Kaposi Sarcoma

Synonyms and related keywords: Kaposi's sarcoma, KS, Kaposi tumor, Kaposi's tumor, Kaposi malignancy, Kaposi's malignancy, epidemic AIDS-related Kaposi sarcoma, immunocompromised Kaposi sarcoma, classic Kaposi sarcoma, endemic African Kaposi sarcoma


INTRODUCTION

Background: Kaposi sarcoma (KS) was described initially in 1872 by a Hungarian dermatologist, Moritz Kaposi. KS 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. KS can occur in several different clinical settings.

Epidemic AIDS-related KS: This entity occurs in patients with advanced HIV infection, and is the most common presentation of KS. In the United States, KS serves as an AIDS-defining illness in 10-15% of HIV-infected homosexual men. In Africa and developing regions, epidemic AIDS-related KS is common in heterosexual adults and occurs less often in children. Visceral involvement is common. AIDS-related KS is the most clinically aggressive form of KS.

Immunocompromised KS: This entity can occur following solid-organ transplantation or in patients receiving immunosuppressive therapy. However, individuals with congenital immunodeficient states are not at increased risk for developing KS. The average time to development of KS following transplantation is 30 months. Visceral involvement is common.

Classic KS: This entity typically occurs in elderly men of Mediterranean and Eastern European background. Classic KS usually carries a protracted and indolent course. Common complications include venous stasis and lymphedema. As many as 30% of patients with classic KS subsequently may develop a second malignancy. Visceral involvement is uncommon.

Endemic African KS: This entity occurs in men who are HIV seronegative in Africa and may carry an indolent or aggressive course.

Pathophysiology: KS is caused by an excessive proliferation of spindle cells thought to have an endothelial cell origin. Molecular studies suggest that KS originates from a single cell clone rather than a multifocal origin. Human herpes virus 8 (HHV-8) genomic sequences have been identified by polymerase chain reaction in more than 90% of all types of KS lesions (including epidemic and endemic forms), suggesting a causative role. These 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 KS in individuals infected with HHV-8 and HIV include an abnormal cytokine milieu associated with HIV infection (interleukin [IL]-6, IL-1, granulocyte-macrophage colony-stimulating factor [GM-CSF], basic fibroblast growth factor [bFGF], oncostatin M, tumor necrosis factor [TNF]) and the HIV-tat protein, which acts as a mitogen for KS cells.

Frequency:

• In the US: KS currently is the most common AIDS-associated malignancy. KS serves as the presenting manifestation of AIDS in approximately 15% of homosexual men and in approximately 2% of patients with HIV infection in other risk groups.

• Internationally: In Europe, the highest rates of classic KS 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).

Mortality/Morbidity: AIDS-related KS, unlike other forms of KS, tends to have an aggressive clinical course. Morbidity may occur from extensive cutaneous, mucosal, or visceral involvement. In patients receiving highly active antiretroviral therapy (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.

Race:

• In Africa and developing regions, epidemic AIDS-related KS is common in heterosexual adults and occurs less often in children.

• Classic KS typically occurs in elderly men of Mediterranean and Eastern European background.

• Endemic African KS occurs in HIV seronegative men in Africa.

Sex:

• AIDS-related KS: In the United States, this condition occurs primarily in homosexual males, bisexual men, and in the female sexual partners of bisexual men.

• African KS occurs in heterosexual men and women with equal frequency.

• Classic KS occurs primarily in males, with a male-to-female ratio of 10:1.

Age:

• AIDS-related KS generally occurs in adults.

• Classic KS typically occurs in patients aged 50-70 years.

• African KS occurs in people of a younger age (35-40 y).

CLINICAL

History: AIDS-related 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 occasionally may 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

• 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 gastrointestinal tract

• Often asymptomatic and clinically indolent

• Odynophagia, dysphagia

• Nausea, vomiting, abdominal pain

• Hematemesis, hematochezia, melena

• Bowel obstruction

• Pulmonary - May be difficult to distinguish from opportunistic infections

• Cough

• Dyspnea

• Hemoptysis

• Chest pain

• Asymptomatic radiographic finding

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, and oncostatin M

DIFFERENTIALS

Bacillary Angiomatosis

Other Problems to be Considered:

Bacillary angiomatosis: This entity often is difficult to distinguish clinically from KS. 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, KS lesions display slitlike vascular spaces containing lymphoplasmacytic infiltrates. A skin biopsy is required to establish diagnosis.

Hematoma
Hemangioma
Dermatofibroma
Pyogenic granuloma
Purpura

WORKUP

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 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 KS from infection. Pulmonary KS lesions typically demonstrate intense thallium uptake and no gallium uptake, whereas infection often is gallium avid and thallium negative.

Procedures:

• A punch biopsy of the skin or an endoscopic, pleural, or transbronchial biopsy is necessary to establish a definitive diagnosis.

• Bronchoscopy: Pulmonary involvement typically is characterized by a slightly raised (submucosal) cherry-red lesion. Biopsy generally is avoided due to the risk of bleeding.

• Esophagogastroduodenoscopy (EGD) or colonoscopy: Gastrointestinal lesions frequently are 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: KS does not lend itself to conventional tumor, node, metastases (TNM) classification. Although no staging system has been accepted, several have been proposed. 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 KS staging classification

• Good risk
  • Tumor (T) - Confined to skin and/or lymph nodes and/or minimal oral disease
  • Immune system (I) - CD4 greater than 200/mm³
  • Systemic illness (S) - No history of opportunistic infection, 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 KS, gastrointestinal KS, KS in other non-nodal viscera
  • Immune system (I) - CD4 less than 200/mm³
  • Systemic illness (S) - History of opportunistic infection, 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

• An accurate assessment of response to treatment for KS often is difficult because the lesions may not be subject to conventional bidimensional tumor measurements.

• New KS response criteria, using an assessment of the impact of treatment on tumor-related symptoms, currently are 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 KS is more difficult because it does not lend itself to measurement.

TREATMENT

Medical Care:

• Antiretroviral therapy: Optimal control of HIV infection using HAART is an integral part of successful KS therapy. 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.

• 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 also is well suited for individuals with significant comorbidities and refractory or resistant disease. Local therapy fails to halt the development of new KS lesions.

• Radiation therapy: This is the most widely used and effective local therapy. 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. Patients with HIV are more prone to develop radiation-induced mucositis.
• Intralesional vinblastine commonly is used and generally is well tolerated. Adverse effects include skin discoloration and superficial erythema. The lesion is injected with 0.1 mL/cm² (at a concentration of 0.2 mg/mL).
• Cryotherapy entails liquid nitrogen applied topically and may be useful for small facial lesions. Cryotherapy may cause skin hypopigmentation.
• Topical retinoids: IL-6 is a cytokine implicated in the pathogenesis of KS. 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 generally is well tolerated but may cause local erythema and irritation.

• Systemic therapy is indicated for extensive or symptomatic visceral disease, rapidly progressive mucocutaneous disease, and symptomatic lymphedema.

• Interferon-alfa: Clinical activity in KS may be mediated by its antiangiogenic, antiviral, and immunomodulatory properties. Time to clinical response is long (ie, 4 mo). Interferon-alfa is most effective when the CD4 count is greater than 150-200/mL or when administered in conjunction with antiretroviral therapy. This therapy entails subcutaneous administration daily or 3 times weekly. Response may occur with low (1 million U/m²), intermediate (30 million U/m²), or high doses (50 million U/m²). Toxicity is more common and severe with higher doses; symptoms may include fatigue, flulike symptoms, myalgia, arthralgia, fever, myelosuppression, and hepatotoxicity.

• Chemotherapy is not used with curative intent. It is capable of achieving rapid tumor regression and palliation of tumor-related symptoms. Chemotherapy is indicated for symptomatic visceral or rapidly progressive mucocutaneous disease. Several cytotoxic agents are approved by the Food and Drug Administration (FDA) for AIDS-related KS and include liposomal doxorubicin (Doxil), liposomal daunorubicin (DaunoXome), and paclitaxel (Taxol).

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

MEDICATION

The goals of pharmacotherapy are to eradicate the sarcoma, reduce morbidity, and prevent complications.

Drug Category: Taxanes -- Inhibit cell growth and differentiation by preventing depolymerization of microtubules.

Drug Name	Paclitaxel (Taxol) -- 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.
Adult Dose	100 mg/m2 IV q2wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; documented hypersensitivity to polyoxyethylated castor oil; peripheral neuropathy; bone marrow suppression; liver failure; severe cardiac disease
Interactions	Coadministration with cisplatin may further increase myelosuppression
Pregnancy	D - Unsafe in pregnancy
Precautions	Premedicate with steroids, H1 blockers, and H2 blockers to decrease risk of hypersensitivity reactions; myelosuppression, alopecia, arthralgia/myalgias, and cardiac arrhythmia may occur

Drug Category: Anthracyclines -- Inhibit cell growth and differentiation by inhibiting topoisomerase II and producing free radicals, which may cause the destruction of DNA.

Drug Name	Doxorubicin HCL liposome (Doxil) -- 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.
Adult Dose	20 mg/m2 IV q3wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe CHF; cardiomyopathy; preexisting myelosuppression; impaired cardiac function
Interactions	Toxicity increases with cyclophosphamide, cyclosporine, mercaptopurine, verapamil, streptozocin, paclitaxel, and progesterone; phenobarbital decreases effect; decreased toxicity with digoxin; phenytoin levels are decreased
Pregnancy	D - Unsafe in pregnancy
Precautions	May produce severe local toxicity in irradiated tissues, even when the 2 therapies are not administered concomitantly; caution in patients who have received radiotherapy; cardiomyopathy is a well-known characteristic of doxorubicin; monitor for drug-induced cardiomyopathy; mortality rate is >50% once cardiomyopathy has developed

Drug Name	Daunorubicin citrate liposome (DaunoXome) -- Liposomal preparation of daunorubicin. Inhibits DNA and RNA synthesis by intercalating between DNA base pairs.
Adult Dose	40 mg/m2 IV q2wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; CHF; arrhythmias; cardiopathy
Interactions	None reported
Pregnancy	D - Unsafe in pregnancy
Precautions	Extravasation may occur, resulting in severe tissue necrosis; caution with impaired hepatic, renal, or biliary function

Drug Category: Interferons -- Naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha, beta, and gamma interferons may be administered topically, systemically, and intralesionally.

Drug Name	Interferon-alfa 2b (Intron) -- 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.
Adult Dose	30 million U/m2 SC 3 times per wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; anaphylactic sensitivity to mouse immunoglobulin (IgG), egg protein, or neomycin
Interactions	Potential risk of renal failure when administered concurrently with IL-2; theophylline may increase INF-alfa toxicity by reducing its clearance
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Depression and suicidal ideation may be adverse effects of treatment; infrequently, severe or fatal GI hemorrhage has been reported in association with INF-alfa therapy; prior to therapy initiation, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cell, and bone marrow hairy cells; monitor periodically (eg, monthly) during treatment to determine treatment response; if a patient does not respond within 6 mo, discontinue treatment; if a response occurs, continue treatment until no further improvement is observed (whether continued treatment after that time is beneficial is not known)

Drug Category: Retinoids -- May reduce potential for malignant degeneration.

Drug Name	Alitretinoin gel 0.1% (Panretin) -- Naturally occurring endogenous retinoid. Inhibits growth of KS by binding to retinoid receptors.
Adult Dose	0.1% gel, apply topically bid/qid to affected cutaneous lesions
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Increases toxicity of DEET if used concurrently
Pregnancy	D - Unsafe in pregnancy
Precautions	Preexisting cutaneous T cell lymphoma; do not use occlusive dressing; avoid UV light exposure of treated areas

Drug Category: Vinca alkaloids -- Inhibit microtubule formation, which in turn disrupts the formation of mitotic spindle, causing cell proliferation to arrest at metaphase.

Drug Name	Vinblastine sulfate (Velban) -- Vinca alkaloid derived from the periwinkle plant. Induces arrest of cell division by inhibiting microtubule formation.
Adult Dose	0.1 mL/cm2 (at a concentration of 0.2 mg/mL) administered intralesionally
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; preexisting severe granulocytopenia
Interactions	Phenytoin plasma levels may be reduced when administered concomitantly with vinblastine; with mitomycin, the toxicity of vinblastine may increase significantly
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in patients diagnosed with impaired liver function and neurotoxicity; when patient is receiving mitomycin C, monitor closely for shortness of breath and bronchospasm

FOLLOW-UP

In/Out Patient Meds:

• Emerging investigational therapies

• Signal transduction inhibitors

• Anti–HHV-8 agents

• Cytokine inhibitors

• Antiangiogenesis agents: Vascular endothelium growth factor (VEGF) inhibitor, eg, 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 KS lesions may be cosmetically disfiguring and often generate significant psychologic distress for individuals infected with AIDS

Prognosis:

• Patients with pulmonary KS lesions often are symptomatic and may present emergently with respiratory failure

MISCELLANEOUS

Medical/Legal Pitfalls:

• Biopsy of pulmonary lesions generally is avoided due to an increased risk of bleeding