MD2B - Pediatric Oncology: Neuroblastoma

Overview

Neuroblastoma is a tumor that arises from developing sympathetic nerve tissue (the part of the nervous system that allows the body to respond to stress by adjusting heart rate, blood pressure, hormone levels, and digestion). This special type of nervous tissue is found next to the spinal cord, along the paths of nerve fibers, and in the adrenal glands (two organs which sit above each kidney and produce various hormones needed by the body). Neuroblastoma is a cancer that occurs most frequently in infants and young children and is rarely seen in children older than ten years of age. It is the leading form of cancer in infants and is the most common type of solid extra-cranial (outside the head) tumor in children. There are over 800 cases of neuroblastoma diagnosed each year in the United States. Overall prognosis depends on age (infants do better), stage (spread of disease), and the absence/presence of molecular and genetic markers in tumor cells.

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 (area around the lungs) can cause breathing difficulties, facial swelling, and droopy eyes due to the Superior Vena Cava Syndrome and Horner's Syndrome, respectively. Tumors located along the spinal cord or along various nerve fibers can present with any type of neurologic dysfunction including weakness, loss of sensation, pain, bladder and bowel incontinence, or paralysis. Spinal tumors can also cause scoliosis (curvature of the spine). Other symptoms that can be seen in association with neuroblastoma include bulging eyes or dark circles around the eyes (from metastases into the orbital sockets that hold the eyes), the appearance of two different colored eyes, p ainless bluish lumps under the skin in infants, complaints of back pain or limb pain (from spinal or bone metastases), watery diarrhea (from elevated levels of the substance "VIP"), jerky body movements or uncontrolled eye movements (from autoimmune antibodies), swelling of various body parts (from lymphatic blockage), hypertension (high blood pressure), or fatigue, bruising and bleeding (due to decreased amounts of blood cells when cancer overtakes the bone marrow).

Diagnosis

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

Imaging tests

• Ultrasound: Ultrasonography uses sound waves to produce images of internal organs and to distinguish benign (not harmful) conditions from malignant (cancerous) tumors. This is often the first imaging study to be done if a tumor is appreciated in the abdomen because it is painless and noninvasive.
• CT/ CAT scan: CT scan uses x-rays to create cross sectional pictures of the tumor. Often, dye will be placed through an IV into the child's veins to help make the pictures more clear.
• MRI: An MRI scan uses radio waves and strong magnets rather than x-rays to create pictures of the tumor. MRI gives more detailed images than CT and ultrasound
• MIBG: MIBG is a compound similar to the hormone norepinephrine which is found specifically in sympathetic nervous tissue (the type of tissue that makes up a neuroblastoma tumor). MIBG can be labeled with radioactive iodine allowing it to then be visualized with scintigraphy. Thus, MIBG scans can show "hot spots" throughout the body where tumor is located. Bone scans are often done in conjunction with MIBG scans to look for bone lesions.
• Additional tests to look for metastases (spread of tumor): chest x-ray to look for cancer in the lungs, bone scan or bone radiographs to look for cancer in the bones, brain MRI to look for cancer in the brain.

Lab tests

• CBC: a blood test to look at the number of each type of blood cell
• Blood Chemistry Panel:: a blood sample is taken to look for elevated levels of two hormones, dopamine and norepinephrine, which when elevated can be a sign of neuroblastoma
• 24 hour urinalysis: urine is collected for 24 hours to look for abnormal levels of two hormones, homovanillic acid (HMA) and vanillyl mandelic acid (VMA), which when elevated can be a sign of neuroblastoma

Tissue sampling

A tissue diagnosis is needed for definite diagnosis of neuroblastoma and to aid in staging and prognosis. Biopsies (tissue samples) will be taken from the tumor site and bone marrow will be aspirated from both the right and left hip bones. These cell samples will be viewed carefully under a microscope to look for specific molecular and genetic tumor findings.

Prognosis

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

• Age: Infants and younger children have a much more favorable prognosis. Children under the age of one are more likely to have localized tumor while older children frequently have metastases at time of diagnosis. In addition, younger children tend to have less aggressive tumors and tumors that are more responsive to therapy. Five-year survival rates for neuroblastoma are 83, 55, and 40 percent for children younger than 1 year, 1 to 4 years, and 5 to 9 years, respectively.
• Stage: An important factor in prognosis is the extent of tumor spread at the time of diagnosis. Although local lymphatic spread (presence of cancer in local lymph nodes) does not hurt survival chances, metastatic disease to distant organs or to the bone marrow brings a much worse prognosis. One exception to this rule is stage 4S disease. In this form of neuroblastoma found only in children less than one year of age, infants have primary tumors that can be removed by surgery and have metastases to the liver, skin, or bone marrow. Despite these metastases, the children do exceptionally well and have survival rates around 85% because the tumor often spontaneously regresses (goes away on its own).
• Tumor histology (what the tumor looks like under the microscope) and tumor biology (molecular and genetic structure of the tumor): Favorable tumors are ones that are more differentiated (you can recognize the specific type of cell under the microscope). "Ploidy" (amount of DNA content of the tumor) and "MYC-N amplification" are two additional molecular genetic findings that affect prognosis.

Treatment

Treatment of neuroblastoma depends on stage. In low and intermediate risk tumors, surgical removal of the primary tumor is the initial treatment and combinations of various chemotherapy drugs are added when needed. In high risk tumors where the long term probabilities of survival are less than 15%, treatment involves intensive combinations of chemotherapy agents, surgery, bone marrow transplantation, and radiation therapy. When these conventional modalities fail and disease recurs, novel therapies are attempted including retinoic acid, topotecan, immunologic agents, anti-angiogenic agents, and MIBG radionuclide therapy.