Peripheral Neuroblastic Tumours

 

 

Epidemiology and Etiology:

    • Most common solid extracranial malignancy in first 2 years
    • 96% occur in the first decade
    • 3.5% in the second decade

 

Common Sites:

    • Adrenals (40%)
    • Sympathetic ganglia:
      • Abdominal (25%)
      • Thoracic (15%)
        • Posterior mediastinum
      • Cervical
      • Pelvic
      •  

 

Gross features:

    • Calcifications frequently
    • Neuroblastoma:
      • 1-10cm
      • Encapsulated
      • Soft, grey-tan mass
      • Hemorrhagic often
      • Cystic change maybe
    • Ganglioneuroblastoma and ganglioneuroma:
      • Firmer
      • Tan-white
      • Nodular ganglioneuroblastoma has nodules of softer maybe hemorrhagic tissue within the firm tan-white tissue

 

Histologic features:

    • One or more of the following elements:
      • Undifferentiated neuroblasts
      • Neuropil
      • Differentiating neuroblasts
      • Ganglion cells
      • Mature neuritic processes
      • Schwann cells
      • Fibrous tissue
    • Classification here is INPC which is modified Shimada classification (see reference)
    • Neuroblastoma (schwannian stroma-poor):
      • Small round blue cells
      • Dark nuclei
      • Scant cytoplasm
      • Poorly-defined cell borders
      • Solid sheets of cells
      • Neuropil (faint eosinophilic fibrillary material) in background
      • Homer-Wright pseudorosettes (neuropil in the middle) maybe
      • Lacking prominent Schwannian stroma (Schwannian stroma-poor)
        • May rarely have microscopic, irregular foci of ganglioneuromatous component
      • May have differentiating neuroblasts and abundant neuropil
        • Definitive prominent nucleolus
        • Cytoplasm expanded so that size of cell is 2x size of nucleus
      • Necrosis, hemorrhage, calcifications common
      • Undifferentiated subtype:
        • No neuropil or differentiation
        • Requires supplementary techniques (ex. Immune)
        • Pleomorphic subtype of undifferentiated subtype:
          • Large with pleomorphic nuclei
          • Prominent nucleoli
          • Moderate to abundant cytoplasm
          • Rhabdoid features maybe
      • Poorly-differentiated subtype:
        • Neuropil background evident
        • < 5% of cells show differentiation
        • Readily recognizable neuropil in background
      • Differentiating subtype:
        • >= 5% of cells show differentiation
    • Ganglioneuroblastoma (schwannian stroma-rich):
      • Foci of neuroblastic elements in an expanding Schwannian stroma comprising > 50% of tumour volume
        • Atypical variant of nodular ganglioneuroblastoma may consist of neuroblastomatous elements with only thin rim of ganglioneuromatous component
      • Neuroblastic foci composed of a mixture of neuroblastic cells with various stages of differentiation
      • Intermixed subtype:
        • Neuroblastic foci are not grossly visible
      • Nodular subtype:
        • Neuroblastic components are grossly visible
    • Signs of differentiation:
      • Ganglion cells
      • Schwannian stroma
    • Ganglioneuroma (schwannian stroma-dominant):
      • Predominantly Schwannian stroma with only individually distributed neuronal elements
        • No nesting of neuroblastomatous elements (differentiating neuroblasts, maturing and mature ganglion cells)
      • Maturing:
        • Presence of scattered foci of differentiating neuroblasts along with fully mature ganglion cells

 

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Neuron-specific enolase

 

 

Chromogranin A

 

 

Synapophysin

 

 

NFP

 

 

Nestin

High

Not specific

TrkA (NGFR)

Favorable prognostic

 

S100 (Schwann cells)

 

 

Tyrosine hydroxylase

 

Negative in Ewing usually

Protein gene product 9.5

 

 

GD2

 

 

NB84

 

 

CD99 (neg)

 

 

Desmin (neg)

 

 

LMWK (neg)

 

 

CD45 (neg)

 

 

Vimentin (neg)

Undifferentiated may be positive

 

 

Molecular features:

    • 17q gain (unfavorable)
    • 1p deletion (unfavorable)
    • 14q deletion (unfavorable)
    • 11q deletion (unfavorable)
    • N-myc amplification (2p) (unfavorable)
      • DMs and HSRs
      • Myc-max protein complex in the nucleus inhibits cellular differentiation and promotes proliferation and apoptosis
      • Usually seen in undifferentiated and poorly-differentiated neuroblastomas
      • Usually correlates with high MKI
      • Correlated with 1p deletions, esp. del(1p36.3)
      • Detected by FISH or Southern
      • May rarely be seen in other SRCTs or leukemia
    • DNA hyperdiploidy, near triploidy (favorable if < 1y )
    •  

 

Staging:

    • Stage 1:
      • complete gross excision (with or without microscopic residual)
      • non-adherent nodes are negative
    • Stage 2A:
      • Incomplete gross resection
      • Non-adherent nodes are negative
    • Stage 2B:
      • Positive ipsilateral nodes
      • Negative contralateral nodes
    • Stage 3:
      • Tumor crosses the midline OR positive contralateral nodes
    • Stage 4S:
      • Tumor does not cross the midline
      • Distant mets limited to skin, liver, and/or bone marrow (but not cortical bone; MIBG must be negative)
    • Stage 4:
      • Distant spread beyond 4S.

 

Prognostic Indicators:

Variable:

Favorable:

Unfavorable:

Stage

1, 2, 4S

3, 4

Age

<= 1.5 year

> 5 year

Histology

Differentiation

Low MK index (<=100/5000)

Calcification present

No differentiation

High MK index (>200/5000)

Calcification absent

DNA ploidy

Hyperdiploid

Near-triploid

Diploid or near-diploid

Near-tetraploid

N-myc

Not amplified

Amplified

(ratio of N-myc to centromere of 2 averages at least 10)

17q gain

Absent

Present

1p loss

Absent

Present

Trk-A expression (NGFR)

Present

Absent

Telomerase expression

Low/absent

Highly expressed

MRP expression

Absent

Present

CD44 expression

Present

Absent

Serum markers:

Ferritin

LDH

 

Normal

<=1500 U/mL

 

Elevated

>1500 U/mL

IPMN favorable/unfavorable histology (see table in reference)

 

 

 

Molecular features:

    • .

 

Other features:

    • EM:
      • Neurosecretory granules (dense core granules of neurosecretory type)
      • Neuritic processes with microtubules
    • Clinical features:
      • Abdominal mass
      • Spinal cord compression
      • Horner’s syndrome
      • Diarrhea (VIP)
      • Proptosis (orbital mass)
      • Cutaneous nodules
      • Ondine’s cures (impairment of autonomic control of respiration)
      • Opsoclonus-myoclonus syndrome (eye movements) (cross-reactive antibodies to cerebellum)
    • Elevation of urinary catecholamines
    • MIBG scan positive (85%)
    • Serum:
      • LDH (worse prognosis with high levels)
      • NSE (worse prognosis with high levels)
      • Ferritin (worse prognosis when elevated)

 

References:

    • Robbins & Cotran Pathologic Basis of Disease (2005)
    • WHO Pathology and Genetics of Tumours of the Nervous System (2000)
    • Joshi VV. Peripheral neuroblastic tumors: pathologic classification based on recommendations of international neuroblastoma pathology committee (Modification of shimada classification). Pediatr Dev Pathol. 3(2):184-99.