|This article has been reviewed by the NeuroWiki Editorial Board|
Neuroblastoma is the most common extracranial solid cancer in infancy and childhood. It is a neuroendocrine tumor, arising from any neural crest element of the sympathetic nervous system. Close to 50 percent of neuroblastoma cases occur in children younger than two years old.1
Neuroblastoma is a cancer of the sympathetic nervous system -- a nerve network that carries messages from the brain throughout the body. Its solid tumors, which take the form of a lump or mass, commonly begin in one of the adrenal glands, though they can also develop in nerve tissues in the neck, chest, abdomen, or pelvis.
The cause of neuroblastoma is unknown, though most physicians believe that it is an accidental cell growth that occurs during normal development of the adrenal glands.
Neuroblastoma is one of the rare human malignancies known to demonstrate spontaneous regression from an undifferentiated state to a completely benign cellular appearance.
A Canadian study, believed to be the largest of its kind, reported in February 2007 that expectant mothers who take folic acid-fortified prenatal vitamins before and during the first three months of pregnancy lower the risk their babies will develop neuroblastoma by 47%. One theory is that a shortage of folic acid may impair DNA synthesis and repair, or change the way genes that normally suppress cancer, or turn cancer on, are read.2
The first symptoms of neuroblastoma are often vague and may include fatigue and loss of appetite. Later symptoms depend on tumor locations. In the abdomen, a tumor may cause a swollen belly and constipation. A tumor in the chest may cause breathing problems. Tumors pressing on the spinal cord cause a feeling of weakness. A tumor in the head may cause the eyes to start to swell outwards and turn black due to the pressure from behind. Often because symptoms are so unclear, half of all neuroblastomas have already spread metastasized to other parts of the body by the time suspicions are raised and a diagnosis is made.
Diagnosis of neuroblastoma can be complicated. It has been called the "great masquerader" because its symptoms mimic so many other diseases. Even a pathological study (biopsy) might reveal cells that can resemble other small round blue tumor cells, like lymphomas and rhabdomyosarcomas. Only a pathologist familiar with neuroblastoma can distinguish the difference (and neuroblastoma is rare). Other characteristics of the suspected neuroblastoma cells can be studied by immunohistochemistry and electron microscopy. In about 90% of cases of neuroblastoma, elevated levels of catecholamines or its metabolites are found in the urine or blood. Catecholamines and their metabolites include dopamine, homovanillic acid (HVA), and/or vanillylmandelic acid (VMA).
Another way to detect neuroblastoma is the mIBG scan (meta-iodobenzylguanidine), but it doesn't diagnose the disease in 100% of the cases. It works like this: mIBG is taken up by sympathetic neurons, and is a functioning analog of the neurotransmitter norepinephrine. When it is radio-ionated with I-131 (a radioactive iodine), it is a very good radiopharmaceutical for diagnosis of this disease.
Other tumors also have similar origins and show a wide pattern of differentiation ranging from benign ganglioneuroma to partially differentiated ganglioneuroblastoma to highly malignant neuroblastoma.
Antibody to neuron specific enolase can differentiate neuroblastoma from lymphoma, Ewing's sarcoma, and rhabdomyosarcoma. Rosette patterns (Homer-Wright pseudo-rosettes) in a highly cellular tumor is an additional characteristic of neuroblastoma. Moreover, neuroblastoma rarely metastasizes to the lungs, which differentiates it from Wilms' tumor. In February 2007, Althea Technologies announced the development of a molecular diagnostic capable of clearly differentiating various types of childhood cancers, developed in cooperation with the U.S. National Cancer Institute (NCI).3
Neuroblastoma is characterized by its progression:
- Stage 1: Localized tumor confined to the area of origin.
- Stage 2A: Unilateral tumor with incomplete gross resection; identifiable ipsilateral and contralateral lymph node negative for tumor.
- Stage 2B: Unilateral tumor with complete or incomplete gross resection; with ispilateral lymph node positive for tumor; identifiable contralateral lymph node negative for tumor.
- Stage 3: Tumor infiltrating across midline with or without regional lymph node involvement; or unilateral tumor with contralateral lymph node involvement; or midline tumor with bilateral lymph node involvement.
- Stage 4: Dissemination of tumor to distant lymph nodes, bone marrow, bone, liver, or other organs except as defined by Stage 4S.
- Stage 4S: Localized primary tumor as defined in Stage 1 or 2, with dissemination limited to liver, skin, or bone marrow (less than 10 percent of nucleated bone marrow cells are tumors).
In a controlled study whose results were published in 2002, screening of all healthy infants' urine for markers of neuroblastoma was compared to deaths of infants whose urine was not tested. The overall death rate from the cancer was the same. Screening identified infants with harmless neuroblastomas that would have melted away without treatment; the infants were then subjected to surgery and chemotherapy.4
When the lesion is localized, it is generally curable. However, long-term survival for children with advanced disease is poor despite aggressive multimodality therapy.
Recent biologic and genetic characteristics have been identified, which, when added to classic clinical staging, has allowed accurate patient assignment to risk groups so that treatment strategies can be more effectively undertaken. These criteria include the age of the patient, extent of disease spread, microscopic appearance, and several other biological features, most importantly MYCN oncogene amplification, into low, intermediate, and high risk disease. The therapy for these different risk categories is very different. Low risk patients can frequently be observed without any treatment at all, while intermediate risk patients are treated with chemotherapy. High-risk neuroblastoma is treated with intensive chemotherapy, surgery, radiation therapy, bone marrow transplantation, and biological-based therapy with Cys-Retinoic acid (Accutane). With current treatments, patients with low and intermediate risk disease have an excellent prognosis with cure rates above 90%. In contrast, therapy for high-risk neuroblastoma results in cures only about 30% of the time.
After it is declared that the disease is gone, it often comes back. Further treatment is then required. This can be problematic because some treatments, such as chemotherapy, have cumulative effects and side-effects therefore can increase significantly if used again.
Intensive chemotherapy and radiation therapy have known long-term negative consequences. An estimated two of three survivors of childhood cancer will ultimately develop at least one chronic and sometimes life-threatening health problem within 20 to 30 years after the cancer diagnosis.5,6
- Janet Sassi, "Cellular Communication: Unraveling the Secrets of Histone Proteins", Fordham University, February 16, 2007
- Sharon Kirkey, "Prenatal vitamins cut cancer risk in kids", CanWest News Service, February 22, 2007
- "Althea Technologies Announces the Development of a Diagnostic Capable of Differentiating Multiple Forms of Childhood Cancer", press release, February 20, 2007
- Darshak Sanghavi, "Screen Alert: How an Ounce of RX Prevention can Cause a Pound of Hurt", Slate magazine, November 28, 2006
- "Childhood Cancer Survivors Face Increased Sarcoma Risk", HealthDay News, February 21, 2007
- Oeffinger et al., "Chronic Health Conditions in Adult Survivors of Childhood Cancer", New England Journal of Medicine, October 12, 2006
- Neuroblastoma: biological insights into a clinical enigma. Brodeur GM. Nature Reviews Cancer. 2003 Mar;3(3):203-16. PMID 12612655
- Current aspects of biology, risk assessment, and treatment of neuroblastoma. Haase GM, Perez C, Atkinson JB. Semin Surg Oncol. 1999 Mar;16(2):91-104. PMID 9988866
- i. Very rare embryonal neuroepithelaial neoplasm occurring usually within the first 2 decades in a supratentorial location and a median survival of only 4 years
- ii. Small cells with sparse cytoplasm and hyperchromatic nuclei; exhibits focal neuronal differentiation in the form of Homer-Wright rosettes and immunoreactivity for neurofilament protein and synaptophysin