Review
Update on Kaposi's sarcoma and other HHV8 associated diseases. Part 1: epidemiology, environmental predispositions, clinical manifestations, and therapy

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Summary

Kaposi's sarcoma (KS) is a mesenchymal tumour involving blood and lymphatic vessels. Only recently has the pathogenesis of this extraordinary neoplasm been elucidated. Viral oncogenesis and cytokine-induced growth together with some state of immunocompromise represent important conditions for this tumour to develop. In 1994, a novel virus was discovered and termed human herpesvirus 8 (HHV8), also known as Kaposi's sarcoma-associated herpes virus, which can be found in all types of KS, whether related to HIV or not. In the era of highly active antiretroviral therapy (HAART), the incidence of AIDS-KS has considerably declined, probably due to enhanced immune reconstitution and anti-HHV8-specific immune responses. If HAART is able to prevent spreading of KS, local therapy of KS may become an essential component of patient management. Part 1 of the review covers the epidemiology, environmental predispositions, clinical manifestations, and therapy of KS. Newer treatments such as pegylated liposomal anthracyclines and experimental strategies are discussed. We also present rationales and graduated treatment algorithms for local and systemic therapy in patients with KS to appropriately meet the challenges of this extraordinary neoplasm. Part 2, to be published next month, will summarise recent insights in the pathogenesis of KS and will discuss other HHV8-related diseases such as Castleman's disease and primary effusion lymphoma.

Section snippets

Transmission of HHV8

The modes of transmission of HHV8 are yet to be fully elucidated. In the USA, sex between men may be an important route of transmission,1 but in the South African population, the correlation with increasing numbers of heterosexual partners is not great.2 However, throughout sub-Saharan Africa, where KS was seen in children even before the advent of AIDS, other routes of transmission must occur. The presence of HHV8 antibodies in infants suggests the transmission of HHV8 from mother-to-child.3

Clinical manifestation

Several different manifestations of KS can be distinguished (figure 2). In the following section they will be discussed.

Classic KS

Classic KS was described in 1872 by the Hungarian Moriz Kaposi as “sarcoma idiopaticum multiplex hemorrhagicum”, who presented the case histories of five elderly men with skin lesions.40

Classic KS is primarily a skin disease affecting elderly men (male/female-ratio 10–15/1) of Mediterranean, east European, or Jewish heritage with a peak incidence after the 6th decade of life. Classic KS appears as multiple firm, purple-reddish-brown plaques and nodules on the lower extremities. Classic KS has a

Endemic African KS

In the early 1960s, an unusually high prevalence of up to 12·8% KS was noted in localised geographic areas throughout sub-Saharan Africa.20, 35 Endemic African KS presents in one of four clinically distinct patterns: (1) benign nodular cutaneous disease mimicking classic KS, predominantly in young adults (mean age 35 years, male/female-ratio 13–17/1); (2) aggressive localised cutaneous disease invading soft tissue and bone, which is usually fatal within 5–7 years; (3) florid mucocutaneous and

Iatrogenic, immunosuppressive KS

KS has also been described in iatrogenic immunosuppressed organ transplant recipients and in a wide spectrum of patients receiving chronic immunosuppressive therapy.47 It occurs most frequently in organ-transplant recipients of certain ethnic groups accounting for 0·5–0·6%, an average of 16·5 months after transplantation.48 Although the course may be chronic or rapidly progressive, spontaneous remission after discontinuation of immunosuppressive therapy is the norm.49

That HHV8 seems to be

AIDS-KS

By 1989, 15% of all reported AIDS cases in US residents had KS as the primary AIDS-defining illness.51 The overall risk of KS in AIDS patients was estimated to be more than 20 000-times greater than that of the general population and 300-times that of other immunosuppressed patients.51 In addition, striking differences in risk for acquiring AIDS-KS exist between different HIV transmission groups, varying from as high as 21% for homosexual men to as low as 1% for men with haemophilia.51, 52

Organ manifestations

Though its dermatological manifestations can be alarming, the involvement of visceral organs is more commonly life-threatening. AIDS-KS causes significant morbidity with organ dysfunction such as lymphatic obstruction or rapidly progressive pulmonary failure. Other organs such as the pharynx, heart, bone marrow, urogenital tract (prostate, testis, bladder, and penis), kidney and penile glans are less commonly affected. Brain and intraocular lesions are extremely rare, which is probably due to

Mucocutaneous involvement

Initial clinical presentations at mucocutaneous surfaces begin typically as macular and papular lesions that progress to plaque-like or nodular tumours (figure 3). Lesions vary in size and shape and are generally non-pruritic and painless. The colours of the lesions range from pink to deep purple and appear brownish in classic KS. While lesions can be found on any body surface they seem to have a predilection for the upper body, head, and neck areas in AIDS-KS. Classic and iatrogenic KS most

Visceral involvement

Visceral involvement is common in AIDS-KS but is often symptomless (figure 4). Post-mortem studies suggest that more than 25% of patients with AIDS-KS also have visceral lesions. They most commonly involve the stomach, bowel, liver, spleen, and lungs. Gastric outlet obstruction, enteropathy with small bowel involvement, and occasionally bleeding of ulcerated KS lesions have been reported. Gastrointestinal KS has a typical red, raised appearance and is difficult to diagnose by biopsy because of

Histology

Multicentric neoformation of atypical lymphatics represents the primary process in histogenesis of KS. Important cell interactions are presumed to occur between fibroblasts, monocytes and endothelial cells. The remarkable symmetry of lesions and the concept of multicentric origin of KS fit well with this hypothesis.

Patch-stage KS, the earliest pattern, typically arises in the reticular dermis as a clinically macular lesion. A proliferation of small, irregular and jagged endothelium-lined spaces

Disease management

Care for patients with KS must take into account the type of KS, the extent of the tumour and the organs involved, but also its potential effect on the patient's overall clinical condition and virological, immune, and haematological status. A recent review of four available staging systems for epidemic KS confirmed the importance of CD4 cell numbers and other HIV-related prognostic factors for predicting survival in KS patients.74 The AIDS Clinical Trials Group (ACTG) classification provides a

Local therapy

Several different treatment modalities are available for local therapy of KS (panel). They generally induce a mild inflammatory response leading to tumour flattening or disappearance. However, recurrences are frequent.

Systemic therapy

For patients with more widely disseminated, progressive or symptomatic disease, systemic therapy with cytotoxic chemotherapy or interferon-α is generally warranted (figure 7). As a general rule, the same treatment modalities apply to all different forms of KS, while response rates and their duration may vary.

Thalidomide

Thalidomide has antiangiogenic activity independent of its inhibitory effect on TNFα (panel).127, 128 Thalidomide (100 mg per day for 8 weeks) was shown to have clinical activity (partial response in 35%) in a phase II study with 17 KS patients on antiretroviral therapy. In addition, thalidomide was found to decrease the HHV8 DNA load by at least three logs in three of five virologically assessable partial responders.129 Preliminary results of two additional studies with thalidomide at doses of

Search strategy and selection criteria

Searching for relevant articles was done in PubMed with “HHV-8”, “KSHV”, and “Kaposi's sarcoma” as keywords. Publications in English were selected. Case reports were considered only if there was no larger study available. Selected previous reviews are included to give readers a more systematic overview.

References (140)

  • SilvermanS et al.

    Oral findings in people with or at high risk for AIDS: a study of 375 homosexual males

    J Am Dent Assoc

    (1986)
  • RL Modlin et al.

    Kaposi's sarcoma in homosexual men: an immunohistochemical study

    J Am Acad Dermatol

    (1983)
  • LC Meade-Tollin et al.

    Expression of multiple matrix metalloproteinases and urokinase type plasminogen activator in cultured Kaposi sarcoma cells

    Acta Histochem

    (1999)
  • DM Aboulafia

    Regression of acquired immunodeficiency syndrome-related pulmonary Kaposi's sarcoma after highly active antiretroviral therapy

    Mayo Clin Proc

    (1998)
  • AM Levine et al.

    Clinical aspects and management of AIDS-related Kaposi's sarcoma

    Eur J Cancer

    (2001)
  • AM Berson et al.

    Radiation therapy for AIDS-related Kaposi's sarcoma

    Int J Radiat Oncol Biol Phys

    (1990)
  • de WitR et al.

    Palliative radiation therapy for AIDS-associated Kaposi's sarcoma by using a single fraction of 800 cGy

    Radiother Oncol

    (1990)
  • KJ Stelzer et al.

    A randomized prospective trial of radiation therapy for AIDS-associated Kaposi's sarcoma

    Int J Radiat Oncol Biol Phys

    (1993)
  • MD Evans et al.

    Surface applicators for high dose rate brachytherapy in AIDS-related Kaposi's sarcoma

    Int J Radiat Oncol Biol Phys

    (1997)
  • EB Watkins et al.

    Enhanced mucosal reactions in AIDS patients receiving oropharyngeal irradiation

    Int J Radiat Oncol Biol Phys

    (1987)
  • JN Martin et al.

    Sexual transmission and the natural history of human herpesvirus 8 infection

    N Engl J Med

    (1998)
  • F Sitas et al.

    Antibodies against human herpesvirus 8 in black South African patients with cancer

    N Engl J Med

    (1999)
  • D Bourboulia et al.

    Serologic evidence for mother-to-child transmission of Kaposi sarcoma-associated herpesvirus infection

    JAMA

    (1998)
  • M Andreoni et al.

    Primary human herpesvirus 8 infection in immunocompetent children

    JAMA

    (2002)
  • L Strichman-Almashanu et al.

    No significant association between HLA antigens and classic Kaposi sarcoma: molecular analysis of 49 Jewish patients

    J Clin Immunol

    (1995)
  • PJ Veugelers et al.

    Associations of age, immunosuppression, and AIDS among homosexual men in the Tricontinental Seroconverter Study

    J Acquir Immune Defic Syndr Hum Retrovirol

    (1997)
  • AR Lifson et al.

    Kaposi's sarcoma in a cohort of homosexual and bisexual men. Epidemiology and analysis for cofactors

    Am J Epidemiol

    (1990)
  • DR Hoover et al.

    Epidemiologic analysis of Kaposi's sarcoma as an early and later AIDS outcome in homosexual men

    Am J Epidemiol

    (1993)
  • CS Rabkin et al.

    Kaposi's sarcoma in three HIV-1-infected cohorts

    J Acquir Immune Defic Syndr

    (1990)
  • Y Lunardi-Iskandar et al.

    Tumorigenesis and metastasis of neoplastic Kaposi's sarcoma cell line in immunodeficient mice blocked by a human pregnancy hormone

    Nature

    (1995)
  • PS Gill et al.

    The effects of preparations of human chorionic gonadotropin on AIDS-related Kaposi's sarcoma

    N Engl J Med

    (1996)
  • Z Darzynkiewicz

    The butler did it: search for killer(s) of Kaposi's sarcoma cells in preparations of human chorionic gonadotropin

    J Natl Cancer Inst

    (1999)
  • M Montella et al.

    Is volcanic soil a cofactor for classic Kaposi's sarcoma?

    Eur J Epidemiol

    (2000)
  • M Luppi et al.

    Bone marrow failure associated with human herpesvirus 8 infection after transplantation

    N Engl J Med

    (2000)
  • E Oksenhendler et al.

    Transient angiolymphoid hyperplasia and Kaposi's sarcoma after primary infection with human herpesvirus 8 in a patient with human immunodeficiency virus infection

    N Engl J Med

    (1998)
  • JL Ziegler et al.

    Kaposi's sarcoma in childhood: an analysis of 100 cases from Uganda and relationship to HIV infection

    Int J Cancer

    (1996)
  • HR Wabinga et al.

    Cancer in Kampala, Uganda, in 1989–91: changes in incidence in the era of AIDS

    Int J Cancer

    (1993)
  • F Sitas et al.

    Kaposi's sarcoma in South Africa

    J Natl Cancer Inst

    (2001)
  • SF Purvis et al.

    High incidence of Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus in tumor lesions and peripheral blood mononuclear cells from patients with Kaposi's sarcoma in Uganda

    J Infect Dis

    (1997)
  • G Boivin et al.

    Evaluation of the human herpes virus 8 DNA load in blood and Kaposi's sarcoma skin lesions from AIDS patients on highly active antiretroviral therapy

    AIDS

    (2000)
  • DH Kedes et al.

    The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission

    Nat Med

    (1996)
  • SJ Gao et al.

    Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma

    N Engl J Med

    (1996)
  • N Renwick et al.

    Seroconversion for human herpesvirus 8 during HIV infection is highly predictive of Kaposi's sarcoma

    AIDS

    (1998)
  • M Melbye et al.

    Risk factors for Kaposi's-sarcoma-associated herpesvirus (KSHV/HHV8) seropositivity in a cohort of homosexual men, 1981–1996

    Int J Cancer

    (1998)
  • TR O'Brien et al.

    Evidence for concurrent epidemics of human herpesvirus 8 and human immunodeficiency virus type 1 in US homosexual men: rates, risk factors, and relationship to Kaposi's sarcoma

    J Infect Dis

    (1999)
  • DH Osmond et al.

    Prevalence of Kaposi sarcoma-associated herpesvirus infection in homosexual men at beginning of and during the HIV epidemic

    JAMA

    (2002)
  • JL Jones et al.

    Effect of antiretroviral therapy on recent trends in selected cancers among HIV-infected persons. Adult/Adolescent Spectrum of HIV Disease Project Group

    J Acquir Immune Defic Syndr

    (1999)
  • I Chitsike et al.

    Seroprevalence of human immunodeficiency virus type 1 infection in childhood malignancy in Zimbabwe

    Cent Afr J Med

    (1998)
  • HR Wabinga et al.

    Trends in cancer incidence in Kyadondo County, Uganda, 1960–1997

    Br J Cancer

    (2000)
  • P Cook-Mozaffari et al.

    The geographical distribution of Kaposi's sarcoma and of lymphomas in Africa before the AIDS epidemic

    Br J Cancer

    (1998)

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