The association between HIV infection and the development of cancer was noted early in the acquired immunodeficiency syndrome (AIDS) epidemic. The AIDS-defining malignancies are Kaposi’s sarcoma, intermediate- or high-grade B-cell non-Hodgkin’s lymphoma (NHL), and cervical cancer. All of these cancers feature specific infectious agents in their etiology. These agents are human herpesvirus 8/Kaposi’s sarcoma-associated herpesvirus, or HHV-8/KSHV (implicated in Kaposi’s sarcoma), Epstein-Barr virus, or EBV (in primary central nervous system lymphoma and a subset of systemic B-cell NHL) and human papillomavirus, or HPV (in cervical cancer).[1]
The Effect of HAART
Although the types of related cancers have not substantially changed since the beginning of the AIDS epidemic, the incidence of certain cancers has markedly changed with the use of highly active antiretroviral therapy (HAART). Populations with access to HAART have shown a substantially reduced incidence of Kaposi’s sarcoma and primary central nervous system lymphoma and a much smaller decrease in other types of NHL.[2] However, long-term cancer risks are as yet unknown. Kaposi’s sarcoma remains the most commonly diagnosed AIDS-related cancer.[3] NHL, a late and frequently systemic complication of AIDS, occurs in approximately 5% of cases.[4]
The non-AIDS-defining tumors with particular relevance for the human immunodeficiency virus (HIV) population include invasive anal cancer and the preneoplastic lesions in the anus and cervix. These tumors and lesions are also etiologically associated with HPV. The relative risk of invasive anal cancer in HIV-positive men and women is 37.9 and 6.8, respectively.[5] The incidence of high-grade squamous intraepithelial (anogenital or cervical) lesions and invasive cancer is higher in HIV-positive/HPV-positive individuals than in the HIV-negative/HPV-positive population. In addition, there is an increased risk of progression from low-grade to high-grade lesions,[6] and HAART has shown little effect on the natural history of these lesions in some studies.[7,8]
The longer life expectancy of HIV-positive individuals with access to HAART may increase their cumulative risk of developing cancer. In this context, we may see an increase in incidence of the following: (1) non-AIDS-defining cancers including Hodgkin’s disease and lung cancer (Hodgkin’s disease is currently the most frequently diagnosed non-AIDS-defining cancer that is clearly related to immunosuppression)[9,5]; (2) progression of high-grade squamous intraepithelial lesions to cancer; (3) T-cell NHL[10]; and (4) possibly a resurgence of Kaposi’s sarcoma. Advances in the understanding of the pathogenesis of AIDS malignancies have allowed the development of targeted treatment strategies. This, coupled with the decreased morbidity from cancer therapies in HAART-treated HIV-positive patients, provides the opportunity for more targeted or more aggressive regimens that have the potential to lengthen the patient’s survival.
Treatments of AIDS malignancies have followed conventional cytotoxic chemotherapy approaches and also newer, targeted approaches aimed at intervening in critical pathogenic pathways. The following examples are given for Kaposi’s sarcoma, NHL, and the anogenital dysplasias.
AIDS-Related Kaposi’s Sarcoma
AIDS-related Kaposi’s sarcoma is a tumor of the vascular endothelium that may present with cutaneous lesions, either with or without visceral organ involvement, or with lymphadenopathy. The etiology of the disease includes an intricate relationship between HHV-8/KSHV, aberrant cytokine production, angiogenic factors, and immune dysregulation. Multiple treatment options aimed at each of the players in the pathogenesis of Kaposi’ sarcoma are available.[11,12] Local therapies include cryotherapy, laser therapy, local radiation, intralesional injection of chemotherapy, topical alitretinoin gel, and surgical excision. However, because Kaposi’s sarcoma is a systemic disease, recurrence is common with local therapy.
Disseminated disease is treated with systemic agents, either with drugs or biologic agents, such as the vinca alkaloids, liposomal anthracyclines, paclitaxel(Drug information on paclitaxel), and interferon-alpha. Therapeutic approaches that target pathogenic pathways have shifted the focus to include: (1) the antiangiogenesis compounds thalidomide(Drug information on thalidomide) (Thalomid), COL-3, and IM862; (2) retinoids that inhibit interleukin (IL)-6, a cytokine involved in tumor growth of Kaposi’s sarcoma; and (3) IL-12, which has immunomodulatory, antiviral, and antiangiogenic effects. Another intriguing but as yet untested possibility is the use of antiviral agents to inhibit HHV-8/KSHV gene expression.
Systemic AIDS-NHL
Systemic AIDS-NHL is a histologically heterogeneous group of malignancies normally of B-cell phenotype, although cases of T-cell AIDS-NHL have been described.[9,10] Chronic B-cell stimulation from HIV infection, increased expression of cytokines involved in B-cell proliferation, and expression of certain EBV genes are involved in various aspects of the pathogenesis of NHL. Standard treatment regimens include cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar), doxorubicin(Drug information on doxorubicin) HCl, vincristine (Oncovin), and prednisone(Drug information on prednisone) (CHOP), and variations of CHOP with infusion regimens such as cyclophosphamide, doxorubicin, and etoposide(Drug information on etoposide) (CDE) and etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) with some studies reporting response rates above 70%.[13,9] However, the relapse rate is high with most of the bolus CHOP regimens, and overall survival rates are not clearly improved.
Cytotoxic regimens can be combined with immune system modulators such as IL-2 or IL-12, or with monoclonal antibodies against malignant cell targets such as anti-CD20.[14] Other interesting approaches include stem cell transplantation to both restore immune function and treat lymphoma via a graft-vs-lymphoma effect[15], or generation of cytotoxic T lymphocytes against EBV genes expressed in NHL.[16]
Anal and Cervical Cancer
Anal and cervical cancers are thought to arise from the progression of squamous intraepithelial lesions to invasive tumors. Progression correlates with persistence of high-risk HPV genotypes. HPV oncogenes E6 and E7 bind to and inactivate the key cell-cycle regulatory proteins p53 and Rb, resulting in dysregulated cellular proliferation and transformation.[17] However, a fully malignant phenotype occurs only in a subset of chronically infected cells, presumably resulting from an accumulation of additional mutations.[18] Treatment of HPV-related lesions might include surgical removal or local destruction.[19] However, surgery for anal high-grade intraepithelial lesions is not as successful as that for cervical high-grade squamous intraepithelial lesions.
The induction of a cell-mediated response to human papillomavirus type 16 (HPV16), specifically to the viral protein E7, appears to be protective against cervical intraepithelial neoplasia (CIN).[20] Thus, vaccines designed to elicit cell-mediated immunity to E6 and E7 may be a basis for immunotherapy of HPV-related cancers.[21] The AIDS Malignancy Consortium (described below) is currently developing a trial to treat anal intraepithelial neoplasia using a therapeutic vaccine designed to elicit a humoral and cellular response to E7-expressing cells in the anal lesion.
A 70-year-old man with a history of localized prostate cancer treated with whole-pelvis radiation therapy with a boost to the prostate, in conjunction with androgen deprivation therapy 7 years prior, presented with lower back pain. A bone scan revealed an area of activity in the sacrum. What is the most likely diagnosis?
