AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Kaposi sarcoma (Kaposi's sarcoma, KS) was described initially in 1872 by a Hungarian dermatologist, Moritz Kaposi. Kaposi sarcoma is a spindle-cell tumor thought to be derived from endothelial cell lineage. This condition carries a variable clinical course ranging from minimal mucocutaneous disease to extensive organ involvement. Kaposi sarcoma can be primarily categorized into four types: epidemic of AIDS-related, immunocompromised, classic or sporadic, and endemic (African).

• 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 the most common malignancy seen in HIV-infected patients, especially where access to HAART (highly active antiretroviral therapy) is limited.¹ 
  • In the United States, Kaposi sarcoma serves as an AIDS-defining illness in 2-3% of HIV-infected homosexual men. In the mid 1990s, it was the initial presentation in approximately 15% of homosexual men. In Africa and developing regions, epidemic AIDS-related Kaposi sarcoma is common in heterosexual adults and occurs less often in children. Visceral involvement is widespread.
  • AIDS-related Kaposi sarcoma is the most clinically aggressive form of Kaposi sarcoma.
  • Seroconversion to human herpesvirus 8 (HHV-8) positivity predates the development of epidemic Kaposi sarcoma by 5-10 years. The interval for development of Kaposi sarcoma is shortened in patients where HIV infection precedes seroconversion to HHV-8 positivity.^{2, 3}
  • The presence of decreased CD4 counts and increased HIV-1 viral loads are independent prognostic factors in the development of epidemic Kaposi sarcoma. Less than one-sixth of HIV-infected patients have CD4 count of over 500 per microliter. The disease usually develops in HIV infected patients with severe immunodeficiency.⁴
  • Cigarette smoking may be protective for Kaposi sarcoma risk in HHV-8 seropositive patients infected with HIV. 
  • Relative affluence may increase the risk of Kaposi sarcoma in HIV positive patients.⁵
• Immunocompromised Kaposi sarcoma
• • This entity can occur following solid-organ transplantation or in patients receiving immunosuppressive therapy. The incidence of Kaposi sarcoma is increased 100-fold in transplant patients^{6, 7} However, individuals with congenital immunodeficient states are not at increased risk for developing Kaposi sarcoma.
  • This form of Kaposi sarcoma is rare⁸ but is more common in patients at risk for classic Kaposi sarcoma.⁹
  • The average time to development of Kaposi sarcoma following transplantation is 15-30 months. An aggressive course is the rule with visceral involvement being common. However, withdrawal of immunosuppression may cause regression of the disease.¹⁰ This is further evidence for the important role that immune suppression may play in the development of Kaposi sarcoma. Immune activation and suppression both play roles to affect the natural history of HHV-8 in a very complex manner.¹¹ 
  • • Clearly the immunotherapy required to prevent rejection puts patients at greater risk for developing Kaposi sarcoma. One such drug, sirolimus (Rapamune) has been shown to have simultaneous antitumor effect as well as the immunosuppressive effect required to prevent graft rejection.^{12, 13, 14}
    • In a study of 15 kidney-transplant patients switched from cyclosporine to sirolimus with biopsy-proven Kaposi sarcoma, all cutaneous lesions in all patients disappeared. levels of Flk-1/KDR, phosphorylated Akt, p70S6, and vascular endothelial growth factor (VEGF) were increased in Kaposi sarcoma cells. It appears as though sirolimus has an anti-Kaposi sarcoma mechanism of action independent of its immunosuppressive mechanism.
    • No rejection was noted in the patients on this drug. The mechanism may be related to both its antiangiogenesis effect with reduction of VEGF and its Flk-1/KDR receptor on the tumor cells and inhibition of the mTOR pathway by blocking of Akt. mTor can activate various mediators of proliferation and affect control points of translation in the cell cycle. This dual activity may be helpful in providing immunosuppressive therapy without increased risk of Kaposi sarcoma development in patients undergoing organ transplantation.
• 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 carries a protracted and indolent course. Common complications include venous stasis and lymphedema. This form of the disease rarely has lymph node, mucous membrane, or visceral involvement.⁴ As many as 30% of patients with classic KS subsequently may develop a second malignancy, typically a non-Hodgkin lymphoma.⁴ Its occurrence may be due to immune suppression from age, host genetics, history of other neoplasm, and possible concurrent infections such as malaria.^{15, 16, 17} Contradictory evidence suggests that immune activation is requisite for the development of classic Kaposi sarcoma. Indeed both hypotheses may be correct,^{18, 19} 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 among Italian patients.²⁰ Topical use of steroids is associated with increased risk, either indicating an effect of chronic dermatitis or of the steroids themselves. A finding similar to that seen in epidemic AIDS-related Kaposi sarcoma with regard to the 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 in Africa and may carry an indolent or aggressive course. It was relatively common before the AIDS epidemic. Since the advent of AIDS, it has increased about 20-fold. In the African countries of Malawi, Swaziland, Uganda, Zambia, and Zimbabwe.^{21, 8}
  • Kaposi sarcoma has become the most prevalent form of cancer in men and the second in incidence among women.²² It represents about 9% of all cancers seen in Ugandan males. The disease involves lymph nodes more commonly than the classic variant. Factors associated with risk among HHV-8 seropositive patients are not as well characterized.
  • The rare wearing of shoes is associated with an increase of endemic Kaposi sarcoma.²³ Relative affluence in Ugandan patients is associated with Kaposi sarcoma, a finding similar to that of Kaposi sarcoma in AIDS patients. Whether this represents local immune suppression due to chronic lymphatic obstruction from fine soil particles may go hand in hand with the association of classic KS with use of topical steroids.²⁰

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 poor prognosis with a 100% fatality rate at 3 years. 

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.²⁴ Restoration of NK cell cytoxic effect may explain regression of Kaposi sarcoma in AIDS patients treated with HAART.²⁵ There may be immune activation in Kaposi sarcoma as well with a role for inflammatory cytokines such as gamma interferon and the initiation of HHV-8 infected cell proliferation by HIV-tat protein.^{18, 19} 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. 

Finally, there have been several reports of epidemic Kaposi sarcoma in homosexual men without a shred of evidence of HIV infection. These men usually have CD4 counts of greater than 300/mL. This has been seen in primarily an indolent cutaneous form. There may be other factors than HIV at play in this case.²⁶

Pathophysiology

Kaposi sarcoma (Kaposi's sarcoma, KS) is caused by an excessive proliferation of spindle cells thought to have an endothelial cell origin. Despite their heterogeneity, the tumors are predominantly composed of Kaposi sarcoma human herpesvirus (KSHV) genomic material with immunohistochemical markers of both lymphoid, spindle, and endothelial cells.¹ Although the origin is still unknown, there is 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 spindle cells.²⁷ This would suggest 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 in the either the reticular dermis (patch stage) or the entire thickness of the dermis (plaque or nodular stage).⁴ 

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 Kaposi sarcoma patients 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.²⁸ 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 independent occurring at multiple sites. These data are primarily applicable to initially less aggressive cutaneous Kaposi sarcoma. They may not apply for de novo more aggressive visceral Kaposi sarcoma, which may be less likely to respond to therapy. 

Human herpesvirus 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. 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 with angiogenic cytokines—IL-1 beta, basic fibroblast growth factor (bFGF), acidic fibroblast growth factor, endothelial growth factor, and vascular endothelial growth factor. 

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.⁴ Indeed the later TAT 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.^{29, 30}

Thus, it appears that 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.³¹

Frequency

United States

Before the AIDS epidemic, Kaposi sarcoma (Kaposi's sarcoma, KS) was rare. Between 1975 and 1980, the incidence in males aged 20-54 years was 19 cases 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 homosexual men as one of the harbingers of the AIDS epidemic.²² At the beginning of the AIDS epidemic, just before 1980, 40-50% of homosexual men with AIDS developed Kaposi sarcoma. 

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 1999-2000.³² In the United States, the risk of Kaposi sarcoma among sexually active homosexual men is much greater than among others infected with HIV.³³ 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 homosexual men 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 HAART in the mid 1990s due to improved immune reconstitution.^{33, 34} The dramatic decrease supports the hypothesis of the need for severe immunosuppression for the presumed sexual transmission of an infection agent such as Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8).⁴

Men in the San Francisco area manifested the most profound decrease from 7.9 to 1.6 cases per 100,000.³² The incidence in other HIV risk groups initially was 10% in IV drug abusers, 4% in hemophiliacs, and 3% in children with AIDS.³⁵ It has decreased in these groups as well to a relatively steady rate of 2%, which is now the same rate for homosexual men. 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.³⁶

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. 

Approximately 2,500 cases of Kaposi sarcoma occur yearly in the United States at the present time. The incidence among African-American men peaked somewhat later than in white males, 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. Now the highest rate is seen in African-American males 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 attributable 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 (OI).³⁷ Maurer et al³⁸ have, however, reported a cluster of cutaneous, refractory HIV-associated Kaposi sarcoma in patients in the San Francisco area with CD4 count above 300 cells/mL and suppressed viral loads below 300 copies for at least 2 years. All patients presented between November, 2004 and November, 2006 and were being treated with one protease inhibitor or non-nucleoside RTI. There was no history of opportunistic infection. All the courses were indolent. The hypothesis generated to explain this is that there are a larger number of aging patients infected with both HIV and HHV8. 

Also, the specific HAART regimen may be important as the drugs may also act as antitumor or antiangiogenic agents. This phenomenon may not be as rare as previously thought and will require greater monitoring in the future with attention to age, duration of HIV infection, HHV8 viral load, and patterns of viral gene expression.³⁹

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 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). 

See related CME at Global Burden of Sexually Transmitted Infections (Slides With Transcripts). 

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 History and Physical). Pulmonary involvement is the most common cause of mortality with uncontrolled pulmonary hemorrhage.

Race

• 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 in Africa.

Sex

• AIDS-related Kaposi sarcoma: In the United States, this condition occurs primarily in homosexual males, 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 males, with a male-to-female ratio of 10-15:1.

Age

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

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

AIDS-related Kaposi sarcoma (Kaposi's sarcoma, KS) carries 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 have been reported in autopsy series involving virtually every organ.

• Cutaneous lesions occur in virtually all patients.
• • 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 over years 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.
• The brain is spared.

Physical

• 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.

Causes

• 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 TNF-alpha, IL-6, bFGF, HIV-tat protein, and oncostatin M

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Bacillary angiomatosis: This entity is often difficult to distinguish clinically from Kaposi sarcoma. It is caused by Rochalimaea species, a slow-growing, fastidious, gram-negative bacillus that is readily treated with antibiotics. Bacillary angiomatosis lesions typically possess capillary proliferation and neutrophilic inflammation. In contrast, Kaposi sarcoma lesions display slitlike vascular spaces containing lymphoplasmacytic infiltrates. A skin biopsy is required to establish diagnosis.

Hematoma
Hemangioma
Dermatofibroma
Pyogenic granuloma
Purpura

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

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

Imaging Studies

• Chest radiographs: Radiographic findings in patients with Kaposi sarcoma (Kaposi's sarcoma, KS) are variable and nonspecific. They may include diffuse reticulonodular infiltrates, interstitial infiltrates, pleural effusions, hilar or mediastinal lymphadenopathy, or 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 has become less of an issue in the era of HAART. Prior to that, with the decreasing incidence of Pneumocystis carinii 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%.⁴⁰ Presently, this type of scanning has little clinical relevance, and diagnosis must be suspected on more clinical grounds.

Other Tests

Prevention

• Primary Kaposi sarcoma
• • Prophylaxis against exposure to the etiology agents of HIV and HHV-8 is the most effective methods of preventing Kaposi sarcoma. Sexual abstinence, monogamy, condom use, avoidance of IV drug use, and 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.
• Secondary Kaposi sarcoma
• • The use of HAART decreases risk of Kaposi sarcoma in patients already infected with HIV and may be equally efficacious in treating Kaposi sarcoma.³³
  • As of 2003, an estimated 6 million people in developing nations were urgently in need of HAART. Major efforts are underway to provide such antiretroviral treatment to these people.⁴¹

Procedures

• 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.

Histologic Findings

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

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^{42, 1, 43}
• • 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 (T₀S₀, T₁S₀, and T₀S₁) and poor risk (T₁S₁) 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.⁴⁴ 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/mL. The most important appears to be opportunistic infection (OI), with a survival of only 7 months versus 20 months without an OI.⁴⁵
  • 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.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

All therapies for Kaposi sarcoma (Kaposi's sarcoma, KS) have been markedly influenced by HAART (highly active antiretroviral therapy), which has decreased the incidence and severity of this disease.  

• Antiretroviral therapy: The introduction of HAART (highly active antiretroviral therapy) has significantly reduced the incidence of Kaposi sarcoma and changed its clinical course. Optimal control of HIV infection using HAART is an integral part of successful Kaposi sarcoma therapy. It should be the first step in therapy. Response to such therapy can be anywhere from 20-80% based on stage of disease and the amount of pretreatment.⁴⁶ 
• • It is, however, very unusual for patients with poor risk Kaposi sarcoma to respond to HAART alone. In addition, a flare phenomenon may be noted associated with HAART initiation consistent with a reactivation of the immune system and associated inflammatory response.^{47, 44}
  • 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. Since its inception, HAART treatment has changed the goal in Kaposi sarcoma treatment from short-term palliation to long-term remission and control. 
  • HAART may be the sole modality used in nonvisceral disease. For visceral disease, chemotherapy may be added. For locally symptomatic disease, radiation therapy may be introduced.⁴
• Local therapy: Local therapy is best suited for individuals who require palliation of locally advanced symptomatic disease (eg, radiation) or for individuals who have cosmetically unacceptable lesions. This therapy is also well suited for individuals 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 is the most widely used and effective local therapy. This can palliate bleeding, pain, or unsightly lesions. This may be given in the form of low-voltage (100 kv) photons or electron-beam radiotherapy. Responses occur in 80-90% of patients. A higher cumulative dose (40 Gy) results in better local control than lower doses (8 Gy or 20 Gy). Electron beam therapy is reserved for treatment of superficial lesions. This is usually giving once weekly in 4 Gy fractions. Recurrence may be common in adjacent, untreated areas, leading some authors to recommend extended- field radiotherapy to affect a higher cure rate. Patients with HIV are more prone to develop radiation-induced mucositis as well and hyperpigmentation, desquamation, and ulceration of treated lesions.^{4, 48, 49}
  • In patients with widespread skin involvement, extended-field electron 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 type of therapy is also given in 4-Gy fractions weekly for 6-8 weeks. 
  • 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. 
  • 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 where 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 treatment. 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, its use is relatively limited. Also, systemic vinca alkaloid therapy may be equally effective and cause less localized skin toxicity. 
  • Cryotherapy entails liquid nitrogen applied topically and may be useful for small facial lesions less than 1 cm in dimensions. Cryotherapy may cause skin hypopigmentation. 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.⁴ It has limited penetration and is not ideal for large, deep lesions. 
  • Laser and surgical therapies can be used locally. 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. Surgery is usually limited to 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 as well.  
  • Topical retinoids: 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 [Panretin]) gel 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 at a time interval of 2-14 weeks after initiation of therapy.⁴ Common side effects of local inflammation and depigmentation. 
• Palliative systemic therapy is indicated for symptomatic or life-threatening visceral disease, rapidly progressive mucocutaneous disease with pain or ulceration, and symptomatic lymphedema. No randomized prospective clinical trials compare one adjuvant therapy to the other for classic Kaposi sarcoma. What follows applies primarily to epidemic Kaposi sarcoma. 
• • 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 clinical response. Interferon-alfa is most effective when the CD4 count is greater than 150-200/mm³ or when administered in conjunction with antiretroviral therapy.
  • • Objective response rates have been seen in about 40% of patients.^{50, 51} Responses are dependent on extent of disease, immunocompetence of the patient, prior treatment with chemotherapy, presence of circulating acid-labile interferon alpha, and beta-2 microglobulin levels. Immunocompetent patients have about a 4-fold increase in response compared with those with poor prognostic features.⁴
    • As a rule, combination interferon and chemotherapy has been no better than chemotherapy or interferon alone. This therapy entails 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). 
    • These agents, interferon alpha-2a and interferon alpha-2b, were approved in the pre-HAART era. Interferon-alfa has activity against HIV by suppressing mRNA 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 today in the era of HAART.
    • Because HAART alone is quite effective, lower doses of interferon-alpha are now the rule. Dose-limiting toxicity is neutropenia. Phase I trials with interferon and zidovudine have been completed with doses of interferon in the range of 4-5 million units with 200 mg of zidovudine being tolerated.⁵² Trials with moderate doses of 1-10 million units combined with less myelosuppressive antiretrovirals are in progress. Toxicity is more common and severe with higher doses; symptoms may include fatigue, flulike symptoms, myalgia, arthralgia, fever, myelosuppression, and hepatotoxicity. 
  • Interleukin-12 has shown a response rate of 71% (95% confidence interval, 48-89%) among 24 evaluable patients in a phase I/II trial.⁵³
  • Chemotherapy is used with palliative intent. Chemotherapy 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.
  • • Initially, vincristine-, vinblastine-, and bleomycin-containing regimens were used. Etoposide and doxorubicin regimens were the second-line standards. These agents are capable of achieving rapid tumor regression and palliation of tumor-related symptoms but at a cost of myelosuppression and risk of opportunistic infections.
    • Combination therapy with regimens such as ABV (actinomycin D, bleomycin, and vincristine) versus single-agent therapy such as doxorubicin cause higher response rates but similar time to progression and overall survival. Prior to the availability of growth factor support, toxicity due to myelosuppression was significant. Combination chemotherapy results in about double the response rate, 45-60% versus 20-25% for single agents. 
    • Several single cytotoxic agents are approved by the Food and Drug Administration (FDA) for AIDS-related Kaposi sarcoma and include liposomal doxorubicin (Doxil) for previously treated patients, liposomal daunorubicin (DaunoXome) for first-line use, and paclitaxel (Taxol) for second-line use. 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.^{54, 55, 56} 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 refractory to other chemotherapeutic agents.⁴³ Response rates have been seen from 50-71% in two phase II trials for untreated patients.^{57, 58}
    • 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 out of the 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.
  • Because chemotherapy can be given long-term, treatment-related toxicities may prevent its ongoing administration.    
  • Potential new avenues of therapy are being investigated. 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 patients with Kaposi sarcoma with HIV serology resulted in a 40% response rate with median duration of response of 7 months. Most of the patients were on HAART.⁴ Combination chemotherapy of antiangiogenic and cytotoxic agents is being considered.⁵³
  • Other compounds such as 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.⁴³ Because of its male predominance, another way of treating the disease may be through hormonal manipulation. Work is being done to look at the potential inhibitory effect of beta-HCG. 
  • Because of its etiologic link to Kaposi sarcoma human herpesvirus (KSHV) (HHV-8), antiviral therapy with foscarnet and ganciclovir may be effective. A randomized clinical trial of oral ganciclovir versus ganciclovir ocular implants has shown a lower rate of Kaposi sarcoma.⁵³
  • • Further studies are needed in this area.⁴ Yet, antiherpes drugs have been ineffective. Activation of drugs by KSHV-kinases is an approach that needs further investigation. Also, the c-kit oncogene is up-regulated by KSHV. This would make it a rational target for blockade. 
    • A small study with imatinib mesylate (Gleevec) has shown response in 4 of 5 patients.⁵⁹ 
    • 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.⁶⁰               

Despite effective therapies and promising activity of novel agents, the investigation of new targeted therapies continues.

See related CME at Co-receptor Inhibitors (Slides with Transcript); FDA Approvals: PrandiMed, Doryx, Doxil; and FDA Safety Changes: Levaquin, Nexavar, AndroGel.

Consultations

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.

MEDICATION

Section 7 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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

Drug Category: Taxanes

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

Drug Category: Anthracyclines

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

Drug Category: Interferons

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

Drug Category: Retinoids

Retinoids may reduce potential for malignant degeneration.

Drug Category: Vinca alkaloids

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

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

In/Out Patient Meds

Emerging investigational therapies for Kaposi sarcoma (Kaposi's sarcoma, KS) include the following: 

• Signal transduction inhibitors
• Anti–HHV-8 agents
• Cytokine inhibitors
• Antiangiogenesis agents: Vascular endothelium growth factor (VEGF) inhibitor, such as, SU-5416 (a recent trial using an intranasal VEGF inhibitor [IM862] reported an overall response rate of 36%, with an acceptable toxicity profile); TNP-470; thalidomide

Complications

Cutaneous Kaposi sarcoma lesions may be cosmetically disfiguring and often generate significant psychologic distress for individuals infected with AIDS.

Prognosis

Patients with pulmonary Kaposi sarcoma lesions are often symptomatic and may present emergently with respiratory failure.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

Biopsy of pulmonary lesions in patients with Kaposi sarcoma (Kaposi's sarcoma, KS) is generally avoided due to an increased risk of bleeding.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Endoscopic view of a Kaposi sarcoma lesion situated in the gastric antrum.
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Media file 2:  Epidemic Kaposi sarcoma (KS). Large violaceous truncal nodules with typical linear and symmetric distribution pattern.
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Media file 3:  Kaposi sarcoma (KS), facial. Confluent, violaceous nodules involving the chest wall; extensive facial involvement with accompanied edema.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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