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Pediatric Neuroblastoma

  • Author: Norman J Lacayo, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
 
Updated: Mar 17, 2016
 

Background

Neuroblastoma is the most common extracranial solid tumor of 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 patterns of distribution of these cells correlates with the sites of primary neuroblastoma 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 are shown in the image below.

Histologic subtypes of neuroblastoma. Top right pa 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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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 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. Loss of heterozygosity at 11q23 has been described and is an independent prognostic factor. 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.

A study by Challagundla et al reported that exosomic microRNAs released within the neuroblastoma environment affect resistance to chemotherapy.[2]

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 shows 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.[3] 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 includes the following:

  • 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 includes the following:

  • 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.[4] The INPC system remains age-dependent.

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Epidemiology

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.[5]

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.[6]

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.[5] 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.[7]

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 randomized studies of this approach are ongoing.[8]

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.[5]

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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, 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.

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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).
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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