Epidemiology

Neuroblastoma is the most common extracranial solid tumor in children and the most commonly diagnosed malignancy in infants. Approximately 600 new cases are diagnosed each year in the USA, accounting for 8-10% of childhood malignancies and one third of cancers in infants. Neuroblastoma accounts for >15% of the mortality from cancer in children. The median age of children at diagnosis of neuroblastoma is 22 months, and 90% of cases are diagnosed by 5 years of age. The incidence is slightly higher in boys and in whites.

Pathology

Neuroblastoma, which is derived from primordial neural crest cells, consists of a spectrum of tumors with variable degrees of neural differentiation, ranging from tumors with primarily undifferentiated small round cells (neuroblastoma) to tumors containing mature and maturing schwannian stroma with ganglion cells (ganglioneuroblastoma or ganglioneuroma). The tumors may resemble other small round blue cell tumors, such as rhabdomyosarcoma, Ewing sarcoma, and non-Hodgkin lymphoma. The prognosis of children with neuroblastoma varies with the histologic features of the tumor, and prognostic factors include the presence and amount of schwannian stroma, the degree of tumor cell differentiation, and the mitosis-karyorrhexis index.

Pathogenesis

The etiology of neuroblastoma in most cases remains unknown. Familial neuroblastoma accounts for 1-2% of all cases, is associated with a younger age at diagnosis, and has been linked to mutations in the Phox2B and ALK genes. Neuroblastoma is associated with other neural crest disorders, including Hirschsprung disease, central hypoventilation syndrome, and neurofibromatosis type I, and potentially congenital cardiovascular malformations (Table 492-1). Children with Beckwith-Wiedemann syndrome and hemihypertrophy also have a higher incidence of neuroblastoma. Increased incidence of neuroblastoma is associated with some maternal and paternal occupational chemical exposures, farming, and work related to electronics, although no single environmental exposure has been shown to cause neuroblastomas.

Table 492-1 SYNDROMES ASSOCIATED WITH NEUROBLASTOMA

From Park JR, Eggert A, Caron H: Neuroblastoma: biology, prognosis, and treatment, Pediatr Clin North Am 55:97-120, 2008.

Genetic characteristics of neuroblastoma tumor tissue that are of prognostic importance include amplification of the MYCN (N-myc) proto-oncogene and tumor cell DNA content, or ploidy (Tables 492-2 to 492-4). Amplification of MYCN is strongly associated with advanced tumor stage and poor outcomes. Hyperdiploidy confers better prognosis if the child is <1 yr of age at diagnosis. Other chromosomal abnormalities, including loss of heterozygosity (LOH) of 1p, 11q, and 14q, and gain of 17q, are commonly found in neuroblastoma tumors and are associated with worse outcomes. In addition, many other biologic factors have been shown to be associated with neuroblastoma outcomes, including tumor histology and vascularity and the expression levels of nerve growth factor receptor (TrkA, TrkB), ferritin, lactate dehydrogenase, ganglioside GD2, neuropeptide Y, chromogranin A, CD44, multidrug resistance–associated protein, and telomerase. These factors and many others are under investigation in clinical trials to determine whether they can be used to reduce therapy for children predicted to fare well with minimal therapy and to intensify therapy for those predicted to be at high risk for relapse.

Clinical Manifestations

Neuroblastoma may develop at any site of sympathetic nervous system tissue. Approximately half of neuroblastoma tumors arise in the adrenal glands, and most of the remainder originate in the paraspinal sympathetic ganglia. Metastatic spread, which is more common in children >1 yr of age at diagnosis, occurs via local invasion or distant hematogenous or lymphatic routes. The most common sites of metastasis are the regional or distant lymph nodes, long bones and skull, bone marrow, liver, and skin. Lung and brain metastases are rare, occurring in less than 3% of cases.

Neuroblastoma can mimic many other disorders and may be difficult to diagnose. The signs and symptoms of neuroblastoma reflect the tumor site and extent of disease. Metastatic disease can cause a variety of signs and symptoms, including fever, irritability, failure to thrive, bone pain, cytopenias, bluish subcutaneous nodules, orbital proptosis, and periorbital ecchymoses (Fig. 492-1). Localized disease can manifest as an asymptomatic mass or as mass-related symptoms, including spinal cord compression, bowel obstruction, and superior vena cava syndrome.

Figure 492-1 Periorbital metastases of neuroblastoma with proptosis and ecchymoses.

Children with neuroblastoma can also present with neurologic signs and symptoms. Neuroblastoma originating in the superior cervical ganglion can result in Horner syndrome. Paraspinal neuroblastoma can invade the neural foramina, causing spinal cord and nerve root compression. Neuroblastoma can also be associated with a paraneoplastic syndrome of autoimmune origin, termed opsoclonus-myoclonus-ataxia syndrome. Some tumors produce catecholamines that can cause increased sweating and hypertension, and some release vasoactive intestinal peptide, causing a profound secretory diarrhea. Children with extensive tumors can also experience tumor lysis syndrome and disseminated intravascular coagulation. Infants <1 yr of age also can present in unique fashion, termed stage 4S, with widespread subcutaneous tumor nodules, massive liver involvement, limited bone marrow disease, and a small primary tumor without bone involvement or other metastases.

Diagnosis

Neuroblastoma is usually discovered as a mass or multiple masses on plain radiography, CT, or MRI (Fig. 492-2). On plain radiography or CT, the mass often contains calcification and hemorrhage. Prenatal diagnosis of neuroblastoma on maternal ultrasound scans is sometimes possible. Tumor markers, including catecholamine metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) in urine, are elevated in 95% of cases and help to confirm the diagnosis. A pathologic diagnosis is established from tumor tissue obtained by biopsy. Neuroblastoma can be diagnosed without a primary tumor biopsy if small round blue tumor cells are observed in bone marrow samples (Fig. 492-3) and an elevation of VMA or HVA is found in the urine.

Figure 492-2 Top, CT scan of a thoracic neuroblastoma with intraspinal extension at diagnosis. Middle, CT scan of an adrenal primary with extensive lymph node involvement. Bottom, Bone scintigraphy scan with technetium diphosphonate demonstrating diffuse skeletal involvement.

Figure 492-3 Neuroblastoma cells aspirated from the bone marrow. Clumps of cells often contain ≥3 cells with or without evidence of rosette formation. Rosettes of cells surrounding an inner mass of fibrillary material are characteristic of neuroblastoma.

Evaluations for metastatic disease should include CT or MRI of the chest and abdomen, bone scans to detect cortical bone involvement, and at least two independent bone marrow aspirations and biopsies to evaluate for marrow disease. Iodine-123 meta-iodobenzylguanidine (¹²³I-MIBG) studies may also be used to better define the extent of disease (Fig. 492-4). MRI of the spine should be performed in cases with suspected or potential spinal cord compression, but imaging of the brain with either CT or MRI is not routinely performed unless dictated by the clinical presentation.

Figure 492-4 Metaiodobenzylguanidine (MIBG)–avid neuroblastoma. Increased uptake of radiolabeled tracer can be detected in multiple sites of disease, including bone and soft tissue.

(Figure provided by K Matthay, University of California, San Francisco; from Maris JM, Hogarty MD, Bagatell R, et al: Neuroblastoma, Lancet 369:2106–2120, 2007.)

The International Neuroblastoma Staging System (INSS) now is currently used to stage patients with neuroblastoma after initial surgical resection (see Table 492-3). INSS stage 1 tumors are confined to the organ or structure of origin and are completely resected. INSS stage 2 tumors extend beyond the structure of origin but not across the midline, either with (stage 2B) or without (stage 2A) ipsilateral lymph node involvement. INSS stage 3 tumors extend beyond the midline, with or without bilateral lymph node involvement, whereas INSS stage 4 tumors are disseminated, with metastases to bones, bone marrow, liver, distant lymph nodes, and other organs. INSS stage 4S refers to neuroblastoma in children less <1 yr of age with dissemination to liver, skin, and/or bone marrow without bone involvement and with a primary tumor that would otherwise be staged as INSS stage 1 or 2. A new International Neuroblastoma Risk Group Staging System (INRGSS) is currently being developed to allow for more effective comparisons of treatments and outcomes worldwide.

Treatment

Treatment strategies for neuroblastoma have changed dramatically over the past 20 years, with significant reduction in treatment intensity for children who have localized, low-risk tumors and continued increased treatment intensity and addition of new agents for treatment of children who have high-risk neuroblastoma. Currently the patient’s age and tumor stage are combined with cytogenetic and molecular features of the tumor to determine the treatment risk group and estimated prognosis for each patient (see Tables 492-2 to 492-4). The usual treatment for low-risk neuroblastoma is surgery for stages 1 and 2 and observation for stage 4S with cure rates generally >90% without further therapy. Treatment with chemotherapy or radiation for the rare child with local recurrence can still be curative. Children with spinal cord compression at diagnosis also may require urgent treatment with chemotherapy, surgery, or irradiation to avoid neurologic damage. Stage 4S neuroblastomas have a very favorable prognosis, because many regress spontaneously. Chemotherapy or resection of the primary tumor does not improve survival rates, but for infants with massive liver involvement and respiratory compromise, small doses of cyclophosphamide or low-dose hepatic irradiation may alleviate symptoms. For children with stage 4S neuroblastoma who require treatment for symptoms, the survival rate is 81%.

Treatment of intermediate-risk neuroblastoma includes surgery, chemotherapy, and, in some cases, radiation therapy. The chemotherapy usually includes moderate doses of cisplatin or carboplatin, cyclophosphamide, etoposide, and doxorubicin given for several months. Radiation therapy is used for tumors with incomplete response to chemotherapy. Children with intermediate-risk neuroblastoma, including children with stage 3 disease and infants with stage 4 disease and favorable characteristics, have an excellent prognosis and >90% survival with this moderate treatment. In this intermediate-risk group, obtaining adequate diagnostic material for determination of the underlying biologic features of the tumor, such as the Shimada pathologic classification and MYCN gene amplification, is critical, so that children with unfavorable characteristics can receive more aggressive treatment and those with favorable features can be spared excessive toxic therapy.

Children with high-risk neuroblastoma have long-term survival rates between 25% and 35% with current treatment that consists of intensive chemotherapy, autologous stem cell transplantation (ASCT), surgery, irradiation, and 13-cis-retinoic acid (isotretinoin, Accutane). Current induction chemotherapy for children with high-risk neuroblastoma includes combinations of cyclophosphamide, topotecan, doxorubicin, vincristine, cisplatin, and etoposide. After completion of induction chemotherapy, resection of the residual primary tumor is followed by focal irradiation to areas with residual tumor. Induction chemotherapy is then followed by high-dose chemotherapy with ASCT. A national cooperative group trial demonstrated significantly better survival with ASCT and chemotherapy than with chemotherapy alone. The further addition of 13-cis-retinoic acid after ASCT resulted in further improvements in survival rates.

Cases of high-risk neuroblastoma are associated with frequent relapses, and children with recurrent neuroblastoma have a <50% response rate to alternative chemotherapy regimens. New treatment strategies and agents are needed for children with both high-risk and recurrent neuroblastoma. Therapies currently under investigation include new chemotherapeutic agents, radiolabeled targeted agents (such as ¹³¹I-MIBG), monoclonal antibodies (anti–tumor-associated GD2) combined with growth factors (GM-CSF), and antitumor vaccines. It also is hoped that biologic studies of neuroblastoma will eventually lead to the identification of new molecular and genetic targets for therapy.