PATIENT PRESENTATION

A 68-year-old Caucasian male presented with a 10-year history of multiple 2-cm to 3-cm tender exophytic violaceous or tan nodules with hemorrhagic crust on the lower extremities. The patient also had violaceous macules and patches on the lower extremities. In the past, the patient had several similar lesions excised. The patient was HIV-negative and the rest of his personal and family medical or surgical histories were non-contributory.

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Diagnosis: Kaposi’s Sarcoma

Kaposi’s Sarcoma (KS) is a vascular violaceous neoplasm that can affect the skin, lymph nodes, gastrointestinal tract and lungs, as well as other organ systems.1 KS was first described by Dr. Moriz Kaposi in 1872 as “idiopathisches multiples Pigmentsarkom der Haut.”2 Dr. Kaposi originally reported five men with “idiopathic multiple pigmented sarcomas of the skin” as well as neoplasms in their larynx, trachea, stomach, liver and colon.3,4 Dr. Kaposi’s original five patients all died within 3 years of their diagnosis.3,4 These cases were similar to what would later be called HIV-associated Kaposi’s sarcoma.2

Historical Note

Until the early 1980s, KS was thought of as an indolent neoplasm.2 In what would later be called classical Kaposi’s sarcoma, Dr. Kaposi’s documented cases followed a non-aggressive course.2 Later, however, what Dr. Kaposi described as “aggressive KS” played a prominent role in the AIDS epidemic in the early 1980s. KS was mentioned in 1981 by the Centers for Disease Control in their original three case reports of AIDS.4 In 1981, 79% of patients diagnosed with HIV also had KS. By 1989, 25% of patients diagnosed with HIV had KS. By 1997, <1% of patients diagnosed with HIV had KS.1 The decrease in the incidence of KS among HIV patients is most likely due to the widespread use of highly active antiretroviral therapy (HAART).4

Clinical Presentation and Classification

KS may present with multiple vascular and mucosal morphologies in the same individual. Its numerous presentation forms include: as a patch, as localized (nondestructive) plaques; as exophytic KS, infiltrative KS, generalized lymphadenopathic KS with cutaneous nodules, disseminated and visceral KS, keloidal KS, ecchymotic or lymphangioma-like KS, or cavernous KS.4

KS often starts as firm-to-hard ecchymotic purple-brown macules and evolves into violaceous, red, pink or tan plaques or nodules that eventually develop a green hemosiderin color. Lesions can become confluent tumors and develop secondary changes (ie, erosion, ulceration, crusting and hyperkeratosis).5

Four specific variants of Kaposi’s sarcoma have been described: classical Kaposi’s sarcoma, African-endemic Kaposi’s sarcoma, HIV-associated Kaposi’s sarcoma, and iatrogenic immunosuppression-associated Kaposi’s sarcoma.5

Classical Kaposi’s sarcoma most often occurs in patients with an Eastern European heritage (ie, Ashkenazi Jews or those from the Mediterranean).5 KS has been reported to occur in the Mediterranean population at a 10-fold higher rate than other parts of Europe or the United States.4 KS has a male to female ratio of 10:1 to 15:1.4 Patients often present between the ages of 40 to 70 with purple-blue or red patches, and plaques and nodules on their hands or feet that progress over several years to involve their arms, legs, lymph nodes or abdominal viscera. Patients can have lymphedema before or after the cutaneous lesions develop.2,3,5

African-endemic KS presents in patients in Africa, with 9% to 12.8% of cases occurring in Zaire.5 Patients are often either children (mean age of 3 years) or young adults (mean age of 35 years). While this kind of KS affects children of both sexes in equal proportions, it affects males to females in a ratio of 15:1 in teenagers and older adults.4 African-endemic Kaposi’s sarcoma is an enormous concern in the African population because this type of KS makes up 25% to 50% of soft-tissue sarcomas in children, and 2% to 10% of all cancers in children.3

Four clinical patterns of African-endemic Kaposi’s sarcoma have been identified: nodular, florid or vegetating, infiltrative, or lymphadenopathic. The nodular pattern often resembles classic KS and lasts from 5 to 8 years. The florid or vegetating type is more aggressive and can extend into the subcutis, muscle and bone. The infiltrative type extends further than the florid or vegetating type and often involves the mucoucutaneous and visceral tissue. Finally, the lymphadenopathic type occurs most often in children and young adults in the lymph nodes and visceral tissue with occasional skin and mucous membrane involvement.5

HIV-associated KS occurs primarily in homosexual males. Patients who are HIV-positive are 20,000 times more likely to develop KS than those who are HIV-negative, and 300 times more likely to develop KS than other immunosuppressed patients. HIV-associated KS often presents in individuals with a CD4+ T cell count ≤ 500. 5 In patients with HIV, KS often appears as erythematous-to-violaceous bilaterally symmetric nodules on the upper body, head and neck. In these patients, KS can rapidly involve the rest of the skin and viscera, causing organ failure and death.4

Iatrogenic immunosuppression-associated KS can occur in patients who have received solid-organ transplants or those who have received long-term immunosuppressive therapy. Patients who have received an organ transplant are 400 to 500 times more likely than the general population to have KS.4 Patients often present with KS lesions within 16 and a half months after transplantation. The KS lesions often resolve when immunosuppressive therapy is stopped.5

Histology

Upon skin biopsy, KS lesions often show a normal epidermis and have increased spindle cells and vascular components in the dermis among a network of reticular fibers and collagen. Extravasated red blood cells and hemosiderin-laden macrophages are often present.4

There are three distinct histological stages of KS: patch, plaque, and nodular.5 In the patch stage there is an increase in uneven and jagged endothelial-lined spaces with normal dermal vessels and adnexal structures. There may be plasma cell infiltrate. In the plaque stage, spindle cells form irregular clefts of vascular channels with erythrocytes, hemosiderin deposits, and eosinophilic hyaline globules near dermal collagen. There may be a peripheral perivascular inflammatory infiltrate. The nodular stage is characterized by layers of spindle cells with mild to moderate atypia, single cell necrosis and red blood cells that are stuck in the network of small vascular spaces.5

Differential Diagnosis

Clinicians may also consider blue rubber bleb nevus syndrome, pyogenic granuloma, tufted angiomas, melanocytic nevi, melanoma, cavernous hemangioma, angiokeratoma, Stewart-Treves syndrome, basal cell and squamous cell carcinomas, nodular myofibromatoma, spindle cell hemangioendothelioma, arteriovenous malformation, severe stasis dermatitis (pseudo-KS), acral angiodermatitis, junctional melanocytic nevi, nevus flammeus, and bacillary angiomatosis.2,4

Pathogenesis

The connection between KS and HIV transactivating gene (tat) and Human Herpes Virus 8 (HHV-8) has been postulated. In one study, the HIV type 1 (HIV-1) tat gene caused KS-like nodules in 33 of 37 male transgenic mice, and caused KS-like nodules in 0 of 15 female transgenic mice. This report may imply that the HIV virus plays a pathogenic role in KS.

HHV-8 (also known as KS-associated herpes virus), has been identified in more than 95% of KS lesions.3 The connection between HHV-8 and KS is not totally understood, but HHV-8 appears to be necessary but not sufficient to develop KS.2 For example, HHV-8 expresses a cytokine called “scatter factor” that causes endothelial cells to develop a KS tumor-like phenotype. Scatter factor (along with a cytokine called oncostatin-M) appears to work in combination with the HIV tat gene, Interleukin-1, Interleukin-6, tumor necrosis factor, and basic fibroblastic growth factor to induce KS lesions.4 During infection with HHV-8, the virus inserts itself into several host cell genes, causing increased cell growth, preventing apoptosis, inducing angiogenesis, decreasing the host’s immune response, and interfering with the host’s interferon-signaling pathway.3,4

Although there is data supporting HIV and HHV-8 as factors in the development of KS, there are several other potential cofactors. HHV-6 has been shown to act synergistically with HHV-8 to increase viral replication and viral load. Other researchers have postulated that lymphedema may lead to immunosuppression and promote the development of KS. Finally, additional potential co-factors are arthropods, angiotensin-converting enzyme inhibitors, hemodialysis, and iron.4

Management

When determining the best management option for a patient, the physician should consider the patient’s clinical type of KS, progression pattern, morphology of lesions, distribution of lesions and immune status.2,4

For classical KS, patients will often have a limited number of lesions, and if asymptomatic, may be managed with close follow-up. If patients are symptomatic and have a few lesions, the first step can be an excisional biopsy. If there is a larger but limited area affected, then a single treatment with radiation (8-12 Gy) can be used. Radiation has been shown to be more successful on new rather than recurrent KS lesions. There also have been successful reports of treating KS with 585-nm using a pulsed dye laser, a high-energy pulsed carbon dioxide laser, and argon laser photocoagulation. Intralesional chemotherapy can also be used for specific nodules. If patients have widespread or recurrent lesions, they can be treated with excision, radiation and chemotherapy with vinblastine, doxorubicin, bleomycin, etoposide, actinomycin D, paclitaxcel , docetaxel or dacarbazine. Another option is to use only chemotherapy.3,4

For African-endemic KS, patients can be treated with radiation or chemotherapy. One study in South Africa looked at 36 HIV-negative patients treated with radiation or chemotherapy. In this study, 80% responded to radiation and 17% responded to chemotherapy.3

For HIV-associated KS, the best treatment is to start HAART therapy. HAART therapy helps reduce the HIV viral load and shrink KS lesions. If HAART therapy is not successful, radiation or chemotherapy can be considered, but they are less successful than in patients with classical KS. Radiation and chemotherapy often serve as palliative treatment for HIV-associated KS patients. Another option for HIV-associated KS is to use immunotherapy with biological interferon alpha agents or imiquimod 5% cream. The success of these drugs appears to correlate with the baseline CD4+ T cell count and whether the patient is taking HAART therapy. Other potential experimental therapies include vascular endothelial growth factor inhibitors, thalidomide, human chorionic gonadotropin, sirolimus, antiandrogenic agents, anti HHV-8 medications (ie, cidofovir), and retinoids. 3,4

In iatrogenic immunosuppression-associated KS, patients often will see regression of the KS lesions once they stop their immunosuppressive therapy. However, this “treatment” for KS often results in the loss of the transplanted graft or organ. For example, in one study, 50% of patients lost their transplanted kidney after terminating immunosuppressive therapy. Patients with kidney transplants have the option of stopping immunosuppressive therapy and going back on dialysis. However, heart or liver transplant patients do not have the option to stop immunosuppressive therapy. These patients can try to decrease their immunosuppressive therapy to treat KS. Some success has been reported using radiation along with chemotherapy to treat iatrogenic immunosuppression-associated KS. 3,4

Prognosis

The KS prognosis depends on the clinical classification, distribution of lesions, aggressiveness of the disease and immune status of the host. Those who have localized KS or iatrogenic KS tend to have the best prognosis. It has been said that these patients will “die with KS rather than from KS.”4 Locally aggressive KS has a 3-year survival rate of approximately 64%. However, for those with HIV associated KS — who often have widespread invasive KS — there is little to no survival without treatment. One study showed that in HIV-positive patients treated with HAART, 81% were still alive 18 months after starting chemotherapy for KS. In the HIV-positive group not treated with HAART, only 18% were still alive 18 months after starting therapy.

Summary & Patient Management

In conclusion, Kaposi’s sarcoma is a vascular violaceous neoplasm that most often affects the skin but can also affect other organ systems, such as the lymph nodes, gastrointestinal tract and lungs. KS can manifest in various morphologies from purple-brown macules to violaceous, red, pink or tan plaques or nodules, to confluent tumors with secondary change. The four types of KS include classical Kaposi’s sarcoma, African-endemic Kaposi’s sarcoma, HIV-associated Kaposi’s sarcoma, and iatrogenic immunosuppression-associated Kaposi’s sarcoma. KS has been postulated to be caused by HHV-8 or the HIV tat gene; however, the exact pathogenesis remains unknown.

Our patient was diagnosed with classical (Mediterranean type) KS. Previously, he had had several individual small lesions excised. He is currently undergoing radiotherapy to clear the remaining nodules and macules.

Zoey Glick is a medical student at George Washington University Medical School in Washington, DC.
Dr. Khachemoune, the Section Editor of Derm Dx, is with Department of Dermatology, State University of New York, Brooklyn, NY.

Disclosure: The authors have no conflict of interest with any material presented in this month’s column.