«Մասնակից:Shush.hovsepyan/Ավազարկղ»–ի խմբագրումների տարբերություն

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* A tumor in the bones around the eyes or [[Orbit (anatomy)|orbits]] may cause distinct bruising and swelling.

 

 

 

Rare but characteristic presentations include transverse [[myelopathy]] (tumor spinal cord compression, 5% of cases), treatment-resistant diarrhea (tumor [[vasoactive intestinal peptide]] secretion, 4% of cases), [[Horner's syndrome]] (cervical tumor, 2.4% of cases), [[opsoclonus myoclonus syndrome]]<ref name="pmid19430769">{{cite journal | vauthors = Rothenberg AB, Berdon WE, D'Angio GJ, Yamashiro DJ, Cowles RA | title = The association between neuroblastoma and opsoclonus-myoclonus syndrome: a historical review | journal = Pediatric Radiology | volume = 39 | issue = 7 | pages = 723–6 | date = July 2009 | pmid = 19430769 | doi = 10.1007/s00247-009-1282-x | s2cid = 24523263 }}</ref> and [[ataxia]] (suspected [[paraneoplastic]] cause, 1.3% of cases), and [[hypertension]] ([[catecholamine]] secretion or kidney artery compression, 1.3% of cases).<ref>{{cite book |last=Cheung |first=Nai-Kong |title=Neuroblastoma |publisher=[[Springer-Verlag]] |pages=66–7 |year=2005 |isbn=978-3-540-40841-3 }}</ref>

 

The cause of neuroblastoma is not well understood. The great majority of cases are sporadic and nonfamilial. About 1–2% of cases run in families and have been linked to specific gene mutations. Familial neuroblastoma in some cases is caused by rare germline mutations in the [[anaplastic lymphoma kinase]] (''ALK'') gene.<ref name="pmid18724359">{{cite journal | vauthors = Mossé YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, Laureys G, Speleman F, Kim C, Hou C, Hakonarson H, Torkamani A, Schork NJ, Brodeur GM, Tonini GP, Rappaport E, Devoto M, Maris JM | display-authors = 6 | title = Identification of ALK as a major familial neuroblastoma predisposition gene | journal = Nature | volume = 455 | issue = 7215 | pages = 930–5 | date = October 2008 | pmid = 18724359 | pmc = 2672043 | doi = 10.1038/nature07261 | bibcode = 2008Natur.455..930M }}</ref> Germline mutations in the ''[[PHOX2B]] ''or ''[[KIF1B]]'' gene have been implicated in familial neuroblastoma, as well. Neuroblastoma is also a feature of [[neurofibromatosis type 1]] and the [[Beckwith-Wiedemann syndrome]].

 

Other studies have examined possible links with [[atopy]] and exposure to [[infection]] early in life,<ref>{{cite journal | vauthors = Menegaux F, Olshan AF, Neglia JP, Pollock BH, Bondy ML | title = Day care, childhood infections, and risk of neuroblastoma | journal = American Journal of Epidemiology | volume = 159 | issue = 9 | pages = 843–51 | date = May 2004 | pmid = 15105177 | pmc = 2080646 | doi = 10.1093/aje/kwh111 }}</ref> use of hormones and fertility drugs,<ref name="Olshan et al. 1999">{{cite journal | vauthors = Olshan AF, Smith J, Cook MN, Grufferman S, Pollock BH, Stram DO, Seeger RC, Look AT, Cohn SL, Castleberry RP, Bondy ML | display-authors = 6 | title = Hormone and fertility drug use and the risk of neuroblastoma: a report from the Children's Cancer Group and the Pediatric Oncology Group | journal = American Journal of Epidemiology | volume = 150 | issue = 9 | pages = 930–8 | date = November 1999 | pmid = 10547138 | doi = 10.1093/oxfordjournals.aje.a010101 | url = http://aje.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10547138 | doi-access = free }}</ref> and maternal use of hair dye.<ref name="McCall EE,''et al.'' 2005">{{cite journal | vauthors = McCall EE, Olshan AF, Daniels JL | title = Maternal hair dye use and risk of neuroblastoma in offspring | journal = Cancer Causes & Control | volume = 16 | issue = 6 | pages = 743–8 | date = August 2005 | pmid = 16049813 | doi = 10.1007/s10552-005-1229-y | s2cid = 24323871 }}</ref><ref name="pmid19159399">{{cite journal | vauthors = Heck JE, Ritz B, Hung RJ, Hashibe M, Boffetta P | title = The epidemiology of neuroblastoma: a review | journal = Paediatric and Perinatal Epidemiology | volume = 23 | issue = 2 | pages = 125–43 | date = March 2009 | pmid = 19159399 | doi = 10.1111/j.1365-3016.2008.00983.x }}</ref>

 

The diagnosis is usually confirmed by a [[anatomical pathology|surgical pathologist]], taking into account the clinical presentation, microscopic findings, and other laboratory tests. It may arise from any [[neural crest]] element of the [[sympathetic nervous system]] (SNS).

 

[[Esthesioneuroblastoma]], also known as olfactory neuroblastoma, is believed to arise from the [[olfactory epithelium]] and its classification remains controversial. However, since it is not a sympathetic nervous system malignancy, esthesioneuroblastoma is a distinct clinical entity and is not to be confused with neuroblastoma.<ref>{{EMedicine|article|278047|Esthesioneuroblastoma}}</ref><ref>{{cite book |last=Cheung |first=Nai-Kong |title=Neuroblastoma |publisher=[[Springer-Verlag]] |page=73 |year=2005 |isbn=978-3-540-40841-3 }}</ref>

 

In about 90% of cases of neuroblastoma, elevated levels of [[catecholamines]] or their metabolites are found in the urine or blood. Catecholamines and their metabolites include [[dopamine]], [[homovanillic acid]] (HVA), and/or [[vanillylmandelic acid]] (VMA).<ref name="pmid16732582">{{cite journal | vauthors = Strenger V, Kerbl R, Dornbusch HJ, Ladenstein R, Ambros PF, Ambros IM, Urban C | title = Diagnostic and prognostic impact of urinary catecholamines in neuroblastoma patients | journal = Pediatric Blood & Cancer | volume = 48 | issue = 5 | pages = 504–9 | date = May 2007 | pmid = 16732582 | doi = 10.1002/pbc.20888 }}</ref>

 

Another way to detect neuroblastoma is the [[mIBG|meta-iodobenzylguanidine]] scan, which is taken up by 90 to 95% of all neuroblastomas, often termed "mIBG-avid".<ref name="pmid17544628"/> The mechanism is that mIBG is taken up by sympathetic neurons, and is a functioning analog of the neurotransmitter [[norepinephrine]]. When it is radio-iodinated with [[I-131]] or I-123 (radioactive iodine [[isotopes]]), it is a very good [[radiopharmaceutical]] for diagnosis and monitoring of response to treatment for this disease. With a [[half-life]] of 13 hours, I-123 is the preferred isotope for imaging sensitivity and quality. I-131 has a half-life of 8 days and at higher doses is an effective therapy as targeted radiation against relapsed and refractory neuroblastoma.<ref name="pmid15653652">{{cite journal | vauthors = Pashankar FD, O'Dorisio MS, Menda Y | title = MIBG and somatostatin receptor analogs in children: current concepts on diagnostic and therapeutic use | journal = Journal of Nuclear Medicine | volume = 46 Suppl 1 | issue = Suppl 1 | pages = 55S–61S | date = January 2005 | pmid = 15653652 | url = http://jnm.snmjournals.org/cgi/pmidlookup?view=long&pmid=15653652 }}</ref> As mIBG is not always taken up by neuroblastomas, researchers have explored in children with neuroblastoma whether another type of nuclear imaging, fluoro-deoxy-glucose - positron emission tomography, often termed "F-FDG-PET", might be useful.<ref name=Blee2015>{{cite journal | vauthors = Bleeker G, Tytgat GA, Adam JA, Caron HN, Kremer LC, Hooft L, van Dalen EC | title = 123I-MIBG scintigraphy and 18F-FDG-PET imaging for diagnosing neuroblastoma | journal = The Cochrane Database of Systematic Reviews | issue = 9 | pages = CD009263 | date = September 2015 | pmid = 26417712 | pmc = 4621955 | doi = 10.1002/14651858.cd009263.pub2 }}</ref> Evidence suggests that this might be advisable to use in children with neuroblastoma for which mIBG does not work, but more research is needed in this area.<ref name=Blee2015/>

 

On microscopy, the tumor cells are typically described as small, round and blue, and [[Rosette (design)|rosette]] patterns ([[Homer Wright pseudorosettes]]) may be seen. Homer Wright pseudorosettes are tumor cells around the [[neuropil]], not to be confused with a true rosettes, which are tumor cells around an empty lumen.<ref>{{cite book |title=Robbins and Cotran pathologic basis of disease |date=2015 |publisher=Elsevier |isbn=978-1455726134 |edition=9}}</ref> They are also distinct from the pseudorosettes of an ependymoma which consist of tumor cells with [[glial fibrillary acidic protein]] (GFAP)–positive processes tapering off toward a blood vessel (thus a combination of the two).<ref>{{EMedicine|article|277621|Ependymoma}}</ref> A variety of immunohistochemical stains are used by pathologists to distinguish neuroblastomas from histological mimics, such as [[rhabdomyosarcoma]], [[Ewing's sarcoma]], [[lymphoma]] and [[Wilms' tumor]].<ref>{{cite journal | vauthors = Carter RL, al-Sams SZ, Corbett RP, Clinton S | title = A comparative study of immunohistochemical staining for neuron-specific enolase, protein gene product 9.5 and S-100 protein in neuroblastoma, Ewing's sarcoma and other round cell tumours in children | journal = Histopathology | volume = 16 | issue = 5 | pages = 461–7 | date = May 1990 | pmid = 2163356 | doi = 10.1111/j.1365-2559.1990.tb01545.x }}</ref>

 

Neuroblastoma is one of the peripheral neuroblastic [[tumors]] (pNTs) that have similar origins and show a wide pattern of differentiation ranging from [[benign]] [[ganglioneuroma]] to [[stroma (animal tissue)|stroma]]-rich [[ganglioneuroblastoma]] with neuroblastic cells intermixed or in nodules, to highly malignant neuroblastoma. This distinction in the pre-treatment tumor pathology is an important prognostic factor, along with age and [[mitosis]]-[[karyorrhexis]] index (MKI). This pathology classification system (the Shimada system) describes "favorable" and "unfavorable" tumors by the International Neuroblastoma Pathology Committee (INPC) which was established in 1999 and revised in 2003.<ref name="pmid14601099">{{cite journal | vauthors = Peuchmaur M, d'Amore ES, Joshi VV, Hata J, Roald B, Dehner LP, Gerbing RB, Stram DO, Lukens JN, Matthay KK, Shimada H | display-authors = 6 | title = Revision of the International Neuroblastoma Pathology Classification: confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular | journal = Cancer | volume = 98 | issue = 10 | pages = 2274–81 | date = November 2003 | pmid = 14601099 | doi = 10.1002/cncr.11773 | s2cid = 27081822 | url = https://semanticscholar.org/paper/03500f75a146ff420becfd3492bd1a8edee8e460 }}</ref>

 

The "International Neuroblastoma Staging System" (INSS) established in 1986 and revised in 1988 stratifies neuroblastoma according to its anatomical presence at diagnosis:<ref>{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfessional/page3#Section_185 |title=Neuroblastoma Treatment—National Cancer Institute |access-date=2008-07-30 |url-status=live |archive-url=https://web.archive.org/web/20081002182158/http://www.cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfessional/page3#Section_185 |archive-date=2008-10-02 |date=1980-01-01 }}</ref><ref name="pmid3199170">{{cite journal | vauthors = Brodeur GM, Seeger RC, Barrett A, Berthold F, Castleberry RP, D'Angio G, De Bernardi B, Evans AE, Favrot M, Freeman AI | display-authors = 6 | title = International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma | journal = Journal of Clinical Oncology | volume = 6 | issue = 12 | pages = 1874–81 | date = December 1988 | pmid = 3199170 | doi = 10.1200/JCO.1988.6.12.1874 | url = https://espace.library.uq.edu.au/view/UQ:394412/UQ394412_OA.pdf }}</ref><ref name="pmid8336186">{{cite journal | vauthors = Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, De Bernardi B, Evans AE, Favrot M, Hedborg F | display-authors = 6 | title = Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment | journal = Journal of Clinical Oncology | volume = 11 | issue = 8 | pages = 1466–77 | date = August 1993 | pmid = 8336186 | doi = 10.1200/JCO.1993.11.8.1466 }}</ref>

 

 

Although international agreement on staging (INSS) has been used, the need for an international consensus on risk assignment has also been recognized in order to compare similar cohorts in results of studies. Beginning in 2005, representatives of the major pediatric oncology cooperative groups have met to review data for 8,800 people with neuroblastoma treated in Europe, Japan, USA, Canada, and Australia between 1990 and 2002. This task force has proposed the International Neuroblastoma Risk Group (INRG) classification system. Retrospective studies revealed the high survival rate of 12–18 month old age group, previously categorized as high-risk, and prompted the decision to reclassify 12–18 month old children without N-''myc'' (also commonly referred to as [[MYCN]]) amplification to intermediate risk category.<ref name="pmid16116154">{{cite journal | vauthors = Schmidt ML, Lal A, Seeger RC, Maris JM, Shimada H, O'Leary M, Gerbing RB, Matthay KK | display-authors = 6 | title = Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study | journal = Journal of Clinical Oncology | volume = 23 | issue = 27 | pages = 6474–80 | date = September 2005 | pmid = 16116154 | doi = 10.1200/JCO.2005.05.183 }}</ref>

The new INRG risk assignment will classify neuroblastoma at diagnosis based on a new International Neuroblastoma Risk Group Staging System (INRGSS):

 

 

The new risk stratification will be based on the new INRGSS staging system, age (dichotomized at 18 months), tumor grade, [[N-myc]] amplification, unbalanced 11q aberration, and [[ploidy]] into four pre-treatment risk groups: very low, low, intermediate, and high risk.<ref name=Lancet2007/><ref>{{cite journal | vauthors = Cohn SL, London WB, Monclair T, Matthay KK, Ambros PF, Pearson AD |year=2007 |title=Update on the development of the international neuroblastoma risk group (INRG) classification schema |journal=Journal of Clinical Oncology |volume=25 |issue=18 Suppl |pages=9503 |doi=10.1200/jco.2007.25.18_suppl.9503 |url=http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/9503 |archive-url=https://web.archive.org/web/20160110164845/http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/9503 |url-status=dead |archive-date=2016-01-10 }}

</ref>

 

Urine [[catecholamine]] level can be elevated in pre-clinical neuroblastoma. Screening asymptomatic infants at three weeks, six months, and one year has been performed in Japan, Canada, Austria and Germany since the 1980s.<ref name="pmid11932470">{{cite journal | vauthors = Woods WG, Gao RN, Shuster JJ, Robison LL, Bernstein M, Weitzman S, Bunin G, Levy I, Brossard J, Dougherty G, Tuchman M, Lemieux B | display-authors = 6 | title = Screening of infants and mortality due to neuroblastoma | journal = The New England Journal of Medicine | volume = 346 | issue = 14 | pages = 1041–6 | date = April 2002 | pmid = 11932470 | doi = 10.1056/NEJMoa012387 }}</ref><ref name="pmid12880955">{{cite journal | vauthors = Schilling FH, Spix C, Berthold F, Erttmann R, Sander J, Treuner J, Michaelis J | title = Children may not benefit from neuroblastoma screening at 1 year of age. Updated results of the population based controlled trial in Germany | journal = Cancer Letters | volume = 197 | issue = 1–2 | pages = 19–28 | date = July 2003 | pmid = 12880955 | doi = 10.1016/S0304-3835(03)00077-6 }}</ref> Japan began screening six-month-olds for neuroblastoma via analysis of the levels of [[homovanillic acid]] and [[vanilmandelic acid]] in 1984. Screening was halted in 2004 after studies in Canada and Germany showed no reduction in deaths due to neuroblastoma, but rather caused an increase in diagnoses that would have disappeared without treatment, subjecting those infants to unnecessary surgery and chemotherapy.<ref name="pmid15128908">{{cite journal | vauthors = Tsubono Y, Hisamichi S | title = A halt to neuroblastoma screening in Japan | journal = The New England Journal of Medicine | volume = 350 | issue = 19 | pages = 2010–1 | date = May 2004 | pmid = 15128908 | doi = 10.1056/NEJM200405063501922 }}</ref><ref>{{cite web |url=http://www.cancer.gov/cancertopics/pdq/screening/neuroblastoma/HealthProfessional/page3 |title=Neuroblastoma Screening |publisher=National Cancer Institute |access-date=2008-07-30 |url-status=live |archive-url=https://web.archive.org/web/20081001234010/http://www.cancer.gov/cancertopics/pdq/screening/neuroblastoma/HealthProfessional/page3 |archive-date=2008-10-01 |date=1980-01-01 }}</ref><ref>Darshak Sanghavi, [http://www.slate.com/id/2154563/ "Screen Alert: How an Ounce of RX Prevention can Cause a Pound of Hurt"] {{webarchive|url=https://web.archive.org/web/20061201153438/http://www.slate.com/id/2154563 |date=2006-12-01 }}, ''Slate'' magazine, November 28, 2006</ref>

 

When the [[lesion]] is localized, it is generally curable. However, long-term survival for children with advanced disease older than 18 months of age is poor despite aggressive [[multimodal therapy]] (intensive [[chemotherapy]], [[surgery]], [[radiation therapy]], [[stem cell transplant]], [[differentiation (cellular)|differentiation]] agent [[isotretinoin]] also called 13-''cis''-retinoic acid, and frequently [[immunotherapy]]<ref name="pmid18081947">{{cite journal | vauthors = Johnson E, Dean SM, Sondel PM | title = Antibody-based immunotherapy in high-risk neuroblastoma | journal = Expert Reviews in Molecular Medicine | volume = 9 | issue = 34 | pages = 1–21 | date = December 2007 | pmid = 18081947 | doi = 10.1017/S1462399407000518 }}</ref> with anti-[[GD2]] [[monoclonal antibody therapy]]).

 

Chemotherapy agents used in combination have been found to be effective against neuroblastoma. Agents commonly used in induction and for stem cell transplant conditioning are platinum compounds ([[cisplatin]], [[carboplatin]]), alkylating agents ([[cyclophosphamide]], [[ifosfamide]], [[melphalan]]), [[topoisomerase]] II inhibitor ([[etoposide]]), [[anthracycline]] antibiotics ([[doxorubicin]]) and vinca [[alkaloids]] ([[vincristine]]). Some newer regimens include topoisomerase I inhibitors ([[topotecan]] and [[irinotecan]]) in induction which have been found to be effective against recurrent disease.

 

By data from [[England]], the overall [[5-year survival]] rate of neuroblastoma is 67%.<ref>{{cite web|url=https://www.childrenwithcancer.org.uk/childhood-cancer-info/cancer-types/neuroblastoma/|website=[[Children with Cancer UK]]|title=Neuroblastoma overview|accessdate=2020-07-01}}</ref> Between 20% and 50% of high-risk cases do not respond adequately to induction high-dose chemotherapy and are progressive or refractory.<ref>{{cite journal | vauthors = Kushner BH, Kramer K, LaQuaglia MP, Modak S, Yataghene K, Cheung NK | title = Reduction from seven to five cycles of intensive induction chemotherapy in children with high-risk neuroblastoma | journal = Journal of Clinical Oncology | volume = 22 | issue = 24 | pages = 4888–92 | date = December 2004 | pmid = 15611504 | doi = 10.1200/JCO.2004.02.101 }}</ref><ref name="Kreissman et al 2007">{{cite journal | vauthors = Kreissman SG, Villablanca JG, Diller L, London WB, Maris JM, Park JR, Reynolds CP, von Allmen D, Cohn SL, Matthay KK |year=2007 |title=Response and toxicity to a dose-intensive multi-agent chemotherapy induction regimen for high risk neuroblastoma (HR-NB): A Children's Oncology Group (COG A3973) study |journal=Journal of Clinical Oncology |volume=25 |issue=18 Suppl |pages=9505 |url=http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/9505 |archive-url=https://web.archive.org/web/20160110164845/http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/9505 |url-status=dead |archive-date=2016-01-10 |doi=10.1200/jco.2007.25.18_suppl.9505}}</ref> Relapse after completion of frontline therapy is also common. Further treatment is available in phase I and phase II clinical trials that test new agents and combinations of agents against neuroblastoma, but the outcome remains very poor for relapsed high-risk disease.<ref name="pmid16395684">{{cite journal | vauthors = Ceschel S, Casotto V, Valsecchi MG, Tamaro P, Jankovic M, Hanau G, Fossati F, Pillon M, Rondelli R, Sandri A, Silvestri D, Haupt R, Cuttini M | display-authors = 6 | title = Survival after relapse in children with solid tumors: a follow-up study from the Italian off-therapy registry | journal = Pediatric Blood & Cancer | volume = 47 | issue = 5 | pages = 560–6 | date = October 2006 | pmid = 16395684 | doi = 10.1002/pbc.20726 }}</ref>

 

Most long-term survivors alive today had low or intermediate risk disease and milder courses of treatment compared to high-risk disease. The majority of survivors have long-term effects from the treatment. Survivors of intermediate and high-risk treatment often experience hearing loss, growth reduction, thyroid function disorders, learning difficulties, and greater risk of secondary cancers affect survivors of high-risk disease.<ref name="pmid17974716">{{cite journal | vauthors = Gurney JG, Tersak JM, Ness KK, Landier W, Matthay KK, Schmidt ML | title = Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors: a report from the Children's Oncology Group | journal = Pediatrics | volume = 120 | issue = 5 | pages = e1229-36 | date = November 2007 | pmid = 17974716 | doi = 10.1542/peds.2007-0178 | s2cid = 10606999 }}</ref><ref name="pmid17724446">{{cite journal | vauthors = Trahair TN, Vowels MR, Johnston K, Cohn RJ, Russell SJ, Neville KA, Carroll S, Marshall GM | display-authors = 6 | title = Long-term outcomes in children with high-risk neuroblastoma treated with autologous stem cell transplantation | journal = Bone Marrow Transplantation | volume = 40 | issue = 8 | pages = 741–6 | date = October 2007 | pmid = 17724446 | doi = 10.1038/sj.bmt.1705809 | doi-access = free }}</ref> An estimated two of three survivors of childhood cancer will ultimately develop at least one chronic and sometimes life-threatening health problem within 20 to 30 years after the cancer diagnosis.<ref>{{cite web |first=Alan |last=Mozes |date=February 21, 2007 |title=Childhood Cancer Survivors Face Increased Sarcoma Risk |publisher=[[HealthDay]] |url=http://consumer.healthday.com/cancer-information-5/bone-cancer-news-92/childhood-cancer-survivors-face-increased-sarcoma-risk-602068.html |url-status=live |archive-url=https://web.archive.org/web/20150908085659/http://consumer.healthday.com/cancer-information-5/bone-cancer-news-92/childhood-cancer-survivors-face-increased-sarcoma-risk-602068.html |archive-date=September 8, 2015 }}</ref><ref>{{cite journal | vauthors = Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows AT, Friedman DL, Marina N, Hobbie W, Kadan-Lottick NS, Schwartz CL, Leisenring W, Robison LL | display-authors = 6 | title = Chronic health conditions in adult survivors of childhood cancer | journal = The New England Journal of Medicine | volume = 355 | issue = 15 | pages = 1572–82 | date = October 2006 | pmid = 17035650 | doi = 10.1056/NEJMsa060185 }}</ref><ref>{{cite journal | vauthors = Laverdière C, Liu Q, Yasui Y, Nathan PC, Gurney JG, Stovall M, Diller LR, Cheung NK, Wolden S, Robison LL, Sklar CA | display-authors = 6 | title = Long-term outcomes in survivors of neuroblastoma: a report from the Childhood Cancer Survivor Study | journal = Journal of the National Cancer Institute | volume = 101 | issue = 16 | pages = 1131–40 | date = August 2009 | pmid = 19648511 | pmc = 2728747 | doi = 10.1093/jnci/djp230 }}</ref>

 

Based on a series of 493 neuroblastoma samples, it has been reported that overall genomic pattern, as tested by [[Virtual Karyotype|array-based karyotyping]], is a predictor of outcome in neuroblastoma:<ref name="pmid19171713">{{cite journal | vauthors = Janoueix-Lerosey I, Schleiermacher G, Michels E, Mosseri V, Ribeiro A, Lequin D, Vermeulen J, Couturier J, Peuchmaur M, Valent A, Plantaz D, Rubie H, Valteau-Couanet D, Thomas C, Combaret V, Rousseau R, Eggert A, Michon J, Speleman F, Delattre O | display-authors = 6 | title = Overall genomic pattern is a predictor of outcome in neuroblastoma | journal = Journal of Clinical Oncology | volume = 27 | issue = 7 | pages = 1026–33 | date = March 2009 | pmid = 19171713 | doi = 10.1200/JCO.2008.16.0630 | url = http://www.hal.inserm.fr/inserm-00369944/file/JCO.Janoueix-2009.pdf }}</ref>

*Tumors presenting exclusively with whole chromosome copy number changes were associated with excellent survival.

[[Virtual Karyotype|Virtual karyotyping]] can be performed on fresh or paraffin-embedded tumors to assess copy number at these loci. SNP array virtual karyotyping is preferred for tumor samples, including neuroblastomas, because they can detect copy neutral loss of heterozygosity (acquired uniparental disomy). Copy neutral LOH can be biologically equivalent to a deletion and has been detected at key loci in neuroblastoma.<ref>{{cite journal | vauthors = Carén H, Erichsen J, Olsson L, Enerbäck C, Sjöberg RM, Abrahamsson J, Kogner P, Martinsson T | display-authors = 6 | title = High-resolution array copy number analyses for detection of deletion, gain, amplification and copy-neutral LOH in primary neuroblastoma tumors: four cases of homozygous deletions of the CDKN2A gene | journal = BMC Genomics | volume = 9 | pages = 353 | date = July 2008 | pmid = 18664255 | pmc = 2527340 | doi = 10.1186/1471-2164-9-353 }}</ref> ArrayCGH, FISH, or conventional cytogenetics cannot detect copy neutral LOH.

 

Neuroblastoma comprises 6–10% of all childhood cancers, and 15% of cancer deaths in children. The annual mortality rate is 10 per million children in the 0- to 4-year-old age group, and 4 per million in the 4- to 9-year old age group.<ref>{{cite book |first1=Garrett M. |last1=Brodeur |first2=Michael D. |last2=Hogarty |first3=Yael P. |last3=Mosse |first4=John M. |last4=Maris |chapter=Neuroblastoma |editor1-first=Philip A. |editor1-last=Pizzo |editor2-first=David G. |editor2-last=Poplack | name-list-style = vanc |title=Principles and Practice of Pediatric Oncology |edition=6th |year=1997 |pages=886–922 |isbn=978-1-60547-682-7}}</ref>

 

The highest number of cases is in the first year of life, and some cases are [[congenital]]. The age range is broad, including older children and adults,<ref name="pmid9149032">{{cite journal | vauthors = Franks LM, Bollen A, Seeger RC, Stram DO, Matthay KK | title = Neuroblastoma in adults and adolescents: an indolent course with poor survival | journal = Cancer | volume = 79 | issue = 10 | pages = 2028–35 | date = May 1997 | pmid = 9149032 | doi = 10.1002/(SICI)1097-0142(19970515)79:10<2028::AID-CNCR26>3.0.CO;2-V }}</ref> but only 10% of cases occur in people older than 5 years of age.<ref name="pmid17544628">{{cite journal | vauthors = Howman-Giles R, Shaw PJ, Uren RF, Chung DK | title = Neuroblastoma and other neuroendocrine tumors | journal = Seminars in Nuclear Medicine | volume = 37 | issue = 4 | pages = 286–302 | date = July 2007 | pmid = 17544628 | doi = 10.1053/j.semnuclmed.2007.02.009 }}</ref> A large European study reported less than 2% of over 4000 neuroblastoma cases were over 18 years old.<ref name="pmid18545256">{{cite journal | vauthors = Ladenstein R, Pötschger U, Hartman O, Pearson AD, Klingebiel T, Castel V, Yaniv I, Demirer T, Dini G | display-authors = 6 | title = 28 years of high-dose therapy and SCT for neuroblastoma in Europe: lessons from more than 4000 procedures | journal = Bone Marrow Transplantation | volume = 41 Suppl 2 | issue = Suppl 2 | pages = S118-27 | date = June 2008 | pmid = 18545256 | doi = 10.1038/bmt.2008.69 | doi-access = free }}</ref>

 

[[File:Rudolf Virchow.jpg|thumb|[[Rudolf Virchow]]: the first to describe an abdominal tumor in a child as a "glioma"]]

In 1864 German physician [[Rudolf Virchow]] was the first to describe an abdominal tumor in a child as a "glioma". The characteristics of tumors from the sympathetic nervous system and the adrenal medulla were then noted in 1891 by German pathologist [[Felix Jacob Marchand|Felix Marchand]].<ref>{{cite book |first1=Frank |last1=Berthold |first2=Thorsten |last2=Simon | name-list-style = vanc |chapter=Clinical Presentation |chapter-url=https://books.google.com/books?id=p4f-IkKNSKMC&pg=PA63 |pages=63–85 |editor1-first=Nai-Kong V. |editor1-last=Cheung |editor2-first=Susan L. |editor2-last=Cohn |year=2006 |title=Neuroblastoma |publisher=Springer |isbn=978-3-540-26616-7}}</ref><ref>{{cite journal | vauthors = Beckwith JB, Perrin EV | journal = The American Journal of Pathology | volume = 43 | pages = 1089–104 | date = December 1963 | pmid = 14099453 | pmc = 1949785 | title = In Situ Neuroblastomas: A Contribution to the Natural History of Neural Crest Tumors }}</ref> In 1901 the distinctive presentation of stage 4S in infants (liver but no bone metastases) was described by William Pepper. In 1910 [[James Homer Wright]] understood the tumor to originate from primitive neural cells, and named it neuroblastoma. He also noted the circular clumps of cells in bone marrow samples which are now termed "Homer Wright rosettes". Of note, "Homer-Wright" with a hyphen is grammatically incorrect, as the eponym refers to just Dr. Wright.<ref name="pmid19034443">{{cite journal | vauthors = Rothenberg AB, Berdon WE, D'Angio GJ, Yamashiro DJ, Cowles RA | title = Neuroblastoma-remembering the three physicians who described it a century ago: James Homer Wright, William Pepper, and Robert Hutchison | journal = Pediatric Radiology | volume = 39 | issue = 2 | pages = 155–60 | date = February 2009 | pmid = 19034443 | doi = 10.1007/s00247-008-1062-z | s2cid = 19611725 }}</ref>

 

 

===Legislative efforts===

[[U.S. Representative]] [[Chet Edwards]] of [[Waco, Texas|Waco]], [[Texas]], successfully introduced legislation to earmark $150 million toward a cure for neuroblastoma and other cancers. The measure was signed into law in July 2008 by [[U.S. President]] [[George W. Bush]]. Edwards was inspired in the endeavor by the illness and subsequent death of Erin Channing Buenger (1997–2009) of [[Bryan, Texas|Bryan]], daughter of one of his constituents, [[Walter L. Buenger]], head of the history department at [[Texas A&M University]].<ref name=eagle>{{cite web|url=http://www.theeagle.com/editorial/Erin-Buenger-had-a-zest-for-living-life-fully|archive-url=https://archive.is/20110611084936/http://www.theeagle.com/editorial/Erin-Buenger-had-a-zest-for-living-life-fully|url-status=dead|archive-date=June 11, 2011|title=Erin Buenger had a zest for living life fully |date=April 12, 2009 |work=The Bryan College Station Eagle}}</ref>

 

[[File:BiggeggSH-SY5Y.jpg|thumb|Microscopic view of a NB cell line (SH-SY5Y) used in preclinical research for testing new agents]]

 

Neuroblastoma [[patient derived tumor xenografts]] (PDXs) have been created by [[orthotopic]] implantation of tumor samples into immunodeficient mice.<ref name="Braekeveldt2015">{{cite journal | vauthors = Braekeveldt N, Wigerup C, Gisselsson D, Mohlin S, Merselius M, Beckman S, Jonson T, Börjesson A, Backman T, Tadeo I, Berbegall AP, Ora I, Navarro S, Noguera R, Påhlman S, Bexell D | display-authors = 6 | title = Neuroblastoma patient-derived orthotopic xenografts retain metastatic patterns and geno- and phenotypes of patient tumours | journal = International Journal of Cancer | volume = 136 | issue = 5 | pages = E252-61 | date = March 2015 | pmid = 25220031 | pmc = 4299502 | doi = 10.1002/ijc.29217 }}</ref> PDX models have several advantages over conventional [[Immortalised cell line|cancer cell lines (CCL)]]s.<ref name="one mouse">{{cite journal | vauthors = Malaney P, Nicosia SV, Davé V | title = One mouse, one patient paradigm: New avatars of personalized cancer therapy | journal = Cancer Letters | volume = 344 | issue = 1 | pages = 1–12 | date = March 2014 | pmid = 24157811 | pmc = 4092874 | doi = 10.1016/j.canlet.2013.10.010 }}</ref> Neuroblastoma PDXs retain the genetic hallmarks of their corresponding tumors and PDXs display infiltrative growth and [[metastasis]] to distant organs.<ref name="Braekeveldt2015" /> PDX models are more predictive of clinical outcome as compared to conventional cancer cell line xenografts.<ref name="Tentler 2012">{{cite journal | vauthors = Tentler JJ, Tan AC, Weekes CD, Jimeno A, Leong S, Pitts TM, Arcaroli JJ, Messersmith WA, Eckhardt SG | display-authors = 6 | title = Patient-derived tumour xenografts as models for oncology drug development | journal = Nature Reviews. Clinical Oncology | volume = 9 | issue = 6 | pages = 338–50 | date = April 2012 | pmid = 22508028 | pmc = 3928688 | doi = 10.1038/nrclinonc.2012.61 }}</ref> Neuroblastoma PDXs might thus serve as clinically relevant models to identify effective compounds against neuroblastoma.<ref name="Braekeveldt2015" />

 

Recent focus has been to reduce therapy for low and intermediate risk neuroblastoma while maintaining survival rates at 90%.<ref>{{cite web|url=http://www.curesearch.org/our_research/index_sub.aspx?id=1767 |title=Neuroblastoma Committee—Current Focus of Research |access-date=2008-01-13 |url-status=dead |archive-url=https://web.archive.org/web/20060925060348/http://www.curesearch.org/our_research/index_sub.aspx?id=1767 |archive-date=September 25, 2006 }}</ref> A study of 467 people that are at intermediate risk enrolled in A3961 from 1997 to 2005 confirmed the hypothesis that therapy could be successfully reduced for this risk group. Those with favorable characteristics (tumor grade and response) received four cycles of chemotherapy, and those with unfavorable characteristics received eight cycles, with three-year event free survival and overall survival stable at 90% for the entire cohort. Future plans are to intensify treatment for those people with aberration of 1p36 or 11q23 chromosomes as well as for those who lack early response to treatment.<ref>{{cite journal | vauthors = Baker DL, Schmidt ML, Cohn SL, Maris JM, London WB, Buxton A, Stram D, Castleberry RP, Shimada H, Sandler A, Shamberger RC, Look AT, Reynolds CP, Seeger RC, Matthay KK | display-authors = 6 | title = Outcome after reduced chemotherapy for intermediate-risk neuroblastoma | journal = The New England Journal of Medicine | volume = 363 | issue = 14 | pages = 1313–23 | date = September 2010 | pmid = 20879880 | pmc = 2993160 | doi = 10.1056/NEJMoa1001527 | url = http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/9504 | url-status = dead | archive-url = https://archive.is/20130113023927/http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/9504 | archive-date = 2013-01-13 }}</ref><ref name="pmid20879880">{{cite journal | vauthors = Baker DL, Schmidt ML, Cohn SL, Maris JM, London WB, Buxton A, Stram D, Castleberry RP, Shimada H, Sandler A, Shamberger RC, Look AT, Reynolds CP, Seeger RC, Matthay KK | display-authors = 6 | title = Outcome after reduced chemotherapy for intermediate-risk neuroblastoma | journal = The New England Journal of Medicine | volume = 363 | issue = 14 | pages = 1313–23 | date = September 2010 | pmid = 20879880 | pmc = 2993160 | doi = 10.1056/NEJMoa1001527 }}</ref>

 

By contrast, focus the past 20 years or more has been to intensify treatment for high-risk neuroblastoma. Chemotherapy induction variations, timing of surgery, stem cell transplant regimens, various delivery schemes for radiation, and use of monoclonal antibodies and retinoids to treat minimal residual disease continue to be examined. Recent phase III [[clinical trials]] with randomization have been carried out to answer these questions to improve survival of high-risk disease:

 

Chemotherapy with topotecan and cyclophosphamide is frequently used in refractory setting and after relapse.<ref name="MorgensternBaruchel2013">{{cite journal | vauthors = Morgenstern DA, Baruchel S, Irwin MS | title = Current and future strategies for relapsed neuroblastoma: challenges on the road to precision therapy | journal = Journal of Pediatric Hematology/Oncology | volume = 35 | issue = 5 | pages = 337–47 | date = July 2013 | pmid = 23703550 | doi = 10.1097/MPH.0b013e318299d637 | s2cid = 5529288 }}</ref>

 

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{{Reflist}}

 

*{{Curlie|Health/Conditions_and_Diseases/Cancer/Brain_and_CNS/Neuroblastoma/}}