Clinical Futures

• Belong to the family of neuroblastic tumors that include ganglioneuromas, ganglioneuroblastomas and neuroblastomas. Neuroblastic tumors are of the sympathetic nervous system that originate 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.

Gross Findings

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.

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

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

• Deletion of 1p36.1-2

• N-myc amplification

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.

• 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.

• Certain genetic factors can also affect the 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. Deletion of the short arm of chromosome 1 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.

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

• http://enjoypath.com/sp/case-37/case-37.htm