Adrenal gland and paraganglia
Neuroblastic tumors
Neuroblastoma

Author: Carmen Perrino, M.D. (see Authors page)
Editor: Debra Zynger, M.D.

Revised: 25 January 2016, last major update April 2015

Copyright: (c) 2002-2016, PathologyOutlines.com, Inc.

PubMed Search: Neuroblastoma [title] adrenal

See subtypes below: In situTreatment effect

Cite this page: Neuroblastoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/adrenalneuroblastoma.html. Accessed December 4th, 2016.
Definition / General
  • Primitive neoplasm of neuroectodermal origin
  • Composed of immature neuroblasts
Epidemiology
Sites
Etiology
  • 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)
Diagnosis
Laboratory
  • Urine biochemistry for catecholamines or their metabolites (dopamine, vanillylmandelic acid, homovanillic acid)
  • Non-specific 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

Classification
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
    Undifferentiated
    • 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
    Differentiating
    • 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
Staging
  • 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
      1
      • 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
      2A
      • Localized tumor with incomplete gross excision
      • Ipsilateral lymph nodes negative for tumor microscopically
      2B
      • Localized tumor with / without complete gross excision
      • Ipsilateral, nonadherent lymph nodes positive for tumor
      • Enlarged contralateral lymph nodes must be negative for tumor microscopically
      3
      • Unresectable unilateral tumor infiltrating across the midline (midline is defined as the vertebral column)
      • with / without regional lymph node involvement
        OR
      • Localized unilateral tumor
      • With contralateral regional lymph node involvement
        OR
      • Midline tumor
      • With bilateral extension by infiltration (unresectable) or by lymph node involvement
      4
      • Disseminated tumor to distant lymph nodes, bone, bone marrow, liver, skin and/or other organs (except as defined for stage 4S)
      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
      L1
      • Localized tumor not involving vital structures as defined by list of image-defined risk factors (IDRF)
      • Confined to one body compartment
      L2
      • Locoregional tumor
      • One / more IDRF
      M
      • Distant metastases (except stage MS)
      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
Treatment
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

Micro 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
Micro Images
Flickr mages courtesy of 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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Post treatment

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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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Pale, pink-staining neurofibrillary stroma

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Small round blue cell

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Neuroblasts

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Mats of neuropil and focal resetting

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Neuroblastoma on ovary

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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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Clump of neuroblastoma cells

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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)
Differential Diagnosis