Neuroblastoma+(Child)

Committee (INSS), a diagnosis of neuroblastoma requires either the presence of neuroblastoma in the bone marrow and higher than normal levels of one of the main chemicals produced by the nervous system, called catecholamine, in the urine, or a tumor biopsy showing neuroblastoma cells. In addition to a physical examination, the following tests may be used to evaluate a child who may have neuroblastoma: Normal nerve cells communicate with each other by releasing certain chemicals called neurotransmitters. Catecholamines are neurotransmitters. Eventually the body breaks down the catecholamine molecules into smaller pieces, called metabolites, which are then passed out of the body in the urine. About 90% of the time, neuroblastoma cells produce enough catecholamines to be found in blood or urine tests. The two catecholamine metabolites most often measured are:
 * Epidemiology: || 650 new cases of neuroblastoma in children each year in the United States (U.S). Neuroblastomas account for 7.8% of pediatric cancers in the U.S. This equates to an incidence of 9.5 occurrences per 1 million children. Most pediatric cases present with metastatic disease. Incidence is higher in whites versus African-Americans; however, race does not play a role in outcome. It occurs slightly more often in males than females. Most cases occur in patients younger than 10 years of age with the peak incidence in children less than 1 year. 1 It can occur anywhere in sympathetic nervous system with the adrenal medulla being 30-40%, paraspinal ganglia in the abdomen or pelvis 25%, thoracic 15% and head and neck 5%. 2 ||
 * Etiology: || Neuroblastoma has no known cause; however, research centers on the time before conception and the time during gestation. 3 ||
 * Signs & Symptoms: || Signs & symptoms at presentation are as follows: pain, weight loss, anorexia, malaise, fever. Many of these symptoms are due to the fact that most patients present with widely metastatic disease. If there is a primary lesion in the neck, it can coincide with Horner's syndrome. Spinal cord compression can occur with dumbbell tumors originating along the sympathetic ganglia. Metastatic disease to the orbits can cause ecchymosis and proptosis. 4 ||
 * Diagnostic Procedures: || 
 * Blood and urine tests. ** Complete blood counts (CBC) are tested to determine if the child has signs of anemia. Liver and kidney function are tested, and urine is collected to determine if any tumor markers or other substances produced by a neuroblastoma tumor are present. A tumor marker is a substance found in higher than normal amounts in the blood, urine, or body tissues of people with certain kinds of cancer.
 * Homovanillic acid (HVA)
 * Vanillylmandelic acid (VMA)
 * Biopsy. ** A biopsy is the removal of a small amount of tissue for examination under a microscope. Other tests can suggest that cancer is present, but only a biopsy can make a definite diagnosis. The sample removed from the biopsy is analyzed by a pathologist (a doctor who specializes in interpreting laboratory tests and evaluating cells, tissues, and organs to diagnose disease). The type of biopsy performed depends on the location of the tumor. If the doctor determines that the entire tumor can be removed safely at the same time as the biopsy, the whole tumor is surgically removed.
 * Molecular genetic studies. ** Tests of neuroblastoma cell DNA are used to find an abnormality in the oncogene //MYCN//, a gene that regulates cell growth. Multiple copies, called amplification, of the //MYCN// gene are associated with a more aggressive tumor, which is more difficult to treat successfully. A non-amplified //MYCN// gene is associated with a less aggressive tumor. Additional tests are done to determine if the tumor has changes in chromosomes 1p, 11q, and 17q. Changes to these chromosomes are associated with more aggressive neuroblastoma.
 * Bone marrow aspiration. ** This procedure is done to find if any neuroblastoma cells have spread to the bone marrow. For this test, the back of the patient’s hip is numbed, and a small amount of bone marrow is removed from the hip with a needle and examined under a microscope. The tissue sample may also be sent for additional tests to find if very small numbers of neuroblastoma cells are present.
 * Computed tomography (CT or CAT) scan. ** A CT scan creates a three-dimensional picture of the inside of the body with an x-ray machine. A computer then combines these images into a detailed, cross-sectional view that shows any abnormalities or tumors. Sometimes, a contrast medium (a special dye) is injected into a patient’s vein to provide better detail.
 * Magnetic resonance imaging (MRI). ** For neuroblastoma, an MRI uses magnetic fields, not x-rays, to produce detailed images of the brain and spinal column. A contrast medium may be injected into a patient’s vein to create a clearer picture. An MRI is better at showing tumors around the spine, and is essential when evaluating a tumor that is located near where nerves exit the spinal column, which can press on the spinal cord.
 * <span style="color: fuchsia; font-family: 'Times New Roman','serif';">Bone scan. **<span style="color: fuchsia; font-family: 'Times New Roman','serif';"> A bone scan uses a radioactive tracer to look at the inside of the bones. The tracer is injected into a patient’s vein. It collects in areas of the bone and is detected by a special camera. Healthy bone appears gray to the camera, and areas of injury, such as those caused by cancer, appear dark.
 * <span style="color: fuchsia; font-family: 'Times New Roman','serif';">MIBG scan. **<span style="color: fuchsia; font-family: 'Times New Roman','serif';"> A newer type of scan using radioactive MIBG can find neuroblastoma if it has spread to the bone or other parts of the body. MIBG stands for meta-iodobenzylguanidine scintiscan. Because the thyroid will also absorb this radioactive agent, iodine is taken by mouth for a number of days before the scan to protect the patient’s thyroid.
 * <span style="color: fuchsia; font-family: 'Times New Roman','serif';">Positron emission tomography (PET) scan. **<span style="color: fuchsia; font-family: 'Times New Roman','serif';"> A PET scan is a way to create pictures of organs and tissues inside the body. A small amount of a radioactive substance is injected into a patient’s body and absorbed by the organs or tissues being studied. This substance gives off energy that is detected by a scanner, which produced the images. The use of PET scans for the detection and follow-up of metastatic disease is being evaluated and compared to MIBG scanning. <span style="color: fuchsia; font-family: 'Times New Roman','serif'; font-size: 8.4pt; vertical-align: super;">5 <span style="color: #ff00ff; font-family: 'Times New Roman','serif'; font-size: 12pt;">

|| Neuroblastomas are derived from primitive neural crest cells arising from within sympathetic ganglia. Three types of tumors are recognized, representing different degrees of differentiation. Ganglioneuroma consists of mature ganglion cells, Schwann’s cells, and nerve bundles and benign in appearance and nature. It is frequently calcified and may represent a matured neuroblastoma. Ganglioneuroblastoma is the intermediate form between ganglioneuroma and neuroblastoma; both mature ganglion cells and undifferentiated neuroblasts are evident. Neuroblastoma, a small round blue cell tumor composed of dense nests of hyperchromatic cells, is at the undifferentiated end of the spectrum of these neural crest tumors. 6 || lymph nodes, bone, bone marrow, skin (or subcutaneous tissue), or liver Organs usually not involved include the lungs and CNS. 7 || Stage I - Tumor confined to the organ or structure of origin Stage II - Tumor extending in continuity beyond the organ or structure of origin but not crossing midline; regional lymph nodes on the ipsilateral side Stage III - Tumor extending in continuity beyond the midline; possible involvement of regional lymph nodes bilaterally Stage IV - Remote disease involving the skeleton, bone marrow, soft tissue, and distant lymph node groups, etc Stage IV-S - Patients who would otherwise be in stage I or II but have remote disease confined to the liver, skin, or bone marrow (without radiographic evidence of bone metastases on a complete skeletal survey)²
 * Histology: ||
 * Lymph Node Drainage: || Spreads to regional lymph nodes. 6 ||
 * Metastatic Spread: || Over 70% of patients present with metastases most commonly to the:
 * Grading: || No separate grading system specified. A diagnosis of Neurobastoma itself indicates a Neural crest tumor that is poorly differentiated. 8 ||
 * Staging: || Evans and D'Angio

Pediatric Oncology Group Stage A - Complete gross resection of primary tumor, with or without microscopic residual; intracavitary lymph nodes, not adhered to and removed with primary (nodes adhered to or within tumor resection may be positive for tumor without upstaging patient to stage C), histologically free of tumor; if primary in abdomen or pelvis, liver histologically free of tumor Stage B - Grossly unresected primary tumor; nodes and liver same as in stage A Stage C - Complete or incomplete resection of primary; intracavitary nodes not adhered to primary histologically positive for tumor; liver as in stage A Stage D - Any dissemination of disease beyond intracavitary nodes (i.e. extracavitary nodes, liver, skin, bone marrow, bone). 8

International Stage 1: Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (i.e., nodes attached to and removed with the primary tumor may be positive). Stage 2A: Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically. Stage 2B: Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically. Stage 3: Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement. Stage 4: Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs, except as defined for stage 4S. Stage 4S: Localized primary tumor, as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, and/or bone marrow. 8 || Radiation therapy techniques - Radiation ther apy portals to a primary tumor site should treat the gross residual tumor with at least 2 cm margin from the tumor to the block edge. Regional lymph nodes should be covered if involved. Parallel-opposed anterior and posterior portal may suffice in many cases for tumor control. The patient's life expectancy should influence the selection of irradiation portals, field shaping, and dose factionation. This dose and fractionation is represented in table 1. 1 Radiation Therapy is also used for treating metastatic disease sites and total-body irradiation has been useful as part of a bone marrow transplant for high risk metastatic disease. 9
 * Radiation Side Effects: || Long term effects from radiation therapy and chemotherapy depend on site irradiated and the total dose of both modalites utilized. Limb shortening or spinal deformities such as kyphosis and scoliosis and other skeletal anomolies are influenced by the age at time of treatment. This also influences the risks and severities. Generally, younger children are more prone to late injury than older children and chemotherapy may increase the risk of irradiation sequelae and reduce the expected tolerance. ||
 * Prognosis: || The two most important facts influencing outcome are patient age and stage at initial presentation. Generally more than 75% of infants and children less than 2 years old will survive as well as 90% to 100% of children with International Neuroblastoma Staging System (INSS) stages 1 and 2. 75% of infants under 12 months old with metastatic disease confined to the liver, bone marrow (not bone), or skin (stage 45) have a good prognosis with little or no treatment. Patients with more differentiated tumors, such as ganglioneuroma or ganglioneuoblastoma, fare better than children with poorly differentiated or undifferentiated neuroblastomas. Poor prognosis with elevated serum ferritin (greater than 142 ng per ml), neuron-specific enolase (greater than 100 ng per ml), and lactate dehydrogenase (greater than 1500 IU) which are associated with advanced disease. An increased number of MYCN (N-myc) gene copies is associated with an extremely poor prognosis (less than 5% survival). A tumor with a deoxyribonucleic acid index of 1 (disploid or near diploid) gives a worse prognosis than tumors that are aneuploid. 9 ||
 * Treatments: || Surgery for low-stage resectable tumors. For unresectable low stage tumors-preoperative chemotherapy and occassionally irradiation is used to convert them to resectable tumors. For palliative management radiation therapy plays an extremely important role in patients with end-stage symptomatic neuroblastoma.

|| 11 || 1. Lacayo NJ, Neyssa M, Packard L, et. al. //Neuroblastoma//. Available at: [|//http://emedicine.medscape.com/article/988284-overview]//.// Accessed February 11, 2010. 2. Chao KS, Perez CA., Brady LW. //Radiation Oncology - Management Decisions//. 2nd ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2002:649. 3. Lacayo NJ, Neyssa M, Packard L, et. al. //Neuroblastoma//. Available at: [|//http://emedicine.medscape.com/article/988284-overview]//.// Accessed February 11, 2010. 4. Chao KS, Perez CA., Brady LW. //Radiation Oncology - Management Decisions//. 2nd ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2002:649. 5. [|www.cancer.net/Cancer+Types/Neuroblastoma.com] Accessed Febuary 11, 2010 6. Chao KS, Perez CA., Brady LW. Radiation Oncology- Management Decisions. 2nd edition. Philadelphia, PA: Lippincott, Williams & Wilkins; 2002.pg 650 7. Chao KS, Perez CA, Brady LW. //Radiation Oncology-Management Decisions//. 2nd ed. Philadelphia, PA: Lippincot, Williams & Wilkins; 2003 8. Washington CM, Leaver D. // Principles and Practice of Radiation Therapy //. 2nd ed. St. Louis, MO: Mosby. 2004  9. Chao KS, Perez CA, Brady LW. Radiation Oncology-Management Decisions. 2nd ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2002 10. Hand CM, Kim SJW, Waldow SM. Overview of radiobiology. In: Washington CM, Leaver D, eds. //Principles and Practice of Radiation Therapy//. 2nd ed. St. Louis, MO: Mosby; 2004:80-81. 11. United Hospital. Eclipse Planning System. Retrieved February 11, 2010.
 * TD5/5: || The normal tissue tolerance dose of the major organs at risk would depend solely upon the region of metastatic disease. If the disease is along the sympathetic nervous system or near the spinal cord, the following TD5/5 values would apply: spinal cord - infarction, necrosis 45 Gy for 10 cm 2 and peripheral nerves - neuritis 60 Gy. 10 ||
 * Treatment Plan and Fields || [[image:neuroblastoma1resize.jpg width="540" height="404" caption="Neuroblastoma RAO/LPO Treatment Plan"]]
 * __References__ **