AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

In 1872, Moritz Kaposi (1837-1902) of Kaposvar, Hungary, a dermatology faculty member at the University of Vienna, first described idiopathisches multiples Pigmentsarkom der Haut, which has become known as Kaposi sarcoma (KS). KS had brownish red–to–bluish red cutaneous nodules that tended to enlarge into dome-shaped tumors. Kaposi observed similar neoplasms of the mucosa, especially of the larynx, trachea, stomach, liver, and colon. Kaposi's original 1872 description of 5 patients is more similar to the KS seen in AIDS (KS-AIDS) than the KS expected in elderly men of Italian, Jewish, or Mediterranean linkage, in whom the disease behavior is benign. Kaposi's original 5 patients died within 2-3 years. Kaposi later updated his data, noting that all of his 16 patients were men with a prognosis that remained unfavorable.

In 1882, Tommaso De Amici, Professor and Head, Dermatology, University of Naples, Italy published in monograph form a detailed analysis of 12 patients with KS.^{1, 2}

For most of the first 3 quarters of the 20th century, KS was viewed as an indolent slowly growing cancer, and patients were expected to die with, rather than of, KS. The aggressive course originally noted by Kaposi has become part of the devastation of AIDS, especially among men who are homosexual.

American AIDS was identified relatively recently (1981) in 3 reports of KS as an original defining element of AIDS (plus an important editorial and a Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report bulletin). Two of the reports were from New York City, and 1 was from San Francisco. For some time, KS was seen in 30-40% of patients with AIDS, often as the presenting sign. The incidence of KS has fallen markedly in recent times, although its prevalence has not. The challenge remained to explain the reason patients who are homosexual and have AIDS exhibited KS much more commonly than did patients with AIDS unassociated with homosexuality, with the exception of small foci of homosexuals in isolated midwestern communities.

The breakthrough came in 1994, when the KS-associated herpes virus (human herpesvirus type 8 [HHV-8]) was identified using representational difference analysis. HHV-8 has been linked closely with all 4 types of KS, ie, classic (traditional), endemic (African), epidemic (AIDS related), and iatrogenic (related to immunosuppression). Since then, much research has shown that HHV-8 appears to be necessary to, but not sufficient for, the development of KS.

Nevertheless, 2 critical questions remain. Is KS a hyperplasia or a neoplasm? Is it always multicentric or can it be metastatic as well? The authors favor the latter interpretation of both points.

Medscape CME courses that may be of interest include Update on Opt-Out Testing and Initial Antiretroviral Therapy - CROI 2007 and IAS 2007: Advances in Antiretroviral Strategies for Highly Experienced Patients.

The HIV Pathogenesis Resource Center, HIV Transmission & Prevention Resource Center, and Antiretroviral Drug Resistance and Testing Resource Center also may be helpful.

Pathophysiology

HIV transactivating (tat) gene, cytokine, and HHV-8 stories in KS are fascinating. Each begins with a classic study. In 1988, the human immunodeficiency virus type 1 (HIV-1) tat gene was introduced into transgenic mice, inducing nodules that resembled KS in 33 of 37 males but in none of 15 females. Therefore, it appeared that HIV could play a direct role in causing KS.

The second saga was a result of efforts to grow KS cells in culture, requiring a long-term growth factor. Conditioned medium from T cells infected with human T-cell leukemia virus type II (rather than HIV-1 or human T-cell leukemia virus type I) best supported the growth and long-term culture of KS cells derived from KS-AIDS lesions. In 1992, this growth factor proved to be a cytokine previously termed oncostatin M, since it had been identified earlier for its inhibitory effects on a variety of cancer cells. Another cytokine scatter factor was found in large quantities in this medium, inducing endothelial cells to demonstrate a KS tumor cell-like phenotype. The importance of oncostatin M, scatter factor, and the tat protein has been shown in the pathogenesis of KS.

Other cytokines, including interleukin 1 (IL-1), tumor necrosis factor, interleukin 6 (IL-6), and basic fibroblastic growth factor (bFGF), may work synergistically with the HIV tat gene product. Scatter factor may be involved both in initiation and in maintenance of KS. Scatter factor stimulates endothelial cells to migrate nearby and become factor XIIIa–positive c-Met-expressing spindle-shaped KS cells. The cells further expand neovascularization by producing cytokines and promoting autocrine-mediated and paracrine-mediated growth of KS cells. The scatter factor receptor, c-Met proto-oncogene, is expressed by KS cells; the oncogene int-2 of the fibroblast growth factor family also may be evident.

Herpes-type viruses have been linked with KS for more than 3 decades. A landmark study showed short DNA sequences of a unique human herpesvirus in KS tissues via a new molecular biological technique termed representational difference analysis. They resembled herpesvirus saimiri but proved to be a new type of human herpesvirus now termed HHV-8. This virus appears to interact with the HIV tat protein, excess levels of basic fibroblast growth factor, scatter factor, and IL-6. For example, HHV-8–encoded IL-6 has been found to induce endogenous human IL-6 secretion. An HHV-8 oncogene, Kaposin (ORF K12), has been characterized; however, additional factors remain to be found. For example, a 53% prevalence of HHV-8 subtype E in Brazilian Indians does not appear to be linked with the development of KS in this population.

Classic KS is seen in Italy with hot spots being in the Po River Valley, Sardinia, and southern Italy. It has been suggested that volcanic soil or birthplace/residency in areas abundant with bloodsucking insects may be a risk factor.³ A survey evaluated the correlation between HHV-8 infection and classic KS incidence in northern Sardinia.⁴ It revealed that seroprevalence was 35%, within a range of 15.3-46.3% in the five areas. Age was as an important risk factor. Subjects aged older than 50 years had a higher seroprevalence to HHV-8 as compared with younger individuals. A strong direct correlation between HHV-8 prevalence and classic KS incidence was also observed.

KS-associated herpesvirus (KSHV), or human herpesvirus 8 (HHV-8), is the most frequent cause of malignancy in patients with AIDS.⁵ KSHV and related herpesviruses have pirated cellular cDNAs from the host genome. Many of the viral regulatory homologs encode proteins that directly inhibit host adaptive and innate immunity. Other viral proteins may target retinoblastoma protein and p53 control of tumor suppressor pathways, which play key effector roles in intracellular immune responses. The immune evasion strategies used by KSHV in targeting tumor suppressor pathways activated during immune system signaling, may lead to inadvertent cell proliferation and tumorigenesis in susceptible hosts.

The origin of the spindle cell, the hallmark cell of KS, is unknown. Most research favors a lymphatic endothelial cell or an endothelial-cell precursor evolving into a lymphatic phenotype, both preferentially targeted by KSHV.⁶

Frequency

United States

The incidence of KS has been estimated at 0.02-0.06%. Traditional KS of middle-aged and older American men of Mediterranean and Eastern European (Ashkenazi) Jewish lineage represents approximately 0.2% of cancer cases in the United States. Iatrogenic KS has a 400% increased incidence compared to the American population at large. The incidence of KS among American renal transplant recipients is approximately 0.4%. In the AIDS grouping, KS originally accounted for as many as 35% of patients, an incidence that has been declining with early detection of AIDS, although KS prevalence may remain high. In the United States, a few emigrants arrive from KS-endemic regions (primarily Africa). The largest immigrant population in this category may be Haitians; however, recent evidence suggests that Haitian AIDS originated directly in New York rather than Africa.

International

Four groups are predisposed to KS including (1) older men of Mediterranean and Jewish lineage; (2) Africans from areas including Uganda, the Congo Republic, Congo (Brazzaville), and Zambia; (3) persons who are iatrogenically immunosuppressed; and (4) men who are homosexual. KS traditionally is an uncommon disease in middle-aged and elderly European men of Mediterranean or Jewish lineage. A similar focus of KS exists in the same age and sex groups in Africa. If a crudely calculated incidence of 28 cases of KS per 100,000 in the Arabian population is correct, KS may be more common among Arabians than among Mediterranean people. A previously unrecognized genetic predisposition for KS among Arabians has been suggested. The incidence of KS among renal transplant recipients may be as high as 3.5% or higher in regions endemic for KS, which is significantly higher than the 0.4% incidence renal transplant recipients in the United States and Western Europe.

Endemic African KS has accounted for 10% of cancers and has been seen in a male-to-female ratio of 15:1. The Kampala Cancer Registry, one of the continent's first and foremost, has shown a significant alteration in the incidence of KS in the era of AIDS. In Uganda, KS has caused almost one half (48.9%) of cancer cases in men and 17.9% in women. The incidence in men (30.1 cases per 100,000) represents a more than 10-fold increase in men since the 1950s and is approximately 3 times the incidence found in women (11 cases per 100,000). The incidence in boys and girls was approximately the same in childhood (birth to 14 y), with small peaks in girls younger than 5 years and boys aged 5-9 years. Subsequently, a progressive rise in incidence peaked in women aged 25-29 years and in men aged 35-39 years. Lymphadenopathic KS affected 12% of total cases; 42% of childhood cases were of this type.

In neighboring Zambia, the disorder was particularly aggressive among children, more than 80% of whom were HIV seropositive. KS was found to represent as much as 25% of childhood cancers. The average male-to-female ratio was 1.76:1, with male predominance higher in children older than 5 years (2.5:1 ratio) than in children younger than 5 years (1.4:1 ratio). The prevalence of HIV-related KS seems to be increasing in Nigeria, probably owing to more females having HIV disease.⁷

In Italy, KS-AIDS has produced notable epidemiologic changes. A doubling of KS incidence rates was noted in Italian men younger than 50 years from 1976-1984 to 1985-1990; however, no change, or possibly a decline, was observed in older men. The incidence of KS was estimated in the region around Venice, Italy, with rates higher in the coast and alpine valleys; in the latter, there was an excess of cases for both sexes combined (SIR = 191.1; CI = 113.2-302.0).³

Classic KS in Greece seems to have an older age of onset; lower male-to-female ratio; endemic clustering; and disseminated skin disease at diagnosis, often accompanied by lymphedema and not unusual visceral or lymph node involvement.⁸ A clustering was noted, with a high proportion of the patients being born in Peloponnesos (42.42%) and residing in Athens (51.51%) or in Peloponnesos (24.24%).

The incidence rates of classic KS in Italy after the spread of AIDS was evaluated.⁹ The rates were 1 case per 100,000 population in men and 0.4 case per 100,000 population in women, varying from 0.3 cases per 100,000 population for men in Umbria and 4.7 cases per 100,000 population for men in Sassari in men and from 0.1 case per 100,000 population for women in Parma and 1.7 cases per 100,000 population for women in Sassari.

The rate of classic KS in southern Sardinia (Italy) from 1998-2002 was found to be 2.49 cases per 100 000 population per year (standardized), which was the highest rate recorded in the island.¹⁰

Mortality/Morbidity

Patients with traditional KS tend to die with KS rather than of KS. Patients with KS-AIDS usually die from associated opportunistic infections or from gastrointestinal KS with hemorrhage. The mean survival rate of patients with KS-AIDS has been approximately 15-24 months, although the introduction into the United States of apparent immune system reconstitution using highly active antiretroviral therapy (HAART) has extended survival substantially. KS also may be fatal as a result of gut perforation, cardiac tamponade, massive pulmonary obstruction or, rarely, brain metastases.

• In Kaposi's original description, death usually ensued within 3 years and was linked to fever, diarrhea, and hemoptysis. Inanition may be an important factor, and death may ensue as a result of bulky tumor obstructing the bronchi or larynx.
• Patients with AIDS-related KS often have widespread visceral KS, although KS limited to the skin also is common.
• Patients with iatrogenic KS tend to have gut bleeding resulting from KS, although termination or reduction of immunosuppression often, but not always, results in regression of KS.

Race

KS is an uncommon disease of middle-aged and elderly American and European men of Mediterranean or Jewish lineage. This propensity also is seen in individuals with iatrogenically induced KS but not among persons in the KS-AIDS group. KS is rare in American blacks, despite its large foci among blacks in certain regions of Africa.

Sex

Classic KS has an overwhelming male predominance, with a male-to-female ratio of approximately 10-15:1.

• For endemic KS in Central Africa, the male-to-female ratio is near unity in childhood KS cases but often rises in puberty to 15:1.
• In Corsica and Sardinia (where classic KS is endemic), with the arrival of AIDS, the ratio of male-to-female cases has dropped from 10:1 to 3:1. Children of women who are HIV-1 seropositive without KS have an aggressive form of childhood HIV-associated KS. A male-to-female ratio of 1.5:1 was observed.
• A male-to-female ratio of 1.5:1 also was evident among renal transplant recipients in Arabia.
• In Zambia, KS represents up to 25% of childhood cancers and has an average male-to-female ratio of 1.76:1, with male predominance higher in children older than 5 years (2.5:1) than in children younger than 5 years (1.4:1).

Age

Age distribution depends on the type of KS.

• In the United States and Europe, traditional KS has a peak incidence between 40-70 years, with a wide range of up to 89 years.
• Young men with KS-AIDS who are homosexual also show a wide age range but tend to be much younger, averaging 20-40 years at age of onset.
• For endemic KS in Uganda, the incidence in boys and girls was approximately the same in childhood (birth to 14 y), with a small peak in girls younger than 5 years and boys aged 5-9 years. Subsequently, a progressive rise in incidence peaked in women aged 25-29 years and in men aged 35-39 years.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• KS is a neoplasm that often manifests with multiple vascular nodules in the skin and other organs.
• Although true metastases appear to occur, a multifocal origin is most common.
• The pattern of KS is variable, with a course ranging from indolent (only skin manifestations) to fulminant (extensive visceral involvement).
• KS also may arise primarily in the oral mucosa, lymph nodes, and/or viscera without skin involvement.
• KS initially may be evident in any organ of the body.
• Chronic lymphedema may precede KS.
• Professor Ruocco's term isotopic response applies to the occurrence of KS with new cutaneous nodules at the site of other, unrelated, and already healed skin diseases.¹¹
• Although primary penile KS is uncommon in HIV negative men, one should consider this possibility when treating nonspecific penile lesions.¹² A minimal penile lesion with nondistinctive clinical features may be the exclusive manifestation of KS. In addition, it may appear as a skin-colored nodule suggestive of a primary squamous cell carcinoma.¹³ Clearly, in both cases, histologic evaluation is mandated to establish the diagnosis.

Physical

KS is described in 3 forms including localized nodular, locally aggressive, and generalized KS. KS typically occurs in these 3 forms and in 6 stages including patch, plaque, nodular, exophytic, infiltrative, and lymphadenopathic.

• Cutaneous KS usually begins as discrete red or purple patches that are bilaterally symmetric and initially tend to involve the lower extremities.
• Patches become elevated, evolving into nodules and plaques.
• Nodules may be spongy to the touch.
• KS also occurs as a large infiltrating mass or as multiple cone-shaped friable tumors. These 2 variants, termed locally aggressive KS, may adhere firmly to underlying anatomic structures including bone.
• Early KS may appear as violaceous patches (patch stage KS), which occasionally resemble large junctional melanocytic nevi or may appear as irregular-shaped patches similar to the nevus flammeus.
• More commonly, KS is evident as violaceous plaques or nodules on the lower extremities. The nodules tend to enlarge into dome-shaped tumors.
• Cutaneous KS rarely may be infiltrative or exophytic. To the authors' knowledge, infiltrative KS has not been described outside of Africa. Exophytic KS may erode downward into bone.
• Lymphadenopathic KS may demonstrate skin lesions.
• At times, a Köbner phenomenon appears evident, with nodules at sites of trauma.
• A few unusual varieties of KS also exist.
• • Telangiectatic KS is an eruption of pink translucent nodules with prominent telangiectasia.
  • Ecchymotic KS appears as periorbital ecchymoses. Histologically, there is a large amount of extravasated red blood cells, no evidence of amyloidosis, and a dermis containing foci of proliferating moderately atypical spindle cells, vascular slits, erythrophagocytosis, and other features of KS. On the trunk, lesions often follow skin tension lines.
  • Keloidal KS is evident as somewhat brown-to-violaceous keloidal nodules. Histologically, these are KS nodules with a keloidal component.
  • Cavernous KS is a rare type of locally aggressive KS characterized by cutaneous tumors that histologically resemble cavernous hemangiomas; however, the endothelial cells and their nuclei are large and prominent, bulging into the cavity.
  • Lymphangiomalike KS is a rare variant in which dilated vascular spaces produce a bullous-appearing eruption, typically on the lower legs. The lesions are easily compressible and appear clinically to be fluid-filled. The vascular channels are lined by banal-appearing endothelial cells permeating the dermis in the absence of spindle cell proliferation.

Causes

HHV-8 has been linked convincingly with all 4 types of KS, an association that is necessary, but not sufficient, to develop KS; therefore, other factors also are important. At this point, immunosuppression appears to be the most significant cofactor.

The use of prednisolone as an adjunct to treatment in HIV-1–associated pleural tuberculosis in Uganda was associated with a significantly higher incidence of KS (4.2 cases per 100 person-years, compared with 0 cases per 100 person-years [P = .02]),¹⁴ which is a dramatic example of the induction of KS by immunosuppressive therapy with corticosteroids.

DIFFERENTIALS

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
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• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Melanoma
Cavernous hemangioma
Angiokeratoma
Carcinoma cutis (especially renal cell carcinoma)
Nodal myofibromatoma
Arteriovenous malformations (pseudo-KS)
Severe statis dermatitis (pseudo-KS)
Reactive angioendotheliomatosis¹⁵

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Serum glucose levels may reflect an increased incidence of diabetes mellitus in patients with classic KS. Ketoacidosis is unusual in these patients.
• Immunohistochemical detection of human herpes virus-8 latent nuclear antigen-1 has been claimed as useful in the diagnosis of KS.¹⁶
• Hemogram in nonimmunosuppressed patients with KS tends to be within normal limits, but occasionally, monocytosis or eosinophilia has been noted. Eosinophilia is seen especially in African patients and patients who are homosexual, in whom parasitosis may be common.
• In KS-AIDS, cytopenia of 1 or more cell lines is frequent.
• Anemia, if present, may result from gastrointestinal bleeding or may be associated with an autoimmune hemolytic anemia or a hematologic malignancy.
• Assays for HHV-8 have been challenging. At present, no universally accepted method exists.
• Polymerase chain reaction often is used but may have false-positive results because of its high susceptibility to contamination.
• Methods based on both lytic and latent-phase viral antigens remain promising.

Imaging Studies

• Computed tomography (CT) may be valuable, especially abdominal CT scans in patients with AIDS.
• • In AIDS-related KS, early lymphatic and hepatosplenic involvement may be evident.
  • Consider CT-directed fine needle aspiration to provide tissue confirmation, since lymphomas and atypical mycobacterial and other infections may appear similar.
• Consider endoscopic and conventional radiographic studies; however, these modalities may miss gastrointestinal KS, while selective angiography may demonstrate KS.
• Radionucleotide scans may be useful in demonstrating visceral KS and associated lymphoma.
• With lung nodules, the distinction between KS, lymphoma, and/or opportunistic infection may be challenging.
• In both adults and children with pulmonary KS, chest radiography shows perihilar and lower zone involvement.¹⁷ Pleural effusions appear to be more common on radiographs in children.

Other Tests

• Evaluation for KS should include a complete physical examination and a biopsy of suspected lesions including lymph nodes. CT scan used to guide a fine needle for tissue specimens appears promising.
• The cell of origin in KS remains a subject of dispute, although the following tests may be useful:
• • Ultrastructural and immunohistochemical testing favor the endothelial cell.
  • The presence of factor VIII–related antigen, human leukocyte antigen DR (HLA-DR), von Willebrand factor, and the lectin Ulex europaeus I (which all are markers for endothelial cells) is highly suggestive.
  • Reactivity with 2 monoclonal antibodies (EN4 and PAL E) implies that KS is derived from endothelium of lymphatic origin; however, KS spindle cells express CD34 antigen, a glycoprotein expressed by endothelial cells of small blood vessels (but not those of lymphatic origin).

Histologic Findings

KS tends to demonstrate increased spindle cells with vascular slits and vascular structures with a predominance of endothelial cells. Extravasated erythrocytes and hemosiderin-laden macrophages often are evident. Some spindle cells may show nuclear pleomorphism. Early KS may resemble granulation tissue with a diffuse chronic inflammatory infiltrate and capillaries dilated and increased in number. This pattern also is seen in lymph nodes and viscera.
 
Histopathologic classification is based on relative contribution of spindle cells, fibrosis, and nuclear pleomorphism, sometimes divided into 3 histopathologic forms, which include (1) a mixed form with an equal amount of spindle cells, vascular clefts, and capillaries, (2) a mononuclear type with 1 cell type predominating, and (3) an anaplastic form with cellular pleomorphism and numerous mitotic figures. In 2007, intravascular KS was recognized as a morphological variant of KS that seems to be unassociated with an increased risk of aggressive behavior.¹⁸

Cutaneous KS probably evolves through the early inflammatory or patch stage, progresses to the nodular stage, and then, to the late proliferative or plaque stage. The authors believe that the glomeruluslike vascular formations in early patch stage KS and in some later lesions may reflect the histogenesis of KS. The late plaque stage shows diffuse involvement of the dermis, exhibiting the histologic features of the nodular stage. The lesions may resolve, with involution of the vascular components and formation of scar tissue, or occasionally, they become extremely pleomorphic and invade deeper tissues.

KS specimens may be stained for iron and HHV-8.¹⁹ Iron staining of dermal tissue may suggest KS. Immunohistochemical stains for HHV-8 should be positive in most typical KS. Iron staining and immunohistochemical HHV-8 staining in combination may be reliable markers for KS compared with interstitial granuloma annulare.

The lymphadenopathy in KS may show marked follicular hyperplasia and hypervascularity, nonspecific inflammation in regional lymph nodes that drain ulcerated KS, and lymphomas or actual lymph node KS, with or without cutaneous involvement. More than 1 of these processes may be evident in the same node. The authors view localized lymphadenopathic KS as a type of localized nodular KS. KS in nodes shows the typical proliferation of spindle cells separated by slitlike spaces containing red blood cells and is accompanied by marked follicular hyperplasia and plasmacytic infiltration. The earliest changes occur in the subcapsular and trabecular sinuses, with extension into the entire node and, later, the perinodal tissues. KS of lymph nodes may be localized or generalized. The lymphocytic, plasmacytic, and immunoblastic proliferation may simulate a lymphoma.

The electron microscopy and immunohistochemical features of KS may be important. Staining with CD34, factor VIII–related antigen, the lectin Ulex europaeus I, and HLA-DR antigen may be useful to support or confirm the diagnosis of KS. The authors prefer CD34 antigen, which is expressed by KS cells, and find it helpful in distinguishing KS from pseudo-KS (acroangiodermatitis).

Staging

Stage the patient's disease and note any extracutaneous involvement. Staging this multicentric disorder has been a challenge.

• The AIDS Clinical Trials Group classification by Krown et al²⁰ in 1989 uses the following 3 categories, although the tumor/immune/system/systemic (TIS) illness grading method has limitations.
• • Tumor (T) - Good or bad risk signs (good when KS is confined to skin and/or lymph nodes and/or demonstrates minimal oral disease)
  • Immune system (I) - CD4 cell levels equal to or greater than 150/µL (good risk) versus less than 150/µL (poor risk)
  • Systemic illness (S) - Good or poor risk
• Another classification formula developed by Mitsuyasu in 1987²¹ divides KS into 4 stages.
• • Stage I - Localized nodular KS in elderly men in North America and Europe
  • Stage II - Localized, invasive, and aggressive KS (mostly seen in Africa)
  • Stage III - Disseminated mucocutaneous KS in African children and patients who are homosexual
  • Stage IV - Stage III with visceral involvement
• In 1984, the authors originally proposed and currently prefer the following classification system (including new recommended modifications):
• • Stage I represents localized nodular KS, with more than 15 cutaneous lesions or involvement restricted to 1 bilateral anatomic site, and few, if any, gut nodules.
  • Stage II includes both exophytic destructive lesions and locally infiltrative cutaneous lesions as locally aggressive KS.
  • Stage III (generalized lymphadenopathic KS) has widespread lymph node involvement, with or without skin lesions, but with no visceral involvement.
  • Stage IV (disseminated visceral KS) has widespread KS, usually progressing from Stage II or Stage III, with involvement of multiple visceral organs.
  • The authors modify each stage as follows:
  • • A: Associated opportunistic infection(s) is evident.
    • B: Patient is HIV-I seropositive.
    • C: Cutaneous anergy or other evidence of severe immunodeficiency is present.

TREATMENT

Section 6 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Since the natural history of KS is variable, assessment of therapy may be difficult. Treatment usually is based on the extent of disease and the patient's immune status. The optimal therapy of KS-AIDS is yet to be determined. The challenge is to treat KS-AIDS effectively without immunocompromising the patient further, or better, with reconstitution of the immune system.

Management modalities for KS include nonintervention, surgical removal of skin nodules or severely affected areas (eg, areas of the extremities, intussuscepted bowel), laser surgery, conventional and megavoltage radiotherapy, chemotherapy, immunotherapy, antiviral drugs, and cessation of immunosuppressive therapy in iatrogenically immunosuppressed patients.

• Indolent skin tumors in elderly white patients may not require specific therapy early in the course of the disease; however, systemic vinblastine (or other chemotherapy) attacks both cutaneous and visceral lesions.
• Localized nodular disease may respond well to surgical excision, radiotherapy, and intralesional and outpatient low-dose vinblastine chemotherapy. The latter combination of local and systemic regimens may be preferable. The authors usually inform patients that this is a multicentric disease that has silent gut lesions that also may regress with the systemic approach.
• The efficacy of taxanes (eg, paclitaxel, docetaxel), as agents with antiangiogenic properties, has been shown for patients with AIDS-associated KS and in those with refractory or life-threatening KS without HIV infection.²² Pegylated liposomal doxorubicin is now being used as a second-line therapy in the treatment of patients with advanced classic Kaposi sarcoma.²³
• Radiotherapy is an option for some KS patients.
• • Radiotherapy often produces good therapeutic results with classic nodular KS but tends to be only palliative in patients with KS and AIDS.
  • In localized nodular KS, conventional radiotherapy is highly effective.
  • Electron-beam radiotherapy, which has limited penetration beyond the dermis, may be a good modality for superficial lesions.
  • Deeper or unresponsive KS may be treated using standard non–electron-beam radiation or other options.
  • Initial response to radiotherapy usually is complete or demonstrates marked regression of the nodules. The more extensive the involvement, the less responsive it tends to be.
  • Radiotherapy may be more effective on new, rather than chronic, lesions and may provide local KS control in patients with KS-AIDS.
  • Radioisotope scanning using technetium Tc 99m may detect occult KS infiltration in the subcutaneous and muscular tissues and draining lymph nodes. This allows improved efficiency of large-field radiotherapy.
• Laser therapy: Argon laser photocoagulation therapy also may be beneficial in classic KS lesions.

Surgical Care

Solitary KS lesions may be excised surgically or removed using laser surgery.

Consultations

Treating patients with advanced KS often requires a team approach.

• Medical oncologists often administer systemic chemotherapy.
• Radiation oncologists tend to favor radiotherapy options.
• Infectious diseases/HIV specialists may be needed for HIV and opportunistic infections.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The authors' preference often is the Klein²⁴ regimen of weekly outpatient intravenous vinblastine titered against white cell count levels to avoid falling below 4000/µL. The authors recommend intralesional injections of vinblastine for persistent cutaneous nodules and intraarterial vinblastine in certain settings for locally aggressive KS. Systemic vinblastine (3.5-10 mg IV weekly with, at times, 1 intralesional injection of 0.1 mg) usually is best for both the patient with classic KS and, occasionally, patients with KS-AIDS.

Although the authors prefer low-dose vinblastine, a number of other chemotherapeutic agents may be effective. Drugs with proven efficiency include vincristine, vinblastine, dacarbazine, doxorubicin, and actinomycin D. Alkylating agents (eg, cyclophosphamide, chlorambucil, bleomycin, doxorubicin, etoposide) also may be of value. Multiagent intravenous chemotherapy, rather than single agent usage, is preferred by some for disseminated aggressive KS. No particular combination regimen has been established yet. The combination of doxorubicin, bleomycin, vinblastine, and dacarbazine may be effective.

Alternating vincristine and vinblastine in patients with KS-AIDS can be both effective and well tolerated, but leukopenia and a propensity to opportunistic infections makes aggressive chemotherapy difficult. Patients with KS-AIDS usually succumb either to disseminated KS or to an intervening opportunistic infection within 3 years of diagnosis, regardless of the form of therapy (except with HAART therapy). All of these therapies (except low-dose vinblastine) are significantly immunosuppressive and, perhaps, accelerate the disease. Combining chemotherapy for KS with chemotherapy for HIV is an attractive option. Interferon also may be used in this way. Thus, the combination of zidovudine, interferon, and low-dose intravenous vinblastine may be used for patients with KS-AIDS.

Experimental treatments for KS and HHV-8 infections are myriad. Many come under the rubric of immunotherapy, pioneered for KS by Klein in the early 1960s. Other agents (in addition to interferon) used for immunomodulation include bovine-thymic extracts, thymosin, Imreg-l, thalidomide, endothelial growth factor inhibitor (SU5416), human chorionic gonadotropin, isoprinosine, thymopoietin, monoclonal antibodies to T-suppressor (T8) cells, BCG vaccine, and cord factor.
 
The value of recombinant interferon alfa and other modalities may depend on the pretreatment immune status of the patient as the best predictor of response. The degree of reduction in the helper-inducer T-cell (T4) subpopulation as manifested in the T4:T8 ratio may correlate highest with prognosis and be a good measure of immune status for this purpose. Thalidomide therapy may be of value in non-AIDS–related KS; in 2 of 3 patients, complete remission was achieved after 12 months of treatment.²⁵

In iatrogenic KS, cessation of immunosuppressive therapy may be the most effective treatment. Patients on immunosuppressive therapy, specifically corticosteroids and cytotoxic drugs, may have partial or complete regression when therapy is discontinued. If possible, immunosuppressive medication doses should be reduced or discontinued before beginning specific therapy for iatrogenic KS. Sirolimus has the advantage of decreased risk of malignancies, including KS, associated with its use compared with other immunosuppressants, namely calcineurin inhibitors, and possibly KS regression.^{26, 27}

In some patients, KS-AIDS may resolve clinically with the use of HAART. Resolution of conjunctival KS after use of HAART alone has been described.²⁸ Antiviral therapy with foscarnet may not only reduce progression of KS in patients, but may lower its occurrence substantially in patients with HIV disease.

Patients with KS-AIDS, the most common tumor in Zimbabwe, were randomized and evaluated for the effectiveness of supportive care versus 3 intervention approaches, namely oral etoposide, a 3-drug combination, and radiotherapy, using quality of life as the primary measure of success.²⁹ No patient used antiretroviral therapy. Oral etoposide resulted in a significantly better quality of life and may represent a pragmatic approach to treating epidemic KS in an environment where antiretroviral drugs are not universally available.

Drug Category: Chemotherapy agents

Inhibit cell growth and proliferation. Vincristine 2 mg IV alternating with vinblastine 0.1 mg/kg IV qwk is effective. Doxorubicin, an anthracycline, is used effectively as ABV combination (doxorubicin A=anthracycline [20 mg/m² IV], B=bleomycin [10 U/m² IV], V=vincristine [1.4 mg/m² IV q2wk]). The combination may produce alopecia, neuropathy, neutropenia, nausea and vomiting, oral erosions, or palmoplantar erythrodysesthesia.

Drug Category: Retinoids

Decrease cohesiveness of abnormal hyperproliferative keratinocytes and may reduce potential for malignant degeneration. Modulate keratinocyte differentiation. Have been shown to reduce risk of skin cancer formation in renal transplant patients.

Drug Category: Antiviral agents

Active against HHV-8 and represent an important potential intervention and prevention option.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Careful follow-up monitoring is essential for patients with KS.

Deterrence/Prevention

• Reducing the HHV-8 infection rate prevents KS development.
• Suggestions have been made that some antiherpetic agents, particularly foscarnet, may lower the HHV-8 infection rate.
• Screening transplant recipients for HHV-8 infection may be beneficial.
• Use of the highly active anti-HIV therapy HAART appears to reduce the risk of developing new KS significantly.

Complications

• The most common complications include secondary malignancy and secondary infections. In particular, secondary infection occurs with the KS-AIDS group of patients. A relatively common clinical concern is to distinguish KS from opportunistic infection and lymphoma.
• In patients with classic KS, lymphoma develops in approximately 35%, usually after a number of years.
• KS may produce clinical problems including edema from impaired lymphatic draining (sometimes resulting in pain), difficulty ambulating, friability of cutaneous nodules, or secondary localized skin infection.

Prognosis

• Clinical classification of KS may be the best prognosticator, comparing localized nodular disease, locally aggressive disease, and generalized KS.
• Cutaneous skin testing for anergy may correlate with clinical disease type and prognosis.
• Prognosis appears to correlate with the CD4 count.
• Localized nodular KS has the best prognosis, with few deaths directly attributable to KS.
• Locally aggressive KS has an intermediate prognosis.
• The authors do not disagree with an old African estimate of a 3-year survival rate of 64%. Generalized KS, the form seen most commonly in patients with KS-AIDS, has a 3-year survival rate closer to 0% without therapy.
• The low level of access to antiretroviral drugs in HIV-infected patients explains the morbidity and mortality from AIDS-associated KS in much of Africa, including Togo.³⁰

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to detect this systemic disorder in the at-risk population can have significant legal complications. All persons at high risk for KS should be evaluated for it periodically.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Man who is homosexual and has HIV infection and Kaposi sarcoma.
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Media file 2:  Man who is homosexual and has HIV infection and Kaposi sarcoma.
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Media file 3:  Man who is homosexual and has HIV infection and Kaposi sarcoma.
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Media file 4:  Elderly man of Mediterranean lineage with hyperkeratotic nodule of Kaposi sarcoma on sole of foot.
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Media file 5:  Man who is homosexual and has HIV infection and Kaposi sarcoma.
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Media file 6:  Man who is homosexual and has HIV infection and Kaposi sarcoma.
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Media file 7:  Man who is homosexual and has HIV infection and Kaposi sarcoma.
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Media file 8:  A 35-year-old man with dome-shaped locally aggressive tumors, an example of exophytic Kaposi sarcoma with cavernous hemangiomalike histology.
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Media file 9:  Ecchymotic Kaposi sarcoma in a man who is homosexual.
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Media file 10:  Elderly American man of Armenian origin with characteristic violaceous plaques of the legs, a good example of classic Kaposi sarcoma.
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Media file 11:  Intermediate lesion showing moderately enlarged spindle cells, some of which line poorly formed blood vessels that open into the interstitium with extravasation of erythrocytes. Erythrophagocytosis by these spindle cells is noted in places (hematoxylin and eosin, magnification X80).
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Media file 12:  Early lesion showing increased cellularity of the dermis with slightly enlarged spindle cells of focally fine stellate blood vessels that open at their corners into the interstitium (hematoxylin and eosin, magnification X40).
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Media file 13:  Keloidal Kaposi sarcoma demonstrating features both of keloids and Kaposi sarcoma (hematoxylin and eosin, magnification X80).
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Media file 14:  Oral Kaposi sarcoma.
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Media file 15:  Kaposi sarcoma of the leg.
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Media file 16:  Late lesion showing masses of moderately atypical spindle cells in a haphazard array, some of which line poorly formed blood vessels. Many of the spindle cells show erythrophagocytosis (hematoxylin and eosin, magnification X40).
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Media file 17:  Late lesion showing atypical spindle cells, some of which are lining poorly formed blood vessels, with prominent erythrophagocytosis by the cells (hematoxylin and eosin, magnification X80).
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

1. Ronchese F. Kaposi's sarcoma; an overlooked essay of 1882. AMA Arch Derm. May 1958;77(5):542-5. [Medline].
2. Schiavo AL, Ruocco V, Marino F, Ferraiolo S, Pinto F, Orlando G. Tommaso de Amicis, Augusto Ducrey, Lodovico Tommasi: three Neapolitan stars in the dermatovenereology firmament. Int J Dermatol. Jan 1996;35(1):57-62. [Medline].
3. Ascoli V, Zambon P, Manno D, Guzzinati S, Zorzi M, Arca B, et al. Variability in the incidence of classic Kaposi's sarcoma in the Veneto region, Northern Italy. Tumori. Mar-Apr 2003;89(2):122-4. [Medline].
4. Santarelli R, De Marco R, Masala MV, Angeloni A, Uccini S, Pacchiarotti R, et al. Direct correlation between human herpesvirus-8 seroprevalence and classic Kaposi's sarcoma incidence in Northern Sardinia. J Med Virol. Oct 2001;65(2):368-72. [Medline].
5. Moore PS, Chang Y. Kaposi's sarcoma-associated herpesvirus immunoevasion and tumorigenesis: two sides of the same coin?. Annu Rev Microbiol. 2003;57:609-39. [Medline].
6. Dupin N, Grange PA. Looking for the target cell of Kaposi's sarcoma-associated herpesvirus. J Invest Dermatol. Mar 2006;126(3):545-7. [Medline].
7. Onunu AN, Okoduwa C, Eze EU, Adeyekun AA, Kubeyinje EP, Schwartz RA, et al. Kaposi's sarcoma in Nigeria. Int J Dermatol. Mar 2007;46(3):264-7. [Medline].
8. Stratigos JD, Potouridou I, Katoulis AC, Hatziolou E, Christofidou E, Stratigos A, et al. Classic Kaposi's sarcoma in Greece: a clinico-epidemiological profile. Int J Dermatol. Oct 1997;36(10):735-40. [Medline].
9. Dal Maso L, Polesel J, Ascoli V, Zambon P, Budroni M, Ferretti S, et al. Classic Kaposi's sarcoma in Italy, 1985-1998. Br J Cancer. Jan 17 2005;92(1):188-93. [Medline].
10. Atzori L, Fadda D, Ferreli C, Pastorelli C, Iannelli P, Rais M, et al. Classic Kaposi's sarcoma in southern Sardinia, Italy. Br J Cancer. Oct 4 2004;91(7):1261-2. [Medline].
11. Wolf R, Brenner S, Ruocco V, Filioli FG. Isotopic response. Int J Dermatol. May 1995;34(5):341-8. [Medline].
12. Micali G, Nasca MR, De Pasquale R, Innocenzi D. Primary classic Kaposi's sarcoma of the penis: report of a case and review. J Eur Acad Dermatol Venereol. May 2003;17(3):320-3.