Kaposi's Sarcoma

Classic KS primarily affects older men (m:w approx. 15:1) of Eastern European-Mediterranean or Jewish origin with an age peak in the 7th decade of life. Multiple, reddish-bluish-brown plaques and nodules are often found, especially in the lower extremities. The overall course is not markedly progressive over years or decades and rarely involves other organs. Sometimes lymphedema or hyperkeratosis are found.

Histologically, there are infiltrates of spindle-cell endothelia, slit-like new thin-walled, partly incomplete blood vessels with erythrocyte extravasations and hemosiderin deposits, furthermore a lymphocytic inflammatory infiltrate.

Since the middle of the last century, an increasing incidence of KS in sub-Saharan Africa has been reported. In 1971, KS accounted for 3% to 9% of all cancers in Uganda. In 1983, a dramatic increase in the incidence of KS was reported in Zambia. Once the acquired immunodeficiency syndrome (AIDS) could be reliably diagnosed, it was possible to distinguish HIV-negative endemic Kaposi's sarcoma from HIV-positive epidemic KS. Four clinical courses are described for African endemic KS:

1. relatively benign: nodular skin lesions similar to those seen in classic KS. This mainly affects young men around the age of 35;

2. aggressively localized: cutaneous form of progression with infiltration into soft tissue and bone with fatal outcome within 5 to 7 years;

3. diffuse: mucocutaneous involvement and visceral involvement;

4. fulminant course: lymphadenopathy and involvement of visceral organs usually without skin involvement, occurring preferably in young children.

KS has been described as a consequence of iatrogenic immunosuppression, usually associated with organ transplantation, but also in other types of immunosuppression. In this regard, there appears to be an increased risk in certain ethnic groups, which are also at increased risk for classic KS. Although the course can be both chronic and rapidly progressive, remission usually occurs after cessation of immunosuppressive therapy.

In 1981, Friedmann-Kien et al. described fifty previously healthy young homosexual men with KS, affecting lymph nodes, visceral organs, mucosa and skin. At the same time, life-threatening opportunistic infections were present in association with a massive defect in T-cell-mediated immunity. Shortly after that, this disease was described as Acquired Immunodeficiency Syndrome (AIDS) and HIV infection was proven to be the cause. Although the incidence of Kaposi's sarcoma has now decreased significantly as a result of effective antiretroviral therapy for HIV infection, this tumor remains the most common AIDS-associated malignancy in the United States. The same is true for Germany [13]. Overall, the risk for HIV patients to develop KS is increased by 20,000-fold compared to the normal population and by 300-fold compared to other immunosuppressed patients [2]. Among the different HIV transmission groups, the risk of developing KS is 20-fold higher in homosexual men than in patients with hemophilia. KS rarely occurs in women.

In recent years, an increasing number of HIV-associated KS have also been reported in patients with higher T helper cell counts and low HIV viral load, including patients on successful cART (combined Anti-Retroviral Therapy) [26].

At first diagnosis - usually in HIV-infected persons who have not yet received antiretroviral treatment - a multilocular manifestation is typically present. The characteristic skin lesions may develop within a few days. They begin as macules in the skin cleavage lines and progress to papules or papular tumors. Before the cART era, oral lesions were found as the primary manifestation in many patients, but lesions on the penis were also typically found.

While the skin lesions can be highly stigmatizing for the affected patient, organ involvement is clinically most relevant. Since almost all organs, including the entire gastrointestinal tract, but also the heart, liver and lungs can be affected, life-threatening complications may rapidly emerge. Involvement of the CNS and the eyes is rare.

In recent years, KS has been increasingly reported in younger HIV-negative men who have sex with men (MSM) from geographic regions with low HHV-8 seroprevalence (e.g., France, England, or Germany) [10, 17, 21].

Similar to classic KS, the course is rather indolent, lesions occur on the entire integument, whereas visceral or organ involvement is very rare. CD4 cell count and CD4/CD8 ratio seem to correlate with disease severity. Because of these features and differences from the previously 4 recognized subtypes of KS, this form is newly classified as an additional (5th) epidemiologic subtype [5, 6].

A stepwise diagnostic approach is recommended. It starts with confirming the diagnosis, see Table 1, followed by staging procedures, see Table 2.

1. Sporadic, classic KS

2. KS associated with iatrogenic immunosuppression

3. Endemic, African KS

4. Epidemic, HIV-associated KS

5. KS in men who have sex with men (MSM) without HIV infection.

In classical KS, individualized treatment concepts and often only local therapy are preferred due to the typically higher age of the patients [22]. Since KS is radiosensitive, fractionated soft X-ray therapy, irradiation with fast electrons or cobalt irradiation are suitable [11]. Cryotherapies may also be used locally, as well as intralesionally applied vinca alkaloids, bleomycin, or interferons [4, 20]. Excision should be considered only in cases of functionally compromising changes and rapid need for action. Systemic chemotherapy, usually with pegylated liposomal doxorubicin, is indicated for extensive primaries, systemic involvement, and progressive courses [12, 23].

The endemic African KS usually responds well to systemic therapy, with the exception of the lymphadenopathic variant.

In iatrogenic immunosuppression-associated KS, tumor lesions usually regress completely after cessation of immunosuppression.

In epidemic AIDS-associated KS, initiation of combined antiretroviral therapy (cART) in previously non-antiretrovirally treated patients often leads to an arrest of progression or even complete disappearance of the sarcoma lesions [7]. Therefore, antiretroviral therapy should be initiated at the latest with the occurrence of KS in HIV patients. The type of cART does not play a crucial role in KS response, but rather its virologic efficacy and cART-related immune reconstitution. In some cases, a transient, often substantial worsening of the condition may occur as part of the immune reconstitution syndrome. These patients should be treated additionally with systemic chemotherapy. Also, in cases of concurrent new diagnosis of advanced KS with organ involvement and HIV infection, concurrent initiation of antiretroviral and systemic KS therapy as described below is also recommended. If KS is diagnosed in patients already receiving antiretroviral therapy, its effectiveness should be reviewed and eventually be optimized using resistance testing.

Regardless of the clinical course, progressive KS should be treated systemically. In the past, a variety of substances were used for this purpose. These include interferon, vinca alkaloids, bleomycin and anthracyclines [9].

Standard therapy for AIDS-associated or advanced KS consists of administration of pegylated liposomal doxorubicin at a dose of 20 mg per m² of body surface area at two to three weeks intervals until complete clinical remission. Generally, clinical follow-up is scheduled at 2-3 months. In case of good regression of tumor lesions without complete remission, further course is awaited after 4-6 months.

As with any initiation of anthracycline therapy, cardiac evaluation with echocardiography should be performed to determine left ventricular ejection fraction, as there is a risk of cardiotoxicity in addition to myelotoxicity. Painful macular erythema (palmoplantar erythrodysesthesia) may occur on the hands and feet associated with the administration of liposomal doxorubicin. However, this side effect is rarely observed at the doses recommended for KS, and more often at higher single doses.

The taxane paclitaxel is available for second-line therapy. In the original report by Gill et al., a dose of 100 mg/m² every two weeks was used [25]. However, since weekly administration at reduced doses has now been shown to be better tolerated and at least as effective in other diseases such as breast carcinoma, weekly administration may also be discussed in KS, see Onkopedia Female Breast Cancer. Myelotoxicity, alopecia, and onychodystrophy should also be noted. Interactions with cART should be considered in HIV-infected patients with KS.

In HIV-associated KS, systemic interferons can be used alternatively if CD4 cell counts are good (>350 cells/µl) or immune status is good. Pegylated interferons (weekly administration possible, better tolerated than classical interferons) are not approved for KS, but may be more effective and easier to administer, as shown by case reports in AIDS-associated, but also in classical Kaposi's sarcoma [16].

For local compromising (feet, face) KS lesions, local surgery or local drug application are often sufficient. These are inexpensive and well tolerated. Recurrence in the scars is common after surgical excision. KS are radiosensitive, so radiotherapy may also be used, preferably fractionated single doses of soft X-rays [8]. Other local therapies range from camouflage to intralesional injection of vincristine and to experimental topical use of retinoids [3].

After successful treatment of KS, esthetically disturbing postinflammatory hyperpigmentation often remains visible for a long time, which should not be confused with active KS.