Neuroblastoma

Symptoms and signs of neuroblastoma depend on the site of the primary cancer and pattern of disease spread. The most common symptoms are abdominal pain, discomfort, irritability, decreased appetite, and a sense of fullness due to an abdominal mass.

Certain symptoms may result from metastases. These include bone pain due to widespread bone metastases, periorbital ecchymosis and proptosis due to retrobulbar metastasis, and abdominal distention and respiratory problems due to liver metastases, especially in infants. Children with bone marrow involvement can have anemia (may have pallor) and thrombocytopenia (petechiae). The tumor can metastasize to the skin as well, presenting with blue, blue-gray, or violaceous subcutaneous nodules or papules.

Children occasionally present with focal neurologic deficits or paralysis due to direct extension of the cancer into the spinal canal. Tumors in the neck or upper chest may cause Horner syndrome (ptosis, miosis, anhidrosis). Children may also present with a paraneoplastic syndrome, such as cerebellar ataxia, opsoclonus-myoclonus, watery diarrhea, or hypertension. Specifically, opsoclonus-myoclonus-ataxia syndrome (OMAS) occurs in approximately 2 to 4% of patients and is associated with long-term neurologic sequelae despite treatment of the primary tumor (1).

Rare diseases that are associated with neural crest tumors (neuroblastoma, ganglioneuroblastoma, and ganglioneuroma) include ROHHADNET (rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neuroendocrine tumors) and congenital central hypoventilation syndrome (2).

• Usually CT or MRI

• Biopsy with tumor molecular profiling

• Blood and sometimes urine tests

• Sometimes bone marrow aspirate or marrow core biopsy plus measurement of urinary catecholamine intermediates

Routine prenatal ultrasound occasionally detects neuroblastoma.

Patients presenting with abdominal symptoms or a mass ultimately require CT or MRI. Diagnosis of neuroblastoma is then confirmed by biopsy of any identified mass (1).

Neuroblastoma (CT Scan)

Image

This axial noncontrast T1-weighted image through the upper chest/thorax shows a large, heterogeneous, posterior mediastinal mass that extends through and enlarges an adjacent neural foramen with epidural extension of tumor into the spinal canal.

Living Art Enterprises/SCIENCE PHOTO LIBRARY

Alternatively, diagnosis can be established without biopsy or surgery of the primary tumor by finding characteristic cancer cells in a bone marrow aspirate or core biopsy plus elevated urinary catecholamine intermediates. These methods of diagnosis are not commonly used but can be useful in situations where biopsy and/or surgery is considered high risk because of patient or tumor characteristics.

Routine blood tests include complete blood count and comprehensive metabolic panel (1). Urinary vanillylmandelic acid (VMA), homovanillic acid (HVA), or both are elevated in ≥ 90% of patients. A 24-hour urine collection can be used, but a spot urine test is usually sufficient. If the primary site of the neuroblastoma is adrenal, it must be differentiated from Wilms tumor and other renal masses. It may also need to be differentiated from rhabdomyosarcoma, hepatoblastoma, lymphoma, and tumors of genital origin.

• Surgical resection

• Usually chemotherapy

• Sometimes high-dose chemotherapy followed by stem cell transplantation with stem cell rescue

• Isotretinoin and other immunotherapy for maintenance therapy in high-risk disease

• Sometimes radiation therapy or iodine-131 metaiodobenzylguanidine (131I-MIBG) therapy

• Eflornithine for continuation therapy in high-risk disease

Treatment of neuroblastoma is based on the risk category (see also the National Cancer Institute's Neuroblastoma Treatment—Health Professional Version).

Surgical resection is important for low-risk and intermediate-risk disease (1). For patients with intermediate-risk disease, it is often delayed until neoadjuvant chemotherapy is given to improve the chance of adequate surgical resection.

Chemotherapy is usually necessary for children with intermediate-risk or high-risk disease. Typical agents include vincristine, cyclophosphamide, doxorubicin, cisplatin, carboplatin, ifosfamide, and etoposide.

A tandem autologous stem cell transplant (2 consecutive rounds of high-dose chemotherapy with stem cell rescue) is recommended as the standard consolidation for the majority of children with high-risk disease (1).

Isotretinoin is frequently used for children with high-risk disease. Neuroblastoma is unique in that it can undergo spontaneous differentiation and regression, particularly in infants. Isotretinoin exploits this property pharmacologically. A trial showed that 6 months of high-dose pulse isotretinoin after consolidation significantly improved 3-year event-free survival compared to no further therapy (2).

Immunotherapy using monoclonal antibodies against neuroblastoma antigens combined with granulocyte-macrophage colony stimulating factor and isotretinoin is used as maintenance therapy in children with high-risk disease.

Eflornithine, also known as difluoromethylornithine, is used as continuation therapy for patients with high-risk disease who have responded to anti-disialoganglioside (anti-GD2) immunotherapy. Eflornithine is an irreversible inhibitor of the enzyme ornithine decarboxylase (ODC), which is the rate-limiting enzyme in polyamine synthesis. Polyamines (putrescine, spermidine, and spermine) are small positively charged molecules that are essential for cell growth, DNA stabilization, transcription, translation, and cellular proliferation (3).

Radiation therapy is a standard part of treatment for local control of high-risk disease. It is sometimes needed for children with intermediate-risk disease or for children with inoperable tumors (1).

In relapsed/refractory neuroblastoma, the combination of immunotherapy with chemotherapy leads to impressive clinical responses (4). The combination of irinotecan/temozolomide plus an anti-GD2 antibody (dinutuximab or naxitamab) has become standard treatment for first relapse or refractory disease, with reproducible objective response rates of approximately 40% (1), and is being evaluated further.

GD2-CART01 is a chimeric antigen receptor T-cell therapy that modifies the patient's own T cells and has shown promising early results (5).

For patients with MIBG-avid disease, 131I-MIBG (a type of radioisotope) is a standard treatment option for recurrent or refractory disease. Neuroblastoma cells are known to accumulate MIBG, and > 90% of neuroblastomas are MIBG-avid, which allows for targeted radiation treatment to all sites of disease. Several studies have shown efficacy of 131I-MIBG in the relapses setting, and it is currently being evaluated as first-line therapy (6, 7).

Prognosis for neuroblastoma depends on age at diagnosis, stage, and biologic factors (eg, histopathology, tumor cell ploidy in younger patients, MYCN amplification). Young children with localized disease have the best outcome.

Overall survival rates for low-risk and intermediate-risk disease are approximately 95 to 97%; the rate for high-risk disease is 50 to 70% (1, 2).

The following English-language resources may be useful. Please note that The Manual is not responsible for the content of these resources.

1. Children's Oncology Group (COG) and the International Neuroblastoma Risk Group (INRG) classification: COG and INRG risk group stratification systems

2. National Cancer Institute: Neuroblastoma Treatment—Health Professional Version