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). To interpret the literature, it is necessary to make comparisons between the INSS and the two other staging systems, because differences can be significant. INSS stage 1 is similar to stages I and A. Stage 4 is essentially the same as stages IV and D, and stage 4S is the same as IVS and D-S. The greatest differences are in the middle stages (II and III; B and C). In the INSS system, stage 2 is divided into 2A (incompletely excised tumor) and 2B (ipsilateral lymph node involvement). The INSS has also formalized definitions of response to treatment in an attempt to facilitate cross-study comparisons.¹⁷

TABLE 70-2 International Neuroblastoma Staging System

* The midline is defined as the vertebral column. Tumors originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column.

† Marrow involvement in stage 4S should be minimal, that is, less than 10% of total nucleated cells identified as malignant on bone marrow biopsy or on marrow aspirate. More extensive marrow involvement would be considered to be stage 4. The MIBG scan (if performed) should be negative in the marrow.

Data from Brodeur GM, Seeger RC, Barrett A, et al: International criteria for diagnosis, staging and response to treatment in patients with neuroblastoma, J Clin Oncol 6:1874-1881, 1988; and Brodeur GM, Pritchard J, Berthold F, et al: Revisions in the international criteria neuroblastoma diagnosis, staging and response to treatment, J Clin Oncol 11:1466-1477, 1993.

Current protocols for neuroblastoma are based on risk stratification. The proposed risk groups based on clinical and biologic features are outlined in Table 70-3. Survival varies from 85% to 99% for low-risk patients to 20% to 40% for high-risk patients. Disease stage and patient age at diagnosis, as well as biologic characteristics (MYCN, ploidy), have major prognostic significance. The International Neuroblastoma Pathology Classification, based on the original Shimada system, is likely to become the new international standard.

Primary Therapy

The therapeutic approach for neuroblastoma varies tremendously, depending on risk group stratification. The available treatment modalities include surgery, chemotherapy, RT, and a number of newer treatments such as immunotherapy. The following is a discussion of therapy for low-, intermediate-, and high-risk disease, with an emphasis on the role of RT. A basic treatment algorithm for each risk group is shown in Figure 70-1.

Figure 70-1 Treatment algorithm for low-risk (A), intermediate-risk (B), and high-risk (C) neuroblastoma.

Recurrent Disease and Palliation

Current approaches for treating recurrent or refractory neuroblastoma include novel cytotoxic agents and targeted delivery of radionuclides, retinoids, and immunotherapy. Topotecan, paclitaxel, irinotecan, rebeccamycin, and oral etoposide are the most frequently investigated cytotoxic agents.^32–36 RT plays an important role in palliation for neuroblastoma. Patients with incurable disease often live for an extended period of time. However, they often suffer severe pain and functional impairment from metastases, most commonly to bone. External beam radiation therapy (EBRT) is the most effective tool for managing painful metastases. Fractionation schemes depend on the site, field size, marrow reserves, and anticipated life span of the patient. A high-functioning child may benefit from 2-Gy fractions to 30 Gy, whereas a patient with end-stage disease may be better served by a single fraction of 7 to 8 Gy.

Irradiation Techniques

Irradiation techniques depend on the site being treated. Most commonly, patients with high-risk disease have a primary tumor arising from the adrenal gland. Radiation volume for localized neuroblastoma is determined by the surgeon’s operative findings and presurgical imaging studies. Margins and normal tissue-sparing parameters vary from protocol to protocol. Based on patterns of failure data, it is important to include the para-aortic lymph nodes in the radiation field.³⁷ Computed tomographic planning is imperative to delineate precisely the target region as well as normal tissues, including the kidneys, liver, and, in some cases, ovaries. Treatment should encompass entire vertebral bodies to reduce the risk of scoliosis. Simple anterior and posterior beams, as demonstrated in Figure 70-2, are often the best solution, but intensity-modulated radiation therapy (IMRT) may be helpful if standard techniques do not provide adequate sparing of critical organs. Bone metastases are also often best treated with simple opposed beams. However, more sophisticated approaches, such as IMRT, may be needed when treating sites in the head and neck because of the complex anatomy and critical structures.

Figure 70-2 Typical anterior and posterior RT field for adrenal neuroblastoma. Generous coverage of para-aortic lymph nodes is recommended. Adequate kidney sparing is accomplished by treating postchemotherapy tumor volume.

Neuroblastoma is common in very young children, necessitating the frequent use of anesthesia for RT. In this case, propofol is safe and well tolerated, even for twice-daily treatments.

Treatment Algorithms, Controversies, Challenges, Future Possibilities, and Clinical Trials

Intraoperative radiation therapy (IORT) has been studied as an alternative to EBRT. Gillis and colleagues³⁸ reported results for 31 patients who received IORT with electron-beam energies that ranged from 4 to 16 MeV, and the median dose was 10 Gy (range, 7 to 15 Gy). They concluded that IORT for the primary tumor produced excellent local control after a gross total resection but was inadequate after a subtotal resection. However, a follow-up publication by the University of California, San Francisco, group reported a high rate of severe aortic complications in patients receiving IORT.³⁹ Memorial Sloan-Kettering Cancer Center reported a relatively favorable 50% rate of local control and low rate of complications for 44 patients who underwent subsequent surgery and re-irradiation with IORT for locally relapsed neuroblastoma.⁴⁰

Iodine-131(¹³¹I)-labeled MIBG therapy is one example of targeted radiation. ¹³¹I-MIBG is bound at the cell membrane and is actively transported into cells by most neuroblastomas. Therapeutic use of ¹³¹I-MIBG has been used in patients with unresectable disease with excellent results. Trials combining ¹³¹I-MIBG with chemotherapy, surgery, and RT are currently in progress. In addition to 13-cis-retinoic acid, new retinoids are being developed to treat recurrent or refractory disease. Fenretinide is one such compound that induces apoptosis even in cells resistant to 13-cis-retinoic acid.³⁹

The Memorial Sloan-Kettering Cancer Center has excellent long-standing results using the 3F8 murine monoclonal antibody against GD2.⁴⁰ More recently, a randomized study⁴¹ confirmed superior event-free and overall survival when high-risk patients received consolidation with immunotherapy. They used a chimeric human-murine anti-GD2 monoclonal antibody that was given in alternating sequence with granulocyte-monocyte colony-stimulating factor and interleukin-2. Two-year event-free survival was 66% with immunotherapy compared with 46% in the control group.

Consideration for long-term complications is critical when treating neuroblastoma. Patients treated years ago with higher doses of radiation frequently suffered from spinal deformities secondary to surgery and RT.⁴² Major orthopedic problems from RT still occur but are infrequent with a dose of 21 Gy. Symmetric treatment of vertebral bodies is recommended.

It is possible that the kidneys of infants and young children are more sensitive to RT than are those of adults and older children. Abnormal creatine clearance has been reported in infants with stage IVS disease who received 12.25 and 14 Gy.⁴³ As a general rule, it is desirable to limit as much of each kidney as possible to doses less than 15 to 18 Gy to prevent major impairment in renal function. One must also inform parents about the low risk of second malignancies.⁴⁴ A recent study of long-term survivors of high-risk neuroblastoma shows that the majority have late complications of therapy, including hearing loss, hypothyroidism, ovarian failure, musculoskeletal abnormalities, and pulmonary dysfunction. However, most complications were considered to be of mild-to-moderate severity.⁴⁵ All members of multimodality teams that care for neuroblastoma patients must be mindful of late effects and strive to minimize complications while ensuring the best chance for cure.