Ganglioneuroblastoma

Adrenal gland & paraganglia

Neuroblastic tumors

Authors: Carmen Perrino, M.D., Debra Zynger, M.D.

Topic Completed: 1 August 2014

Minor changes: 8 December 2019

Copyright: 2002-2019, PathologyOutlines.com, Inc.

PubMed Search: Ganglioneuroblastoma [title]

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Table of Contents

Cite this page: Perrino C. Ganglioneuroblastoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/adrenalganglioneuroblastoma.html. Accessed June 7th, 2020.

Definition / general

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

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

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

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

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

Image hosted on other servers:

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

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)

Case reports

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

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

Contributed by Dr. Carmen Perrino and Dr. Debra Zynger

Stroma-rich, intermixed type

Focal undifferentiated component

Stroma-rich, nodular type

With treatment-related changes

Microscopic (histologic) 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

Microscopic (histologic) images

Contributed by Dr. Carmen Perrino and Dr. Debra Zynger

Neuroblast cell component

Numerous ganglion cells

Homer Wright pseudorosettes

Vaguely formed Homer Wright pseudorosettes

Hemorrhagic component

Stroma-rich, nodular type

Focal undifferentiated component and calcification

Image hosted on other servers:

Differentiated ganglion cells

Virtual slides

Images hosted on other servers:

Andrenal ganglioneuroblastoma,
therapy associated

Adrenal and retroperitoneal
ganglioneuroblastoma,
differentiating type

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

Contributed by Dr. Carmen Perrino and Dr. Debra Zynger

Numerous ganglion cells

Positive stains

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

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

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

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)

Molecular / cytogenetics images

Kindly provided by LeicaBiosystems Amsterdam

MYCN (2p24) / AFF3 (2q11)

Differential diagnosis