Etiology and Epidemiology

Neuroblastoma accounts for 8% to 10% of all childhood cancers, with approximately 650 cases diagnosed annually in the United States.¹ It is the most common extracranial solid tumor in children and the most common malignancy of infants. The median age at diagnosis is 17 months, and the male-to-female ratio is 1.1 : 1. Forty percent of patients are diagnosed when younger than 1 year of age, 89% are younger than 5 years of age, and 98% are younger than 10 years of age.²

Most primary neuroblastoma tumors occur in an anatomic distribution that is consistent with the location of neural crest tissue because the tumor arises from primitive adrenergic neuroblasts. The adrenal gland is the most common primary tumor site, accounting for 35% of cases overall. However, children younger than 1 year of age have a tumor arising from the adrenal gland in only 25% of cases. Other common sites include the low thoracic and abdominal paraspinal ganglia (30%) and posterior mediastinum (19%). Ganglia in the pelvic and cervical regions account for 2% to 3% of tumors, and in 1% a primary site is never known.³

Prevention and Early Detection

Because neuroblastomas frequently produce high levels of catecholamines, which can be detected in the urine, mass screening for the disease in infants has been studied in a number of countries. Extensive trials in numerous countries have shown that tumors detected by screening tend to be extremely favorable. Unfortunately, screening has not had an impact on survival or early detection of high-risk neuroblastoma.⁴

The development and subsequent regression of clusters of neuroblastoma is a normal embryologic event, and the development of clinically detectable neuroblastoma appears to be a consequence of disruption of this process. Microscopic neuroblastoma-like nodules frequently can be found at autopsy in infants who die of unrelated causes.⁵ Furthermore, clusters of cells consistent with neuroblastoma occur uniformly in the adrenal glands of all fetuses, peaking at between 17 and 20 weeks of gestation, and then spontaneously regress by birth or in early infancy.⁶

The cause of neuroblastoma is not known in most cases. Prenatal or postnatal exposure to drugs, chemicals, or radiation has never been proven to be associated with an increased incidence of the disease.² A small fraction of neuroblastomas are considered familial and are associated with a germline mutation. At least 20% of patients with familial neuroblastoma have bilateral or multifocal disease, which tends to present at an earlier age.⁷

Biologic Characteristics and Molecular Biology

Specific molecular characteristics of neuroblastoma have been well described and have a significant influence on prognosis and selection of therapy. Two of the most notable alterations are deletion of the short arm of chromosome 1 (1p) and MYCN (also known as N-myc) amplification. The former is thought to result in the loss of a tumor suppressor gene on 1p, whereas MYCN is a proto-oncogene found on the distal short arm of chromosome 2. There is a strong correlation between these genetic events, and both are found more commonly in advanced disease and are associated with a significantly worse prognosis.⁸ MYCN amplification occurs in 25% of primary neuroblastomas overall but in only 5% to 10% in patients with low-stage and stage 4S disease and 30% to 40% in patients with advanced disease.⁹

Chromosomal ploidy or DNA index (DI) is another significant marker of prognosis that is particularly useful in infants younger than 18 months of age. Near-diploid or pseudo-diploid tumors have near-normal nuclear DNA content but often have structural chromosomal abnormalities, including MYCN amplification. Hyperdiploid or near-triploid tumors typically lack MYCN amplification and 1p deletion and are more likely to have a favorable outcome.¹⁰

Pathology and Pathways of Spread

Neuroblastoma is one of many small, round, blue cell tumors of childhood, but it can be distinguished by staining for neuron-specific enolase, synaptophysin, and neurofilament. Electron microscopy can also be used and typically reveals neurosecretory granules that contain catecholamines, microfilaments, and parallel arrays of microtubules within the neuropil.¹¹ The characteristic histologic appearance is that of small, uniform cells containing dense, hyperchromatic nuclei and scant cytoplasm with neuropil. Homer-Wright pseudorosettes representing neuroblasts surrounding areas of eosinophilic neuropil are seen in up to 50% of cases.

Histologic subtypes represent different points along the maturation pathway and include (in order of increasing differentiation) neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Ganglioneuromas are considered benign and consist of mature ganglion cells, neuropil, and Schwann cells. Ganglioneuroblastomas have pathologic characteristics of both neuroblastoma and ganglioneuroma and have an intermediate behavior as well.

A variety of different classification systems have been used to help define the prognosis for neuroblastoma. The International Neuroblastoma Pathology Committee (INPC) system is the most widely used and validated. Characteristics of this system are listed in Table 70-1. This represents a modification of the Shimada system that classifies tumors according to the degree of differentiation toward ganglion cells, amount of Schwann cell stroma present, whether the tumor is nodular, degree of calcification, and the mitotic-karyorrhexis index.

Neuroblastoma commonly spreads via lymphatics to regional lymph nodes, often in the para-aortic chain, and less commonly to the next echelon of lymphatics, such as the left supraclavicular fossa (Virchow node) in patients with abdominal tumors. Hematogenous spread often occurs to bone marrow, bone, and liver. Neuroblastoma appears to have a proclivity for the bones of the skull and especially the posterior orbit, which can cause the clinical presentation of “raccoon eyes” from periorbital ecchymosis. Lung and brain metastases are rare at presentation. However, with improvements in systemic therapy, isolated parenchymal brain metastases are now occurring with a relatively high incidence in high-risk patients after apparent disease remission. These central nervous system relapses require craniospinal radiation therapy (RT) because of a high risk of leptomeningeal dissemination.¹²

Clinical Manifestations, Patient Evaluation, and Staging

The clinical presentation for neuroblastoma is highly variable because of the wide variety of disease sites. Primary tumor location and extent of disease vary with age. Most children (57%) younger than 1 year of age have locoregional disease at the time of diagnosis, whereas most children (81%) older than 1 year of age have disseminated disease. Children with abdominal tumors may present with abdominal pain, distention, or gastrointestinal disturbances. Many with disseminated disease present with bone pain, weight loss, fever, or failure to thrive. Paraneoplastic syndromes, such as opsomyoclonus (myoclonic jerking and random eye movement) are rare, occurring in less than 4% of patients. The catecholamines secreted from most neuroblastomas are not likely to cause hypertension, flushing, or tachycardia.

A plain radiograph of the chest or abdomen may show a soft tissue mass representing the primary tumor, and calcifications are present in 85% of tumors. Staging of neuroblastoma requires numerous imaging modalities. The primary tumor and regional lymph nodes should be imaged with computed tomography or magnetic resonance imaging.^13,14 These studies should also be used to assess for metastases in the liver as well as spinal extension and resectability of the primary tumor. They also may be used to clarify the extent of bone metastases in specific locations, such as the skull.

Bone metastases may be determined with technetium-99m (^99mTc)–labeled bone scintigraphy, with metaiodobenzylguanidine (MIBG) scintigraphy, and/or with ¹⁸F-fluorodeoxyglucose-labeled positron emission tomography (FDG-PET). For high-risk patients, it may be worthwhile to perform all three studies because different forms of imaging may be more useful than others for different patients. MIBG is a sensitive and specific method (close to 90%) to assess the primary tumor and metastatic disease. A ^99mTc bone scintiscan is typically used for detection of bone metastases even if MIBG studies are used.^15,16 Studies regarding the utility of FDG-PET for neuroblastoma are ongoing. Complete staging includes two bilateral posterior iliac crest bone marrow aspirates and biopsies. A single positive result is sufficient for the documentation of bone marrow involvement.¹⁷

Because excess catecholamines are produced in most cases, urine catecholamines and their metabolites, specifically norepinephrine, vanillylmandelic acid, 3-methoxy-4-hydroxyphenylglycol, and/or homovanillic acid are typically measured. Urinary levels of catecholamines are often given as ratios to the urinary creatinine value.¹⁸

Previous staging systems including the Evans and D’Angio classification,¹⁹ historically used by the Children’s Cancer Group, and a system formerly used by the Pediatric Oncology Group^20,21 have been replaced by the International Neuroblastoma Staging System (INSS) as the standard staging system (Table 70-2