Neuroblastoma

Definition

• A neuroblastic, Schwannian stroma-poor tumors; the proportion of tumor tissue with stroma-rich histology should not exceed 50%.

Clinical Futures

• Belong to the family of neuroblastic tumors that include ganglioneuromas, ganglioneuroblastomas and neuroblastomas. Neuroblastic tumors are of the sympathetic nervous system that originates from neural crest sympathogonia.

• Neuroblastoma is the most common extracranial pediatric solid neoplasm and the third most common pediatric malignancy after leukemia and CNS tumors. The incidence in USA is about 8.7 per million.

• Most cases (88%) less than 5-year-old, median age 21 months.

• Neuroblastomas can arise from anywhere along the sympathetic chain. They most commonly occur in the adrenal medulla (35-38%). Usually only one adrenal gland is involved, and bilateral involvement is rare, followed by extraadrenal in the abdomen (30%), and thorax (14-20%).

• They have been associated with a number of disorders, such as Hirschsprung disease, fetal alcohol syndrome, DiGeorge syndrome, Von Recklinghausen disease, and Beckwith-Wiedemann syndrome.

• Approximately 45-54% of patients with neuroblastoma have a palpable abdominal mass. These patients may have abdominal pain. Nearly 10% of patients develop hypertension as a result of renal vein compression. Hypertension in patients with neuroblastoma may also be related to renal arterial compression and excess catecholamine production. Extradural extension of neuroblastomas can present with focal or diffuse paralysis and bowel or bladder dysfunction. Pelvic neuroblastomas can also cause bowel or bladder dysfunction.

• Unusual manifestations or associations with childhood neuroblastoma: (1), "blueberry muffin" baby with cutaneous metastasis; (2), opsoclonus/myoclonus, 2-7%; (3), alopecia; (4), heterochromia iridis; (5), Horner's syndrome; (6), Watery diarrhea due to secretion of VIP, 6%; (7), Asymmetric crying syndrome; (8), Cushing's syndrome.

• Two thirds of patients with neuroblastoma present with metastases at the time of diagnosis. Hutchinson syndrome:  bone metastases with limping and irritability. Pepper syndrome: massive liver metastases.

Gross Findings

• Gross specimens of neuroblastomas can appear well circumscribed or infiltrative. They do not have capsules. They range from minute nodules or in situ lesions to large masses weighing more than 1 kg.

• Calcification may be apparent on gross inspection as punctuate, opaque foci, or a gritty sensation.

Microscopic Findings

• Architectural patterns: lobular growth with delicate and often incomplete fibrovascular septa (not as well developed as in pheochromocytoma); May have more diffuse or solid areas;

• Cytological morphology: tumor cells are small, round or ovoid with little cytoplasm; nuclei are dark with small indistinct nucleoli, and the chromatin is dispersed with a "salt and pepper" pattern. Homer-Wright rosettes, circular, ovoid or angular zones of pale-stained fibrillary material that is surrounded by tumor cells. They are typical of neuroblastomas but are not present in all cases.

• Alterations in stroma: hemorrhage, necrosis, calcification or cystic changes can be present.

• Three histology subtypes

  • Neuroblastoma, undifferentiated:

    • Tumor cells: small-to-medium in size, with indiscernible-to-thin rims of cytoplasm and vaguely defined cytoplasmic borders.

    • Nuclei: vary in shape, rounded to elongated, salt-and-pepper chromatin,  may contain distinct nucleoli.

    • Absent background neuropil.

  • Neuroblastoma, poorly differentiated:

    • With a background of variable neuropils.

    • More importantly: <5% differentiating neuroblasts.

  • Neuroblastoma, differentiating:

    • Abundant neuropil, >5% differentiating neuroblasts.

Differential Diagnosis

• Ewing's sarcoma: t(11;22)(q24;q12)

• Desmoplastic small round cells tumor: t(11;22)(p13;q12 or q11.2)

• Malignant rhabdoid tumor.

• Acute lymphocytic/myeloid lymphoma/leukemia for undifferentiated neuroblastoma.

• Pheochromocytoma

Immunohistochemical Findings

• Positive for NSE, chromogranin A, synaptophysin, microtubule-associated proteins (MAP-1 or MAP-2), S100+ in stellate to dendritic cells adjacent to the vessels;

Electron Microscope

• Small, dense core neurosecretory granules can be identified, but usually sparse; neurofilaments (8-12nm) and neurotubules (24-26 nm in diameter) can be seen.

Cytogenetic Studies

• Del(1p36.1-2 )

• N-myc amplification

Prognosis

• Age: better prognosis if <1.5 years old.

• MKI: <2% good prognosis, 2-4% intermediate, >4% unfavorable.

• N-MYC amplification, unfavorable prognosis. N-MYC is a proto-oncogene located on chromosome arm 2p. If it is present in multiple copies (10 or more), it promotes rapid tumor growth and indicates a bad prognosis.

• Del(1p36.1-2) , bad prognpsis. This deletion causes rapid tumor growth due to a presumed loss of a tumor suppressor gene, indicating a bad prognosis.

• Cells with normal or near normal DNA content (DNA index = 1) are associated with aggressive tumor activity. Hyperdiploid cells (DNA index >1) are associated with a better prognosis since this DNA complement may stimulate the proliferation of Schwann cells and promote maturity. More stroma, less nodules of immature neuroblastic cells, better prognosis.

• High HVA, good prognosis. Neuroblastomas exhibit a great variety of tumor biologic behaviors that can be used to determine a patient's prognosis. About 95% of neuroblastomas secrete catecholamines (vanillylmandelic acid [VMA] and homovanillic acid [HVA]). HVA is a dopamine metabolite and is a more mature catecholamine than VMA, which is a metabolite of epinephrine and norepinephrine. Increased levels of HVA in the urine are correlated with maturity of the tumor and an improved prognosis. Nearly 7% of neuroblastomas secrete vasoactive intestinal peptide (VIP). These tumors are more mature; therefore, patients with VIP-producing tumors have a prognosis better than that of other patients. Elevated levels of serum ferritin (>142 ng/mL) and neurospecific enolase (>100 ng/mL) are associated with a bad prognosis.

Reference

• Rha SE, Byun JY, Jung SE, et al: Neurogenic tumors in the abdomen: tumor types and imaging characteristics. Radiographics 2003 Jan-Feb; 23(1): 29-43

• AFIP, Tumor of the adrenal gland and extra-adrenal paraganglia, 3rd series

• http://www.webpathology.com/ (For gross and slides of ganglioneuroma)

• http://www.emedicine.com/radio/topic293.htm

• http://www.emedicine.com/RADIO/topic472.htm

• Cancer 1999;86:349-63