Neuroblastoma

Neuroblastoma is a malignancy that arises from the neural crest cell derivatives along the sympathetic chain (neuroblasts) and is most commonly located in the adrenal medulla. The tumor often presents in childhood with a flank mass that crosses the midline. Neuroblastoma can also manifest as opsoclonus-myoclonus paraneoplastic syndrome. The tumor is diagnosed through biopsy, and supporting data include measuring the catecholamine breakdown products such as vanilmandelic acid (VMA) and homovanillic acid (HVA) in urine. Imaging studies are needed to localize the tumor. Management depends on several factors such as the stage of malignancy and the patient’s age at the time of diagnosis. Prognosis is favorable in the early stages of neuroblastoma.

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Overview

Definition

Neuroblastoma, an extracranial malignant solid tumor, is a neuroendocrine malignancy originating from sympathetic nervous system stem cells (neuroblasts).

Classification of nervous system tumors

Table: Classification of nervous system tumors
Categories Specific tumors
Neuroepithelial tumors in the CNS
  • Astrocytomas, including glioblastoma multiforme
  • Oligodendroglioma
  • Ependymoma and choroid-plexus tumors
  • Medulloblastomas (embryonal tumors)
Meningeal tumors
  • Meningiomas
  • Hemangioblastomas
Sellar region tumors
  • Craniopharyngioma
  • Pituitary adenoma
  • Pinealoma/pinealoblastoma
Primary CNS lymphoma Primary CNS lymphoma
Metastasis to the brain (5x more common than primary brain tumors) Most commonly arising from:
  • Lung, breast, and renal cell carcinomas
  • Melanoma
Peripheral tumors
  • Schwannomas, including acoustic neuroma
  • Neuroblastoma

Epidemiology

  • Prevalence: 1 in 7,000 live births
  • 3rd most common malignancy in children < 14 years of age, after CNS tumors and leukemia 
  • Most patients have metastatic disease by the time of diagnosis.
  • Mean age at diagnosis: 1–3 years 
  • More common in boys than girls

Etiology

  • Personal risk factors: genetic syndromes such as Beckwith-Wiedemann syndrome, neurofibromatosis, Hirschprung disease, and Turner syndrome
  • Maternal risk factors: opioid use, folate deficiency, and gestational diabetes mellitus
  • Genetics:
    • Amplification of N-Myc protooncogene: growth-promoting transcription factor, the overexpression of which causes unregulated cellular proliferation
    • Deletion of 1p chromosomal region: Tumor suppressor gene KIF1B is present in this chromosomal region.

Clinical Presentation

  • Nonspecific symptoms:
    • Low-grade fever
    • Anorexia and weight loss
    • Hypertension:
      • Most commonly caused by renal artery compression by neuroblastoma
      • Renal arterial compression activates RAAS.
      • Activated RAAS causes vasoconstriction and sodium retention.
      • Less commonly caused by catecholamine secretion from neuroblastoma
  • Location-specific symptoms: 
    • Abdomen (most common location of tumor):
      • Irregular flank mass that crosses the midline (unlike Wilms tumor, which does not cross the midline)
      • Abdominal pain
    • Chest:
      • Neuroblastoma in chest arises from paravertebral ganglia.
      • Back pain, weakness, and sensory loss due to spinal cord compression
      • Shortness of breath and inspiratory stridor due to tracheal compression
    • Orbit: periorbital ecchymosis (“racoon eyes”) due to bleeding in the periorbital soft tissue
    • Neck:
      • Horner syndrome due to compression of the sympathetic plexus
      • Nodules under the skin
    • Bone pain
  • Paraneoplastic syndromes:
    • Opsoclonus-myoclonus syndrome (dancing eyes–dancing feet syndrome): characterized by irregular eye movements, ataxia, and rhythmic jerking motions of the limbs
    • Hypertension: due to catecholamine secretion
    • Diarrhea: due to vasoactive intestinal peptide (VIP) production

Diagnosis

Laboratory studies

  • Urine: increased catecholamine (e.g., homovanillic acid (HVA), vanillylmandelic acid (VMA)) breakdown products in 24-hour urine 
  • Blood:
    • Increased catecholamine breakdown products (HVA, VMA, dopamine)
    • Increased neuron-specific enolase (NSE)
    • Increased ferritin and lactate dehydrogenase (LDH)
  • Renal function tests: Evaluate for renal metastasis.
  • Liver function tests: Evaluate for hepatic metastasis.

Imaging studies

  1. Abdominal ultrasound to identify neuroblastoma in the adrenal medulla
  2. MRI or CT scan are alternative imaging studies for abdominal ultrasound.
  3. Metaiodobenzylguanidine (MIBG) scan:
    • MIBG is chemically similar to norepinephrine.
    • MIBG is taken up by neuroblastoma or pheochromocytoma cells.

Biopsy

  • Biopsy is confirmatory for the diagnosis.
  • Sample is evaluated for amplification of MYCN protooncogene.
  • Sample is evaluated for NSE and bombesin positivity.
  • Sample is evaluated for Homer Wright pseudorosettes:
    • Tumor cells surrounding the neuropil
    • Seen in neuroblastoma, medulloblastoma, and primitive neuroectodermal tumors
Neuroblastoma gross and histologic appearance

Neuroblastoma in gross and histologic appearance: macroscopic (left) and microscopic (right) images of neuroblastoma

Image: “Radiological and pathological findings of a metastatic composite paraganglioma with neuroblastoma in a man: a case report” by Fritzsche FR, Bode PK, Koch S, Frauenfelder T. License: CC BY 2.0

Staging (international neuroblastoma staging system)

  • Stage 1:
    • Localized malignancy
    • No ipsilateral lymph node metastasis
  • Stage 2A:
    • Localized malignancy with an incomplete resection
    • No ipsilateral lymph node metastasis
  • Stage 2B:
    • Localized malignancy
    • Ipsilateral lymph node metastasis
  • Stage 3: malignancy with contralateral lymph node metastasis or tumor crossing midline or tumor with bilateral lymph node involvement
  • Stage 4:
    • Malignancy with distant metastasis (e.g., skin, liver)
    • Metastases other than those defined in stage 4S
  • Stage 4S: malignancy in infants < 12 months with metastasis confined to skin, liver, or bone marrow

Management

Management of neuroblastoma depends on whether the patient is considered to have a low-, intermediate-, or high-risk neuroblastoma. Localized disease is often curable. 

Risk stratification depends on the stage of the malignancy at the time of the diagnosis, MYCN amplification, chromosome 1p deletion, and age at the time of the diagnosis (later age of diagnosis = worse prognosis).

Low-risk neuroblastoma

  • Observation for:
    • Early-stage neuroblastoma without MYCN amplification
    • Stage 4S neuroblastoma
  • Treatment: surgical excision

Intermediate-risk neuroblastoma

  • Preoperative chemotherapy 
  • Surgical excision
  • Postoperative chemotherapy
  • Consider radiation therapy if neuroblastoma progresses after surgery and chemotherapy.

High-risk neuroblastoma

  • Chemotherapy: Preoperative chemotherapy is considered for downstaging a large tumor.
  • Surgical excision
  • Radiation therapy
  • Bone marrow/hematopoietic stem cell transplantation
  • Additional therapy:
    • Dinutuximab: monoclonal antibody against GD2 ganglioside expressed on neuroblastoma cells
    • IL-2
    • Cis-retinoic acid

Differential Diagnosis

  • Wilms tumor: malignancy, also known as nephroblastoma, caused by the proliferation of metanephric blastema in the kidneys and the most common renal malignancy in children. Wilms tumor commonly presents as a firm, nontender, smooth RUQ abdominal mass that does not cross the midline. The tumor is diagnosed with abdominal ultrasonography and histopathologic studies (from biopsy or resection). Wilms tumor is most often treated with nephrectomy and chemotherapy. Unlike neuroblastoma, WIlms tumor rarely causes calcification and is seen in older children (average age of diagnosis between 3 and 5 years of age).
  • Pheochromocytoma: a catecholamine-secreting tumor derived from chromaffin cells. The majority of these tumors originate in the adrenal medulla but can also arise from sympathetic ganglia. Symptoms include episodic hypertension, tachycardia, headache, and sweating. The classic triad of symptoms is headache, diaphoresis, and tachycardia. Pheochromocytoma is diagnosed by measuring the catecholamine breakdown products (e.g., HVA, VMA, metanephrine) in the blood or 24-hour urine. Treatment is surgical excision. Patients with a complete resection have a good prognosis. Unlike neuroblastoma, pheochromocytoma causes significant sympathetic symptoms.
  • Burkitt lymphoma: a non-Hodgkin B cell lymphoma that presents in adolescents and young adults. This malignancy is caused by dysregulation of the c-Myc gene. Burkitt lymphoma presents either as a jaw lesion in endemic form or pelvic or abdominal lesion in sporadic form. Burkitt lymphoma may also be associated with HIV and EBV. The disease is diagnosed with a lymph node biopsy, which usually shows a “starry sky” pattern of large, pale, tingible-body macrophages. Treatment is mostly chemotherapy. The cure rate is excellent with appropriate treatment. Unlike neuroblastoma, patients with Burkitt lymphoma are often immunocompromised (e.g., HIV) and present in their adolescent or young-adult years.
  • Rhabdomyosarcoma: malignancy composed of rhabdomyoblasts, which come from mesenchymal cells that are unable to complete normal development as myocytes. The majority of cases develop in children. This neoplasm is most often found in the head, neck, genitourinary area, or extremities. Treatment depends on the tumor location and extent of disease. Treatment options include chemotherapy, surgery, and radiation. The prognosis is poor as this is an aggressive cancer. Unlike neuroblastoma, rhabdomyosarcoma less commonly develops in the abdomen.

References

  1. Shohet, J.M., Nuchtern, J.G. (2020). Clinical presentation, diagnosis, and staging evaluation of neuroblastoma. UpToDate. Retrieved May 24, 2021, from https://www.uptodate.com/contents/clinical-presentation-diagnosis-and-staging-evaluation-of-neuroblastoma
  2. Shohet, J.M., Lowas, S.R. (2020). Treatment and prognosis of neuroblastoma. UpToDate. Retrieved May 24, 2021, from https://www.uptodate.com/contents/treatment-and-prognosis-of-neuroblastoma?search=neuroblastoma
  3. Joyner, B.D. (2021). Neuroblastoma: Practice essentials, background, history of the procedure. Medscape. Retrieved May 24, 2021, from https://emedicine.medscape.com/article/439263-overview

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