Dr. Alexandra Levine, from the University of Southern California, gave a comprehensive overview of HIV-related malignancies, including Kaposi's sarcoma, non-Hodgkin's lymphoma, and anogenital cancers.
The evidence is now quite convincing that Kaposi's sarcoma (KS) is caused by human herpesvirus-8 (HHV-8, also known as Kaposi's sarcoma associated herpesvirus, or KSHV). This virus has been found in all forms of KS, which include:
- endemic KS: the African variety, an aggressive tumor affecting individuals of all ages
- classic KS: an indolent disease affecting the lower extremities of elderly men in the Mediterranean region
- transplant-associated KS: KS resulting from immunosuppressive therapy used in transplant patients
- epidemic, or HIV-associated KS
KS is predominately a disease of HIV-infected gay and bisexual men. It is much less common among patients who acquired HIV through drug use, heterosexual contact, or transfusions. When it does occur in women, it is most common among those who acquired HIV through sex with a bisexual man. All of these epidemiologic factors point to a sexually-transmitted infectious cause of KS, and that now appears to be HHV-8. HHV-8 is found in 100% of KS tissue, but is absent in uninvolved tissue in patients with KS. It is probably necessary for the development of KS, but not sufficient. Inflammatory cytokines and angiogenesis factors, as well as the HIV tat protein, probably all play a role in the development of KS.
In the MACS cohort, the median time between HHV-8 seroconversion and the development of KS was 33 months. In U.S. blood donors, anywhere from 3 to 30% of donors test positive for HHV-8, depending on the test used. In general, the seroprevalence is low in normal controls, and increases in populations at risk. Thus, the seroprevalence is low in the United States and the United Kingdom, higher in the Mediterranean, and higher still in Africa.
HHV-8 is found in sperm, semen, B-lymphocytes, endothelial cells, saliva, nasal secretions, and respiratory fluid of patients with pulmonary KS. The mode of transmission is uncertain, but it is almost certainly transmitted sexually, perhaps more efficiently through receptive anal sex or through oral-anal contact. It is unclear whether perinatal transmission or transmission through drug use occurs.
Since HHV-8 is a herpesvirus, attention has naturally focused on whether anti-herpes drugs might have activity against it, and thereby be able to prevent or treat KS. The data are conflicting. Acyclovir has no activity, either in vitro or in vivo, against HHV-8. Foscarnet, ganciclovir, and cidofovir appear to have in vitro activity, but it is not clear whether they have activity in vivo.
Treatment option for KS depend on the site and extent of disease. In mild cutaneous disease that is not spreading rapidly it may be reasonable to do nothing other than to optimize antiretroviral therapy. If treatment of cutaneous lesions is desired for cosmetic reason, local therapy may be used. Local therapy may include laser therapy or cryotherapy with liquid nitrogen; local injections using interferon-alpha, vincristine, or vinblastine, radiation therapy; or surgical excision. When disease is more extensive, alpha-interferon (in combination with antiretroviral therapy) may be helpful, especially in patients without advanced immunosuppression (CD4 > 200). Chemotherapy is indicated in patients with pulmonary KS, rapidly progressive KS, lymphatic blockage resulting in lymphedema, or symptomatic visceral disease.
Single agent chemotherapy is now becoming the standard of care, as excellent results are seen with Doxil (liposomal doxorubicin) and DaunoXome (liposomal daunorubicin). The main side effect seen with these drugs is acute back pain during the infusion, which can be treated by stopping the infusion, hydrating the patient, and restarting it at a lower rate. Taxol is also highly effective for patients with refractory KS.
Hormonal therapies with beta-HCG (APL) shows some promise for the treatment of KS. Anti-angiogensis factors (Tecogalen, Fumagillan, AGM 470) have shown little efficacy so far. Therapies designed to blunt the cytokine cascade have also been attempted: interleukin-4 has shown little efficacy, and retinoids, which downregulate IL-6, are being studied.
HIV-related lymphoma probably results from years of antigenic stimulation and B-cell expansion. In many cases, Epstein Barr virus also plays a role in the pathogenesis of lymphoma. HIV-related lymphomas are unusual in that they are widely disseminated at the time of diagnosis and occur in unusual, extranodal sites. Systemic (body) lymphomas involve the central nervous system approximately 20% of the time, but this involvement is in the leptomeninges and should be distinguished from primary CNS lymphoma, which causes brain lesions in patients with advanced HIV disease. In the case of systemic lymphomas, CNS involvement does not adversely affect prognosis provided it is diagnosed and treated appropriately.
The treatment for systemic lymphomas is usually with low dose M-BACOD, which has been shown to be as effective as full dose chemotherapy and much less toxic. MGBG (mitoguazone, or Zyrakamine) is an investigational agent available through compassionate use programs. Other investigational therapies include monoclonal antibodies and IL-2.
Primary CNS lymphoma has a poorer prognosis than systemic lymphoma, in part because patients with CNS lymphoma almost always have advanced immunosuppression at the time of diagnosis. The treatment is usually with radiation therapy, which has minimal effect on prognosis but which generally improves quality of life and neurologic function. Patients with untreated CNS lymphoma have an average survival of approximately one month, compared to four months if radiation therapy is given. The strategy of using chemotherapy followed by radiation therapy is being studied.
Human papillomavirus (HPV) causes cervical and anal carcinoma, which are more aggressive in patients with HIV infection. Cervical cancer is now an AIDS-defining condition according the to 1993 CDC case definition for AIDS. There are numerous subtypes of HPV; those most likely to cause cancer are types 16, 18, 45, and 56. 58% of HIV-infected women are infected with HPV, 50% with high-risk subtypes. Approximately 40% have abnormal PAP smears and/or evidence of CIN (a precancerous lesion) by colposcopy. 17% of women with normal PAP smears will have high-grade cervical lesions on colposcopy.
Most low-grade CIN lesions (CIN I) regress spontaneously, but higher grade lesions (CIN II or III) may eventually progress to invasive cervical cancer. Therapy for high-grade lesions includes cryotherapy, laser therapy, cone biopsy, or loop excision; however, relapse is common.
In the MACS cohort, there have been increases in the incidence of other malignancies seen in HIV-infected individuals. These include Hodgkin's lymphoma, oropharyngeal cancer (due to HPV), seminoma, multiple myeloma, and melanoma. Other investigators have reported increases in the incidence or severity of lung cancer associated with HIV disease.