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 (KA-po-she), a Hungarian dermatologist practicing at the University of Vienna in 1872. It became more widely known as one of the AIDS defining illnesses in the 1980s. The viral cause for this cancer was discovered in 1994. Although KS is now well-established to be caused by a virus infection, there is widespread lack of awareness of this even among persons at risk for KSHV/HHV-8 infection.

Restated, Kaposi’s sarcoma (KS) is a systemic disease which can present with cutaneous lesions with or without internal involvement. Four subtypes have been described: Classic KS, affecting middle aged men of Mediterranean and Jewish descent, African endemic KS, KS in iatrogenically immunosuppressed patients, and AIDS-related KS. The erythematous to violaceous cutaneous lesions seen in KS have several morphologies: macular, patch, plaque, nodular, and exophytic. The cutaneous lesions can be solitary, localized or disseminated. KS can involve the oral cavity, lymph nodes, and viscera. Classic KS tends to be indolent, presenting with erythematous or violaceous patches on the lower extremities. African endemic KS and AIDS-related KS tend to be more aggressive. The AIDS-related KS lesions often rapidly progress to plaques and nodules affecting the upper trunk, face, and oral mucosa. The diagnosis can be made with a tissue biopsy and, if clinically indicated, internal imaging should be done.

Once the diagnosis of KS has been made, treatment is based on the subtype and the presence of localized versus systemic disease. Localized cutaneous disease can be treated with cryotherapy, intralesional injections of vinblastine, alitretinoin gel, radiotherapy, topical immunotherapy (imiquimod), or surgical excision. Extensive cutaneous disease and/or internal disease may require IV chemotherapy and immunotherapy. Discontinuation or reduction of immunosuppressive therapy is recommended when KS arises in the setting of iatrogenic immunosuppression. However, with AIDS-related KS, HAART has been shown to prevent or induce regression of KS. Some AIDS patients have complete resolution of the lesions and prolonged remission while continuing the therapy. Therefore, HAART should be considered first-line treatment for these patients, though they may require other concomitant treatments.

Classification
HHV-8 is responsible for all varieties of KS.

Classic KS as originally described was a relatively indolent disease affecting elderly men from the Mediterranean region, or of Eastern European descent. Countries bordering the Mediterranean basin have higher rates of KSHV/HHV-8 infection than the remainder of Europe

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 not related to HIV infection. KS is prevalent worldwide.

Transplant Related KS had been described, but only rarely until the advent of calcineurin inhibitors (such as ciclosporines, which are inhibitors of T-cell function) for transplant patients in the 1980s, when its incidence grew rapidly. The tumor arises either when an HHV 8-infected organ is transplanted into someone who has not been exposed to the virus or when the transplant recipient already harbors pre-existing HHV 8 infection.

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. In this case, HHV 8 is sexually transmitted among people who are also at risk for sexually transmitted HIV infection.

Types
Since Moritz Kaposi first described this malignant neoplasm, the disease has been reported in five separate clinical settings, with different presentations, epidemiology, and prognoses :
 * Classic Kaposi sarcoma
 * African cutaneous Kaposi sarcoma
 * African lymphadenopathic Kaposi sarcoma
 * AIDS-associated Kaposi sarcoma
 * Immunosuppression-associated Kaposi sarcoma

Signs and symptoms
KS lesions are nodules or blotches that may be red, purple, brown, or black, and are usually papular (i.e. 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 is associated with significant mortality and morbidity.

Skin
Commonly affected areas include the lower limbs, back, 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. 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.

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. 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. KSHV proteins are uniformly detected in KS cancer cells.

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, definite diagnosis can only be made by biopsy and microscopic examination, which will show the presence of spindle cells. Detection of the KSHV protein LANA in tumor cells confirms the diagnosis.

Transmission
In Europe and North America KSHV is transmitted through saliva. Thus, kissing is a theoretical risk factor for transmission although transmission between heterosexuals appears to be rare. Higher rates of transmission among gay and bisexual men has been attributed to "deep kissing" sexual partners with KSHV. Another alternative theory suggests that use of saliva as a sexual lubricant might be a major mode for transmission. Prudent advice is to use commercial lubricants when needed and avoid deep kissing with partners who have KSHV infection or have unknown status.

KSHV is transmissible during organ transplantation and to a lesser extent through blood transfusion. Testing for the virus before these procedures is likely to effectively limit iatrogenic transmission.

Treatment and prevention
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 their sexual partner, or if an organ is infected prior to transplantation. Unfortunately, these tests are not available except as research tools and thus there is little screening for persons at risk for becoming infected with KSHV, such as transplant patients.

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.

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.

Relationship to AIDS
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. The disease was erroneously referred to as the "AIDS rash".

In 2007, San Francisco doctors reported a Kaposi's sarcoma cluster among gay men. All 15 patients undergoing treatment were long-term HIV patients whose HIV infections were firmly controlled with antiviral drugs. None appeared to be in any danger. The new cases were not aggressive, invasive or lethal as was typical with uncontrolled HIV during the 1980s. The unsightly, difficult-to-treat lesions raised questions about the immune response of ageing HIV patients.

Viral cause isolated
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)&mdash;now known as Kaposi's sarcoma-associated herpesvirus (KSHV)&mdash;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 into its genome cellular genes that cause tumors ("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. KSHV is readily found in all forms of KS. The virus is sexually transmitted and can be transmitted through organ donation. In Africa, high rates of KSHV infection has led to KS becoming the most common cancer in sub-Saharan Africa. KSHV infection is thought to be life-long so that persons infected with KSHV may develop KS years later if they develop AIDS or other immunosuppression.

Awareness
Only 6% of homosexual men are aware that KS is caused by a virus different from HIV. Thus, there is little community effort to prevent KSHV infection. Similarly, no systematic screening of organ donations is in place.

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.

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.