Neuroblastoma pathophysiology

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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]

Overview

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.

Pathogenesis

• Neuroblastoma arises from neural crest cells, which are normally involved in the development of the sympathetic nervous system and adrenal glands.
• 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)

Genetics

• Development of neuroblasotma is the result of multiple genetic mutations.
• 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.

Associated Conditions

• Neuroblastoma is associated with a number of syndromes that include:

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

Gross Pathology

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

• Fibrous pseudocapsule
• Necrosis
• Hemorrhage
• Calcification

Microscopic Pathology

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

• 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:

Subtypes	Description
Undifferentiated Neuroblastoma	Completely formed by neuroblasts with no maturity of ganglion cells
Poorly Differentiated Neuroblastoma	Mostly formed by neuroblasts with less the 5% maturing ganglion cells
Differentiating Neuroblastoma	Predominantly formed by neuroblasts but with more than 5% mature ganglion cells

Gallery

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

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  Adrenal neuroblastoma

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  Adrenal neuroblastoma

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  Adrenal neuroblastoma

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  Adrenal neuroblastoma

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  Adrenal neuroblastoma

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  Adrenal neuroblastoma

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  Adrenal neuroblastoma

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  Adrenal neuroblastoma

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  Adrenal neuroblastoma

References

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