General
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• Neoplasm of neuroectodermal origin comprised of mixture of neuroblasts and ganglion cells in varying proportions
• On a spectrum, from least → most differentiated: neuroblastoma → ganglioneuroblastoma → ganglioneuroma

Terminology
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• Neuroblastoma = composed only of immature neuroblasts; Schwannian stroma-poor, click here
• Ganglioneuroblastoma = composed of mixture of immature neuroblasts and ganglion cells; Schwannian stroma-rich
• Ganglioneuroma = composed only of ganglion cells; Schwannian stroma-dominant, click here

Epidemiology
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• 4th most common tumor in childhood
• 75-85% occur within first 4 years of life
• M=F

Sites
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• Occur anywhere in anatomic distribution of sympathoadrenal neuroendocrine system
• ~80% arise within abdomen or adrenal gland,
• ~20% within thoracic cavity

Etiology
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• Clonal proliferation of immature cells of neural crest origin

Clinical features
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• Asymptomatic
• Abdominal/back mass
• Watery diarrhea, due to production of vasoactive intestinal polypeptide (Lack: Tumors of the Adrenal Glands and Extraadrenal Paraganglia, Volume 8, AFIP, Series 4)
• Patients with favorable histology lesions usually present with localized disease (stage I, II, III) (Pediatr Blood Cancer 2009;53:563)
• Patients with unfavorable histology lesions present with distant metastases in >50% of cases (stage IV) (Pediatr Blood Cancer 2009;53:563)

Diagnosis
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• 60-70% are advanced stage (III, IV) or have metastases at diagnosis (J Clin Oncol 1993;11:1466)

Laboratory
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• Increased urine catecholamine metabolites (homovanillic acid, vanillylmandelic acid)
• Increased urine/serum dopamine as adjunct laboratory test

Radiology
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• MRI: hypointensity on T1-weighted image with rapid enhancement and hyperintensity on T2-weighted image (Intern Med 1995;34:1168)

Radiology images
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Spiral CT: hyperechoic mass

Prognostic factors
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• Multiple classification systems have been developed with the goal of stratifying patients into prognostic groups; the most widely utilized are discussed below (Shimada Classification and INPC Classification)
  
  
• International Neuroblastoma Staging System (INSS), applies to ganglioneuroblastoma (J Clin Oncol 1993;11:1466)
  • I: localized, complete gross excision with/without microscopic residual disease, negative lymph nodes
  • IIA: localized, incomplete gross excision, negative lymph nodes
  • IIB: localized, with/without complete gross excision, positive ipsilateral lymph nodes, negative contralateral lymph nodes
  • III:
    • Unilateral, unresectable, crosses midline, with/without positive regional lymph nodes
    • Localized, positive contralateral regional lymph nodes
    • Midline, bilateral extension or lymph node involvement
  • IV: positive distant lymph nodes, bone, bone marrow, liver, and/or other organs (except those in IV-S)
  • IV-S: localized (stage I or II) with dissemination to liver, skin, and/or bone marrow
  
  
• Shimada Classification (J Natl Cancer Inst 1984;73:405)
  • Stroma-rich = extensive Schwannian component
    • Well-differentiated: mostly mature ganglioneuromatous tissue, few aggregates of immature neuroblastic cells that do not form nests
    • Intermixed: ganglioneuromatous tissue with interspersed, sharply defined, unencapsulated nests of variably differentiated neuroblastic cells
    • Nodular: grossly identifiable nodule(s) of immature, stroma-poor tissue in a mature matrix, usually has encapsulated edge
  • Stroma-poor = neuroblasts separated by thin septa of fibrovascular tissue
    • Differentiation
      • Undifferentiated: <5% differentiating elements
      • Differentiating: ≥5% differentiating elements
    • Mitosis-karyorrhexis index (MKI) (based on 5,000 cell count from random fields)
      • Low: <100
      • Intermediate: 100-200
      • High: >200
    • Age
      • <1.5 years
      • 1.5-5 years
      • >5 years
  
  

  Shimada Classification: Stratification into Prognostic Groups

  	Favorable	Unfavorable
  Stroma-rich	1. Well differentiated 2. Intermixed	1. Nodular
  Stroma-poor	1. <1.5 years, any maturation, <200 MKI 2. 1.5-5 years, differentiating, <100 MKI	1. <1.5 years, any maturation, >200 MKI 2. 1.5-5 years, undifferentiated, any MKI 3. >5 years, any maturation, any MKI

  
  
  
• International Neuroblastoma Pathology Classification System (INPC)
  • Minor differences from Shimada Classification
  • 1993 updates (Cancer 1999;86:364)
    1. "Undifferentiated" subtype subdivided into "undifferentiated" and "poorly differentiated groups"
    2. "Stroma-rich, well differentiated" category changed to "ganglioneuroma, maturing"
  • 2003 updates (Cancer 2003;98:2274)
    1. Ganglioneuroblastoma, stroma-rich, nodular subtype divided into 2 prognostic subsets
    • Favorable subset: composed of Schwannian-rich, stroma-dominant component favorable nodule(s) (definition below)
      • Poorly differentiated or differentiating neuroblastoma, MKI ≤200, <1.5 years
      • Differentiating neuroblastoma, MKI <100, 1.5–5 years
    • Unfavorable subset: composed of unfavorable nodule(s) (definition below)
      • Any neuroblastoma, MKI >200, any age
      • Any neuroblastoma, MKI 100-200, >1.5 years
      • Undifferentiated neuroblastoma, any age,
      • Poorly differentiated neuroblastoma, >1.5 years
      • Any neuroblastoma, >5 years

Additional prognostic factors
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• Favorable
  • Location: neck, thorax, primary site above diaphragm (Lack: Tumors of the Adrenal Glands and Extraadrenal Paraganglia, Volume 8, AFIP, Series 4)
  • Tumor stage 1, 2, 4S (Cancer 1999;86:364)
  • Positive S100 immunohistochemical staining (Cancer 1990;65:255)
  • Positive Galectin-3 immunohistochemical staining (Cell Death Dis 2014;5:e1100)
• Poor
  • Advanced clinical stage (Cancer 1999;86:364)
  • Loss of S100 immunohistochemical staining (Cancer 1990;65:255)
  • Positive ALK immunohistochemical staining (Am J Pathol 2012;180:1223, Exp Mol Pathol 2013;95:124)
  • N-myc (MYCN) amplification (J Clin Pathol 1989;42:1148, J Clin Pathol 1989;42:52, Cancer 1999;86:364, N Engl J Med 1996;334:225)
  • Chromosome 1p loss (Cancer 1999;86:364, N Engl J Med 1996;334:225)
  • Chromosome 17q amplification (N Engl J Med 1996;334:225)
  • Nearly diploid DNA content (N Engl J Med 1996;334:225)

Significant data to include in pathologic report
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• Final diagnostic line
  • Morphologic category and subtype
  • Note if tumor cells are present at margin without concluding if residual tumor is microscopic/macroscopic
• Microscopic description/comment
  • Quantify amount of Schwannian stroma
  • Presence/absence of macroscopic nodularity
  • Degree of neuroblastic differentiation
  • MKI
  • Percentage of neuroblastic/ganglion cells versus Schwannian/other cells in tissue used for molecular analysis
  • Prognostic evaluation incorporating patient age
  • Results of genetic and molecular studies

Case reports
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• 20 month old girl with adrenocortical carcinoma and ganglioneuroblastoma (J Med Genet 1998;35:328)
• 22 month old girl with ganglioneuroblastoma presenting as dilated cardiomyopathy (Arch Dis Child 2003;88:162)
• 26 month old boy with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation and neural crest tumor (Endocr Pract 2013;19:e12)
• 3 year old girl with catecholamine-secreting tumour (Gut 1983;24:954)
• 25 year old woman with adrenal pheochromocytoma and ganglioneuroblastoma (Intern Med 2000;39:58)
• 35 year old man with primary adrenal ganglioneuroblastoma (Intern Med 1995;34:1168)
• 35 and 42 year old men with pheochromocytoma diagnosed as mixed neuroendocrine-neural tumor (Intern Med 1995;34:683)
• 47 year old woman with ganglioneuroblastoma with disseminated bone marrow infiltration (Intern Med 1992;31:1322)

Treatment
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• Depends on prognostic stage (Pediatr Blood Cancer 2009;53:563, UpToDate - Treatment and prognosis of neuroblastoma)
  • Low risk
    • Surgical resection alone is mainstay
    • Chemotherapy only if tumor is unresectable or symptoms of spinal cord/respiratory/bowel compromise
    • Expectant observation in some infants with small adrenal masses, localized neuroblastoma, or asymptomatic stage 4S disease
  • Intermediate risk
    • Surgical resection
    • Moderate chemotherapy
    • Radiation only if disease progresses despite surgery/chemotherapy
  • High risk
    • Induction: intensive chemotherapy
    • Local control: surgical resection, radiation
    • Consolidation: chemotherapy, myeloablative therapy, autologous stem cell transplant
    • Maintenance: cis-retinoic acid or immunotherapy

Gross description
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• More homogeneous and mature appearance than neuroblastoma
• Varies by subtype, from circumscribed ovoid mass to large multilobulated tumor
• Stroma-rich, nodular subtype: area(s) of stroma-poor, immature tumor are usually hemorrhagic with well defined borders (J Natl Cancer Inst 1984;73:405)
• Calcification (chalky white, yellow areas) and cystic degeneration may occur
• If large, adrenal gland may be difficult to identify

Gross images
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Stroma-rich, intermixed type

Focal undifferentiated component

   

Stroma-rich, nodular type

With treatment-related changes

Multiple haemorrhagic foci

Micro description
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• Architecture: lobular, diffuse/solid, organoid
• Neuroblasts
  • Homer Wright pseudorosettes = circular, ovoid, angular zones of pale-staining neuritic cell processes surrounded by tumor cell nuclei; may rarely palisade
  • Minimal cytoplasm, may have cytoplasmic tail
  • Round to ovoid nuclei with stippled salt and pepper chromatin, inconspicuous nucleoli
• Ganglion cells
  • Abundant granular eosinophilic cytoplasm (Nissl substance = rough endoplasmic reticulum)
  • Distinct cell borders
  • Nuclear enlargement, eccentric nuclei, prominent nucleoli
• May see neuromelanin pigment (brown, finely granular; rarely present), cystic degeneration, hemorrhage, dystrophic calcification

Micro images
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Numerous ganglion cells

Hemorrhagic component

Stroma-rich, nodular type

Focal undifferentiated component and calcification

Vaguely formed Homer Wright pseudorosettes

Homer Wright pseudorosettes

Neuroblast cell component

Differentiated ganglion cells

Virtual slides
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Andrenal ganglioneuroblastoma,
therapy associated

Adrenal and retroperitoneal
ganglioneuroblastoma,
differentiating type

Adrenal ganglioneuroblastoma

Cytology description
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• Ganglion cells: larger cells, abundant cytoplasm, fine chromatin, prominent nucleoli
• Neuroblasts: uniform, small, blue cells with scant, eosinophilic, fibrillary cytoplasm; hyperchromatic to vesicular chromatin
  • May form Homer Wright pseudorosettes

Cytology images
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Numerous ganglion cells

Positive stains
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• Neuroblasts: neuron specific enolase (NSE), CD57, CD56, protein gene product 9.5 (PGP 9.5), Leu7, GD2, NB84, synaptophysin, chromogranin, neurofilament protein, ALK1 (>90%) (Am J Pathol 2012;180:1223), PHOX2B (Am J Surg Pathol 2012;36:1141), Galectin3 (Cell Death Dis 2014;5:e1100)
• Schwannian stroma: S100, Galectin3 (Cell Death Dis 2014;5:e1100)
• Ganglion cells: S100, synaptophysin, neurofilament protein (NF), glial fibrillary acidic protein (GFAP), PGP 9.5, type IV collagen (Dabbs: Diagnostic Immunohistochemistry: Theranostic and Genomic Applications, 3rd Edition, 2010)

Negative stains
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• EMA, cytokeratin, vimentin, HMB45, WT1, CD99, CD45, desmin, myogenic markers (myogenin, MyoD1) (Dabbs: Diagnostic Immunohistochemistry: Theranostic and Genomic Applications, 3rd Edition, 2010)

Electron microscopy description
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• Neuritic processes with neurotubules and neurofilaments, regular/uniform dense core granules measuring <200 nm in diameter (Lack: Tumors of the Adrenal Glands and Extraadrenal Paraganglia, Volume 8, AFIP, Series 4)

Molecular / cytogenetics description
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• Considered molecularly heterogeneous, but much of genetic basis remains unexplained (Cancer 2003;98:2274)
• ALK gene mutations have been implicated in some cases of ganglioneuroblastoma (Am J Pathol 2012;180:1223)
• Ganglioneuroblastoma, stroma-rich, nodular subtype, is considered a composite tumor consisting of separate clones (less aggressive stroma-rich component; nodular component consisting of a favorable/unfavorable/both clones) (Cancer 2003;98:2274)

Differential diagnosis
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• Desmoplastic small round cell tumor
• Ewing's sarcoma/primitive neuroectodermal tumor (PNET)
• Ganglioneuroma
• Lymphoid malignancy
• Malignant rhabdoid tumor
• Melanoma, metastatic
• Neuroblastoma
• Schwannoma/neurilemmoma with neuroblastoma-like features

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