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; the vast majority of cases are diagnosed before age 5 years. [1, 2] It accounts for 6% of pediatric malignancies [1] 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 and a good outcome might be achieved, even if residual tumor is left behind. Stages I and II neuroblastoma is managed surgically. Multiple-agent chemotherapy is the conventional therapy for patients with more advanced stages of neuroblastoma.
Neuroblastoma continues to be one of the most frustrating childhood tumors to manage. Although the tumor has been studied extensively and great efforts have been extended to determine appropriate therapy and achieve a cure, little has altered the prognosis in affected children over the past 20 years. Further consensus data are needed to provide more definitive information regarding risk stratification, treatment, and prognosis in patients with neuroblastoma.
Targeted therapy is the subject of current research. Agents directed against tumors with amplification of the MYCN oncogene are in various stages of development. [4] For neuroblastoma with ALK mutations, crizotinib and other ALK kinase inhibitors have shown efficacy in selected cases. [5]
In vitro cultures demonstrate that neuroblastoma is radiosensitive, but results from clinical trials have been inconsistent and inconclusive. As a primary treatment modality, radiation therapy can be used in regional lymph node metastases with sequential cyclophosphamide therapy, in infants with stage-4 disease who have Pepper syndrome (to control respiratory compromise), and in total-body irradiation combined with autologous bone marrow transplantation.
No curative treatment exists for relapsed high-risk neuroblastoma patients. Clonally acquired somatic alterations that occur under the selective pressure of cytotoxic chemoradiotherapy offer clinically tractable targets, and this strategy is currently being studied in a prospective trial. [6]
Bosse and colleagues have identified Glypican-2 (GPC2) as a molecule specifically expressed by NB cells and not by normal tissues. GPC2 expression has been detected on the cell surface in the majority of high-risk NB, and such expression correlated with worse prognosis of NB patients. GPC2 expression is driven by somatic gain of chromosome 7q (where GPC2 gene is localized) and by MYCN amplification. Additionally, they developed a GPC2-directed antibody-drug conjugate, with a potent cytotoxic activity against GPC2-expressing NB cells which may represent a promising immunotherapeutic target for high-risk NB patients. [7]
Background
Virchow first described neuroblastoma in 1864; at that time, it was referred to as a glioma. [8] In 1891, Marchand histologically linked neuroblastoma to sympathetic ganglia. [9] 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. [10]
In 1927, Cushing and Wolbach further characterized neuroblastoma by describing the transformation of malignant neuroblastoma into its benign counterpart, ganglioneuroma. [11] Everson and Cole reported that this type of transformation is rare in children older than 6 months. [12] In 1957, Mason published a report of a child with neuroblastoma whose urine contained pressor amines. [13] 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. [14]
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. [15] 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. [6]
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 the following , has also been Malignant transformation and maintenance of the dedifferentiated state of neural crest cells may result from failure of thaose 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.
Epidemiology
Frequency
Neuroblastoma is the most common cancer in infants. Approximately 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 prognosticators in children with neuroblastoma. In 1984, Shimada classified neuroblastoma, relating its histopathologic features to its clinical behavior. [16] To this end, Shimada 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 2005, a large group of patients from Europe, Japan, the United States, Canada, and Australia diagnosed with neuroblastoma between 1974 and 2002 was reviewed in an effort to develop an International Neuroblastoma Risk Group (INRG). Consensus was reached to consider age (dichotomies around 18 mo), stage assessed before treatment, and N-myc status in the risk-group schema. Once the final statistical analyses are available, the specific criteria will be included in the final INRG report.
The COG recently developed a process called the Neuroblastoma Risk Stratification System (NRSS), which is used for treatment stratification. Like the Shimada Index, this new system is based on clinical and biological factors that are predictive of outcome. The NRSS is different in that it is based on the INRG system and is used for treatment-stratification purposes. Patients are assigned to low-, intermediate-, or high-risk categories based on age at diagnosis, INSS stage, histopathology, N-myc amplification status, and DNA index.
However, certain biological variables that affect the prognosis of children with neuroblastoma have been identified. Specific examples include aneuploidy of tumor DNA and N-myc oncogene amplification. N-myc amplification occurs in 20% of primary neuroblastoma tumors and is associated with a subset of neuroblastomas that have high metastatic potential and, consequently, a poor prognosis. [17] N-myc is thought to contribute to the aggressive behavior of neuroblastoma. However, the precise role of N-myc in nonamplified tumors is unknown.
Hyperdiploid tumor DNA is associated with a favorable prognosis. N-myc amplification is associated with a poor prognosis in children older than 1 year but not in children younger than 1 year. The N-myc amplification is linked to the deletion of chromosome arm 1p and a gain of the long arm of chromosome 17. In neuroblastoma, consistent areas of chromosomal loss of heterozygosity (LOH) include chromosome bands 1p36, 11q23, and 14Q23qter. 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 N-myc amplification yet remains highly associated with other high-risk features.
Other variables carry varying degrees of prognostication. These include the site of the primary tumor, serum ferritin levels, NSE, 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.
