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Table of Contents
Definition / general | Terminology | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Molecular / cytogenetics images | Differential diagnosisCite this page: Perrino C, Zynger D. Ganglioneuroblastoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/adrenalganglioneuroblastoma.html. Accessed April 20th, 2019.
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
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
- Differentiation
Shimada Classification: Stratification into Prognostic Groups Favorable Unfavorable Stroma-rich 1. Well differentiated
2. Intermixed1. Nodular Stroma-poor 1. <1.5 years, any maturation, <200 MKI
2. 1.5-5 years, differentiating, <100 MKI1. <1.5 years, any maturation, >200 MKI
2. 1.5-5 years, undifferentiated, any MKI
3. >5 years, any maturation, any MKI
- Stroma-rich = extensive Schwannian component
- International Neuroblastoma Pathology Classification System (INPC)
- Minor differences from Shimada Classification
- 1993 updates (Cancer 1999;86:364)
- "Undifferentiated" subtype subdivided into "undifferentiated" and "poorly differentiated groups"
- "Stroma-rich, well differentiated" category changed to "ganglioneuroma, maturing"
- 2003 updates (Cancer 2003;98:2274)
- 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
- Low risk
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
Image hosted on other servers:
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
Image hosted on other servers:
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
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
Images hosted on other servers:
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)
