Neuroblastoma, Ganglioneuroblastoma and Ganglioneuroma

Definition

• Neoplasm arising from either the dorsal root ganglion of the spinal cord or the medulla of the adrenal gland, exhibiting variable degrees of neuroblastic maturation

Diagnostic Criteria

• Composed of neuroblasts exhibiting variable degrees of differentiation up to ganglion cells
  • Neuroblasts
    • Small round nuclei with stippled ("salt and pepper") chromatin
      • Large cell/large nucleolar phenotype
        • Comprises approximately 8-10% of all neuroblastomas
        • Nuclei 1.5 to 2 times larger than those of typical neuroblastoma cells
        • 1-4 prominent nucleoli
        • Usually seen in the undifferentiated and poorly differentiated subtypes of neuroblastoma (see below)
        • Associated with MYCN amplification and a poor prognosis
    • Scant eosinophilic cytoplasm
    • Indistinct cell borders
  • Ganglion cells
    • Large round nuclei with prominent nucleoli
    • Abundant eosinophilic cytoplasm
    • Nissl substance in cytoplasm
      • Basophilic granules/bodies composed of endoplasmic reticulum
• Background stroma also shows different levels of differentiation
  • Schwannian stroma resembles collagen
    • Requires S100 stain (positive) for identification
  • Neuropil
    • Pink, fibrillary extracellular material
  • Dense lymphoid infiltrate occasionally present
    • Lymphoid follicles may be present
    • Often seen in patients with Opsoclonus-Myoclonus-Ataxia (OMA) paraneoplastic syndrome
• Seven subtypes of neuroblastic tumors are recognized according to the degree of neuroblastic maturation and the amount of background schwannian stroma
  • Neuroblastoma, undifferentiated
    • Composed entirely of neuroblasts, no ganglion cell maturation
      • Immunohistochemistry is often required to confirm neuroblastic lineage
    • Schwannian stroma poor
      • Less than 50% of background stroma is schwannian
        • May be absent
  • Neuroblastoma, poorly differentiated
    • Predominantly neuroblasts, <5% maturing/mature ganglion cells
    • At least one focus of neuropil
    • Schwannian stroma poor
      • Less than 50% of background stroma is schwannian
        • May be absent
  • Neuroblastoma, differentiating
    • Predominantly neuroblasts but >5% maturing/mature ganglion cells
    • At least one focus of neuropil
    • Schwannian stroma poor
      • Less than 50% of background stroma is schwannian
        • May be absent
  • Ganglioneuroblastoma, nodular
    • Predominantly maturing/mature ganglion cells but at least one well circumscribed nodule of residual neuroblasts
      • Neuroblast nodules may correspond to hemorragic nodules in gross specimen
    • Schwannian stroma rich
      • 50% or more of background stroma is schwannian
  • Ganglioneuroblastoma, intermixed
    • Predominantly maturing/mature ganglion cells but at >1 foci of residual neuroblasts intermixed with ganglion cells
      • No distinct hemorragic nodules in gross specimen
    • Schwannian stroma rich
      • 50% or more of background stroma is schwannian
  • Ganglioneuroblastoma, maturing
    • Entirely composed of maturing and mature ganglion cells, no residual neuroblasts
      • No distinct hemorragic nodules in gross specimen
    • Schwannian stroma rich
      • 50% or more of background stroma is schwannian
  • Ganglioneuroblastoma, mature
    • Entirely composed of mature ganglion cells, no residual neuroblasts
      • No distinct hemorragic nodules in gross specimen
    • Schwannian stroma rich
      • 50% or more of background stroma is schwannian

Florette K. Gray Hazard MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates: 1/11/11, 1/29/11

Supplemental studies

Immunohistology

Genetic Study

• MYCN oncogene amplification
  • May be assessed by PCR or fluorescence in situ hybridization (FISH)
  • In general, patients with MYCN amplified tumors have a worse prognosis

Differential Diagnosis

• Differential diagnosis is generally only a problem with the undifferentiated subtype presenting as a metastasis
  • In such cases, immunohistochemistry may be required

	Nblast	ALL	Ewing Sarc (PNET)	Rhabdo	MNTI	DSCT	Wilms Tumor
Synapto	pos	neg	neg	neg	pos	neg	neg
NB84	pos	neg	neg	neg	neg	neg	neg
CD45RB (LCA)	neg	pos	neg	neg	neg	neg	neg
CD99	neg	pos	pos	neg	rare	neg	neg
Myogenin	neg	neg	neg	pos	rare	neg	neg
MyoD1	neg	neg	neg	pos	neg	neg	neg
Keratin	neg	neg	rare	rare	pos	pos	neg
Desmin	neg	neg	neg	pos	rare	pos	neg
WT1(C)	neg	neg	neg	neg	neg	pos	pos
S100	neg	neg	rare	neg	rare	neg	neg
HMB45	neg	neg	neg	neg	pos	neg	neg

Nblast = Neuroblastoma; ALL = Precursor T Lymphoblastic Leukemia; Rhabdo = Rhabdomyosarcoma; MNTI = Melanotic Neuroectodermal Tumor of Infancy; DSCT = Desmoplastic Small (Round) Cell Tumor; Synapto = Synaptophysin

Grading / Staging

Clinical staging classifies patients into low, intermediate and high risk groups based on:

• Patient age (most important)
• International Neuroblastoma Pathology Classification (INPC)
• MYCN oncogene amplification status
• Tumor stage (International Neuroblastoma Staging System, INSS)
• DNA ploidy

Grading

• International Neuroblastoma Pathology Classification
  • Classifies tumors into unfavorable and favorable histology based on
    • Tumor subtype
    • Patient age
    • Mitosis-karyorrhexis index (MKI)
      • Not calculated overall for ganglioneuroblastoma or ganglioneuroma
        • Should be calculated only for nodules of neuroblasts in ganglioneuroblastoma
      • Mitotic figures + karyorrhectic cells / 5000 neoplastic cells

        	Expressed as Percent	Expressed as Cell Count
        Low MKI	<2%	<100 / 5000 cells
        Intermediate MKI	2-4%	100-200 / 5000 cells
        High MKI	>4%	>200 / 5000 cells

  • Unfavorable histology

  Tumor Subtype	MKI	Patient Age
  Undifferentiated NB	Any MKI	Any age
  Poorly differentiated NB	High MKI	Any age
  Poorly differentiated NB	Intermediate MKI	Age ≥ 1.5 yrs
  Poorly differentiated NB	Low MKI	Age ≥ 1.5 yrs
  Differentiating NB	High MKI	Any age
  Differentiating NB	Intermediate MKI	Age ≥ 1.5 yrs
  Differentiating NB	Not applicable	Age ≥ 5 yrs
  Ganglioneuroblastoma, Nodular*	Not applicable	Any age

  * At least one nodule of neuroblasts has unfavorable histology
  • Favorable histology

Tumor Subtype	MKI	Patient Age
Poorly differentiated NB	Intermediate MKI	Age < 1.5 yrs
Poorly differentiated NB	Low MKI	Age < 1.5 yrs
Differentiating NB	Intermediate MKI	Age < 1.5 yrs
Differentiating NB	Low MKI	Age < 5 yrs
Ganglioneuroblastoma, Intermixed	Not applicable	Any age
Ganglioneuroblastoma, Nodular*	Not applicable	Any age
Ganglioneuroma	Not applicable	Any age

* All nodules of neuroblasts must have favorable histology

Staging

• International Neuroblastoma Staging System (INSS)

Stage 1	Complete gross excision of localized tumor, with or without positive microscopic margins	Negative ipsilateral non-adherent lymph node(s) (lymph node(s) attached to and removed with the primary tumor may be positive)
Stage 2A	Incomplete gross excision of localized tumor	Negative ipsilateral non-adherent lymph node(s) (lymph node(s) attached to and removed with the primary tumor may be positive)
Stage 2B	Complete or incomplete gross excision of localized tumor	Positive ipsilateral non-adherent lymph node(s); contralateral lymph node(s) negative for tumor
Stage 3	a.  Unresectable unilateral tumor infiltrating across the midline OR b.  Localized unilateral tumor OR c.  Unresectable midline tumor with bilateral extension	a.  Positive or negative regional lymph node(s) OR b.  Contralateral positive regional lymph node(s) OR c.  May be “unresectable” due to positive bilateral lymph node(s)
Stage 4	Any primary tumor with involvement of distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except 4S)
Stage 4S	Any localized primary tumor with involvement of skin, liver, and/or less than 10% of bone marrow cellularity (ONLY applies to children less than 1 year of age)

Pathology Report

A sample summary table detailing the information that should be included in each report is as follows:

Clinical

• Neuroblastoma is the most common extra-cranial solid tumor diagnosed in children age 5 years and younger
• Opsoclonus-Myoclonus-Ataxia (OMA) paraneoplastic syndrome affects 2-3% of patients with neuroblastoma
  • These children are more likely to experience long term neurologic dysfunction and varying degrees of developmental delay
• Renal cell carcinomas have been reported to arise in the kidneys of patients with a history of neuroblastoma
  • Most present about 10 years post diagnosis of neuroblastoma
  • Most have been in treated patients but rare cases reported without radiation or chemotherapy

Classification / Lists

Small round blue cell tumors

• Cellular myxoid liposarcoma
• Desmoplastic small cell tumor
• Melanotic neuroectodermal tumor of infancy
• Mesenchymal chondrosarcoma
• Nephroblastoma
• Neuroblastoma
• Peripheral primitive neuroectodermal tumor
• Poorly differentiated synovial sarcoma
• Precursor B lymphoblastic leukemia / lymphoma
• Precursor T lymphoblastic leukemia / lymphoma
• Rhabdomyosarcoma
• Small cell osteosarcoma

Bibliography

• Brodeur GM, Pritchard J, Berthold F, et al:: Revisions of the International Criteria for Neuroblastoma Diagnosis, Staging, and Response to Treatment. Journal of Clinical Oncology 1993;11(8):1466-1477.
• Cooper R, Khakoo Y, Matthay KK, et al:: Opsocolonus-Myoclonus-Ataxia Syndrome in Neuroblastoma: Histopathologic Features - A Report from the Children's Cancer Group. Medical and Pediatric Oncology 2001;36623-629.
• Rudnick E, Khakoo Y, Antunes NL, et al:: Opsoclonus-Myoclonus-Ataxia Syndrome in Neuroblastoma: Clinical Outcome and Antineuronal Antibodies - A Report from the Children's Cancer Group Study. Medical and Pediatric Oncology 2001;36612-622.
• Shimada H, Umehara S, Monobe Y, et al:: International Neuroblastoma Pathology Classification for Prognostic Evaluation of Patients with Peripheral Neuroblastic Tumors: A Report from the Children's Cancer Group. Cancer 2001;92(9):2451-2461.
• Tornoczky T, Kalman E, Kajtar PG, et al:: Large Cell Neuroblastoma: A Distinct Phenotype of Neuroblastoma with Aggressive Clinical Behavior. Cancer 2004;100(2):390-397.
• Tornoczky T, Semjen D, Shimada H, et al:: Pathology of Peripheral Neuroblastic Tumors: Significance of Prominent Nucleoli in Undifferentiated/Poorly Differentiated Neuroblastoma. Pathology Oncology Research 2007;13(4):269-275.