Epidemic Kaposi’s Sarcoma

Introduction

Kaposi’s sarcoma (KS) is the most common malignancy associated with human immunodeficiency virus-1 (HIV-1) infection.[1] It is the presenting manifestation of the acquired immunodeficiency syndrome (AIDS) in 10% to 15% of HIV-infected homosexual men and occurs in 1% to 2% of HIV-infected patients from other risk categories.[2] The proportion of HIV-seropositive patients who present with KS as their AIDS-defining illness has declined over the last decade, whereas the overall incidence of KS has remained stable.[3]

Increasingly, KS presents in the setting of advanced HIV-associated immunosuppression. Despite this, mortality for patients with AIDS-associated KS has decreased since 1985.[4] This is likely a result of improvements in the diagnosis and treatment of opportunistic infections, as well as the availability of highly active antiretroviral therapy.

To date, the underlying immunosuppression and its complications, rather than the tumor characteristics, are the most important predictors of survival.[5] The majority of patients with AIDS-related KS die from opportunistic infections, rather than from progressive tumor.[6]

Pathogenesis

Histologically, epidemic KS is indistinguishable from the classic or endemic forms of the disease. This highly vascular tumor is characterized by slit-like spaces lined with spindle cells, a prominent mononuclear cell infiltrate, and red blood cells.[5] Although the cell of origin is unclear, it is likely a mesenchymal progenitor cell of either monocyte-macrophage or endothelial derivation.[7]

Kaposi’s sarcoma is, at least initially, a cytokine-driven proliferative process. Receptors for multiple cytokines, including interleukin-1 (IL-1), IL-2, IL-6, platelet-derived growth factor, IL-8, and tumor necrosis factor (TNF), have been demonstrated on KS spindle cells.[9] Increases in TNF and IL-1 levels associated with the occurrence of opportunistic infections suggest an explanation for the progression of KS frequently observed in the setting of opportunistic infections.[7-9]

HIV may play an indirect role in KS pathogenesis. The HIV tat gene product is mitogenic for KS spindle cells in vitro and may promote the development and/or progression of KS in HIV-infected patients.[10]

Role of a New Herpesvirus

In view of the epidemiology of AIDS-related KS, an infectious copathogen with an essential role in the pathogenesis of KS has long been suspected. In 1994, Chang et al identified DNA sequences of a new herpesvirus,KS-associated herpesvirus (KSHV), or human herpesvirus 8 (HHV-8), in AIDS-associated KS lesions.[11] Human herpes virus 8 is a member of the rhadinovirus family, the same family as Epstein-Barr virus, and has been identified in the great majority of KS lesions, whether HIV-associated or not.[11-13] In addition, HHV-8 has been demonstrated in peripheral blood mononuclear cells of patients with AIDS-related KS and in the peripheral blood of about 20% of HIV-seropositive individuals without KS.[14]

The presence of antibodies to HHV-8 identifies a group of patients at high risk for the development of KS. It is estimated that 50% of HIV-infected patients with detectable HHV-8 antibodies will develop KS within 18 to 24 months.[14] The detection of antibodies to HHV-8 in HIV-infected patients prior to the development of KS provides the scientific foundation for future KS prevention trials.

Clinical Manifestations

The clinical course of KS is variable, although, for the majority of patients, the disease is ultimately progressive. Kaposi’s sarcoma may present as limited, asymptomatic cutaneous lesions or as widespread, rapidly progressive disease with edema and/or visceral involvement.

Mucocutaneous Disease

Cutaneous lesions may appear anywhere but are often concentrated on the face, trunk, and lower extremities. Not infrequently, lesions appear in a somewhat symmetrical distribution and may follow Langer’s lines. Early lesions appear as faint, pink-red or light brown macules, which can be difficult to distinguish from other skin lesions, particularly in dark-skinned individuals. Cutaneous lesions typically deepen in color as the disease progresses and develop dark violet or brown-to-black discoloration.

In addition to changes in color, lesion topography changes as the disease advances. Flat lesions become nodular, and papules may coalesce to form plaques and nodules. Lesions may ulcerate and become painful, especially in edematous areas.

Tumor-associated edema most frequently involves the lower extremities and, to a lesser degree, the external genitalia and periorbital soft tissue. Edema may be extensive and interfere with function, eg, decreasing range of motion of joints or causing difficulty in opening the eyes. Lower extremity edema, typically nonpitting edema, may appear out of proportion to the extent of cutaneous disease and probably results from obstruction of subcutaneous lymphatics or from local cytokine production (eg, IL-1, vascular endothelial growth factor [VEGF]) from KS spindle cells. Extensive lower extremity edema rarely results from proximal lymph node enlargement.

Oral lesions are common in epidemic KS. The mouth is the initial site of KS in about 45% of patients and is not infrequently first identified during a dental examination.[15] Lesions may occur anywhere in the oral cavity, including the palate, gingiva, tongue, lips, and tonsils. Early lesions generally appear as flat, pink or purplish discoloration of the hard palate. Although oral cavity disease is often asymptomatic, it may become exophytic, bulky, and/or ulcerated and cause pain, bleeding, and functional abnormalities, such as interference with speech or oral intake.

Disseminated Disease

Autopsy studies highlight the disseminated nature of epidemic KS. It can involve any organ, including the bone marrow and brain.[16,17] Lymph nodes are the most common extracutaneous site of involvement, followed by the gastrointestinal (GI) tract and lungs. Visceral involvement infrequently occurs without accompanying cutaneous disease.

Gastrointestinal tract KS is usually asymptomatic and has little impact on overall prognosis. Extensive GI disease or strategically located lesions, eg, at the appendiceal orifice, may lead to symptoms, including bleeding, pain, or obstruction.

Radiographic examinations are generally not useful for the detection of GI KS. Endoscopy, with visualization of pink-red nodules, is the diagnostic procedure of choice. Biopsies of GI lesions are frequently nondiagnostic due to the submucosal location of the lesions.

Pulmonary KS occurs in the absence of mucocutaneous disease in 15% to 20% of patients.[18] Because the presenting symptoms and radiologic findings are nonspecific, it is difficult to distinguish pulmonary KS from opportunistic infections.[19,20] Radiographic abnormalities may include interstitial, alveolar, or nodular infiltrates, with or without pleural effusions.

Pleural effusions may develop quite rapidly and become relatively large. Occasionally, the presence of pleural effusions may help distinguish KS from opportunistic pneumonias; eg, Pneumocystis carinii pneumonia is rarely associated with pleural effusions. The diagnostic yield of thoracentesis and pleural biopsy is low.

Hilar and mediastinal adenopathy occur infrequently with KS. Visualization of the characteristic erythematous submucosal plaque lesions at bronchoscopy, with or without biopsy-proven skin lesions, is the "gold standard" for the diagnosis of pulmonary KS.[19,20] These lesions are generally not biopsied because of the risk of bleeding. In the case of a nondiagnostic bronchoscopy, thallium-gallium scanning may be useful. Although these tests have not been validated for the diagnosis of KS, infection is usually gallium-avid and thallium-negative, whereas KS is thallium-avid and gallium-negative.[21]

Staging

Epidemic KS is a multicentric disease and, as such, does not lend itself well to the standard tumor, nodal, metastasis (TNM) system of staging. Furthermore, survival in HIV-infected patients with KS is more heavily influenced by the depth of immunosuppression than by tumor burden.

The most widely used staging system, the AIDS Clinical Trials Group (ACTG) staging classification (Table 1), characterizes patients as good(0)- or poor(1)-risk on the basis of tumor burden (T), immune function (I), and the presence of systemic illness (S).[22] In a recently reported study validating the ACTG staging system, immune function was identified as the single most important predictor of survival.[23] Tumor bulk was of significant predictive value only in patients with a CD4+ lymphocyte count of ³ 200 cells/mm³. The presence or absence of systemic illness was not an independent prognostic factor, probably because it is an indirect marker of immune function and less specific than CD4+ lymphocyte count.

It is likely that further refinement of the KS staging system, with integration of more specific markers of HIV biology, such as viral load, will improve our ability to accurately assess prognosis.

Patient Evaluation

The assessment of a patient with KS should begin with a complete history and physical examination. Special attention should be focused on the history of opportunistic infections, past and current antiretroviral treatment, an assessment of the tempo of the disease (ie, how rapidly new lesions are developing), and lesion-associated symptoms (ie, pain, edema, and functional impairment). A complete review of systems should also be conducted, with special focus on the respiratory and GI systems.

A thorough skin examination should be performed, with careful inspection of the retroauricular area and ears, the oral cavity, scalp, soles of the feet

and between the toes, genitalia, and perirectal area. The number of lesions in each anatomic site and the lesions’ characteristics, including size and nodularity, should be noted. The presence of edema and/or ulcerations should be documented. Measurement of the circumference of the extremities in relation to a bony landmark may be helpful for serial evaluations of edema.

Five discrete "marker" lesions with reproducible, bidimensional measurements should be identified for future response assessment. At least one lesion should be biopsied, both to confirm the diagnosis of KS and to rule out other treatable conditions, such as bacillary angiomatosis.

Routine laboratory evaluation should include a complete blood count, an assessment of renal and hepatic function, CD4+ lymphocyte count, and measurement of viral load. A chest roentgenogram should be obtained to rule out occult pulmonary disease. In the presence of pulmonary or GI symptoms, further testing, such as endoscopy or bronchoscopy, may be indicated.

Treatment Overview

Treatment of patients with AIDS-related KS begins with optimal antiretroviral therapy and prophylaxis and treatment of opportunistic infections. Control of HIV-1 replication with currently available highly active antiretroviral therapy has anecdotally been associated with regression of KS, as well as maintenance of KS response after discontinuation of cytotoxic therapy.[24] The observation of progressive KS in the setting of uncontrolled infections underlines the importance of integrating state-of-the art HIV care into a KS treatment strategy.

For patients with persistent and/or progressive KS despite "best" HIV care, a variety of treatments that produce KS responses, palliation of symptoms, and improvement in and/or maintenance of quality of life are available. For patients who have localized disease (particularly on the face) or severe HIV-induced immunosuppression and serious comorbid illness, local therapy may be considered. Patients with extensive symptomatic cutaneous disease or visceral KS are candidates for systemic therapy.