Sandbox:patho2

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 observed along the sympathetic nervous system structures. Specific sites may include:

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

• 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 catecholamines such as:

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

• Neuroblastoma may demonstrate spontaneous regression from an undifferentiated state to a completely benign cellular state.

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

• MYCN oncogene amplification is a common finding among neuroblastoma patients.

Associated Conditions

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

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

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 positivity
• Monoclonal antibody NB84 positivity
• Synaptophysin positivity
• CD99 marker negativity

• Neuroblastic tumors may be grouped according to International Neuroblastoma Pathology Classification (Shimada classification) into two groups: schwannian stroma rich group and a schwannian stroma poor group as illustrated below:

Neuroblastic tumors

Schwannian stroma rich group

Schwannian stroma poor group

Undifferentiated neuroblastoma Poorly differentiated neuroblastoma Differentiating neuroblastoma

Nodular ganglioneuroblastoma Intermixed ganglioneuroblastoma Maturing ganglioneuroma Mature ganglioneuroma

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

• Undifferentiated neruoblastoma
• Poorly differentiated neuroblastoma
• Differentiating neuroblastoma

• The table below summarizes the differnces between the three histological subtypes of neurublastoma:

Risk Factor	Description
Undifferentiated neruoblastoma	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

• Shown below is a series of microscopic images of different subtypes of meningioma: