if treatment is not being administered. Also, recurrence of Kaposi sarcoma after chemotherapy does not necessarily mean resistance, making retreatment with the same regimen a reasonable option.

In refractory or relapsed cases that progressed despite one or both first-line therapies, options include the following:

• Pomalidomide,
• Bevacizumab
• Etoposide
• Gemcitabine
• Imatinib
• Thalidomide
• Vinorelbine

However data for these agents are limited and derived from studies with small treatment populations.

Immunomodulation with interferon-alfa has clinical activity in Kaposi sarcoma that may be mediated by its antiangiogenic, antiviral, and immunomodulatory properties. Time to clinical response is long (ie, 4-6 mo). Therefore, it should be reserved for patients who do not require a prompt clinical response. Interferon-alfa is most effective when the CD4 count is greater than 150-200/μL or when administered in conjunction with antiretroviral therapy. Combination interferon and chemotherapy has been no more effective than chemotherapy or interferon alone. 

Objective response rates have been seen in about 40% of patients.^{[90, 91]} Responses depend on extent of disease, immunocompetence of the patient, prior treatment with chemotherapy, presence of circulating acid-labile interferon alpha, and beta-2 microglobulin levels. Response rates are about 4-fold higher in immunocompetent patients than in those with poor prognostic features.

Interferon is given by subcutaneous administration daily or 3 times weekly. Response may occur with low (1 million U/m²), intermediate (3-10 million U/m²), or high doses (50 million U/m²). 

Interferon alpha-2a and interferon alpha-2b were approved for treatment of Kaposi sarcoma in the pre-HAART era. Interferon-alfa has activity against HIV by suppressing messenger RNA translation into protein, preventing the assembly of intact viral particles. Thus, it has synergy with antiretroviral drugs. High-dose monotherapy was used then because there was little else to offer. High-dose therapy is rarely used at present; instead, interferon is typically given in doses of 4 to 18 million units, together with antiretroviral therapy. Dose-limiting toxicity is neutropenia.

Because of its highly vascular nature, Kaposi sarcoma has been thought of as a natural target for angiogenesis inhibition. A phase II study of thalidomide in 20 HIV-infected patients with Kaposi sarcoma resulted in a 40% response rate with median duration of response of 7 months. Most of the patients were on HAART.^[31]  SImilarly, a phase I/II trial evaluating the efficacy of pomalidomide in 22 patients, 77% of whom had relapsed disease, found a 60% overall response rate in the HIV-positive group.^[92]  Combination chemotherapy with antiangiogenic and cytotoxic agents is being considered.^[81]

Bevacizumab is a VEGF inhibitor that has been studied in AIDS-associated Kaposi sarcoma. A phase II study of 17 HIV-infected patients with KS showed a 31% overall response rate, with a complete response seen in 19% of patients.^[93]  

Other compounds (eg, fumagillin analogs and peptidoglycan analogs produced by bacteria, which are potent blockers of angiogenesis) have shown minimal benefit as single agents. Glufanide disodium, an antiangiogenic dipeptide from solubilized fraction of thymic extract, has shown benefit with response rates of 36% when used as a nasal formulation.^[75] Because of its male predominance, another way of treating the disease may be through hormonal manipulation. The potential inhibitory effect of beta human chorionic gonadotropin is also under study.

A small study with imatinib mesylate (Gleevec) has shown response in 4 of 5 patients.^[94]  In a study of nine patients with HIV-associated Kaposi sarcoma, immune checkpoint blockade with nivolumab or pembrolizumab produced partial responses in six patients and complete response in one patient, with low toxicity.^[95]

Finally, evaluation of the multiple pathways of potential pathogenesis may lead to inhibitors of both autocrine and paracrine factors. An inhibitor of basic fibroblast growth factor (bFGF) has been studied. Also, newer antiangiogenic compounds such as inhibitors of matrix metalloproteinases and oligonucleotides may show promise.^[96]

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Local Therapy

Local therapy is best suited for patients who require palliation of locally advanced symptomatic disease (eg, radiation) or for those who have cosmetically unacceptable lesions. This therapy is also well suited for patients with significant comorbidities and disease refractory to systemic modalities. It can provide better cosmesis; control bulky lesions that cause bleeding, pain or, edema; and treat extensive skin disease. Local therapy fails to halt the development of new Kaposi sarcoma lesions.

Radiation therapy

Radiation therapy is the most widely used and effective local therapy.^[97]  It can palliate bleeding, pain, and unsightly lesions. Kaposi sarcoma is very radiosensitive, with reported response rates of 68%-92%. A study assessing the efficacy of radiation on 97 previously untreated cutaneous Kaposi sarcoma lesions showed a response rate of 87% with a complete response seen in 30% of treated sites.^[98]  

The type and dose of radiation varies depending on site, depth, and diameter of lesion. Low-voltage (100 kv) photons or electron-beam radiotherapy may be used. The standard regimen is 24 Gy in 12 fractions; however, hypofractionated regimens (eg, 20 Gy in 5 fractions) have shown to be equally effective.^[99] Patients with HIV are more prone to develop radiation-induced mucositis as well as hyperpigmentation, desquamation, and ulceration of treated lesions.^{[31, 100, 101]}

In patients with widespread skin involvement, extended-field external beam radiation therapy (EBRT) has been effective in controlling the disease. This approach appears to give better long-term control than piecemeal radiation of individual lesions. This form of therapy is also given in 4-Gy fractions weekly for 6-8 weeks.

Surgical excision

Surgical excision may be of benefit for patients with small superficial lesions. The major problem is local recurrence. The presence of clear surgical margins does not mean that Kaposi sarcoma has been permanently controlled at a given anatomical site. Local recurrence is very common. Yet over the course of many years, multiple small excisions may be a reasonable approach to achieve good control of disease. 

Surgery may also be indicated for patients with a visceral crisis such as obstruction or bleeding or for very deep, localized, painful lesions. The risk of transmission of HIV to the operating room team limits its use in AIDS-associated Kaposi sarcoma.

Intralesional chemotherapy

Intralesional therapy with vinca alkaloids with low-dose vincristine or vinblastine as well as bleomycin has been used in a limited fashion—primarily for the classic form of Kaposi sarcoma, in which localized skin disease predominates. Responses occur in 60-90% of patients with little in the way of systemic side effects with duration of 4-6 months. Dosing is done at about one-tenth the systemic dose of drug with 3- to 4-week intervals between treatments. Side effects include changes in pigmentation, swelling, blistering, ulceration, and pain on injection as well as localized but usually transient neuropathic symptoms.

Because the disease recurs in other areas, intralesional chemotherapy has relatively limited use. Also, systemic vinca alkaloid therapy may be equally effective and cause less localized skin toxicity.

Cryotherapy

Cryotherapy entails liquid nitrogen applied topically and may be useful for small facial lesions less than 1 cm in dimensions. It induces response in more than 85% of cases. Cryotherapy has the advantage of short duration, minimal discomfort, and ability to be used repeatedly and in combination with other forms of treatment.^[31]  Cryotherapy may cause skin hypopigmentation. It has limited penetration and is not ideal for large, deep lesions.

Laser therapy

Laser photocoagulation can shrink smaller lesions and be used to palliate bleeding and pain in larger lesions. Similar to cryotherapy, it has limited application to deep, bulky lesions. 

Topical therapies

Interleukin-6 (IL-6) is a cytokine implicated in the pathogenesis of Kaposi sarcoma. In vitro, retinoic acid down-regulates IL-6 receptor expression. A 0.1% alitretinoin gel (Panretin) is available commercially and may be applied topically 2-4 times daily. This agent is generally well tolerated but may cause local erythema and irritation. It induces responses in one third to one half of the patients after 2-14 weeks of therapy.^[31]  Common side effects include local inflammation and depigmentation.

Imiquimod, a topical immune response modulator, has shown safety and efficacy in patients with limited cutaneous classic or transplant-associated Kaposi sarcoma. A phase I/II trial of 17 patients showed a 47% response rate in 17 patients receiving imiquimod 5% cream 3 times per week for 24 weeks.^[102]

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Consultations

Local therapies—including topical agents, cryotherapy, laser therapy, and intralesional therapy—should be administered by a dermatologist who has experience in the treatment of Kaposi sarcoma. Obtain a radiation oncology consultation when considering the use of radiation as definitive therapy for palliation of locally advanced symptomatic disease or a cosmetically disturbing cutaneous lesion.

All patients with AIDS-associated Kaposi sarcoma should be referred to an HIV infectious disease specialist. Care coordination between the HIV specialist and oncology team is important. The infectious disease team can help diagnose and treat co-existing opportunistic infections; monitor HIV viral load; and optimize immune system recovery, which is a key component of AIDS-associated Kaposi sarcoma management.

Patients who experience significant Kaposi sarcoma–related lymphedema should be referred to a lymphedema specialist to help improve symptom control.

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Complications

The complications of Kaposi sarcoma are largely dependent on the location of lesions. Kaposi sarcoma can involve almost any organ, but the most common visceral sites include the oral cavity, gastrointestinal tract, and respiratory system. Profound lymphedema can result in cellulitis, skin infections, and poor wound healing. Patients with involvement of the gastrointestinal tract can develop anemia from chronic blood loss. Pulmonary involvement can cause life-threatening hemoptysis and refractory pleural effusions requiring long-term indwelling pleural catheter placement.

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Prevention

Prevention of exposure to HIV and HHV-8 is the most effective method of preventing Kaposi sarcoma. Sexual abstinence, monogamy, or condom use and avoidance of IV drug use or use of sterile needles and syringes are the best methods.

Similar measures are recommended for those who are already infected with HIV, to prevent infecting others and to avoid co-infection with other sexually transmitted and hematogenous infections. The use of antiretroviral therapy decreases risk of Kaposi sarcoma in patients already infected with HIV and may be equally effective in treating Kaposi sarcoma.^[60]

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Long-Term Monitoring

Currently, no treatment that can eradicate HHV-8 is available. Therefore, all patients with Kaposi sarcoma are at risk for recurrence or relapse even if they achieve a complete remission. Patients should have routine physical examinations every 3-4 months to assess for any new skin lesions, edema, or symptoms/signs suggestive of visceral involvement.

Patients with AIDS-associated Kaposi sarcoma should also be monitored with a complete blood cell count and differential, complete metabolic profile, T-cell subsets, and HIV viral load. HIV control and immune function are imperative in preventing relapse and progression, so compliance with antiretroviral therapy should be assessed and emphasized at each encounter.

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Medication Summary

The goals of pharmacotherapy for Kaposi sarcoma (KS) are to eradicate the sarcoma, reduce morbidity, and prevent complications.

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Paclitaxel (Taxol)

• Dosing, Interactions, etc.

Clinical Context:  Promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. FDA-approved for the treatment of patients with AIDS-related KS.

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Class Summary

Taxanes inhibit cell growth and differentiation by preventing depolymerization of microtubules.

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Doxorubicin HCL liposome (Doxil)

• Dosing, Interactions, etc.

Clinical Context:  Binds to DNA and impairs nucleic acid synthesis. Doxil is doxorubicin encapsulated in a pegylated liposome. This technology allows for longer area under the time-concentration curve than with free doxorubicin. Additionally allows for increased selective drug delivery to tumor tissues. Doxorubicin and daunorubicin currently serve as first-line treatment for individuals with advanced KS. An ongoing clinical trial being conducted by the Eastern Cooperative Oncology Group (ECOG) is comparing paclitaxel to Doxil in chemo-naïve patients with advanced symptomatic KS.

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Daunorubicin citrate liposome (DaunoXome)

• Dosing, Interactions, etc.

Clinical Context:  Liposomal preparation of daunorubicin. Inhibits DNA and RNA synthesis by intercalating between DNA base pairs.

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Class Summary

Anthracyclines inhibit cell growth and differentiation by inhibiting topoisomerase II and producing free radicals, which may cause the destruction of DNA.

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Interferon alfa 2b (Intron)

• Dosing, Interactions, etc.

Clinical Context:  Thought to exert activity in KS through antiproliferative tumor effect and antiviral properties. Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity is not understood clearly; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

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Class Summary

Interferons are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha-, beta-, and gamma-interferons may be administered topically, systemically, and intralesionally.

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Alitretinoin gel 0.1% (Panretin)

• Dosing, Interactions, etc.

Clinical Context:  Naturally occurring endogenous retinoid. Inhibits growth of KS by binding to retinoid receptors.

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Class Summary

Retinoids may reduce potential for malignant degeneration.

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Vinblastine sulfate (Velban)

• Dosing, Interactions, etc.

Clinical Context:  Vinca alkaloid derived from the periwinkle plant. Induces arrest of cell division by inhibiting microtubule formation.

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Class Summary

Vinca alkaloids inhibit microtubule formation, which in turn disrupts the formation of mitotic spindle, causing cell proliferation to arrest at metaphase.

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