Kaposi's Sarcoma

Kaposi's sarcoma is a form of skin cancer that can involve internal organs. It is most often found in patients with acquired immunodeficiency syndrome (AIDS), and can be fatal.

Description

Kaposi's sarcoma (KS) was once a very rare form of cancer, primarily affecting elderly men of Mediterranean and eastern European background, until the 1980s, when it began to appear among AIDS patients. It manifests in four distinct forms. The first form, called classic KS, was described by the Austrian dermatologist Moricz Kaposi more than a century ago. Classic KS usually affects older men of Mediterranean or eastern European backgrounds by producing tumors on the lower legs. Though at times painful and disfiguring, they are not generally life-threatening. The second form of the disease, African endemic KS, primarily affects boys and men. It can appear as classic KS, or in a more deadly form that quickly spreads to tissues below the skin, the bones and lymph system, leading to death within a few years of diagnosis. Another form of KS, iatrogenic KS, is observed in kidney and liver transplant patients who take immunosuppressive drugs to prevent rejection of their organ transplant. Iatrogenic KS usually reverses after the immunosuppressive drug is stopped. The fourth form of KS, AIDS-related KS, emerged as one of the first illnesses observed among those with AIDS. Unlike classic KS, AIDS-related KS, tumors generally appear on the upper body, including the head, neck, and back. The tumors also can appear on the soft palate and gum areas of the mouth, and in more advanced cases, they can be found in the stomach and intestines, the lymph nodes, and the lungs,

Kaposi's sarcoma is reported to be found in 20% of homosexual men who have HIV, 3% in heterosexual intravenous drug users, 3% in women and children, 3% in transfusion recipients, and 1% in hemophiliacs. Once regarded as only a defining illness for AIDS, KS has proven to be a progressive, fatal disease on its own, especially when the disease becomes systemic. Yet, involvement throughout the body is not the only factor in patient mortality. Research in 2000 found that patients with KS in oral mucosa had a higher risk of death than those with KS appearing only on the skin.

Causes and symptoms

Causes

A variety of factors appear to contribute to the development of KS. One of the first avenues offered as causal agents was genetic predisposition. People with classic KS, and those who develop the tumors after transplantation, are more likely than others to possess a genetically determined immune factor called HLA-DR. Cases of KS that run in families, however, are rare.

The fact that the disease is more likely to afflict men than women suggests sex hormones, such as testosterone in men, may stimulate the growth of KS tumors, and that estrogen in women may retard their growth.

Immune suppression was the next likely cause since liver, kidney, and bone marrow patients who take immunosuppressive drugs to prevent transplant rejection frequently develop KS lesions. Similarly, KS has been observed in patients receiving systemic treatment with high-dose corticosteroids, which also suppresses the immune system. Immune suppression is the hallmark of AIDS.

The current theory is the discovery of an infectious agent. A number of viruses have been proposed as possible causes, including cytomegalovirus and human papilloma virus, fragments of which have been found in KS

This HIV-positive patient is afflicted with Kaposi's sarcoma inside the mouth. (Custom Medical Stock Photo. Reproduced by permission.)

tumor specimens. A more likely candidate, however, is a new herpes virus that has been called human herpes virus 8 (HHV-8) or KS-associated herpes virus (KSHV). Since fragments of the virus were first disclosed in KS samples in 1994, they have since been found in KS samples taken from patients with classic KS, African endemic KS, and KS in transplant patients. Fragments of HHV-8, however, have also been found in patients who have other skin diseases but who do not have KS,

Studies in 2000 showed that HHV-8 was indeed the culprit behind KS. Nevertheless, it does not work alone. In combination with a patient's altered response to cytokines (regulatory proteins that are produced by the immune system) and the HIV-1 transactivating protein Tat which promotes the growth of endothelial cells, HHV-8 can then encode interleukin 6 viral proteins, specific cytokines that stimulate cell growth in the skin. This becomes KS.

HHV-8 destroys the immune system further by directing a cell to remove the major histocompatibility complex (MHC-1) proteins that protect it from invasion. These proteins are then transferred to the interior of the cell and are destroyed. This leaves the cell unguarded and vulnerable to invaders which would normally be targeted for attack by the immune system.

Research in early 2001 showed that transmission of HHV-8 virus can be more casual than was once thought, giving rise to incidence among women and children. Women who are intravenous drug users and who also have had a sexually transmitted disease have been found to harbor HHV-8. This evidence shows that women can contract HHV-8 through blood. In addition, researchers in 2000 found that HHV-8 could be transmitted orally though kissing. This study found more HHV-8 virus in oral samples than in genital secretions. In fact, HHV-8 was difficult to find in genital samples. This may indicate why children and women who were not intravenous drug users have had KS.

Symptoms

Kaposi's sarcoma produces pink, purple, or brown tumors on the skin, mucous membranes, or internal organs.

Diagnosis

Many physicians will diagnose KS based on the appearance of the skin tumors and the patient's medical history. Unexplained cough or chest pain, as well as unexplained stomach or intestinal pain or bleeding, could suggest that the disease has moved beyond the skin. The most certain diagnosis can be achieved by taking a biopsy sample of a suspected KS lesion and examining it under high-power magnification. For suspected involvement of internal organs, physicians will use a bronchoscope to examine the lungs or an endoscope to view the stomach and intestinal tract.

Treatment

Treatment goals for KS are simple: to reduce the severity of symptoms, shrink tumors, and prevent disease progression. Unfortunately, there is no single best treatment plan that can achieve all of those goals. Treatments range from topical agents for mild disease with few tumors to more aggressive systemic chemotherapy for more serious KS that has spread to large areas of skin or the internal organs. Physicians will frequently combine topical, radiation, and various systemic chemotherapy drugs, depending on the sites of the body affected, the speed at which it is progressing, and the patient's overall health, among other considerations.

Local therapy

When the number of KS tumors is small and the disease appears to be progressing slowly, physicians have had great success with the application, by the patient, of a topical gel containing alitretinoin. This product is a naturally occurring retinoid (a derivative of vitamin A) that can inhibit cell growth and activate apoptosis (cell death). Patients tolerate the product well with only mild to moderate skin irritation at the site of application in some individuals. Duration of treatment is long term, with the patient seeing results after four to eight weeks of therapy. Treatment slows the progress of the disease and reduces the size of the lesions.

Other local treatments include cryotherapy (using a liquid nitrogen spray or probe to freeze the tumor), injections of vinblastine (a drug also used for systemic chemotherapy) directly into the tumor, laser therapy, or radiation therapy targeted at the tumor sites. These methods have some success, but they also have unpleasant side effects. Vinblastine injections are about 70% effective, but they do not resolve the lesions completely.

Systemic chemotherapy

With widespread KS lesions over the body surface, or evidence of spread to other parts of the body, physicians will consider systemic chemotherapy drugs. A new class of chemotherapy drugs, called liposomal anthracyclines, appears to produce good results with fewer toxic side effects than do more conventional chemotherapy drugs. Two of these drugs, liposomal doxorubicin (Doxil) and liposomal daunorubicin (DaunoXone) have become the treatment of choice. These drugs last longer in the human body, demonstrate higher concentrations of the drug in tumors, and have fewer toxic side effects,

Paclitaxel (Taxol) is the newest drug in the KS arsenal. It has a 75% effective rate and is very effective in patients who are resistant to anthracycline drugs. The 3-hour infusion time and the incidence of bone marrow suppression, hair loss, and joint and muscle pain make it less attractive to patients.

Antiviral therapy

Evidence suggests that for some individuals, the class of AIDS drugs called protease inhibitors, in combination with other anti-HIV drugs, can reduce the levels of detectable HIV in the blood to nearly zero, and in some patients stabilize or reverse KS tumors. More research is needed in this area. Since the discovery of HHV-8, interest in an antiviral approach to KS has increased. There is no evidence, however, that two antiviral drugs commonly prescribed for herpes, acyclovir and ganciclovir, have any effect on the disease. One study of 20,000 patients with HIV and AIDS found that those who took foscarnet, another antiviral medication that works in a different way than acyclovir and ganciclovir, were less likely to develop KS tumors.

Another treatment source is interferon-alpha, which is made by the body and has powerful effects on the immune system. Investigators have tried injecting it directly into lesions, and also in combination with other

Kaposi's sarcoma usually appears on the lower extremities, as evidenced on this patient's hip. (Custom Medical Stock Photo. Reproduced by permission.)

anti-HIV drugs such as zidovudine, with some success. It has been used with patients who have KS limited only to the skin and who have little immunosuppression. Inter-feron-alpha has had poor tumor response and significant toxic effects in patients, especially those with seriouslydepressed immune systems.

Still other avenues of therapy being researched are sex hormones, thalidomide, SU5516 (an endothelial growth factor inhibitor), and angiogenesis inhibitors, which prevents the growth of blood vessels within a cell that supplies oxygen and nutrients. There is also some research involving the oral administration of alitretinoin.

Alternative treatment

The Bastyr University AIDS Research Study has been investigating and collecting data on treatment for KS and other opportunistic conditions that are AIDS-related. Among the treatments under investigation are nutritional and herbal therapies (both internal and external). Bastyr University is located in Seattle, Washington.

Prognosis

The prognosis for patients with classic KS is good. Tumors can frequently be controlled and patients frequently die of other causes before any serious spread. African endemic KS can progress rapidly and lead to premature death, despite treatment. In AIDS-related KS, milder cases can frequently be controlled; the prognosis for more advanced and rapidly progressing cases is less certain and dependent on the patient's overall medical condition. There are indications that KS can be stabilized or reversed in patients whose level of HIV in the blood is reduced to undetectable levels via antiretroviral therapy.

Prevention

Safer sex practices may help to prevent AIDS-related KS by decreasing the risk of transmission of HHV-8 through sexual means. However, the addition of avoidance of deep kissing to those precautions may be necessary. Intravenous drug users should still be urged not to share needles. Treatment with antiretrovirals may help to preserve the function of the immune system in HIV patients and delay the appearance and progression of KS lesions.