eMedicine Specialties > Pediatrics: General Medicine > Oncology

Neuroblastoma

Author: Norman J Lacayo, MD, Assistant Professor, Department of Pediatrics, Division of Hematology-Oncology, Stanford University and Lucile Salter Packard Children's Hospital
Coauthor(s): Neyssa Marina, MD, Professor, Department of Pediatrics, Division of Pediatric Hematology-Oncology, Lucile Packard Children's Hospital and Stanford University; Kara L Davis, DO, Fellow, Department of Pediatric Hematology/Oncology, Stanford University School of Medicine
Contributor Information and Disclosures

Updated: Jul 31, 2009

Introduction

Background

Neuroblastoma is the most common extracranial solid tumor in infancy. It is an embryonal malignancy of the sympathetic nervous system arising from neuroblasts (pluripotent sympathetic cells). In the developing embryo, these cells invaginate, migrate along the neuraxis, and populate the sympathetic ganglia, adrenal medulla, and other sites. The pattern of distribution of these cells correlates with the sites of primary disease presentation.

Age, stage, and biological features encountered in tumor cells are important prognostic factors and are used for risk stratification and treatment assignment. The differences in outcome for patients with neuroblastoma are striking. Patients with low-risk and intermediate-risk neuroblastoma have excellent prognosis and outcome. However, those with high-risk disease continue to have very poor outcomes despite intensive therapy. Unfortunately, approximately 70-80% of patients older than 18 months present with metastatic disease, usually in the lymph nodes, liver, bone, and bone marrow. Less than half of these patients are cured, even with the use of high-dose therapy followed by autologous bone marrow or stem cell rescue.

Histologic subtypes of neuroblastoma. Top right p...

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.

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Histologic subtypes of neuroblastoma. Top right p...

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.

Pathophysiology

Chromosomal and molecular markers
Over the last 2 decades, many chromosomal and molecular abnormalities have been identified in patients with neuroblastoma. These biologic markers have been evaluated to determine their value in assigning prognosis, and some of these have been incorporated into the strategies used for risk assignment. 

The most important of these biologic markers is MYCN. MYCN is an oncogene that is overexpressed in approximately one quarter of cases of neuroblastoma via the amplification of the distal arm of chromosome 2. This gene is amplified in approximately 25% of de novo cases and is more common in patients with advanced-stage disease. Patients whose tumors have MYCN amplification tend to have rapid tumor progression and a poor prognosis, even in the setting of other favorable factors such as low-stage disease or 4S disease.

In contrast to MYCN, expression of the H-ras oncogene correlates with lower stages of the disease. Cytogenetically, the presence of double-minute chromatin bodies and homogeneously staining regions correlates with MYCN gene amplification. Deletion of the short arm of chromosome 1 is the most common chromosomal abnormality present in neuroblastoma and confers a poor prognosis. The 1p chromosome region likely harbors tumor suppressor genes or genes that control neuroblast differentiation. Deletion of 1p is more common in near-diploid tumors and is associated with a more advanced stage of the disease. Most of the deletions of 1p are located in the 1p36 area of the chromosome.

A relationship between 1p loss of heterozygosity (LOH) and MYCN amplification has been described. Other allelic losses of chromosomes 11q, 14q, and 17q have been reported, suggesting that other tumor suppressor genes may be located in these chromosomes. Another characteristic of neuroblastoma is the frequent gain of chromosome 1.

DNA index is another useful test that correlates with response to therapy in infants. Look et al demonstrated that infants whose neuroblastoma have hyperdiploidy (ie, DNA index >1) have a good therapeutic response to cyclophosphamide and doxorubicin.1 In contrast, infants whose tumors have a DNA index of 1 are less responsive to the latter combination and require more aggressive therapy. DNA index does not have any prognostic significance in older children. In fact, hyperdiploidy in children more frequently occurs in the context of other chromosomal and molecular abnormalities that confer a poor prognosis.

Three neurotrophin receptor gene products, TrkA, TrkB, and TrkC, are tyrosine kinases that code for a receptor of members of the nerve growth factor (NGF) family. Their ligands include p75 neurotrophin receptor (p75NTR) NGF, and brain-derived neurotrophic factors (BDNFs). Interestingly, TrkA expression is inversely correlated with the amplification of the MYCN gene, and the expression of the TrkC gene is correlated with TrkA expression. In most patients younger than 1 year, a high expression of TrkA correlates with a good prognosis, especially in patients with stages 1, 2, and 4S. In contrast, TrkB is more commonly expressed in tumors with MYCN amplification. This association may represent an autocrine survival pathway.

Disruption of normal apoptotic pathways may also play a role in neuroblastoma pathology. Disruption of these normal pathways may play a role in therapy response as a result of epigenetic silencing of gene promoters in apoptotic pathways. Drugs that target DNA methylation, such as decitabine, are being explored in preliminary studies. 

Other biologic markers associated with poor prognosis include increased levels of telomerase RNA and lack of expression of glycoprotein CD44 on the tumor cell surface. P-glycoprotein (P-gp) and multidrug resistance protein (MRP) are 2 proteins expressed in neuroblastoma. These proteins confer a multidrug-resistant (MDR) phenotype in some cancers. Their role in neuroblastoma is controversial. Reversal of MDR is one target for novel drug development. 
 
Anatomic
Origin and migration pattern of neuroblasts during fetal development explains the multiple anatomic sites where these tumors occur; location of tumors varies with age. Tumors can develop in the abdominal cavity (40% adrenal, 25% paraspinal ganglia) or other sites (15% thoracic, 5% pelvic, 3% cervical tumors, 12% miscellaneous). Infants more commonly present with thoracic and cervical tumors, whereas older children more frequently have abdominal tumors.

Most patients present with signs and symptoms related to tumor growth, although small tumors have been detected due to the common use of prenatal ultrasonography. Large abdominal tumors often result in increased abdominal girth and other local symptoms (eg, pain). Paraspinal dumbbell tumors can extend into the spinal canal, impinge on the spinal cord, and cause neurologic dysfunction.

Stage of the tumor at the time of diagnosis and age of the patient are the most important prognostic factors. Although patients with localized tumors (regardless of age) have an excellent outcome (80-90% 3-year event-free survival [EFS] rate), patients older than 18 months with metastatic disease fare poorly. Generally, more than 50% of patients present with metastatic disease at the time of diagnosis, 20-25% have localized disease, 15% have regional extension, and approximately 7% present during infancy with disseminated disease limited to the skin, liver, and bone marrow (stage 4S).

Physiologic and biochemical
More than 90% of patients have elevated homovanillic acid (HVA) and/or vanillylmandelic acid (VMA) levels detectable in urine. Mass screening studies using urinary catecholamines in neonates and infants in Japan, Quebec, and Europe have demonstrated the ability to detect neuroblastoma before it is clinically apparent. However, most of the tumors identified occur in infants with a good prognosis. None of these studies show that mass screening decreases deaths due to high-risk neuroblastoma. Markers associated with a poor prognosis include (1) elevated ferritin levels, (2) elevated serum lactate dehydrogenase (LDH) levels, and (3) elevated serum neuron-specific enolase (NSE) levels. However, these markers have become less important due to the discovery of more relevant biomarkers (ie, chromosomal and molecular markers). In fact, ferritin was not included in the recent formulation of the International Neuroblastoma Risk Group Classification System because it was not found to be of prognostic difference in the high risk group. 

Histologic
Pluripotent sympathetic stem cells migrate and differentiate to form the different organs of the sympathetic nervous system. The normal adrenal gland consists of chromaffin cells, which produce and secrete catecholamines and neuropeptides. Other cells include sustentacular cells, which are similar to Schwann cells, and scattered ganglion cells. Histologically, neural crest tumors can be classified as neuroblastoma, ganglioneuroblastoma, and ganglioneuroma, depending on the degree of maturation and differentiation of the tumor.

The undifferentiated neuroblastomas histologically present as small, round, blue cell tumors with dense nests of cells in a fibrovascular matrix and Homer-Wright pseudorosettes. These pseudorosettes, which are observed in 15-50% of tumor samples, can be described as neuroblasts surrounding eosinophilic neuritic processes. The typical tumor shows small uniform cells with scant cytoplasm and hyperchromatic nuclei. A neuritic process, also called neuropil, is a pathognomonic feature of neuroblastoma cells. NSE, chromogranin, synaptophysin, and S-100 immunohistochemical stains are usually positive. Electron microscopy can be useful because ultrastructural features (eg, neurofilaments, neurotubules, synaptic vessels, dense core granules) are diagnostic for neuroblastoma.

In contrast, the completely benign ganglioneuroma is typically composed of mature ganglion cells, Schwann cells, and neuritic processes, whereas ganglioneuroblastomas include the whole spectrum of differentiation between pure ganglioneuromas and neuroblastomas. Because of the presence of different histologic components, the pathologist must thoroughly evaluate the tumor; the regions with different gross appearance may demonstrate a different histology.
Neuroblastic nodules are present in the fetal adrenal gland and peak at 17-18 weeks' gestation. Most of these nodules spontaneously regress and likely represent remnants of fetal development. Some of these may persist and lead to the development of neuroblastoma.

Shimada histopathologic classification system
Shimada et al developed a histopathologic classification in patients with neuroblastoma.2 This classification system was retrospectively evaluated and correlated with outcome in 295 patients with neuroblastoma who were treated by the Children's Cancer Group (CCG). Important features of the classification include (1) the degree of neuroblast differentiation, (2) the presence or absence of Schwannian stromal development (stroma-rich, stroma-poor), (3) the index of cellular proliferation (known as mitosis-karyorrhexis index [MKI]), (4) nodular pattern, and (5) age. Using these components, patients can be classified into the following histology groups:

  • Favorable histology group
    • Patients of any age with stroma-rich tumors without a nodular pattern
    • Patients younger than 18 months with stroma-poor tumors, an MKI of less than 200/5000 (200 karyorrhectic cells per 5000 cells scanned), and differentiated or undifferentiated neuroblasts
    • Patients younger than 60 months with stroma-poor tumors, an MKI of less than 100/5000, and well-differentiated tumor cells
  • Unfavorable histology group
    • Patients of any age with stroma-rich tumors and a nodular pattern
    • Patients of any age with stroma-poor tumors, undifferentiated or differentiated neuroblasts, and an MKI more than 200/5000
    • Patients older than 18 months with stroma-poor tumors, undifferentiated neuroblasts, and an MKI more than 100/5000
    • Patients older than 18 months with stroma-poor tumors, differentiated neuroblasts, and an MKI of 100-200/5000
    • Patients older than 60 months stroma-poor, differentiated neuroblasts, and an MKI less than 100

Shimada et al's original classification was adopted and integrated into the International Neuroblastoma Pathology Classification (INPC). This was most recently revised.3 The INPC system remains age-dependent.

Frequency

United States

Neuroblastoma accounts for approximately 7.8% of childhood cancers in the United States. Approximately 650 new cases are diagnosed in the United States each year. According to the Surveillance, Epidemiology, and End Report (SEER), incidence is approximately 9.5 cases per million children.4

International

Incidence in other industrialized nations appears to be similar to that observed in the United States. International reports have shown that the incidence rates of neuroblastoma are highest among high income countries in Europe and North America, and lower in low income countries in Africa, Asia, and Latin America. No published data are available on the incidence in the emerging high-income countries of Asia.5

Mortality/Morbidity

According to the SEER data, the overall 5-year survival rate for children with neuroblastoma has improved from 24% in 1960-1963 to 55% in 1985-1994.4 In part, this increase in survival rate may be due to better detection of low-risk tumors in infants. The survival rate 5 years from diagnosis is approximately 83% for infants, 55% for children aged 1-5 years, and 40% for children older than 5 years. Improvements in diagnostic imaging modalities, medical and surgical management, and supportive care have contributed to the improved survival rates.

Most patients with neuroblastoma present with disseminated disease, which confers a poor prognosis and is associated with a high mortality rate. Tumors in these patients usually have unfavorable pathologic and/or molecular features. The 3-year EFS for high-risk patients treated with conventional chemotherapy, radiation therapy, and surgery is less than 20%. Differentiating agents and dose intensification of active drugs, followed by autologous bone marrow transplant, have been reported to improve the outcome for these patients, contributing to an EFS of 38%. A recent single-arm study of tandem stem cell transplantation reported a 3-year EFS of 58%, but this has not been tested in a randomized fashion.6

Morbidity of high-dose chemotherapy approaches can be substantial, although the treatment-related mortality rates have decreased with improvements in supportive care and hematopoietic support with growth factors and stem cells instead of bone marrow.

Race

Incidence of neuroblastoma is higher in white children than in black children. However, race does not appear to have any effect on outcome.

Sex

Males have a slightly higher incidence of neuroblastoma than females, with a male-to-female ratio of 1.2:1.

Age

Age distribution is as follows: 40% of patients are younger than 1 year when diagnosed, 35% are aged 1-2 years, and 25% are older than 2 years when diagnosed. According to SEER, incidence decreases every consecutive year up to age 10 years, after which the disease is rare.4

Clinical

History

  • 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

  • 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.

Causes

  • The cause of neuroblastoma is unknown, and no specific environmental exposure or risk factors have been identified.
  • Because of young age of onset with this disease, investigators have focused on events before conception and during gestation.
  • According to SEER data, factors investigated for which evidence is limited or inconsistent include medications, hormones, birth characteristics, congenital anomalies, previous spontaneous abortion or fetal death, alcohol or tobacco use, and paternal occupational exposures.
  • The vast majority of neuroblastoma arises sporadically without family history of the disease. However, 1-2% of newly diagnosed cases do have a family history of neuroblastoma. 
    • Patients with familial neuroblastoma often present at earlier age or with several distinct primary tumors. 
    • Neuroblastoma has been known to occur in the setting of other disorders that are linked to abnormal development of neural crest tissues, such as Hirschsprung disease or central congenital hypoventilation syndrome. 
    • Recent work using genome-wide analysis of neuroblastoma from these rare familial cases has identified a genetic defects involved in these cases.
    • Cases of neuroblastoma that accompany other congenital abnormalities of the neural crest have been associated with a germline mutation in PHOX2B. This gene is a homeobox gene that acts as a regulator of autonomic nervous system development. 
    • In familial neuroblastoma cases that are not associated with other congenital disorders of neural crest development, ALK mutations have been identified in the germline.7  These mutations largely occur in the kinase domain causing activation of ALK signaling. Efforts are ongoing to investigate the incidence of ALK mutations across all subsets of neuroblastoma, but initial evidence indicates that somatic mutations of the ALK gene are also present in some cases of sporadic neuroblastoma.

More on Neuroblastoma

Overview: Neuroblastoma
Differential Diagnoses & Workup: Neuroblastoma
Treatment & Medication: Neuroblastoma
Follow-up: Neuroblastoma
Multimedia: Neuroblastoma
References
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Further Reading

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Keywords

neuroblastoma, sympathetic nervous system tumors of childhood, cancer, tumor, malignancy, neuroblasts, paraspinal dumbbell tumors, ganglioneuroblastoma, ganglioneuroma, hypertension, periorbital ecchymosis, thoracic neuroblastoma, cervical neuroblastoma, Horner syndrome, rubella, opsoclonus, myoclonus, Ewing sarcoma, stem cell transplantation, blueberry muffin baby, treatment, diagnosis

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Contributor Information and Disclosures

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, and Children's Oncology Group
Disclosure: Nothing to disclose.

Coauthor(s)

Neyssa Marina, MD, Professor, Department of Pediatrics, Division of Pediatric Hematology-Oncology, Lucile Packard Children's Hospital and Stanford University
Neyssa Marina, MD is a member of the following medical societies: American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

Kara L Davis, DO, Fellow, 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.

Medical Editor

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
Stephan A Grupp, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Steven K Bergstrom, MD, Assistant to the Chairman, 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, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and International Society for Experimental Hematology
Disclosure: Nothing to disclose.

CME Editor

Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada
Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

 
 
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