What Is Kaposi Sarcoma? Its History and the Current State of Treatment

Kaposi sarcoma is a cancer arising from endothelial cells that line lymph or blood vessels, and is a type of soft tissue sarcoma. It generally develops in tissue beneath the skin or in the lining of the mouth, nose or anus, but can also develop in internal organs. It is a rare cancer.

The skin manifestations of Kaposi sarcoma are generally red or brown papules that progress to form nodules and plaques as they infiltrate the skin and subcutaneous tissues. The clinical course may be indolent or aggressive.

Types and Clinical Characteristics of Kaposi Sarcoma

Kaposi Sarcoma is a multifocal tumor of vascular origin associated with Human Herpesvirus-8 (HHV-8). It has four main clinical forms. These share the same underlying pathophysiological mechanisms but differ in the circumstances of onset, geographical distribution, course and prognosis.

Classic Kaposi Sarcoma

• More common in men of Mediterranean, Eastern European and Middle Eastern origin
• Generally over the age of 50
• Slowly progressive, with a chronic course
• Symmetrical purple-red macules, papules or nodules on the lower limbs (especially the legs)
• Usually limited to the skin; internal organ involvement is rare
• Low mortality; generally controlled with local treatment.

Endemic (African) Kaposi Sarcoma

• In areas of Central and Southern Africa with a high prevalence of HHV-8
• May occur in HIV-positive or HIV-negative people
• More common in men; may occur at younger ages
• More aggressive course
• Lymph node and internal organ involvement is common alongside skin lesions
• In some cases, only a lymphatic form (especially in children)
• Survival may be shorter in the aggressive form.

Epidemic (AIDS-Associated) Kaposi Sarcoma

• One of the most common malignancies in patients with HIV/AIDS
• Risk increases markedly in those with a CD4 cell count <200/mm³
• May involve the skin, mucous membranes, lymph nodes and visceral organs (lungs, GIS)
• Lesions may grow and spread rapidly
• Antiretroviral therapy (ART) can lead to marked regression of lesions
• After ART begins, lesions may flare suddenly due to immune reconstitution inflammatory syndrome (5–10%)
• Can be controlled with ART; advanced cases require systemic chemotherapy.

Iatrogenic (Transplant-Associated) Kaposi Sarcoma

• In patients receiving immunosuppressive treatment after solid organ transplantation
• More often after kidney transplantation
• Skin lesions are common; visceral involvement may also occur
• May regress when immunosuppressive treatment is reduced

• Lymph node involvement was absent, so Dr. Kaposi assumed the disorder was a preexisting systemic disease. He concluded that it was a small-cell sarcoma with an unfavorable prognosis (disease course).

  Dr. Kaposi noted that some skin lesions regressed spontaneously. Having observed bleeding within lesions histologically, he attributed the spontaneous regression to bleeding. He considered various causes of Kaposi sarcoma, including infection, vasculopathy and hyperplasia arising from neuromuscular disease.

  In addition to describing Kaposi sarcoma, Dr. Kaposi described several other conditions, including xeroderma pigmentosum, diabetic dermatitis, cutaneous spread of herpes infection and lupus erythematosus. 

  A prolific writer and renowned academic, Dr. Kaposi produced over 100 academic publications, was a member of Emperor Leopold's Imperial Order and served as president of the second International Congress of Dermatology in Vienna in 1892. He died in 1902.

  The Current View of Kaposi Sarcoma

  • Kaposi sarcoma (KS) is an angioproliferative disease resulting from infection with human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus (KSHV).
  • Various HHV-8 viral gene products affect both cell cycle regulation and the control of apoptosis, and segments of the HHV-8 genome contain viral oncogenes important in the pathogenesis of tumor formation.
  • KS is classified into four types according to the clinical circumstances in which it develops: classic, endemic, iatrogenic and AIDS-associated. The clinical courses and treatment approaches of these four types differ.
  • Classic KS is most frequently diagnosed in men from the Mediterranean basin and Central and Eastern Europe, or their descendants.
  • HHV-8 infection is necessary for classic KS to develop, but not everyone infected develops the disease. Immunosuppression (suppression of the immune system with drugs) is a well-defined risk factor for KS.
  • Three main pathological stages are described in the progression of KS lesions: patch stage, plaque stage and nodular stage.

  Kaposi Sarcoma Treatment

  The aim of KS treatment is to control the disease and relieve tumor-related symptoms and complications. There is no method that provides a definitive cure. Specific treatment recommendations vary according to the extent of disease and the presence or absence of accompanying HIV infection. Asymptomatic lesions may be monitored without direct treatment.

  Starting antiretroviral therapy (ART) in patients with HIV infection and KS generally leads to regression of Kaposi lesions and durable clinical response rates above 50%, along with a reduced viral load and increased CD4 cell count. This is standard for all patients with HIV/AIDS and may be sufficient treatment by itself in some cases.

  Sometimes, KS lesions may flare suddenly after treatment begins in patients receiving ART. Known as immune reconstitution inflammatory syndrome, this results from an immune response to pathogens and may occur from weeks to several months after ART starts. In a cohort study of 150 patients with HIV-associated KS who started ART as their only KS treatment, 10 patients (6.6%) developed KS associated with progressive immune reconstitution inflammatory syndrome. ART can generally be continued successfully in these situations, but chemotherapy may also be needed for a time to control KS growth.

  Classic KS in HIV-negative patients is generally indolent, usually limited to the skin and managed with local treatments except in advanced cases. Decisions about KS-specific local or systemic antitumor treatment should consider the extent of disease, sites of involvement, rate of progression, patient-specific psychological factors and the presence of organ dysfunction.

  Local Treatment

  Local treatment may be possible for patients with limited, nonbulky and accessible lesions. Alitretinoin gel (0.1%) is the only patient-applied topical treatment approved by the FDA for AIDS-associated KS.

  Other local treatments for KS include intralesional chemotherapy, radiotherapy (RT), laser treatment and cryotherapy. All can be effective in controlling local tumor growth. RT has a role in KS treatment particularly when disease is bulky and symptomatic or rapid tumor shrinkage is needed.

  Systemic Treatment

  KS patients with edema, extensive mucocutaneous disease or symptomatic pulmonary or gastrointestinal disease require a rapid response, best achieved with systemic treatment.

  Liposomal forms of doxorubicin and daunorubicin are standard first-line treatments for patients with extensive or advanced disease or those requiring rapid tumor shrinkage. In HIV-associated KS, each of the two available liposomal anthracyclines has been found superior in response rate and toxicity profile to conventional chemotherapy (bleomycin and vincristine ± nonliposomal doxorubicin) , based on randomized prospective clinical trial results. Liposomal doxorubicin also shows substantial activity in classic KS.

  Patients whose KS tumors initially respond well to this treatment may require additional treatment. Low-dose weekly paclitaxel is an established second-line treatment for KS and is effective even in patients with HIV-associated KS resistant to anthracyclines.

  Pomalidomide is an agent shown to be effective in both HIV-positive and HIV-negative patients. In a representative study, it was given at 5 mg daily on days 1–21 of a 28-day cycle, with an overall response rate of 73% in the HIV-positive group and 100% in the HIV-negative group. Based on this and other studies, pomalidomide received FDA approval for AIDS-associated KS that does not respond to highly active ART, and for KS in HIV-negative adults.

  More recently, pembrolizumab demonstrated activity in a single-arm phase 2 study of patients with classic or endemic KS, with a best overall response rate of 71%. Oral etoposide, vinorelbine, gemcitabine, bevacizumab and imatinib have also been evaluated individually in anthracycline-treated KS patients and shown objective responses.

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  Key Points

  • When disease burden is limited and asymptomatic, KS may be monitored without antineoplastic treatment.
  • ART is standard first-line treatment for all patients with HIV-associated KS.
  • In HIV-associated KS, tumor flare (immune reconstitution syndrome) may occur in 5–10% after ART begins.
  • Liposomal anthracyclines are standard first-line chemotherapy for patients requiring treatment because of tumor growth, symptoms or visceral organ involvement.
  • Paclitaxel is effective in anthracycline-resistant KS.
  • Pomalidomide is FDA-approved for advanced KS in both HIV-positive and HIV-negative patients.