Neuroblastoma overview
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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]
Overview
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.
Historical Perspective
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.
Classification
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.
Pathophysiology
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.
Causes
There are no known established causes for neuroblastoma.
Differentiating Multiple Myeloma from other Diseases
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.
Epidemiology and Demographics
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.
Risk Factors
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.
Screening
There is insufficient evidence to recommend the routine screening for neuroblastoma as it has no mortality benefits.
Natural History, Complications and Prognosis
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.
Diagnosis
Staging
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.
History and Symptoms
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
Physical examination findings of neuroblastoma include; fever, hypertension, tachycardia, pallor, ecchymoses, nystagmus, proptosis, ptosis, abdominal mass, brisk reflexes, sensory loss and ataxia.
Laboratory Findings
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
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
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
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.
Echocardiography or Ultrasound
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.
Other Imaging Findings
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.
Other Diagnostic Studies
The definitive diagnosis of nueroblastoma is confirmed by a biopsy. Charecterstic findings for neuroblastoma on microscopic histopathological analysis can be found here.
Treatment
Medical Therapy
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.
Surgery
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.