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Diagnosis and Treatment of Neuroblastoma

Definition

Neuroblastoma is a malignant embryonal tumor in children originating from cells of the adrenal medulla or the sympathetic trunk.

Epidemiology

Neuroblastoma is the most common extracranial tumor in children (10% of all childhood tumors). Inzidence 1/100.000. 75% of neuroblastomas arise before four years of age, and the median age of onset is 21 months.

Many neuroblastomas show spontaneous regression and are not clinically significant. In autopsy studies, smaller neuroblastomas are found 40 times more frequently than children develop clinical disease.

Pathology

Histological INPC classification:

Neuroblastic tumors consist of neuroblasts and Schwannian stroma. Depending on differentiation and stroma content, the following tumor types are distinguished: ganglioneuromas (with mature ganglion cells and dominant stroma), ganglioneuroblastomas (mixed), and neuroblastomas (immature cells with little stroma). Neuroblastomas with little Schwannian stroma have a poor prognosis.

Localization:

75% of tumors develop retroperitoneally from the adrenal gland or the sympathetic trunk. Possible are tumors of the neck, chest, or pelvis.

Metastasis:

70% of patients present with metastases at diagnosis.

Tumor stages of the International Neuroblastoma Staging System (INSS)

• Stage 1: localized tumor with complete gross excision with or without microscopic residual disease.
• Stage 2: localized tumor with incomplete gross excision. Stage 2A without ipsilateral lymph node metastasis, stage 2B with ipsilateral lymph node metastases.
• Stage 3: unresectable unilateral tumor infiltrating across the midline with or without regional lymph node metastases or
  Localized tumor with contralateral regional lymph node metastases.
• Stage 4: distant metastasis.
• Stage 4S: metastases in infants under one year of age (metastasis limited to skin, bone marrow (less than 10%) or liver) and a localized tumor stage 1–2B.

Signs and Symptoms of Neuroblastoma

• Abdominal pain and abdominal tumor.
• Signs of metastasis: bone pain, cough, respiratory distress, neurologic symptoms due to infiltration of the spinal cord, orbital metastasis with bleeding (raccoon eyes).
• Symptoms due to compression: urinary retention, constipation, respiratory distress.
• Paraneoplastic symptoms: paroxysmal hypertension, palpitations, headache due to catecholamine release. Watery diarrhea and hypokalemia due to secretion of VIP (vasoactive intestinal peptide). Myoclonia, nystagmus, and ataxia due to paraneoplastic antibodies.

Diagnosis

• 24-hour urine collection: elevated catecholamines or metanephrines in more than 90% of patients.
• Laboratory tests: neuron-specific enolase (NSE) is used as a nonspecific tumor marker.
• Imaging: abdominal CT or MRI. Chest CT and MIBG scintigraphy for staging.
• Bone marrow biopsy at multiple sites is necessary for correct grouping.
• Tumor biopsy: indicated in stages 3 and 4 if bone marrow biopsy is inconclusive. The final classification of the patients is only possible after genetic testing of the tumor.

Screening:

With urine tests, significantly more neuroblastomas are identified. However, screening did not reduce the proportion of advanced neuroblastomas and mortality in prospective controlled studies. Detecting clinically insignificant neuroblastomas showing natural regression explains the missing benefit. Screening with urine tests is not recommended.

Treatment of Neuroblastoma

Treatment is stratified by tumor stage (see above) and molecular genetic findings. Further molecular genetic markers are currently undergoing clinical testing.

Low-risk Neuroblastoma:

Low-risk neuroblastoma includes patients without MYCN amplification and INSS stage 1, INSS stage 2 without aberrations in chromosome 1p, INSS stage 3 under two years of age without aberrations in chromosome 1p, and INSS stage 4S. A localized primary tumor is surgically removed (if completely possible), or a surgical tumor biopsy is performed. Chemotherapy is only necessary for tumor-associated symptoms (weight loss, organ failure, spinal compression) and is discontinued once the disease is stable. Since the overall prognosis is excellent and spontaneous regression is likely, extensive surgery or radiotherapy is not indicated.

Intermediate-risk Neuroblastoma:

Intermediate-risk neuroblastoma includes patients without MYCN amplification and INSS stage 2 with aberrations of chromosome 1p, INSS stage 3 under two years of age with aberrations in chromosome 1p, INSS stage 3 over two years of age, and INSS stage 4 under 18 months of age. A localized primary tumor is surgically removed (if completely possible), or a surgical tumor biopsy is performed. Treatment includes induction chemotherapy (N5c and N6); if necessary, the primary tumor is removed during induction chemotherapy. Maintenance chemotherapy is necessary after induction chemotherapy. Additional radiotherapy is unnecessary in patients with complete remission.

High-risk Neuroblastoma:

High-risk neuroblastoma includes all patients over 18 months of age with stage 4 and all patients with MYCN amplification. A localized primary tumor is surgically removed (if completely possible), or a surgical tumor biopsy is performed. Further treatment consists of multimodal chemotherapy (induction chemotherapy with resection of the primary tumor if necessary – high-dose chemotherapy with autologous stem cell transplantation – and maintenance therapy with radiotherapy if necessary). Further options are scintigraphic therapy with iodine-131-MIBG and immunotherapy with the anti-GD2 antibody dinutuximab.

Prognosis

Tumor stages 1, 2, and 4S have a good prognosis (90% five-year survival or better), and many tumors show spontaneous regression without therapy. The prognosis of high-risk neuroblastoma (stage 4, age over 18 months, and MYCN amplification) is poor; despite intensive multimodal therapy, the survival rate is at most 50%.

References

Koyle u.a. 2001 KOYLE, M. A. ; HATCH, D. A. ; FURNESS, 3rd ; LOVELL, M. A. ; ODOM, L. F. ; KURZROCK, E. A.: Long-term urological complications in survivors younger than 15 months of advanced stage abdominal neuroblastoma.
In: J Urol
166 (2001), Nr. 4, S. 1455–8

Woods et al., Screening of infants and mortality due to neuroblastoma.
In: N Engl J Med
346 (2002), Nr. 14, S. 1041–6

T. Simon, “S1-Leitlinie: Neuroblastom.” [Online]. Available: https://register.awmf.org/assets/guidelines/025-008l_S1_Neuroblastom_2019-07_01.pdf

  Deutsche Version: Diagnose und Therapie des Neuroblastoms