Neuroblastoma
Summary
Neuroblastoma is the most common extracranial solid tumour in childhood and the most common cancer in infants. It arises from Neural Crest Cells (Primitive sympathetic nervous system cells) and can occur anywhere along the sympathetic chain, most commonly in the Adrenal Medulla (~40%) and Abdominal Paraspinal Sympathetic Ganglia (~25%). The clinical presentation varies enormously – from a small incidental adrenal mass that may spontaneously regress, to widely metastatic disease at diagnosis. Classic presentations include an abdominal mass, proptosis and periorbital ecchymoses ("Raccoon Eyes") from orbital metastases, and Opsoclonus-Myoclonus Syndrome (Dancing eyes, Dancing feet – a paraneoplastic phenomenon). Tumour biology (MYCN amplification, Chromosomal abnormalities) is a critical determinant of prognosis and guides risk stratification. Treatment ranges from observation (4S stage – Spontaneous regression) to intensive multimodal therapy (Surgery, Chemotherapy, Radiotherapy, High-dose Chemotherapy with ASCT, Immunotherapy with Anti-GD2) for high-risk disease. Survival for high-risk neuroblastoma has improved significantly but remains ~50%. [1,2,3]
Clinical Pearls
"Crossed Abdominal Mass = Neuroblastoma, Doesn't Cross = Wilms": Neuroblastoma often crosses the midline. Wilms tumour (Renal) typically does not.
"Raccoon Eyes": Periorbital ecchymoses from orbital bone metastases. Classic neuroblastoma finding.
"Stage 4S – Special Stage": Infants less than 18 months with localized primary + Limited metastases (Liver, Skin, Bone marrow less than 10%). Remarkably good prognosis – Often spontaneous regression.
"MYCN Amplification = Bad": Key adverse prognostic marker. Associated with aggressive disease and poor outcome.
Demographics
| Factor | Notes |
|---|---|
| Age | Median age at diagnosis: 17 months. ~90% diagnosed less than 5 years. Most common cancer in infants. |
| Incidence | ~8 per million children less than 15 years per year. |
| Sex | Slight male predominance. |
| Hereditary | Rare familial cases (~1-2%). Associated with ALK mutations, PHOX2B mutations (Congenital central hypoventilation syndrome). |
Origin
| Site | Frequency |
|---|---|
| Adrenal Medulla | ~40% |
| Abdominal Paraspinal Ganglia | ~25% |
| Posterior Mediastinum (Thoracic) | ~15% |
| Neck (Cervical Ganglia) | ~5% |
| Pelvis | ~5% |
Origin: Neural Crest Cells
- Embryologically, Neural Crest Cells give rise to the Sympathetic Nervous System (Adrenal medulla, Sympathetic ganglia).
- Neuroblastoma arises from these primitive cells.
Tumour Biology (Critical for Prognosis)
| Factor | Significance |
|---|---|
| MYCN Amplification | Most important adverse factor. Present in ~20% of cases. Associated with rapid progression and poor survival (Even with intensive therapy). |
| DNA Ploidy | Hyperdiploid (Favourable). Diploid/Near-tetraploid (Unfavourable). |
| Segmental Chromosomal Abnormalities | 1p deletion, 11q deletion, 17q gain – Unfavourable. |
| Histology (Shimada) | Favourable vs Unfavourable based on grade of differentiation and stroma. |
| Age | less than 18 months = More favourable biology. >18 months = More aggressive. |
Catecholamine Synthesis
- Neuroblastoma cells produce catecholamines (Dopamine, Norepinephrine, Epinephrine).
- Breakdown products (HVA – Homovanillic Acid, VMA – Vanillylmandelic Acid) are elevated in urine in ~90% of cases.
INRGSS Staging System (International Neuroblastoma Risk Group)
| Stage | Definition |
|---|---|
| L1 | Localised tumour, NO Image-Defined Risk Factors (IDRFs). |
| L2 | Localised tumour, WITH one or more IDRFs. |
| M | Metastatic disease (Excluding MS). |
| MS | Metastatic "Special" – Age less than 18 months with Metastases confined to Skin, Liver, Bone Marrow (less than 10%). (Formerly 4S). Favourable prognosis. |
Image-Defined Risk Factors (IDRFs)
- Factors that increase surgical difficulty/risk:
- Encasement of major vessels (Aorta, IVC, Renal vessels).
- Intraspinal extension (Dumbbell tumour).
- Involvement of vital structures.
Risk Stratification (INRG)
| Risk Group | Typical Features | 5-Year Survival |
|---|---|---|
| Very Low | Stage L1, Favourable biology, less than 18m | >95% |
| Low | Stage MS, Favourable biology | ~90% |
| Intermediate | Stage L2, Non-MYCN amplified, Intermediate biology | ~80-90% |
| High | MYCN amplified, Stage M >18m, Unfavourable biology | ~50% |
Symptoms by Location
| Location | Presentation |
|---|---|
| Abdominal (Most Common) | Palpable abdominal mass. Often hard, Fixed, May cross midline. Abdominal distension. |
| Thoracic | Cough, Dyspnoea, Horner's Syndrome (If cervical sympathetic involvement). Incidental CXR finding. |
| Cervical | Neck mass. Horner's Syndrome (Ptosis, Miosis, Anhidrosis). Heterochromia iridis. |
| Paraspinal (Dumbbell Tumour) | Spinal cord compression – Back pain, Weakness, Bowel/Bladder dysfunction. Emergency! |
Metastatic Features
| Site | Presentation |
|---|---|
| Bone | Bone pain, Limp, Irritability. |
| Bone Marrow | Anaemia, Thrombocytopenia, Pancytopenia. |
| Orbit | Periorbital Ecchymoses ("Raccoon Eyes"), Proptosis. (Orbital bone metastases). |
| Liver | Hepatomegaly (Especially Stage MS). Massive in infants. |
| Skin | Blue/Purple subcutaneous nodules ("Blueberry Muffin" lesions – Stage MS). |
Paraneoplastic Syndromes
| Syndrome | Features |
|---|---|
| Opsoclonus-Myoclonus Syndrome (OMS) | "Dancing eyes, Dancing feet". Rapid, Multidirectional eye movements + Myoclonic jerks. Autoimmune. Associated with FAVOURABLE tumour biology but may have long-term neurological sequelae. |
| Secretory Diarrhoea (VIPoma-like) | Watery diarrhoea. VIP secretion by tumour. Rare. |
| Hypertension | Catecholamine secretion. Less common than in phaeochromocytoma. |
First-Line Investigations
| Test | Findings |
|---|---|
| Urine Catecholamines (HVA, VMA) | Elevated in ~90%. Diagnostic marker. |
| FBC | Anaemia, Thrombocytopenia (Bone marrow infiltration). |
| LDH | Elevated. Prognostic marker. |
| Ferritin | Elevated in advanced disease. Prognostic. |
| Neuron-Specific Enolase (NSE) | Elevated. Tumour marker. |
Imaging
| Modality | Findings |
|---|---|
| Ultrasound Abdomen | Initial. Solid suprarenal mass. |
| CT/MRI | Staging. Assess tumour extent, IDRFs, Vessel encasement, Intraspinal extension. MRI better for spinal/paraspinal. |
| MIBG Scan (123I-Metaiodobenzylguanidine) | Specific for neuroblastoma. Shows primary tumour and metastases (Bone, Bone marrow). Used for staging and response assessment. |
| Bone Scan / PET-CT | Alternative if MIBG non-avid. |
Biopsy and Tissue Diagnosis
| Test | Notes |
|---|---|
| Tumour Biopsy | Required for diagnosis and molecular profiling. |
| MYCN Amplification | FISH or PCR. Critical prognostic marker. |
| Chromosomal Analysis | 1p deletion, 11q deletion, 17q gain. |
| Bone Marrow Aspirate/Trephine | Assess for metastatic involvement. Bilateral samples. |
Management Algorithm
NEUROBLASTOMA DIAGNOSED
(Biopsy-confirmed, Staging complete)
↓
RISK STRATIFICATION
- Stage (L1, L2, M, MS)
- Age (less than 18m or >18m)
- MYCN status
- Histology
- Ploidy
- Chromosomal abnormalities
┌────────────────┴────────────────────────────────┐
LOW / VERY LOW RISK INTERMEDIATE RISK HIGH RISK
↓ ↓ ↓
Observation +/- Surgery Chemotherapy + Intensive Multimodal
(May regress spontaneously) Surgery Therapy
Low / Very Low Risk
| Treatment | Notes |
|---|---|
| Observation | Many tumours (Especially in infants, Stage L1, MS) spontaneously regress. Close monitoring with imaging and urine catecholamines. |
| Surgery Alone | Complete resection if feasible and safe. May be only treatment needed. |
Intermediate Risk
| Treatment | Notes |
|---|---|
| Chemotherapy | Moderate intensity. Carboplatin, Etoposide, Cyclophosphamide, Doxorubicin. |
| Surgery | After chemotherapy to reduce tumour size (Delayed resection). |
High Risk
| Treatment | Notes |
|---|---|
| Induction Chemotherapy | Intensive. Multiple cycles. Platinum agents, Alkylating agents. |
| Surgery | Resection of primary tumour after induction. |
| High-Dose Chemotherapy + Autologous Stem Cell Transplant (ASCT) | Myeloablative therapy. |
| Radiotherapy | To primary tumour bed and persistent metastatic sites. |
| Immunotherapy (Maintenance) | Anti-GD2 Antibody (Dinutuximab) + GM-CSF + IL-2 + Isotretinoin. Targets GD2 ganglioside on neuroblastoma cells. |
| Isotretinoin (13-cis-Retinoic Acid) | Differentiation agent. Maintenance therapy. |
Emergencies
| Emergency | Management |
|---|---|
| Spinal Cord Compression | Urgent MRI. Dexamethasone. Chemotherapy (If chemosensitive) or Surgery/Radiotherapy. |
| Respiratory Compromise (Massive Hepatomegaly in MS) | Supportive care. Low-dose chemotherapy. |
| Complication | Notes |
|---|---|
| Spinal Cord Compression | Dumbbell tumour. Emergency. |
| Respiratory Failure (Stage MS) | Massive hepatomegaly in infants. |
| OMS Neurological Sequelae | Long-term learning difficulties, Ataxia. Even if tumour cured. |
| Treatment-Related | Chemotherapy toxicity, Infection, Growth/Endocrine late effects, Secondary malignancy, Hearing loss (Platinum agents). |
| Factor | Prognosis |
|---|---|
| Low Risk | >95% survival. |
| Intermediate Risk | ~80-90% survival. |
| High Risk | ~50% survival (Improved with immunotherapy). |
| MYCN Amplified | Poor prognosis. Aggressive disease. |
| Stage MS | Excellent prognosis (~90%). Spontaneous regression common. |
| Age less than 18 months | Generally more favourable. |
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Neuroblastoma Treatment Guidelines | COG (Children's Oncology Group) | Risk stratification. Multimodal therapy for high-risk. |
| INRG Classification | INRG Task Force | Staging (INRGSS). Pre-treatment risk stratification. |
Landmark Trials
| Trial | Findings |
|---|---|
| COG ANBL0032 | Anti-GD2 immunotherapy (Dinutuximab) + Isotretinoin improves EFS and OS in high-risk neuroblastoma. |
What is Neuroblastoma?
Neuroblastoma is a type of cancer that develops from nerve cells in very young children. It most often starts in the adrenal glands (Small glands on top of the kidneys) but can also occur in the chest, neck, or pelvis.
Who gets it?
It is the most common cancer in babies. Most children diagnosed are under 5 years old.
What are the symptoms?
- A lump in the tummy.
- Bone pain or limping.
- Bruising around the eyes ("Raccoon eyes").
- A lump in the neck.
- Some babies have very large livers (Stage MS).
Is it serious?
It depends. Some neuroblastomas are low-risk and may even go away on their own without treatment (Especially in very young babies). Others are high-risk and need intensive treatment including chemotherapy, surgery, and immunotherapy.
What is the treatment?
- Low-risk: Observation or surgery alone.
- High-risk: Chemotherapy, Surgery, Stem cell transplant, Radiotherapy, and Immunotherapy (A medicine that helps the immune system attack the cancer).
What is the outlook?
For low-risk neuroblastoma, the cure rate is over 95%. For high-risk disease, about half of children are cured, and research is ongoing to improve this.
Primary Sources
- Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010;362(23):2202-2211. PMID: 20558371.
- Cohn SL, et al. The International Neuroblastoma Risk Group (INRG) classification system. J Clin Oncol. 2009;27(2):289-297. PMID: 19047291.
- Yu AL, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324-1334. PMID: 20879881.
Common Exam Questions
- Most Common Extracranial Solid Tumour in Children: "What is the most common extracranial solid tumour in childhood?"
- Answer: Neuroblastoma.
- Crosses Midline: "Which abdominal tumour in children typically crosses the midline – Neuroblastoma or Wilms?"
- Answer: Neuroblastoma (Wilms tumour – Renal – typically does not cross midline).
- Raccoon Eyes: "What is the significance of periorbital ecchymoses in a child?"
- Answer: Suggests Orbital Bone Metastases from Neuroblastoma.
- Key Prognostic Marker: "What is the most important adverse prognostic marker in neuroblastoma?"
- Answer: MYCN Amplification.
Viva Points
- Stage MS (4S): Special stage in infants. Limited metastases. Excellent prognosis. Spontaneous regression.
- MIBG Scan: Specific imaging for neuroblastoma. Shows primary and metastatic disease.
- HVA/VMA: Urine catecholamine metabolites. Elevated in ~90%. Diagnostic.
- Opsoclonus-Myoclonus: Paraneoplastic. Associated with favourable tumour biology but long-term neurological problems.
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