(CANCER RESEARCH 58. 448-452. February 1. I998| A Lack of Neuroblastoma in Down Syndrome: A Study from 11 European Countries1 Daniel Satgé,2Annie J. Sasco, Niels L. T. Carlsen, Charles A. Stiller, HervéRubie, Barbara Hero, Bruno de Bernardi, Jan de Kraker, Carole Coze, Per Kogner, Froydis Langmark, Friederike G. A. J. Hakvoort-Cammel, Daniel Beck,3 Nicolas von der Weid, Sheila Parkes, Olivier Hartmann, Robert J. J. Lippens, Willem A. Kamps, and Daniele Sommelet Laboratory of Pathologv. Centre Hospitalier. 19000 Tulle. Frunce ¡D.S.]: Epideiniologv for Cancer Prevention, 1ARC, 69372 Lyon, France ¡A.J. S.j; Pediatrie Hematology Oncolngy. Odense University Hospital, DK-5000 Odense C, Denmark ¡N.L T. C.¡; Childhood Cancer Research Group, Department of Pediatrics. Oxford OX6HJ. United Kingdom {C.A.S.f: Pediatrie Hemalologv Oneologv. MédecineInfantile G, Centre Hospitalier Universitaie Purpan, 31059 Toulouse, France ¡H.R.f: Pediatrie Hematologv Oncnlngy, Klinik fürKinderheilkunde, D-5IXM) Cologne. Germany ¡B.H.¡:Department of Hemalology Oncology. Giannina Gaslini Children's Hospital, 1614K Genova. Italy IB. d. B.I: PédiatrieHetnatologv Oncologi: Emma Kinder Ziekenhuis. Academic Medical Center. 1I05AZ Amsterdam, the Netherlands [J. d. K.I: Pediatrie Oncology. University Hospital Lit Tiimme. 133N5 Marseille, France /C. C/; Childhood Cancer Research Unit. Department of Pediatrics. Karolinska Hospital. S-17176 Stockholm. Sweden ¡P.K.j: The Cancer Registry of Nonvav. Institute for Epidemiological Research Mtmtebello. 0310 Oslo. Nonvav IF. L.j: Pediatrie Hetnatologv Oneologv: Sophia Children's Hospital, 60 3015 (ij Rotterdam, rite Netherlands ¡F.G. A. J. H-C.j: Pediatrie Hemalology Onetilogy, Centre Hospitalier Universitaire. Vaudois, 1011 Lausanne, Switzerland ¡D.B.¡;Pediatrie Heniaíoli>gvOncologi', Inselspital, 3010 Hern. Switzerland ¡N.v. d.W.¡; West Middlands Regional Children's Tumour Research Group, Birmingham Children's Hospital. Birmingham B16 RET, United Kingdom ¡S.P.j: Pediatrie Hetnatology Oncology. Institut Gustave Roussy, Rue Camille Desmoulins, 94805 Villejuif, France ¡O.H.]: Pediatrie Hemuiology Oncology, University Hospital Nijmegen. 6.500 HB Nijmegen. the Netherlands ¡R.J.J.Lj: Pediairic Hematology Oncology. Beatrix Children's Hospital. 9700 RB Groningen, the Netherlands ¡W.A. K.J: and Pediatrie Hematology Oncology, University Hospital, 54511 Nancy, France ¡D.SJ ABSTRACT neuroblastoma is the most frequent solid cancer found in children before the age of 5 years, accounting for 6 to 10% of all childhood An epidemiológica! investigation in 11 European countries comprising cancers (7), we suspected that this finding could be the indication of u total childhood population of 54.1 million children and using 8 separate a lower incidence of this neoplasm in this constitutional chromosomal data sources was conducted to evaluate the occurrence of neurohlastoma anomaly. We investigated this hypothesis by studying a series of more in Down syndrome IDS). No cases of US were detected among 6724 infants and children with neurohlastoma, although more than five were expected. than 6000 cases of neuroblastoma compiled in 11 European countries. This highly significant result (P = 11.11045according to the Poisson test) is consistent with data in the literature, which contains only two poorly detailed cases in epidemiológica! studies and one ganglioneuroma in a DS MATERIALS AND METHODS mosaic patient. Like other tumors, such as leukemias, testicular germ cell tumors and lymphomas are in excess in US patients; the lack of neuro- Cases were identified in 11 European countries. 6 of them through pediatrie blastomas does not reflect a general decreased incidence of cancer but cancer registries: the British National Registry on Childhood Tumors for Great rather a specific underrepresentation of this precise tumor. S-100 h pro Britain; the German Childhood Tumor Registry for Germany; and the Nordic tein, the gene for which maps to the long arm of chromosome 21, (a) is Childhood Cancer Registry for Finland. Iceland. Norway, and Sweden. The overproduced in DS patients, (/>) produces growth inhibition and differ data from Denmark came from the Danish Cancer Registry. In Germany, the entiation of neural cells in vitro, (c) is abundant in good-prognosis neuro- National Childhood Cancer Registry began in 1980, and coverage was less hlastomas, and u/> has been shown to induce growth inhibition and complete in the early years (8). These German data include only the former differentiation and cell death in several human and murine neuroblas- West Germany and not East Germany before reunification. In the Netherlands, toma cell lines and could be responsible for this variation. Additional cases came from the four regional pediatrie oncology centers that cover the epidemiológica! and experimental studies are warranted to confirm our whole geographic area. The Swiss data about incidence of pediatrie cancer interpretation of these data. were provided through the network of the Swiss Pediatrie Oncology Group, which includes all (n = 8) Swiss institutions involved in the management of childhood cancer in this country. In Switzerland, this coverage is considered to INTRODUCTION be close to 100%. In France and Italy, cases were gathered from centralized sources that hold data on children with neuroblastoma who are seen in France by the members of the SociétéFrançaised'Oncologie Pédiatriqueand in Italy An association between congenital anomalies and childhood can cers is now clearly demonstrated: thus, a better knowledge of this link by the members of the Cooperative Group for Neuroblastoma. These two data sources are considered to cover 90c/c of the whole population. To gather as may help identify genes involved in cancer development ( 1). Among genetic diseases, there are several, such as DS,4 neurofibromatosis many cases as possible, we included the longest period available for each type 1, Beckwith-Wiedemann syndrome, and tuberous sclerosis, registry or centralized data source varying from 5 to 48 years. Although the upper limit for age varied according to each registry, inclusion of the age range which are associated with an excess of various neoplasms (2). As far between 14 and 18 years does not lead to any substantial problem, given the as we know, a decreased incidence of a specific neoplasm in a fact that neuroblastomas occur mainly before 10 years of age (7). Eligible cases particular genetic disease has never been reported. An updated review were those diagnosed as histologically proven peripheral neuroblastomas, of the literature on solid tumors in DS patients (3) yielded only two including, tor some registries, in situ neuroblastomas and central nervous cases of neuroblastoma (4, 5) and one ganglioneuroma (6). Because system neuroblastomas. In situ neuroblastomas are minute, incidentally en countered adrenal neuroblastomas usually found during autopsies of infants Received 8/28/97; accepted 12/2/97. (9). In five national registries, systematic recording of the conditions associ The costs of publication of (his article were defrayed in part by the payment of page ated with each case is provided, permitting the detection of DS cases. In the charges. This article must therefore be hereby marked advertisement in accordance with others, systematic registration was not indicated, but major malformations 18 U.S.C. Section 1734 solely to indicate this fact. 1This study was supported by u grant from Ligue pour la Lutte contre le Cancer. were mentioned, and it was possible to indicate the presence or absence of DS Division Corrézienne. The Childhood Cancer Research Group was supported by the in children. Moreover, cancer treatment for a DS patient raises difficult Department of Health, the Scottish Home and Health Department, and the Cancer therapeutic problems due to enhanced drug toxicity (well documented for Research Campaign. leukemias; Ref. 10). which would have attracted the attention of clinicians and - To whom requests for reprints should be addressed, at Laboratory of Pathology. alerted them to the condition. For comparison purposes, we checked the Centre Hospitalier. 19000 Tulle. Trance. Phone: (33) 555-29-79-13; Fax: (33) 555-29- 79-31. presence of three other conditions clinically associated with neuroblastomas; 1Deceased. neurofibromatosis type 1. Hirschsprung's disease, and Beckwith-Wiedemann 4 The abbreviation used is: DS. Down syndrome. syndrome (11. 12). 448 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1998 American Association for Cancer Research. DOWN SYNDROMK AND NEUROBLASTOMA We evaluated the DS population based on the rate at birth as indicated by in every 5,000 infants born alive births and its diagnosis is made the European Registration of Congenital Anomalies (13). which gives the mostly during the 1st year of life (18). the only case observed in this crude rates during the years 1990-1994 in the 25 registries at around 10.4 DS study does not support the idea of an excess of neuroblastoma in this per 10,000 live births (or one for 961.5 births). Because prenatal screening has condition. Taken together, these results indicate that in this population improved during the last decade (14). we think that this value underestimates of 0-18 years of age. infants and children with diseases known to be the DS population at birth for the first years of the study. Life expectancy is at risk for this nervous system neoplasm were not missed. lower in individuals with DS compared to the general population, with only 76.6% of individuals still alive at age 15. This allowed us to calculate a minimum estimate of the proportion of the population ages 0-14 years with DISCUSSION DS in the study regions (15). This study failed to detect a single case of DS among 6724 infants We used the Poisson statistic test to compare the number of cases of neuroblastoma observed in the DS population with the number expected based and children with neuroblastoma, whereas according to our estimation on general population rates. of the DS population, more than 5 cases were expected.