Neuroblastoma: A Complete Review for Pediatric Oncologists

Introduction

Neuroblastoma is a complex and highly aggressive form of cancer that primarily affects young children, often appearing before the age of five. As one of the most common solid tumors outside the brain in children, neuroblastoma originates from the embryonic cells of the neural crest, which later develop into the sympathetic nervous system. This malignancy predominantly arises in the adrenal glands but can also occur in nerve tissues along the spine, chest, abdomen, or pelvis.

The diagnosis and treatment of neuroblastoma require a multidisciplinary approach, often involving pediatric oncologists, surgeons, radiologists, and pathologists. Due to its variable presentation and biological behavior, neuroblastoma presents unique challenges for clinicians. In this article, we will explore neuroblastoma in depth, covering its pathophysiology, clinical presentation, diagnostic workup, treatment modalities, and prognosis, providing healthcare professionals with a detailed understanding of this aggressive pediatric cancer.

Pathophysiology of Neuroblastoma

Neuroblastoma arises from neural crest cells, which are multipotent progenitor cells that give rise to the peripheral nervous system. These cells are typically involved in the development of the sympathetic nervous system, and neuroblastomas most commonly originate in the adrenal medulla (a component of the adrenal glands). However, these tumors can also develop in sympathetic ganglia, located along the spinal column from the neck to the pelvis.

One of the hallmarks of neuroblastoma is its biological heterogeneity. Some neuroblastomas can spontaneously regress, particularly in infants, while others may progress rapidly, even with aggressive treatment. The tumor’s behavior is closely associated with its genetic and molecular features.

Genetic Factors
The most important genetic abnormality associated with neuroblastoma is the amplification of the MYCN oncogene. MYCN amplification is found in approximately 20-25% of neuroblastoma cases and is a strong prognostic factor for poor outcomes. MYCN is a transcription factor that regulates cell proliferation and survival, and its overexpression is linked to more aggressive tumor behavior.

Additionally, other chromosomal aberrations, such as deletions of chromosome 1p and 11q, are often seen in neuroblastoma and are associated with poor prognosis. In contrast, tumors without MYCN amplification and with favorable genetic profiles tend to have a more indolent course.

Tumor Differentiation
Neuroblastomas exhibit varying degrees of differentiation. Well-differentiated tumors, known as ganglioneuromas, are benign and contain mature ganglion cells. On the other hand, poorly differentiated neuroblastomas are highly aggressive and contain immature neuroblasts. This differentiation is critical in determining the tumor’s clinical behavior and the patient’s prognosis.

Epidemiology of Neuroblastoma

Neuroblastoma is a rare cancer, but it is the most common extracranial solid tumor in children. It accounts for approximately 6-10% of all childhood cancers and around 15% of cancer-related deaths in children. In terms of incidence, there are approximately 700 new cases of neuroblastoma diagnosed annually in the United States, and the disease predominantly affects infants and young children, with a median age at diagnosis of 17 months.

The incidence of neuroblastoma decreases significantly with age, and it is rare in adults. Most cases are sporadic, but familial neuroblastoma accounts for about 1-2% of cases and follows an autosomal dominant inheritance pattern with incomplete penetrance.

Clinical Presentation

The clinical presentation of neuroblastoma is highly variable and depends on the tumor’s location, size, and extent of metastasis. Neuroblastomas can manifest with a wide array of signs and symptoms, ranging from asymptomatic masses to severe, life-threatening complications.

1. Abdominal Mass

The most common presentation of neuroblastoma is an abdominal mass, often in the region of the adrenal gland. Parents may notice a firm, non-tender lump in the child’s abdomen. This mass can grow large enough to cause discomfort, abdominal distention, and even bowel or bladder dysfunction.

2. Paraspinal Tumors and Neurological Symptoms

Tumors arising from the sympathetic chain along the spine can invade nearby structures, leading to neurological symptoms. Paraspinal neuroblastomas may compress the spinal cord, resulting in symptoms such as weakness, paralysis, or sensory loss in the lower extremities.

3. Metastatic Disease

Neuroblastoma has a high propensity for metastasis, and many patients present with disseminated disease. Common metastatic sites include bone marrow, bones, liver, lymph nodes, and skin. In advanced cases, children may exhibit systemic symptoms such as:

• Bone pain due to skeletal metastasis.
• Periorbital ecchymoses, also known as "raccoon eyes," a sign of orbital metastasis.
• Hepatomegaly (enlarged liver) and respiratory distress due to extensive liver involvement, especially in infants.
• "Blueberry muffin" appearance, where the skin develops bluish nodules due to cutaneous metastases.

4. Paraneoplastic Syndromes

In rare cases, neuroblastoma can be associated with paraneoplastic syndromes, such as opsoclonus-myoclonus syndrome (OMS), characterized by rapid, involuntary eye movements (opsoclonus) and jerky movements of the extremities (myoclonus). OMS is believed to result from an autoimmune response to neuroblastoma cells.

Diagnostic Workup

The diagnosis of neuroblastoma requires a comprehensive evaluation, including clinical, radiological, and laboratory investigations.

1. Imaging Studies

Initial imaging studies are crucial for detecting the primary tumor and assessing the extent of disease.

• Ultrasound is often the first imaging modality used to detect an abdominal mass in young children.
• Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) provide detailed information about the tumor’s size, location, and involvement of surrounding structures. MRI is particularly useful for evaluating paraspinal tumors and detecting spinal cord compression.
• Metaiodobenzylguanidine (MIBG) Scan: MIBG is a norepinephrine analog that selectively accumulates in neuroblastoma cells. MIBG scintigraphy is a sensitive imaging technique for detecting primary tumors and metastatic sites, particularly in bone marrow and bones.

2. Biopsy and Histopathology

A tissue biopsy is essential for confirming the diagnosis of neuroblastoma. The biopsy specimen is examined under a microscope, and immunohistochemical staining can confirm the presence of neuroblastoma cells. Key markers include neuron-specific enolase (NSE), chromogranin, and synaptophysin. Additionally, the degree of differentiation and the presence of mitotic-karyorrhectic index (MKI) are evaluated to classify the tumor's aggressiveness.

3. Urine Catecholamines

Neuroblastoma cells produce catecholamines, and elevated levels of catecholamine metabolites, such as vanillylmandelic acid (VMA) and homovanillic acid (HVA), in the urine are often indicative of neuroblastoma. Urine catecholamine testing is non-invasive and can be used both for diagnosis and monitoring treatment response.

4. Bone Marrow Biopsy

Given neuroblastoma’s propensity for bone marrow involvement, a bone marrow biopsy is commonly performed to assess the extent of metastatic disease. Bone marrow infiltration is a common finding in advanced-stage neuroblastoma.

Staging and Risk Stratification

The prognosis of neuroblastoma largely depends on the stage of the disease at diagnosis, the patient’s age, and the tumor's genetic profile. Several staging systems are used to classify neuroblastoma, with the International Neuroblastoma Staging System (INSS) being the most widely accepted.

INSS Staging

1. Stage 1: Localized tumor with complete gross excision and no lymph node involvement.
2. Stage 2A: Localized tumor with incomplete excision and no lymph node involvement.
3. Stage 2B: Localized tumor with or without complete excision, with ipsilateral lymph node involvement.
4. Stage 3: Tumor crossing the midline or with contralateral lymph node involvement.
5. Stage 4: Metastatic disease involving distant lymph nodes, bone marrow, liver, or skin.
6. Stage 4S: A unique subset for infants under 1 year of age with localized primary tumors and metastasis limited to the liver, skin, and bone marrow. These tumors often have a favorable prognosis and may regress spontaneously.

Risk Stratification

Patients with neuroblastoma are classified into low, intermediate, and high-risk groups based on a combination of factors:

• Age at diagnosis: Infants under 18 months generally have a better prognosis.
• MYCN status: MYCN amplification is a strong predictor of poor outcome.
• Histopathological classification: The degree of differentiation and mitotic index are important prognostic factors.
• Chromosomal abnormalities: Certain genetic markers, such as 1p and 11q deletions, are associated with worse outcomes.

Treatment Modalities

The treatment of neuroblastoma is highly individualized and depends on the risk group classification. Treatment typically involves a combination of surgery, chemotherapy, radiation therapy, and, in some cases, stem cell transplantation.

1. Surgery

Surgical resection is the primary treatment for localized neuroblastoma. In low-risk patients, complete excision of the tumor may be curative. However, in high-risk or metastatic cases, surgery is often combined with chemotherapy to shrink the tumor before resection.

2. Chemotherapy

Chemotherapy is a cornerstone of neuroblastoma treatment, particularly for intermediate and high-risk patients. Commonly used chemotherapy agents include:

• Cyclophosphamide
• Doxorubicin
• Vincristine
• Cisplatin

In high-risk cases, chemotherapy is given in high doses, often followed by autologous stem cell transplantation to restore bone marrow function.

3. Radiation Therapy

Radiation therapy is typically reserved for high-risk neuroblastoma, particularly when complete surgical resection is not possible or when there is a risk of recurrence. Radiation is also used for palliation in cases of bone metastasis.

4. Immunotherapy

Recent advances in immunotherapy have shown promise in the treatment of high-risk neuroblastoma. Anti-GD2 monoclonal antibodies, such as dinutuximab, target a surface antigen expressed on neuroblastoma cells. When combined with cytokines and other therapies, immunotherapy can improve survival rates in high-risk patients.

5. Stem Cell Transplantation

Autologous stem cell transplantation is often performed after high-dose chemotherapy in patients with high-risk neuroblastoma. This procedure aims to rescue the bone marrow and improve long-term survival.

6. Retinoid Therapy

13-cis-retinoic acid (isotretinoin) is used as maintenance therapy in high-risk patients to promote the differentiation of residual neuroblastoma cells, reducing the risk of relapse.

Prognosis

The prognosis of neuroblastoma varies widely depending on the stage and biological characteristics of the tumor. Overall, the survival rates for neuroblastoma have improved significantly over the past few decades, particularly for low and intermediate-risk patients. The 5-year survival rate for low-risk neuroblastoma exceeds 90%, while the survival rate for high-risk cases remains lower, around 40-50%, despite aggressive treatment.

In infants with stage 4S disease, the prognosis is excellent, and many tumors spontaneously regress without intensive treatment.

Conclusion

Neuroblastoma remains a challenging pediatric malignancy, particularly in high-risk patients with aggressive disease. While advancements in chemotherapy, surgery, and immunotherapy have improved outcomes, there is still much to be done in understanding the genetic and molecular mechanisms underlying this complex cancer. Early diagnosis, appropriate risk stratification, and a multidisciplinary approach are essential in providing the best possible care for children affected by neuroblastoma.