Kaposi’s Sarcoma

Basics

Kaposi’s sarcoma (KS) was originally described in 1872 by a Hungarian dermatologist named Moritz Kaposi.

Description

  • Malignant condition characterized by vascular tumors in the skin and other organs, associated with human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV)
  • An infrequent tumor of unknown cause, but with a higher impact in immunosuppressed individuals, particularly in HIV and transplant patients
  • 4 major forms are seen:
    • AIDS-related (epidemic) KS: KS is an AIDS-defining illness in HIV patients.
    • Iatrogenic/immunosuppressive KS: Most commonly organ transplant–associated
    • African (endemic) KS: Seen in equatorial Africa, especially sub-Saharan
    • Indolent (classic) KS: Rare, typically seen in older men of Mediterranean and Jewish descent
  • Systems affected: Hemolytic/Lymphatic/Immunologic; Skin/Exocrine; GI; Pulmonary
  • Synonym(s): Endotheliosarcoma; Multiple idiopathic hemorrhagic sarcoma

Epidemiology

  • Predominant age: 16–70 years; African KS predominantly affects young adults and children; classic KS typically in those aged 50–70 years; and AIDS-related KS most commonly in middle-aged adults aged 20–54 years
  • Predominant sex: Male to female ratio for epidemic KS in the US is approximately 50:1, while male to female ratio is approximately 10:1 for classic and endemic KS.
  • Among those with HIV, most common in homosexual or bisexual men

Incidence

  • The US incidence of KS after transplantation is estimated to be <1% (1).
  • Incidence of KS among HIV-seropositive individuals has decreased greatly with the advent of highly active antiretroviral therapy (HAART): 15.2/1,000 from 1992–1996 compared with 4.9/1,000 from 1997–1999 (1).
  • Approximately 2,500 cases of KS occur annually in the US

Prevalence

  • Before HAART became available, KS was >20,000 times more common in AIDS patients than in the general population and 300 times more common in an AIDS host than in other immunosuppressed hosts; with the advent of HAART, this ratio has decreased. AIDS-related KS in the US decreased 10% per year from 1990–1997 (1).
  • The seroprevalence of KSHV in the US is 1–5%; in certain parts of Africa, rates are > 70% (2,3).
  • KS previously was the most common malignancy in HIV-infected patients; some new studies have demonstrated that non-AIDS-defining malignancies may be more common in HIV-infected patients on HAART (4).
  • AIDS-related KS may occur at normal CD4 cell counts, though is more common at CD4 <200 3 cells/m.
  • In eastern and southern Africa, KS represents nearly 20% of all pediatric cancers (1); in sub-Saharan Africa, KS is also the most frequent cancer among men and the 3rd most frequent cancer among women (5).
  • Fulminant lymphadenopathic disease is a subtype of endemic KS occurring in young children with a mean age of 3 years (1).

Risk Factors

  • HIV infection
  • Living in endemic areas (e.g., Zimbabwe, Uganda)
  • Immunosuppression (e.g., immunosuppressant medications, transplantation, chemotherapy)
  • High-risk sexual practices
  • Maternal–fetal or -child transmission
  • Injection drug use
  • Exposure to infectious saliva
  • Contact with KS skin lesions
  • Blood transfusions (may transmit HHV-8)
  • HHV-8 viremia (detection of HHV-8 in peripheral blood associated with >10-fold increased risk of developing KS)
  • High antibody titers to HHV-8 related to faster development of KS

Genetics

Genetic predisposition is suggested by the occurrence of classic KS in men of Mediterranean or eastern European Ashkenazi descent, although no specific gene has been identified (1).

General Prevention

Safe sex practices, antiviral prophylaxis medication, avoid needle sharing, and careful screening of transplant organs

Pathophysiology

  • KS is a low-grade vascular tumor associated with HHV-8.
  • KS develops through incompletely understood mechanisms involving HHV-8-induced viral oncogenesis, cytokine-induced growth, and angiogenesis in a setting of immunocompromise.
  • HHV-8 may interfere with host cell apoptosis and other cellular defenses in order to promote persistent viral infection.
  • There is ongoing debate about whether KS is a clonal malignancy vs polyclonal inflammatory response that can progress to sarcoma given a certain set of host characteristics (6).
  • HIV infection may promote KS progression by inducing cytokines as well as indirectly by impairing host immunity.
  • Certain HIV gene products may play a role in promoting tumorigenesis in KS; for instance, the TAT gene may be responsible for conversion of the KS cell into a malignant phenotype (6).

Etiology

  • HHV-8 was identified as the etiologic agent in 1994; HHV-8 is necessary but not sufficient to induce KS.
  • HHV-8, immunocompromised status, and cytokine-induced growth represent preconditions for development of KS (6).
  • HHV-8 can be transmitted through blood transfusions, solid-organ transplants and possibly through saliva.
  • Recent epidemiologic data suggest that sexual transmission is not a major source of HHV-8 infection in the general population (7).

Commonly Associated Conditions

HIV infection/AIDS; Lymphoma

Malignant condition characterized by vascular tumors in the skin and other organs, associated with human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV)

Diagnosis

History

  • Elicit prognostic factors: Age at onset of KS and/or AIDS (in AIDS-related KS), immunologic status (CD4 count), occurrence of tumor before/after onset of AIDS, comorbid conditions
  • Most commonly first presents with cutaneous involvement
  • May have tumor-associated lymphedema, with lower extremity and/or facial swelling
  • GI involvement is usually clinically indolent and asymptomatic, but in some cases may present as nausea/vomiting, abdominal pain, dysphagia, or bowel obstruction.
  • Pulmonary involvement may be asymptomatic or present with symptoms such as cough, dyspnea, hemoptysis, or chest pain.

Physical Exam

  • Full physical exam, including dermatologic exam to evaluate for cutaneous involvement
  • The skin lesions characterized by:
    • Macular, papular, nodular, or plaquelike appearance
    • Can be discrete or confluent, typically in symmetric distribution
    • Variable color (can be brown, pink, red, or violaceous) and can be difficult to assess in dark-skinned individuals
    • Size varies from millimeters to several centimeters in diameter
    • Nearly all palpable and nonpruritic
    • May be located anywhere on body, but typically found on lower extremities and head/neck region, with mucous membrane involvement common

Diagnostic Tests & Interpretation

Lab

  • Serostatus can be determined with enzyme-linked immunoassay for antibody to KSHV (ELISA)
  • Viral load of KSHV can be measured with quantitative PCR testing.
  • CD4 lymphocyte count and HIV viral load determination should be performed in those with HIV infection.

Imaging

  • CXR, CT scan, or MRI (chest, abdomen) to assess organ involvement
  • Thallium or gallium scans may help to differentiate pulmonary KS from infection.

Diagnostic Procedures/Surgery

  • Biopsy of skin or lymph node
  • Bronchoscopy with biopsy of suspicious lung lesions
  • Endoscopy

Pathological Findings

  • Neovascularization with aberrant proliferation of small vessels
  • Atypical spindle-shaped cell with leukocytic infiltration
  • Angiogenesis
  • Extravasated red blood cells
  • Hemosiderin-laden macrophages

Differential Diagnosis

  • Bacillary angiomatosis
  • Granuloma faciale
  • Vascular proliferation
  • Purpuric lesions
  • Dermatofibrosarcoma protuberans

Treatment

Because the history of KS varies from patient to patient, treatment is usually based on the extent of disease, performance status, degree of immunosuppression, and comorbid medical conditions.

Medication

First Line

  • Localized therapy for limited, cutaneous disease: Radiation for individualized lesions, intralesional chemotherapy (e.g., with vinblastine), topical alitretinoin gel, cryotherapy, laser therapy, photodynamic therapy, surgical excision (1,2,8)[A]
  • Cytotoxic chemotherapy for disseminated disease: Liposomal anthracyclines (e.g., pegylatedlipo-somaldoxorubicin (PLD) (2)[A], daunorubicin); liposomal formulations offer improved outcome with less toxicity (8)[A].

Second Line

  • Cytotoxic chemotherapy: Paclitaxel (8)[A]
  • Other chemotherapy agents (use limited by side effects): Vinca alkaloids, bleomycin

Additional Treatment

General Measures

  • In AIDS-related KS, optimize control of HIV replication with HAART; HAART increases KSHV-specific immune responses and reduces the risk of progression from KSHV to Kaposi’s sarcoma by 90% (5)[A].
  • Recommendation is for viral suppression with continuous HAART rather than interrupted CD4 T-cell-guided HAART (4)[A].
  • In immunosuppressant medication–related KS, reduce dosage or stop if possible.
  • Treatment otherwise is determined by the extent and location of the disease.

Issues for Referral

  • Primary care providers should consider referral of patients with AIDS-related KS to an HIV specialist to maximize HAART.
  • Refer to oncologist, surgeon, and/or dermatologist as needed by clinical course and provider’s comfort with specific therapies.

Additional Therapies

  • Experimental therapies: Include recombinant interleukin-12, thalidomide (9)[B], imatinib, temsirolimus, intralesional human chorionic gonadotropin (hCG), vitamin D analogues, and interferon-alfa
  • Interferon-alfa is not used frequently due to poor tumor response and high toxicity compared with pegylated liposomal doxorubicin.
  • Antiviral therapy against HHV-8: Some studies show treatment benefit with foscarnet and ganciclovir; acyclovir has no activity against HHV-8 and is not recommended (10)[A].

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

  • In HIV patients with KS, other opportunistic infections must be treated aggressively.
  • Since non-AIDS-defining malignancies are becoming more common than KS in the HIV population, standard cancer preventative measures should be encouraged (4)[B].

Diet

No particular diet recommended

Patient Education

  • HIV risk prevention
  • Injection drug rehabilitation
  • Promoting adherence to HAART for patients with AIDS-related KS

Prognosis

  • AIDS-related KS tends to have aggressive clinical course; however, improved HIV treatments have resulted in enhanced survival for patients with AIDS-related KS.
  • Prognostic factors: Immunologic status as measured by CD4 count, age at onset, occurrence of tumor before/after onset of AIDS, comorbid conditions, organ involvement
  • Pulmonary involvement is a poor prognostic factor; most common cause of mortality with KS is uncontrolled pulmonary hemorrhage
  • Indolent/classic KS: 10-to 15-year survival; rarely metastasizes; most deaths due to unrelated cause
  • Endemic KS: Some subtypes can be rapidly fatal.
  • AIDS-related KS: With appropriate HAART, course typically chronic; no cure, rarely fatal
  • Iatrogenic/transplant KS: Course can be chronic or rapidly progressive, and spontaneous remission after discontinuation of immunosuppressive therapy is typical.

Complications

  • Extensive pulmonary involvement may lead to hypoxemia.
  • Extensive lymphatic involvement may lead to severe edema.
  • Pediatric intussusception can be caused by AIDS-associated Kaposi’s sarcoma (11).
  • KS may develop as an immune reconstitution inflammatory syndrome (IRIS) among HIV-seropositive individuals at the advent of HAART (12).

References

1. Hengge UR, Ruzicka T, Tyring SK, et al. Update on Kaposi’s sarcoma and other HHV8 associated diseases. Part 1: epidemiology, environmental predispositions, clinical manifestations, and therapy. Lancet Infect Dis. 2002;2:281–92.

2. Dedicoat M, Vaithilingum M, Newton R. Treatment of Kaposi’s sarcoma in HIV-1 infected individuals with emphasis on resource-poor settings. Cochrane Database Sys Rev. 2003;3:CD003256, DOI, 1002/14651858.CD003256.

3. Kaplan JE, Benson C, Holmes KK, et al. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and children. MMWR Recomm Rev. 2009;58:1–198.

4. Silverberg MJ, Neuhaus J, Bower M, et al. Risk of cancers during interrupted antiretroviral therapy in the SMART study. AIDS. 2007;21:1957–63.

5. Sullivan SG, Hirsch HH, Franceschi S, Steffen I, Amari EB, Mueller NJ, Magkouras I, Biggar RJ, Rickenbach M, Clifford GM, the Swiss HIV Cohort Study et al. Kaposi sarcoma herpes virus antibody response and viremia following highly active antiretroviral therapy in the Swiss HIV Cohort study. AIDS. 2010;24(14):2245–52.

6. Hengge UR, Ruzicka T, Tyring SK, et al. Update on Kaposi’s sarcoma and other HHV8 associated diseases. Part 2: pathogenesis, Castleman’s disease, and pleural effusion lymphoma. Lancet Infect Dis. 2002;2:344–52.

7. de Sanjose S, Mbisa G, Perez-Alvarez S, et al. Geographic Variation in the Prevalence of Kaposi Sarcoma-Associated Herpesvirus and Risk Factors for Transmission. J Infect Dis. 2009;199:1449–56.

8. Di Lorenzo G, Konstantinopoulos PA, Pantanowitz L, et al. Management of AIDS-related Kaposi’s sarcoma. Lancet Oncol. 2007;8:167–76.

9. Chen M, Doherty SD, Hsu S, et al. Innovative uses of thalidomide. Dermatol Clin. 2010;28:577–86.

10. Glesby MJ, Hoover DR, Weng S, et al. Use of antiherpes drugs and the risk of Kaposi’s sarcoma: data from the Multicenter AIDS Cohort Study. J Infect Dis. 1996;173(6):1477–80.

11. Ramdial PK, Sing Y, Hadley GP, Chotey NA, Mahlakwane MS, Singh B, et al. Paediatric intussusception caused by acquired immunodeficiency syndrome-associated Kaposi sarcoma. Pediatric Surg Int. 2010;26(8):783–7.

12. Feller L, Lemmer J. Insights into pathogenic events of HIV-associated Kaposi sarcoma and immune reconstitution syndrome related Kaposi sarcoma. Infect Agent Cancer. 2008;3:1.

Codes

ICD9

  • 176.0 Kaposi’s sarcoma, skin
  • 176.1 Kaposi’s sarcoma, soft tissue
  • 176.2 Kaposi’s sarcoma, palate
  • 176.3 Kaposi’s sarcoma, gastrointestinal sites
  • 176.4 Kaposi’s sarcoma, lung
  • 176.5 Kaposi’s sarcoma, lymph nodes
  • 176.8 Kaposi’s sarcoma, other specified sites
  • 176.9 Kaposi’s sarcoma, unspecified site
  • 042 Human immunodeficiency virus (hiv) disease

Snomed

  • 109385007 Kaposi’s sarcoma (disorder)
  • 109386008 Kaposi’s sarcoma of skin (disorder)
  • 188029000 Kaposi’s sarcoma of soft tissue (disorder)
  • 109388009 Kaposi’s sarcoma of palate (disorder)
  • 109389001 Kaposi’s sarcoma of gastrointestinal tract (disorder)
  • 109390005 Kaposi’s sarcoma of lung (disorder)
  • 109391009 Kaposi’s sarcoma of lymph nodes (disorder)
  • 86406008 human immunodeficiency virus infection (disorder)

Clinical Pearls

  • HHV-8 (also known as KSHV) is the etiologic agent for KS.
  • HHV-8, immunocompromise, and cytokine-induced growth represent preconditions for the development of KS.
  • Incidence of AIDS-related KS has decreased greatly with the advent of HAART.
  • AIDS-related KS can occur at normal CD4 counts.
  • Staging for KS is usually based on the system of the AIDS Clinical Trial Group (ACTG), consisting of extent of tumor (T), immune status (I), and severity of systemic illness (S).
  • Cytotoxic chemotherapy is the gold standard for treatment of disseminated disease, although new experimental therapies are under development.

Jean-Paul Marat

Many tips are based on recent research, while others were known in ancient times. But they have all been proven to be effective. So keep this website close at hand and make the advice it offers a part of your daily life.

Leave a Reply