MD2B - Pediatric Oncology: Neuroblastoma

Overview

Neuroblastoma is a neuroendocrine tumor that arises from developing sympathetic nerve tissue, the part of the nervous system responsible for regulating the body's response to stress by adjusting heart rate, blood pressure, hormone levels, and digestion. This specialized nervous tissue is located alongside the spinal cord, along nerve fiber pathways, and in the adrenal glands—two organs above the kidneys that produce essential hormones. Neuroblastoma primarily affects infants and young children and is rarely seen in children over ten years of age. It is the most common cancer in infants and the leading type of solid extracranial tumor in children. In the United States, approximately 800 cases of neuroblastoma are diagnosed each year. Prognosis depends on factors such as age (with infants having a better outcome), disease stage, and the presence or absence of specific molecular and genetic markers in the tumor cells.

Etiology

Neuroblastoma tumors can develop anywhere along the sympathetic chain, but they most commonly occur in the abdomen. Nearly all cases of neuroblastoma result from sporadic mutations. The MYCN gene, a transcription factor, is amplified in approximately 25% of cases.

Symptoms

Most patients with neuroblastoma present with signs and symptoms that are related to primary and metastatic tumor growth. Tumors located in the abdomen can cause abdominal pain, constipation, bladder dysfunction and abdominal swelling. Tumors located in the thorax may cause breathing difficulties, facial swelling (due to superior vena cava syndrome), and droopy eyes (due to ipsilateral Horner syndrome). Tumors located along the spinal cord or nerve fibers can result in neurological dysfunction, including weakness, loss of sensation, pain, bladder or bowel incontinence, or paralysis. Spinal tumors can also cause scoliosis (abnormal curvature of the spine).

Other symptoms associated with neuroblastoma include bulging eyes or dark circles around the eyes (due to metastasis to the orbital sockets), heterochromia (two differently colored eyes), painless bluish lumps under the skin in infants, and complaints of back or limb pain (from spinal or bone metastasis). Other symptoms include watery diarrhea (from elevated levels of vasoactive intestinal peptide, or VIP), opsoclonus-myoclonus syndrome (characterized by jerky body movements or uncontrolled eye movements due to the presence of autoimmune antibodies), swelling of body parts (from lymphatic blockage), hypertension, fatigue, bruising or bleeding (due to decreased blood cell counts when cancer infiltrates the bone marrow).

Diagnosis

A physician will perform a detailed history and physical examination, schedule imaging tests, and order laboratory tests to determine if a child has neuroblastoma. This will also aid in cancer staging and treatment.

Imaging tests

• Ultrasound (sonography): A diagnostic imaging test that uses high-frequency sound waves to create images of blood vessels and internal structures. This is often the first study to be done if an abdominal tumor is suspected.
• Computed Tomography (CT or CAT) Scan: A diagnostic imaging procedure that combines X-rays and computer technology to produce cross-sectional images of the body, often used to visualize soft tissues. Often, contrast dye is given to aid in tissue visualization.
• Magnetic Resonance Imaging (MRI): A diagnostic imaging procedure that uses large magnets, radio frequencies, and a computer to generate detailed images of internal structures.
• MIBG: MIBG is a compound similar to the hormone norepinephrine, which specifically targets sympathetic nervous tissue, the type of tissue involved in neuroblastoma tumors. MIBG can be labeled with radioactive iodine, allowing it to be visualized using scintigraphy. MIBG scans can highlight "hot spots" throughout the body where tumor tissue is present. Bone scans are often performed alongside MIBG scans to detect bone lesions.
• Abdominal x-rays: often show calcification of tumors.
• Additional tests such as a chest x-ray, bone radiographs or brain MRI may be performed to detect metastatic (distant) spread of cancer.

Lab tests

• CBC (complete blood count) with differential: A blood sample is taken to assess the number and shape of various blood cells, including red blood cells, white blood cells, and platelets.
• Blood Chemistry Panel: A blood sample is analyzed to measure levels of dopamine and norepinephrine, which, when elevated, can indicate the presence of neuroblastoma.
• 24-hour urinalysis: Urine is collected over a 24-hour period to measure levels of homovanillic acid (HMA) and vanillyl mandelic acid (VMA), which, when elevated, can be a sign of neuroblastoma.

Tissue sampling

A tissue sample is needed for the diagnosis of neuroblastoma and helps determine cancer staging and prognosis. Biopsies will be taken from the tumor site and bone marrow aspirations will be performed in both the right and left hip bones. These samples will be examined under a microscope to identify small round blue cells. They will also be analyzed for specific molecular and genetic markers.

Prognosis

Neuroblastoma is a heterogeneous disease. There are several factors that affect prognosis and response to therapy:

• Age: Infants and younger children generally have a more favorable prognosis. Children under the age of one are more likely to present with localized tumors, whereas older children often have metastases at time of diagnosis. Additionally, younger children tend to have less aggressive tumors that are more responsive to therapy. Five-year survival rates for neuroblastoma are 83% for children under 1 year, 55% for those aged 1 to 4 years, and 40% for children aged 5 to 9 years.
• Stage: The extent of tumor spread at the time of diagnosis is a key prognostic factor. While local lymphatic spread does not significantly impact survival, metastatic disease to distant organs or bone marrow results in a poor prognosis. Approximately 70% of patients present with metastases, most commonly in the bones. An exception to this is stage 4S disease, which occurs only in infants under one year of age. These infants have primary tumors that can be surgically removed, with metastases to the liver, skin, or bone marrow. Despite these metastases, stage 4S neuroblastoma has an excellent prognosis, with survival rates around 85%, as the tumor spontaneously regresses.  
• Tumor Histology and Biology: Favorable tumors are those that are more differentiated, meaning the specific cell type can be clearly identified under a microscope. Two key molecular findings that affect prognosis are tumor ploidy (the amount of DNA content in the tumor) and MYCN amplification.

Treatment

Treatment for neuroblastoma depends on the stage of disease. In low and intermediate risk tumors, the primary treatment is surgical removal, with chemotherapy added as needed.

For high-risk tumors where the long-term survival rates are less than 15%, treatment involves intensive combinations of chemotherapy, surgery, bone marrow transplantation, and radiation therapy. Retinoids are routinely used, as they can induce differentiation of neuroblastoma cells, limiting their ability to divide. The immunotherapy dinutuximab may also be used, though it carries a risk of toxicity. In one trial, the combination of dinutuximab and retinoids improved both event-free survival and overall survival at two years.