Neuroblastoma is the most common extracranial solid tumor in children, and the most common malignancy in infants. About half of the neuroblastomas reported occurred in children that are younger than 2 years of age. It is also more common in Caucasians and in males.1
Etiology:
While it is still unknown what causes neuroblastoma, there are some links to genetic mutations. Neuroblastomas that run in families are typically caused by a mutation to the anaplastic lymphoma kinase gene. There is also some recent links to alcohol, smoking, and drug use during pregnancy that has caused a neuroblastoma in newborns.1
Signs & Symptoms:
Pain is the most common presenting symptom.1 Others include weight loss, anorexia, malaise, and fever. Respiratory distress may be present with massive hepatomegaly, especially in infants with stage IV-S disease. Spinal cord compression and orbital metastasis could be present in severe cases.
Diagnostic Procedures:
The diagnosis must be made by pathology by obtaining tissue from the tumor site and involved lymph nodes, but a complete physical exam along with bone marrow biopsies and a host of laboratory studies.1 CT and MRI are also helpful to determine the extent of the disease.
Histology:
Neuroblastomas arise from sympathetic ganglia derived from primitive neural crest cells.1 The three different types of histology, which represent different degrees of differentiation, are ganglioneuroma, ganglioneuroblastoma, and neuroblastoma. Ganglioneuroma are often calcified and can represent a mature neuroblastoma. They consist of mature ganglion cells, Schwann’s cells, and nerve bundles and can be benign in appearance. Ganglioblastomas have both mature ganglion cells and undifferentiated neuroblast. Ganglioblastomas are the intermediate cell formation between ganglioneuroma and neuroblastoma. Neuroblastomas are characterized by a “small round blue cell” tumor composed of dense nests of hyperchromatic cells. Neuroblastomas are undifferentiated cells of the neural crest tumors.
Lymph node drainage:
The most frequent lymphatic drainage is at the nodal origin of the renal artery followed by the interaorticovenous nodes.2 The lymphatic drainage then goes to the paraaortic nodes and the nodes around the hemiazgos vein in cases of left adrenal neuroblastoma, and in the paracaval nodes and the nodes around the azygos vein in cases of right adrenal neuroblastoma.
Metastatic spread:
Many neuroblastomas arise in the abdomen. Unfortunately, 70% of patients present with metastatic disease.1 The most frequent sites of distant metastasis include lymph nodes, bone, bone marrow, skin, and liver. Less commonly, the lungs and central nervous system could be involved.
Grading:
Neuroblastomas are categorized as favorable or nonfavorable depending on their grade of differentiation and stromal development.3
microscopic residual or positive en-bloc (adherent) local nodes acceptable
Stage 2A
localized tumour
incomplete gross excision
contralateral nodes negative for tumor
Stage 2B
localized tumor
complete or incomplete resection
positive ipsilateral (non-adherent) nodes
contralateral nodes negative for tumor
Stage 3
unresectable lateral tumor that crosses the midline OR
midline tumor OR
contralateral nodes positive for tumor
Stage 4S
< 1 year of age
localized tumor (stage 1, 2A or 2B)
distant metastases confined to skin, liver and/or bone marrow
Stage 4
distant metastases not fulfilling stage 4S
In the majority of cases (60 - 80%), patients present with stage 3 or 4 tumors
Radiation side effects:
Possible side effects of external radiation therapy may include mild skin reactions, nausea, diarrhea, or fatigue.5
Prognosis:
Neuroblastoma can be cured with surgery and can spontaneously regress or mature to a benign ganglioneuroma.1
Age and stage are two most important factors influencing prognosis.
75% survival of infants and children age 2 or less.
90%-100% of children with stage 1 or 2 using the INSS staging system.
Poor prognosis if tumor is in regional lymph nodes.
MYCN (N-myc) is a proto-oncogene that resides on the short arm of chromosome 2. A poor prognosis of less than 5% survival results with an increased number of MYCN gene copies.
A tumor with deoxyribonucleic acid index of 1 gives a worse prognosis than tumors that are aneuploid.
Patients older than 18 months have a 70% chance of developing metastatic disease.6
Treatments:
Surgical resection of local disease is very effective in early stage cases.6 Multiagent chemotherapy can also be used and with more advanced stage III tumors, radiation to the tumor bed can be beneficial. Radiation is directed to residual disease after surgery and chemotherapy. Not areas of initial disease.6 Radiation Therapy is used when surgical margins are positive and care must be taken to minimize the risk of late effects, but not compromise chance for cure.1
Fields should include gross residual tumor remaining after surgery and chemotherapy, with at least a 2 centimeter margin from tumor to block edge.
If the child is not sedated, a greater margin may be required to allow for movement.
Radiographically or pathologically diagnosed positive nodes should be covered.
Parallel-opposed anterior and posterior fields may be adequate for tumor coverage.
Orbital metastases may require treatment to the entire orbit.
Life expectancy should influence fields and complexity of treatment.
Dose for neuroblastoma is still being debated. Age 1 or less, a dose of 12 Gy. Age 12-48 months, dose of at least 25 Gy. Children over 4 years frequently develop local failure even with doses higher than 25 Gy.
Palliative cases for metastatic disease should receive doses between 5-20 Gy in 1 to 5 daily fractions.
TD 5/5:
Neuroblastomas may arise from any site along the sympathetic nervous system.1 The most common sites are the structures of the head and neck, the genitourinary region, and extremities. Potential critical structures may include: Brain: 45 Gray (Gy) Liver: 30 Gy Lung: 17.5 Gy for whole lung, 30 Gy for 2/3 of lung, 45 Gy for 1/3 of lung Kidney: 23 Gy Lens: 10 Gy Optic chiasm: 50 Gy Optic nerve: 50 Gy Retina: 45 Gy Testis: 1 Gy Ovaries: 2-3 Gy
Additional images:
The images below are computed tomography (CT) slices at the level of the kidneys showing isodose distributions in a child with a midline abdominal neuroblastoma. Both intensity-modulated radiation therapy (IMRT) techniques had less kidney dose compared to conventional radiation therapy.7 Reprinted from Pediatric Blood Cancer, 2013.7 Image A: AP/PA fields Image B: IMRT Image C: IMRT with inclusion of adjacent spine in the CTV
References:
Chao K, Perez C, Brady L. Radiation Oncology Management Decisions. 3rd ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2011.
Tokiwa K, Nakamura K, Ogita S, et al. Lymphatic drainage of the adrenal neuroblastoma. US National Library of Medicine National Institute of Health, 1993:28(7):927-9. PMID: 7693905. Accessed July 4,2013.
Others include weight loss, anorexia, malaise, and fever.
Respiratory distress may be present with massive hepatomegaly, especially in infants with stage IV-S disease.
Spinal cord compression and orbital metastasis could be present in severe cases.
http://bmi.osu.edu/~gurcan/neuroblastoma.php
- Stage 14
- localized tumour
- complete gross excision
- contralateral nodes negative for tumor
- microscopic residual or positive en-bloc (adherent) local nodes acceptable
- Stage 2A
- localized tumour
- incomplete gross excision
- contralateral nodes negative for tumor
- Stage 2B
- localized tumor
- complete or incomplete resection
- positive ipsilateral (non-adherent) nodes
- contralateral nodes negative for tumor
- Stage 3
- unresectable lateral tumor that crosses the midline OR
- midline tumor OR
- contralateral nodes positive for tumor
- Stage 4S
- < 1 year of age
- localized tumor (stage 1, 2A or 2B)
- distant metastases confined to skin, liver and/or bone marrow
- Stage 4
- distant metastases not fulfilling stage 4S
In the majority of cases (60 - 80%), patients present with stage 3 or 4 tumorsRadiation Therapy is used when surgical margins are positive and care must be taken to minimize the risk of late effects, but not compromise chance for cure.1
Brain: 45 Gray (Gy)
Liver: 30 Gy
Lung: 17.5 Gy for whole lung, 30 Gy for 2/3 of lung, 45 Gy for 1/3 of lung
Kidney: 23 Gy
Lens: 10 Gy
Optic chiasm: 50 Gy
Optic nerve: 50 Gy
Retina: 45 Gy
Testis: 1 Gy
Ovaries: 2-3 Gy
Reprinted from Pediatric Blood Cancer, 2013.7
Image A: AP/PA fields
Image B: IMRT
Image C: IMRT with inclusion of adjacent spine in the CTV
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