Neuroblastoma

What is neuroblastoma, how common is it and why does it occur?
Neuroblastoma is a tumor that may arise at any site in the sympathetic nervous system, including the brain, neck (3%), chest next to the spine (20%), abdomen on either side of the aorta (24%), pelvis (3%), and adrenal gland (50%) (Figure 1). It is the second most common solid tumor of infancy and childhood, being exceeded only by brain tumors. More than 25% of cases are diagnosed before 1 year of age; 50% of cases by age 2 years, and 90% by age 8 years.

Figure 1. This graph shows the sites of tumor occurrence for infants and children with neuroblastoma. Most cases occur in the adrenal gland and in the "sympathetic chain" in the back of the body next to the spine.

Approximately 500 new cases of neuroblastoma per year in the United States. Neuroblastoma occurs more frequently in boys (1.2:1). This tumor occurs in 8 to 10 cases per 1 million people per year.

Neuroblastomas may occur in patients with other conditions, especially those related to problems with the “neural crest” (neurocristopathies, neural crest = area in the fetus from which numerous nerve cells to various organs arise), including Hirschsprung’s disease , Klippel-Feil syndrome, Waardenburg’s syndrome, and Ondine’s curse (congenital hypoventilation syndrome); patients with Beckwith-Weidemann syndrome; patients with fetal alcohol syndrome; and mothers taking phenylhydantoin for seizure disorders (fetal hydantoin syndrome).

Alcohol has been established as a cause if it is taken by the mother during pregnancy. The association of neuroblastoma and increased adrenal gland hormone production (Cushing’s syndrome) also has been observed. Instances of neuroblastoma running in the family have been reported in identical twins and a mother and daughter. Evidence of the tumor in the fetus with products from the tumor causing high blood pressure in the mother, sweating, headaches, and abnormal heartbeats has been documented. Further evidence of the fetal occurrence of neuroblastoma includes cases associated with death before birth, instances of placental involvement by the tumor, and reports of prenatal diagnosis by ultrasound in fetuses.

A specific genetic chromosome abnormality has not been detected in patients with neuroblastoma, although many chromosome abnormalities are noted in many neuroblastoma cells. The most frequent are on chromosome 1 and are associated with advanced stages of the disease, indicating that this area of chromosome 1 may contain a gene which keeps tumors from growing. N-myc, ras, and other cancer genes have been identified; most are poor prognosis factors.

“Neuroblasts” (a type of immature nerve cell) can be identified in 7-week old fetuses and form nodules by 12 weeks gestation. These nodules increase in size and number until 15 to 17 weeks of gestation. Examination of fetal adrenal glands shows the presence of neuroblastoma (naturally occurring cells but confined to a specific location) in 100% of adrenal glands studied at 17 to 20 weeks’ gestation but in only 1:39 to 1:263 adrenal glands in newborns or infants younger than 3 months of age who die from other causes.

These observations suggest that neuroblastoma in the adrenal glands may go away, or change to a noncancerous form and not present as a clinical case of neuroblastoma. The development of a neuroblastoma may be related to a problem which either prevents them from going away or further develops as a cancer.

Neuroblastoma cells secrete many products, including hormones (e.g., vasoactive substances (substances that affect the blood vessels), including catecholamines (the “fight or flight” hormones that raise our heart rate and blood pressure when we are scared) and their byproducts (homovanillic acid [HVA], vanillylmandelic acid [VMA], 3-methoxytyramine, metanephrines, and dopamine).

How does neuroblastoma show up?
Presenting symptoms in cases of neuroblastoma vary according to the location of the main tumor and whether or not the tumor has spread to other places in the body (metastasis). The most common sites of tumor metastases are the bone marrow, the bone itself (cortex), the liver, and the skin; rarely the lung and brain may have metastases. The tumor spreads through the blood stream to these sites. Metastases to lymph nodes are also common. One can feel a mass in the abdomen in more than 50% of patients when the main tumor is located here. The mass is often large, hard, nodular, and sometimes painful to touch.

Manifestations that affect the whole body, such as anemia (low blood count), weight loss or failure to gain weight, and malnutrition, often are noted in advanced cases. Children with bone metastases affecting the legs may refuse to walk because of severe leg pain. Hypertension (high blood pressure) may accompany this lesion in 35% of cases as a result of release of catecholamine hormones from the tumor or from pressure on the adjacent kidney.

Paraplegia (paralysis of the lower part of the body) or other loss of neurologic function may occur as a result of tumor extending into the spine and pressing on the spinal cord. A pelvic mass may press on the bladder or blood vessel. More unusual problems include cerebellar ataxia (muscular incoordination) and opsomyoclonus (jerking movements) and nystagmus (a swirling movement of the eyeballs, also called dancing-eye syndrome). These are probably caused by an immune reaction affecting the cerebellum (part of the brain) and not from a tumor metastasis.

Some patients develop watery diarrhea syndrome, resulting from release of certain hormones (vasoactive intestinal peptide = VIP) from the tumor. Some babies and young infants may have an enlarged liver related to tumor involvement. These patients also may have respiratory (lung) problems due to the large liver pushing up on the diaphragm, gastroesophageal reflux, and a blood clotting disorder.

Neuroblastoma may be detected in an otherwise normal fetus on a prenatal ultrasound. Figure 2 shows various presentations of children with neuroblastoma. In picture (A) the child has a very large abdomen either because of a large tumor mass or because of an enlarged liver from tumor spread throughout the liver. Picture (B) shows some of the skin masses that may be associated with the disease and (C) shows a lump on the scalp from metastatic neuroblastoma.

The diagnosis of neuroblastoma in most cases is confirmed by obtaining a series of x-ray and laboratory studies. Plain x-rays of the involved area (e.g., neck, chest, abdomen) often show white calcification on the x-ray within the tumor mass, which is highly suspicious of a neuroblastoma (Figure 3).

Many cases that present in the first year of life may not involve the adrenal gland. Ultrasound is often the first study used for neck or abdominal masses. Ultrasound or computed tomography (CT) reveals a solid mass, often with many lobes or extensions. The exception is neonatal adrenal neuroblastoma, which may look like cyst (fluid-filled). CT usually can distinguish Wilms’ tumor (a childhood kidney tumor) from neuroblastoma in cases of tumors in the back of the abdomen. (see Figure 4).

CT also is useful to determine the presence of liver spread (metastasis). Magnetic resonance imaging (MRI) is the most useful test to document whether the tumor is near the spine and may show the presence of bone marrow involvement and tumor involving the major blood vessels.

Bone scans and bone x-rays usually show the presence of bone metastases. Iodine-123-labeled metaiodobenzylguanidine (MIBG), which is processed by the adrenal gland tissue, is a nuclear medicine test that is useful in identifying the tumor and metastases. Needle aspiration of the bone marrow in the middle of the bones may show metastasis as may bone marrow biopsy of the pelvic bone.

Studies indicate that blood samples may identify circulating neuroblasts, documenting tumor spread throughout the body. A urine specimen is obtained in which VMA and HVA are measured and compared to the creatinine levels in the urine (VMA and HVA are byproducts of hormones made by a neuroblastoma and creatinine is a normal muscle byproduct in the blood that ends up in the urine); these levels are abnormal in 90% of cases. Metanephrine and normetanephrine levels (other tumor hormone byproducts) may be obtained when VMA and HVA levels are normal. When the levels are elevated, all are useful to follow the response of the disease to treatment of to watch for recurrence.

Additional preoperative studies include obtaining blood samples for serum alanine aminotransferase and bilirubin, both of which assess for problems in the liver; creatinine to evaluate kidney function; and lactic dehydrogenase (LDH), neuron-specific enolase (NSE), and ferritin. An increased LDH is a marker for more advanced disease, just as are increased NSE (a protein associated with neural cells) and ferritin, which are produced by the tumor cells. The red blood cell and white blood cell counts should be checked as should the platelet count and the blood clotting ability.

What are the stages and treatment of neuroblastoma?
Tumor staging is important to guide treatment and to determine the prognosis. Several staging systems have been used in the past, of which the Evans staging system is the most widely used in North America (see Table 1).

A variant of this, the international staging system, is now widely used in clinical trials (Table 2).

This system of staging takes into account preoperative problems, and histologic assessment (microscopic appearance) of the tumor and lymph nodes. The peculiar 4-S stage occurs almost exclusively in infants younger than 1 year old and represents a special group of patients with an excellent prognosis despite the presence of distant spread of tumor, but only to the liver, skin/subcutaneous tissue, or bone marrow (Figure 2). Large abdominal or thoracic tumors that cross the midline (middle of the body), surround the great vessels, and are not resectable at diagnosis are automatically considered stage 3. (Figure 4)

In the absence of metastases and when the tumor appears resectable, surgery is indicated with the goal of complete resection (Figure 5). For abdominal tumors, inspection of the liver with biopsy of any suspicious findings and extensive removal of lymph nodes are required, even if they appear normal. This includes lymph nodes around the aorta and vena cava (the big vein returning blood from the lower body to the heart). A minimum of six to nine lymph nodes representing these areas is preferred for adequate staging.

For chest or neck tumor, the same principles apply except that nodes on the opposite side of the body are not sought, and fewer lymph nodes are necessary for adequate staging. (Figure 6 and 7)

The main tumor is sent immediately to pathology so that tissue may be assessed for the N-myc cancer gene and electron microscopy before being fixed in formalin (a type of preservative). After fixation in formalin, the tissue is examined under the microscope. Typically, neuroblastomas are composed of small round blue cells under the microscope. The tumor is also examined to establish the Shimada classification (Table 3) because this helps give a prognosis for this tumor.

Neuroblastoma is unusual in that it can “mature” into a non-cancerous form of tumor called a ganglioneuroma. In some instances within the same patient, neuroblastoma is noted with varying stages of maturation to ganglioneuroblastoma and ganglioneuroma. Sometimes neuroblastoma may be difficult to distinguish from other tumor types, including lymphoma, Ewing’s tumor, primitive neuroectodermal tumor (PNET), and certain cases of embryonal rhabdomyosarcoma. An accurate diagnosis usually can be made by immunohistochemistry which involves extensively evaluating the tissue for certain “markers” and by “cytogenetics” which examines the gene makeup of the tumor.

For patients with metastatic disease and a large tumor and for patients with a tumor that appears that it cannot be completely removed, the diagnosis can still be made without removal of the tumor by the appearance of the tumor on CT scan and elevation of catecholamines (VMA, HVA) in the urine. Enough tumor cells still are required, however, to assess important prognostic factors, such as N-myc cancer gene, the type of DNA, and the Shimada classification. This assessment ideally is accomplished by an open biopsy.

Alternatively, percutaneous biopsies (through the skin) with a needle or bone marrow biopsies may provide a sufficient number of cells, especially if the patient is not in good shape for a biopsy by an operation. Depending on the age of the patient and other prognostic factors, various types of chemotherapy can be used to shrink the tumor. When the tumor has decreased in size, plans are made for a “second-look” surgery after 3 months with the goal of achieving complete removal. This second-look surgery should be done even if the tumor appears to be gone because the CT scan may miss small amounts of remaining neuroblastoma, especially in the abdomen.

In more recent years, classification of the risk of an individual tumor has helped to guide therapy greatly (Table 4). For low-risk patients, surgery is usually curative and chemotherapy, which is not without risks in these infants and children, is used only in patients with return or progression of disease. Intermediate-risk patients are treated with chemotherapy. The safest, most effective agents currently seem to be cyclophosphamide, doxorubicin, carboplatin, and etoposide (VP-16); vincristine, cisplatin, and other agents also may be helpful. A medicine called granulocyte colony-stimulating factor is used to decrease the length of periods of low white blood count in order to minimize the risk of infection.

For high-risk patients, the poor prognosis justifies a much more intense chemotherapy using a combination of chemotherapy agents (cisplatin, etoposide, vincristine, doxorubicin, cyclophosphamide, ifosfamide, and carboplatin), followed by surgery to attempt to achieve a complete removal of the tumor. Radiation therapy may be used at this point or later in the treatment for any additional tumor that had to be left behind. In general, attempts are made to preserve all other structures when the neuroblastoma is removed.

Nephrectomy (removal of a kidney involved with tumor) may be warranted if it would allow complete removal of the tumor. Some protocols call for peripheral blood stem cell collection (gathering stem cell from the blood stream that can regenerate the bone marrow) before chemotherapy. After the metastases have been completely or partially destroyed, doses of chemotherapy agents are used that destroy the bone marrow followed by giving the peripheral blood stem cells back (bone marrow transplant) in order to safely get the neuroblastoma out of the bone marrow.

Sometimes a second similar course of chemotherapy with different agents, again followed by administration of stem cells to replace the bone marrow is used. Radiation therapy may be given to the site of the original tumor because of the high rate of return of tumor at the original site.

Tumors can present with special features, such as a massively enlarged liver causing respiratory (breathing) difficulty and neurologic problems from the tumor pressing on the spinal cord. This is caused by the tumor growing into the spinal canal. Infants with stage 4-S neuroblastoma may present with a massively enlarged liver from tumor in the liver and respiratory (lung) problems because the enlarged liver pushes up on the diaphragm (Figure 8).

Renal failure may occur as well as gastroesophageal reflux with malnutrition and pneumonia. This may occur because the tumor can take up so much room in the abdomen that it affects all the other organs. When these complications occur, urgent treatment is required, but these infants tolerate therapy less well than older children.

Low-dose chemotherapy with or without low-dose radiation therapy is usually effective in stopping tumor growth. When breathing remains inadequate despite placement of a breathing tube and use of a ventilator (breathing machine) or poor kidney function is present, it may be necessary to enlarge the abdominal cavity with the use of a piece of plastic sewn to the abdomen at the edges in order to enlarge the internal space for the organs. Although there are risks of infection, this is the only solution in some cases. Tube feedings into the stomach or small intestine or total parenteral nutrition (feeding through an IV, TPN) may be required for several days or weeks.

The enlarged liver may stabilize, but it may take months to shrink completely. Although the tumor may completely go away in stage 4-S disease in young infants, most clinicians currently advocate low-dose chemotherapy in patients if they have unfavorable tumor characteristics that increase the risk for ongoing or worsening disease (Table 4).

Some children may present with weakness, paralysis, loss of sensation, or walking problems from the spinal cord being pressed upon by the tumor. This happens most often with tumors in the chest next to the spine, which tend to spread into the nerves near the spinal cord. In the past, the operation on the spine allowed some of the tumor to be removed, but was associated with long-term problems with spine growth. The same was true for radiation therapy. As such, the current trend is to use chemotherapy to shrink the tumor by the spinal cord.

Surgical removal is used in patients who show worsening neurologic problems after starting chemotherapy. Children without neurologic problems who have a significant amount of tumor in the spinal canal discovered by CT or magnetic resonance imaging (MRI) should be treated in the same fashion because of the risks of swelling or bleeding into the spinal cord area at the time of removal of the tumor in the chest. The original neuroblastoma mass is later removed (if possible).

During removal of neuroblastomas in the chest, it is often impossible to avoid leaving small amounts of tumor along the nerves as they emerge from the spine. These patients with chest neuroblastomas still have a good prognosis as long as the N-myc cancer gene levels are low, even when small amounts of tumor are left behind by the spinal cord nerves.

Prognosis
The two key factors which affect survival in instances of neuroblastoma are the age of the patient and stage of disease at diagnosis. Although age older than 1 year is associated with more advanced stages, at equal stage patients less than 1 year of age still have a better survival.

Overall survival in infants younger than 1 year of age has been reported in one large series of patients to be 76%, whereas it is 32% for children older than 1 year. Survival in stage I cases may be as high as 100%; in stage II, 81%, in stage III, 38%, in stage IV, 12%; and in stage IV-S, 81%. Children with tumors affecting the neck or pelvis have been reported in some series to have 100% survival, whereas patients with chest tumors had 81% survival in the same series.

The worst prognosis has been observed in infants and children with tumors of the back of the abdomen (retroperitoneum, adrenal and paraspinal). A relatively improved outlook can be expected for patients who are younger than 1 year of age; especially with stage I, II, or IV-S disease. Infants who unexpectedly did poorly almost universally were found to have an increase in the N-myc cancer gene.

Favorable Shimada tumor histology when looking at the tumor under the microscope, abnormal amounts of DNA, good nutrition, and primary tumors located in the neck, pelvis, and chest have an improved survival. Children with VIP hormone secretion–related watery diarrhea syndrome and children with opsomyoclonus (dancing eyes- see above) have a greater than 90% survival and often have more mature tumors (for example, ganglioneuroblastomas). The latter cases usually involve low-stage (I, II) tumors with favorable predictive factors.

Despite excellent survival, patients with opsomyoclonus often have continued neurologic problems and learning disabilities even after removal of the tumor. The observation that patients with opsomyoclonus who had received chemotherapy because of their initial disease stage made a better neurologic recovery than patients who had surgery alone has led to new studies examining the usefulness of chemotherapy in these patients. The use of immunoglobulins also is being explored because of the possibility that opsomyoclonus is an antibody-related problem.

In contrast, a poor outlook can be expected for patients with stage III or IV (advanced) neuroblastoma, increases in the N-myc cancer gene, unfavorable histology, age greater than 1 year, or tumor in the abdomen. Intermediate-risk patients have an estimated 3-year survival greater than 80% with moderately intensive chemotherapy, whereas 3-year survival is less than 30% in the high-risk group despite intensive therapy; this contrasts with a greater than 90% survival for low-risk patients, most of whom are cured with surgery alone. Tumors in the back of the abdomen, an elevated HVA when compared to VMA, elevated serum LDH and ferritin levels, normal amounts of DNA, and malnutrition at diagnosis may be other markers of a poor expected outlook.

New and more effective chemotherapy programs bring the neuroblastoma tumor cell from the resting phase (where it is relatively resistant to tumor kill) to an active phase where it is dividing so that it can be killed by chemotherapy and radiation therapy. Therapy with antibodies labeled with chemotherapy agents that attach to the neuroblastoma, heating the tumor, and intraoperative radiation therapy have been used to treat advanced cases but so far have been clinically ineffective.

Iodine-123-labeled MIBG is picked up by the neuroblastoma cell and can be used as a method of detecting sites of tumor spread. It also has been used for therapy but by itself does not cure the neuroblastoma. Activating the immune system against the neuroblastoma using interleukin-2 and white blood cells has produced a tumor response in patients with malignant melanoma (another neural crest tumor) and has been effective in reducing the amount of tumor in neuroblastoma in the laboratory. Other paths being explored are the use of cis-retinoic acid, a type of vitamin A, which causes neuroblastoma cells to mature and other therapies that kill the blood vessels going to the tumor.

Many more genetic and biologic factors may have value in predicting how patients will do with neuroblastoma. A better understanding of the neural crest cell; an improved understanding of the immune aspects of neuroblastoma; an understanding of how best to use screening programs; and a more careful selection of patients for aggressive treatment based on age, stage, tumor type, tumor markers, amount of DNA, the presence of the N-myc gene, and other factors undoubtedly would prove useful in improving the outcome of this pediatric malignancy.

Although therapy is being increased in high-risk groups, it is being lessened or altered in low-risk and intermediate-risk groups to avoid long-term complications of chemotherapy, such as cardiotoxicity (heart injury caused by doxorubicin), kidney toxicity and ototoxicity (hearing injury caused by cisplatin), and sterility and the formation of second cancers from chemotherapy such as leukemia (etoposide, topotecan, alkylating agents), and complications of radiation therapy, such as decreased or uneven growth and development of other cancers (especially sarcomas).

SUGGESTED READINGS

Brodeur GM, Maris JM: Neuroblastoma. In Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric Oncology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2002, p 895.
This chapter in an oncology textbook provides an up-to-date review of the genetics, the ways that neuroblastomas develop, staging, and treatment (includes 572 references).

Grosfeld JL: Neuroblastoma. In O’Neill JA, Rowe MI, Grosfeld JL, et al (eds): Pediatric Surgery, 5th ed. St Louis, Mosby–Year Book, 1998.
This chapter in a major pediatric surgery textbook covers the subject in great depth.

Grosfeld JL, Rescorla FJ, West KW, et al: Neuroblastoma in the first year of life: Clinical and biologic factors influencing outcome. Semin Pediatr Surg 2:37, 1993.
This article describes the development of neural crest cells, development of neuroblasts, and the maturation of neuroblastoma to non-cancerous tissue in the first year of life. The article describes the factors that influence the relatively high survival rate of patients less than one year of age compared with older children.

Haase GM, Perez C, Atkinson JB: Current aspects of biology, risk assessment, and treatment of neuroblastoma. Semin Surg Oncol 16:91, 1999.
This is an excellent review (includes 166 references).

Katzenstein HM, Kent P, London WB, et al: Treatment and outcome of 83 children with intraspinal neuroblastoma: The Pediatric Oncology Group experience. J Clin Oncol 19:1047, 2002.
This report examines the various approaches available for the treatment of chests tumors extending into the spinal canal. It indicates that intensive chemotherapy is an effective initial approach.

Knudson AG Jr, Meadows AT: Regression of neuroblastoma IV-S: A genetic hypothesis. N Engl J Med 302:1254, 1980.
This classic report explores the cause of Stage IV-S neuroblastoma going away.

Nakagawara A, Arima-Nakagawara M, Scavarda NJ, et al: Association between high levels of expression of the trk gene and favorable outcome in human neuroblastoma. N Engl J Med 328:847, 1993.
This important article documents that high levels of the proto-oncogene trk improves the outcome in neuroblastoma.

Shimada H, Ambros IM, Dehner LP, et al: The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 86:364, 1999.
This article describes the most recent modifications to the Shimada classification.

Shimada H, Chatten J, Newton WH Jr, et al: Histopathologic prognostic factors in neuroblastoma: Definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastoma. J Natl Cancer Inst 73:405, 1984.
This article describes the original Shimada histologic classification of neuroblastoma, which categorizes stroma-rich and stroma-poor tumors and how they influence prognosis.

Article and graphics adapted from O'Neill: Principles of Pediatric Surgery. © 2003, Elsevier.

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