{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T12:29:20Z","timestamp":1789216160828,"version":"build-2803163510"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T00:00:00Z","timestamp":1667520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Neuroblastic tumors (NBTs) are the most common extra-cranial solid tumors of childhood. Neurofibromatosis type 1 (NF1) is the most common neurocutaneous disorder with a predisposition to tumors. The co-occurrence of NBTs in the setting of NF1 has been occasionally reported, suggesting a non-casual association and likely configuring a spectrum of neural crest\u2013derived disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim of the study<\/jats:title><jats:p>To explore the occurrence of NBTs within NF1 and to report on its natural history, therapeutic strategies, and outcomes in an Italian cohort of children with NF1 and in the literature.<\/jats:p><\/jats:sec><jats:sec><jats:title>Subjects and Methods<\/jats:title><jats:p>Study (a): a retrospective analysis of questionnaire-based data [years 1979\u20132017] derived from the databases of the Italian Registry for Neuroblastoma (RINB) of the Italian Society of Pediatric Onco-Haematology (AIEOP); and Study (b): a systematic review search on NF1\/NB co-occurrence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Study (a) identified eight children with NBTs, 0.2% of patients registered in the RINB, fulfilling the diagnostic criteria for NF1. The primary site of NBTs was abdominal in six patients. The NBTs were neuroblastoma (NB) in five patients, ganglioneuroblastoma (GNB) in one, patient, and ganglioneuroma (GN) in two. Metastatic diffusion occurred in three out of eight children. <jats:italic>MYCN<\/jats:italic> gene testing, performed in the tumors of five patients, resulted not-amplified. The major features of NF1 included the following: NF1 family history in four patients, caf\u00e9-au-lait spots in all, freckling in six, Lisch nodules in three, and neurofibromas in three. With regard to the outcome, four children survived three of these for the progression of NB and one for a second tumor. Study (b) identified 12 patients with NF1\/NB from the years 1966\u20132017, and the median age at diagnosis was 27 months (range\u2009=\u20090\u2013168 months). The primary site of NB was thoracic. The prevalent histotype was NB in nine patients, GNB in two, and GN in one. Eight\/nine NBs were metastatic. The <jats:italic>MYCN<\/jats:italic> gene was amplified in the only studied case. The NF1 features included NF1 family history in seven patients; the major NF1 features were caf\u00e9-au-lait spots in nine patients, freckling in one, Lisch nodules in none, and neurofibromas in six. The outcome was good for only two children, while eight children died of neuroblastoma, at a median age of 49.5\u2005months (range\u2009=\u20092.4\u2013174\u2005months), with a median survival time of 21.75\u2005months after diagnosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>To our knowledge, this represents the first systematic study on the occurrence of NBTs in NF1. This confirms that NBs are rare <jats:italic>per se<\/jats:italic> in the setting of NF1 (0.2% of all NBs) and even if compared to the overall frequency of malignancies in NF1 (i.e., 14.7%). The male:female ratio in study (a) (0.6) was different from what was recorded in study (b) (1.5) and in line with the overall increased frequency of malignancies in females with NF1. The median ages at diagnosis of NB in either study (a) or (b) were concordant with what occurred in the NB population. In study (a) versus study (b), the frequency of metastatic diffusion was lower, likely indicating less awareness on work-ups for malignancies in old NF1 series in the literature. The outcome was much better in study (a) than in study (b), indicating that multidisciplinary treatment for NB is highly recommended.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fped.2022.950911","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T10:43:29Z","timestamp":1667558609000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Neuroblastic tumors and neurofibromatosis type 1: A retrospective multicenter study in Italy and systematic review of the literature"],"prefix":"10.3389","volume":"10","author":[{"given":"Federica","family":"Puglisi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachele","family":"Soma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Podda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Vetrella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Rabusin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Tropia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariaclaudia","family":"Meli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Russo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Sorrentino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Erminio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Pulvirenti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martino","family":"Ruggieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Di Cataldo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2493","DOI":"10.1016\/j.ejca.2011.08.008","article-title":"Rare cancers are not so rare: the rare cancer burden in Europe","volume":"47","author":"Gatta","year":"2011","journal-title":"Eur J Cancer"},{"key":"B2","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1200\/JCO.1992.10.2.323","article-title":"A population-based study of neuroblastoma incidence, survival, and mortality in North America","volume":"10","author":"Bernstein","year":"1992","journal-title":"J Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1592","DOI":"10.1200\/JCO.2003.05.191","article-title":"Disseminated neuroblastoma in children older than one year at diagnosis: comparable results with three consecutive high-dose protocols adopted by the Italian co-operative group for neuroblastoma","volume":"21","author":"De Bernardi","year":"2003","journal-title":"J Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1016\/s0959-8049(00)00058-7","article-title":"Clinical prognostic factors in 1277 patients with neuroblastoma: results of The European Neuroblastoma Study Group \u201cSurvey\u201d 1982\u20131992","volume":"36","author":"Cotterill","year":"2000","journal-title":"Eur J Cancer"},{"key":"B5","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1016\/s0959-8049(01)00003-x","article-title":"Survival of children with neuroblastoma. Time trends and regional differences in Europe, 1978\u20131992","volume":"37","author":"Spix","year":"2001","journal-title":"Eur J Cancer"},{"key":"B6","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1038\/sj.bjc.6604922","article-title":"Unchanged incidence and increased survival in children with neuroblastoma in Denmark 1981\u20132000: a population-based study","volume":"100","author":"Schroeder","year":"2009","journal-title":"Br J Cancer"},{"key":"B7","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1016\/s0022-3476(97)70090-8","article-title":"Neuroblastoma and related tumors in Turner's syndrome","volume":"131","author":"Blatt","year":"1997","journal-title":"J Pediatr"},{"key":"B8","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1002\/ajmg.a.30603","article-title":"High incidence of malformation syndromes in a series of 1,073 children with cancer","author":"Merks","year":"2005","journal-title":"Am J Med Genet A"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1002\/ajmg.a.33405","article-title":"Kabuki syndrome and cancer in two patients","author":"Tumino","year":"2010","journal-title":"Am J Med Genet A"},{"key":"B10","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/s0887-8994(03)00010-9","article-title":"Neurocristopathies presenting with neurologic abnormalities associated with Hirschsprung\u2019s disease","volume":"28","author":"Shahar","year":"2003","journal-title":"Pediatr Neurol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1097\/00043426-200302000-00015","article-title":"Treatment of neuroblastoma in patients with neurocristopathy syndromes","volume":"25","author":"Nemecek","year":"2003","journal-title":"J Pediatr Hematol Oncol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1016\/0022-3468(95)90027-6","article-title":"The complete spectrum of neurocristopathy in an infant with congenital hypoventilation, Hirschsprung\u2019s disease, and neuroblastoma","volume":"30","author":"Stovroff","year":"1995","journal-title":"J Pediatr Surg"},{"key":"B13","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1200\/JCO.1985.3.1.117","article-title":"Synchronous neuroblastoma and von Recklinghausen\u2019s disease: a review of the literature","volume":"3","author":"Kushner","year":"1985","journal-title":"J Clin Oncol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1001\/archderm.141.1.71","article-title":"Prevalence of neurofibromatosis 1 in German children at elementary school enrollment","volume":"141","author":"Lammert","year":"2005","journal-title":"Arch Dermatol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1506","DOI":"10.1038\/s41436-021-01170-5","article-title":"Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation","volume":"23","author":"Legius","year":"2021","journal-title":"Genet Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1002\/ajmg.a.33139","article-title":"Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service","author":"Evans","year":"2010","journal-title":"Am J Med Genet A"},{"key":"B17","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1007\/bf00197259","article-title":"Preferential mutation of the neurofibromatosis type 1 gene in paternally derived chromosomes","volume":"88","author":"Stephens","year":"1992","journal-title":"Hum Genet"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1212\/wnl.56.11.1433","article-title":"The clinical and diagnostic implications of mosaicism in the neurofibromatoses","volume":"56","author":"Ruggieri","year":"2001","journal-title":"Neurology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1038\/bjc.2012.535","article-title":"Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study","volume":"108","author":"Seminog","year":"2013","journal-title":"Br J Cancer"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1086\/320121","article-title":"Mortality in neurofibromatosis 1: an analysis using U.S. death certificates","volume":"68","author":"Rasmussen","year":"2001","journal-title":"Am J Hum Genet"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1056\/NEJM198604173141603","article-title":"Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms","volume":"314","author":"Sorensen","year":"1986","journal-title":"N Engl J Med"},{"key":"B22","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/1750-1172-6-18","article-title":"Mortality associated with neurofibromatosis 1: a cohort study of 1895 patients in 1980-2006 in France","volume":"6","author":"Duong","year":"2011","journal-title":"Orphanet J Rare Dis"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1038\/ejhg.2011.113","article-title":"Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989","volume":"19","author":"Evans","year":"2011","journal-title":"Eur J Hum Genet"},{"key":"B24","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1002\/1098-2272(200101)20:1%3C75::AID-GEPI7%3E3.0.CO;2-Z","article-title":"Neoplasms in neurofibromatosis 1 are related to gender but not to family history of cancer","volume":"20","author":"Airewele","year":"2001","journal-title":"Genet Epidemiol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1038\/jid.2014.465","article-title":"Incidence and mortality of neurofibromatosis: a total population study in Finland","volume":"135","author":"Uusitalo","year":"2015","journal-title":"J Invest Dermatol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/sj.bjc.6603227","article-title":"A prospective study of neurofibromatosis type 1 cancer incidence in the UK","volume":"95","author":"Walker","year":"2006","journal-title":"Br J Cancer"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1002\/cncr.21751","article-title":"Neuroblastoma in adolescents: the Italian experience","volume":"106","author":"Conte","year":"2006","journal-title":"Cancer"},{"key":"B28","first-page":"211","article-title":"Italian Cancer figures, report 2012: cancer in children and adolescents","volume":"37","year":"2013","journal-title":"Epidemiol Prev"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1466","DOI":"10.1200\/JCO.1993.11.8.1466","article-title":"Revisions of the international criteria for neuroblastoma diagnosis, staging and response to treatment","volume":"11","author":"Brodeur","year":"1993","journal-title":"J Clin Oncol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1200\/JCO.2008.16.6876","article-title":"The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report","volume":"27","author":"Monclair","year":"2009","journal-title":"J Clin Oncol"},{"key":"B31","first-page":"42","article-title":"Malignancies in Chinese patients with neurofibromatosis type 1","volume":"19","author":"Cheuk","year":"2013","journal-title":"Hong Kong Med J"},{"key":"B32","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1007\/s00381-005-0009-z","article-title":"Mature neuroblastic tumors with spinal cord compression: report of five pediatric cases","volume":"22","author":"Duhem-Tonnelle","year":"2006","journal-title":"Childs Nerv Syst"},{"key":"B33","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1111\/j.1525-1470.1990.tb01028.x","article-title":"Neurofibromatosis 1: recognition and management of associated neuroblastoma","volume":"7","author":"Hayflick","year":"1990","journal-title":"Pediatr Dermatol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1002\/1097-0142(196607)19:7%3C1032::aid-cncr2820190719%3E3.0.co;2-7","article-title":"Neuroblastoma and ganglioneuroma in a child with multiple neurofibromatosis. Implications for the mutational origin of neuroblastoma","volume":"19","author":"Knudson","year":"1966","journal-title":"Cancer"},{"key":"B35","doi-asserted-by":"publisher","first-page":"2794","DOI":"10.1002\/1097-0142(19850615)55:12%3C2794::aid-cncr2820551213%3E3.0.co;2-l","article-title":"Malignant pheochromocytoma with ganglioneuroblastoma elements in a patient with von Recklinghausen\u2019s disease","volume":"55","author":"Nakagawara","year":"1985","journal-title":"Cancer"},{"key":"B36","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3109\/15513818609068849","article-title":"Neurofibromatosis and associated neuroectodermal tumors: a congenital neurocristopathy","volume":"5","author":"Qualman","year":"1986","journal-title":"Pediatr Pathol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1090","DOI":"10.1001\/archpedi.1982.03970480056012","article-title":"Ganglioneuroma and acute lymphoblastic leukemia in association with neurofibromatosis","volume":"136","author":"Weiner","year":"1982","journal-title":"Am J Dis Child"},{"key":"B38","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1002\/1097-0142(197409)34:3%3C786::aid-cncr2820340339%3E3.0.co;2-9","article-title":"Disseminated neuroblastoma in a child with von Recklinghausen\u2019s disease","volume":"34","author":"Witzleben","year":"1974","journal-title":"Cancer"},{"key":"B39","first-page":"160","article-title":"An epidemiological, clinical and genetic survey of neurofibromatosis type 1 in children under sixteen years of age","volume":"77","author":"McKeever","year":"2008","journal-title":"Ulster Med J"},{"key":"B40","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1002\/humu.20601","article-title":"Germline and somatic NF1 gene mutation spectrum in NF1-associated malignant peripheral nerve sheath tumors (MPNSTs)","volume":"29","author":"Upadhyaya","year":"2008","journal-title":"Hum Mutat"},{"key":"B41","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1046\/j.1365-2990.2000.00258.x","article-title":"Loss of neurofibromatosis 1 (NF1) gene expression in NF1-associated pilocytic astrocytomas","volume":"26","author":"Gutmann","year":"2000","journal-title":"Neuropathol Appl Neurobiol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1002\/ajmg.a.10167","article-title":"Homozygous inactivation of NF1 gene in a patient with familial NF1 and disseminated neuroblastoma","author":"Origone","year":"2003","journal-title":"Am J Med Genet A"},{"key":"B43","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/s0165-4608(96)00259-2","article-title":"Homozygous deletion of the neurofibromatosis-1 gene in the tumor of a patient with neuroblastoma","volume":"95","author":"Martinsson","year":"1997","journal-title":"Cancer Genet Cytogenet"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.1056\/NEJM199906243402504","article-title":"Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma","volume":"340","author":"Bown","year":"1999","journal-title":"N Engl J Med"},{"key":"B45","author":"Goodman","year":"1999"},{"key":"B46","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1002\/1097-0142(197007)26:1%3C162::aid-cncr2820260122%3E3.0.co;2-y","article-title":"A possible relationship of neuroblastoma to Von Recklinghausen\u2019s disease","volume":"26","author":"Bolande","year":"1970","journal-title":"Cancer"},{"key":"B47","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1677\/erc.0.0100099","article-title":"Adrenal ganglioneuroma in a patient presenting with severe hypertension and diarrhea","volume":"10","author":"Koch","year":"2003","journal-title":"Endocr Relat Cancer"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2022.950911\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T10:43:33Z","timestamp":1667558613000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2022.950911\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,4]]},"references-count":47,"alternative-id":["10.3389\/fped.2022.950911"],"URL":"https:\/\/doi.org\/10.3389\/fped.2022.950911","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,4]]},"article-number":"950911"}}