Pediatrics (System-Integrated)

Neuroblastoma: presentation and workup

Clinical Overview and When to Suspect Neuroblastoma

— Arises from primitive neural crest cells of the sympathetic nervous system

— Can occur anywhere along the sympathetic chain: adrenal medulla (~40%), paraspinal abdomen, thorax (posterior mediastinum), neck, pelvis

— Median age at diagnosis: 17–22 months; 90% diagnosed before age 5

— Toddler with abdominal mass that crosses the midline (vs Wilms, which is usually unilateral and confined)

— Periorbital ecchymoses ("raccoon eyes") from orbital bone metastases — a near-pathognomonic clue

— Opsoclonus-myoclonus-ataxia ("dancing eyes, dancing feet") — paraneoplastic

— Horner syndrome (ptosis, miosis, anhidrosis) from a cervicothoracic primary

— Unexplained hypertension in a young child + catecholamine symptoms (sweating, flushing, irritability)

— Intractable secretory diarrhea from tumor VIP secretion

— Bone pain, limp, or pancytopenia in a young child mimicking leukemia — marrow metastases

— Most cases sporadic; ~1–2% familial (germline ALK or PHOX2B mutations)

— Associations with Hirschsprung disease, congenital central hypoventilation syndrome (all PHOX2B), and neurofibromatosis type 1

Neuroblastoma is the most common extracranial solid tumor of childhood and the most common malignancy in infants <1 year

When to suspect in a Step 3 pediatric vignette:

Risk associations:

Board pearl: A child <5 with an abdominal mass + periorbital bruising + bone pain should immediately move neuroblastoma to the top of the differential — order urine catecholamines and abdominal imaging before invasive workup.

Prognosis is age-dependent and biology-dependent: infants <18 months often do remarkably well even with metastatic disease (stage MS), while older children with MYCN amplification have aggressive disease.

Key distinction: Neuroblastoma crosses midline, encases vessels, and calcifies; Wilms tumor displaces vessels and rarely calcifies.

Presentation Patterns and Key History

— Fatigue, irritability, poor feeding, weight loss, intermittent low-grade fevers

— Parents often describe a child who "just isn't acting right" for weeks

— Bone pain and refusal to walk/limp is a classic presentation of metastatic disease and frequently misdiagnosed initially as toddler's fracture, osteomyelitis, or JIA

— Abdominal primary (most common): firm, fixed, nontender mass; abdominal distension; early satiety; constipation; hypertension from renal artery compression or catecholamine excess

— Thoracic (posterior mediastinum): often incidentally discovered on CXR for unrelated reasons (cough, wheeze, pneumonia); may cause Horner syndrome or spinal cord compression via dumbbell extension through neural foramina

— Cervical: neck mass + Horner syndrome; heterochromia iridis if congenital

— Pelvic (organ of Zuckerkandl): urinary retention, constipation, lower extremity weakness

— Paraspinal "dumbbell" tumor: back pain, weakness, bowel/bladder dysfunction — a neurosurgical emergency

— Periorbital ecchymoses + proptosis (orbital bone mets)

— Skin nodules — "blueberry muffin baby" in infants (stage MS)

— Hepatomegaly — massive in infants with stage MS, can cause respiratory compromise

— Pallor, bruising, cytopenias from marrow involvement

— Opsoclonus-myoclonus-ataxia (OMA): chaotic eye movements + myoclonic jerks + ataxia; often associated with lower-stage, favorable tumors but persistent neurologic sequelae

— VIP-secreting tumors: intractable watery diarrhea, hypokalemia, dehydration (Kerner-Morrison syndrome)

— Catecholamine excess: sweating, flushing, hypertension (less prominent than pheochromocytoma)

Constitutional and nonspecific symptoms dominate early history

Site-specific presentations — let location drive the history:

Metastatic clues (50% present with metastases):

Paraneoplastic syndromes (high-yield):

Board pearl: OMA + ataxia in a toddler = image the chest, abdomen, and pelvis looking for occult neuroblastoma, even if the child looks otherwise well.

Step 3 management: Any child with new-onset Horner syndrome without trauma needs MRI of head, neck, and chest to rule out neuroblastoma.

Physical Exam Findings (and Hemodynamic Assessment when relevant)

— Ill-appearing, irritable toddler with pallor; may be cachectic with prolonged disease

— Infant with stage MS may appear surprisingly well despite massive hepatomegaly

— Hypertension in 25% — from renal artery compression or catecholamine excess; measure BP in all four extremities

— Tachycardia, low-grade fever

— Assess for respiratory distress in infants with hepatomegaly (abdominal compartment-like physiology) — high-risk subgroup

— Periorbital ecchymoses ("raccoon eyes") — orbital bony mets, not trauma

— Proptosis, often unilateral

— Horner syndrome: ipsilateral ptosis, miosis, anhidrosis, +/- heterochromia

— Palpable cervical mass; scalp nodules

— Skull mets may produce palpable cranial bumps

— Opsoclonus: rapid, chaotic, multidirectional saccades ("dancing eyes")

— Strabismus from orbital infiltration

— Fundoscopy if increased ICP suspected

— Firm, irregular, fixed mass crossing midline — hallmark finding

— Hepatomegaly, sometimes extending to pelvis in infants

— Mass effect on bladder/rectum

— Bluish, nontender subcutaneous nodules ("blueberry muffin") in infants with stage MS — blanch then develop erythematous halo (catecholamine release on palpation)

— Myoclonus, truncal ataxia with OMA

— Cord compression signs: hyperreflexia, weakness, sensory level, bladder distension — a neurosurgical emergency

— Document baseline motor exam and sphincter tone

— Bone tenderness, refusal to bear weight, pseudoparalysis of a limb

— VIP-secreting tumors → severe dehydration, hypokalemia, metabolic acidosis from chronic diarrhea — assess perfusion, capillary refill

— Tumor lysis risk in bulky disease post-treatment

General appearance

Vital signs

Head and neck

Eye exam

Abdomen

Skin

Neurologic

Musculoskeletal

Hemodynamic considerations

CCS pearl: On a CCS case, if you find raccoon eyes + abdominal mass, immediately order urine catecholamines, CBC, LDH, ferritin, CMP, and abdominal MRI/CT; do not anchor on "child abuse" without imaging.

Key distinction: Periorbital ecchymoses without history of trauma + palpable abdominal mass should never be attributed to NAT before oncologic workup.

Diagnostic Workup — Initial Labs and Imaging

— CBC with differential: anemia, thrombocytopenia from marrow infiltration

— CMP: assess electrolytes (hypokalemia with VIP tumors), creatinine, LFTs

— LDH: marker of tumor burden; high LDH = worse prognosis

— Ferritin: elevated in advanced disease; historic prognostic marker

— Uric acid, phosphorus, calcium: baseline for tumor lysis risk

— Coagulation studies: PT/INR, PTT, fibrinogen — DIC can occur with bulky disease

— Urine or spot urine for catecholamine metabolites: vanillylmandelic acid (VMA) and homovanillic acid (HVA) — elevated in >90% of neuroblastomas; can use spot urine normalized to creatinine

— Serum catecholamines less reliable in children — use urine VMA/HVA

— Abdominal ultrasound: usually the first study; identifies mass, calcifications, vascular encasement

— Chest x-ray: posterior mediastinal mass often incidental; look for paraspinal widening, rib erosion

— CT or MRI of primary site with contrast:

— MRI preferred for paraspinal tumors and to evaluate intraspinal extension

— CT acceptable for abdominal/thoracic primaries; shows stippled calcifications in ~85% (vs Wilms tumor, rarely calcified)

— Document image-defined risk factors (IDRFs) — vascular encasement, organ invasion, midline crossing — these drive staging and surgical resectability

— Heterogeneous, lobulated mass with calcifications

— Encases rather than displaces major vessels (aorta, IVC, celiac, SMA)

— Crosses the midline

— Adrenal origin → displaces kidney inferiorly without distorting renal parenchyma

Initial laboratory studies (order all up front in a suspected case):

Imaging — start with the most accessible:

Classic imaging features:

Board pearl: Calcifications + midline crossing + vascular encasement = neuroblastoma; intrarenal mass distorting collecting system without calcifications = Wilms tumor.

Step 3 management: When ordering imaging, request CT/MRI chest, abdomen, and pelvis to capture the entire sympathetic chain — a "neck-to-pelvis" approach catches multifocal disease and metastases.

Pregnancy testing is not relevant; however, document growth parameters and developmental milestones at diagnosis.

Diagnostic Workup — Advanced and Confirmatory Studies

— Image-guided core needle biopsy or open biopsy of the primary tumor

— Adequate tissue needed for histology + molecular studies (MYCN, ploidy, segmental chromosomal aberrations 1p, 11q, 17q)

— Histology shows small round blue cells with Homer-Wright rosettes and neuropil; immunostains positive for synaptophysin, chromogranin, NSE, PHOX2B

— Differential of small round blue cell tumors: neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, lymphoma, Wilms (less classic) — molecular markers distinguish

— Bilateral bone marrow aspirates and biopsies (two sites) — assess for marrow metastases (>50% have marrow involvement at diagnosis in high-risk)

— ¹²³I-MIBG scintigraphy: highly specific for neuroblastoma; detects primary and metastatic disease; MIBG-avid in ~90% of cases

— If MIBG non-avid, use ¹⁸F-FDG PET/CT as alternative

— Technetium-99m bone scan if MIBG unavailable, but MIBG preferred

— MYCN amplification status — single most important biologic prognostic factor; amplified = high-risk

— DNA ploidy (hyperdiploid favorable in infants)

— Segmental chromosomal aberrations: 1p loss, 11q loss, 17q gain — adverse

— ALK mutation — therapeutic target with crizotinib/lorlatinib

— Histology per INPC (Shimada): favorable vs unfavorable based on MKI, differentiation, age

— L1: localized, no IDRFs

— L2: localized, one or more IDRFs

— M: distant metastatic

— MS: metastatic special (<18 mo, mets limited to skin, liver, minimal marrow)

Tissue diagnosis is required — neuroblastoma cannot be definitively diagnosed by imaging or biomarkers alone

Alternative diagnostic pathway: diagnosis can be made by bone marrow involvement + elevated urinary catecholamines without primary tumor biopsy (if marrow shows tumor cells)

Staging workup — required for all patients:

Molecular and genetic studies on tumor tissue:

Staging system: INRGSS (International Neuroblastoma Risk Group Staging System) — preoperative, based on image-defined risk factors (IDRFs):

Board pearl: MYCN amplification upgrades essentially any neuroblastoma to high-risk, regardless of age or stage.

Key distinction: Stage MS (formerly 4S) in infants has spontaneous regression potential despite metastases — biology trumps stage.

Risk Stratification and First-Line Management Logic

— Age at diagnosis (<18 months vs ≥18 months — pivotal cutoff)

— INRGSS stage (L1, L2, M, MS)

— MYCN amplification status

— DNA ploidy (in infants)

— Histology (favorable vs unfavorable INPC)

— 11q aberration status

— Low-risk (~30%): L1 tumors, MS without MYCN amplification, favorable biology

— Observation alone for select infants (especially small adrenal masses <5 cm in infants — many spontaneously regress)

— Surgery alone often curative; 5-year survival >95%

— Intermediate-risk (~15%): L2 without MYCN amplification in older children, or M in infants without MYCN

— Moderate-dose chemotherapy + surgical resection; survival ~90–95%

— High-risk (~50%): metastatic disease in children ≥18 months, any MYCN-amplified tumor, or unfavorable biology with adverse features

— Multimodality intensive therapy; survival historically ~50%, improving with immunotherapy

— Induction: multiagent chemotherapy (cyclophosphamide, doxorubicin, vincristine, cisplatin, etoposide, topotecan)

— Local control: surgical resection + radiation to primary site

— Consolidation: high-dose chemotherapy with autologous stem cell rescue (often tandem transplants)

— Maintenance: anti-GD2 immunotherapy (dinutuximab) + GM-CSF + IL-2 + isotretinoin (13-cis-retinoic acid)

— Surveillance for relapse

Children's Oncology Group (COG) risk stratification integrates:

Risk groups and overall approach:

High-risk treatment paradigm (5 phases):

Spontaneous regression is unique to neuroblastoma — particularly in infants with stage MS or small adrenal masses; reflects neural crest cell apoptosis/differentiation

Step 3 management: Once neuroblastoma is suspected, refer urgently to pediatric oncology at a tertiary center; do not initiate therapy in community settings. Risk stratification requires central pathology review and molecular testing.

Board pearl: A young infant with stage MS neuroblastoma and favorable biology may receive observation alone — biology dictates aggressiveness, not just metastatic status.

Key distinction: Risk is multifactorial — age, stage, MYCN, ploidy, histology, and 11q all integrate; no single feature except MYCN amplification reliably predicts high-risk status.

Pharmacotherapy — First-Line Regimens

— Cyclophosphamide + topotecan (cycles 1–2)

— Cisplatin + etoposide (cycles 3, 5)

— Cyclophosphamide + doxorubicin + vincristine (cycles 4, 6)

— Goals: cytoreduction, marrow clearance, prepare for stem cell harvest

— Major toxicities: myelosuppression, mucositis, nephrotoxicity (cisplatin), ototoxicity (cisplatin — baseline + serial audiology), cardiotoxicity (anthracyclines — echo monitoring), hemorrhagic cystitis (cyclophosphamide — give mesna + hyperhydration), febrile neutropenia

— Busulfan + melphalan (current standard in Europe/US tandem regimens)

— Or carboplatin + etoposide + melphalan (CEM)

— Tandem transplant (two cycles) improves event-free survival

— Toxicities: VOD/SOS of liver, severe mucositis, prolonged cytopenias, infections

— Surgical resection of primary tumor between induction and consolidation

— External beam radiation to primary tumor bed and persistent metastatic sites

— Dinutuximab — chimeric monoclonal antibody against GD2 (disialoganglioside, highly expressed on neuroblastoma cells)

— Combined with GM-CSF, IL-2, and isotretinoin (13-cis-retinoic acid)

— Mechanism: ADCC and complement-mediated lysis of GD2+ cells

— Hallmark toxicity: severe neuropathic pain during infusion (requires scheduled opioids), capillary leak, hypotension, fever, hypersensitivity

— Premedications: IV opioids (morphine), antihistamines, antipyretics

— Isotretinoin promotes differentiation of residual neuroblasts

— ALK inhibitors (crizotinib, lorlatinib) for ALK-mutated tumors

— ¹³¹I-MIBG therapy for refractory MIBG-avid disease

— G-CSF for neutropenia recovery

— PJP prophylaxis with TMP-SMX

— Antifungal prophylaxis in high-risk neutropenia

— Tumor lysis prevention: hydration, allopurinol or rasburicase

Induction chemotherapy (high-risk) — COG ANBL backbone:

Consolidation: high-dose chemotherapy + autologous stem cell rescue

Local control:

Maintenance/post-consolidation immunotherapy (the major survival advance):

Targeted therapy (emerging/relapsed):

Supportive care during chemotherapy:

Board pearl: Dinutuximab + isotretinoin maintenance transformed high-risk neuroblastoma outcomes — recognize anti-GD2 as the targeted immunotherapy class.

Step 3 management: Always baseline echo and audiogram before cisplatin/anthracycline initiation; document cumulative anthracycline dose for lifelong cardiac surveillance.

Procedures and Local Control

— Image-guided core needle biopsy preferred when feasible — adequate tissue for histology + molecular panel

— Open incisional biopsy if core inadequate or anatomy unfavorable

— Avoid FNA — insufficient for ploidy/MYCN studies

— Coordinate with anesthesia for procedural sedation in young children

— Send specimen fresh for cytogenetics, not just formalin

— Timing depends on risk:

— Low-risk L1 tumors without IDRFs: upfront complete resection often curative

— L2 and high-risk: delayed primary resection after induction chemo to shrink tumor and clear IDRFs

— Goal: gross total resection without compromising vital structures

— Vascular encasement, organ invasion may preclude complete resection — partial resection acceptable in high-risk if 90% removed

— Adrenalectomy + regional lymphadenectomy for adrenal primaries

— Dumbbell paraspinal tumors with intraspinal extension

— Presentation: back pain, weakness, bladder/bowel dysfunction

— Urgent MRI, neurosurgery + oncology consultation

— Treatment options: emergent chemotherapy (preferred, less morbidity), laminectomy/laminoplasty, or radiation; chemo is favored to avoid spinal deformity in young children

— External beam radiation (EBRT) to primary tumor bed after surgery in high-risk patients

— Doses 21–36 Gy depending on residual disease

— Used for symptomatic metastases (bone pain, cord compression)

— Late effects: growth retardation, second malignancies, scoliosis — minimize in young children when possible

— Harvest CD34+ cells after induction cycles 2–4 once marrow cleared of tumor (confirmed by MIBG and morphology)

— Cryopreserve for tandem consolidation transplants

— Targeted radiotherapy for MIBG-avid refractory/relapsed disease

— Requires lead-shielded isolation room and thyroid blockade with potassium iodide to protect normal thyroid

Diagnostic biopsy

Surgical resection of primary tumor

Spinal cord compression — emergency management

Radiation therapy

Stem cell collection and autologous HSCT

¹³¹I-MIBG therapy

CCS pearl: For a child with paraspinal mass + new lower extremity weakness, the orders should read: STAT MRI spine, dexamethasone, neurosurgery consult, pediatric oncology consult, admit to PICU — cord compression is time-sensitive.

Board pearl: Surgical resectability is determined by IDRFs on cross-sectional imaging — vascular encasement is the most common limiting factor.

Special Populations — Renal and Hepatic Considerations

— Cisplatin nephrotoxicity is dose-limiting:

— Monitor serum creatinine, electrolytes (Mg²⁺, K⁺ wasting), GFR

— Vigorous IV hydration before and after cisplatin; consider mannitol-induced diuresis

— Magnesium supplementation routinely; replace K⁺ aggressively

— Avoid concurrent aminoglycosides, vancomycin, NSAIDs, IV contrast where possible

— Ifosfamide (used in relapse regimens) → Fanconi syndrome, proximal tubular dysfunction, hemorrhagic cystitis (mesna required)

— Tumor lysis syndrome prevention in bulky disease: hydration, allopurinol (low-intermediate risk) or rasburicase (high risk, G6PD-tested)

— Renal artery compression from primary tumor → renovascular hypertension — may persist post-resection

— Nephrectomy may be required if tumor invades kidney parenchyma — assess contralateral renal function preoperatively

— Massive hepatomegaly in stage MS infants can cause:

— Respiratory compromise (abdominal compartment physiology)

— Coagulopathy from hepatic dysfunction

— May require low-dose chemotherapy or radiation to reduce liver size despite favorable biology

— Veno-occlusive disease (VOD/SOS) after high-dose busulfan/melphalan consolidation:

— Presents with weight gain, RUQ pain, jaundice, ascites, thrombocytopenia

— Defibrotide is treatment of choice

— Prophylaxis: ursodiol during conditioning

— Anthracycline-related hepatotoxicity is uncommon but check LFTs each cycle

— Dose-reduce vincristine if direct bilirubin >2 — hepatically metabolized

— Hepatitis B/C screening before immunosuppressive therapy

— Cumulative anthracycline dose tracked lifelong; threshold typically <250–300 mg/m² doxorubicin equivalent

— Baseline + serial echo/MUGA; consider dexrazoxane in high cumulative exposure

Although neuroblastoma is a pediatric disease without "elderly" considerations, organ function profoundly affects chemotherapy dosing and tolerability — treat this as the analog of renal/hepatic dosing in adults.

Renal considerations

Hepatic considerations

Cardiac considerations (analogous organ-specific dosing):

Step 3 management: Before any cycle of cisplatin, check creatinine, Mg²⁺, K⁺, and confirm adequate urine output (>2 mL/kg/hr); hold or dose-modify for AKI.

Board pearl: VOD/SOS in a neuroblastoma patient post-HSCT presenting with weight gain + jaundice + thrombocytopenia = start defibrotide early.

Special Populations — Infants, Stage MS, and Familial Disease

— Better prognosis stage-for-stage compared to older children

— Stage MS (metastatic special): infants <18 months with metastases limited to skin, liver, and <10% bone marrow involvement (no cortical bone mets)

— Often spontaneously regresses without therapy

— Treatment reserved for symptomatic disease (respiratory compromise from hepatomegaly, coagulopathy, organ dysfunction)

— Observation is appropriate first-line for asymptomatic stage MS with favorable biology

— Small localized adrenal masses in infants <6 months: many are detected on prenatal/postnatal imaging and represent adrenal neuroblastoma in situ — observation with serial ultrasound often appropriate

— MYCN amplification overrides age favorability — even infants with MYCN-amplified disease are high-risk

— Differential: neuroblastoma vs adrenal hemorrhage

— Serial ultrasounds: hemorrhage shrinks and develops cystic changes; neuroblastoma is solid, may grow

— Urine catecholamines may be normal in small tumors

— COG observation protocols spare many neonates surgery

— Germline ALK mutations (most common familial cause) and PHOX2B mutations

— PHOX2B mutations associated with:

— Congenital central hypoventilation syndrome (CCHS, "Ondine's curse")

— Hirschsprung disease

— Combined "neurocristopathy" phenotype

— Affected families: genetic counseling, screening of siblings with ultrasound + urine catecholamines

— Earlier age at presentation, often bilateral or multifocal primaries

— Neurofibromatosis type 1: modest increased risk

— Beckwith-Wiedemann syndrome: primarily Wilms, but neuroblastoma also reported

— Costello syndrome, Noonan syndrome: RASopathies — increased risk

— Rare; tend to have indolent but treatment-resistant disease with poorer long-term outcomes despite favorable upfront features

Infants (<18 months) — a fundamentally different disease

Neonates with prenatally detected adrenal masses

Familial neuroblastoma (~1–2%)

Predisposition syndromes

Adolescents and young adults

Board pearl: A PHOX2B mutation links three diseases: neuroblastoma + Hirschsprung + CCHS — recognize the neurocristopathy triad.

Step 3 management: A newborn with a prenatally identified adrenal mass without distress should be referred to pediatric oncology/surgery for observation with serial ultrasound + urine catecholamines, not immediate resection.

Key distinction: Stage MS uses age <18 months and limited metastatic pattern — bone cortical involvement disqualifies MS classification.

Complications and Adverse Outcomes

— Spinal cord compression from paraspinal dumbbell tumors → permanent paralysis if untreated

— Renovascular hypertension from renal artery compression

— Hepatic dysfunction and respiratory failure in infants with massive hepatomegaly (stage MS)

— DIC and coagulopathy in widely metastatic disease

— Tumor lysis syndrome with bulky disease at treatment initiation

— Pancytopenia from marrow infiltration → infections, bleeding

— Pathologic fractures from bone metastases

— Catecholamine crisis: hypertensive emergency, sweating, tachycardia (rare vs pheochromocytoma)

— Febrile neutropenia, sepsis — leading cause of treatment-related mortality

— Mucositis, typhlitis (neutropenic enterocolitis)

— Hemorrhagic cystitis (cyclophosphamide/ifosfamide) — prevent with mesna + hyperhydration

— Anaphylaxis and capillary leak with dinutuximab infusions

— Severe pain syndromes during dinutuximab — requires opioid infusion

— VOD/SOS post-HSCT

— Cisplatin-induced AKI, hypomagnesemia, ototoxicity

— Sensorineural hearing loss (cisplatin) — affects up to 50%; lifelong audiologic monitoring; consider sodium thiosulfate otoprotection per recent data

— Cardiomyopathy (anthracyclines) — lifetime echo surveillance every 2–5 years

— Infertility (alkylators, busulfan, melphalan, radiation) — counsel and offer fertility preservation when feasible

— Growth retardation, short stature (radiation, HSCT)

— Hypothyroidism (radiation, ¹³¹I-MIBG without adequate thyroid blockade)

— Secondary malignancies: AML/MDS (alkylators, topoisomerase II inhibitors), thyroid cancer, sarcomas in radiation fields

— Neurocognitive deficits especially in those receiving brain radiation or very young at treatment

— Renal dysfunction, pulmonary fibrosis (busulfan)

— Dental abnormalities, scoliosis from radiation

— Persistent OMA-related neurodevelopmental deficits: developmental delay, behavioral disorders, ataxia — even after tumor cure

— Most relapses occur within 2 years post-therapy; late relapses possible

— Refractory/relapsed high-risk disease has poor prognosis (<20% long-term survival)

Disease-related complications at presentation

Treatment-related complications — acute

Treatment-related complications — long-term (survivorship)

Relapse

Board pearl: Long-term survivors need lifelong, structured survivorship care following COG Long-Term Follow-Up Guidelines — cardiac, audiologic, endocrine, renal, and second-cancer surveillance.

Key distinction: OMA-associated neurodevelopmental sequelae persist independent of tumor cure — early immunomodulatory therapy (IVIG, steroids, rituximab) improves outcomes.

When to Escalate Care — ICU, Consults, and Inpatient Triage

— Spinal cord compression with new neurologic deficits → PICU, neurosurgery, oncology

— Hypertensive emergency from catecholamine excess or renovascular compression

— Respiratory failure from massive hepatomegaly or mediastinal mass

— Septic shock in neutropenic patient

— Tumor lysis syndrome with electrolyte derangements, AKI, or arrhythmia

— DIC with active bleeding

— Severe dinutuximab reactions: anaphylaxis, capillary leak with hypotension

— Pediatric hematology/oncology — central role; coordinates workup, biopsy, treatment

— Pediatric surgery — biopsy planning, future resection

— Pediatric radiology / interventional radiology — image-guided biopsy

— Pediatric anesthesia — sedation/anesthesia planning

— Neurosurgery — if intraspinal extension or paraspinal dumbbell tumor

— Ophthalmology — for OMA, proptosis, orbital metastases

— Social work + child life — family support, decision-making

— Any newly diagnosed neuroblastoma typically admitted for expedited workup and biopsy

— Initiation of chemotherapy (especially high-risk induction)

— Febrile neutropenia (any temperature >38.3°C or sustained >38°C with ANC <500)

— Pain crisis (bone mets, dinutuximab infusion)

— Transfusion needs

— Procedure-related observation (post-biopsy, post-resection, post-HSCT)

— New respiratory distress, neurologic change, severe pain, hemodynamic instability

— Inability to tolerate oral intake; significant dehydration

— Concern for relapse with new symptoms (bone pain, mass, weight loss)

Immediate ICU admission criteria

Urgent (same-day) consults at diagnosis

Inpatient admission indications

Transition to higher level of care from outpatient

Multidisciplinary tumor board review required at diagnosis and key decision points (post-induction, relapse)

CCS pearl: A neuroblastoma patient on induction chemo presenting with fever + ANC <500 requires: blood cultures from each lumen of central line, urinalysis/culture, CXR, broad-spectrum IV antibiotics (e.g., cefepime ± vancomycin) within 1 hour, IV fluids, admit. Do not wait for cultures.

Step 3 management: Any new back pain with weakness in a neuroblastoma patient — STAT MRI spine + dexamethasone + neurosurgery/oncology consult before considering anything else; cord compression is a true emergency.

Board pearl: Treat neuroblastoma at a pediatric tertiary cancer center with COG protocol access — referral itself is the right answer on many vignettes.

Key Differentials — Other Pediatric Solid Tumors

— Age: peak 2–5 years (slightly older than NB)

— Origin: kidney (metanephric blastema)

— Imaging: intrarenal mass distorting collecting system; displaces vessels, does not encase; rarely calcified

— Crosses midline less commonly; well-circumscribed

— Often associated with WAGR, Beckwith-Wiedemann, Denys-Drash, hemihypertrophy

— Catecholamines normal; presentation often well-appearing child with incidental abdominal mass

— Key distinction: Wilms = intrarenal, smooth, no calcification, normal catecholamines; NB = extrarenal, calcified, crosses midline, ↑VMA/HVA

— Young children (<3 years), often associated with Beckwith-Wiedemann, FAP

— Markedly elevated AFP

— Right upper quadrant mass; normal urine catecholamines

— Imaging shows hepatic origin

— Soft tissue origin: head/neck (orbit, parameningeal), GU tract, extremities

— Embryonal (younger) vs alveolar (older) subtypes

— Imaging shows soft tissue mass without calcification; markers include myogenin, MyoD1

— Adolescents typically; bony origin (pelvis, long bones)

— Small round blue cell tumor — distinguished by EWS-FLI1 translocation t(11;22)

— No catecholamine elevation

— Elevated AFP and/or β-hCG

— Cystic + solid components, often with fat/calcifications (teratoma)

— Sacrococcygeal location in infants

— Adrenal medullary tumor in older children/adolescents

— Marked hypertension, headaches, sweating, palpitations

— Plasma free metanephrines elevated (vs urine VMA/HVA in NB)

— Associated with MEN2, VHL, NF1, hereditary paraganglioma syndromes

— Key distinction: Pheochromocytoma → metanephrines + hypertensive paroxysms in older child; NB → VMA/HVA + abdominal mass in toddler

— Older adolescents; intrarenal mass; hematuria

— Cushing or virilization features; cortex-derived; rare

Wilms tumor (nephroblastoma) — the most common confused entity

Hepatoblastoma

Rhabdomyosarcoma

Ewing sarcoma / PNET

Germ cell tumors (sacrococcygeal teratoma, mediastinal)

Pheochromocytoma/paraganglioma

Renal cell carcinoma

Adrenocortical carcinoma

Board pearl: A toddler with an abdominal mass: the workup begins by distinguishing NB (extrarenal, calcified, elevated catecholamines) from Wilms (intrarenal, no calcification, normal catecholamines) — both need urgent referral, but management diverges.

Key Differentials — Non-Oncologic Mimics

— Periorbital ecchymoses from NB orbital metastases frequently misdiagnosed as inflicted injury

— Key distinction: Orbital metastases → bilateral raccoon eyes + palpable abdominal mass + elevated catecholamines; NAT → injuries inconsistent with history, other patterned injuries, normal imaging of abdomen

— Step 3 management: Always image abdomen and obtain urine catecholamines before formal child abuse evaluation in a child with unexplained periorbital ecchymoses

— Bone pain, refusal to walk, pallor, hepatosplenomegaly, cytopenias — overlap with metastatic NB

— Key distinction: Peripheral blast cells on smear, marrow exam reveals lymphoblasts; no primary mass on imaging; catecholamines normal

— Both require marrow exam — pursue in parallel when uncertain

— Refusal to bear weight, bone pain, fever

— Inflammatory markers elevated, focal site usually identifiable

— Bone scan or MRI distinguishes from metastatic NB

— Limp, irritability, fevers

— Joint findings dominate; imaging shows joint inflammation, not bony lesions; ANA/RF pattern; catecholamines normal

— Prenatally or perinatally detected adrenal mass

— Cystic on ultrasound, shrinks over time

— Normal urine catecholamines; serial imaging resolves diagnosis

— Hormonal abnormalities; imaging characteristics differ

— Mimics abdominal mass; resolves with bowel regimen and serial exams

— Don't miss true mass — re-examine after disimpaction

— In a patient with familial neuroblastoma + PHOX2B mutation, the two coexist; recognize the neurocristopathy spectrum

— Post-viral cerebellar ataxia (parainfectious)

— Drug intoxication

— Vestibular dysfunction

— Key distinction: True opsoclonus = chaotic, multidirectional, conjugate saccades — pathognomonic; mandates workup for occult NB even if neurologic features predominate

— VIP-secreting NB mimics infectious or inflammatory diarrhea

— Persistent, secretory, large-volume diarrhea with hypokalemia → measure VIP, image abdomen

Child abuse / non-accidental trauma (NAT)

Acute lymphoblastic leukemia / lymphoma

Osteomyelitis / septic arthritis

Juvenile idiopathic arthritis

Adrenal hemorrhage in neonates

Congenital adrenal hyperplasia / adrenal cyst

Constipation with palpable stool

Hirschsprung disease

Opsoclonus-myoclonus mimics

VIPoma / chronic infectious diarrhea

Board pearl: Persistent "viral" diarrhea with hypokalemia in a toddler who fails to thrive → think VIP-secreting neuroblastoma, not chronic gastroenteritis.

Survivorship, Discharge Planning, and Long-Term Care

— Central venous catheter (port or tunneled line) care education for families

— Sick-day plan: when to call (fever >38°C, vomiting, line issues, bleeding)

— Neutropenic precautions: avoid sick contacts, no live vaccines during therapy, food safety (no unpasteurized products, well-cooked foods)

— Medication list: PJP prophylaxis (TMP-SMX), antifungals, antiemetics, growth factor schedule

— Hydration plan, oral care for mucositis prevention

— Pain management: opioid plan for dinutuximab cycles; bowel regimen

— No live vaccines during chemotherapy and for at least 6 months post-therapy

— Inactivated vaccines may be given but immunogenicity reduced during treatment

— Revaccination series typically initiated 6–12 months after completing chemotherapy (consult institutional protocols and COG guidelines)

— Annual influenza vaccine (inactivated) for patient and household contacts

— Household contacts should receive live vaccines on schedule (except oral polio) — herd protection

— Cardiac: echocardiogram every 2–5 years lifelong (anthracycline exposure)

— Audiology: annual hearing tests post-cisplatin; intervention for losses affecting school performance

— Endocrine: thyroid function annually (radiation, MIBG therapy); growth, puberty monitoring; fertility counseling

— Renal function: annual BP, urinalysis, creatinine; especially after nephrectomy or cisplatin

— Pulmonary: PFTs post-busulfan/lung radiation

— Neurocognitive: school performance, neuropsychological testing

— Dental, dermatologic, ophthalmologic exams annually

— Second cancer surveillance: skin exams, awareness of AML/MDS symptoms, breast surveillance if chest radiation (later in life)

— Clinical exam, urine VMA/HVA, imaging (MIBG, MRI) at intervals per protocol

— Educate families on warning signs: bone pain, new mass, weight loss, fatigue

Discharge planning from initial treatment phase

Immunization schedule during/after therapy

Survivorship care plan (COG Long-Term Follow-Up Guidelines)

Relapse surveillance during first 5 years

Step 3 management: Every neuroblastoma survivor needs a written, transferable survivorship care plan at the end of therapy listing cumulative chemo/radiation exposures and required lifelong surveillance — this is the standard of care and a frequent test point on transitions of care.

Board pearl: Cumulative anthracycline dose + chest radiation are the two strongest predictors of late cardiomyopathy — flag these in the survivorship document.

Follow-Up, Monitoring, and Psychosocial Care

— Pre-each chemotherapy cycle: CBC with differential, CMP, urinalysis, vitals, weight, performance status

— Cardiac monitoring: baseline echo, repeat before each anthracycline cycle and at cumulative milestones (e.g., 150, 300 mg/m²)

— Audiology: baseline before cisplatin, before each cisplatin cycle, end of therapy, then annually

— Renal function: GFR (cystatin C or measured GFR) before cisplatin cycles

— Disease response: imaging (CT/MRI primary site + MIBG) after induction cycles 2 and 4, post-consolidation, and at therapy completion

— Urine VMA/HVA: each restaging time point — should normalize with response

— Year 1–2: clinic visits every 1–2 months

— Year 2–3: every 3 months

— Year 3–5: every 6 months

— After year 5: annually with transition to survivorship clinic

— Imaging frequency tapers similarly; MIBG and MRI/CT periodically

— Physical therapy for deconditioning, post-surgical mobility, neuropathy (vincristine), OMA-related ataxia

— Occupational therapy for fine motor recovery and ADLs

— Speech therapy if needed

— School reintegration plan: 504 plan or IEP for cognitive late effects, fatigue, absences

— Early intervention services for infants/toddlers

— Audiologic devices (hearing aids) if cisplatin ototoxicity

— Mental health screening for patient (depression, PTSD, anxiety) and parents/siblings

— Sibling support: high rates of distress among siblings

— Financial counseling, family medical leave navigation

— Palliative care integration — early consultation for symptom management, not solely end-of-life

— Spiritual care, child life specialists, art/music therapy

— Late-adolescent survivors require structured transition to adult survivorship clinics with documented care plans — a Step 3 emphasis on transitions

— Be honest and stage-appropriate; tailor to risk group

— High-risk survivors face significant late effects even with cure

Active treatment monitoring intervals

Off-therapy surveillance schedule (typical)

Rehabilitation and developmental support

Psychosocial support

Transition to adult care

Counseling families on prognosis

Board pearl: Palliative care is not equivalent to hospice — integrate palliative consultation early in high-risk neuroblastoma for symptom management and goals-of-care discussions, regardless of curative intent.

Step 3 management: Annual survivorship visits with structured screening (cardiac, audiologic, endocrine, renal, neurocognitive, second cancer) are the long-term care backbone — missing them is a board-flagged gap.

Ethical, Legal, and Patient Safety Considerations

— Parents/legal guardians provide consent; assent sought from school-age children and adolescents (typically ≥7 years)

— Discuss alternatives, including observation for stage MS or low-risk infants — overtreatment is a real harm

— Document understanding of late effects (infertility, cardiomyopathy, hearing loss, secondary cancer) — these are foreseeable and require explicit consent

— Fertility preservation counseling before gonadotoxic therapy — ethical obligation even in young patients (ovarian/testicular tissue cryopreservation options)

— Most pediatric oncology care occurs on COG protocols; consent must clearly distinguish standard care from research

— Therapeutic misconception is common — ensure families understand randomization and research aims

— IRB oversight, ongoing assent for adolescents

— Periorbital ecchymoses misattributed to abuse can delay cancer diagnosis; conversely, missing actual abuse is harmful

— Both workups can proceed in parallel — obtain imaging and urine catecholamines while social work evaluates

— Mandatory reporting laws still apply if abuse is suspected; the differential includes NB

— Step 3 management: Always image and order urine catecholamines in a child with unexplained periorbital ecchymoses before finalizing an abuse determination

— High-risk relapsed neuroblastoma has poor prognosis — early palliative care integration is ethically standard

— Advance care planning including code status, DNAR (do-not-attempt-resuscitation) discussions with adolescent assent when developmentally appropriate

— Phase 1 trial enrollment in refractory disease — balance hope, burden, and realistic expectations

— Discharge from inpatient chemotherapy to home: error-prone period

— Reconcile medications, document central line care, ensure access to 24/7 oncology line

— Confirm follow-up appointment scheduled before discharge

— Transfer between facilities: medication errors, missed appointments, lost imaging — use structured handoffs and shared EHR records

— Transition to adult survivorship clinic: high dropout rate — provide written survivorship care plan and warm handoff

— Geographic and insurance barriers to tertiary cancer centers — social work, financial counseling

— Disparities in outcomes among minority and rural populations

— Pediatric chemotherapy dosing (BSA, weight, age) is error-prone; mandate two independent verifications, electronic order sets, and barcoded administration

Informed consent in pediatrics

Clinical trial enrollment

Mandatory reporting and child abuse considerations

End-of-life and goals-of-care

Transitions of care risks

Health systems and equity

Patient safety: chemotherapy errors

Board pearl: An adolescent with relapsed high-risk neuroblastoma can ethically participate in assent for DNAR and palliative care decisions; respect their voice while obtaining parental consent.

High-Yield Associations and Rapid-Fire Facts

— Periorbital ecchymoses (raccoon eyes) — orbital bone mets

— Opsoclonus-myoclonus-ataxia (dancing eyes, dancing feet) — paraneoplastic

— Horner syndrome — cervicothoracic primary

— Blueberry muffin baby — skin mets in infants (stage MS)

— Intractable secretory diarrhea — VIP-secreting tumor

— Hypertension in a young child

— Bone pain, refusal to walk, pancytopenia

— Urine VMA and HVA (catecholamine metabolites) — elevated in >90%

— Elevated LDH, ferritin → adverse prognosis

— Serum NSE — historical marker

Most common extracranial solid tumor of childhood; most common cancer in infants <1 year

Cell of origin: neural crest → sympathetic nervous system

Most common primary site: adrenal medulla (~40%), then abdominal sympathetic ganglia, posterior mediastinum, neck, pelvis

Median age at diagnosis: 17–22 months

Classic clinical clues:

Tumor markers:

Imaging: calcified, midline-crossing, vessel-encasing mass; MIBG scan highly specific

Histology: small round blue cells, Homer-Wright rosettes, neuropil; positive for synaptophysin, chromogranin, PHOX2B, NSE

Most important molecular prognostic marker: MYCN amplification (poor prognosis)

Other adverse markers: 1p loss, 11q loss, 17q gain, unfavorable histology, age ≥18 months

Favorable: hyperdiploidy in infants, MYCN non-amplified, favorable histology, age <18 months, stage L1 or MS

Staging system: INRGSS (L1, L2, M, MS)

Stage MS: <18 months + mets to skin, liver, marrow (<10%, no cortical bone) → often spontaneously regresses

Risk groups: low / intermediate / high (COG)

High-risk treatment: induction chemo → surgery + radiation → tandem autologous HSCT (busulfan/melphalan) → dinutuximab + GM-CSF + IL-2 + isotretinoin maintenance

Targeted immunotherapy: dinutuximab (anti-GD2 monoclonal antibody) — major survival advance

Differentiation agent: isotretinoin (13-cis-retinoic acid) in maintenance

Refractory disease: ¹³¹I-MIBG therapy, ALK inhibitors (crizotinib, lorlatinib)

Familial syndromes: ALK germline mutations; PHOX2B mutations (linked to Hirschsprung + CCHS)

Differential: Wilms tumor (intrarenal, no calcification, normal catecholamines)

Key toxicities to monitor lifelong: cardiomyopathy (anthracyclines), hearing loss (cisplatin), infertility (alkylators), second malignancies, hypothyroidism

Board pearl: Whenever a Step 3 vignette mentions raccoon eyes + abdominal mass + toddler, the answer is neuroblastoma; confirm with urine VMA/HVA + abdominal imaging.

Board Question Stem Patterns

"A 2-year-old presents with a 3-week history of irritability, refusal to walk, and bruising around both eyes. Exam reveals a firm, irregular abdominal mass crossing the midline."

— Answer path: urine VMA/HVA, abdominal MRI/CT, referral to pediatric oncology; expect biopsy showing small round blue cells with Homer-Wright rosettes

"A 14-month-old develops sudden chaotic eye movements, myoclonic jerks, and unsteady gait. Neurologic exam is otherwise unremarkable."

— Answer path: image chest/abdomen/pelvis for occult neuroblastoma — even with normal exam; OMA is paraneoplastic until proven otherwise

"A 3-year-old has new-onset right-sided ptosis, miosis, and anhidrosis without trauma."

— Answer path: MRI of head, neck, and chest looking for sympathetic chain tumor; check urine catecholamines

"A toddler is brought in for evaluation of bilateral periorbital bruising. Skeletal survey is unremarkable, but the abdomen is distended with a palpable mass."

— Answer path: urine VMA/HVA + abdominal imaging; do not finalize NAT report before oncologic workup

"A 3-year-old has an asymptomatic flank mass discovered during bath time. Imaging shows a non-calcified mass arising from the right kidney."

— Answer: Wilms tumor — intrarenal, no calcification, normal catecholamines; NB would cross midline, calcify, and elevate VMA/HVA

"A 4-month-old has a small adrenal mass, hepatomegaly, and bluish skin nodules. Urine VMA elevated; MYCN non-amplified; favorable biology."

— Answer: stage MS; observation or low-dose therapy only if symptomatic

"A 2-year-old with known paraspinal neuroblastoma develops new lower extremity weakness and urinary retention."

— Answer: STAT MRI spine, dexamethasone, emergent chemotherapy (preferred over surgery in young children); admit to PICU

"A child receiving anti-GD2 antibody therapy develops severe diffuse pain, hypotension, and capillary leak during infusion."

— Answer: anticipated dinutuximab toxicity; manage with opioids, fluids, antihistamines, slow infusion; do not discontinue therapy unless severe anaphylaxis

"A 1-year-old has 6 weeks of watery diarrhea, weight loss, and hypokalemia despite formula changes."

— Answer: image for neuroblastoma (organ of Zuckerkandl or adrenal); check urine VMA/HVA and VIP

"Infant with neuroblastoma + history of Hirschsprung and central hypoventilation."

— Answer: PHOX2B mutation — neurocristopathy syndrome; genetic counseling

Stem 1 — Classic presentation

Stem 2 — Opsoclonus-myoclonus

Stem 3 — Horner syndrome in a child

Stem 4 — Periorbital ecchymoses misread as abuse

Stem 5 — Wilms vs neuroblastoma

Stem 6 — Stage MS infant

Stem 7 — Spinal cord compression

Stem 8 — Dinutuximab toxicity

Stem 9 — VIP-secreting tumor

Stem 10 — Familial neuroblastoma

Board pearl: The single most consistent first step on a NB stem is urine VMA/HVA + cross-sectional imaging before invasive workup.

One-Line Recap

Neuroblastoma is a neural crest–derived sympathetic tumor of toddlers presenting with a calcified, midline-crossing abdominal mass, periorbital ecchymoses, opsoclonus-myoclonus, or Horner syndrome — diagnosed by urine VMA/HVA plus cross-sectional imaging and MIBG, biopsy-confirmed with MYCN amplification and INRGSS stage driving risk-stratified COG therapy.

Suspect neuroblastoma in any child <5 with raccoon eyes, an abdominal mass crossing the midline, refusal to walk with bone pain, opsoclonus-myoclonus-ataxia, intractable secretory diarrhea (VIP), or unexplained Horner syndrome — periorbital ecchymoses + abdominal mass is the highest-yield combo

Diagnostic workup: start with urine VMA/HVA, CBC, CMP, LDH, ferritin, abdominal ultrasound, then CT/MRI of chest/abdomen/pelvis (look for calcifications, midline crossing, vascular encasement, IDRFs), MIBG scan, bilateral bone marrow biopsies, and tumor biopsy for histology + MYCN amplification, ploidy, and 1p/11q/17q analysis — INRGSS staging (L1, L2, M, MS) plus age and biology drives risk stratification

Risk-based management: low-risk often resected or observed (especially stage MS infants — spontaneous regression); high-risk (any MYCN-amplified or metastatic ≥18 months) requires induction chemotherapy → surgery + radiation → tandem autologous HSCT (busulfan/melphalan) → dinutuximab (anti-GD2) + isotretinoin maintenance

Long-term survivorship: lifelong surveillance for cardiomyopathy (anthracyclines), hearing loss (cisplatin), infertility, hypothyroidism, second malignancies, and OMA-related neurodevelopmental sequelae per COG guidelines

Board pearl: Toddler + raccoon eyes + crossing-midline abdominal mass = neuroblastoma; confirm with urine catecholamines and imaging before invasive workup, and refer to a pediatric cancer center for COG-protocol care.