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A. Introduction navigator

  1. Indolent sarcoma due to herpes-like virus infection of endothelial cells
  2. Types
    1. Classic - usually affects elderly men of Eastern European and Medierranean Origin
    2. Endemic - usually found in portions of Africa
    3. Immunocompromise Associated KS - HIV, transplantation (most common)
  3. Association with HIV Infection
    1. Highest rates in homosexuals (HIV positive and negative)
    2. Most common neoplasm in patients with AIDS
    3. Rates are also increased in IV drug abusers with HIV
    4. Hemophiliacs with HIV have lower risk of developing KS than other HIV+ persons
    5. Prior to HIV epidemic, extremely rare cancer
    6. HHV-8 is an etiologic agent for KS
  4. Other Immunocompromised Patients
    1. Hodgkin's Disease
    2. Iatrogenic Immunosuppression - usually for transplantation [16], autoimmune disease
    3. d, Neutropenic patients also at risk

B. Pathogenesis [2] navigator

  1. Caused by a human herpesvirus
    1. This virus is called HHV-8 or Kasposi Sarcoma Associated Herpesvirus (KSHV)
    2. Asymptomatic carrier state in many people
    3. Virus causes disease typically in immunocompromised hosts
    4. Antibodies to Human Herpesvirus 8 (HHV-8) are found in >90% of KS patients [13]
    5. HHV-8 has now been propagated from KS cells in vitro [8]
  2. Herpesvirus-like DNA sequences are present in HIV and non-HIV patients with KS
    1. The specific DNA sequences are found in >95% of biopsied lesions in KS patients
    2. Similar sequences are also found in unusual lymphomas from AIDS patients [3]
    3. These were body cavity based lymphomas with effusions
    4. Average levels of HHV-8 are higher in HIV+ than in HIV- persons [13]
  3. Transmission in Relation to KS [6]
    1. Primarily male homosexual transmission through receptive anal intercourse [11]
    2. However, antibodies also found in sexually inactive children
    3. Very low risk of parenteral transmission
    4. Average HIV+ patient seropositive for HHV-8 develops KS within 33 months [5]
    5. Among men with HIV and HHV-8, 10 year probability of KS was ~50% [11]
    6. Women have much reduced seropositivity than men, consistent with KS incidence [9]
  4. HHV-8 (KSHV) [1]
    1. Genome is 165kb and has been completely sequenced
    2. HHV-8 has clearly incorporated several human genes into its genome
    3. These genes include a cyclin, bcl-2 like protein, inhibitor of apoptosis, G-protein coupled receptor, immunoreceptor, IL-6 homolog, inhibitor of interferon signalling
    4. The viral cyclin inhibits the retinoblastoma protein (Rb)
    5. The major latency-associated nuclear antigen of HHV-8 binds to and blocks p53 protein
    6. Viral IL-6 induces B-cell proliferation (only expressed in infected B cells)
    7. Viral chemokines appear to activate angiogenesis and inhibit type 1 T cell responses
    8. The HHV-8 viral interferon regulatory factor blocks interferon from repressing c-myc
    9. Thus, all major cell cycle checkpoint control pathways are altered in HHV-8 infection
  5. Other Viruses in KS Patients
    1. Human Herpesvirus 6 - 34% of KS patients are positive for antibodies
    2. CMV, HPV16, and Mycoplasma penetrans antibodies also found in ~30% of KS patients
    3. KS lesions may also have Epstein-Barr virus DNA in their genomes
  6. DNA sequences from HHV-8 virus are found in healthy adults [4]
    1. Mainly found in healthy men's prostate tissue (44%) and ejaculate (91%)
    2. Isolated from <10% of peripheral blood, and in <10% of female genital tracts
  7. Multicentric tumors are likely derived from monoclonal precursors [10]

C. Presentationnavigator

  1. Skin
    1. Painless, pigmented nodules, non-blanching
    2. Usually occur on lower extremities
    3. Pain occurs when lesions ulcerate
  2. Gastrointestinal Tract
    1. Usually found in stomach and/or duodenum
    2. Generally asymptomatic
  3. Pulmonary
    1. Very serious, often causing death
    2. Diffuse infiltrates are usually found
  4. Oral Cavity - usually asymptomatic
  5. Lymphatic System - LN enlargement, lymphedema

D. Treatmentnavigator

  1. Classic KS
    1. Disease is usually multifocal and lesions often recur after treatment
    2. Single lesions can be removed by excision or by radiation treatment
    3. Observation is appropriate for immunocompetent patients with little progression
    4. Systemic or combination therapy for patients with progressive, multifocal disease
  2. Radiation Therapy
    1. Most effective treatment of single lesions
    2. Also may be used for sites of lymph node obstruction
  3. Interferon (IFN) alpha [14,15]
    1. Systemic administration (3 MU 5X per week) can lead to regression of lesions
    2. For immunosuppressed patients, 50 MU IFNa IV daily 5X per week very effective
    3. Intralesional injection 1-3 MU IFNa2b has few or no systemic side effects
    4. Likely has antiviral effect on HHV-8
    5. Addition of antiretroviral therapy to IFNa may be beneficial
  4. Chemotherapy
    1. Single Agent - vinblastine, vincristine, liposomal daunorubicin (DaunoXome®), liposomal doxorubicin (Doxil®)
    2. Combination - bleomycin (or dactinomycin) + vinblastine (or vincristine)
    3. Remissions usually occur but cures are exceedingly rare
    4. Caution with chemotherapy in patients with immunosuppression
    5. In these patients, liposomal doxorubicin (± PEG conjugation) is typically first line
    6. Paclitaxel (Taxol®) is an excellent second line agent
  5. Human Chorionic Gonadotropin [7]
    1. HCG inhibits growth of KS cells in vitro and in nude mice
    2. Intralesional injections of HCG thrice weekly (tiw) x 2 weeks was tested [7]
    3. Dose response obtained, and 80% of KS injected with 2000 IU tiw had marked response
    4. Tumors apparently underwent apoptosis after HCG injection
    5. Attempts to repeat results have met with varied outcomes, however
  6. KS in Renal Transplant [16]
    1. Associated with cyclosporine immunosuppression
    2. Sirolimus (rapamycin) has antitumor effects against KS
    3. Sirolimus can replace CsA in patients with Kaposi's sarcoma (KS) and renal transplant leading to regression of KS and maintenance of graft function
  7. Prevention of KS
    1. Drugs with activity against HHV-8 have shown promise
    2. Ganciclovir, foscarnet and cidofovir all have in vitro activity against HHV-8
    3. Oral or IV ganciclovir reduces risk of KS in HIV+ persons >75% [12]
    4. IFNa has not been very effective in preventing KS

References navigator

  1. Antman K and Chang Y. 2000. NEJM. 342(14):1027 abstract
  2. Schultz TF, Boshoff CH, Weiss RA. 1996. Lancet. 348:587 abstract
  3. Cesarman E, Chang Y, Moore PS, et al. 1995. NEJM. 332(18):1186 abstract
  4. Monini P, de Lellis L, Fabris M, et al. 1996. NEJM. 334(18):1168 abstract
  5. Gao SJ, Kingsley L, Hoover DR, et al. 1996. NEJM. 335(4):233 abstract
  6. Lennette ET, Blackbourn DJ, Levy JA. 1996. Lancet. 348:858 abstract
  7. Gill PS, Lunardi-Iskandar Y, Louie S, et al. 1996. NEJM. 335(17):1261 abstract
  8. Foreman KE, Friborg J, Kong WP, et al. 1997. NEJM. 336(3):163 abstract
  9. Kedes DH, Ganem D, Ameli N, et al. 1997. JAMA. 277(6):478 abstract
  10. Rabkin CS, Janz S, Lash A, et al. 1997. NEJM. 336(14):988 abstract
  11. Martin JN, Ganem DE, Osmond DH, et al. 1998. NEJM. 338(14):948 abstract
  12. Martin DF, Kuppermann BD, Wolitz RA, et al. 1999. NEJM. 340(14):1063 abstract
  13. Sitas F, Carrara H, Beral V, et al. 1999. NEJM. 340(24):1863 abstract
  14. de Wit R, Schattenkerk JK, Boucher CA, et al. 1988. Lancet. 2(8622):1214 abstract
  15. Lane HC, Kovacs JA, Feinberg J, et al. 1988. Lancet. 2(8622):1218 abstract
  16. Stallone G, Schena A, Infante B, et al. 2005. NEJM. 352(13):1317 abstract