P EDIATRIC M ALIGNANCIES I. INTRODUCTION

P EDIATRIC M ALIGNANCIES I. INTRODUCTION II. Since HAART became the standard of care for HIV-infected people with immunologic suppression, studies in adults have shown a dramatic decrease in the incidence of HIV-related malignancies. 1 Corresponding pediatric analyses have not yet been performed; however, anecdotal reports and logical comparison suggest a similar trend, despite differences in presumed interaction between HIV and malignancies in children as compared to adults. HIV-associated malignancies occur much less frequently in pediatric patients compared with adults. 2 With the exception of children with primary CNS lymphomas, most pediatric patients are not profoundly CD4 cell-depleted at the time of diagnosis of malignancy; this contrasts with HIV-infected adults who are often severely immunosuppressed when malignancy occurs. ETIOLOGY Viral co-infections are frequently seen in HIV-infected patients. As many as 96% of adult patients with AIDS have shown serologic evidence of infection with several viruses, such as cytomegalovirus (CMV), human herpes virus 6 (HHV-6), herpes simplex virus (HSV), and Epstein-Barr virus (EBV). 3 The role of these viruses as well as newly discovered viruses, including HHV-8, in the pathogenesis of AIDS-related malignancies is the subject of ongoing investigation. EBV has been associated epidemiologically and via molecular diagnostic data with the pathogenesis of malignancy in immunodeficient states. For various malignancies, the EBV relationship differs. For example, in HIV-infected adults with systemic NHL, EBV DNA can be detected in 38% to 56% of the tumors but is found in virtually all patients with HIV-related primary CNS lymphoma. 4 In HIV-infected patients, EBV has also been found in the tumor cells of leiomyosarcomas and leiomyomas but not in adjacent tissues. 5 In contrast, EBV is not detected in leiomyosarcomas and leiomyomas in non-hiv-infected persons. HIV-triggered production of cytokines and growth factors are being evaluated as well because these molecules can have a wide range of consequences on the host. Effects range from increased HIV replication to the induction of B cell growth, activation, and differentiation. When immunodeficiency exists, ongoing B-cell proliferation may foster mutations in (or altered expression of) critical oncogenes and tumor suppressor genes, leading to selection of specific clones and the development of monoclonal B-cell lymphomas. 6 Rearrangements of Bcl-6 and c-myc have been shown to occur in 33% and 40%, respectively, of AIDS-related large cell lymphomas, whereas mutations of p53 occur in 25%. The small cell histologies (Burkitt s and Burkitt s-like) are commonly associated with c-myc rearrangements. EBVlatent genes expressed in a type III pattern with latent membrane protein-2, which dysregulates cell growth control and transforms B lymphocytes, have been identified in primary CNS lymphomas in adults as well as lymphomas in HIV-infected children. 7,8 The cells in primary effusion lymphomas (a rare systemic lymphoma associated with HIV) uniformly contain HHV-8 genome and are frequently co-infected with EBV. HHV-8 is a doublestranded DNA virus present prior to tumor formation and has also been found to be present in the tumor cells. HHV-8 is most prevalent in populations with a high incidence of Kaposi s sarcoma (KS) leading to further evidence of causation. 7 1

III. Reports of HHV-8 prevalence in children from Brazil, Central Africa, and South Texas range from 3% to 50%. 9 Prevalence in other populations in the United States is as follows: 1% to 2% in blood donors, 2% in hemophiliacs, 3% to 4% in HIV-infected women, and 25% to 30% in HIVinfected men who have sex with men. HHV-8 conversion risk has been linearly related to the number of male-male sexual encounters. 7 HHV-8 infection is necessary for the development of KS; however, KS will not develop without concomitant immune suppression. TYPES OF MALIGNANCIES RECOMMENDATION: When HIV-infected children present with unexplained constitutional symptoms, such as fever, weight loss, hepatomegaly, splenomegaly, jaundice, abdominal distension, CNS symptoms, pancytopenia, and bone pain, clinicians should evaluate for malignancy. Key Points: Proliferative and neoplastic disorders may clinically mimic an opportunistic infection. 10 The only malignancy found primarily in children with more advanced immunodeficiency is primary CNS lymphoma. The majority of malignancies that affect HIV-infected children are non-hodgkin s lymphomas (NHL). The prevalence of NHL is similar to that seen in the adult HIV-infected population (.36%-.57%). The majority of NHL is extranodal and more likely to involve the CNS or gastrointestinal tract. They exhibit aggressive histology and an increase in the proportion of high-grade B cell types, including the immunoblastic, large-cell, and Burkitt s lymphomas. Mucosa-associated lymphoid tissue tumors, which are rare in HIV-infected adults, represent 10% of the NHL tumors seen in HIV-infected pediatric patients. The relative risk of NHL in HIV-infected children is 1200-fold higher than that in non- HIV-infected children. 2 A registry data collection primarily in the pre-haart era revealed that among children with AIDS, 2.5% were identified as also having cancer. The mean age for developing cancer was 4.5 years (median, 3 years). These children were infected with HIV via exposure to an infected mother (90%) or via contaminated blood or blood products (7.3%). These cancers were predominantly non-hodgkin s lymphomas (81%), with KS in 8%, leiomyosarcoma in 3%, and Hodgkin s disease in 2%. Cancer was more frequent in boys than girls and less frequent in blacks. Primary brain lymphomas, 25% of all NHL in pediatric HIV patients, and lemyosarcomas had a late-onset pattern from the diagnosis of HIV to cancer. 11 Smooth muscle tumors, such as leiomyoma and leiomyosarcoma, occur more frequently in HIV-infected children than in adults. 2,12 A. Lymphoma The most common presentation of lymphoma in children with AIDS is fever and weight loss. HIV-associated NHL tends to be more advanced at presentation with extranodal manifestations, including hepatomegaly, jaundice, abdominal distension, CNS symptoms, pancytopenia, and bone pain. Because these symptoms may be mistakenly attributed to infection, there may be a delay in the diagnosis of lymphoma. Malignancy needs to be carefully considered in HIVinfected children who exhibit any combination of the above symptoms. HIV-infected patients have a 5- to 9-fold increased risk for Hodgkin s disease, particularly the unfavorable histologies of mixed cellularity and lymphocyte depletion. The clinical presentation tends to be atypical and more aggressive with an increase in bone marrow involvement. 13 2

IV. B. Leiomyomas and Leiomyosarcomas Leiomyomas and leiomyosarcomas are the second most common malignancies seen in HIVinfected children. The relative risk that these smooth muscle lesions will develop in an HIVinfected child compared with a non-hiv-infected child is 10,000. 1 Although this cancer is usually seen in the gastrointestinal tract in children who show no evidence of HIV infection, the leiomyosarcomas and leiomyomas seen in HIV-infected children may also involve the lung or spleen. The pulmonary lesions are often visible as nodules on chest CT, whereas the gastrointestinal tumors present with evidence of obstruction, abdominal pain, and bloody diarrhea. C. Kaposi s Sarcoma (KS) KS, a relatively common malignancy in the adult HIV population, is rare in pediatric HIVinfected patients. A reasonable explanation is the linear relationship identified between sexual transmission and the incidence of this tumor. In a few reported cases of childhood Kaposi s sarcoma, the children acquired HIV infection postnatally via contaminated blood or blood products or were born to mothers who were identified as being at high risk for KS, (e.g., mothers infected via heterosexual transmission from a bisexual partner). 14 TREATMENT RECOMMENDATIONS: Clinicians should refer HIV-infected children with malignancies to pediatric oncologists. Clinicians should initiate or continue HAART while the patient is undergoing treatment for the malignancy; however, there is the possibility of an increase in side effects and complex drug-drug interactions. Treatment of HIV-infected children with malignancies should be managed by a multidisciplinary team, including pediatric hematologists/oncologists, pediatric HIV Specialists, and pharmacists. Key Point: Because the regimens used to treat malignancies (particularly those required for treating advanced B-cell lymphomas) are extremely aggressive, it is important to be vigilant for associated toxicities and drug-drug interactions. A diagnosis of AIDS should not be a deterrent to the delivery of optimal treatment of malignancies. Therapy regimens applied to cure these malignancies are generally similar to those used with non-hiv-infected children. The largest retrospective series reported to date includes data and survival rates for children who received treatment (both aggressively and palliatively) as well as those who did not receive any treatment for the malignancy. 2 However, in this study, only a small number of cases were assessable for determination of survival rates, and toxicity data were not reported. Anecdotally, patients treated with the intent to cure, even those on the most aggressive therapies, tolerate therapy well with toxicities similar to patients without HIV infection. In a study of HIV-infected adults with primary CNS lymphoma, survival was prolonged in patients who were receiving HAART. 15 The adult experience of combination HAART and chemotherapy has been very encouraging. The AIDS Malignancy Consortium studied the combination of HAART (stavudine, lamivudine, indinavir) with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone). Clearance rates for doxorubicin and indinavir were not significantly altered. However, cyclophosphamide clearance was reduced by 45% in combination with HAART, although there was no excessive toxicity seen. 4 Others have demon- 3

strated that transiently discontinuing ARV therapy during chemotherapy has been tolerated. Patients with HIV-related malignancies are currently being considered for bone marrow transplantation, a modality previously thought to be too toxic for this population. 7 Because severe immunosuppression is necessary for the development of KS in HHV-8 seropositive patients, optimizing anti-hiv therapy is extremely important for patients with this tumor. HAART alone has been shown to be effective in 86% of adult patients with KS, although those with more aggressive disease require chemotherapy as well. Agents currently used include doxorubicin, bleomycin, vincristine, and paclitaxel. 7 To determine prognosis, it will be necessary to evaluate outcome in HIV-infected children treated in the same manner as non-hiv-infected children. Combination of chemotherapy and HAART therapy also is necessary in the pediatric population. Nucleoside analogs have varying degrees of bone marrow suppressive effects, which may potentiate hematologic toxicity of chemotherapy and may decrease the ability to deliver full doses of chemotherapeutic agents in a timely fashion. All the above considerations may impact overall success. In addition, due to competitive metabolic pathways, the effectiveness of the ARV agents may be impaired. In a study that reported results of chemotherapy regimens in adult patients with lymphoma, there was an unexpected difference in the reduction of CD4 cells based on ARV regimens combined with chemotherapy. 16 Furthermore, due to the increase in vomiting that may accompany chemotherapy, the addition of concomitant ARV therapy may necessitate nasogastric or gastrostomy tube insertion for drug and nutrition delivery. Until data regarding toxicities of ARV agents when combined with chemotherapy are available, clinicians who treat these children are encouraged to work closely with their adult colleagues as well as pharmacists and other healthcare providers specializing in the care of pediatric patients with cancer. REFERENCES 1. International Collaboration on HIV and Cancer. Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst 2000;92:1823-1830. 2. Granovsky MO, Mueller BU, Nicholson HS, et al. Cancer in human immunodeficiency virusinfected children: A case series from the Children's Cancer Group and the National Cancer Institute. J Clin Oncol 1998;16:1729-1735. 3. Fauci AS, Macher AM, Longo DL, et al. NIH Conference. Acquired immunodeficiency syndrome: Epidemiologic, clinical, immunologic, and therapeutic considerations. Ann Intern Med 1984;100:92-106. 4. Gates AE, Kaplan LD. AIDS malignancies in the era of highly active antiretroviral therapy. Oncology 2002;16:441-459. 5. McClain KL, Leach CT, Jenson HB, et al. Association of Epstein-Barr virus with leiomyosarcomas in children with AIDS. N Engl J Med 1995;332:12-18. 6. Levine AM. Acquired immunodeficiency syndrome-related lymphoma. Blood 1992;80:8-20. 7. Scadden DT. AIDS-related malignancies. Ann Rev Med 2003;54:285-303. 8. Preciado MV, Fallo A, Chabay P, et al. Epstein Barr virus-associated lymphoma in HIV-infected children. Pathol Res Pract 2002;198:327-332. 9. Jenson HB. Human herpesvirus 8 infection. Curr Opin Pediatr 2003;15:85-91. 10. Balarezo FS, Joshi VV. Proliferative and neoplastic disorders in children with acquired immunodeficiency syndrome. Adv Anat Pathol 2002;9:360-370. 11. Biggar RJ, Frisch M, Goedert JJ, et al. Risk of cancer in children with AIDS. JAMA 2000;284:205-209. 4

12. Mueller BU. Cancers in human immunodeficiency virus-infected children. J Natl Cancer Inst Mongr 1998;23:31-35. 13. Casari RA, Cattaneo C, Facchetti F, et al. Hodgkin disease developing in patients infected by human immunodeficiency virus results in clinical features and a prognosis similar to those in patients with human immunodeficiency virus-related non-hodgkin lymphoma. Cancer 2001;92:2739-2745. 14. McClain KL, Joshi VV, Murphy SB. Cancers in children with HIV infection. Hematol Oncol Clin North Am 1996;10:1189-1201. 15. Skeist DJ, Crosby C. Survival is prolonged by highly active antiretroviral therapy in AIDS patients with primary central nervous system lymphoma. AIDS 2003;17:1787-1793. 16. Sparano JA, Wiernik PH, Hu X, et al. Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide plus didanosine and filgrastim in patients with human immunodeficiency virus-associated non-hodgkin s lymphoma. J Clin Oncol 1996;14:3026-3035. 5

A PPENDIX A N EW Y ORK S TATE M ALIGNANCY S ITES NEW YORK STATE AIDS MALIGNANCY CONSORTIUM SITES http://www.amc.uab.edu Albert Einstein Comprehensive Cancer Center, Bronx Principal Investigator: Joseph Sparano, MD For more information on the open protocols at this site, contact Una Hopkins at (718) 904-2321. Bronx Lebanon Hospital, Bronx Principal Investigator: Mary Reed, MD Columbia-Presbyterian Hospital, New York Principal Investigator: Mary Keohan, MD For more information on the open protocols at this site, contact Rosalee Liboro at (212) 305-6837. Memorial Sloan-Kettering Cancer Center, New York Principal Investigator: Susan Krown, MD For more information on the open protocols at this site, contact Andrea Martelli at (212) 639-7161. New York University Medical Center, New York Principal Investigator: Alvin Friedman-Kien, MD For more information on the open protocols at this site, contact the Dermpharm Unit at (212) 263-5244. St. Vincent s Hospital, New York Principal Investigator: John Cho, MD For more information on the open protocols at this site, contact Ramune Pliuriene at (212) 367-1737. CHILDREN S ONCOLOGY GROUP: NEW YORK STATE SITES http://www.childrensoncologygroup.org Albany Jennifer Pearce, MD Albany Medical Center 47 New Scotland Avenue Mail Code: MC-24 Albany, New York 12208-3419 (518) 262-5513 Bronx Eva Radel, MD Montefiore Medical Center 111 East 210th Street Bronx, New York 10467-2490 (718) 920-7844 Brooklyn Ludovico Guarini, MD Maimonides Medical Center 4802 Tenth Avenue Brooklyn, New York 11219 (718) 283-8173 6

Sreedhar Rao, MD SUNY Health Science Center at Brooklyn 450 Clarkson Avenue Brooklyn, New York 11203-2098 (718) 270-1693 Kusum Viswanathan, MD Brookdale Hospital Medical Center Room 346 CHC Linden Boulevard at Brookdale Plaza Brooklyn, New York 11212 (718) 240-5904 Swayamprabha Sadanandan, MD Brooklyn Hospital Center 121 DeKalb Avenue Brooklyn, New York 11201 (718) 250-6074 Buffalo Martin Brecher, MD Roswell Park Cancer Institute Pediatrics Elm & Carlton Streets Buffalo, New York 14263 (716) 845-2333 Mineola Mark Weinblatt MD Winthrop University Hospital 200 Old Country Road Suite 440 Mineola, New York 11501 (516) 663-9400 New Hyde Park Arlene Redner, MD Schneider Children s Hospital Pediatric Hematology/Oncology 269-01 76 Avenue New Hyde Park, New York 11040 (718) 470-3460 Arlene Redner, MD Schneider Children s Hospital at North Shore Pediatric Hematology/Oncology 269-01 76 Avenue New Hyde Park, New York 11040 (718) 470-3460 7

New York Jeffrey Allen, MD Beth Israel Medical Center North Division 170 East End Avenue at 87th Street New York, New York 10028 (212) 870-9407 Patricia Giardina, MD New York Hospital-Cornell University Medical Center Department of Pediatric Hematology-Oncology 525 East 68th Street Payson Building #695 New York, New York 10021-4885 (212) 746-3415 Aaron Rausen, MD New York University Medical Center 317 East 34th Street 8th Floor New York, New York 10016 (212) 263-7144 Peter Steinherz, MD Memorial Sloan Kettering Cancer Center 1275 York Avenue Box 411 New York, New York 10021-6094 (212) 639-7951 Linda Granowetter, MD Columbia Presbyterian College of Physicians & Surgeons Division of Pediatric Oncology 161 Fort Washington Avenue Irving 7-748 New York, New York 10032 (212) 305-9770 x8652 Elizabeth Raetz, MD Mount Sinai Medical Center Division of Pediatric Hematology-Oncology 1 Gustave L. Levy Place, Box 1208 New York, New York 10029-6574 (212) 241-7022 Rochester Barbara Asselin, MD University of Rochester Medical Center Pediatric Hematology-Oncology 601 Elmwood Avenue Box 777 Rochester, New York 14642 (585) 275-2981 8

Stony Brook Robert Parker, MD State University of New York at Stony Brook Pediatrics Hematology/Oncology HSC T-11 Room 029 Stony Brook, New York 11794-8111 (631) 444-7720 Syracuse Ronald Dubowy, MD State University of New York at Syracuse Pediatric Hematology/Oncology 750 East Adams Street Syracuse, New York 13210 (315) 464-5294 Valhalla Fevzi Ozkaynak, MD New York Medical College Section of Hematology/Oncology Munger Pavilion, Room 110 Valhalla, New York 10595 (914) 493-7997 9