Neuroblastoma

1. Clinical Overview

Summary

Neuroblastoma is the most common extracranial solid tumour in childhood and the most common malignancy in infants, accounting for 8-10% of all childhood cancers and 15% of paediatric cancer deaths. [1,2] It arises from neural crest cells that form the sympathetic nervous system, presenting anywhere along the sympathetic chain from the neck to the pelvis. The most frequent sites are the adrenal medulla (~40%) and abdominal paraspinal sympathetic ganglia (~25%). [3]

The clinical spectrum is remarkably heterogeneous, ranging from spontaneous regression in low-risk infants to aggressive metastatic disease in older children. This biological diversity reflects profound differences in molecular genetics – particularly MYCN amplification, chromosomal aberrations (1p deletion, 11q deletion, 17q gain), and ALK mutations – which fundamentally determine prognosis. [4,5]

Classic presentations include an abdominal mass that crosses the midline (distinguishing it from Wilms tumour), periorbital ecchymoses ("raccoon eyes") from orbital bone metastases, bone pain and limp from skeletal metastases, and the striking paraneoplastic phenomenon of opsoclonus-myoclonus syndrome ("dancing eyes, dancing feet"). [6,7] The stage MS (metastatic special, formerly 4S) designation describes infants under 18 months with localised primary tumour and limited metastases to liver, skin, or bone marrow (less than 10% infiltration), who paradoxically have excellent prognosis due to spontaneous tumour regression. [8]

Diagnosis relies on elevated urine catecholamine metabolites (VMA – vanillylmandelic acid; HVA – homovanillic acid) in ~90% of cases, MIBG scintigraphy (123I-metaiodobenzylguanidine) for specific tumour localisation and staging, and tissue biopsy for histological confirmation and molecular profiling. [9,10] The International Neuroblastoma Risk Group (INRG) classification system integrates age, stage, MYCN status, chromosomal aberrations, and histology to stratify patients into very low, low, intermediate, and high-risk groups, with 5-year survival ranging from > 95% to ~50% respectively. [11]

Treatment is risk-adapted: very low and low-risk disease may require observation alone or surgery only, intermediate-risk disease receives moderate-intensity chemotherapy plus surgery, whilst high-risk neuroblastoma demands intensive multimodal therapy including induction chemotherapy, surgical resection, high-dose chemotherapy with autologous stem cell transplant (ASCT), radiotherapy, and anti-GD2 immunotherapy (dinutuximab) with isotretinoin maintenance. [12,13,14] The incorporation of anti-GD2 monoclonal antibody therapy has significantly improved outcomes for high-risk disease, representing one of the major advances in paediatric oncology over the past decade. [13]

Long-term complications include treatment-related toxicities (ototoxicity from platinum chemotherapy, growth impairment, endocrine dysfunction, secondary malignancies), opsoclonus-myoclonus neurological sequelae (persistent ataxia, cognitive impairment despite tumour cure), and psychosocial impacts of intensive prolonged therapy. [15,16]

Clinical Pearls

"Crosses Midline = Neuroblastoma; Doesn't Cross = Wilms": Neuroblastoma arises from paraspinal sympathetic ganglia and commonly crosses the midline. Wilms tumour is intrarenal and typically confined to one side.

"Raccoon Eyes": Bilateral periorbital ecchymoses from orbital bone metastases. Highly specific for metastatic neuroblastoma. Not to be confused with periorbital haematoma from trauma (asymmetric, associated with injury).

"Stage MS – Metastatic Special": Infants less than 18 months with localised primary + limited metastases (liver, skin, bone marrow less than 10%). Paradoxically excellent prognosis (~90% survival). May regress spontaneously. Previously termed "Stage 4S".

"MYCN Amplification = High Risk": Single most important adverse prognostic factor. Present in ~20% of cases. Defines high-risk disease regardless of age or stage. Associated with aggressive biology and poor outcome even with intensive therapy.

"HVA/VMA Elevated = Neuroblastoma": Urine catecholamine metabolites elevated in ~90% of cases. Key diagnostic marker. Homovanillic acid (HVA) and vanillylmandelic acid (VMA) measured as spot urine or 24-hour collection.

"MIBG Avidity = Neuroblastoma Imaging": 123I-metaiodobenzylguanidine (MIBG) scintigraphy is specific for neuroblastoma. Shows primary tumour and metastatic sites. Essential for staging and response assessment. ~90% of neuroblastomas are MIBG-avid.

"Anti-GD2 Immunotherapy = Game Changer": Dinutuximab (anti-GD2 monoclonal antibody) + GM-CSF + IL-2 + isotretinoin improves event-free and overall survival in high-risk neuroblastoma. Landmark COG ANBL0032 trial demonstrated 20% improvement in 2-year event-free survival. [13]

---

2. Epidemiology

Incidence and Prevalence

Demographics

Anatomical Distribution

Neuroblastoma can arise anywhere along the sympathetic chain from the neck to the pelvis:

Stage Distribution at Diagnosis

Age-Dependent Stage Distribution:

• Infants (less than 18 months): Higher proportion of localised and stage MS disease (favourable).
• Older Children (> 18 months): Higher proportion of metastatic disease (unfavourable).

---

3. Pathophysiology

Embryological Origin: Neural Crest Cells

Neuroblastoma arises from neural crest cells – multipotent embryonic cells that migrate during early development to form the peripheral nervous system, including:

• Sympathetic ganglia (paraspinal chain, cervical, thoracic, abdominal, pelvic).
• Adrenal medulla (chromaffin cells).
• Enteric nervous system.
• Sensory ganglia.

Normal Development:

• Neural crest cells differentiate into sympathetic neuroblasts, which mature into sympathetic ganglion cells and chromaffin cells.
• Maturation involves progressive differentiation, loss of proliferative capacity, and establishment of neuronal connections.

Neuroblastoma Pathogenesis:

• Neuroblastoma represents an arrest in differentiation at the neuroblast stage.
• Cells retain proliferative capacity and fail to undergo apoptosis.
• In some cases (particularly infants with favourable biology), spontaneous differentiation or apoptosis can occur, leading to spontaneous regression or maturation to ganglioneuroma (benign).

Molecular Genetics and Tumour Biology

Neuroblastoma biology is extraordinarily heterogeneous, driven by distinct molecular subtypes with profoundly different outcomes:

MYCN Amplification (Most Important Prognostic Factor)

Chromosomal Aberrations

Segmental vs Numerical Aberrations:

• Segmental chromosomal aberrations (deletions, unbalanced translocations) = unfavourable biology.
• Numerical aberrations (whole chromosome gains/losses) = favourable biology.

ALK Mutations

DNA Ploidy

Histopathology (Shimada Classification)

The International Neuroblastoma Pathology Classification (Shimada system) categorises neuroblastoma based on:

• Degree of differentiation (undifferentiated, poorly differentiated, differentiating).
• Schwannian stromal content (stroma-rich vs stroma-poor).
• Mitosis-karyorrhexis index (MKI) (low, intermediate, high).
• Age at diagnosis.

Catecholamine Synthesis

Neuroblastoma cells retain the biochemical characteristics of sympathetic neural tissue, synthesising catecholamines:

Catecholamine Pathway:

1. Tyrosine → DOPA → Dopamine → Norepinephrine → Epinephrine
2. Dopamine is metabolised to Homovanillic Acid (HVA).
3. Norepinephrine is metabolised to Vanillylmandelic Acid (VMA).

Clinical Relevance:

• Elevated urine HVA and/or VMA in ~90% of cases. [9]
• Measured as spot urine HVA/VMA:creatinine ratio or 24-hour urine collection.
• Useful for diagnosis, monitoring treatment response, and detecting relapse.
• False positives: dietary sources (bananas, vanilla, caffeine), certain medications.

Catecholamine-Related Symptoms:

• Most patients are asymptomatic from catecholamine secretion (unlike phaeochromocytoma).
• Rarely: hypertension, tachycardia, sweating, flushing.
• Secretory diarrhoea: VIP (vasoactive intestinal peptide) secretion by some tumours causes watery diarrhoea, hypokalaemia, dehydration (VIPoma-like syndrome). [6]

Tumour Metastasis

Common Metastatic Sites:

• Bone (cortical bone): Pain, limp, pathological fractures.
• Bone Marrow: Anaemia, thrombocytopenia, pancytopenia.
• Liver: Hepatomegaly (especially stage MS).
• Lymph Nodes: Locoregional and distant.
• Skin: Subcutaneous nodules ("blueberry muffin" lesions in stage MS).
• Orbit: Periorbital ecchymoses, proptosis.

Uncommon Sites:

• Brain metastases: rare (less than 5% of metastatic cases).
• Lung metastases: rare in primary neuroblastoma (suggests other diagnosis).

Metastatic Mechanism:

• Haematogenous spread predominates.
• MIBG-avid metastases indicate active catecholamine uptake.

---

4. Classification and Staging

INRGSS Staging System (International Neuroblastoma Risk Group Staging System)

The INRGSS is a pre-treatment imaging-based staging system introduced in 2009 to standardise risk stratification across international trials. [11] It replaced the older post-surgical INSS (International Neuroblastoma Staging System).

INRGSS Stages:

Image-Defined Risk Factors (IDRFs)

IDRFs are imaging findings that predict surgical difficulty and risk of complications. Presence of IDRFs upgrades localised disease from L1 to L2.

IDRF Categories:

Clinical Significance:

• L1 disease (no IDRFs): Often amenable to safe complete resection. May not require chemotherapy.
• L2 disease (IDRFs present): Surgical resection hazardous. Usually requires neoadjuvant chemotherapy to shrink tumour before delayed resection.

INRG Risk Stratification System

The International Neuroblastoma Risk Group (INRG) consensus integrates multiple prognostic factors to assign patients to risk categories. [11]

Prognostic Factors:

1. INRGSS Stage (L1, L2, M, MS).
2. Age (less than 18 months vs ≥18 months).
3. Histological Category (Favourable vs Unfavourable – Shimada).
4. Differentiation Grade (Poorly differentiated, Differentiating, Undifferentiated).
5. MYCN Status (Not amplified vs Amplified).
6. 11q Aberration (Absent vs Present).
7. DNA Ploidy (Hyperdiploid vs Diploid).

INRG Risk Groups:

Key Principles:

• MYCN amplification is the dominant adverse factor, conferring high-risk status regardless of age or stage.
• Age less than 18 months is generally favourable (better tumour biology).
• Stage MS is paradoxically favourable despite metastatic spread (spontaneous regression).

Comparison: Old vs New Staging

Clinical Impact:

• INRGSS enables pre-treatment risk stratification for upfront therapy decisions.
• Reduces inter-centre variability.
• Facilitates international trial collaboration.

---

5. Clinical Presentation

Presenting Features by Primary Tumour Location

Abdominal Neuroblastoma (~65% of cases)

Adrenal Primary:

• Abdominal mass: Firm, irregular, fixed, crosses the midline (key differentiating feature from Wilms tumour).
• Abdominal distension.
• Incidental finding: May be detected on antenatal ultrasound or imaging for other reasons.
• Hypertension: Rare, due to renal artery compression or catecholamine secretion.

Paraspinal Abdominal Primary:

• Retroperitoneal mass: Often encases abdominal aorta, inferior vena cava, renal vessels (IDRFs).
• Crosses midline: Classic feature.
• Palpable on deep abdominal palpation.
• Gastrointestinal symptoms: Rarely, bowel obstruction from mass effect.

Thoracic Neuroblastoma (~15%)

Posterior Mediastinal Mass:

• Asymptomatic: ~60% detected incidentally on chest X-ray performed for unrelated reasons.
• Respiratory symptoms: Cough, dyspnoea, recurrent chest infections (if large mass compresses airways).
• Horner Syndrome: Ptosis (drooping eyelid), miosis (constricted pupil), anhidrosis (absent sweating on affected side of face) if tumour involves cervical sympathetic chain. [6]
• Heterochromia iridis: Different coloured eyes in congenital cases (affected eye lighter due to impaired melanin deposition from sympathetic denervation).
• "Dumbbell tumour": Extension through intervertebral foramina into spinal canal → spinal cord compression.

Cervical Neuroblastoma (~5%)

Neck Mass:

• Palpable firm neck mass: Often in supraclavicular region.
• Horner Syndrome: Common (cervical sympathetic chain involvement).
• Heterochromia iridis: Congenital cases.
• Stridor/Dysphagia: Rare, if large mass compresses airway/oesophagus.

Pelvic Neuroblastoma (~5%)

Pelvic Mass:

• Bladder/Bowel symptoms: Urinary retention, constipation, incontinence.
• Palpable on rectal/pelvic examination.
• Lower limb weakness/pain: If extends into spinal canal.
• Sciatic nerve involvement: Rare, causing leg pain/weakness.

Metastatic Presentations

Bone Metastases (Cortical Bone)

Skeletal Symptoms:

• Bone pain: Most common presenting symptom in metastatic disease. Often multifocal.
• Limp: Refusal to weight-bear in young children.
• Irritability: Non-specific in infants (unrecognised bone pain).
• Pathological fractures: Rare presenting feature.
• Skull metastases: Palpable lumps, sutural diastasis (widened skull sutures).

Distribution:

• Metaphyses of long bones (femur, tibia, humerus).
• Skull (orbital bones → periorbital ecchymoses).
• Vertebrae.
• Pelvis, ribs.

Imaging:

• Lytic lesions on X-ray.
• MIBG scan: Highly sensitive for cortical bone metastases.
• MRI: Detailed assessment of bone marrow and cortical bone involvement.

Bone Marrow Infiltration

Haematological Symptoms:

• Anaemia: Pallor, fatigue, lethargy.
• Thrombocytopenia: Bruising, petechiae, mucosal bleeding.
• Pancytopenia: If extensive marrow infiltration.
• Fever: Neutropenia-related or systemic inflammatory response.

Diagnosis:

• Bilateral bone marrow aspirates and trephine biopsies (from posterior iliac crests).
• Immunocytochemistry to detect neuroblastoma cells (GD2, tyrosine hydroxylase, PHOX2B).

Stage MS vs Stage M:

• Stage MS: Bone marrow less than 10% tumour cells (limited infiltration).
• Stage M: Bone marrow ≥10% tumour cells or cortical bone metastases (extensive disease).

Orbital Metastases

Classic "Raccoon Eyes" Sign:

• Bilateral periorbital ecchymoses: Bruising around both eyes without history of trauma.
• Proptosis (bulging eyes): Due to retrobulbar mass.
• Chemosis (conjunctival swelling).
• Limited eye movements: If extensive orbital involvement.

Mechanism:

• Metastatic tumour in orbital bones (sphenoid, maxilla) infiltrates periorbital soft tissues.
• Venous congestion → ecchymoses.

Clinical Pearl:

• Periorbital ecchymoses in a child with no trauma = neuroblastoma until proven otherwise. Requires urgent imaging and investigation.

Hepatomegaly (Stage MS)

Massive Hepatomegaly in Infants:

• Rapidly enlarging liver: Can cause respiratory compromise (diaphragmatic splinting, reduced lung expansion).
• Abdominal distension: Abdomen tense, shiny skin.
• Respiratory distress: Tachypnoea, grunting, desaturations.
• Renal compromise: Compression of renal vessels → renal impairment.
• "Compartment syndrome" of abdomen: Rarely, requires urgent decompression.

Management:

• Supportive: Ventilatory support, nasogastric decompression.
• Low-dose chemotherapy: To shrink liver metastases (avoiding tumour lysis syndrome).
• Surgical decompression: Rarely required in life-threatening cases.

Prognosis:

• Despite dramatic presentation, stage MS has excellent prognosis (~90% survival) with appropriate management. [8]

Skin Metastases (Stage MS)

"Blueberry Muffin" Lesions:

• Subcutaneous nodules: Blue/purple, firm, non-tender.
• Scattered distribution: Face, trunk, limbs.
• Appearance: Resemble blueberries in a muffin.

Differential Diagnosis:

• Congenital leukaemia (leukaemia cutis).
• Congenital infections (TORCH – toxoplasmosis, rubella, CMV, HSV).
• Rhabdomyosarcoma.
• Langerhans cell histiocytosis.

Clinical Significance:

• Presence of skin metastases in infant with primary neuroblastoma = stage MS (if bone marrow less than 10% and no cortical bone metastases).
• Excellent prognosis.

Paraneoplastic Syndromes

Opsoclonus-Myoclonus-Ataxia Syndrome (OMS)

Classical Triad:

1. Opsoclonus: Rapid, chaotic, multidirectional conjugate eye movements ("dancing eyes"). Worse with visual fixation attempts.
2. Myoclonus: Sudden, brief, involuntary muscle jerks ("dancing feet", whole-body jerks).
3. Ataxia: Truncal and limb ataxia, difficulty with coordination.

Additional Features:

• Behavioural changes: Irritability, sleep disturbance, regression.
• Speech difficulties: Dysarthria, verbal regression.
• Hypotonia or tremor.

Epidemiology:

• Occurs in 2-3% of neuroblastoma cases. [7]
• More common in thoracic and localised neuroblastomas.
• Median age: ~18 months.

Pathophysiology:

• Autoimmune phenomenon: Anti-neuronal antibodies (anti-Hu, anti-Ri) cross-react with neuroblastoma antigens and cerebellar/brainstem neurons.
• Immune-mediated neuronal damage.

Tumour Biology:

• Paradoxically associated with favourable tumour biology: Localised disease, MYCN non-amplified, excellent survival.
• BUT: Significant long-term neurological sequelae even after tumour cure. [7,16]

Diagnosis:

• Clinical diagnosis (triad of opsoclonus, myoclonus, ataxia).
• Search for neuroblastoma: Imaging (CT/MRI chest/abdomen), urine catecholamines, MIBG scan.
• CSF analysis: May show mild lymphocytosis, elevated protein. Anti-neuronal antibodies (not routinely available).

Treatment:

• Treat underlying neuroblastoma: Surgery, ± chemotherapy (usually low-risk disease).
• Immunotherapy for OMS:
  • ACTH (adrenocorticotropic hormone) or high-dose corticosteroids.
  • IVIG (intravenous immunoglobulin).
  • Rituximab (anti-CD20) for refractory cases.
  • Cyclophosphamide or other immunosuppression.
• Prolonged treatment: May require months to years to control neurological symptoms.

Prognosis:

• Tumour prognosis: Excellent (> 90% survival).
• Neurological prognosis:
  • ~50-70% have long-term sequelae: cognitive impairment, learning difficulties, behavioural problems, ataxia, speech delay. [16]
  • Earlier and more aggressive immunotherapy may improve neurological outcomes (ongoing trials).

Clinical Pearl:

• Child with "dancing eyes, dancing feet" + neuroblastoma = OMS. Treat tumour AND immune-mediated neurological syndrome aggressively to minimise long-term disability.

VIP-Secreting Neuroblastoma (Secretory Diarrhoea)

Clinical Features:

• Chronic watery diarrhoea: High-volume, secretory (persists with fasting).
• Hypokalaemia: From stool potassium losses.
• Metabolic acidosis: Bicarbonate loss in stool.
• Dehydration: Severe, requiring IV fluid resuscitation.
• Failure to thrive: Chronic malabsorption.

Mechanism:

• Neuroblastoma cells secrete VIP (vasoactive intestinal peptide).
• VIP stimulates intestinal chloride and water secretion.
• Mimics VIPoma syndrome (pancreatic VIP-secreting tumour).

Diagnosis:

• Elevated plasma VIP levels.
• Neuroblastoma on imaging/biopsy.

Treatment:

• Treat neuroblastoma: Chemotherapy, surgery.
• Symptomatic: Fluid and electrolyte replacement. Octreotide (somatostatin analogue) may reduce diarrhoea.
• Diarrhoea resolves with tumour response.

Incidence:

• Rare (~3-4% of neuroblastoma cases). [6]

Hypertension

Mechanism:

• Catecholamine secretion: Norepinephrine → vasoconstriction.
• Renal artery compression: Abdominal mass compressing renal vessels → secondary hypertension.

Incidence:

• Less common than in phaeochromocytoma (adult catecholamine-secreting tumour).
• Occurs in ~10-20% of cases.

Management:

• Treat tumour.
• Anti-hypertensives if severe (alpha-blockers, calcium channel blockers).

---

6. Investigations

First-Line Biochemical Investigations

Urine Catecholamine Metabolites (HVA and VMA)

Gold Standard Diagnostic Test:

Interpretation:

• Elevated HVA and/or VMA in a child with abdominal mass = neuroblastoma highly likely.
• Normal catecholamines: Does not exclude neuroblastoma (~10% are non-secreting). Proceed with imaging and biopsy.

Full Blood Count (FBC)

Biochemistry

Imaging

Ultrasound (First-Line for Abdominal Mass)

Indications:

• Initial assessment of palpable abdominal mass.
• Antenatal detection of suprarenal mass.

Findings:

• Solid suprarenal mass (adrenal primary).
• Retroperitoneal mass with calcification (50-80% have calcification – differentiates from Wilms tumour which rarely calcifies).
• Heterogeneous echotexture.
• Vascular encasement (Doppler assessment).

Limitations:

• Cannot fully assess extent of disease.
• Requires CT or MRI for staging.

CT/MRI (Definitive Staging Imaging)

CT Chest/Abdomen/Pelvis:

• Primary tumour assessment: Size, location, calcification, necrosis.
• IDRFs: Vascular encasement, organ infiltration, intraspinal extension.
• Metastases: Lymph nodes, liver.

MRI:

• Superior for:
  • "Intraspinal extension (dumbbell tumour): Spinal MRI essential if paraspinal mass."
  • "Vascular encasement: Better soft tissue contrast."
  • "Pelvic tumours: Superior pelvic imaging."
• No ionising radiation: Preferred in young children if available.

Findings:

• Crosses midline (abdominal neuroblastoma).
• Encasement of aorta, IVC, coeliac axis, superior mesenteric artery, renal vessels.
• Intraspinal extension: Widening of intervertebral foramina, spinal canal compromise.
• Calcification: 50-80% (distinguishes from Wilms tumour).

MIBG Scintigraphy (123I-Metaiodobenzylguanidine)

Mechanism:

• MIBG is a norepinephrine analogue taken up by sympathetic neural tissue via norepinephrine transporter (NET).
• Neuroblastoma cells express NET → avid MIBG uptake.
• Radiolabelled 123I-MIBG localises to primary tumour and metastases.

Technique:

• IV injection of 123I-MIBG.
• Thyroid blockade (potassium iodide or Lugol's iodine) to prevent radioiodine uptake by thyroid.
• Whole-body planar imaging at 24 and 48 hours post-injection.
• SPECT/CT for anatomical localisation.

Sensitivity and Specificity:

• ~90% of neuroblastomas are MIBG-avid. [10]
• High specificity for neuroblastoma (few false positives).

Clinical Uses:

• Diagnosis: MIBG uptake in mass + elevated urine catecholamines = neuroblastoma (biopsy may not be needed if metastatic disease).
• Staging: Detects bone and bone marrow metastases (more sensitive than bone scan for neuroblastoma).
• Response assessment: Serial MIBG scans to assess treatment response.
• Surveillance: Detect relapse.

MIBG Scoring:

• Curie score: Semi-quantitative scoring system (0-30+) based on extent of metastatic disease on MIBG scan. Higher score = greater disease burden.

MIBG-Negative Neuroblastoma (~10%):

• Poorly differentiated or undifferentiated tumours may lack NET expression.
• Alternative imaging: PET-CT (18F-FDG or 18F-DOPA).

PET-CT (If MIBG-Negative)

18F-FDG PET-CT:

• Detects metabolically active tumour.
• Useful if MIBG non-avid.
• Less specific than MIBG (uptake in inflammation, infection).

18F-DOPA PET-CT:

• DOPA (dihydroxyphenylalanine) is a catecholamine precursor taken up by neuroblastoma cells.
• High sensitivity for neuroblastoma.
• Not widely available.

Bone Scan (Technetium-99m MDP)

Role:

• Historically used to detect bone metastases.
• MIBG scan is more sensitive and specific for neuroblastoma bone metastases.
• Bone scan still useful if MIBG non-avid.

Tissue Diagnosis and Molecular Profiling

Tumour Biopsy

Indications:

• Histological confirmation of neuroblastoma.
• Molecular profiling (MYCN, chromosomal aberrations, ALK).

Methods:

• Core needle biopsy (image-guided): Minimally invasive, diagnostic yield > 90%.
• Open surgical biopsy: If needle biopsy non-diagnostic or resection planned.
• Excisional biopsy: Complete resection of small localised tumour (L1 disease).

Exception:

• Biopsy may be omitted if:
  • Metastatic disease (stage M) + elevated urine catecholamines + MIBG-avid tumour = diagnosis highly likely.
  • Bone marrow biopsy positive for neuroblastoma cells (immunocytochemistry for GD2, tyrosine hydroxylase, PHOX2B).

MYCN Amplification Status

Technique:

• FISH (fluorescence in situ hybridisation) on tumour biopsy.
• qPCR (quantitative PCR).

Definition:

• Amplified: > 10 copies of MYCN.
• Non-amplified: ≤10 copies.

Critical Importance:

• Defines risk stratification.
• MYCN amplification = high risk regardless of age or stage.
• Turnaround time: ~3-7 days (urgent in treatment planning).

Chromosomal Analysis

Aberrations Assessed:

• 1p deletion (FISH).
• 11q deletion (FISH).
• 17q gain (FISH).
• DNA ploidy (flow cytometry).

Clinical Impact:

• Unfavourable chromosomal aberrations (1p deletion, 11q deletion, 17q gain, diploid) → higher-risk category.
• Hyperdiploid with whole chromosome gains → favourable.

Histopathology (Shimada Classification)

Assessment:

• Degree of differentiation.
• Schwannian stromal content.
• Mitosis-karyorrhexis index (MKI).

Outcome:

• Favourable histology → lower-risk category.
• Unfavourable histology → higher-risk category.

Bone Marrow Examination

Indications:

• Staging: Assess for bone marrow involvement in all patients.
• Monitoring: Serial bone marrow assessments during and after treatment (high-risk disease).

Technique:

• Bilateral bone marrow aspirates and trephine biopsies from posterior iliac crests.
• Immunocytochemistry: Anti-GD2, anti-tyrosine hydroxylase, anti-PHOX2B antibodies to detect neuroblastoma cells.

Classification:

• less than 10% tumour cells: Stage MS (if infant with limited metastases).
• ≥10% tumour cells: Stage M.

Summary of Investigations for Newly Diagnosed Neuroblastoma

---

7. Management

Management of neuroblastoma is risk-adapted, with treatment intensity proportionate to risk group. The INRG risk stratification determines therapy.

General Principles

1. Multidisciplinary Team (MDT): Paediatric oncology, surgery, radiology, pathology, nursing, pharmacy, psychosocial support.
2. Centralised Care: Neuroblastoma treated in specialist paediatric oncology centres (complex disease requiring expertise).
3. Risk Stratification: INRG classification determines treatment.
4. Tumour Board Review: Every case discussed pre-treatment.
5. Clinical Trials: Wherever possible, enrol in clinical trials (improve outcomes, advance knowledge).

Management Algorithm

      NEUROBLASTOMA DIAGNOSED
      (Biopsy, Staging, Molecular profiling)
                   ↓
      INRG RISK STRATIFICATION
      - Stage (L1, L2, M, MS)
      - Age (less than 18m vs ≥18m)
      - MYCN status
      - Histology
      - Chromosomal aberrations
                   ↓
   ┌───────────────┴───────────────┬───────────────┬───────────────┐
   ↓                               ↓               ↓               ↓
VERY LOW / LOW RISK      INTERMEDIATE RISK    HIGH RISK      STAGE MS (SPECIAL)
   ↓                               ↓               ↓               ↓
Observation +/- Surgery    Chemotherapy +    Intensive         Supportive +/-
(May regress               Surgery           Multimodal        Low-dose Chemo
spontaneously)                               Therapy           (if symptomatic)

Very Low and Low Risk Neuroblastoma

Features:

• Localised disease (L1), MYCN non-amplified, favourable histology.
• Stage MS with favourable biology.
• Age typically less than 18 months.

Estimated 5-Year Survival: > 90-95%. [11]

Treatment Strategy: Minimise Therapy

Follow-Up:

• Serial imaging (ultrasound or MRI) every 3 months initially.
• Urine catecholamines every 3 months.
• Extend intervals if stable/regressing.
• Lifelong surveillance (risk of late relapse, though rare).

Outcomes:

• Excellent survival (> 95%).
• Minimal late effects (surgery alone, no chemotherapy in many cases).

Intermediate Risk Neuroblastoma

Features:

• L2 disease (with IDRFs), age less than 18 months, MYCN non-amplified.
• Selected M disease, age less than 18 months, MYCN non-amplified, favourable biology.

Estimated 5-Year Survival: 80-90%. [11]

Treatment Strategy: Moderate-Intensity Chemotherapy + Surgery

Chemotherapy

Regimen:

• 4-8 cycles of moderate-intensity chemotherapy.
• Agents: Carboplatin, Etoposide, Cyclophosphamide, Doxorubicin (various combinations).
• Intervals: 21-day cycles.

Goals:

• Shrink tumour to facilitate safe surgical resection (especially if IDRFs present).
• Treat micrometastatic disease.

Example Regimen (COG Intermediate Risk Protocol):

• Cycles 1, 2, 4, 6, 8: Carboplatin + Etoposide.
• Cycles 3, 5, 7: Cyclophosphamide + Doxorubicin.

Surgery

Timing:

• Delayed resection after chemotherapy (tumour shrinkage allows safer surgery).

Extent:

• Gross total resection if safe.
• Subtotal resection acceptable if complete resection would risk major morbidity (vascular injury, nephrectomy).

Outcomes:

• Complete resection not mandatory for cure in intermediate-risk disease (chemotherapy effective).

Radiotherapy

Role:

• Generally NOT required in intermediate-risk neuroblastoma.
• Reserved for symptomatic residual disease or progressive disease.

Follow-Up:

• Serial imaging and catecholamines every 3 months for 2 years, then 6-monthly.

Outcomes:

• 80-90% long-term survival.
• Low rate of late effects (moderate chemotherapy doses).

High Risk Neuroblastoma

Features:

• MYCN amplified (any age, any stage except MS).
• M disease, age ≥18 months.
• L2 disease, age ≥18 months with unfavourable biology.

Estimated 5-Year Survival: 40-50% (improved with anti-GD2 immunotherapy). [13]

Treatment Strategy: Intensive Multimodal Therapy

High-risk neuroblastoma requires the most aggressive treatment in paediatric oncology, comprising five phases:

Phase 1: Induction Chemotherapy

Goal: Achieve maximal tumour reduction (primary and metastatic sites).

Regimen:

• 5-6 cycles of intensive chemotherapy.
• Agents: Cisplatin, Carboplatin, Etoposide, Vincristine, Cyclophosphamide, Doxorubicin, Topotecan.
• Example (COG High-Risk Protocol):
  • "Cycles 1, 2, 4, 6: Cisplatin + Etoposide."
  • "Cycles 3, 5: Vincristine + Cyclophosphamide + Doxorubicin."
  • "Alternate: Topotecan-based regimens."

Monitoring:

• Response assessment after cycles 2, 4, and 6 (CT/MRI, MIBG scan, urine catecholamines, bone marrow).
• Aim: ≥Partial response (> 50% reduction in primary tumour size, clearing of metastases).

Toxicities:

• Myelosuppression: Neutropenic sepsis, blood transfusions.
• Ototoxicity: Cisplatin-induced hearing loss (irreversible). Baseline and serial audiometry. Consider amifostine (otoprotective agent).
• Nephrotoxicity: Cisplatin-induced renal impairment. Hydration, monitor renal function.
• Nausea/Vomiting: Aggressive anti-emetics (ondansetron, aprepitant).
• Cardiomyopathy: Doxorubicin (cumulative dose-related). Monitor echocardiography.

Phase 2: Local Control (Surgery ± Radiotherapy)

Surgery:

Timing:

• After induction chemotherapy (tumour shrinkage facilitates resection).

Goal:

• Maximal safe resection of primary tumour.
• Gross total resection (GTR) preferred if achievable without major morbidity.
• Subtotal resection acceptable if GTR risks critical structure injury (aorta, IVC, renal vessels, spinal cord).

Surgical Considerations:

• IDRFs: Chemotherapy often resolves vascular encasement, allowing safer surgery.
• Intraspinal extension: Neurosurgical input. Laminectomy if needed.
• Residual disease: Microscopic residual acceptable (post-operative chemotherapy/radiotherapy targets residual).

Radiotherapy:

Indications:

• Primary tumour bed: Radiation to tumour bed post-surgery (even if gross total resection) to reduce local relapse.
• Persistent metastatic sites: Radiation to MIBG-avid residual metastases after induction.

Dose:

• 21 Gy to primary tumour bed (conventional fractionation).
• Metastatic sites: 21-24 Gy.

Technique:

• IMRT (intensity-modulated radiotherapy) or proton therapy (if available) to minimise late effects.

Toxicities:

• Depends on site (abdominal RT → GI toxicity, nephrotoxicity; thoracic RT → pulmonary fibrosis, cardiac toxicity).

Phase 3: Consolidation (High-Dose Chemotherapy + Autologous Stem Cell Transplant)

Rationale:

• Myeloablative chemotherapy eradicates residual minimal disease.
• ASCT rescues bone marrow from chemotherapy-induced aplasia.

Process:

1. Stem Cell Harvest:

   • Peripheral blood stem cells (PBSCs) collected after induction chemotherapy (mobilised with G-CSF).
   • Minimum CD34+ cell dose required for engraftment.

2. High-Dose Chemotherapy:

   • Conditioning regimen: Carboplatin + Etoposide + Melphalan (CEM protocol) or Busulfan + Melphalan (BuMel).
   • Myeloablative: Complete bone marrow ablation.

3. Stem Cell Infusion:

   • Day 0: IV infusion of previously harvested stem cells.
   • Stem cells home to bone marrow and engraft.

4. Supportive Care:

   • Isolation (severe immunosuppression).
   • Broad-spectrum antibiotics, antifungals, antivirals.
   • Blood product support (red cells, platelets).
   • TPN (total parenteral nutrition) for mucositis.
   • G-CSF to accelerate neutrophil recovery.

Engraftment:

• Neutrophil recovery: ~14-21 days post-transplant.
• Platelet recovery: ~21-28 days.

Outcomes:

• Improves event-free survival by ~15-20% compared to chemotherapy alone. [14]

Complications:

• Infection: Life-threatening (neutropenic sepsis, fungal infections, viral reactivation).
• Mucositis: Severe oral/GI mucositis (supportive care, pain management).
• Veno-occlusive disease (VOD): Hepatic sinusoidal obstruction syndrome (rare with modern regimens).
• Late effects: Infertility (alkylating agents), growth impairment, endocrine dysfunction.

Phase 4: Immunotherapy (Anti-GD2 Antibody + Cytokines + Isotretinoin)

Landmark Trial:

• COG ANBL0032 (Yu et al., NEJM 2010): Anti-GD2 antibody (dinutuximab) + GM-CSF + IL-2 + isotretinoin improved 2-year event-free survival from 46% to 66% (pless than 0.001) and overall survival from 75% to 86% in high-risk neuroblastoma post-ASCT. [13]

Regimen:

Cycle Schedule:

• 6 cycles, each ~28 days.
• Alternating cycles with and without IL-2.

Toxicities:

Clinical Impact:

• Improved survival: Anti-GD2 immunotherapy is now standard of care for high-risk neuroblastoma post-ASCT. [13]
• Major advance in paediatric oncology.

Phase 5: Isotretinoin Maintenance

After Immunotherapy:

• Continue isotretinoin alone for 6-12 months.
• Dose: 160 mg/m²/day oral, 14 days on, 14 days off.

Mechanism:

• Retinoid-induced differentiation of residual neuroblastoma cells.

Toxicity:

• Dry skin, cheilitis (cracked lips), photosensitivity, mood changes (rare).

Stage MS (Metastatic Special) – Unique Management

Definition:

• Infants less than 18 months with localised primary + limited metastases (liver, skin, bone marrow less than 10%).

Paradoxical Biology:

• Despite metastatic spread, excellent prognosis (~90% survival). [8]
• Spontaneous regression common.

Treatment Strategy: Minimal Intervention

Outcomes:

• ~90% long-term survival with minimal/no therapy. [8]
• Spontaneous regression in 50-70% of cases.

Relapsed/Refractory Neuroblastoma

Prognosis:

• Relapsed high-risk neuroblastoma has very poor prognosis (less than 10% long-term survival).

Salvage Options:

Emergencies in Neuroblastoma

Spinal Cord Compression (Dumbbell Tumour)

Presentation:

• Back pain, leg weakness, sensory loss, bowel/bladder dysfunction.

Investigation:

• Urgent spinal MRI.

Management:

Outcome:

• Early intervention (within 24h) critical to preserve neurological function.

Respiratory Compromise (Massive Hepatomegaly in Stage MS)

Presentation:

• Tachypnoea, desaturations, respiratory distress in infant with massive liver.

Management:

Outcome:

• Liver regression within 1-2 weeks with chemotherapy.
• Survival excellent if crisis managed.

---

8. Complications and Prognosis

Acute Complications (During Treatment)

Long-Term Complications (Survivors)

High-risk neuroblastoma survivors face significant late effects from intensive therapy:

Opsoclonus-Myoclonus Syndrome (OMS) – Long-Term Neurological Sequelae

Despite excellent tumour prognosis (> 90% survival), 50-70% of OMS patients have persistent neurological and cognitive deficits: [16]

• Cognitive impairment: Learning difficulties, memory problems.
• Behavioural problems: ADHD-like symptoms, emotional dysregulation.
• Ataxia: Persistent truncal/limb ataxia (mild-moderate).
• Speech delay: Expressive language difficulties.
• Motor coordination problems.

Management:

• Educational support: Individualised education plans (IEPs).
• Physiotherapy, occupational therapy, speech therapy.
• Ongoing immunotherapy (steroids, IVIG, rituximab) for neurological relapses.

Prognosis by Risk Group

Relapsed High-Risk Neuroblastoma:

• Prognosis very poor (less than 10% long-term survival).

Prognostic Factors Summary

---

9. Evidence and Guidelines

Key International Guidelines

Landmark Clinical Trials

Evidence for Specific Interventions

Anti-GD2 Immunotherapy

Dinutuximab (ch14.18):

• COG ANBL0032 (Yu et al., NEJM 2010): 2-year EFS 66% vs 46% (dinutuximab arm vs control), OS 86% vs 75%. [13]
• Mechanism: Targets GD2 ganglioside (highly expressed on neuroblastoma). ADCC, CDC.
• Standard of care for high-risk neuroblastoma maintenance.

Dinutuximab Beta (ch14.18/CHO):

• European formulation (produced in CHO cells).
• APN311-303 trial (Ladenstein et al., Lancet Oncol 2018): Improved outcomes similar to dinutuximab.

131I-MIBG Therapy (Relapsed Disease)

NANT 2009-02 trial (DuBois et al., JCO 2015):

• 131I-MIBG therapy in relapsed/refractory neuroblastoma: Response rate 30-40%.
• Palliative benefit. May achieve prolonged remission in selected patients.

ALK Inhibitors (Relapsed ALK-Mutated Neuroblastoma)

Phase I/II trials (Mossé et al., Lancet Oncol 2019):

• Crizotinib in ALK-mutated neuroblastoma: Responses in ~15-20%.
• Lorlatinib (next-generation ALK inhibitor): Higher CNS penetration, overcoming resistance.
• Promising for ALK-driven disease. [17]

---

10. Patient and Layperson Explanation

What is Neuroblastoma?

Neuroblastoma is a type of cancer that develops from nerve cells in very young children, usually babies and toddlers. It most often starts in the adrenal glands (small glands on top of the kidneys) but can also develop in the chest, neck, or pelvis.

Who Gets Neuroblastoma?

It is the most common cancer in babies. Most children diagnosed are under 5 years old. Neuroblastoma is very rare in older children and adults.

What Causes It?

In most cases, we don't know why neuroblastoma develops. It is not caused by anything parents did or didn't do. A very small number of cases (1-2%) run in families due to inherited genetic changes.

What Are the Symptoms?

Symptoms depend on where the tumour is and whether it has spread:

• Lump in the tummy: Most common. The tummy may look swollen.
• Bone pain or limping: If the cancer has spread to bones.
• Bruising around the eyes ("raccoon eyes"): From cancer spreading to the skull.
• Lump in the neck.
• Large liver in babies (stage MS): The liver can get very big, making it hard to breathe.
• "Dancing eyes, dancing feet" (opsoclonus-myoclonus): Unusual rapid eye movements and jerky movements. This is the body's immune system reacting to the cancer.

How is Neuroblastoma Diagnosed?

• Urine test: Measures special chemicals (HVA and VMA) made by the tumour. Elevated in 9 out of 10 children with neuroblastoma.
• Scans (CT, MRI, MIBG scan): Show where the tumour is and if it has spread.
• Biopsy: A small sample of the tumour is taken to confirm the diagnosis and check the genetics (MYCN gene).
• Bone marrow test: To see if cancer has spread to the bone marrow.

Is Neuroblastoma Serious?

It depends on the risk group:

• Low-risk neuroblastoma (usually in babies): Over 95% of children are cured. Some tumours even go away on their own without treatment.
• Intermediate-risk: About 80-90% are cured with moderate chemotherapy and surgery.
• High-risk (cancer has spread, or MYCN gene amplified): About 50-60% are cured with intensive treatment. Treatment is very tough and takes 12-18 months, but survival has improved with new immunotherapy treatments.

What Are the Treatments?

Treatment depends on the risk group:

Very Low and Low Risk

• Observation only: Some tumours regress on their own. Doctors monitor with scans.
• Surgery only: If the tumour can be safely removed.

Intermediate Risk

• Chemotherapy (4-8 cycles): Given through a drip to shrink the tumour.
• Surgery: To remove the tumour after chemotherapy.

High Risk (Intensive Treatment – 5 Phases)

1. Induction Chemotherapy (6 months): Strong chemotherapy to shrink the tumour and kill cancer cells.
2. Surgery: To remove the main tumour.
3. High-Dose Chemotherapy + Stem Cell Transplant: Very strong chemotherapy followed by infusion of the child's own stem cells (collected earlier) to rescue the bone marrow.
4. Immunotherapy (6 months): A special antibody (dinutuximab) that helps the immune system attack cancer cells, given with other medicines (GM-CSF, IL-2, isotretinoin). This is a major advance and improves survival.
5. Isotretinoin Maintenance (6-12 months): A vitamin A-like medicine that helps cancer cells mature and stop growing.

Stage MS (Babies with Limited Spread)

• Observation: Many tumours go away on their own.
• Low-dose chemotherapy: If the baby has breathing problems from a large liver.

What Are the Side Effects of Treatment?

• Chemotherapy: Hair loss, nausea, tiredness, infections (due to low white blood cells).
• Immunotherapy (anti-GD2): Pain (neuropathic pain during infusion – requires strong painkillers).
• Long-term effects (high-risk treatment): Hearing loss, kidney problems, infertility, risk of another cancer later in life. Children need lifelong follow-up.

What About "Dancing Eyes, Dancing Feet" (Opsoclonus-Myoclonus)?

This is a special syndrome where the immune system reacts to the cancer, causing:

• Rapid eye movements (opsoclonus).
• Jerky body movements (myoclonus).
• Difficulty with balance (ataxia).

Good news: The cancer associated with this syndrome is usually low-risk and cured easily.
Bad news: Even after the cancer is cured, 50-70% of children have long-term learning and coordination difficulties. Treatment with steroids and other immunotherapy can help, but recovery may be incomplete.

What is the Outlook?

• Low-risk: Over 95% cured. Treatment is minimal (observation or surgery).
• Intermediate-risk: About 85-90% cured with chemotherapy and surgery.
• High-risk: About 50-60% cured with intensive treatment (improved with immunotherapy). Relapse is possible, and further treatment may be needed.

What Happens After Treatment?

Children who have had neuroblastoma need lifelong follow-up to check for:

• Relapse (cancer coming back).
• Late effects of treatment (hearing, kidneys, heart, growth, fertility).
• Support for learning and development (especially after OMS).

Where Can I Get Support?

• Paediatric oncology team: Doctors, nurses, psychologists, social workers.
• Charities: Neuroblastoma UK, Solving Kids' Cancer, American Childhood Cancer Organization.
• Peer support: Connecting with other families who have been through neuroblastoma.

---

11. Examination Focus

High-Yield Exam Topics (MRCPCH, Paediatric Oncology)

Most Common Questions

1. What is the most common extracranial solid tumour in childhood?

   • Answer: Neuroblastoma.

2. What is the most common cancer in infants?

   • Answer: Neuroblastoma.

3. What distinguishes neuroblastoma from Wilms tumour on abdominal examination?

   • Answer: Neuroblastoma crosses the midline. Wilms tumour (renal origin) typically does not cross the midline.

4. What is the significance of "raccoon eyes" in a child?

   • Answer: Periorbital ecchymoses suggest orbital bone metastases from neuroblastoma. Highly specific sign. Requires urgent investigation.

5. What is the most important adverse prognostic factor in neuroblastoma?

   • Answer: MYCN amplification. Defines high-risk disease regardless of age or stage. Associated with aggressive biology and poor survival.

6. What biochemical test is diagnostic for neuroblastoma?

   • Answer: Elevated urine HVA (homovanillic acid) and VMA (vanillylmandelic acid). Elevated in ~90% of cases. HVA/VMA:creatinine ratio or 24-hour urine collection.

7. What imaging modality is specific for neuroblastoma staging?

   • Answer: MIBG scintigraphy (123I-metaiodobenzylguanidine scan). Shows primary tumour and metastatic sites (bone, bone marrow). ~90% of neuroblastomas are MIBG-avid.

8. What is Stage MS (formerly 4S) neuroblastoma?

   • Answer: Infants less than 18 months with localised primary tumour + limited metastases to skin, liver, and/or bone marrow (less than 10%). Paradoxically excellent prognosis (~90% survival) despite metastatic spread. May undergo spontaneous regression.

9. What is opsoclonus-myoclonus syndrome (OMS)?

   • Answer: Paraneoplastic syndrome associated with neuroblastoma. Triad of opsoclonus (rapid chaotic eye movements), myoclonus (jerky movements), and ataxia. Immune-mediated. Associated with favourable tumour biology but long-term neurological sequelae (50-70% have cognitive/motor deficits despite tumour cure).

10. What is the current standard of care immunotherapy for high-risk neuroblastoma?

    • Answer: Anti-GD2 monoclonal antibody (dinutuximab) + GM-CSF + IL-2 + isotretinoin. Improves event-free and overall survival post-ASCT (COG ANBL0032 trial).

Viva Scenarios

Scenario 1: Abdominal Mass in a 2-Year-Old

Question: A 2-year-old presents with abdominal distension and a firm, irregular mass that crosses the midline. What is your differential diagnosis and investigation plan?

Model Answer:

Differential Diagnosis:

1. Neuroblastoma (most likely – crosses midline, age, abdominal paraspinal origin).
2. Wilms tumour (less likely – renal origin, typically doesn't cross midline).
3. Hepatoblastoma (liver primary).
4. Lymphoma (bulky lymphadenopathy).

Investigation Plan:

1. Urine catecholamines (HVA/VMA) – elevated in ~90% of neuroblastoma.
2. Ultrasound abdomen – initial imaging to characterise mass (solid, suprarenal, calcification).
3. CT/MRI abdomen – definitive staging (extent, vascular encasement, IDRFs, intraspinal extension).
4. MIBG scan – specific for neuroblastoma (primary + metastases).
5. Bloods – FBC (bone marrow infiltration), LDH (prognostic), ferritin (prognostic), NSE.
6. Bone marrow aspirate/trephine (bilateral) – assess marrow involvement.
7. Tumour biopsy – histology, MYCN amplification status (critical for risk stratification), chromosomal analysis (1p, 11q, 17q, ploidy).

Risk Stratification (INRG):

• Age ≥18 months + abdominal mass crossing midline + MYCN status + histology → determines risk group (likely intermediate or high risk).

Initial Management:

• MDT discussion at specialist paediatric oncology centre.
• Risk-adapted therapy (chemotherapy, surgery, ± ASCT/immunotherapy depending on risk group).

---

Scenario 2: "Dancing Eyes, Dancing Feet"

Question: A 15-month-old presents with rapid, chaotic eye movements and jerky body movements. Mum noticed regression in motor skills. What is your diagnosis and management?

Model Answer:

Diagnosis: Opsoclonus-Myoclonus-Ataxia Syndrome (OMS) – paraneoplastic syndrome associated with neuroblastoma.

Clinical Features:

• Opsoclonus: Rapid, multidirectional conjugate eye movements.
• Myoclonus: Sudden jerky movements.
• Ataxia: Truncal/limb ataxia, difficulty with coordination.
• Regression: Motor and developmental regression, irritability.

Investigation Plan:

1. Search for neuroblastoma:
   • Urine catecholamines (HVA/VMA).
   • CT/MRI chest and abdomen (thoracic neuroblastoma common in OMS).
   • MIBG scan.
   • Bone marrow (if metastatic disease suspected).
2. CSF analysis: May show lymphocytosis, elevated protein. Anti-neuronal antibodies (research labs).

Management:

1. Treat neuroblastoma: Usually localised, favourable biology → surgery ± minimal chemotherapy. Excellent tumour prognosis.
2. Treat OMS (immunotherapy):
   • ACTH or high-dose corticosteroids (prednisolone/dexamethasone).
   • IVIG (intravenous immunoglobulin).
   • Rituximab (anti-CD20) for refractory cases.
   • Cyclophosphamide if severe/refractory.
3. Prolonged immunotherapy: May require months-years to control neurological symptoms.
4. Neuro-rehabilitation: Physiotherapy, occupational therapy, speech therapy.

Prognosis:

• Tumour: Excellent (> 90% survival).
• Neurological: 50-70% have long-term sequelae – cognitive impairment, learning difficulties, behavioural problems, ataxia. Earlier immunotherapy may improve outcomes.

---

Scenario 3: Infant with Massive Hepatomegaly and Respiratory Distress

Question: A 6-month-old presents with rapidly enlarging abdomen, respiratory distress, and hepatomegaly 8 cm below costal margin. Investigations show elevated urine HVA/VMA, MIBG-avid liver lesions, small adrenal mass, bone marrow with 5% tumour cells. What is your diagnosis and management?

Model Answer:

Diagnosis: Stage MS (Metastatic Special) Neuroblastoma with symptomatic massive hepatomegaly.

Criteria for Stage MS:

• Age less than 18 months (6 months).
• Localised primary (adrenal).
• Metastases confined to liver, skin, and/or bone marrow less than 10% (5% in this case).
• No cortical bone metastases.

Immediate Management (Life-Threatening Respiratory Compromise):

1. Supportive Care:

   • Oxygen / non-invasive ventilation / intubation if severe.
   • NG decompression (gastric decompression).
   • Elevate head of bed.

2. Low-Dose Chemotherapy (Shrink Liver Metastases):

   • Carboplatin + Etoposide or Cyclophosphamide + Vincristine.
   • Low dose: Avoid tumour lysis syndrome (TLS).
   • Caution: Risk of TLS (high tumour burden in liver).

3. Tumour Lysis Syndrome (TLS) Prevention:

   • Hydration (IV fluids).
   • Allopurinol or rasburicase (reduce uric acid).
   • Monitor: Uric acid, potassium, phosphate, calcium, LDH, renal function.

4. Monitor Response:

   • Serial abdominal examination (hepatomegaly should regress within 1-2 weeks).
   • Imaging (ultrasound) to assess liver size.

5. Surgical Decompression (Last Resort):

   • Rarely needed. High mortality. Only if life-threatening and refractory to chemotherapy.

Prognosis:

• Despite dramatic presentation, stage MS has excellent prognosis (~90% survival) with appropriate management.
• Many cases undergo spontaneous regression after initial crisis.

---

Key Differentiating Features: Neuroblastoma vs Wilms Tumour

Clinical Pearl: Abdominal mass that crosses midline = neuroblastoma. Does not cross = Wilms tumour.

---

12. References

Primary Sources

1. Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 2007;369(9579):2106-2120. doi:10.1016/S0140-6736(07)60983-0. PMID: 17586306.

2. Irwin MS, Park JR. Neuroblastoma: Paradigm for precision medicine. Pediatr Clin North Am. 2015;62(1):225-256. doi:10.1016/j.pcl.2014.09.015. PMID: 25435121.

3. Matthay KK, Maris JM, Schleiermacher G, et al. Neuroblastoma. Nat Rev Dis Primers. 2016;2:16078. doi:10.1038/nrdp.2016.78. PMID: 27830764.

4. Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 2003;3(3):203-216. doi:10.1038/nrc1014. PMID: 12612655.

5. Schleiermacher G, Mosseri V, London WB, et al. Segmental chromosomal alterations have prognostic impact in neuroblastoma: a report from the INRG project. Br J Cancer. 2012;107(8):1418-1422. doi:10.1038/bjc.2012.375. PMID: 22929886.

6. Pinto NR, Applebaum MA, Volchenboum SL, et al. Advances in risk classification and treatment strategies for neuroblastoma. J Clin Oncol. 2015;33(27):3008-3017. doi:10.1200/JCO.2014.59.4648. PMID: 26304901.

7. Krug P, Schleiermacher G, Michon J, et al. Opsoclonus-myoclonus in children associated or not with neuroblastoma. Eur J Paediatr Neurol. 2010;14(5):400-409. doi:10.1016/j.ejpn.2009.12.005. PMID: 20097103.

8. Nickerson HJ, Matthay KK, Seeger RC, et al. Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J Clin Oncol. 2000;18(3):477-486. doi:10.1200/JCO.2000.18.3.477. PMID: 10653863.

9. Strenger V, Kerbl R, Dornbusch HJ, et al. Diagnostic and prognostic impact of urinary catecholamines in neuroblastoma patients. Pediatr Blood Cancer. 2007;48(5):504-509. doi:10.1002/pbc.20888. PMID: 16550529.

10. DuBois SG, Kalika Y, Lukens JN, et al. Metaiodobenzylguanidine uptake at diagnosis and at the end of therapy: a prognostic indicator for children with high-risk neuroblastoma. J Clin Oncol. 2004;22(16):3374-3380. doi:10.1200/JCO.2004.11.117. PMID: 15310781.

11. Cohn SL, Pearson ADJ, London WB, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009;27(2):289-297. doi:10.1200/JCO.2008.16.6785. PMID: 19047291.

12. Irwin MS, Naranjo A, Zhang FF, et al. Revised neuroblastoma risk classification system: a report from the Children's Oncology Group. J Clin Oncol. 2021;39(29):3229-3241. doi:10.1200/JCO.21.00278. PMID: 34310177.

13. Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324-1334. doi:10.1056/NEJMoa0911123. PMID: 20879881.

14. Matthay KK, Reynolds CP, Seeger RC, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a Children's Oncology Group study. J Clin Oncol. 2009;27(7):1007-1013. doi:10.1200/JCO.2007.13.8925. PMID: 19171716.

15. Laverdière C, Liu Q, Yasui Y, et al. Long-term outcomes in survivors of neuroblastoma: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2009;101(16):1131-1140. doi:10.1093/jnci/djp230. PMID: 19648511.

16. Matthay KK, Blaes F, Hero B, et al. Opsoclonus myoclonus syndrome in neuroblastoma: a report from a workshop on the dancing eyes syndrome at the advances in neuroblastoma meeting in Genoa, Italy, 2004. Cancer Lett. 2005;228(1-2):275-282. doi:10.1016/j.canlet.2005.01.051. PMID: 15927360.

17. Mossé YP, Lim MS, Voss SD, et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study. Lancet Oncol. 2013;14(6):472-480. doi:10.1016/S1470-2045(13)70095-0. PMID: 23598171.

18. Maris JM, Mosse YP, Bradfield JP, et al. Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N Engl J Med. 2008;358(24):2585-2593. doi:10.1056/NEJMoa0708698. PMID: 18463370.

19. Cheung NK, Dyer MA. Neuroblastoma: developmental biology, cancer genomics and immunotherapy. Nat Rev Cancer. 2013;13(6):397-411. doi:10.1038/nrc3526. PMID: 23702928.

20. Park JR, Bagatell R, London WB, et al. Children's Oncology Group's 2013 blueprint for research: neuroblastoma. Pediatr Blood Cancer. 2013;60(6):985-993. doi:10.1002/pbc.24433. PMID: 23255319.

---

Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists. Neuroblastoma management requires specialist paediatric oncology input and enrolment in clinical trials where available.