Practice Essentials
Neuroblastoma (NB) is a poorly differentiated neoplasm derived from neural crest cells. It is the most common cancer in infants and the most common extracranial solid tumor in childhood. Median age at diagnosis is 17 months; 90% of patients are younger than 5 years at diagnosis, and less than 5% are adolescents or adults. [1, 2] Neuroblastoma accounts for 7% of pediatric malignancies but for more than 10% of childhood cancer-related mortality. [3]
Neuroblastomas originate in the adrenal medulla and paraspinal or periaortic regions. [2] Its presentation varies, depending on the primary site of origin, metastatic burden, and metabolically active by-products, but 65% of primary neuroblastomas occur in the abdomen—40% in the adrenal gland—so most children present with abdominal symptoms, such as fullness or distension.
Neuroblastoma 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 yet a good outcome might be achieved, even if residual tumor is left behind.
Signs and symptoms
Abdominal symptoms such as fullness or distention are the most common symptoms. However, children with localized disease are typically asymptomatic. Children with disseminated neuroblastoma are generally sick and may have systemic manifestations, including the following:
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Unexplained fevers
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Weight loss
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Anorexia
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Failure to thrive
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General malaise
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Irritability
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Bone pain
Infants often present with consequences of compression of the sympathetic ganglia in the thoracic region, such as Horner syndrome (myosis, anhydrosis, and ptosis) or superior vena cava syndrome. Older children typically present with abdominal symptoms; the most common physical examination finding is a nontender, firm, irregular abdominal mass that crosses the midline.
See Presentation for more detail.
Diagnosis
Recommended laboratory studies include the following:
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Complete blood cell (CBC) count and differential
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Urine collection for catecholamines and urinalysis
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Erythrocyte sedimentation rate
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Vanillylmandelic acid–to–homovanillic acid (VMA-to-HVA) ratio
Neuron-specific enolase (NSE), lactate dehydrogenase (LDH), and ferritin are markers useful in the identification of active disease.
Standard diagnostic imaging modalities include the following:
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Plain abdominal radiography (kidneys, ureters, bladder [KUB])
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Renal/bladder ultrasonography
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Bone scintigraphy
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Computed tomography (CT) or magnetic resonance imaging (MRI)
Biopsy is the sine qua non in the diagnostic evaluation of neuroblastoma.
See Workup for more detail.
Treatment
Treatment of neuroblastoma is risk based. [2]
Low-risk neuroblastoma:
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Observation, with or without biopsy
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Surgical resection, then observation
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Chemotherapy, with or without surgery, for symptomatic disease or unresectable progressive disease after surgery
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Radiation therapy (for emergency treatment only)
Intermediate-risk neuroblastoma:
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Multiple-agent chemotherapy (eg, doxorubicin, cyclophosphamide, cisplatin or carboplatin, and etoposide)
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Chemotherapy is often given before definitive resection
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Surgery and observation (in infants).
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Radiation therapy (if needed)
High-risk neuroblastoma:
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Chemotherapy, surgery, tandem cycles of myeloablative therapy and hematopoietic stem cell transplantation, radiation therapy, and dinutuximab, with granulocyte-macrophage colony-stimulating factor (GM-CSF) and isotretinoin.
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Eflornithine, to reduce the risk of relapse after at least partial response to prior multiagent therapy
See Treatment for more detail.
Background
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]
Neuroblastoma is one of the small, blue, round cell tumors of childhood. Other such tumors include the following:
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Undifferentiated soft tissue sarcoma ( rhabdomyosarcoma)
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, in the adrenal glands and in the paraspinal nerves from the neck to the pelvis. [2] The name neuroblastoma is derived from the fact that the cells resemble primitive neuroblasts.
Pathophysiology
Embryologically, tumors of the sympathetic nervous system differentiate along one of two distinct pathways: 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. [12]
Amplification of the MYCN oncogene occurs in 20% of primary neuroblastoma tumors and 50% of high-risk tumors; it is associated with high rates of metastasis and a poor prognosis in children older than 1 year but not in children younger than 1 year. [13] The precise role of MYCN in nonamplified tumors is unknown.
Hyperdiploid tumor DNA is associated with a favorable prognosis. N-myc amplification is associated with a poor prognosis In 2000, Maris et al reported from the Children's Cancer Group (CCG) that 1p deletion independently predicted a lower event-free survival but not overall survival. The clinical relevance of 14q LOH is unclear at this time.
Allelic loss of 11q is present in 35-45% of primary tumors. Notably, this aberration is rarely seen in tumors with MYCN amplification yet remains highly associated with other high-risk features.
Bosse and colleagues identified Glypican-2 (GPC2) as a molecule specifically expressed by neuroblastoma cells and not by normal tissues. GPC2 expression has been detected on the cell surface in the majority of high-risk neuroblastoma, and such expression correlated with worse prognosis of neuroblastoma patients. GPC2 expression is driven by somatic gain of chromosome 7q (where the GPC2 gene is located) and by MYCN amplification. Additionally, Bosse et al developed a GPC2-directed antibody-drug conjugate with a potent cytotoxic activity against GPC2-expressing neuroblastoma cells, which may represent a promising immunotherapeutic target for high-risk neuroblastoma. [14]
Etiology
About 1-2% of patients with neuroblastoma have a family history of the disease. Germline mutations associated with a genetic predisposition to neuroblastoma in these cases include the following [2] :
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ALK mutation - Point mutations in the tyrosine kinase domain of the ALK gene are found in about 75% of familial neuroblastoma cases; somatic activating point mutations in ALK are also seen in about 9% of sporadic neuroblastoma cases. In addition, co-amplification of ALK and MYCN (the two genes are near each other on chromosome 2) occurs in a small proportion of neuroblastoma cases
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PHOX2B mutation - Germline loss-of-function PHOX2B mutations have been identified in rare patients with sporadic neuroblastoma and Ondine curse (congenital central hypoventilation) and/or Hirschsprung disease. Somatic PHOX2B mutations are found in about 2% of patients with sporadic neuroblastoma.
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Deletion at the 1p36 or 11q14-23 locus
Increased risk of malignancies including neuroblastoma have been noted in children with various cancer predisposition syndromes, including Costello syndrome, Noonan syndrome, and neurofibromatosis type 1. [15]
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 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.
Environmental and paternal exposures linked to neuroblastoma have not been identified. [16]
Epidemiology
Frequency
Neuroblastoma is the most common cancer in infants. Approximately 700-800 cases are diagnosed each year in the United States, accounting for about 6% of cancers in children. [1] Clinical frequency is approximately one case per 8000-10,000 children.
Neuroblastoma is more common in whites and is slightly more prevalent in boys than in girls (male-to-female ratio of 1.3:1). In rare cases, neuroblastoma is detected by prenatal ultrasound. About 37% of cases are diagnosed in infancy, and nearly 90% of cases are diagnosed before the age of 5 years. Median age at diagnosis is 19 months. [2] Neuroblastoma is rare in people over the age of 10 years. [1] Neuroblastoma is thought to occur sporadically, with 1-2% of cases considered familial.
Prognosis
For more than 40 years, the age at diagnosis and the stage have been the dominant independent variables used as prognostic factors in children with neuroblastoma. In 1984, Shimada et al classified neuroblastoma by relating its histopathologic features to its clinical behavior. [17] To this end, Shimada et al divided neuroblastoma into favorable and unfavorable categories, depending on the degree of neuroblast differentiation, Schwannian stromal content, mitosis-karyorrhexis index, and age at diagnosis. In 1999, the Shimada classification was modified to the International Neuroblastoma Pathology Classification system.
Because of the various approaches to risk stratification, efforts have been made to develop a consensus approach that will allow comparison of patients around the world. In 2009, the International Neuroblastoma Risk Group (INRG) Task Force published a classification based on the review of a large number of patients from Europe, Japan, the United States, Canada, and Australia diagnosed with neuroblastoma between 1974 and 2002. [18] The Task Force identified the following as the most highly statistically significant and clinically relevant factors:
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Tumor stage
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Patient age
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Tumor histologic category
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Grade of tumor differentiation
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DNA ploidy
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Copy-number status of the MYCN oncogene
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Chromosome 11q status
On the basis of those factors the Task Force identified four broad prognostic clinical categories (see Workup/Risk Groups), which correlated with 5-year event-free survival (EFS) rates as follows [18] :
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Very low risk: EFS > 85%
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Low risk: EFS > 75% to 85%
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Intermediate risk: EFS 50% to 75%
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High risk: EFS < 50%
The Children's Oncology Group (COG) subsequently developed a process called the Neuroblastoma Risk Stratification System (NRSS), which is used for treatment stratification. The NRSS, which was most recently revised in 2021 (see Workup/Risk Groups) classifies patients into low-, intermediate-, or high-risk categories. [19] Five-year EFS and overall survival (OS) rates are as follows:
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Low risk: EFS 90.7% ± 1.1%, OS 97.9% ± 0.5%
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Intermediate risk: EFS 85.1% ± 1.4%, OS 95.8% ± 0.8%
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High risk: EFS 51.2% ± 1.4%, OS 62.5% ± 1.3%
Other variables carry varying degrees of prognostic significance. These include the site of the primary tumor, serum ferritin levels, neuron-specific enolase (NSE) level, and nutritional status.
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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.
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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.
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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.
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Bulky lymph nodes just medial to the left kidney.
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Upper periorbital edema, proptosis, and ocular ecchymosis in a 9-month-old girl.
