Kaposi's sarcoma (KS) is a tumor that typically presents with skin lesions. It develops from the cells lining blood vessels as well as the lymphatic system. Kaposi's sarcoma first moved into the spotlight as an AIDS-defining illness prior to the use of modern medications to control HIV (Human Immunodeficiency Virus). However, through further study over the years, much more has been learned about Kaposi's sarcoma. For example, in 1994, it was discovered that infection with the human herpes virus 8 (HHV-8) was responsible for Kaposi's sarcoma. Although it is necessary to be infected with HHV-8 in order to develop KS, the vast majority of people with HHV-8 infection actually will never develop the disease. This is because our immune systems are very adept at controlling the virus and keeping it from causing the development of tumors.
Kaposi's sarcoma is classified according to the clinical circumstances in which it arises. The four types of Kaposi's sarcoma are as follows:
Classic: This is the first type of Kaposi's sarcoma, described in 1872 at the University of Vienna. Classic Kaposi's sarcoma (CKS) typically presents in middle-aged or elderly patients. Although it can be seen in other parts of the world, it is characteristically seen in individuals from the Mediterranean region, Middle East, or Eastern Europe. CKS more often presents in men (3:1 ratio) in their 60's and70's, and the lesions commonly appear on the lower extremities and feet (soles and toes) as red, purple, or deep blue patches that grow and come to form larger plaques. Infection with HHV-8 is more common in these regions and is likely the cause of CKS cases in these populations. It has been suggested that as these individuals get older, their immune systems weaken, and Kaposi's sarcoma lesions develop. Because individuals with CKS generally have stronger immune systems than those with other types of Kaposi's, the CKS lesions generally develop slower and spread less quickly.
Epidemic (AIDS-related) Kaposi's sarcoma: This subtype of Kaposi's sarcoma was first described during the 1980's when the AIDS epidemic reached its pinnacle, prior to discovery of HAART (highly active antiretroviral therapy). When an individual is infected with HIV, they do not develop AIDS until the virus has damaged his/her immune system to the point that is not functioning well (if at all). As one's immune system is weakened, infections that are controlled by a healthy immune system can develop; these are called opportunistic infections.
It is thought that HHV-8 is sexually transmitted in this population in a manner similar to the HIV virus. Although KS can be seen in any individual with AIDS, it is much more common in homosexual or bisexual men. AIDS-related KS is 15 times more likely in men than women. Since the introduction of HAART, the incidence of KS has dramatically declined in the HIV-infected population.
When the immune system is weak, the HHV-8 virus is much more likely to lead to the development of Kaposi's sarcoma. Because of this, Kaposi's sarcoma was one of the first AIDS–defining illnesses. The lesions associated with AIDS tend to be very different than other forms of KS. These lesions tend to be found on the head, neck, chest, and back, but can also be found in mucous membranes, such as in the GI tract (stomach and intestines) and the lungs. AIDS-related KS is often more aggressive, with many more lesions that progress more quickly than other types.
Iatrogenic (Transplant-related) Kaposi's sarcoma: Following the transplant of an organ from a donor into a recipient, the transplant recipient must take drugs to suppress their immune system to protect the new organ from being attacked by his/her immune system. Kaposi's sarcoma arises in this instance when the transplant recipient harbors the HHV-8 virus or when the transplanted organ is infected with the virus prior to the transplant. After the transplant, suppression of the immune system is critical in maintaining a functional organ, however, this allows the HHV-8 virus to develop KS lesions. Generally, decreasing the immune suppressing medications can control transplant-related KS. The lesions of transplant-related KS tend to be much less aggressive than AIDS-related KS.
Endemic (African-related) Kaposi's sarcoma: This subtype of KS characteristically occurs in the sub-Saharan and tropical African regions. It commonly occurs in young men age 20-50 years old and in the absence of the HIV infection. The percent of adolescents infected with HHV-8 in these regions is much higher than in other parts of the world. It has been hypothesized that geographic and non-sexual environmental factors may be responsible for this phenomenon. The lesions of endemic KS tend to be found on the lower extremities and are often more aggressive and infiltrate deeper than classic KS.
As stated above, HHV-8 infection is required to develop KS. However, HHV-8 is not commonly tested for, and the vast majority of individuals with HHV-8 are not aware that they are infected, nor will they ever develop KS. HHV-8 infection is more common in homosexual and bisexual men and in equatorial Africa.
Immunosuppresssion due to HIV or medications are very strongly associated with development of KS in individuals infected with HHV-8. In classic KS, found in those living in the Mediterranean, increasing age is related to the progression of lesions. This may be attributed to a declining immune system that occurs commonly with the aging process. Endemic, or African KS, has also been demonstrated to occur more frequently in individuals with chronic lower extremity edema, also known as lymphedema. Finally, smoking has been shown to decrease the risk of developing classic KS in individuals from Mediterranean and Eastern European regions for unknown reasons.
Kaposi's sarcoma is characterized by the development of red, purple, or deep blue lesions commonly on the skin and mucosa. The lesions are not painful, generally do not itch and typically have their colored appearance due to blood vessels within the lesions. As noted above, classic KS and endemic KS are commonly seen on the lower extremities. AIDS-related KS and iatrogenic KS can be seen on mucosa-lined surfaces (i.e. GI and respiratory tract) as well on inner organs (i.e. lungs).
KS lesions typically start as small flat lesions that can range in size from millimeters to several centimeters. These lesions are known as macules, which can remain unchanged for years in classic KS, although in rare cases they will progress very rapidly. As the lesions grow, they will frequently coalesce, or grow together, forming larger lesions known as plaques. As the lesions continue to grow, they can form even larger lesions known as nodules. Nodular lesions can ulcerate and bleed if damaged. In the endemic form of KS, lesions can form as fluid filled cysts due to invasion of lymphatic vessels.
Finally, in AIDS-related KS, the lesions can be seen on the lower extremities, the face, the genitalia, and in the mouth. The lesions have similar appearance as other forms of KS; however, the natural progression of AIDS-related KS tends to be much more rapid with nodules developing rather quickly. AIDS-related KS in the GI tract can present as lesions, with no symptoms, found on radiology studies for something else or can present with weight loss, stomach pains, bleeding, or diarrhea. Lesions within the respiratory tract can also be asymptomatic. If symptoms develop, they can involve shortness of breath, cough, chest discomfort, or coughing up blood (hemoptysis).
The diagnosis of Kaposi's sarcoma is generally made on the appearance of the lesions and clinical setting in which they are discovered. The diagnosis may be confirmed with a skin biopsy. Though a lesion may appear to be KS, other diagnoses such as angiosarcoma, hemangiomas and bacterial infections (i.e. Bartonella). These possible alternative diagnoses are referred to as "differential diagnoses" and you may hear the medical team say they need to rule out differential diagnoses.
For individuals with immunosuppression and symptoms, GI tract involvement can be confirmed with an upper or lower endoscope. Respiratory involvement may be identified with chest X Ray or CT scan, but may require bronchoscopy to get a biopsy to confirm the diagnosis.
Staging for KS depends on its clinical scenario. For classic KS, there is no universal staging system. The American Joint Committee on Cancer TNM staging system, which is the standard staging for all cancer types, does not include KS.
A proposed staging system for Classic Kaposi's sarcoma is below:
Stage I (Macronodular Stage) - Small lesions (macules) confined to the lower extremities
Stage II (Infiltrative Stage) - Larger lesions (plaques) confined to the lower extremities
Stage III (Florid Stage) – Multiple larger lesions (plaques and nodules) confined to the lower extremities
Stage IV (Disseminated Stage) – Multiple large lesions extending beyond the lower extremities
For Epidemic, or AIDS-related, KS, the CD4 count and the HIV viral load are important for staging. The AIDS Clinical Trial Group (ACTG) developed a risk stratification system for KS based on the extent of the tumor, the immune status, and the severity of systemic illness (described in the table below).
Confined to skin and/or lymph nodes
-Tumor-associated edema or ulceration
CD4 cell count >200/µL
CD4 cell count <200/µL
-No history of opportunistic infections or thrush
- History of OI or thrush
The primary objectives when treating Kaposi's sarcoma are to improve the patient's symptoms and prevent progression to more aggressive lesions. Because there is no cure for HHV-8, there is no cure for Kaposi's sarcoma; however, the disease can frequently be controlled with treatment. Due to the rare nature of classic KS, there is no consensus on what is the best treatment. Generally, the treatment is based on the experiences of the treating physician, patient preference and the clinical picture (i.e. AIDS related, classic KS in elderly man, etc.).
For classic and endemic KS, surgery, radiation therapy and topical therapies are available. In lesions that are limited and causing no symptoms, observation may be the best option, avoiding treatment related toxicities. For patients with symptomatic lesions, surgical excision of a single lesion can be beneficial; however, additional lesions often development, limiting the effectiveness of this treatment. Radiation therapy is particularly effective for all forms of KS. Although local control tends to be better than 90% with low doses of radiation, recurrences out of the treatment field often occur and limit its use. The use of cryotherapy, laser therapy, injection of chemotherapy into the lesions and topical therapies may also be options for treatment. FDA-approved topical treatments, cis-retinoic acid and imiquimod, are also occasionally used. Unfortunately, these are "local treatments" which work in a small area and do not deal with the multifocal (system-wide) nature of KS.
Several systemic therapies have also been used in treatment of aggressive and advanced classic KS. Indications for chemotherapy include rapidly progressive classic KS that interferes with function and is severely symptomatic. Overall response rates range from 60-90% for doxorubicin, vinblastine, paclitaxel, etoposide, or gemcitabine. Pegylated liposomal doxorubicin is traditionally the first-line agent for treating systemic classic KS. Finally, treatment with immunomodulators, such as recombinant interferon, has shown effectiveness when chemotherapy has failed. There have been no randomized clinical trials demonstrating the optimal agent or duration of treatment to control aggressive, systemic classic KS.
In cases of KS related to immunosuppression, improvement in immune function and treatment of the cause can often lead to stopping the progression of lesions. For individuals with AIDS-related KS, highly active antiretroviral (HAART) is recommended. HAART has proven very effective in the prevention of KS as it improves CD4 counts as well as keeping the viral load low (amount of virus found in the blood). When KS is caused by intentional immunosuppression, as in the case of an organ transplant, a decrease in the level of immune suppression is recommended.
Local therapy is generally reserved for symptomatic lesions and palliation. Similar to classic KS, local therapies include radiation therapy, topical cis-retinoic acid, and intralesional chemotherapy. Prior to the use of HAART, radiation therapy was frequently used for locally advanced disease. Intralesional chemotherapy is generally only used in smaller lesions.
The use of systemic treatments, specifically chemotherapy, is only used in patients with disseminated or rapidly progressive KS. Indications for chemotherapy include widespread skin lesions, edema (swelling) associated with extensive lesions, symptomatic lesions on internal organs, skin lesions that fail to respond to local treatments, and immune reconstitution inflammatory syndrome. Immune reconstitution inflammatory syndrome refers to an acute worsening of KS that can occur within weeks of the initial introduction of HAART. Similar to classic KS, the most frequently used chemotherapy is pegylated liposomal doxorubicin.
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