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Surgical Pathology Criteria
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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
  • 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
    • Ganglioneuroma, 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
    • Ganglioneuroma, 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, 6/23/13

Supplemental studies

Immunohistology

Synaptophysin pos
NB84 pos
Tyrosine hydroxylase pos
Neuron specifc enolase pos
CD45RB, B and T cell markers neg
Desmin, Myogenin, MyoD1 neg
Keratin, HMB45, S100, WT1, CD99 neg
S100 stains Schwannian stroma but not neuroblastoma cells

 

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:

NEUROBLASTOMA TUMOR SUMMARY
Status/Post chemotherapy? (Yes/No)  
MACROSCOPIC FEATURES
 
Specimen type  
Specimen size  
Specimen weight  
Tumor site  
Laterality  
Tumor size (2 dimensions)  
Tumor weight (if separate from total specimen)  
MICROSCOPIC FEATURES
 
International Neuroblastoma Pathology Classification  
Mitosis-Karyorrhexis Index (low, intermediate, high)  
Extent of tumor invasion:  
  Extracapsular extension  
  Distant metastasis  
Lymph node status:  
  Adherent lymph nodes  
  Non-adherent lymph nodes  
Margin status  
Vascular invasion  
Tumor necrosis (%)  
Calcifications (present/absent)  

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

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.
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