2019-03-05T18:07:47Z

Zahir Ali Shaikh:

__NOTOC__
{{Neuroblastoma}}
{{CMG}} {{AE}}{{ZAS}}{{HL}}

==Overview==
Neuroblastoma is the most common solid extracranial [[cancer]] in [[childhood]] and is the most common [[cancer]] in [[Infant|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 gland]]s. It is usually located along the [[sympathetic nervous system]] structures including; [[Adrenal gland|adrenal glands]], [[Retroperitoneal|retroperitoneal organs]], [[Sympathetic chain|paravertebral sympathetic chain]], [[Organ of Zuckerkandl|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 [[Neuron|neural cells]] and could [[Metastasis|metastasize]] to [[bone]]. International neuroblastoma [[pathology]] [[classification]] system is used for the [[classification]] of neuroblastoma [[Tumor|tumors]], which divides it into 02 main categories based on [[Morphology|morphologic features]] of neuroblastoma [[Tumor|tumors]] into: schwannian stroma poor and schwannian stroma rich/dominant. Neuroblastoma [[tumor]] [[Cell (biology)|cells]] secrete [[catecholamine]] by products including [[Vanillylmandelic acid|vanillylmandelic acid (VMA)]] and [[Homovanillic acid|homovanillic acid (HVA)]] and [[Vasoactive intestinal peptide|vasoactive intestinal polypeptide (VIP)]] [[hormone]] as well. The various genes involved in [[pathogenesis]] of neuroblastoma include; [[NBPF10]], [[KIF1B]], ALK, [[LMO1]] and [[PHOX2A]] [[Gene|genes]]. The most common [[genetic mutation]] is [[Gain-of-function mutation|gain]] of [[Chromosome 17|chromosome 17q]] and MYCN [[oncogene]] [[amplification]] predicts more aggressive neuroblastoma. Neuroblastoma can also be associated with a number of [[Syndrome|syndromes]] including; [[neurofibromatosis type 1]], [[Beckwith-Wiedemann syndrome|beckwith-weidemann syndrome]] and [[Hirschsprung's disease|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 [[Microscopy|microscopic picture]], the presence of round blue [[Cell (biology)|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 [[Infant|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. [[Male|Males]] are slightly more affected than [[Female|females]] with 1.2:1 ratio. Neuroblastoma usually affects individuals of the caucasian race. Intra-abdominal neuroblastoma must be differentiated from other [[Disease|diseases]] that cause [[abdominal distension]] and [[constipation]] such as [[Wilms' tumor|Wilms tumor]] and [[ganglioneuroma]]. Intra-thoracic neuroblastoma must be differentiated from other [[Disease|diseases]] that cause [[shortness of breath]] and [[chronic cough]] such as [[intrathoracic]] [[lymphoma]] and extra lobar [[pulmonary]] sequestration. There are no routine [[Screening test|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 [[Symptom|symptoms]] as the [[tumor]] size gradually increases. [[Complication (medicine)|Complications]] of neuroblastoma include; [[Diarrhea|persistent refractory diarrhea]], [[horner's syndrome]], [[hypertension]], [[Transverse myelitis|transverse myelopathy]], [[anemia]] and [[Immunodeficiency|suppressed immunity]]. The [[prognosis]] of neuroblastoma is generally regarded as poor, depending on the [[tumor]] extent at the time of [[diagnosis]]. The other [[Prognosis|prognostic factors]] for nuroblastoma include; [[Patient|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 [[Patient|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|patient's]] [[age]], [[tumor]] grade, and the [[amplification]] of MYCN [[gene]]. General neuroblastoma [[Symptom|symptoms]] include; [[fever]], [[irritability]], [[fatigue]], [[loss of appetite]] and [[weight loss]]. Other [[Symptom|symptoms]] depending upon the [[anatomical]] location of neuroblastoma include; [[abdominal pain]], [[Abdominal distension|distension]] and [[constipation]] ([[abdomen]]), [[shortness of breath]], [[chronic cough]] & [[difficulty swallowing]] ([[posterior mediastinum]]), [[weakness]], [[numbness]], [[paralysis]] ([[retroperitoneum]]), [[visual]] defects, facial [[bruising]] ([[Head and neck anatomy|head & neck]]) and [[pallor]], [[bone pain]] ([[bone marrow]] [[Metastasis|metastases]]). [[Physical examination]] findings of neuroblastoma include; [[fever]], [[hypertension]], [[tachycardia]], [[pallor]], [[ecchymoses]], [[nystagmus]], [[proptosis]], [[ptosis]], [[abdominal mass]], [[Hyperreflexia|brisk reflexes]], [[sensory loss]] and [[ataxia]]. The laboratory findings in neuroblastoma include; ↓ [[hemoglobin]], ↑ [[ferritin]], ↑ [[catecholamine]], ↑ [[dopamine]], ↑ [[Vanillylmandelic acid|vanillylmandelic acid (VMA)]], ↑ [[Homovanillic acid|homovanillic acid (HVA)]], ↑ [[lactate dehydrogenase]] and ↑ [[neuron-specific enolase]] levels. There are increased [[urinary]] [[catecholamine]], [[Vanillylmandelic acid|vanillylmandelic acid (VMA)]] and [[Homovanillic acid|homovanillic acid (HVA)]] levels. [[X-rays|X ray]] findings of neuroblastoma include; intrathoracic or intraabdominal [[soft tissue]] [[mass]], [[calcification]], remodeling of surrounding [[Rib|ribs]] & [[vertebral bodies]], thinning of surrounding [[pedicles]] and ill defined, [[metaphyseal]], lucent bone [[Lesion|lesions]] seen in [[Metastasis|metastases]]. [[Computed tomography|CT scan]] of the [[neck]], [[chest]] and [[abdomen]] is the [[Gold standard (test)|gold standard test]] in neuroblastoma as it can localize the [[tumor]] and determine degree of involvement as well. [[Computed tomography|CT scan]] in neuroblastoma can show the presence of; [[heterogeneous]] [[mass]], [[calcification]], [[necrosis]], compression of surrounding [[Blood vessel|vessels]], invasion of [[Psoas major muscle|psoas muscle]] & [[Kidney|kidneys]] and [[Edema|swollen]] [[Lymph node|lymph nodes]]. [[Magnetic resonance imaging|MRI]] is considered the most useful modality in staging of neuroblastoma. It is superior to [[Computed tomography|CT scan]] when determining [[Marrow infiltration by tumors, leukemias|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 [[Patient|patients]]. COG risk stratification system divides the [[Patient|patients]] into 03 groups: low risk, intermediate risk and high risk patients. Low risk neuroblastoma [[Patient|patients]] are usually managed by either [[observation]] or [[surgical resection]] of the [[tumor]]. Intermediate risk [[Patient|patients]] are managed by [[neoadjuvant therapy]] in advance of a definitive [[surgical resection]]. High risk neuroblastoma [[Patient|patients]] are usually managed by a combination of [[surgery]], [[chemotherapy]], [[radiation therapy]], [[hematopoietic stem cell transplantation]], [[immunotherapy]] and [[isotretinoin]]. [[Surgery|Surgical intervention]] is [[Cure|curative]] as a single therapeutic modality for management of low risk neuroblastoma [[Patient|patients]]. In intermediate risk [[Patient|patients]], [[Surgery|surgical intervention]] must be followed by [[chemotherapy]]. However, the benefits of [[surgery]] to achieve complete [[tumor]] [[resection]] in high risk [[Patient|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 [[Tumor|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 [[Neuron|neural cells]] and could [[Metastasis|metastasize]] to [[bone]].

==Classification==
International neuroblastoma [[pathology]] classification system is used for the classification of neuroblastic [[Tumor|tumors]]. It is subdivided in 02 main categories based on the [[Morphology|morphologic]] features of neuroblastic [[Tumor|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 gland|adrenal glands]]. It is frequently located along the [[sympathetic nervous system]] structures including; [[Adrenal gland|adrenal glands]], [[Retroperitoneal|retroperitoneal organs]], [[Organ of Zuckerkandl|organ of zuckerkandl]], [[Sympathetic chain|paravertebral sympathetic chain]] and [[posterior mediastinum]] among others. Neuroblastoma [[tumor]] [[Cell (biology)|cells]] secrete [[catecholamine]] by products including [[Vanillylmandelic acid|vanillylmandelic acid (VMA)]] and [[Homovanillic acid|homovanillic acid (HVA)]] and [[Vasoactive intestinal peptide|vasoactive intestinal polypeptide (VIP)]] [[hormone]] as well. It can [[Metastasis|metastasize]] to [[bone]], [[liver]], [[Lung|lungs]] and [[brain]]. The various [[Gene|genes]] involved in [[pathogenesis]] of neuroblastoma include; [[NBPF10]], [[KIF1B]], ALK, [[LMO1]] and [[PHOX2A]] [[Gene|genes]]. The most common [[genetic mutation]] is [[Gain-of-function mutation|gain]] of [[Chromosome 17|chromosome 17q]] and MYCN [[oncogene]] [[amplification]] predicts more aggressive neuroblastoma. Neuroblastoma can also be associated with a number of [[Syndrome|syndromes]] including; [[neurofibromatosis type 1]], [[Beckwith-Wiedemann syndrome|beckwith-wiedemann syndrome]] and [[Hirschsprung's disease|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 [[Microscopy|microscopic picture]], the presence of round blue [[Cell (biology)|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 [[Disease|diseases]] that cause [[abdominal distension]] and [[constipation]] such as [[Wilms' tumor|Wilms tumor]] and [[ganglioneuroma]]. Intra-thoracic neuroblastoma must be differentiated from other [[Disease|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 [[Infant|infancy]]. The overall [[incidence]] is 4.9 per 1,000,000 individuals in united states. [[Male|Males]] are slightly more affected than [[Female|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 factor|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 (medicine)|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 [[Symptom|symptoms]] as the [[tumor]] size gradually increases. [[Complication (medicine)|Complications]] of neuroblastoma include; [[Diarrhea|persistent refractory diarrhea]], [[horner's syndrome]], [[hypertension]], [[Transverse myelitis|transverse myelopathy]], [[anemia]] and [[Immunodeficiency|suppressed immunity]]. The [[prognosis]] of neuroblastoma is generally regarded as poor, depending on the [[tumor]] extent at the time of [[diagnosis]]. The other [[Prognosis|prognostic factors]] for nuroblastoma include; [[Patient|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 metastesis. 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, clacification, 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 [[Neuroblastoma pathophysiology|'''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 isotetrinoin.

===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.

==References==
{{reflist|2}}

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