Neuroblastoma is a cancer of the sympathetic nervous system that predominantly arises in children. Neuroblastoma is the third largest paediatric cancer (behind leukemia and brain tumours). Approximately 50-75 children a year are diagnosed with neuroblastoma in Canada and at the time it is found, over 50% of patients have disease which as spread beyond the primary tumour. It is responsible for about 12-15% of paediatric cancer deaths and has the lowest survival rate out of all childhood cancers.
There are a number of excellent definitions of neuroblastoma that can be found online. The following are the most trusted and comprehensive:
Instead of rewriting what others have done well, the following is a sampling of some of the main quotes from the leading scientists involved in researching neuroblastoma. These are the direct words from the Researchers and Doctors. Sometimes knowing exactly what was said, instead of someone’s interpretation, is more valuable.
- “The clinical presentation is highly variable, ranging from a mass that causes no symptoms to a primary tumor that causes critical illness as a result of local invasion, widely disseminate disease, or both” (Maris, 2010, p. 2202). The disease is highly heterogeneous in its presentation (Maris, 2010, p. 2202).
- “The clinical course of neuroblastoma is variable and depends on age at diagnosis, staging, histology, and specific genetic abnormalities, such as MYCN oncogene amplification or aberrations of chromosome 1p or 11p. A subset of tumors will undergo spontaneous regression, whereas others progress despite aggressive therapy” (Mueller and Matthay, 2009, p. 431).
- “The tumor derives from the developing sympathetic nervous system and most primary tumors occur within the abdomen, with at least 50% arising from the adrenal glands” (Mueller and Matthay, 2009, p. 431; Maris, 2007, p. 2106).
The following three clinical scenarios are well recognized with neuroblastoma:
1. Localised Tumours
- “Around 40% of patients will present with localised disease that can range from an incidentally discovered intra-adrenal mass discovered on prenatal ultrasonography to very large and locally invasive tumours anywhere along the sympathetic chain” (Maris, 2007, p. 2106).
- “Paraspinal tumours in the thoracic, abdominal, and pelvic regions occur in 5–15% of patients, and these can extend into the neural foramina causing symptoms related to compression of nerve roots and the spinal cord” (Maris, 2007, p. 2106).
2. Metastatic Disease
- At diagnosis, about half of patients have metastatic disease where the cancer has spread to “distant sites such as cortical bone, bone marrow, liver, and non-contiguous lymph nodes from locoregional spread to lymph nodes adjacent to the primary tumour” (Maris, 2007, p. 2107).
- Children are typically quite ill at diagnosis and have extensive tumour burden.
- “This tumour has an unexplained tendency to metastasise to the bony orbit, and thus periorbital ecchymoses (raccoon eyes), proptosis, or both, are classic signs of disseminated neuroblastoma” (Maris, 207, p. 2107).
- “Widespread bone and bone marrow disease can also cause bone pain, limping, or irritability. Additionally, there can be bone marrow replacement and symptoms of marrow failure.27 Patients have occasionally had renin-mediated hypertension due to compromise of renal vasculature,28 but symptoms of catecholamine excess such as non-renin mediated hypertension and flushing commonly seen in phaeochromo cytoma are rare. Dissemination in the central nervous system is not often seen at diagnosis, but can occur with progression or relapse” (Maris, 2007, p. 2017).
3. 4S Disease
- Seen in about 5% of patients.
- “These infants have small localised primary tumours with metastases in liver, skin, or bone marrow that almost always spontaneously regress” (Maris, 2007, p. 2107).
- “This embryonic neoplasm derives from neural crest precursor cells of the peripheral sympathetic nervous system and usually arises in a paraspinal sympathetic ganglion or the adrenal gland. The histological composition of neuroblastoma varies from primitively undifferentiated neuroblasts without discernible neutopils to mature ganglion cells with abundant neuropils” (Chang and Hsu, 2010, p. 555).
- “The diagnosis of neuroblastoma is based on the presence of characteristic histolopathological features of tumour tissue or the presence of tumour cells in a bone marrow aspirate or biopsy, accompanied by raised concentrations of urinary catecholamines” (Maris, 2007, p. 2107).
- “Tumour-specific genetic markers and histopathological assessment are crucial determinants of treatment planning, especially for children younger than 18 months” (Maris, 2007, p. 2107).
Assessment of the Disease:
- CT Scan and/or MRI for assessment of tumour(s).
- MIBG Scan (metaiodobenzlguanidine) used to locate bone metastases and soft tissue disease.
- “Because MIBG is selectively concentrated in more than 90% of neuroblastomas, MIBG scintigraphy is a highly specific method for assessment of the primary tumour and metastatic disease” (Maris, 2007, p. 2108).
- Bi-lateral bone marrow aspirates and biopsies.
- Ultrasound (i.e., abdominal imaging).
- VMA/HVA urine testing.
Staging of Neuroblastoma:
Neuroblastoma is staged according to the International Neuroblastoma Staging System (INSS). The following is from Brodeur, 1993:
|1||Localised tumour with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumour microscopically (nodes attached to and removed with the primary tumour could be positive).|
|2A||Localised tumour with incomplete gross excision; representative ipsilateral non-adherent lymph nodes negative for tumour microscopically.|
|2B||Localised tumour with or without complete gross excision, with ipsilateral non-adherent lymph nodes positive for tumour. Enlarged contralateral lymph nodes should be negative microscopically.|
|3||Unresectable unilateral tumour infiltrating across the midline, with or without regional lymph node involvement; or localised unilateral tumour with contralateral regional lymph node involvement; or midline tumour with bilateral extension by infiltration (unresectable) or by lymph node involvement.|
|4||Any primary tumour with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, or other organs (except as defi ned by stage 4S).|
|4S||Localised primary tumour in infants younger than 1 year (as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, or bone marrow (<10% malignant cells).|
The histology of the tumour is classified according to the following (Shimada et al, 1984):
|Stroma Poor||Favourable Stroma Poor||Prognosis: Poor||Determined based on the patient’s age at diagnosis, degree of maturation and MKI index (mitosis-karyorrhexis)|
|Unfavourable Stroma Poor||Prognosis: Poor|
|Stroma Rich||Well Differentiated||Prognosis: Good||Determined based on morphology of the immature element in the tumor tissue without consideration of age at diagnosis or quantitative maturation.|
“A small number of neuroblastoma cases (<5%) are inherited in an autosomal dominant manner. Familial neuroblastoma show significant heterogeneity in the clinical presentation, with benign and malignant tumors occurring even within the same family” (Mueller and Matthay, 2009, p. 431).
“MYCN amplification on chromosome 2p24 is present in 25% of primary neuroblastomas and correlates with poor prognosis independent of age, stage, or other genetic alterations” (Mueller and Matthay, 2009, p. 432).
“MYCN functions as a classic dominant oncogene. It encodes a protein with a basic helix-loop-helix domain and activates transcription after dimerization with MAX” (Mueller and Matthay, 2009, p. 432).
Chromosome Losses and Gains:
- “Loss of heterozygosity (LOH) of 1p occurs in up to 36% of all primary tumors and was found to be associated with MYCN amplification. Using DNA-based polymorphisms, the region of consistent deletion was further defined to 1p36.31. In the analysis of a larger cooperative group trial, LOH of 1p36 was associated with MYCN amplification and other adverse prognostic factors such as unfavourable histology, diploidy, and high-risk Children’s Oncology Group (COG) status, and age” (Mueller and Matthay, 2009, p. 431-432).
- “Deletions of the short arm of chromosome 1 (1p) can be identified in 25-35% of neuroblastomas. These deletions correlate not only with MYCN amplification, but also with advanced disease stage” (Maris, 2007, p. 2110).
- “However, evidence suggests that allelic loss of 1p36 predicts an increased risk of relapse in patients with localised tumours” (Maris, 2007, p. 2110).
- “Deletions of chromosome 11q, mapped to 11q23.3, are found in about more than one third of primary tumors. Unlike 1p36 LOG, 11q23 is rarely associated with MYCN amplification” (Mueller and Matthay, 2009, p. 432).
- “Gain of 17q is a common genetic alteration in primary neuroblastomas, present in up to 70% of the tumors and associated with unfavorable outcome. Unbalanced translocations involving chromosome arms 1p, 3p, and 11q most frequently result in 17q gain” (Mueller and Matthay, 2009, p. 432).
- “DNA index is also a prognostic marker for patients younger than 2 years who have disseminated disease. The DNA content of neuroblastomas fall into two broad categories: near-diploid or hyperdiploid (often near triploid). Genetic models of neuroblastoma suggest that less aggressive tumours have a fundamental defect in mitosis associated with whole chromosome gains and losses, which could explain why near-triploidy seems to be favourable. Conversely, more malignant neuroblastomas have a fundamental defect in genomic stability, resulting in chromosomal rearrangements, unbalanced translocations, and maintenance of near-diploid DNA content” (Maris, 2007, p. 2110).
Areas of Future Research:
- “Although we have made some progress in identifying neuroblastoma-specific molecular targets for novel therapeutics, much work still needs to be done in this area. Improved understanding of normal neurodevelopment of the sympathicoadrenal system will help us identify the key mutational events that initiate neuroblastoma tumourigenesis. Defining these events, as well as those that reliably predict for the acquisition of a high-risk phenotype, might ultimately direct us to the key pathways that can be exploited therapeutically” (Maris, 2007, p. 2115).
- “..survivors of high-risk neuroblastoma require ongoing multidisciplinary follow-up to reduce the long-term morbidity that often accompanies cure with the therapy currently provided” (Maris, 2010, p. 2209).
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Cohn, S.L., Pearson, A.D., London, W.B., et al. (2009) The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. Journal of Clinical Oncology, 27, pps. 289–97.
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Mueller, S. and Matthay, K. (2009) Neuroblastom: Biology and Staging. Current Oncology Reports. Vol 11, Num 6, 431-438.
Shimada, H., Chatten, J., Newton, W. Jr., et al. (1984) Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. Journal of National Cancer Institute. 73: 405–16.
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