HIV/AIDS-related cancers

RELATED CONDITIONS: Kaposi sarcoma (KS), non-Hodgkin lymphoma, progressive multifocal leukoencephalopathy (PML), cervical cancer

DEFINITION: The immunodeficiency associated with advanced human immunodeficiency virus (HIV) infection can give rise to a variety of cancers. HIV can alter the regulation of certain types of oncogenes and is responsible for immunosuppression that increases the risk of infection by other types of viruses that may cause cancer.

The most common cancer related to HIV infection and acquired immunodeficiency syndrome (AIDS) is Kaposi sarcoma, a form of the disease that arises from cells of mucous membranes or tissues lining lymphatic vessels. Other types of cancers observed more frequently among HIV-positive individuals include progressive multifocal leukoencephalopathy (PML), non-Hodgkin lymphoma, cervical cancer, and squamous cell carcinomas. A variety of other forms of tissue-specific cancers, including those of the liver and lung, are also observed with greater frequency among patients with HIV or AIDS.

Risk factors: Intravenous drug users and those who engage in unprotected sex (especially with multiple partners) are at high risk of contracting HIV. The form of cancer that is likely to develop as a result of HIV infection is a function of the means of transmission of the virus. Kaposi is associated with transmission through sex and is found primarily in men who have had sex with men. Other forms of HIV- and AIDS-related cancers are the result of immunosuppression, in particular the reduced level of CD4+ T-lymphocyte helper cells and are not limited to those who became infected with HIV through sexual means. Prior to screening methods for HIV in blood transfusions, individuals with hemophilia were also at a higher risk for contracting HIV infection.

Etiology and the disease process: Both Kaposi sarcoma and progressive multifocal leukoencephalopathy have a viral etiology. Since Kaposi sarcoma is most common in men who have had sex with men, HIV researchers long suspected it was a sexually transmitted disease with a viral etiology. In 1994, an agent later termed human herpesvirus 8 (HHV-8) was determined as the cause of HIV-related Kaposi sarcoma. While the virus is relatively common, it replicates in the white cell population of immunosuppressed individuals, eventually triggering the development of Kaposi sarcoma. The increased diagnosis of Kaposi sarcoma in people with an immune system weakened by mechanisms other than AIDS lends support to the hypothesis.

The induction of Kaposi sarcoma in AIDS patients appears to result from an interaction between the two viruses, HIV and HHV-8. Among the gene products produced by HIV is a transactivation protein, TAT, which acts to induce endothelial cell growth. HHV-8, in turn, encodes several cytokines that likewise stimulate cell division within the skin. At the same time, angiogenesis factors induce blood vessel production within the developing tumor. The result is a substantial blood supply that produces the purplish lesions common in Kaposi sarcoma. Because Kaposi sarcoma is more common in men, hormonal factors may also play a role in the process.

Several forms of lymphomas, either non-Hodgkin lymphomas (NHL) or, less commonly, Hodgkin disease, as a group represent the second most common type of HIV- and AIDS-related cancers. Although a viral etiology is suspected for some lymphomas, including Hodgkin disease, the actual cause of these illnesses has yet to be firmly established. In some cases, the underlying cause is mutations of certain oncogenes.

Progressive multifocal leukoencephalopathy is caused by a member of the human papovavirus family, the John Cunningham (JC) virus, which many individuals carry within the central nervous system. Disease associated with the JC virus is rare, occurring almost entirely in persons with a defective immune system.

Incidence: Approximately 9 percent of persons with HIV will develop cancer during treatment. The most common form is Kaposi sarcoma, developing in some 20 percent of HIV-infected persons. Before the onset of the AIDS epidemic in the 1980s, the incidence of Kaposi sarcoma in the United States was about 0.3 per 100,000 people. The incidence peaked nationally at 8.9 per 100,000 by the end of the 1980s, as high as 32 per 100,000 in cities such as San Francisco. Kaposi sarcoma numbers decreased after the introduction of antiretroviral therapy, as well as the decrease in the number of individuals newly infected with HIV. In San Francisco, for example, the incidence of Kaposi sarcoma had dropped to 2.8 per 100,000 by 2000. The number of people affected by Kaposi sarcoma remains high in areas of the world where HIV rates remain elevated with minimal treatment options.

As with Kaposi sarcoma, the incidence of lymphomas showed a significant increase in the 1980s as a result of the AIDS epidemic. The incidence of non-Hodgkin lymphomas rose from 10.7 per 100,000 in the mid-1970s to a peak of 31.4 per 100,000 in the mid-1990s. The introduction of antiretroviral therapy, as well as a leveling and reduction in the number of new cases of HIV infection, resulted in a decline of such lymphomas to 21.6 per 100,000 by the end of the twentieth century.

About 5 percent of HIV-positive persons are estimated to develop progressive multifocal leukoencephalopathy. The actual incidence is unclear because diagnosis is often made during autopsy, resulting in a likely underreporting of the precise number. Progressive multifocal leukoencephalopathy is becoming less common due to better AIDS treatments.

Symptoms: Kaposi sarcoma, associated with HIV and AIDS, is a particularly aggressive form of the disease. A spreading purplish lesion is often the first indication of Kaposi sarcoma, mainly if the individual is HIV-positive. Lymphomas usually begin as lumps or tumors in lymph nodes, with confirmation based on biopsy. Evidence for progressive multifocal leukoencephalopathy is symptomatic, based on evidence of neurological deterioration such as mental disturbances, ataxia, and loss of speech, sight, and other senses.

Screening and diagnosis: A preliminary diagnosis of Kaposi sarcoma is most commonly based on the appearance of purplish lesions. A histological examination of material is used to confirm the diagnosis. The staging system for Kaposi sarcoma differs from that for other cancers that define a stage based on the size or metastasis of the cancer. Staging of Kaposi sarcoma attempts to take into account the extent of immunosuppression as well as the characteristics of the sarcoma by using three criteria: the size or extent of the tumor (T), the level of CD4 cells (I), and the extent of illness (S). Each category has two subgroups, defined as 0 (good risk) or 1 (poor risk).

Diagnosis of the type of non-Hodgkin lymphoma is based on identifying the “appropriate” cell from biopsy material. Based on the older Ann Arbor system, the Lugano classification system is commonly used to stage non-Hodgkin lymphoma.

Treatment and therapy: Since the development of HIV- and AIDS-related cancers is the result of the immunosuppression that follows HIV infection, any form of chemical treatment is carried out in conjunction with the reversal, even if temporary, of the immunosuppressive state. Treatment of the immunosuppressive state involves a combination of drug cocktails and highly active antiretroviral therapy (HAART) that do not cure the disease but may inhibit virus replication for varying periods.

Treatment of Kaposi sarcoma depends on the extent of the cancer, including whether metastasis has taken place. Radiation or surgery may be sufficient if the cancer is localized, such as Kaposi sarcoma localized to the skin or mouth. However, Kaposi sarcoma frequently develops at multiple sites or has already spread by diagnosis, requiring anticancer chemotherapeutic agents such as doxorubicin, daunorubicin, or paclitaxel. Among the more promising forms of chemotherapy are those that inhibit angiogenesis or the formation of blood vessels. Combinations of therapy that include drugs to enhance the immune response are also being tested.

Non-Hodgkin lymphoma treatment also depends on reducing the viral load and restoring immune function. Following HAART, radiation or chemotherapy is the preferred treatment. Other therapies have adapted forms of immunotherapy in conjunction with chemotherapy, including monoclonal antibodies.

Treatment of progressive multifocal leukoencephalopathy is problematic and historically has involved the direct infusion of drugs into the brain. However, if successful, HAART treatment frequently results in the spontaneous remission of the disease.

Prognosis, prevention, and outcomes: The prognosis for Kaposi sarcoma patients depends on the extent of the disease's spread. If the tumor is caught early and immune function has improved, the recovery rate is high. However, once the disease has spread, the chances for recovery become increasingly poor.

The likely prognosis of non-Hodgkin lymphoma is based on the International Prognostic Index, which considers factors such as age, the stage of the disease, and the extent of overall general health, including the state of immunosuppression. If all factors are optimal, especially the level of immune function, approximately 75 percent of patients survive five years or more.

The prognosis in progressive multifocal leukoencephalopathy patients remains poor. Before the development of HAART, 90 percent of patients died within three months of diagnosis. Even in the presence of therapy, the mortality rate remains approximately 60 percent within one year of diagnosis.

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