Adrenal gland and paraganglia
Neuroblastic tumors

Topic Completed: 1 April 2015

Revised: 3 January 2019

Copyright: (c) 2002-2019,, Inc.

PubMed Search: Neuroblastoma adrenal (Review[ptyp] AND "loattrfree full text"[sb])
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Cite this page: Perrino C, Zynger D. Neuroblastoma. website. Accessed April 18th, 2019.
Definition / general
  • Primitive neoplasm of neuroectodermal origin
  • Composed of immature neuroblasts
  • Occurs anywhere in distribution of sympathoadrenal neuroendocrine system
  • Most in adrenal gland (~40%), followed by connective / subcutaneous / soft tissue (~20%), retroperitoneum (~15%), mediastinum (~10%) (SEER Program: NIH Pub No 99-4649; Bethesda, MD, 1999)
  • Clonal proliferation of immature cells of neural crest origin
  • Definitive risk factors not established
Clinical features
  • Clinical features depend on location / extent of tumor
  • Severe ill health, malnourishment, pain all suggest metastatic disease
  • Abdominal mass
  • Watery diarrhea syndrome (6%)
  • Opsoclonus-myoclonus-ataxia syndrome: rapid eye movements, ataxia, irregular muscle movements
  • Heterochromia iridis: cervical, mediastinal neuroblastoma (prenatal / postnatal interruption of sympathetic tracts that mediate pigmentation of iris)
  • Horner's syndrome (damage to sympathetic trunk resulting in miosis, ptosis, enophthalmos, anhidrosis): head, neck, thorax tumors
  • Paralysis: paraspinal tumors
  • Skin bruising associated with metastases to skin
  • Raccoon eyes associated with metastases to orbit cause bruising and proptosis
  • References: J Paediatr Child Health 2012;22:103, Lack: Tumors of the Adrenal Glands and Extraadrenal Paraganglia, AFIP 2007)
  • Urine biochemistry for catecholamines or their metabolites (dopamine, vanillylmandelic acid, homovanillic acid)
  • Nonspecific markers: thrombocytosis, increased ferritin, neuron-specific enolase, lactate dehydrogenase (J Paediatr Child Health 2012;22:103)
Radiology description
  • Irregularly shaped, lobulated, +/- calcification / necrosis / hemorrhage, usually heterogeneous on contrast-enhanced CT (Endocr Relat Cancer 2007;14:587)
Radiology images

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Right adrenal mass

Histologic classification systems
  • Shimada Classification (J Natl Cancer Inst 1984;73:405)
    • Histologic classification system first proposed in 1984 with prognostic implications
  • International Neuroblastoma Pathology Classification System (INPC) (Cancer 1999;86:349)
    • Original Shimada classification system was modified and renamed in 1999
    • New system also shown to have prognostic implications (Cancer 1999;86:364)
    • 3 subtypes of neuroblastoma: undifferentiated, poorly differentiated, differentiating

    Subtype Description
    • Tumor cells small to medium, indiscernible to small amount of cytoplasm, vague cytoplasmic borders
    • Nuclei round to elongated, salt and pepper chromatin, distinct nucleoli
    • No background neuropil
    • Need ancillary studies to establish diagnosis
    Poorly differentiated
    • Background neuropil present
    • ≤ 5% of tumor cells are differentiating neuroblasts
    • Abundant background neuropil
    • ≥ 5% of tumor cells are differentiating neuroblasts
    • % of differentiating neuroblasts is more important criteria than amount of neuropil
    • If present, Schwannian stromal development with mature / maturing ganglion cells <50% of tumor with a continuous transition zone to neuroblastomatous areas

  • NOTE: undifferentiated and poorly differentiated neuroblastoma may have focal / diffuse areas with large, spindled, anaplastic, pleomorphic or even rhabdoid undifferentiated cells

  • 2 main staging systems:
    1. International Neuroblastoma Staging System (INSS) (J Clin Oncol 1993;11:1466)
      • Based on extent of surgical resection
      • Must be applied after surgery for most accurate stage assignment

      Stage Description
      • Localized tumor with complete gross excision, with / without microscopic residual disease
      • Ipsilateral lymph nodes negative for tumor microscopically
      • Lymph nodes attached to and removed with primary tumor may be positive
      • Localized tumor with incomplete gross excision
      • Ipsilateral lymph nodes negative for tumor microscopically
      • Localized tumor with / without complete gross excision
      • Ipsilateral, nonadherent lymph nodes positive for tumor
      • Enlarged contralateral lymph nodes must be negative for tumor microscopically
      • Unresectable unilateral tumor infiltrating across the midline (midline is defined as the vertebral column)
      • with / without regional lymph node involvement
      • Localized unilateral tumor
      • With contralateral regional lymph node involvement
      • Midline tumor
      • With bilateral extension by infiltration (unresectable) or by lymph node involvement
      • Disseminated tumor to distant lymph nodes, bone, bone marrow, liver, skin and/or other organs (except as defined for stage 4S)
      • Localized primary tumor (as defined for stage 1, 2A, or 2B) with dissemination limited to skin, liver and/or bone marrow (<10% of nucleated cells)
      • Only in infants <1 year in age

    2. International Neuroblastoma Risk Group (INRG) Staging System (J Clin Oncol 2009;27:289, J Clin Oncol 2009;27:298)
      • More recent
      • Pre-surgical risk assessment tool
      • Based on clinical features and imaging studies

      Stage Description
      • Localized tumor not involving vital structures as defined by list of image-defined risk factors (IDRF)
      • Confined to one body compartment
      • Locoregional tumor
      • One / more IDRF
      • Distant metastases (except stage MS)
      • Children <18 months of age
      • Metastases confined to skin, liver and/or bone marrow
Prognostic factors
  • 2 staging systems (INSS, INRG) are incorporated into different risk stratification systems:
    1. Children's Oncology Group (Pediatr Blood Cancer 2013;60:985)
      • Uses INSS stage, age, MYCN status, DNA ploidy, INPC histology
      • Assigns one of three prognostic groups (low, intermediate, or high risk)
    2. INRG Criteria (J Clin Oncol 2009;27:289)
      • Uses INRG stage, with age, histologic category, grade of differentiation, MYCN status, 11q status, ploidy
      • Assigns one of four risk stratification groups (very low, low, intermediate, high)
  • Many prognostic factors have been proposed, most robust of which include: histologic subtype, grade of tumor differentiation, stage, age at diagnosis, MYCN status (Pediatr Clin North Am 2015;62:225, J Clin Oncol 2009;27:289)
  • Some additional favorable prognostic factors:
    • Abundant lymphoid infiltrates
    • Location in neck, thorax, pelvis
  • Some additional unfavorable prognostic factors:
    • MYC-N amplification (>10 copies/cell)
    • ALK amplification (Nat Rev Cancer 2013;13:397)
    • Chromosome 1p36.3 or 11q23 deletion
    • Near-diploid DNA content (patients <18 months with metastatic disease)
    • Increasing age
Case reports
Clinical images

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Raccoon eyes, abdominal and brain CT

Gross description
  • Variable, circumscribed, ovoid mass to multilobated tumor
  • Hemorrhagic with vague, bulging lobules
Gross images

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Congenital neuroblastoma

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Caudally located neuroblastoma

Microscopic (histologic) description
  • Small round blue cell tumor
  • Neuroblasts (Cancer 1999;86:349)
    • Undifferentiated: small to medium, salt and pepper chromatin, elongated shape, may contain distinct nucleoli, indiscernible / small amount of cytoplasm, vague cytoplasmic borders
    • Differentiating (toward ganglion cells): synchronous differentiation of nucleus (enlarged, eccentric nucleus with vesicular chromatin and single prominent nucleolus) and abundant, eosinophilic / amphophilic cytoplasm
    • May have anaplastic, pleomorphic, spindled, rhabdoid variants
    • May form Homer-Wright pseudorosettes surrounding delicate, eosinophilic neuropil
  • Coagulation necrosis, fibrin, or collagen may be present (Cancer 1999;86:349)
  • In poorly differentiated or differentiating subtypes, Schwann cells and differentiated / differentiating ganglion cells may be found (especially at tumor periphery) (Cancer 1999;86:349)

Neuroblastoma in situ
  • Usually incidental finding at autopsy in 0.4 to 2.5% of infants less than 3 months
  • May not be neoplastic or may mature into ganglioneuroma
  • Clusters of immature neuroblasts, from 0.7 to 9.5 mm, with frequent cystic change

Treatment effect
  • Cannot grade tumors as favorable or unfavorab
  • Extensive fibrosis and calcification may obscure margin involvement
  • Also necrosis and chronic inflammation
Microscopic (histologic) images

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Contributed by Dr. Carmen Perrino
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With anaplasia

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Anaplasia and a mitotic figure

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Homer-Wright pseudorosettes

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High power pseudorosettes

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Poorly differentiated

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Dystrophic calcification

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Metastatic to bone marrow

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Significant crush artifact

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Small round blue cell

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Mats of neuropil and focal resetting

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Differentiating bladder neuroblastoma

Virtual slides

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Neuroblastoma (cystic)

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Neuroblastoma, neck

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Benign congenital neuroblastoma

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Neuroblastoma, 1 y/o boy

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Neuroblastoma with skull metastases

Cytology description
  • Neuroblasts: uniform, small, blue cells with hyperchromatic to vesicular chromatin and scant, eosinophilic, fibrillary cytoplasm, may form Homer-Wright rosettes
Cytology images

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Occasional rossetting

Electron microscopy description
  • Most characteristic features are arrays of neuritic processes containing microtubules, diffuse intermediate filaments, and sparse dense-core neurosecretory granules (average diameter 100 nm) (Ultrastruct Pathol 1994;18:149)
Electron microscopy images

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C: neurosecretory dense core granules in the cytoplasm

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Poorly differentiated neuroblasts

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Widespread neuritic processes

Molecular / cytogenetics description
  • Familial neuroblastoma (Nat Rev Cancer 2013;13:397)
    • Rare (<2%), due to mutations in genes (PHOX2B, ALK) involved in signaling pathways important for development of sympathoadrenal lineage
    • Genome-wide association studies have revealed several single nucleotide polymorphisms (SNPs) which give rise to and/or contribute to progression of neuroblastoma: LINC00340 and LOC729177 (FLJ44180), BARD1, LMO1, DUSP12, HSD17B12, DDX4-IL31RA, HACE1, LIN28B
  • Sporadic neuroblastoma (Nat Rev Cancer 2013;13:397)
    • ALK amplification associated with poor prognosis
      • 6-10% of neuroblastomas have somatic ALK mutations
      • 3-4% of neuroblastomas have high risk ALK amplifications
    • MYCN amplification (≥ 10 copies for diploid genome or >4 fold signal relative to chromosome 2) associated with poor prognosis
      • Occurs in ~22% of tumors
    • ATRX mutations among most common in sporadic neuroblastomas, but not sufficient for tumorigenesis
      • Association with age at diagnosis
        • No ATRX mutations in very young children (<18 months) with stage 4 disease and better prognosis
        • ATRX mutations occur in 17% of children 18 months to 12 years with stage 4 disease, and in 44% of patients >12 years, all with very poor prognosis
    • Frequent mutations in Rac/Rho pathway and ARID1A and ARRID1B genes identified by whole genome sequencing, significance of each yet to be elucidated (Nat Rev Cancer 2013;13:397)
Molecular / cytogenetics images

Contributed by Leica Biosystems

MYCN (2p24) / AFF3 (2q11)

Differential diagnosis
Board review question #1
The image shown below is a Wright-Giemsa stained bone marrow aspirate smear from a 6 month old child who presented with a 5 cm abdominal mass.

Which of the following answer choices, if present, would result in an improved prognosis for the patient?

  1. FISH shows loss of chromosome 1p
  2. FISH shows loss of chromosome 11q
  3. Molecular diagnostic testing shows N-myc amplification
  4. The child is less than 1 year old
  5. The child is male
Board review answer #1
D. The child is less than 1 year old. The bone marrow aspirate shows clusters of small, round, blue cells with smudged chromatin and nuclear molding; given the history of a child with an abdominal mass, this is consistent with metastatic neuroblastoma in the bone marrow. If the patient is less than 1 year old and has metastatic disease limited to skin, liver and bone marrow, the tumor would be staged as 4S, which has a good prognosis. In contrast, N-myc amplification and loss of chromosomes 1p and 11q are associated with a worse prognosis.

  1. Incorrect: see answer explanation above.
  2. Incorrect: see answer explanation above.
  3. Incorrect: see answer explanation above.
  1. Incorrect: gender does not significantly affect prognosis in neuroblastoma.

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