Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Neuroblastoma

  • Author: Byron D Joyner, MD, MPA; Chief Editor: Brian H Kopell, MD  more...
 
Updated: Mar 27, 2015
 

Background

Neuroblastoma is the most common intra-abdominal malignancy of infancy, the most common cancer in infancy, and the most common extracranial solid tumor of childhood, with an incidence of over 700 cases in the United States every year.[1, 2] Neuroblastoma is the third most common malignancy in children up through 14 years of age, behind acute lymphocytic leukemia and cancers of the brain and central nervous system.[1] It is a poorly differentiated neoplasm derived from neural crest cells that typically affects infants and young children. It accounts for 7% of pediatric malignancies but for more than 10% of childhood cancer-related mortality.[3]

Neuroblastoma is one of the small, blue, round cell tumors of childhood. Other such tumors include the following:

Next

History of the Procedure

Virchow first described neuroblastoma in 1864; at that time, it was referred to as a glioma.[4] In 1891, Marchand histologically linked neuroblastoma to sympathetic ganglia.[5] More substantial evidence of the neural origins of neuroblastoma became apparent in 1914, when Herxheimer showed that fibrils of the tumor stained positively with special neural silver stains.[6]

In 1927, Cushing and Wolbach further characterized neuroblastoma by describing the transformation of malignant neuroblastoma into its benign counterpart, ganglioneuroma.[7] Everson and Cole reported that this type of transformation is rare in children older than 6 months.[8] In 1957, Mason published a report of a child with neuroblastoma whose urine contained pressor amines.[9] This discovery further contributed to the understanding of neuroblastoma and its possible sympathetic neural origin.

Spontaneous regression of microscopic clusters of neuroblastoma cells, called neuroblastoma in situ, was noted to occur quite commonly. According to Beckwith and Perrin in 1963, regression occurs nearly 40 times more often than clinically apparent neuroblastoma.[10]

Previous
Next

Problem

Neuroblastoma is a malignant neural tumor that typically affects very young children. Its presentation varies, depending on the primary site of origin, metastatic burden, and metabolically active by-products. It is remarkable in that it has a documented spontaneous rate of resolution and is also one of the few tumors in which the surgical capsule can be violated and a good outcome might be achieved, even if residual tumor is left behind.

Previous
Next

Epidemiology

Frequency

Clinical frequency is approximately one case per 8000-10,000 children. The American Cancer Society estimated that 710 new cases of neuroblastoma (including gangioneuroblastoma) would be diagnosed in the United States in 2014.[1]

Neuroblastoma is more common in whites and is slightly more prevalent in boys than in girls (male-to-female ratio of 1.3:1). The typical age at diagnosis is younger than that for Wilms tumor. More than one third of cases (36%) are diagnosed in children younger than 1 year. Seventy-nine percent of cases are diagnosed are children younger than 4 years, and 97% are diagnosed by age 10 years. Neuroblastoma is thought to occur sporadically, with 1-2% of cases thought to be familial.

Previous
Next

Etiology

The actual etiology of the tumor is obscure. Environmental and paternal exposures linked to neuroblastoma have not been identified.

Embryologically, tumors of the sympathetic nervous system differentiate along two distinct pathways, either the pheochromocytoma line or the sympathoblastoma line.[11] The sympathoblastomas, also called neurocristopathies, include the well-differentiated ganglioneuroma, the moderately differentiated ganglioneuroblastoma, and the malignant neuroblastoma. All of these tumors arise from primordial neural crest cells, which ultimately populate the sympathetic chain and the adrenal medulla.

Previous
Next

Pathophysiology

According to Knudson and Strong (1972), 20% of neuroblastomas are inherited in an autosomal dominant pattern.[11] Twenty percent of this cohort has bilateral or multifocal primary tumors. Various karyotypic abnormalities occur, but a deletion of the short arm of chromosome 1 is found in 70-80% of all patients with neuroblastomas.

Malignant transformation and maintenance of the dedifferentiated state of neural crest cells may result from failure of those cells to respond to normal signals that are responsible for normal morphologic differentiation. The factors involved in the cascade of events are poorly understood but most likely involve one or more ligand-receptor pathways. One of the most studied and most popular pathways is the nerve growth factor (NGF) and its receptor (NGFR). The dedifferentiated state of neuroblastoma leads to the variable presentations commonly observed in patients with neuroblastoma.

Previous
Next

Presentation

Neuroblastoma has been called the great mimicker because of its myriad clinical presentations related to the site of the primary tumor, metastatic disease, and its metabolic tumor by-products. Sixty-five percent of primary neuroblastomas occur in the abdomen, with most of these occurring in the adrenal gland. As a result, most children present with abdominal symptoms, such as fullness or distension.

Obtaining a complete history and physical examination are paramount to an accurate diagnosis and subsequent management of neuroblastoma. Eliciting a history of the child's general appearance, recent trauma, changes in appetite and weight, and recurrent abdominal pain is important. Symptoms are usually related to either an abdominal mass or bone pain secondary to metastatic neuroblastoma. Reports of fatigue, bone pain, and changes in bowel or bladder habits may contribute to an accurate diagnosis. Physical findings might include hepatomegaly; blanching subcutaneous nodules; or a large, irregular, firm abdominal mass.

Typically, children with localized disease are asymptomatic, whereas children with disseminated neuroblastoma are generally sick and may have systemic manifestations, including unexplained fevers, weight loss, anorexia, failure to thrive, general malaise, irritability, and bone pain. The most common finding upon physical examination is a nontender, firm, irregular abdominal mass that crosses the midline. In contrast, children who present with Wilms tumor have a smooth mobile flank mass that typically does not cross the midline.

At diagnosis, the site of neuroblastoma is predictably age-dependent. Infants often present with compression of the sympathetic ganglia in the thoracic region, which might result, for example, in Horner syndrome (myosis, anhydrosis, and ptosis) or superior vena cava syndrome. Older children typically present with abdominal symptoms because, as stated above, more than 40% of neuroblastomas are adrenal in origin. Children who are preschool aged should have working differential diagnoses for an abdominal mass, including lymphoma, hepatoblastoma, rhabdomyosarcoma, renal cell carcinoma, and neuroblastoma.

More than 50% of patients who present with neuroblastoma have metastatic disease. The fact that many other syndromes related to metastatic neuroblastoma are also common in these patients is not surprising.

For example, Pepper syndrome occurs in infants with overwhelming metastatic neuroblastoma of the liver that results in respiratory compromise. Described by William Pepper in 1901, Pepper syndrome was identified as a localized primary tumor and metastatic disease limited to the skin, liver, and bone marrow in infants. Pepper syndrome has since been associated with stage 4S neuroblastoma, a unique entity that occurs only in infants younger than 1 year. Pepper syndrome generally confers a better prognosis, as it is associated with spontaneous regression. Some infants with stage 4S neuroblastoma, however, die of massive hepatomegaly, respiratory failure, and overwhelming sepsis.

"Blueberry muffin" babies are infants in whom neuroblastoma has metastasized to random subcutaneous sites. When provoked, the nodules become intensely red and subsequently blanch for several minutes thereafter. The response is probably secondary to the release of vasoconstrictive metabolic tumor by-products. These nodules can be diagnostic of neuroblastoma, but leukemic infiltrates that metastasize to the skin should be considered in the differential diagnoses when these children are evaluated.

Widespread metastasis of neuroblastoma to the bone may result in Hutchinson syndrome, which results in bone pain with consequent limping and pathologic fractures. Neuroblastomas that arise in the paraspinal ganglia may invade through the neural foramina, compress the spinal cord, and subsequently cause paralysis.

Infrequently, neuroblastoma can become metastatic to the retrobulbar region, leading to rapidly progressive, unilateral, painless proptosis; periorbital edema; and ecchymosis of the upper lid. This lesion often can be confused with trauma or child abuse. See the image below.

Upper periorbital edema, proptosis, and ocular ecc Upper periorbital edema, proptosis, and ocular ecchymosis in a 9-month-old girl.

Most neuroblastomas produce catecholamines as metabolic by-products, which result in some of the most interesting presentations observed in children with neuroblastoma. For example, Kerner-Morrison syndrome causes intractable secretory diarrhea, resulting in hypovolemia, hypokalemia, and prostration. This syndrome is caused by vasoactive intestinal peptide (VIP) tumor secretion and is more commonly associated with ganglioneuroblastoma or ganglioneuroma. Kerner-Morrison syndrome typically resolves following the complete removal of the tumor.

A wide variety of neoplastic and nonneoplastic lesions might be confused with neuroblastoma. Wilms tumor and lymphoma are 2 malignant lesions that might be mistaken for neuroblastoma. The nonneoplastic lesions are particularly confusing, especially in the 5-11% of neuroblastomas that do not produce catecholamine metabolic by-products. Nonmalignant lesions that might be confused with neuroblastoma include ganglioneuroma and congenital mesoblastic nephroma.

Previous
Next

Indications

In 1988, the Pediatric Oncology Group (POG) released a prospective study showing that patients with localized neuroblastoma who were treated by surgical extirpation had a 2-year disease-free survival rate of 89%.[12] Additionally, chemotherapy appeared to offer no advantage when residual disease was present in these patients. Thus, in patients with low-stage favorable disease, surgery is the mainstay of therapy. The primary goals of surgery are as follows:

  1. To determine an accurate diagnosis
  2. To completely remove all of the primary tumor
  3. To provide accurate surgical staging
  4. To offer adjuvant therapy for delayed primary surgery
  5. To remove residual disease with second-look surgery
Previous
Next

Relevant Anatomy

During the fifth week of embryogenesis, primitive sympathetic neuroblasts migrate from the neural crest to the site where the adrenal anlage eventuates into the developing embryo. These neuroblasts migrate along the entire sympathetic chain; therefore, neuroblastoma can arise anywhere along the sympathetic nervous system. The name neuroblastoma is derived from the fact that the cells resemble primitive neuroblasts.

Previous
Next

Contraindications

High-stage neuroblastoma cannot be managed surgically; therefore, surgery is contraindicated in this setting.

Previous
 
 
Contributor Information and Disclosures
Author

Byron D Joyner, MD, MPA Vice Dean for Graduate Medical Education and Designated Institutional Official Professor, Department of Urology, University of Washington School of Medicine; Pediatric Urologist, Seattle Children's Hospital

Byron D Joyner, MD, MPA is a member of the following medical societies: American Academy of Pediatrics, Society of University Urologists, Washington State Medical Association, Society of Urology Chairpersons and Program Directors, American College of Surgeons, American Urological Association, Association of Military Surgeons of the US, Massachusetts Medical Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Brian H Kopell, MD Associate Professor, Department of Neurosurgery, Icahn School of Medicine at Mount Sinai

Brian H Kopell, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Neurological Surgeons, International Parkinson and Movement Disorder Society, Congress of Neurological Surgeons, American Society for Stereotactic and Functional Neurosurgery, North American Neuromodulation Society

Disclosure: Received consulting fee from Medtronic for consulting; Received consulting fee from St Jude Neuromodulation for consulting; Received consulting fee from MRI Interventions for consulting.

Acknowledgements

Natalya Lopushnyan Yale University School of Medicine

Disclosure: Nothing to disclose.

References
  1. Cancer Facts & Figures 2014. American Cancer Society. Available at http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-041787.pdf. Accessed: January 2, 2015.

  2. Lacayo NJ. Pediatric Neuroblastoma. Medscape Reference. Available at http://p://emedicine.medscape.com/article/988284. Accessed: January 6, 2015.

  3. Irwin MS, Park JR. Neuroblastoma: Paradigm for Precision Medicine. Pediatr Clin North Am. 2015 Feb. 62(1):225-256. [Medline].

  4. Virchow R. Hyperplasie der Zirbel und der Nebennieren. Die Krankhaften Geschwulste. Vol 2: 1864-65.

  5. Marchand F. Beitrage zur Kenntniss der normalen und pathologischen Anatomie der Glandula carotica und der Nebennieren. Festschrift fur Ruduloph. Vichows Arch. 1891. 5:578.

  6. Herxheimer G. Ueber Turmoren des Nebennierenmarkes, insbesondere das Neuroblastoma sympaticum. Beitr Pathol Anat. 1914. 57:112.

  7. Cushing H, Wolback SB. The transformation of a malignant paravertebral sympathicoblastoma into a benign ganglioneuoma. Am J Pathol. 1927. 3:203.

  8. Everson TC, Cole WH. Spontaneous regression of neuroblastoma. Everson TC, Cole WH, eds. Spontaneous Regression of Cancer. Philadelphia, Pa: WB Saunders; 1966. 88.

  9. Mason GA, Hart-Mercer J, Millar EJ, Strang LB, Wynne NA. Adrenaline-secreting neuroblastoma in an infant. Lancet. 1957 Aug 17. 273(6990):322-5. [Medline].

  10. Beckwith JB, Perrin EV. In situ neuroblastomas: A contribution to the natural history of neural crest tumors. Am J Pathol. 1963 Dec. 43:1089-104. [Medline].

  11. Knudson AG Jr, Strong LC. Mutation and cancer: neuroblastoma and pheochromocytoma. Am J Hum Genet. 1972 Sep. 24(5):514-32. [Medline].

  12. Nitschke R, Smith EI, Shochat S, et al. Localized neuroblastoma treated by surgery: a Pediatric Oncology Group Study. J Clin Oncol. 1988 Aug. 6(8):1271-9. [Medline].

  13. Stigliani S, Coco S, Moretti S, Oberthuer A, Fischer M, Theissen J, et al. High genomic instability predicts survival in metastatic high-risk neuroblastoma. Neoplasia. 2012 Sep. 14(9):823-32. [Medline]. [Full Text].

  14. Mullassery D, Sharma V, Salim A, Jawaid WB, Pizer BL, Abernethy LJ, et al. Open versus needle biopsy in diagnosing neuroblastoma. J Pediatr Surg. 2014 Oct. 49(10):1505-7. [Medline].

  15. Schleiermacher G, Javanmardi N, Bernard V, Leroy Q, Cappo J, Rio Frio T, et al. Emergence of new ALK mutations at relapse of neuroblastoma. J Clin Oncol. 2014 Sep 1. 32(25):2727-34. [Medline].

  16. Neuroblastoma risk groups. American Cancer Society. Available at http://www.cancer.org/cancer/neuroblastoma/detailedguide/neuroblastoma-risk-groups. Accessed: January 2, 2014.

  17. Gains J, Mandeville H, Cork N, Brock P, Gaze M. Ten challenges in the management of neuroblastoma. Future Oncol. 2012 Jul. 8(7):839-58. [Medline].

  18. Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010 Sep 30. 363(14):1324-34. [Medline].

  19. Pai Panandiker AS, Beltran C, Billups CA, McGregor LM, Furman WL, Davidoff AM. Intensity modulated radiation therapy provides excellent local control in high-risk abdominal neuroblastoma. Pediatr Blood Cancer. 2012 Sep 28. [Medline].

  20. Molenaar JJ, Domingo-Fernández R, Ebus ME, Lindner S, Koster J, Drabek K, et al. LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nat Genet. 2012 Oct 7. [Medline].

  21. 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. [Medline].

  22. Barone G, Anderson J, Pearson AD, Petrie K, Chesler L. New strategies in neuroblastoma: Therapeutic targeting of MYCN and ALK. Clin Cancer Res. 2013 Nov 1. 19(21):5814-21. [Medline]. [Full Text].

  23. Bostrom B, Nesbit ME Jr, Brunning RD. The value of bone marrow trephine biopsy in the diagnosis of metastatic neuroblastoma. Am J Pediatr Hematol Oncol. 1985 Fall. 7(3):303-5. [Medline].

  24. Brodeur GM, Castleberry RP. Neuroblastoma. Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. Philadelphia, Pa: Lippincott, Williams & Wilkins; 1993. Vol 1: 739-67.

  25. Brodeur GM, Green AA, Hayes FA. Cytogenetic studies of primary human neuroblastomas. Prog Cancer Res Ther. 1980. 12:73.

  26. Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993 Aug. 11(8):1466-77. [Medline].

  27. Brodeur GM, Seeger RC, Barrett A, et al. International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol. 1988 Dec. 6(12):1874-81. [Medline].

  28. Buckley SE, Chittenden SJ, Saran FH, Meller ST, Flux GD. Whole-body dosimetry for individualized treatment planning of 131I-MIBG radionuclide therapy for neuroblastoma. J Nucl Med. 2009 Sep. 50(9):1518-24. [Medline].

  29. Connolly AM, Pestronk A, Mehta S, et al. Serum autoantibodies in childhood opsoclonus-myoclonus syndrome: an analysis of antigenic targets in neural tissues. J Pediatr. 1997 Jun. 130(6):878-84. [Medline].

  30. Evageliou NF, Hogarty MD. Disrupting polyamine homeostasis as a therapeutic strategy for neuroblastoma. Clin Cancer Res. 2009 Oct 1. 15(19):5956-61. [Medline].

  31. Fulda S. The PI3K/Akt/mTOR pathway as therapeutic target in neuroblastoma. Curr Cancer Drug Targets. 2009 Sep. 9(6):729-37. [Medline].

  32. Grosfeld JL. Neuroblastoma. Pediatric Surgery. 1998. Vol 1: 405-19.

  33. Homsy YL, Austin PF. Neuroblastoma. Graham SD Jr, ed. Glenn's Urologic Surgery. 5th ed. Philadelphia, Pa: Lippincott-Raven; 1998. 687-90.

  34. Howman-Giles R, Shaw PJ, Uren RF, Chung DK. Neuroblastoma and other neuroendocrine tumors. Semin Nucl Med. 2007 Jul. 37(4):286-302. [Medline].

  35. Kim S, Chung DH. Pediatric solid malignancies: neuroblastoma and Wilms' tumor. Surg Clin North Am. 2006 Apr. 86(2):469-87, xi. [Medline].

  36. Kushner BH, Helson L. Coordinated use of sequentially escalated cyclophosphamide and cell- cycle-specific chemotherapy (N4SE protocol) for advanced neuroblastoma: experience with 100 patients. J Clin Oncol. 1987 Nov. 5(11):1746-51. [Medline].

  37. Lessig MK. The role of 131I-MIBG in high-risk neuroblastoma treatment. J Pediatr Oncol Nurs. 2009 Jul-Aug. 26(4):208-16. [Medline].

  38. 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. [Medline].

  39. Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 2007 Jun 23. 369(9579):2106-20. [Medline].

  40. Matthay KK, Sather HN, Seeger RC, et al. Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy. J Clin Oncol. 1989 Feb. 7(2):236-44. [Medline].

  41. Meany HJ, Sackett DL, Maris JM, Ward Y, Krivoshik A, Cohn SL, et al. Clinical outcome in children with recurrent neuroblastoma treated with ABT-751 and effect of ABT-751 on proliferation of neuroblastoma cell lines and on tubulin polymerization in vitro. Pediatr Blood Cancer. 2010 Jan. 54(1):47-54. [Medline]. [Full Text].

  42. Mora J, Cheung NK, Kushner BH, et al. Clinical categories of neuroblastoma are associated with different patterns of loss of heterozygosity on chromosome arm 1p. J Mol Diagn. 2000 Feb. 2(1):37-46. [Medline].

  43. Mueller S, Matthay KK. Neuroblastoma: biology and staging. Curr Oncol Rep. 2009 Nov. 11(6):431-8. [Medline].

  44. Mullassery D, Dominici C, Jesudason EC, McDowell HP, Losty PD. Neuroblastoma: contemporary management. Arch Dis Child Educ Pract Ed. 2009 Dec. 94(6):177-85. [Medline].

  45. Nyalendo C, Sartelet H, Barrette S, Ohta S, Gingras D, Béliveau R. Identification of membrane-type 1 matrix metalloproteinase tyrosine phosphorylation in association with neuroblastoma progression. BMC Cancer. 2009 Dec 4. 9:422. [Medline]. [Full Text].

  46. Reid GS, Shan X, Coughlin CM, Lassoued W, Pawel BR, Wexler LH, et al. Interferon-gamma-dependent infiltration of human T cells into neuroblastoma tumors in vivo. Clin Cancer Res. 2009 Nov 1. 15(21):6602-8. [Medline]. [Full Text].

  47. Roberts S, Creamer K, Shoupe B, et al. Unique management of stage 4S neuroblastoma complicated by massive hepatomegaly: case report and review of the literature. J Pediatr Hematol Oncol. 2002 Feb. 24(2):142-4. [Medline].

  48. Ross JA, Davies SM. Screening for neuroblastoma: progress and pitfalls. Cancer Epidemiol Biomarkers Prev. 1999 Feb. 8(2):189-94. [Medline].

  49. Rufini V, Calcagni ML, Baum RP. Imaging of neuroendocrine tumors. Semin Nucl Med. 2006 Jul. 36(3):228-47. [Medline].

  50. Russo C, Cohn SL, Petruzzi MJ, de Alarcon PA. Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Med Pediatr Oncol. 1997 Apr. 28(4):284-8. [Medline].

  51. Tonini GP, Boni L, Pession A, et al. MYCN oncogene amplification in neuroblastoma is associated with worse prognosis, except in stage 4s: the Italian experience with 295 children. J Clin Oncol. 1997 Jan. 15(1):85-93. [Medline].

  52. Van Maerken T, Vandesompele J, Rihani A, De Paepe A, Speleman F. Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14(ARF)-MDM2-p53 axis. Cell Death Differ. 2009 Dec. 16(12):1563-72. [Medline].

  53. Weinstein JL, Katzenstein HM, Cohn SL. Advances in the diagnosis and treatment of neuroblastoma. Oncologist. 2003. 8(3):278-92. [Medline].

 
Previous
Next
 
CT scan in a 2-week-old boy noted to have an abdominal mass on a prenatal sonogram. This postnatal abdominal CT scan revealed a left suprarenal mass with mass effect of the spleen.
Abdominal CT scan in a 2-week-old boy noted to have an abdominal mass on a prenatal sonogram. A postnatal abdominal CT scan revealed a left suprarenal mass with mass effect of the spleen (see the previous image). This abdominal CT scan represents a more caudal view. Note the very large left mass with central necrosis. The mass effect of the spleen is apparent.
A 2-week-old boy is noted to have an abdominal mass on prenatal ultrasound. A postnatal abdominal CT scan revealed a left suprarenal mass with mass effect of the spleen (see the first image above). A more caudal view revealed the very large left mass with central necrosis (see the second image above). This is a more caudal view of the CT scan than in the previous 2 images. The left kidney comes into view, as it is inferiorly displaced and laterally rotated by the large superior neuroblastoma.
Bulky lymph nodes just medial to the left kidney.
Upper periorbital edema, proptosis, and ocular ecchymosis in a 9-month-old girl.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.