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© 2000 American Society for Clinical Oncology Human Immunodeficiency Virus–Related Cancer in Children: Incidence and Treatment Outcome—Report of the Italian RegisterFrom the Clinica Pediatrica and Servizio di Biometria ed Epidemiologia Clinica, Direzione Scientifica, Instituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, Pavia; Clinica Pediatrica, Università di Firenze, Firenze; and Clinica Pediatrica, Università di Torino, Torino, Italy. Address reprint requests to D. Caselli, MD, Clinica Pediatrica, Instituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, 27100 Pavia, Italy; email caselli{at}smatteo.pv.it
PURPOSE: To outline the incidence, presenting features, treatment response, and outcome of human immunodeficiency virus (HIV)–associated malignancies in infancy and childhood, together with the estimated risk of HIV-associated cancer in children born to mothers infected with HIV. PATIENTS AND METHODS: The Italian Register for HIV Infection in Children collected data by specific registration and follow-up forms. By March 1999, 5,060 children were recruited, including 4,889 with perinatal exposure to HIV-1. Overall, 1,331 infected children were enrolled onto the Register and classified according to current Centers for Disease Control criteria; of them, 1,163 were vertically infected (24% of those with perinatal exposure). Of these 1,163, 569 (49%) were considered to have been prospectively followed-up since they had been registered at birth or within the first 3 months of age. RESULTS: Of the 1,331 children observed for a median time of 6.5 years, 35 developed 36 malignancies, four of which occurred in patients with blood-borne risk. For the 1,163 vertically infected children, the cumulative number of years of observation was 7,178 child-years and the cumulative incidence of HIV-associated tumors was 4.18 per 1,000 children/yr (95% confidence interval [CI], 2.92 to 5.98). When only the 569 vertically infected children prospectively followed up since birth were considered, the cumulative number of years of observation was 2,803 child-years. In this group, 10 tumors were observed, with a cumulative incidence of HIV-associated tumors of 3.57 per 1,000 children per year (95% CI, 1.92 to 6.63). CONCLUSION: The risk of cancer was significantly higher but not restricted to symptomatic and/or immune-compromised children. Cancer-directed treatment should be given promptly to these patients, who have a fair chance to survive their tumor in view of potential highly aggressive antiretroviral therapy–associated improvement in survival and quality of life.
AS DO OTHER congenital or acquired immunodeficiencies, human immunodeficiency virus (HIV) infection may promote malignancy.1,2 In adults, the exact frequency of HIV-associated malignancies has been difficult to define, because malignancies are reported mainly as an AIDS-defining condition. In an Italian cohort of 1,255 HIV seroconverters, Non-Hodgkin’s lymphomas (NHL) were 157 times more frequent in comparison with general population rates.3 In children, the reported prevalence of HIV-associated malignancies is estimated to be approximately 2%.4-6 Prolonged survival of HIV-positive children treated with antiretroviral or even with highly aggressive antiretroviral therapy (HAART) may result in a higher or lower incidence of HIV-associated malignancies. Thus, a timely diagnosis and appropriate treatment of such tumors should be available in referral centers. Concern regarding the rapidly fatal clinical course and treatment-related toxicity of HIV-associated childhood cancer prevented initial cases of this disease from receiving adequate cancer therapy.7 Recently, the efficacy and safety of cancer-directed treatment in HIV-positive patients has been assessed.4 In particular, several clinical trials, especially those studying Kaposi sarcoma (KS) and lymphoma in HIV-infected adults, have been carried out.8-13 In contrast, little experience with this disease in children is available, with most reports concerning small series of patients.4-7,14,15 In Italy, the majority of HIV-infected children are enrolled onto the Italian Register for HIV Infection in Children, a prospective, nationwide study that started in 1985.16-21 This has provided us the opportunity to outline the incidence, presenting features, treatment response, and outcome of HIV-associated malignancies in infancy and childhood. This article is a report of the estimated risk of HIV-associated cancer in children born to HIV-infected mothers; their presenting features and treatment response are also illustrated.
The Italian Register for HIV Infection in Children was begun in 1985 by collecting data from all children with HIV infection or who were born to seropositive mothers.16 The number of the participating centers distributed throughout Italy has reached 106. Data were collected by specific registration and follow-up forms, as previously described16-18; data quality checks were made by the two coordinating centers before the data were entered in a specific database. On the basis of an anonymous sero-survey, it may be estimated that approximately 700 newborns were delivered from HIV-positive mothers during 1990.22 In accordance with a transmission rate of 13% to 20%, the expected number of the HIV-infected children in 1990 in Italy ranged between 90 and 140, and so the observed number of 95 cases falls nicely in the expected range for the same year. Therefore, the Register represents an extremely reliable source of information on perinatally HIV-infected children in Italy.20,22 By March 1999, 5,060 children were recruited. Of these, 15 infected children had an indeterminate risk factor, 147 were infected by parental route, six were born in one endemic country (one of whom was not infected), three were born to a HIV-2–infected mother (one infected), and 4,889 had perinatal exposure to HIV-1; of this last group, 3,261 (66.7%) seroreverted and were taken to be uninfected, 1,163 (23.7%) were infected, and 465 were still in an indeterminate infection status. Of the 1,163 children with vertically acquired infection, 569 (48.8%) were considered to have been prospectively observed since they had been registered at birth or within the first 3 months of age. Overall, 1,331 infected children were enrolled onto the Register and classified according to current Centers for Disease Control (CDC) criteria. During most of the study period, conventional anti-HIV therapy was recommended, whereas HAART was recommended since 1998. After the identification of cancer cases, additional specific data were recorded. These included presenting features, histopathologic evaluation, clinical course, response to treatment, and outcome. As a result of the survey, 35 children were observed to have developed 36 tumors; four of them had occurred in patients with blood-borne risk. The analysis of the HIV-associated cancer risk was performed only on the cohort of patients with vertical HIV transmission who reported to the Register before the diagnosis of cancer.
Statistical Analysis The analysis was performed on the part of the cohort who had been followed up since birth and was repeated on the whole case series; estimates from both analyses were compared. A P value of less than 0.05 was retained for statistical significance. Stata 6.0 software (Stata Corporation, College Station, TX) was used for computation.
Of the 1,331 HIV-infected children observed for a median time of 6.5 years (1st quartile, 3.0 years; 3rd quartile, 10.1 years), 35 children developed 36 malignancies. The main presenting features of the 31 vertically infected children are summarized in Table 1. The male/female ratio was 1.8; 31 patients were born to HIV-infected mothers, whereas four tumors were observed in four children with blood-borne infection. Because the Register is not representative of the HIV infection in children with parenteral risk factor, statistical analysis was performed only on the 31 vertically infected patients. The calendar years of diagnosis of cancer were as follows: 1987 (n = 2), 1988 (n = 3), 1989 (n = 2), 1990 (n = 3), 1992 (n = 1), 1993 (n = 2), 1994 (n = 3), 1995 (n = 4), 1996 (n = 4), 1997 (n = 4), 1998 (n = 1), and 1999 (n = 1). Only one patient had been exposed to prenatal antiretroviral therapy. The age at which the tumor was diagnosed ranged between 0.3 and 13.1 years (median age, 5.6 years).
Risk of Developing Cancer for Children Born to Infected Mothers When the 1,163 children vertically infected were considered, the cumulative number of years of observation was 7,178 child-years. Thus, the cumulative incidence of HIV-associated tumors in this group was 4.18 per 1,000 children per year (95% confidence interval [CI], 2.92 to 5.98) (Fig 1). The probability of 5-year EFS was 98% (95% CI, 97.0% to 98.9%). Overall, 393 children in this group died at a median age of 3.0 years (range, 0.10 to 14.4 years), with a death rate of 54.4 per 1,000 children per year (95% CI, 49.3% to 60.1%).
When only the 569 vertically infected children who were prospectively followed up since the first period of life were taken into account, the cumulative number of years of observation was 2,803 child-years. In this group, 10 tumors were observed. Thus, the cumulative incidence of HIV-associated tumors in this group was 3.57 per 1,000 children per year (95% CI, 1.92 to 6.63) (Fig 2). The probability of 5-year EFS was 98.7% (95% CI, 96.7% to 99.5%). Overall, 196 children in this group died at a median age of 1.7 years (range, 0.1 to 10.9 years), with a death rate of 69.8 per 1,000 children per year (95% CI, 60.7% to 80.3%).
Relationship Between Risk of Developing Cancer and Immunodeficiency Although in most patients (19 [61%] of 31,) HIV infection was fully symptomatic with overt immunodeficiency (C3 CDC class), asymptomatic or paucisymptomatic and immunocompetent children also developed cancer, as suggested by the A1-A2, B1-B2 CDC class status in eight of the 31 children. The CD4 count at the time of cancer diagnosis is reported in Table 1. The tumor incidence rate for immunologic CDC class 3 was 5.8 per 1,000 patients per year (95% CI, 3.9 to 8,6), whereas for classes 1 and 2, it was 1.8 (95% CI, 0.7 to 4.2; hazards ratio, 3.29 [range, 1.26 to 8.59]; P = .006) (Fig 3). For patients in the clinical CDC class C, the tumor incidence rate was 9.2 for 1,000 patients per year (95% CI, 6.3 to 13.3), whereas for N, A, and B classes, it was 0.5 (95% CI, 0.1 to 1.9; hazards ratio, 21.5 [range, 5.1 to 90.7]; P = .001) (Fig 4).
NHL Twenty-four (81%) of the 32 tumors were NHL. Six patients (25%) had primary involvement of the CNS, whereas five were primarily nodal and 13 were extranodal: bone and bone marrow in four (16%), abdominal in six (25%), parotidis in two, and tonsil in one. In three cases, CNS NHL was multifocal. NHL occurred at a median age of 5.6 years (range, 0.3 to 13 years). The median age at onset of CNS NHL was 1 year (range, 0.3 to 13 years), compared with 7.3 years in the remaining 18 non-CNS NHL cases. In 11 cases (34%), NHL occurred in children without severe immunodepression (CDC category 1 or 2). In 20 of the 22 evaluated cases, the immunophenotype was characteristic of the B-cell lineage. Furthermore, the presence of the Epstein-Barr virus (EBV) genome in the tumor tissue was documented in eight (72%) of the 11 cases investigated.
Other Tumors
Treatment Outcome
The existence of a national pediatric register for HIV infection allowed us to provide a precise estimate of the cumulative risk of HIV-related cancer in childhood. This information has not been available before. Because some patients, also in this series, were diagnosed with cancer only at postmortem examination, the incidence we observed is to be considered as a minimal estimate of a likely more frequent event. The modality of accrual into the Register might influence the estimated incidence of tumor. Overestimation could result if patients are reported as HIV-infected only on the occasion of symptomatic disease; on the other hand, underreporting of HIV-infected patients could result from early death. To address this issue, we have conducted two different analyses, one on the whole population enrolled onto the Register and another considering only the HIV-infected children who were diagnosed within the first 3 months of life and then prospectively followed up. The evaluation of this prospective group provided an estimate that was not different from that obtained from the whole population. Because early death of HIV-infected newborns or infants has become unusual with the recent prophylactic and treatment strategies, we considered that performing the analysis on the whole population, whose median age at accrual was 0.4 years, did not introduce a significant bias in this evaluation. We report a large series of HIV-associated tumors observed during the last 16 years. In keeping with previous observations,1-5,25,26 most of these tumors were NHL. This has been attributed to the challenging effect of EBV infection.27,28 Is HIV-associated cancer truly opportunistic? In a recent study, the frequency of EBV infection in HIV-infected children during the first few years of life was comparable to that of HIV-uninfected children (78% v 85% cumulative infection rate at 3 years), but they had more frequent oropharyngeal EBV shedding (50% v 28%; P < .001) and a higher mean CD8 cell count in the absence of an independent effect on CD4 cell count, immunoglobulin G or HIV-1 RNA level, lymphadenopathy, hepatomegaly, or splenomegaly.29 Furthermore, EBV-positive children with vertically acquired HIV infection tended to have a detectable blood level of EBV DNA over a period of years, and this level often exceeded 10,000 copies/0.1 mL of blood—hundreds of times higher than levels typically found in EBV-positive, HIV-uninfected children of the same age.30 Altogether, the above data may suggest that although the rate of infection is comparable, HIV-infected children might be more prone to EBV-induced complications, even without overt immunodeficiency. Although the results of our study do not allow for the assessment of any role of EBV in these patients, the observation that 41% of children with tumors in this series did not show overt immunodeficiency might be in keeping with this concept. A selective rather than overt immunodeficiency could be an explanation for this apparent discrepancy, which would be in agreement with recent evidence that viruses are capable of developing several molecular mechanisms responsible for downgrading cytotoxic T-cell responses.31 In particular, a decline in the number of EBV-specific T cells before the development of EBV lymphoma has recently been traced.32 In this respect, HIV-associated tumors might be regarded as the product of viral superinfection in the HIV-infected child. This may explain why HIV-related cancer does not reflect the usual childhood cancer frequency profile.33-35 Incidence of KS has changed the expected profile of malignant disease among black children in South Africa, and this was clearly associated with a higher seroprevalence of anti–HHV-8 antibodies.36 The rarity of KS among Italian HIV-infected children seems related to different environmental factors. Thus in transplant recipients, viral and especially EBV-driven lymphoproliferative disorders in children who survive HIV infection with a variable degree of immune suppression are to be considered in the future as an even more frequent complication that, nevertheless, may be controlled with specific therapy. Improvements on antiretroviral therapy have substantially changed the duration and quality of life for HIV-infected children. Whether this may increase or decrease the risk of HIV-associated cancer remains to be elucidated.37 The shorter life expectancy together with the fear of excessive infectious complications prevented HIV-infected children from receiving adequate cancer-directed therapy in the past. In our series, nine of the 13 patients with NHL who were given an intensive Berlin-Frankfurt-Munster–based polychemotherapy achieved sustained remission; the overall 5-year EFS for all patients was 45%. Thus, we suggest that any HIV-infected child should have access to an adequate cancer-directed treatment, which might be intense and of short duration, as most of the mature B-lineage lymphoproliferative disorders require.24 In conclusion, the observed cumulative incidence of HIV-associated cancer in our series was 3.57 per 1,000 children per year, which compares unfavorably with the 0.1795 per 1,000 children per year observed in the Italian control population recorded in the Registry of Piedmont38; thus, referral centers caring for large series of HIV-infected children who are adequately treated with current HAART therapy are expected to cope with HIV-associated tumors, mainly NHL. Adequate cancer-directed treatment should be given promptly to these patients, who may have, despite their immune deficiency, a fair chance to survive their tumor if treatment is delivered in the appropriate setting39 and in view of potential HAART-associated improvement in survival and quality of life.40,41
Centers that contributed cases: C. Giaquinto, V. Giacomet (Pediatric Department, University of Padova); G. Castelli Gattinara, S. Livadiotti (Instituto di Ricovero e Cura a Carattere Scientifico Bambin Gesù Roma); L. Minoli and A. Maccabruni (Pediatric and Infectious Disease Department, University of Pavia); C. Fundarò (Pediatric Department, Policlinico Gemelli, University of Roma); L. Galli (Pediatric Department, University of Firenze); P. Osimani (Pediatric Division Ancona); T. Bezzi (Pediatric Department, University of Ferrara); A. Guarino (Pediatric Department, University of Napoli); A. De Maria (Infectious Disease Department, University of Genova); G. Rossi (Pediatric Department I, University of Cagliari); C. Dessì (Pediatric Department II, University of Cagliari); A. Viganò (Pediatric Department IV, University of Milano); A. Plebani (Pediatric Department I, University of Milano); C. Gabiano and C. Riva (Pediatric Department I, University of Torino); D. DeMattia (Pediatric Department, University of Bari); G. Benaglia (Pediatric Division Parma); C. Salvatore (Pediatric Department University of Trento); and A. Mazza (Pediatric Division Trento). Participants in the Italian Register for HIV Infection in Children for this analysis: Patrizia Osimani, MD, Ancona; Cesare Di Bari, MD, and Domenico Larovere, MD, Bari; Maurizio Ruggeri, MD, Bergamo; Massimo Masi, MD, and Fernando Specchia, MD, Bologna; Laura Battisti, MD, Bolzano; Marzia Duse, MD, Paola Crispino, MD, and Paolo Carrara, MD, Brescia; Carlo Pintor, MD, Maurizio Dedoni, MD, Carlo Dessì MD, and Daniela Loriano, MD, Cagliari; Elisa Anastasio, MD, Catanzaro; Teresa Bezzi, MD, Ferrara; Marco De Luca, MD, Silvia Farina, MD, and Alberto Vierucci, MD, Florence; Dante Bassetti, MD, Paola Pedemonte, MD, Federica Toscanini, MD, Maria Grazia Marazzi, MD, and Loredana Tasso, MD, Genua; Annamaria Plebani MD, Filippo Salvini, MD, Raffaella Pinzani, MD, Dorella Bricalli, MD, Alessandra Viganò, MD, Natascia Sala, MD, Gian Vincenzo Zuccotti, MD, Enrica Riva, MD, Marcello Giovannini, MD, Rita Lipreri, MD, Stefania Conio, MD, and Gabriele Ferraris, MD, Milan; Monica Cellini, MD, and Cecilia Baraldi, MD, Modena; Alfredo Guarino, MD, Eugenia Bruzzese, MD, and Luigi Tarallo, MD, Naples; Carlo Giaquinto, MD, Vania Giacomet, MD, and Osvalda Rampon, MD, Padua; Ernesto Renato Dalle Nogare, MD, Adriana Sanfilippo, MD, and Amelia Romano, MD, Palermo; Giorgio Benaglia, MD, and Icilio Dodi, MD, Parma; Desirèe Caselli, MD, Anna Maccabruni, MD, and Ilaria Pacati, MD, Pavia; Rita Consolini, MD, and Annalisa Legitimo, MD, Pisa; Maria Teresa Cecchi, MD, and Vico Vecchi, MD, Rimini; Gianfranco Anzidei, MD, Stefano Cerilli, MD, Rosa Chiodi, MD, Guido Castelli Gattinara, MD, Caterina Cancrini, MD, Stefania Bernardi MD, Carlo Fundarò, MD, Orazio Genovese, MD, Giuseppe Segni, MD, Salvatore Catania, MD, and Camilla Ajassa, MD, Rome; Antonio Mazza, MD, Trento; Sara Garetto, MD, Elvia Palomba, MD, and Carlo Scolfaro, MD, Turin.
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Brinkman K, Delnoy PP, de Pauw B: Highly active antiretroviral therapy (HAART) and prolonged survival of a patient with an HIV-related Burkitt lymphoma, despite an intracardiac relapse. Int J STD AIDS 9: 773-775, 1998 Submitted January 24, 2000; accepted June 16, 2000. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
