Neuroblastoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Zahir Ali Shaikh, MD[2]Haytham Allaham, M.D. [3]

Neuroblastoma is the most common solid extracranial cancer in childhood and is the most common cancer in infancy. It is a malignant tumor that arises from neural crest cells, which are normally involved in the development of the sympathetic nervous system and adrenal glands. It is usually located along the sympathetic nervous system structures including; adrenal glands, retroperitoneal organs, paravertebral sympathetic chain, organ of zuckerkandl and posterior mediastinum. It was first described by Rudolf Virchow in 1864 as an abdominal tumor in a child as “glioma“. James Homer Wright in 1910, described circular clumps of bone marrow (now named Homer-Wright pseudorosettes) and advanced the understanding that tumor originated from primitive neural cells and could metastasize to bone. International neuroblastoma pathology classification system is used for the classification of neuroblastoma tumors, which divides it into 02 main categories based on morphologic features of neuroblastoma tumors into: schwannian stroma poor and schwannian stroma rich/dominant. Neuroblastoma tumor cells secrete catecholamine by products including vanillylmandelic acid (VMA) and homovanillic acid (HVA) and vasoactive intestinal polypeptide (VIP) hormone as well. The various genes involved in pathogenesis of neuroblastoma include; NBPF10, KIF1B, ALK, LMO1 and PHOX2A genes. The most common genetic mutation is gain of chromosome 17q and MYCN oncogene amplification predicts more aggressive neuroblastoma. Neuroblastoma can also be associated with a number of syndromes including; neurofibromatosis type 1, beckwith-weidemann syndrome and hirschsprung disease. On gross pathology, the characteristic finding of neuroblastoma is a well defined, bulky and tan colored mass, that can be associated with fibrous pseudocapsule, necrosis or hemorrhage. On microscopic picture, the presence of round blue cells separated by thin fibrous septa are a characteristic finding. There are no known established causes for neuroblastoma. The risk factors for neuroblastomas diagnosed during infancy include; maternal anemia during pregnancy, neonatal respiratory distress syndrome and low 1 minute Apgar score. However, the risk factors for neuroblastoma cases diagnosed at age 1 year or above is not known. The overall incidence is 4.9 per 1,000,000 individuals in united states. Males are slightly more affected than females with 1.2:1 ratio. Neuroblastoma usually affects individuals of the caucasian race. Intra-abdominal neuroblastoma must be differentiated from other diseases that cause abdominal distension and constipation such as Wilms tumor and ganglioneuroma. Intra-thoracic neuroblastoma must be differentiated from other diseases that cause shortness of breath and chronic cough such as intrathoracic lymphoma and extra lobar pulmonary sequestration. There are no routine screening tests for neuroblastoma due to lack of any mortality benefits. Neuroblastoma may progress to develop fatigue, loss of appetite, joint pain and fever if left untreated. There is gradual development of site specific symptoms as the tumor size gradually increases. Complications of neuroblastoma include; persistent refractory diarrhea, horner’s syndrome, hypertension, transverse myelopathy, anemia and suppressed immunity. The prognosis of neuroblastoma is generally regarded as poor, depending on the tumor extent at the time of diagnosis. The other prognostic factors for nuroblastoma include; patient’s age, tumor stage and grade, genetic mutations and response to treatment. According to the conventional International Neuroblastoma Staging System (INSS), there are 6 stages of neuroblastoma based on the tumor size, lymph node involvement, and presence of metastasis. However, according to a newly proposed International Neuroblastoma Risk Group Staging System (INRGSS), there are four stages of neuroblastoma based on the extent of dissemination and image findings. Neuroblastoma patients are risk stratified according to the Children Oncology Group (COG) risk stratification system into a low risk group, an intermediate risk group, and a high risk group based on the tumor INSS stage, the patient’s age, tumor grade, and the amplification of MYCN gene. General neuroblastoma symptoms include; fever, irritability, fatigue, loss of appetite and weight loss. Other symptoms depending upon the anatomical location of neuroblastoma include; abdominal pain, distension and constipation (abdomen), shortness of breath, chronic cough & difficulty swallowing (posterior mediastinum), weakness, numbness, paralysis (retroperitoneum), visual defects, facial bruising (head & neck) and pallor, bone pain (bone marrow metastases). Physical examination findings of neuroblastoma include; fever, hypertension, tachycardia, pallor, ecchymoses, nystagmus, proptosis, ptosis, abdominal mass, brisk reflexes, sensory loss and ataxia. The laboratory findings in neuroblastoma include; ↓ hemoglobin, ↑ ferritin, ↑ catecholamine, ↑ dopamine, ↑ vanillylmandelic acid (VMA), ↑ homovanillic acid (HVA), ↑ lactate dehydrogenase and ↑ neuron-specific enolase levels. There are increased urinary catecholamine, vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels. X ray findings of neuroblastoma include; intrathoracic or intraabdominal soft tissue mass, calcification, remodeling of surrounding ribs & vertebral bodies, thinning of surrounding pedicles and ill defined, metaphyseal, lucent bone lesions seen in metastases. CT scan of the neck, chest and abdomen is the gold standard test in neuroblastoma as it can localize the tumor and determine degree of involvement as well. CT scan in neuroblastoma can show the presence of; heterogeneous mass, calcification, necrosis, compression of surrounding vessels, invasion of psoas muscle & kidneys and swollen lymph nodes. MRI is considered the most useful modality in staging of neuroblastoma. It is superior to CT scan when determining marrow infiltration and intra spinal tumor extension. The definitive diagnosis of nueroblastoma is confirmed by a biopsy. Children oncology group (COG) risk stratification system determines the protocol of management used for neuroblastoma patients. COG risk stratification system divides the patients into 03 groups: low risk, intermediate risk and high risk patients. Low risk neuroblastoma patients are usually managed by either observation or surgical resection of the tumor. Intermediate risk patients are managed by neoadjuvant therapy in advance of a definitive surgical resection. High risk neuroblastoma patients are usually managed by a combination of surgery, chemotherapy, radiation therapy, hematopoietic stem cell transplantation, immunotherapy and isotretinoin. Surgical intervention is curative as a single therapeutic modality for management of low risk neuroblastoma patients. In intermediate risk patients, surgical intervention must be followed by chemotherapy. However, the benefits of surgery to achieve complete tumor resection in high risk patients with metastatic disease is not clearly demonstrated.

Neuroblastoma was first described by Rudolf Virchow in 1864 as an abdominal tumor in a child as “glioma“. Felix Marchand described characteristics of tumors from adrenal medulla and sympathetic nervous system in 1891. James Homer wright in 1910, described circular clumps of bone marrow ( now named “Homer-Wright pseudorosettes) and advanced the understanding that tumor originated from primitive neural cells and could metastasize to bone.

International neuroblastoma pathology classification system is used for the classification of neuroblastic tumors. It is subdivided in 02 main categories based on the morphologic features of neuroblastic tumors into; schwannian stroma-poor and schwannian stroma-rich/dominant.

Neuroblastoma arises from the neural crest cells, which are normally involved in development of sympathetic nervous system and adrenal glands. It is frequently located along the sympathetic nervous system structures including; adrenal glands, retroperitoneal organs, organ of zuckerkandl, paravertebral sympathetic chain and posterior mediastinum among others. Neuroblastoma tumor cells secrete catecholamine by products including vanillylmandelic acid (VMA) and homovanillic acid (HVA) and vasoactive intestinal polypeptide (VIP) hormone as well. It can metastasize to bone, liver, lungs and brain. The various genes involved in pathogenesis of neuroblastoma include; NBPF10, KIF1B, ALK, LMO1 and PHOX2A genes. The most common genetic mutation is gain of chromosome 17q and MYCN oncogene amplification predicts more aggressive neuroblastoma. Neuroblastoma can also be associated with a number of syndromes including; neurofibromatosis type 1, beckwith-wiedemann syndrome and hirschsprung disease. On gross pathology, the characteristic finding of neuroblastoma is a well defined, bulky and tan colored mass, that can be associated with fibrous pseudocapsule, necrosis or hemorrhage. On microscopic picture, the presence of round blue cells separated by thin fibrous septa are a characteristic finding.

There are no known established causes for neuroblastoma.

Intra-abdominal neuroblastoma must be differentiated from other diseases that cause abdominal distension and constipation such as Wilms tumor and ganglioneuroma. Intra-thoracic neuroblastoma must be differentiated from other diseases that cause shortness of breath and chronic cough such as intrathoracic lymphoma and extra lobar pulmonary sequestration.

Neuroblastoma is the most common solid extracranial cancer in childhood and is the most common cancer in infancy. The overall incidence is 4.9 per 1,000,000 individuals in united states. Males are slightly more affected than females with 1.2:1 ratio. Neuroblastoma usually affects individuals of the caucasian race.

The risk factors for neuroblastomas diagnosed during infancy include; maternal anemia during pregnancy, neonatal respiratory distress syndrome and low 1 minute Apgar score. However, the risk factors for neuroblastoma cases diagnosed at age 1 year or above is not known.

There is insufficient evidence to recommend the routine screening for neuroblastoma as it has no mortality benefits.

Neuroblastoma may progress to develop fatigue, loss of appetite, joint pain and fever if left untreated. There is gradual development of site specific symptoms as the tumor size gradually increases. Complications of neuroblastoma include; persistent refractory diarrhea, horner’s syndrome, hypertension, transverse myelopathy, anemia and suppressed immunity. The prognosis of neuroblastoma is generally regarded as poor, depending on the tumor extent at the time of diagnosis. The other prognostic factors for nuroblastoma include; patient’s age, tumor stage and grade, genetic mutations and response to treatment.

According to the conventional International Neuroblastoma Staging System (INSS), there are 6 stages of neuroblastoma based on the tumor size, lymph node involvement, and presence of metastasis. However, according to a newly proposed International Neuroblastoma Risk Group Staging System (INRGSS), there are four stages of neuroblastoma based on the extent of dissemination and image findings. Neuroblastoma patients are risk stratified according to the Children Oncology Group (COG) risk stratification system into a low risk group, an intermediate risk group, and a high risk group based on the tumor INSS stage, the patient’s age, tumor grade, and the amplification of MYCN gene.

A detailed history of presenting symptoms, family history and other associated symptoms should be undertaken when evaluating a patient of neuroblastoma. General neuroblastoma symptoms include; fever, irritability, fatigue, loss of appetite and weight loss. Other symptoms depending upon the anatomical location of neuroblastoma include; abdominal pain, distension and constipation (abdomen), shortness of breath, chronic cough & difficulty swallowing (posterior mediastinum), weakness, numbness, paralysis (retroperitoneum), visual defects, facial bruising (head & neck) and pallor, bone pain (bone marrow metastases).

Physical examination findings of neuroblastoma include; fever, hypertension, tachycardia, pallor, ecchymoses, nystagmus, proptosis, ptosis, abdominal mass, brisk reflexes, sensory loss and ataxia.

The laboratory findings in neuroblastoma include; ↓ hemoglobin, ↑ ferritin, ↑ catecholamine, ↑ dopamine, ↑ vanillylmandelic acid (VMA), ↑ homovanillic acid (HVA), ↑ lactate dehydrogenase and ↑ neuron-specific enolase levels. There are increased urinary catecholamine, vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels.

X ray findings of neuroblastoma include; intrathoracic or intraabdominal soft tissue mass, calcification, remodeling of surrounding ribs & vertebral bodies, thinning of surrounding pedicles and ill defined, metaphyseal, lucent bone lesions seen in metastases.

CT scan of the neck, chest and abdomen is the gold standard test in neuroblastoma as it can localize the tumor and determine degree of involvement as well. CT scan in neuroblastoma can show the presence of; heterogeneous mass, calcification, necrosis, compression of surrounding vessels, invasion of psoas muscle & kidneys and swollen lymph nodes.

MRI is considered the most useful modality in staging of neuroblastoma. It is superior to CT scan when determining marrow infiltration and intra spinal tumor extension.MRI findings in neuroblastoma patients include; hypointense heterogeneous mass on T1 weighted image, heterogeneous/hyperintense enhancement due to necrosis and cyst formation seen on T2 weighted images.

Ultrasound in the neuroblastoma shows heterogeneous solid masses due to vascular, necrotic and calcified content of the masses. When it is present in the adrenal, it displaces the kidneys inferiorly.

Nuclear medicine studies used for diagnosis of neuroblastoma include fluorodeoxyglucose-18F positron emission tomography (18F- FDG PET) scan and metaiodobenzylguanidine (123I-MIBG) scintigraphy. 18F-FDG PET scan may distinguish stage 1 and 2 neuroblastoma from other differential diagnoses. 123I- MIBG scintigraphy distinguishes stage 3 and 4 neuroblastoma other differential diagnoses.

The definitive diagnosis of nueroblastoma is confirmed by a biopsy. Charecterstic findings for neuroblastoma on microscopic histopathological analysis can be found here.

Children oncology group (COG) risk stratification system determines the protocol of management used for neuroblastoma patients. COG risk stratification system divides the patients into 03 groups: low risk, intermediate risk and high risk patients. Low risk neuroblastoma patients are usually managed by either observation or surgical resection of the tumor. Intermediate risk patients are managed by neoadjuvant therapy in advance of a definitive surgical resection. High risk neuroblastoma patients are usually managed by a combination of surgery, chemotherapy, radiation therapy, hematopoietic stem cell transplantation, immunotherapy and isotretinoin.

Surgical intervention is curative as a single therapeutic modality for management of low risk neuroblastoma patients. In intermediate risk patients, surgical intervention must be followed by chemotherapy. However, the benefits of surgery to achieve complete tumor resection in high risk patients with metastatic disease is not clearly demonstrated.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Zahir Ali Shaikh, MD[2]

Neuroblastoma was first described by Rudolf Virchow in 1864 as an abdominal tumor in a child as “glioma“. Felix Marchand described characteristics of tumors from adrenal medulla and sympathetic nervous system in 1891. James Homer wright in 1910, described circular clumps of bone marrow ( now named “Homer-Wright pseudorosettes) and advanced the understanding that tumor originated from primitive neural cells and could metastasize to bone.

• In 1864, Rudolf Virchow (german physician) first described an abdominal tumor in a child as “glioma“.^[1]
• In 1891, Felix Marchand (german pathologist) described the characteristics of tumors from adrenal medulla and sympathetic nervous system.^[2]
• In 1901, William Pepper described a neuroblastoma stage 4S presentation in infants that was metastatic to liver.
• In 1910, James Homer Wright described circular clumps of cells in bone marrow ( now named “Homer-Wright pseudorosettes) and advanced the understanding that tumor originated from primitive neural cells and could metastasize to bone.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Zahir Ali Shaikh, MD[2]

International neuroblastoma pathology classification system is used for the classification of neuroblastic tumors. It is subdivided in 02 main categories based on the morphologic features of neuroblastic tumors into; schwannian stroma-poor and schwannian stroma-rich/dominant.

• International neuroblastoma pathology classification, a system based on the framework of Shimada classification with minor modifications is proposed for international use in classification of neuroblastic tumors. ^[1][2][3]
• It is a biologically relevant and pathologically significant classification system based on the morphologic features of neuroblastic tumors,i-e,neuroblastoma, ganglioneuroblastoma and ganglioneuroma.^[4][5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2] Zahir Ali Shaikh, MD[3]

Neuroblastoma arises from the neural crest cells, which are normally involved in development of sympathetic nervous system and adrenal glands. It is frequently located along the sympathetic nervous system structures including; adrenal glands, retroperitoneal organs, organ of zuckerkandl, paravertebral sympathetic chain and posterior mediastinum among others. Neuroblastoma tumor cells secrete catecholamine by products including vanillylmandelic acid (VMA) and homovanillic acid (HVA) and vasoactive intestinal polypeptide (VIP) hormone as well. It can metastasize to bone, liver, lungs and brain. The various genes involved in pathogenesis of neuroblastoma include; NBPF10, KIF1B, ALK, LMO1 and PHOX2A genes. The most common genetic mutation is gain of chromosome 17q and MYCN oncogene amplification predicts more aggressive neuroblastoma. Neuroblastoma can also be associated with a number of syndromes including; neurofibromatosis type 1, beckwith-wiedemann syndrome and hirschsprung disease. On gross pathology, the characteristic finding of neuroblastoma is a well defined, bulky and tan colored mass, that can be associated with fibrous pseudocapsule, necrosis or hemorrhage. On microscopic picture, the presence of round blue cells separated by thin fibrous septa are a characteristic finding.

• Neuroblastoma arises from neural crest cells, which are normally involved in the development of the sympathetic nervous system and adrenal glands.^{[1][2][3][4][5]}
• Neuroblastoma is frequently located along the sympathetic nervous system structures. Specific sites may include:

• Adrenal glands (35% of the cases)
• Retroperitoneal organs (30% of the cases) such as:

• Organ of Zuckerkandl
• Coeliac axis
• Paravertebral sympathetic chain

• Posterior mediastinum (20% of the cases)
• Nerve tissues in the neck (1-5% of the cases)
• Nerve tissues in the pelvis (2-3% of the cases)

• Neuroblastoma tumor cells secrete catecholamine by-products such as:

• Vanillylmandelic acid (VMA)
• Homovanillic acid (HVA)

• Neuroblastoma tumor cells may secrete vasoactive intestinal peptide (VIP) hormone.
• Neuroblastoma may demonstrate spontaneous regression from an undifferentiated state to a completely benign cellular state.
• Spontaneous regression occurs only in neuroblastomas characterized by the following features:

• Near triploid number of chromosomes
• No MYCN amplification
• No loss of chromosome 1p

• Metastatic disease is common and has a variety of patterns:

• Bone (most common)
• Liver (diffuse infiltration that is more common in stage 4S neuroblastoma)
• Lungs and pleura (present as discrete nodules or diffuse consolidations)
• Brain and meninges (dural metastases can be diffuse or nodular)

• Development of neuroblasotma is the result of multiple genetic mutations.^{[1][6][7][8][9][10][11]}
• The vast majority of neuroblastoma cases are sporadic.
• 1-2% of neuroblastoma cases may demonstrate a familial predilection.
• Genes involved in the pathogenesis of neuroblastoma include:

• NBPF10 gene located on chromosome 1
• KIF1B gene located on chromosome 1
• ALK gene located on chromosome 2
• LMO1 gene located on chromosome 11
• PHOX2A gene located on chromosome 11

• Gain of chromosome 17q is the most common genetic mutation among neuroblastoma patients.
• MYCN oncogene (chromosome 2p24) amplification predicts a more aggressive nature of neuroblastomas.
• Deletion of chromosome 1p36 is associated with an increased recurrence rate following resection of localized neuroblastomas.
• Deletions of chromosome 11q is associated with poor prognosis among nueroblastoma patients.

• Neuroblastoma is associated with a number of syndromes that include:^[1][6]

• Neurofibromatosis type 1 (von Recklinghausen disease)
• Beckwith-Wiedemann syndrome
• DiGeorge syndrome
• Hirschsprung disease
• Hutchinson syndrome
• Pepper syndrome

• On gross pathology, a well defined, bulky, and tan colored mass is a characteristic finding of neuroblastoma.^[1][12]
• Other associated findings of neuroblastoma on gross pathology may include:

• Fibrous pseudocapsule
• Necrosis
• Hemorrhage
• Calcification

• On microscopic histopathological analysis the presence of round blue cells separated by thin fibrous septa are characteristic findings of neuroblastoma.^[13]
• Other findings of neuroblastoma on light microscopy may include:^[12]

• Homer-Wright rosettes (rosettes with a small meshwork of fibers at the center)
• Neuropil-like stroma (paucicellular stroma with a cotton candy-like appearance)

• On electron microscopy neuroblastoma is characterized by:

• Dendritic processes with longitudinally oriented microtubules
• Membrane bound electron-dense granules that contain catecholamines
• Presence of desmosomes
• Absence of glycogen

• On immunohistochemistry neuroblastoma is characterized by:

• Protein gene product (PGP) 9.5 +ve
• Monoclonal antibody NB84 +ve
• Synaptophysin +ve
• CD99 marker -ve

• Based on the degree of the cellular maturity and composition, neuroblastoma may be classified into three subtypes according to the International Neuroblastoma Pathology Classification which include:^[14]

• Illustrated below is a series of microscopic images demonstrating neuroblastoma:

• 
  Adrenal neuroblastoma^[12]
• 
  Adrenal neuroblastoma^[12]
• 
  Adrenal neuroblastoma^[12]
• 
  Adrenal neuroblastoma^[12]
• 
  Adrenal neuroblastoma^[12]
• 
  Adrenal neuroblastoma^[12]
• 
  Adrenal neuroblastoma^[12]
• 
  Adrenal neuroblastoma^[12]
• 
  Adrenal neuroblastoma^[12]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2] Zahir Ali Shaikh, MD[3]

There are no known established causes for neuroblastoma.

• There are no known established causes for neuroblastoma.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Zahir Ali Shaikh, MD[2]Haytham Allaham, M.D. [3]

Intra-abdominal neuroblastoma must be differentiated from other diseases that cause abdominal distension and constipation such as Wilms tumor and ganglioneuroma. Intra-thoracic neuroblastoma must be differentiated from other diseases that cause shortness of breath and chronic cough such as intrathoracic lymphoma and extra lobar pulmonary sequestration.

Abbreviations

ACTH: Adrenocorticotropic hormone, ARR: Aldosterone-renin ratio, CAM: Cellular adhesion molecules, ERCP: Endoscopic retrograde cholangiopancreatography, ESR: Erythrocyte sedimentation rate, CT: Computerized tomography, Fluorescence in situ hybridization, FDG: Fluorodeoxyglucose, FSH: Follicle stimulating hormone, GI: Gastrointestinal, H&E stain: Hematoxylin and eosin stain, LCA: Leukocyte common antigen, LDH: Lactate dehydrogenase, LH: Luteinizing hormone, MEN: Multiple endocrine neoplasia, MRCP: Magnetic resonance cholangiopancreatography, MRI: Magnetic resonance imaging, N/A: Not applicable/Not available, N/L: Normal, PAS stain: Periodic acid–Schiff stain, PET: Position emission tomography, PGP: Protein gene product 9.5, TB: Tuberculosis, U/S: Ultrasound, ZF: Zona fasciculata, ZG: Zona granulosa, ZR: Zona reticularis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2] Zahir Ali Shaikh, MD[3]

Neuroblastoma is the most common solid extracranial cancer in childhood and is the most common cancer in infancy. The overall incidence is 4.9 per 1,000,000 individuals in United states. Males are slightly more affected than females with 1.2:1 ratio. The incidence of neuroblastoma decreases with age and the highest incidence is in the first year of life. Neuroblastoma usually affects individuals of the Caucasian race.

• The overall incidence rate of neuroblastoma is approximately 4.9 per 1,000,000 individuals in the United States.^[1][2]

• Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy.^[3][4][5]

• The incidence of neuroblastoma decreases with age; the highest incidence is in the first year of life.^[6]
• The incidence of neuroblastoma according to specific age groups is approximately:^[1]

• 25.3 per 1,000,000 individuals aged between (0-4) years
• 2.3 per 1,000,000 individuals aged between (5-9) years
• 0.7 per 1,000,000 individuals aged between (10-14) years
• 0.2 per 1,000,000 individuals aged between (20-24) years
• 0.3 per 1,000,000 individuals aged between (25-29) years

• Males are slightly more commonly affected with neuroblastoma than females. The male to female ratio is approximately 1.12 to 1.^[7]
• The incidence rate of neuroblastoma among males is approximately 5.1 per 1,000,000 individuals in the United States.
• The incidence rate of neuroblastoma among females is approximately 4.6 per 1,000,000 individuals in the United States.^[1]

• Neuroblastoma usually affects individuals of the Caucasian race. African Americans, Native Indians, and Asians are less likely to develop neuroblastoma.^[8]
• The incidence rate of neuroblastoma among Caucasians is approximately 5.1 per 1,000,000 individuals in the United States.
• The incidence rate of neuroblastoma among African Americans is approximately 4.1 per 1,000,000 individuals in the United States.
• The overall incidence rate of neuroblastoma among Native Indians and Asians is approximately 3.8 per 1,000,000 individuals in the United States.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Zahir Ali Shaikh, MD[2]

The risk factors for neuroblastomas diagnosed during infancy include; maternal anemia during pregnancy, neonatal respiratory distress syndrome and low 1 minute Apgar score. However, the risk factors for neuroblastoma cases diagnosed at age 1 year or above is not known.

• The risk factors for neuroblastoma are not well known. However, following risk factors may be associated with neuroblastomas diagnosed during infancy:^{[1][2][3][4][5][6][7][8][9][10][11]}
  • Maternal anemia during pregnancy
  • Maternal opiate consumption
  • Maternal folate deficiency
  • Toxic exposures
  • Small or large for gestational age
  • Gestational diabetes mellitus
  • Neonatal respiratory distress syndrome
  • Low 1 minute Apgar score
  • Familial neuroblastoma
  • Genetic factors
    • Turner syndrome
    • Neurofibromatosis type 1
    • Germline chromosomal abnormality single-nucleotide polymorphisms (SNPs) at LMO1
    • Germline mutations in SDHB, APC, ALK, and BRCA2
• The risk factors for neuroblastomas diagnosed at age 1 year or above is not known.^[12]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Zahir Ali Shaikh, MD[2]Haytham Allaham, M.D. [3]

There is insufficient evidence to recommend the routine screening for neuroblastoma as it has no mortality benefits.

• There is insufficient evidence to recommend the routine screening for neuroblastoma by measuring the vanillylmandelic acid and homovanillic acid at 6 months or 1 year or age, as it does not have the mortality benefits.^[1][2][3][4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Zahir Ali Shaikh, MD[2]Haytham Allaham, M.D. [3]

Neuroblastoma may progress to develop fatigue, loss of appetite, joint pain and fever if left untreated. There is gradual development of site specific symptoms as the tumor size gradually increases. Complications of neuroblastoma include persistent refractory diarrhea, horner’s syndrome, hypertension, transverse myelopathy, anemia and suppressed immunity. The prognosis of neuroblastoma is generally regarded as poor, depending on the tumor extent at the time of diagnosis. The other prognostic factors for nuroblastoma include patient’s age, tumor stage and grade, genetic mutations and response to treatment.

• Neuroblastoma patients may initially present with vague symptoms making the diagnosis of such patients difficult.^[1][2]
• If left untreated, patients with neuroblastoma may progress to develop fatigue, loss of appetite, joint pain, and fever.
• Gradual development of site specific symptoms may occur as the tumor size gradually increases.^[3]

• Complications of neuroblastoma may include:^[4][5][6]

• Persistent refractory diarrhea (due to vasoactive intestinal polypeptide secretion)
• Horner’s syndrome (due to cervical sympathetic chain compression)
• Opsoclonus myoclonus syndrome and ataxia (due to a paraneoplastic syndrome)
• Hypertension (due to either catecholamine secretion or renal artery compression)
• Transverse myelopathy (due to tumor spinal cord compression)
• Anemia and suppressed immunity (due to bone marrow metastasis)

• Depending on the extent of the tumor at the time of diagnosis, the prognosis may vary. However, the prognosis of neuroblastoma is generally regarded as poor.^{[7][8][9][10]}
• INSS stage 1, stage 2, and stage 4S neuroblastomas are associated with a 3 year survival rate of 75-90%.
• INSS stage 3 neuroblastoma is associated with a 3 year survival rate of 80-90% among patients younger than 1 year of age.
• INSS stage 3 neuroblastoma is associated with a 3 year survival rate of 50% among patients older than 1 year of age.
• INSS stage 4 neuroblastoma is associated with a 3 year survival rate of 60-75% among patients younger than 1 year of age.
• INSS stage 4 neuroblastoma is associated with a 3 year survival rate of 15% among patients older than 1 year of age.
• The table below lists the prognostic factors for neuroblastoma patients:^{[11][12][13][14]}

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