Kaposi's sarcoma

Kaposi's sarcoma (KS) is a tumor caused by Human herpesvirus 8 (HHV8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV). It was originally described by Moritz Kaposi, a Hungarian dermatologist practicing at the University of Vienna in 1872.^[1] It became more widely known as one of the AIDS defining illnesses in the 1980s.

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Epidemiological varieties

Classic KS as originally described was a relatively indolent disease affecting elderly men from the Mediterranean region, or of Eastern European Jewish descent.^[2][3]

Endemic KS was described later in young African people, mainly from sub-Saharan Africa, as a more aggressive disease which infiltrated the skin extensively, especially on the lower limbs. This, it should be noted, is unrelated to HIV infection.^[4][5]

Transplant Related KS had been described, but only rarely until the advent of calcineurin inhibitors (such as ciclosporin, which are inhibitors of T-cell function) for transplant patients in the 1980s, when its incidence grew rapidly.^[6][7]

Epidemic KS was described during the 1980s as an aggressive disease in AIDS patients (HIV also causes a defect in T-cell immunity). It is over 300 times more common in AIDS patients than in renal transplant recipients. ^[8]

Note that HHV-8 is responsible for all varieties of KS.

Clinical features

KS lesions are nodules or blotches that may be red, purple, brown, or black, and are usually papular (ie palpable or raised).   They are typically found on the skin, but spread elsewhere is common, especially the mouth, gastrointestinal tract and respiratory tract. Growth can range from very slow to explosively fast, and be associated with significant mortality and morbidity.^[9]

Skin

The skin lesions most commonly affect the lower limbs, face, mouth and genitalia. The lesions are usually as described above, but may occasionally be plaque like (often on the soles of the feet) or even involved in skin breakdown with resulting fungating lesions. Associated swelling may be from either local inflammation or lymphoedema (obstruction of local lymphatic vessels by the lesion). Skin lesions may be quite disfiguring for the sufferer, and a cause of much psychosocial pathology.

Mouth

Is involved in about 30%, and is the initial site in 15% of AIDS related KS. In the mouth, the hard palate is most frequently affected, followed by the gums ^[10]. Lesions in the mouth may be easily damaged by chewing and bleed or suffer secondary infection, and even interfere with eating or speaking.

Gastrointestinal tract

Involvement can be common in those with transplant related or AIDS related KS, and it may occur in the absence of skin involvement. The gastrointestinal lesions may be silent or cause weight loss, pain, nausea/vomiting, diarrhea, bleeding (either vomiting blood or passing it with bowel motions), malabsorption, or intestinal obstruction.^[11]

Respiratory tract

Involvement of the airway can present with shortness of breath, fever, cough, hemoptysis (coughing up blood), or chest pain, or as an incidental finding on chest x-ray.^[12] The diagnosis is usually confirmed by bronchoscopy when the lesions are directly seen, and often biopsied.

Pathophysiology and diagnosis

Despite its name, it is generally not considered a true sarcoma, which is a tumor arising from mesenchymal tissue. KS actually arises as a cancer of lymphatic endothelium and forms vascular channels that fill with blood cells, giving the tumor its characteristic bruise-like appearance.

KS lesions contain tumor cells with a characteristic abnormal elongated shape, called spindle cells. The tumor is highly vascular, containing abnormally dense and irregular blood vessels, which leak red blood cells into the surrounding tissue and give the tumor its dark color. Inflammation around the tumor may produce swelling and pain.

Although KS may be suspected from the appearance of lesions and the patient's risk factors, a definite diagnosis can only be made by biopsy and microscopic examination, which will show the presence of spindle cells. Detection of the viral protein LANA in tumor cells confirms the diagnosis.

Treatment and prevention

Kaposi's sarcoma is not curable, in the usual sense of the word, but it can often be effectively palliated for many years and this is the aim of treatment. In KS associated with immunodeficiency or immunosuppression, treating the cause of the immune system dysfunction can slow or stop the progression of KS. In 40% or more of patients with AIDS-associated Kaposi's sarcoma, the Kaposi lesions will shrink upon first starting highly active antiretroviral therapy (HAART). However, in a certain percentage of such patients, Kaposi's sarcoma may again grow after a number of years on HAART, especially if HIV is not completely suppressed. Patients with a few local lesions can often be treated with local measures such as radiation therapy or cryosurgery. Surgery is generally not recommended as Kaposi's sarcoma can appear in wound edges. More widespread disease, or disease affecting internal organs, is generally treated with systemic therapy with interferon alpha, liposomal anthracyclines (such as Doxil) or paclitaxel.

With the decrease in the death rate among AIDS patients receiving new treatments in the 1990s, the incidence and severity of epidemic KS also decreased. However, the number of patients living with AIDS is increasing substantially in the United States, and it is possible that the number of patients with AIDS-associated Kaposi's sarcoma will again rise as these patients live longer with HIV infection.

Blood tests to detect antibodies against KSHV have been developed and can be used to determine if a patient is at risk for transmitting infection to his or her sexual partner, or if an organ is infected prior to transplantation.

History and theories

Discovery

The disease is named after Moritz Kaposi (1837–1902), a Hungarian dermatologist who first described the symptoms in 1872. Research over the next century suggested that KS, like some other forms of cancer, might be caused by a virus or genetic factors, but no definite cause was found.

AIDS symptom

With the rise of the AIDS epidemic, KS, as initially one of the most common AIDS symptoms, was researched more intensively in hopes that it might reveal the cause of AIDS.

Resurgence in AIDS patients

San Francisco doctors reported a Kaposi's sarcoma cluster among gay men. All 15 patients undergoing treatment are long-term HIV survivors whose HIV infections are firmly controlled with antiviral drugs. None appears to be in any danger. The new cases are not aggressive, invasive or lethal as was typical with uncontrolled HIV during the 1980s. The lesions are unsightly, difficult to treat and raise questions about the immune response aging of HIV survivors.^[13]

Virus caused

In 1994, Yuan Chang, Patrick S. Moore, and Ethel Cesarman at Columbia University in New York isolated genetic pieces of a virus from a KS lesion. They used representational difference analysis (a method to subtract out all of the human DNA from a sample) to isolate the viral genes. They then used these small DNA fragments as starting points to sequence the rest of the viral genome in 1996. This, the eighth human herpesvirus (HHV-8)—now known as Kaposi's sarcoma-associated herpesvirus (KSHV)—has since been found in all KS lesions tested, and is considered the cause of the disease. KSHV is a unique human tumor virus that has incorporated cellular genes that cause tumors into its genome ("molecular piracy"); the stolen cellular genes may help the virus escape from the immune system, but in doing so it also causes cells to proliferate. It is related to Epstein-Barr virus, a very common herpesvirus that can also cause human cancers.

Unknown factors

KSHV infection does not always lead to KS; it is still unclear what other factors may be required, such as pre-existing immune system damage, or a specific interaction with HIV or other viruses. However, research in Africa has shown that even in the absence of HIV/AIDS, KS is more common in men than women although KSHV infection is equal between both sexes. This suggests that sex hormones may either protect from or predispose to KS in persons infected with the virus.

KS awareness

In AIDS patients, Kaposi's sarcoma is considered an opportunistic infection, a disease that is able to gain a foothold in the body because the immune system has been weakened. With the rise of HIV/AIDS in Africa, where KSHV is widespread, KS has become the most frequently reported cancer in some countries, such as Zimbabwe.

Nigerian bandleader Fela Kuti succumbed to the disease in 1997.

Because of their highly visible nature, external lesions are sometimes the presenting symptom of AIDS. Kaposi's sarcoma entered the awareness of the general public with the release of the film Philadelphia, in which the main character was fired after his employers found out he was HIV-positive due to visible lesions. Unfortunately, by the time KS lesions appear, it is likely that the immune system has already been severely weakened.

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