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Epidemic Kaposi’s Sarcoma

Epidemic Kaposi’s Sarcoma

ABSTRACT: Kaposi’s sarcoma (KS) is the most common malignancy associated with human immunodeficiency virus-1 (HIV-1) infection and can result in significant morbidity. The clinical course of KS is quite variable, although for the majority of patients, KS is ultimately a progressive disease requiring systemic therapy. For early indolent KS, local therapies may be appropriate and may provide significant palliation. For patients with more advanced or rapidly progressive disease, systemic therapy is the treatment of choice. Interferon-alfa (Intron A, Roferon-A), with or without antiretroviral agents, is particularly useful for patients with relatively preserved immune function. For patients with symptomatic visceral disease, pulmonary disease, or rapidly progressive cutaneous disease, chemotherapy is the treatment of choice. An increasing number of agents are now available for the treatment of KS. Pathogenesis-based treatment and/or preventive therapies based on the recognized association between KS-associated herpesvirus (KSHV) and KS are likely to be available in the near future. [ONCOLOGY 12(9):1375-1385, 1998]

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.

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