HIV Curriculum for the Health Professional HIV-Associated Malignancies Parth S. Mehta, M.D. Objectives for Disease Control and Prevention (CDC) described a clustering of cases of Kaposi sarcoma (KS), until then 1. Describe the types of malignancies commonly a rare form of cancer, among homosexual men in New found in children and adolescents with human York and California. The following year, the CDC reported immunodeficiency virus (HIV)/AIDS. a clustering of cases of gay men in San Francisco with 2. Present an overview of the following HIV- diffuse, undifferentiated non-Hodgkin’s lymphoma associated pediatric and adolescent cancers: non- (NHL), another rare cancer. In time, it became apparent Hodgkin’s lymphoma (NHL), Kaposi sarcoma that these unusual forms of cancer were appearing as a (KS), leiomyosarcoma, cervical carcinoma, and result of infection with HIV. However, this association anal cancer. would not be limited to these two forms of malignancy. 3. Discuss the clinical manifestations and treatment Many other neoplastic disorders, most notably of the various HIV-associated malignancies. primary central nervous system (CNS) lymphoma, 4. Discuss the specific supportive-care measures leiomyosarcoma, anal cancer, and cervical cancer, have necessary for children receiving chemotherapy also been linked to HIV infection. and radiation therapy. This module will discuss the relationship between HIV Key Points and malignancy, with special attention to the tumors 1. Children with HIV infection are at increased risk most commonly seen in the pediatric and adolescent of developing malignancies as a result of the populations. An overview of the epidemiology of HIV- dysregulated immune system and the interplay of related malignancy will be followed by discussions of the other oncogenic viruses. pathogenesis, clinical manifestations, and treatment of 2. The most common malignancies found in each cancer. children with HIV/AIDS are NHL, KS, and leiomyosarcoma. Epidemiology and Pathogenesis 3. Treatment for HIV-associated malignancies Malignancy occurs much more commonly in HIV-infected may be complicated by HIV-associated organ children than in uninfected children. HIV-infected dysfunction, infectious complications, and children are at about a 40 times higher risk of developing drug interactions between chemotherapy malignancy than the general population. Among HIV- and antiretroviral drugs as well as combined infected children in the United States, the incidence immunosuppression between HIV infection and of malignancy is about one case per 1,000 children per chemotherapy. year. In contrast, the incidence of cancer among all U.S. 4. Treatment of HIV infection with highly active children is about one to two cases per 10,000 per year. antiretroviral therapy is critical to the treatment of HIV-related malignancies and must be Children with HIV also have a predilection for developing instituted alongside chemotherapy. rare tumors. In the general U.S. pediatric population, leukemia and brain tumors make up almost all new cases Overview of malignancy each year. However, among U.S. children Evidence of the relationship between human immuno- infected with HIV, NHL is the most common type of deficiency virus (HIV) and cancer became evident early cancer, followed by KS and leiomyosarcoma. in the HIV/AIDS epidemic. In 1981, the U.S. Centers 162 162 HIV-Associated Malignancies In response to these epidemiologic data, the CDC added The pathogenesis of HIV-related malignancy is related to NHL, primary CNS lymphoma (PCNSL), and KS to the several factors. HIV weakens the immune system, thus list of Category C symptoms (AIDS-defining illnesses) diminishing the body’s innate tumor surveillance ability, for children and has added leiomyosarcoma to the list much in the way that immunosuppressive agents put of Category B (symptomatic HIV-infection entities not transplant patients at risk of malignancy. Furthermore, included in Category C) symptoms. The World Health viruses such as the Epstein-Barr virus (EBV), human Organization lists all of these under Clinical Stage 4 and papilloma virus (HPV), and HHV-8 interact with HIV does not classify leiomyosarcoma. (See the chapter on to create an environment that enhances tumor growth. HIV/AIDS diagnostic criteria for a discussion of the CDC The relationship between HIV-related malignancy and and WHO clinical categories.) certain viruses is well established. For example, nearly every case of KS is linked with the presence of HHV-8, Furthermore, invasive cervical cancer occurs much more and nearly every case of HIV-related PCNSL is linked with commonly in female HIV-infected adolescents (and the presence of EBV infection. Also, EBV is often isolated adults) than in the general population. As a result, the from HIV-related leiomyosarcoma, systemic NHL, and CDC included invasive cervical cancer as a Category C Hodgkin’s disease. symptom for HIV-infected adolescents (and adults) and has added cervical dysplasia (moderate to severe) and Common Cancers Diagnosed noninvasive cervical carcinoma to the list of Category in HIV-Infected Children and B symptoms for adolescents (and adults). The WHO Adolescents classifies invasive cervical cancer as Clinical Stage 4 and does not classify cervical dysplasia and noninvasive Non-Hodgkin’s Lymphoma cervical cancer. The spectrum of HIV lymphoid malignancies spans lymphoproliferative disease such as lymphoid interstitial Though not listed in the CDC revised classification or pneumonitis to high-grade NHL and CNS lymphoma WHO Clinical Staging classification systems, cancers such as well as Hodgkin’s disease. NHL is the most common as Hodgkin’s disease, anal cancer, lung cancer, lip cancer, HIV-related malignancy (HRM) and usually presents as and testicular cancer are also more common with HIV an extranodal high-grade B-cell lymphoma, although infection. T-cell malignancies can be seen as well. One study from Malawi demonstrated that more than half of the cancers The incidence of cancer is lower among children with in children with HIV infection were lymphomas. HIV than among adults with HIV (0.1% per year versus 4% per year). Also, the relative incidence of specific NHL accounts for about 7% of cancers among all U.S. cancers differs between children and adults. For children younger than 20 years. In contrast, NHL is one example, in the United States, KS is the most common of the most common types of malignancy among HIV- HIV-associated cancer in adults with HIV, whereas it is infected children, accounting for more than 80% of HIV- much less common in children with HIV. In contrast, related cancers. HIV-infected children most commonly leiomyosarcoma is found more commonly among children develop Burkitt’s (small noncleaved cell) lymphoma and than among adults with HIV. immunoblastic (large cell) lymphoma. Regional variations in the prevalence of pediatric HIV- Clinical presentation. HIV-infected children who are related malignancy exist. Although NHL is the most diagnosed with NHL often have extranodal disease common pediatric HIV-related malignancy in the United (disease spread outside the lymph nodes) at the time States, KS remains the most common pediatric HIV- of presentation. Indeed, the cancer will probably have related malignancy in sub-Saharan Africa. Why these already metastasized to such places as the brain, bone differences exist is not entirely clear. However, the marrow, and gastrointestinal tract. prevalence of human herpesvirus 8 (HHV-8), the virus necessary for the development of KS, is much higher in Symptoms of cancer, including NHL, can be central Africa than in the United States. indistinguishable from symptoms of chronic HIV infection. Symptoms such as fever, fatigue, weight 163 HIV Curriculum for the Health Professional use of computed tomography (CT) scans (particularly of the head, abdomen, and pelvis), bone marrow biopsy, and cerebrospinal fluid (CSF) analysis. Prognosis is better in patients with CD4+ counts greater than 100 per microliter, a near-normal serum lactate dehydrogenase level, no history of opportunistic infections, and a good performance status (i.e., the ability to function at a near-normal ability during daily activities). Treatment. The therapies used in HIV NHL in chil- dren have been varied, including standard chemo- therapy regimens, the current first line of which is CHOP, a regimen combining cyclophosphamide, hydroxydaunomycin (doxorubicin), vincristine (Oncovin), and prednisone. Other variations such as BACOD (bleomycin, Adriamycin, cyclophosphamide, Oncovin, dexamethasone) and ABVD (Adriamycin, bleomycin, vincristine, dexamethasone) or some combination of these have been attempted in small case series. The results were poor, with median survival of 6 months. The experience in adults in the pre-highly active antiretroviral therapy (HAART) era has been equally disappointing. However, meta-analysis of these various regimens revealed cyclophosphamide and methotrexate to be Figure 1. Romanian child with abdominal NHL most active, whereas dose escalation of doxorubicin, prednisone, and vincristine was clinically and statistically loss, night sweats, anorexia, hepatosplenomegaly, and insignificant. These studies have led to the use lymphadenopathy may reflect underlying HIV infection, cyclophosphamide and methotrexate at high dose rates but they may also reflect the presence of lymphoma. NHL with successful treatment of children along with well- includes many organ-specific symptoms Table( 1). tolerated toxicity (per National Cancer Institute