History

The following may be noted in patients with neuroblastoma:

Signs and symptoms of neuroblastoma vary with site of presentation. Generally, symptoms include abdominal pain, emesis, weight loss, anorexia, fatigue, and bone pain. Hypertension is an uncommon sign of the disease and is generally caused by renal artery compression, not catecholamine excess. Chronic diarrhea is a rare presenting symptom secondary to tumor secretion of vasoactive intestinal peptide secretion.
Because more than 50% of patients present with advanced stage disease, usually to the bone and bone marrow, the most common presentation includes bone pain and a limp. However, patients may also present with unexplained fever, weight loss, irritability, and periorbital ecchymosis secondary to metastatic disease to the orbits. The presence of bone metastases can lead to pathologic fractures.
Approximately two thirds of patients with neuroblastoma have abdominal primaries. In these circumstances, patients can present with an asymptomatic abdominal mass that usually is discovered by the parents or a caregiver. Symptoms produced by the presence of the mass depend on its proximity to vital structures and usually progress over time.
Tumors that arise from the paraspinal sympathetic ganglia can grow through the spinal foramina into the spinal canal and impinge on the spinal cord. This may result in the presence of neurologic symptoms, including weakness, limping, paralysis, and even bladder and bowel dysfunction.
Thoracic neuroblastomas (posterior mediastinum) may be asymptomatic and are usually diagnosed by imaging studies obtained for other reasons. Presenting signs or symptoms may be insignificant and involve mild airway obstruction or chronic cough, leading to chest radiography.
Thoracic tumors extending to the neck can produce Horner syndrome. Primary cervical neuroblastoma is rare but should be considered in the differential diagnosis of masses of the neck, especially in infants younger than 1 year with feeding or respiratory difficulties.
In a small proportion of infants younger than 6 months, neuroblastoma presents with a small primary tumor and metastatic disease confined to the liver, skin, and bone marrow (stage 4S). If this type of tumor develops in neonates, skin lesions may be confused with congenital rubella, and, if the patient has severe skin involvement, the term "blueberry muffin baby" may be used.
Approximately 2% of patients present with opsoclonus and myoclonus a paraneoplastic syndrome characterized by the presence of myoclonic jerking and random eye movements. These patients often have localized disease and a good long-term prognosis. Unfortunately, the neurologic abnormalities can persist or progress and can be devastating.
Finally, intractable diarrhea is a rare paraneoplastic symptom and is associated with more differentiated tumors and a good prognosis.

Physical Examination

The following may be noted in patients with neuroblastoma:

Children are usually referred to a pediatric oncologist by primary care providers who have identified a persistent unexplained symptom or sign, either upon physical examination or based on screening test findings.
In patients with suspected neuroblastoma, performing a thorough examination with careful attention to vital signs (eg, blood pressure), neck, chest, abdomen, skin, and nervous system is essential.
Metastatic lesions of the skin are common in infants younger than 6 months and may represent stage 4S disease.
Examination of the abdomen may reveal an abdominal mass, leading to the appropriate workup.
Neurologic examination may reveal Horner syndrome. In the case of dumbbell tumors, compression of the spinal cord may produce lower extremity weakness or paraplegia. Patients with neurologic involvement by tumor should be treated emergently, secondary to the risk of permanent neurologic sequelae.

Differential Diagnoses

Look AT, Hayes FA, Shuster JJ, et al. Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol. 1991 Apr. 9(4):581-91. [QxMD MEDLINE Link].
Challagundla KB, Wise PM, Neviani P, Chava H, Murtadha M, Xu T, et al. Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. J Natl Cancer Inst. 2015 Jul. 107 (7):[QxMD MEDLINE Link].
[Guideline] Shimada H, Chatten J, Newton WA Jr, et al. Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J Natl Cancer Inst. 1984 Aug. 73(2):405-16. [QxMD MEDLINE Link].
[Guideline] Cohn SL, Pearson AD, London WB, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009 Jan 10. 27(2):289-97. [QxMD MEDLINE Link]. [Full Text].
Mosse YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 2008 Oct 16. 455(7215):930-5. [QxMD MEDLINE Link]. [Full Text].
Schleiermacher G, Javanmardi N, Bernard V, et al. Emergence of New ALK Mutations at Relapse of Neuroblastoma. J Clin Oncol. 2014 Sep 1. 32(25):2727-34. [QxMD MEDLINE Link].
De Brouwer S, De Preter K, Kumps C, Zabrocki P, Porcu M, Westerhout EM. Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification. Clin Cancer Res. 2010 Sep 1. 16(17):4353-62. [QxMD MEDLINE Link].
Capasso M, Devoto M, Hou C, et al. Common variations in BARD1 influence susceptibility to high-risk neuroblastoma. Nat Genet. 2009 Jun. 41(6):718-23. [QxMD MEDLINE Link]. [Full Text].
Diskin SJ, Hou C, Glessner JT, Attiyeh EF, Laudenslager M, Bosse K. Copy number variation at 1q21.1 associated with neuroblastoma. Nature. 2009 Jun 18. 459(7249):987-91. [QxMD MEDLINE Link].
Wang K, Diskin SJ, Zhang H, Attiyeh EF, Winter C, Hou C. Integrative genomics identifies LMO1 as a neuroblastoma oncogene. Nature. 2011 Jan 13. 469(7329):216-20. [QxMD MEDLINE Link].
Nguyen le B, Diskin SJ, Capasso M, Wang K, Diamond MA, Glessner J. Phenotype restricted genome-wide association study using a gene-centric approach identifies three low-risk neuroblastoma susceptibility Loci. PLoS Genet. 2011 Mar. 7(3):e1002026. [QxMD MEDLINE Link].
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021 Jan. 71 (1):7-33. [QxMD MEDLINE Link]. [Full Text].
National Cancer Institute. SEER Pediatric Monograph. National Cancer Institute. Available at http://www-seer.ims.nci.nih.gov/Publications/PedMono/sympathetic.pdf. Accessed: February 25, 2002.
Stiller CA, Parkin DM. International Variations in the incidence of neuroblastoma. International Journal of Cancer. 1992. 52:538-543.
Haupt R, Garaventa A, Gambini C, et al. Improved Survival of Children with Neuroblastoma Between 1979 and 2005: A Report of the Italian Neuroblastoma Registry. J Clin Oncol. 2010 Mar 29. [QxMD MEDLINE Link].
George RE, Li S, Medeiros-Nancarrow C, et al. High-risk neuroblastoma treated with tandem autologous peripheral-blood stem cell-supported transplantation: long-term survival update. J Clin Oncol. 2006 Jun 20. 24(18):2891-6. [QxMD MEDLINE Link].
[Guideline] Monclair T, Brodeur GM, Ambros PF, et al. The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol. 2009 Jan 10. 27(2):298-303. [QxMD MEDLINE Link]. [Full Text].
London WB, Castleberry RP, Matthay KK, et al. Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol. 2005 Sep 20. 23(27):6459-65. [QxMD MEDLINE Link].
London WB, Castleberry RP, Matthay KK, Look AT, Seeger RC, Shimada H. Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol. 2005 Sep 20. 23(27):6459-65. [QxMD MEDLINE Link].
Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 2007 Jun 23. 369(9579):2106-20. [QxMD MEDLINE Link].
Strother DR, London WB, Schmidt ML, et al. Outcome After Surgery Alone or With Restricted Use of Chemotherapy for Patients With Low-Risk Neuroblastoma: Results of Children's Oncology Group Study P9641. J Clin Oncol. 2012 May 20. 30(15):1842-8. [QxMD MEDLINE Link].
Baker DL, Schmidt ML, Cohn SL, et al. Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med. 2010 Sep 30. 363(14):1313-23. [QxMD MEDLINE Link].
FDA grants accelerated approval to naxitamab for high-risk neuroblastoma in bone or bone marrow. Food and Drug Administration. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-naxitamab-high-risk-neuroblastoma-bone-or-bone-marrow. November 25, 2020; Accessed: April 10, 2021.
Naranjo A, Parisi MT, Shulkin BL, et al. Comparison of ¹²³I-metaiodobenzylguanidine (MIBG) and ¹³¹I-MIBG semi-quantitative scores in predicting survival in patients with stage 4 neuroblastoma: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2011 Jul 1. 56(7):1041-5. [QxMD MEDLINE Link].
Mueller S, Yang X, Sottero TL, Gragg A, Prasad G, Polley MY. Cooperation of the HDAC inhibitor vorinostat and radiation in metastatic neuroblastoma: efficacy and underlying mechanisms. Cancer Lett. 2011 Jul 28. 306(2):223-9. [QxMD MEDLINE Link].
Federico SM, McCarville MB, Shulkin BL, Sondel PM, Hank JA, Hutson P, et al. A Pilot Trial of Humanized Anti-GD2 Monoclonal Antibody (hu14.18K322A) with Chemotherapy and Natural Killer Cells in Children with Recurrent/Refractory Neuroblastoma. Clin Cancer Res. 2017 Sep 22. [QxMD MEDLINE Link].
Ladenstein R, Valteau-Couanet D, Brock P, et al. Randomized Trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with high-risk neuroblastoma: the European HR-NBL1/SIOPEN study. J Clin Oncol. 2010 Jul 20. 28(21):3516-24. [QxMD MEDLINE Link].
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Media Gallery

Histologic subtypes of neuroblastoma. Top right panel, neuroblastoma: A monotonous population of hyperchromatic cells with scant cytoplasm. Bottom left panel, ganglioneuroblastoma: Increased schwannian stroma. Bottom right panel, ganglioneuroma: Mature ganglion cell with schwannian stroma.
CT scan of abdomen in a patient with a retroperitoneal mass arising from the upper pole of the left kidney and elevated urine catecholamines.
MRI of a left adrenal mass. The mass was revealed by fetal ultrasonography at 30 weeks' gestation. During infancy, the mass was found on the inferior pole of the left adrenal and was completely resected. Before surgery, the metastatic workup was negative. Surgical pathology service confirmed a diagnosis of neuroblastoma. After 3 years of follow-up care, no recurrence was observed.
A one-week-old neonate had abdominal ultrasonography for evaluation of projectile vomiting. A right adrenal mass (100% cystic) was an incidental finding. Evaluation of the mass by CT was consistent with an adrenal bleed (3.6 x 3.1 x 2.4 cc). The infant was followed at 2 weeks (2-dimensional size diminished to 1.5 x. 2.4 cm2 on ultrasonography) and then at 6 weeks to document that the adrenal bleed continued to involute. Urine catecholamines were normal.
Table. A Consensus Pretreatment Classification schema by the International Neuroblastoma Risk Group (INRG). This schema is based in the INRG stage, age, histologic category, tumor grade of differentiation, MYCN sastus, 11q-aberrations and DNA ploidy. A combination of these characteristics results in four risk groups noted in the last column: very low, low, intermediate and high risk, with the following 5 year EFS: >85%, >75%-85%, >50%-75%, and < 50%. These risk groups are distributed among the different stages and labeled alphabetically from A to R (without letters L and M to avoid confusion with the INRG stage notation). Notations in the table are as follow: L1, localized tumor confined to one body compartment; L2, locoregional tumor with presence of one or more risk factors defined radiologically; M, distant metastatic disease (except stage MS); MS, metastatic disease confined to skin, liver and/or bone marrow in children < 18 months of age. GN, ganglioneuroma; GNB, ganglioneuroblastoma; Amp, amplified; n/amp, not amplified. (Adapted from The International Neuroblastoma Risk Group (INRG) Classifications System: An INRG Task Force Report by Cohn, et al. Journal of Clinical Oncology 27(2):289-297, 2009).

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Table 1. Current COG Neuroblastoma Risk Stratification

Table 1. Current COG Neuroblastoma Risk Stratification

Risk Group	Stage	Age	MYCN Amplification Status	Ploidy	Shimada
Low	1	Any	Any	Any	Any
Low	2a/2b	Any	Non-amp	Any	Any
High	2a/2b	Any	Amp	Any	Any
Intermediate	3	< 547d	Non-amp	Any	Any
Intermediate	3	≥547d	Non-amp	Any	Favorable
High	3	Any	Amp	Any	Any
High	3	≥547d	Non-amp	Any	Unfavorable
High	4	< 365d	Amp	Any	Any
Intermediate	4	< 365d	Non-amp	Any	Any
High	4	365-547d	Amp	Any	Any
High	4	365-547d	Any	Diploid	Any
High	4	365-547	Any	Any	Unfavorable
Intermediate	4	365-547d	Non-amp	Hyper	Favorable
High	4	≥547d	Any	Any	Any
Low	4s	< 365d	Non-amp	Hyper	Favorable
Intermediate	4s	< 365d	Non-amp	Diploid	Any
Intermediate	4s	< 365d	Non-amp	Any	Unfavorable
High	4s	< 365d	Amp	Any	Any

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Author

Norman J Lacayo, MD Assistant Professor, Department of Pediatrics, Division of Hematology-Oncology, Stanford University and Lucile Salter Packard Children's Hospital

Norman J Lacayo, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Hematology, Children's Oncology Group

Disclosure: Nothing to disclose.

Coauthor(s)

Kara L Davis, DO Instructor, Department of Pediatric Hematology/Oncology, Stanford University School of Medicine

Kara L Davis, DO is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Steven K Bergstrom, MD Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland

Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, Children's Oncology Group, American Society of Clinical Oncology, International Society for Experimental Hematology, American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA Executive Vice President, Chief Medical and Academic Officer, Renown Heath

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American College of Healthcare Executives, American Society of Pediatric Hematology/Oncology, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Stephan A Grupp, MD, PhD Director, Stem Cell Biology Program, Department of Pediatrics, Division of Oncology, Children's Hospital of Philadelphia; Associate Professor of Pediatrics, University of Pennsylvania School of Medicine

Stephan A Grupp, MD, PhD is a member of the following medical societies: American Association for Cancer Research, Society for Pediatric Research, American Society for Blood and Marrow Transplantation, American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Pediatric Neuroblastoma Clinical Presentation

History

Physical Examination

References

Tables

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