Neuroblastoma in Childhood
Neuroblastoma in Childhood
Key Points:
- Neuroblastoma is the most common extracranial solid tumor in children
- It accounts for about 7-10% of all pediatric cancers
- Median age at diagnosis is 17 months; rarely occurs after age 10
- Arises from neural crest cells of the sympathetic nervous system
- Highly variable in clinical presentation and prognosis
- Risk stratification is crucial for treatment planning
Neuroblastoma is a complex and heterogeneous malignancy that arises from neural crest cells of the sympathetic nervous system. It is the most common extracranial solid tumor in children and the most frequently diagnosed cancer in infants. Neuroblastoma can develop anywhere along the sympathetic nervous system, but most commonly originates in the adrenal medulla or paraspinal ganglia.
The clinical behavior of neuroblastoma is remarkably variable, ranging from spontaneous regression to aggressive metastatic disease. This variability is largely attributed to the tumor's biological and genetic characteristics, which play a crucial role in determining prognosis and guiding treatment decisions.
Pathophysiology
Neuroblastoma develops from neural crest cells, which are embryonic cells that normally differentiate into various components of the sympathetic nervous system. The pathophysiology of neuroblastoma involves several key processes:
- Genetic Alterations:
- MYCN amplification: Present in about 20% of cases, associated with poor prognosis
- ALK mutations: Found in about 14% of sporadic cases and most familial cases
- Chromosomal abnormalities: e.g., 1p deletion, 11q deletion, 17q gain
- Impaired Differentiation: Neuroblastoma cells fail to differentiate properly, leading to the accumulation of immature neuroblasts
- Altered Cell Signaling: Dysregulation of key signaling pathways involved in cell growth, survival, and differentiation
- Tumor Microenvironment: Interactions between tumor cells and surrounding stroma contribute to tumor growth and metastasis
- Catecholamine Production: Many neuroblastomas produce catecholamines, leading to elevated levels of urinary catecholamine metabolites
Understanding the pathophysiology of neuroblastoma is crucial for developing targeted therapies and improving risk stratification. Recent advances in molecular profiling have led to the identification of key genetic and biological factors that influence tumor behavior and treatment response.
Clinical Presentation
The clinical presentation of neuroblastoma is highly variable and depends on the primary tumor location, presence of metastases, and any paraneoplastic syndromes. Common signs and symptoms include:
- Abdominal Mass:
- Most common presentation, often discovered incidentally
- May cause abdominal pain, distension, or constipation
- Respiratory Symptoms:
- Dyspnea or persistent cough in thoracic tumors
- Neurological Symptoms:
- Spinal cord compression from paraspinal tumors
- Horner's syndrome in cervical or thoracic tumors
- Bone Pain: In cases with bone metastases
- Constitutional Symptoms:
- Fever, weight loss, fatigue
- More common in advanced disease
- Paraneoplastic Syndromes:
- Opsoclonus-myoclonus syndrome: Rapid eye movements, ataxia, and myoclonus
- Vasoactive intestinal peptide (VIP) secretion: Causing watery diarrhea
- Metastatic Sites:
- Orbital metastases: Periorbital ecchymoses ("raccoon eyes")
- Skin metastases: Subcutaneous nodules
- Bone marrow involvement: Pancytopenia
It's important to note that some cases of neuroblastoma, particularly in infants, may be asymptomatic and discovered during routine examinations or prenatal ultrasounds. The diverse clinical presentations underscore the importance of maintaining a high index of suspicion, especially in young children with unexplained symptoms or masses.
Large abdominal mass and petechiae, purpura due to DIC in patient with neuroblastoma. (source)
Diagnosis
The diagnosis of neuroblastoma involves a comprehensive approach, including clinical evaluation, imaging studies, laboratory tests, and pathological analysis. The diagnostic process typically includes:
- Clinical Examination:
- Thorough physical examination, including neurological assessment
- Evaluation for signs of metastatic disease or paraneoplastic syndromes
- Imaging Studies:
- Computed Tomography (CT) or Magnetic Resonance Imaging (MRI): To visualize primary tumor and regional spread
- Metaiodobenzylguanidine (MIBG) Scintigraphy: Highly specific for neuroblastoma, used for staging and response assessment
- Positron Emission Tomography (PET): May be used if MIBG is negative
- Bone Scan: To evaluate for bone metastases
- Laboratory Tests:
- Urine Catecholamine Metabolites: Elevated homovanillic acid (HVA) and vanillylmandelic acid (VMA)
- Serum Markers: Lactate dehydrogenase (LDH), ferritin, neuron-specific enolase (NSE)
- Complete Blood Count: To assess for bone marrow involvement
- Tumor Biopsy:
- Essential for definitive diagnosis and biological characterization
- May be core needle biopsy, open biopsy, or complete resection if feasible
- Bone Marrow Aspiration and Biopsy:
- To evaluate for metastatic disease
- Bilateral samples are recommended
- Pathological Analysis:
- Histopathology: To confirm diagnosis and assess tumor differentiation
- Immunohistochemistry: For tumor marker expression (e.g., synaptophysin, chromogranin A)
- Molecular and Genetic Studies:
- MYCN amplification status
- DNA ploidy
- Chromosomal abnormalities (e.g., 1p deletion, 11q deletion, 17q gain)
- ALK mutation analysis
Histopathology demonstrating sheets of neuroblastoma cells infiltrating pancreatic parenchyma (hematoxylin and eosin stain, × 33 [A], and × 132 [B]).a 21-month-old female presenting to the neurology clinic with ataxia and erratic eye movements.Metaiodobenzylguanidine scan demonstrates focal intense uptake in the pancreatic body.The patient's diagnosis was confirmed with biopsy, and her malignancy responded well to conventional chemotherapy. (source)
The combination of these diagnostic modalities allows for accurate diagnosis, staging, and risk stratification, which are crucial for determining the appropriate treatment strategy and prognosis.
Staging and Risk Stratification
Accurate staging and risk stratification are crucial for treatment planning in neuroblastoma. The International Neuroblastoma Risk Group (INRG) Staging System and Classification are widely used:
INRG Staging System:
- L1: Localized tumor confined to one body compartment and with no image-defined risk factors (IDRFs)
- L2: Locoregional tumor with one or more IDRFs
- M: Distant metastatic disease (except MS)
- MS: Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow
Risk Stratification:
Risk group assignment is based on a combination of factors:
- INRG stage
- Age at diagnosis
- Histologic category
- Grade of tumor differentiation
- MYCN status
- 11q aberration
- DNA ploidy
Patients are classified into four risk groups:
- Very Low Risk
- Low Risk
- Intermediate Risk
- High Risk
This risk stratification guides treatment intensity and helps predict prognosis. It is a dynamic process, and ongoing research continues to refine and improve risk assessment strategies.
Treatment
Treatment of neuroblastoma is risk-adapted and may involve a combination of surgery, chemotherapy, radiation therapy, immunotherapy, and differentiation therapy. The specific treatment plan depends on the risk group classification:
1. Very Low and Low-Risk Disease:
- Observation alone for some asymptomatic infants (spontaneous regression may occur)
- Surgery alone for resectable tumors
- Minimal chemotherapy for symptomatic or progressive disease
2. Intermediate-Risk Disease:
- Combination of surgery and moderate-intensity chemotherapy
- Radiation therapy in select cases
3. High-Risk Disease:
- Intensive multimodal therapy, including:
- Induction chemotherapy
- Surgery
- High-dose chemotherapy with autologous stem cell rescue
- Radiation therapy
- Immunotherapy with anti-GD2 antibodies
- Differentiation therapy with isotretinoin
Specific Treatment Modalities:
- Surgery:
- Complete resection when possible
- May be performed upfront or after neoadjuvant chemotherapy
- Chemotherapy:
- Common agents: Cisplatin, etoposide, doxorubicin, cyclophosphamide, vincristine
- Intensity varies based on risk group
- Radiation Therapy:
- External beam radiation to primary site and areas of residual disease
- MIBG therapy for refractory or relapsed disease
- Immunotherapy:
- Anti-GD2 monoclonal antibodies (e.g., dinutuximab) combined with cytokines (GM-CSF, IL-2)
- Significantly improves survival in high-risk patients
- Differentiation Therapy:
- Isotretinoin (13-cis-retinoic acid) to induce tumor cell differentiation
- Targeted Therapies:
- ALK inhibitors for ALK-mutated tumors
- MTOR inhibitors and other targeted agents under investigation
Treatment of neuroblastoma is complex and often requires a multidisciplinary approach. Clinical trials investigating novel therapies and treatment strategies are ongoing, aiming to improve outcomes while minimizing long-term toxicities.
Prognosis
The prognosis for children with neuroblastoma varies widely depending on several factors:
- Risk Group: The most significant prognostic factor
- Age at Diagnosis: Generally better prognosis for children <18 months
- MYCN Status: MYCN amplification associated with poor prognosis
- Tumor Biology: Favorable histology and higher degree of differentiation associated with better outcomes
- Stage: Localized disease has better prognosis than metastatic disease
- Response to Initial Therapy: Early response often predictive of long-term outcome
Overall survival rates vary significantly based on risk group:
- Very Low and Low-Risk: >95% 5-year overall survival
- Intermediate-Risk: 90-95% 5-year overall survival
- High-Risk: 40-50% 5-year overall survival with current multimodal therapy
It's important to note that even within risk groups, individual outcomes can vary. Some specific prognostic considerations include:
- Spontaneous Regression: Observed in some infants with localized disease or 4S/MS stage
- Opsoclonus-Myoclonus Syndrome: Associated with better tumor prognosis but risk of long-term neurological sequelae
- ALK Mutations: May be associated with more aggressive disease but also offer potential for targeted therapy
- Relapsed Disease: Generally poor prognosis, especially in high-risk patients
Long-term follow-up is essential due to the risk of late effects from tumor and treatment, including:
- Endocrine dysfunction
- Hearing loss
- Cardiac toxicity
- Secondary malignancies
- Growth and developmental issues
Quality of life considerations are increasingly important in treatment planning and long-term care, particularly for survivors of high-risk disease who may face significant long-term sequelae.
Future Directions
Research in neuroblastoma continues to advance, with several promising areas of investigation:
- Precision Medicine:
- Further refinement of risk stratification based on molecular profiling
- Development of targeted therapies based on tumor genetics (e.g., ALK inhibitors)
- Immunotherapy Advancements:
- Optimization of anti-GD2 therapy regimens
- Development of CAR T-cell therapies targeting neuroblastoma-specific antigens
- Exploration of checkpoint inhibitors in combination with other therapies
- Novel Drug Development:
- Investigation of MTOR inhibitors, BET inhibitors, and other targeted agents
- Development of new differentiation agents
- Improved Radiotherapy Techniques:
- Refinement of MIBG therapy, including combination with radiosensitizers
- Investigation of proton beam therapy to reduce long-term toxicities
- Minimal Residual Disease (MRD) Detection:
- Development of more sensitive techniques for MRD detection
- Integration of MRD monitoring into treatment decision-making
- Survivorship and Quality of Life:
- Development of strategies to mitigate long-term treatment toxicities
- Investigation of biomarkers to predict and monitor late effects
- Liquid Biopsy:
- Exploration of circulating tumor DNA and circulating tumor cells for non-invasive monitoring
- International Collaboration:
- Continued efforts to conduct large-scale clinical trials and share data globally
These areas of research aim to improve outcomes for all risk groups, with particular emphasis on increasing survival rates for high-risk patients while minimizing long-term toxicities. As our understanding of neuroblastoma biology deepens, the hope is to develop more effective and less toxic therapies, ultimately leading to better outcomes and quality of life for children affected by this complex disease.
4 day history of fevers, pallor, lethargy with associated generalised abdominal pain and distension. Normal birthing and developmental milestones and nil prior history of similar episodes or presentations. Nil haematuria, nausea, vomiting, weight loss or other constitutional symptoms. On examination vitals were within normal parameters but the patient appeared pale. Abdomen was moderately distended and taut at rest with a palpable left flank mass. Baseline blood results showed a microcytic anaemia (Hb 66, MCV 58).
A large soft tissue opacification is noted in the left upper quadrant which is displacing adjacent bowel and raising the left hemidiaphragm. (source: Candice Norris)
There is a large heterogeneous mass occupying the left flank and upper quadrant. It measures 14 cm craniocaudally, 10 cm anteroposteriorly and 11.5 cm transversely. No obvious calcification in the lesion is identified. A claw sign is present with some normal appearing renal parenchyma in the left renal lower pole at the inferior edge of the lesion, suggestive of a mass arising from the left kidney. Extrinsic compression of the left renal vein but no thrombus within the left renal vein or within the inferior vena cava. No active bleeding within the tumour mass is seen. There is mild hydronephrosis of the lower pole of the left kidney. There is soft tissue in the left para-aortic position, displacing and partially compressing the abdominal aorta, including some soft tissue at the anterior, posterior and left side of the abdominal aorta, with the lower half of the abdominal aorta being displaced to the right. The splenic vessels and pancreas are displaced anteriorly due to the left abdominal mass. No involvement of the spleen and no splenomegaly. No focal liver lesions. The gallbladder is normal in appearance. The right kidney is normal. A small amount of free fluid is present in the pelvis, posterior left upper quadrant and posterior to the spleen. No free gas. (source: Candice Norris)
Neuroblastoma in Childhood
- What is the most common extracranial solid tumor in children?
Neuroblastoma - From which embryonic tissue does neuroblastoma originate?
Neural crest cells - What is the median age of diagnosis for neuroblastoma?
18 months - Which genetic alteration is associated with poor prognosis in neuroblastoma?
MYCN amplification - What is the most common primary site for neuroblastoma?
Adrenal gland - Which staging system is currently used for neuroblastoma?
International Neuroblastoma Risk Group Staging System (INRGSS) - What is the characteristic finding in urine catecholamine metabolites in neuroblastoma patients?
Elevated homovanillic acid (HVA) and vanillylmandelic acid (VMA) - Which imaging modality is preferred for initial evaluation of suspected neuroblastoma?
CT scan or MRI - What is the name of the benign counterpart of neuroblastoma?
Ganglioneuroma - Which chromosome abnormality is associated with favorable prognosis in neuroblastoma?
11q deletion - What is the typical presentation of stage 4S neuroblastoma?
Small primary tumor with metastases to liver, skin, and/or bone marrow in infants - Which tumor marker is commonly elevated in neuroblastoma patients?
Neuron-specific enolase (NSE) - What is the name of the syndrome associated with bilateral neuroblastomas?
Beckwith-Wiedemann syndrome - Which imaging modality is used for detecting bone marrow metastases in neuroblastoma?
MIBG (metaiodobenzylguanidine) scan - What is the characteristic histological feature of neuroblastoma?
Small round blue cells with Homer Wright rosettes - Which treatment modality is used for consolidation in high-risk neuroblastoma?
High-dose chemotherapy with autologous stem cell rescue - What is the most common site of metastasis in neuroblastoma?
Bone marrow - Which immunohistochemical marker is positive in neuroblastoma cells?
Synaptophysin - What is the name of the phenomenon where neuroblastoma spontaneously regresses?
Spontaneous regression - Which targeted therapy is used in relapsed or refractory neuroblastoma?
Anti-GD2 monoclonal antibody therapy - What is the characteristic clinical finding in infants with spinal cord compression due to neuroblastoma?
"Dumbbell tumor" appearance - Which chromosomal abnormality is associated with unfavorable prognosis in neuroblastoma?
1p deletion - What is the name of the rare paraneoplastic syndrome associated with neuroblastoma?
Opsoclonus-myoclonus syndrome - Which radioisotope is used in MIBG therapy for neuroblastoma?
Iodine-131 - What is the most common presenting symptom of abdominal neuroblastoma?
Abdominal mass - Which gene is commonly mutated in familial neuroblastoma?
ALK (Anaplastic Lymphoma Kinase) - What is the characteristic eye finding in metastatic neuroblastoma?
Raccoon eyes (periorbital ecchymoses) - Which differentiation agent is used in the treatment of high-risk neuroblastoma?
13-cis-retinoic acid - What is the name of the international risk classification system for neuroblastoma?
International Neuroblastoma Risk Group (INRG) Classification System - Which molecular pathway is targeted by ALK inhibitors in neuroblastoma treatment?
RAS-MAPK pathway
