The incidence of neuroblastoma in the United States is approximately 650 new cases annually, and almost half of neuroblastomas occur in children under two years of age. The malignancy develops from neural crest cells.

These cells form, among other tissues, the nerves and structures of the sympathetic nervous system (the nerve network that controls the flight or fight response) during embryonic development. Neuroblastoma develops when these cells do not respond to signaling, and do not therefore mature into proper functioning cells. More than 40% of neuroblastomas affect the adrenal glands, but they can also develop in the neck, spinal cord, nerves near the spine, chest, pelvis, or abdomen.

Most cases of neuroblastoma are sporadic and have no identifiable cause. About 20% are inherited. Only one copy of the mutated chromosome need be inherited for a child to develop neuroblastoma

Signs and Symptoms

The most common symptom of neuroblastoma (when it affects the adrenal glands) is a swollen or distended abdomen with or without constipation. Tumors in the bone produce bone pain and impair walking. Those pressing against the back of the eyes can cause bulging, black eyes.

Compression of the lungs causes difficulty breathing and tumors in the spinal tissues can cause weakness and paralysis as well as back pain and difficult urination and bowel movements. Neuroblastoma that has spread to form patches just below the skin anywhere on the body produces painless, bluish lumps.

Neuroblastoma symptoms can present in a cluster and constitute a syndrome: Horner syndrome, superior vena cava syndrome, Kerner-Morrison syndrome, Opsoclonus-myoclonus, and Hutchinson syndrome.

Diagnosis

Diagnoses begin with a physical exam that includes tests of neurologic function (mental status, reflexes, coordination). The most common form of neuroblastoma – affecting the adrenal glands – can often be first detected as a firm, irregular lump in the abdomen.

However, urine tests are necessary to make a definitive diagnosis. Children with neuroblastoma excrete large amounts of the chemical messengers norepinephrine and dopamine and their breakdown products.

Imaging scans and biopsies are needed to assess the extent and severity of the malignancy. One of the most common imaging techniques used for neuroblastoma is metaiodobenzylguanadine scintography. Metaiodobenzylguanadine is an analog of norepinephrine, and it accumulates in adrenal glands and nerve cells.

The compound contains a radioactive form of iodine, which can be detected and used to image unusual growths. Ultrasonography (ultrasound), computed tomography (CT, computerized tomography), and X-rays are also used to aid diagnosis. Biopsies are necessary, in addition to a urine test, to make a definitive diagnosis. Tumor cells removed during biopsy are stained with dyes or other molecules to to detect changes characteristic of neuroblastoma. To do this, the biopsied samples

Stages

Neuroblastoma is classified into one of several stages:

• Stage 1: The tumor is restricted to one region and surgery removes all the visible tumor
• Stage 2: Subdivided into two stages; stage 2A tumors are restricted to one region but surgery cannot remove all the visible tumor; stage 2B similar to stage 1 except tumor cells have spread to a lymph node near the tumor site
• Stage 3: One of the following is required: (1) surgery cannot fu8lly remove the tumor and the tumor has spread from one side of the body to the other, and may have spread to local lymph nodes; (2) the tumor is restricted to one region on one side of the body and has spread to lymph nodes on the other side; (3) a tumor situated in the middle of the body and has spread to lymph nodes and tissues on both sides of the body, and surgery would not remove the tumor
• Stage 4: Cancer cells have spread to lymph nodes distant from the original tumor, to the skin, or other regions of the body; for stage 4S, children must be less than one year of age, the tumor spread to the skin, liver, and/or bone marrow, the tumor is restricted to one region and can be completely removed with surgery and/or lymph nodes near the tumor harbor malignant cells

Treatment

The Children’s Oncology Group Neuroblastoma Risk Stratification System is used to classify disease into low, intermediate-, and high-risk groups to guide treatment.

Surgery is the typical treatment for many low-risk malignancies. Chemotherapy is used to treat tumors that cannot be removed with surgery. Radiotherapy is reserved for tumors that are unresponsive to chemotherapy. Children at intermediate-risk are treated with chemotherapy followed by radiotherapy or surgery.

Children at high-risk are first treated with high-dose chemotherapy to shrink the tumor followed by surgery and sometimes radiotherapy. Stem cell transplants and the experimental 13-cis retinoic acid are also used following chemotherapy. High-dose chemotherapy is also used for children in the late stages of disease.

Progressive neuroblastoma (continues to grow despite treatment) or recurring neuroblastoma is treated with surgery or chemotherapy with stem cell transplantation and 13-cis retinoic acid.

Prognosis

Approximately 10% of neuroblastomas revert to a benign state; this is one of the few cancers with this characteristic. But the cancer also has a high recurrence: the malignancy returns in more than 50% of children with advanced disease. Age at diagnosis and cancer stage are the two most important predictors of outcome. Ultimately, neuroblastoma causes approximately 15% of cancer-related deaths in children.