Kaposi's sarcoma

Kaposi's sarcoma (KS) is a kind of sarcoma caused by a herpesvirus infection in which cancerous cells, as well as abnormal growth of blood vessels, form solid lesions in connective tissue. KS was historically very rare and found mainly in older men of Mediterranean or African origin (classic KS) or patients with severely weakened immune systems, such as after an organ transplant (immunosuppressive treatment related KS). However, in the early 1980s a more aggressive form, epidemic KS, began to be seen in AIDS patients and was one of the first clues to the existence of the AIDS epidemic. The infectious agent responsible for all forms of the disease is known as Kaposi's sarcoma-associated herpesvirus (KSHV).

Symptoms

KS lesions are nodules or blotches that may be red, purple, brown, or black, usually painless but sometimes painful and swollen. They most often appear under the surface of the skin or on mucous membranes, where they are only dangerous if they cause enough swelling to obstruct circulation, breathing, or eating. They may also be found in internal organs, particularly the respiratory system or gastrointestinal system; internal lesions are most commonly seen in epidemic KS, and can cause fatal bleeding.

KS can occur among transplant patients, in whom the tumor can disseminate. Stopping immunosuppression can eliminate KS but also can cause rejection of the transplanted organ.

Pathophysiology and diagnosis

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. KS is a harmful structure.

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 cryotherapy. 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 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 infecton.

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

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.

With the advent 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. Some researchers suspected that HIV itself directly caused KS; others thought that it was simply a result of the immune system losing its ability to protect against some common cancer-causing agent; and others took it as a sign that AIDS was not primarily a viral disease at all but an effect of toxic chemicals that can damage the immune and vascular systems. Early in the pandemic, it was thought, but later dismissed, that products such as nitrite poppers might be associated with KS.

In 1994, Yuan Chang, Patrick S. Moore, and Ethel Cesarman (a team 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.

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. The fact that KS occurs much more often in males than in females has not been entirely explained. In the early years of the AIDS epidemic in North America and Western Europe, the incidence of KS almost exclusively among male homosexual AIDS patients suggested that it was spreading as a sexually transmitted infection within that population, or was due to other lifestyle factors. 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 and AIDS

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

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.

Unlike most other AIDS malignancies, Kaposi's sarcoma is far more prevalent in gay men than in the non-gay male AIDS population. This was one clue that led scientists to look for an infectious agent other than HIV as the cause of KS. But it is still not clear why this cancer preferentially involves gay men. There is evidence that KSHV is secreted in saliva, and it is possible that use of saliva as a lubricant may contribute to its spread in this population. Dean Hamer of the National Institutes of Health has offered that the cancer may have a genetic underpinning somehow related to a gay gene and his research on the topic in the early 1990s and postulation of such a gene caused a political firestorm as described in biology and sexual orientation. There is little recent evidence to support this hypothesis, and most scientists now conclude that the virus causing KS (rather than a "gay gene") is more efficiently spread through homosexual than heterosexual activities. Once infected with KSHV, however, both heterosexuals and homosexuals are equally at risk for KS if they have immunodeficiency. In developing countries, KSHV is transmitted through nonsexual infection (the precise route is unknown) and up to 70% of sub-Saharan African populations are asymptomatically infected with this virus compared to infection rates among Americans and Europeans of 2-5%. Pandemic spread of HIV has uncovered this otherwise asymptomatic infection--resulting in an epidemic of KS in Africa.

References

Kaposi, M. 1872. Idiopathisches multiples Pigmentsarkom der Haut. Arch. Dermatol. Syph. 4:265-273.
Antman K, Chang Y. Kaposi's sarcoma. New Engl J Med 2000;342(14):1027-38
Chang Y, Cesarman E, Pessin M, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 1994;266:1865-9.
Yarchoan R, Tosato G, Little RF. Therapy insight: AIDS-related malignancies - the influence of antiviral therapy on pathogenesis and management. Nature Clin Prac Oncology 2005;2(8):406-15.

External links

http://www.thachers.org/internal_medicine.htm
http://hivinsite.ucsf.edu/InSite?page=kb-authors&doc=kb-06-02-01
Kaposi's Sarcoma
"What About the Relationship Between Alkyl Nitrites and KS?, Christine Weber, B.Sc.

HIV/AIDS | Eponymous diseases | Oncology