Adrenal gland and paraganglia
Neuroblastic tumors
Ganglioneuroblastoma

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

Revised: 20 January 2016, last major update August 2014

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

PubMed Search: Ganglioneuroblastoma [title]
Definition / General
  • Neoplasm of neuroectodermal origin comprised of mixture of neuroblasts and ganglion cells in varying proportions
  • On a spectrum, from leastmost differentiated: neuroblastoma → ganglioneuroblastoma → ganglioneuroma
Terminology
  • 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
  • 4th most common tumor in childhood
  • 75-85% occur within first 4 years of life
  • M=F
Sites
  • Occur anywhere in anatomic distribution of sympathoadrenal neuroendocrine system
  • ~80% arise within abdomen or adrenal gland,
  • ~20% within thoracic cavity
Etiology
  • Clonal proliferation of immature cells of neural crest origin
Clinical Features
Diagnosis
Laboratory
  • Increased urine catecholamine metabolites (homovanillic acid, vanillylmandelic acid)
  • Increased urine/serum dopamine as adjunct laboratory test
Radiology Description
  • 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
  • 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, 1.55 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
Case Reports
Treatment
  • 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
  • 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

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Focal undifferentiated component

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Stroma-rich, nodular type

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With treatment-related changes


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Multiple haemorrhagic foci

Micro Description
  • 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

Significant data to include in pathologic report

See Cancer 1999;86:364

  • 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
Micro Images
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Numerous ganglion cells

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Hemorrhagic component

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Stroma-rich, nodular type

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Focal undifferentiated component and calcification

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Vaguely formed Homer Wright pseudorosettes

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Homer Wright pseudorosettes

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Neuroblast cell component


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Differentiated ganglion cells

Virtual Slides
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Andrenal ganglioneuroblastoma,
therapy associated

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Adrenal and retroperitoneal
ganglioneuroblastoma,
differentiating type

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Adrenal ganglioneuroblastoma

Cytology Description
  • 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
Negative Stains
Electron Microscopy Description
Molecular / Cytogenetics Description
  • 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)