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Kaposi's sarcoma

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Kaposi's sarcoma
SpecialtyOncology

Kaposi sarcoma (/ˈkæpəʃi sɑːrˈkoʊmə/; KS) is a tumor caused by infection with human herpesvirus 8 (HHV8), also known as Kaposi sarcoma-associated herpesvirus (KSHV) or KS agent. It was originally described by Moritz Kaposi, a Hungarian dermatologist practicing at the University of Vienna in 1872.[1] 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.[2] Although KS is now well-established to be caused by a viral infection, there is widespread lack of awareness of this even among persons at risk for KSHV/HHV-8 infection.[3]

Kaposi sarcoma (KS) is a systemic disease that can present with cutaneous lesions with or without internal involvement. Four subtypes have been described: Classic KS, affecting middle aged men of Mediterranean 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 intravenous 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, highly active antiretroviral therapy (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 treatments at the same time.[4][5][6][7][8]

Classification

An example of Kaposi's sarcoma

The Kaposi's sarcoma-associated herpesvirus (KSHV), also called HHV-8, is responsible for all varieties of KS. Since Moritz Kaposi first described this malignant neoplasm, the disease has been reported in five separate clinical settings, with different presentations, epidemiology, and prognoses.[9]: 599  All of these forms are infected with KSHV and are different manifestations of the same disease but have differences in clinical aggressiveness, prognosis and treatment.

  • Classic Kaposi sarcoma most commonly appears early on the toes and soles as reddish, violaceous, or bluish-black macules and patches that spread and coalesce to form nodules or plaques.[9]: 599  A small percentage of these patients may have visceral lesions. In most cases the treatment involves surgical removal of the lesion. The condition tends to be indolent and chronic, affecting elderly men from the Mediterranean region, Arabian countries[10] or of Eastern European descent. Countries bordering the Mediterranean basin have higher rates of KSHV/HHV-8 infection than the remainder of Europe.[11][12]
  • Endemic KS, which has two types. Although this may be present worldwide, it has been originally described later in young African people, mainly from sub-Saharan Africa. This variant is not related to HIV infection and is a more aggressive disease that infiltrates the skin extensively.[13][14]
    • 'African lymphadenopathic Kaposi sarcoma is aggressive, occurring in children under 10 years of age, presenting with lymph node involvement, with or without skin lesions.[9]: 599  These lesions are not related to HIV infection.[15][16]
    • African cutaneous Kaposi sarcoma presents with nodular, infiltrative, vascular masses on the extremities, mostly in men between the ages of 20 and 50, and is endemic in tropical Africa.[9]: 599  These lesions are not related to HIV infection.[15][16]
  • Immunosuppression-associated Kaposi sarcoma 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.[17][18] Unlike classic Kaposi sarcoma, the site of presentation is more variable.[9]: 600 
An HIV-positive patient presented with an intraoral Kaposi’s sarcoma lesion with an overlying candidiasis infection
  • AIDS-associated Kaposi sarcoma typically presents with cutaneous lesions that begin as one or several red to purple-red macules, rapidly progressing to papules, nodules, and plaques, with a predilection for the head, back, neck, trunk, and mucous membranes. In more advanced cases, they can be found in the stomach and intestines, the lymph nodes, and the lungs.[9]: 599  KS-AIDS stimulated the greatest interest as one of the first illnesses associated with AIDS, and was first described in 1981.[19][20][21] 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 also at risk for sexually transmitted HIV infection.[22]

Signs and symptoms

KS lesions are nodules or blotches that may be red, purple, brown, or black, and are usually papular (in other words, 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.[23]

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

The mouth is involved in about 30% of cases, 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.[24] 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.[25]

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.[26] The diagnosis is usually confirmed by bronchoscopy when the lesions are directly seen, and often biopsied.

Transmission

In Europe and North America, KSHV is transmitted through saliva. Thus, kissing is a theoretical risk factor for transmission. Higher rates of transmission among gay and bisexual men have been attributed to "deep kissing" sexual partners with KSHV.[27] 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 with KSHV infection or whose status is unknown.

KSHV is also transmissible via organ transplantation[28] and blood transfusion.[7] Testing for the virus before these procedures is likely to effectively limit iatrogenic transmission.

Pathology and diagnosis

Micrograph of a Kaposi sarcoma showing the characteristic spindle cells, high vascularity and intracellular hyaline globs. H&E stain.

Despite its name, in general it is not considered a true sarcoma,[29][30] which is a tumor arising from mesenchymal tissue. The histogenesis of KS remains controversial.[31] KS may arise as a cancer of lymphatic endothelium[32] 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 most typical feature of Kaposi sarcoma is the presence of spindle cells forming slits containing red blood cells. Mitotic activity is only moderate and pleomorphism is usually absent.[33] 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. Variously sized PAS positive hyaline bodies are often seen in the cytoplasm or sometimes extracellularly.

The spindle cells of Kaposi sarcoma differentiate toward endothelial cells, probably of lymph vessel rather than blood vessel nature.[34] The consistent immunoreactivity for podoplanin supports the lymphatic nature of the lesion.

HHV8 is present in almost 100% of Kaposi sarcoma lesions, whether HIV-related, classic, endemic, or iatrogenic.[35]

Although KS may be suspected from the appearance of lesions and the patient's risk factors, definite diagnosis can be made only by biopsy and microscopic examination. Detection of the KSHV protein LANA in tumor cells confirms the diagnosis.

In differential diagnosis, arteriovenous malformations, pyogenic granuloma and other vascular proliferations can be microscopically confused with KS.[36]

Prevention

Blood tests to detect antibodies against KSHV have been developed and can be used to determine whether a person is at risk for transmitting infection to their sexual partner, or whether an organ is infected prior to transplantation. However, 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 people following a transplant.

Treatment

Kaposi sarcoma is not curable (in the usual sense of the word), but it can often be treatable for many years. 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 peoples with AIDS-associated Kaposi sarcoma, the Kaposi lesions will shrink upon first starting highly active antiretroviral therapy (HAART). However, in a certain percentage of such people, Kaposi sarcoma may again grow after a number of years on HAART, especially if HIV is not completely suppressed.

People with a few local lesions can often be treated with local measures such as radiation therapy or cryosurgery.[37][38] Weak evidence suggests that antiretroviral therapy in combination with chemotherapy is more effective than either of those two therapies individually.[39] In general, surgery is not recommended, as Kaposi sarcoma can appear in wound edges. In general, more widespread disease, or disease affecting internal organs, is treated with systemic therapy with interferon alpha, liposomal anthracyclines (such as Doxil) or paclitaxel.[40][41]

Reactivation

KSHV has been shown to be reactivated from latency by IL-4 in vitro.,[42] which may be produced during infection, in a laboratory test in mice infected with helminths, the related virus reactivated due to immune signal IL-4 in vivo.

Epidemiology

With the decrease in the death rate among people with HIV/AIDS receiving new treatments in the 1990s, the rates and severity of epidemic KS also decreased. However, the number of people living with HIV/AIDS is increasing in the United States, and it is possible that the number of people with AIDS-associated Kaposi sarcoma will again rise as these people live longer with HIV infection.

Awareness

It has been reported that only 6% of men who have sex with men are aware that KS is caused by a virus different from HIV.[3] Thus, there is little community effort to prevent KSHV infection. Likewise, no systematic screening of organ donations is in place.

In people with AIDS, Kaposi 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.

Because of their highly visible nature, external lesions are sometimes the presenting symptom of AIDS. Kaposi 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. By the time KS lesions appear, it is likely that the immune system has already been severely weakened.

References

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