Overview
- Solid tumours constitute a significant proportion of childhood malignancies, second in frequency only to leukaemia and CNS tumours.
- The spectrum includes embryonal tumours (neuroblastoma, Wilms tumour, hepatoblastoma), sarcomas (rhabdomyosarcoma, Ewing sarcoma, osteosarcoma), germ cell tumours, and retinoblastoma.
- Each tumour type has a characteristic age distribution, molecular biology, and therapeutic approach.
- Management requires integration of clinical recognition, molecular pathology, staging, and multidisciplinary care within the framework of international cooperative groups, the Children's Oncology Group (COG) and the International Society of Paediatric Oncology (SIOP).
- All major Australian and New Zealand paediatric oncology centres operate within the COG framework.
Epidemiology and Aetiology
Incidence and Age Distribution
| Tumour Type | Peak Age | Relative Frequency |
|---|---|---|
| Neuroblastoma | Infancy-3 years | ~8-10% of childhood cancers |
| Wilms tumour (nephroblastoma) | 3-4 years | ~5-6% |
| Hepatoblastoma | <3 years | ~1% |
| Retinoblastoma | <5 years | ~3% |
| Rhabdomyosarcoma | Bimodal: 2-6 yrs, adolescence | ~3-4% |
| Osteosarcoma | Adolescence | ~3% |
| Ewing sarcoma | Adolescence | ~2% |
| Germ cell tumours | Infancy + adolescence | ~3-4% |
- Neonatal solid tumours account for approximately 2-3% of all paediatric cancers.
- Neuroblastoma is the most common neonatal solid malignancy; soft-tissue tumours account for ~25% of neonatal tumours (benign in >two-thirds of cases).
- Rhabdoid tumours and rhabdomyosarcoma are rare neonatal malignancies but carry a poor prognosis.
Genetic Predisposition Syndromes
| Syndrome / Gene | Associated Tumour |
|---|---|
| WAGR (WT1 deletion, 11p13) | Wilms tumour |
| Denys-Drash (WT1 mutation) | Wilms tumour |
| Beckwith-Wiedemann (IGF2/CDKN1C, 11p15) | Wilms tumour (4-10% risk), hepatoblastoma |
| Li-Fraumeni (TP53) | Osteosarcoma, rhabdomyosarcoma, brain tumours |
| Neurofibromatosis type 1 (NF1) | Optic pathway glioma, GIST, MPNST |
| Retinoblastoma (RB1 germline) | Retinoblastoma; second primaries (osteosarcoma) |
| Familial adenomatous polyposis (APC) | Hepatoblastoma, desmoid tumours |
| Down syndrome | Reduced risk of most solid tumours; increased risk of testicular GCTs (~50× general population) |
Recognition of predisposition syndromes is essential for family counselling, cascade testing, and tumour surveillance planning.
Pathophysiology
Paediatric solid tumours arise predominantly from embryonic precursor cells that fail to undergo normal differentiation, reflected histologically as small round blue cells or undifferentiated stroma. Key molecular mechanisms:
- Tumour suppressor gene loss (e.g. WT1 in Wilms tumour, RB1 in retinoblastoma)
- Proto-oncogene amplification (e.g. MYCN amplification, major adverse prognostic factor in neuroblastoma)
- Chromosomal translocations producing fusion oncoproteins:
- EWS-FLI1 (and other EWS-ETS fusions), Ewing sarcoma
- PAX3/7-FOXO1, alveolar rhabdomyosarcoma
- ETV6-NTRK3, infantile fibrosarcoma
- Loss of imprinting (IGF2 dysregulation, Beckwith-Wiedemann-associated tumours)
- ALK mutations, PHOX2B mutations, segmental chromosomal aberrations (1p loss, 11q loss, neuroblastoma biology)
Precision oncology enables molecular stratification and identification of targetable driver mutations for risk-adapted therapy.
Clinical Features
General Red Flags
- Unexplained abdominal mass
- Unexplained weight loss, anorexia, fatigue
- Persistent bone pain (especially nocturnal or at rest)
- Proptosis, leukocoria, or sudden visual change
- Unexplained hypertension (neuroblastoma, Wilms tumour)
- Persistent lymphadenopathy >2 cm unresponsive to antibiotics
Neuroblastoma
- Arises from neural crest cells in the adrenal medulla or sympathetic chain.
- Most common extracranial solid tumour in children under 5 years.
Clinical features:
- Abdominal mass (most common primary site, adrenal gland)
- Paravertebral or posterior mediastinal mass
- Periorbital bruising ("panda eyes"), metastatic orbital disease
- Opsoclonus-myoclonus syndrome (paraneoplastic, 2-3%)
- Horner syndrome (cervical/thoracic primary)
- Hypertension, secretory diarrhoea (excess VIP), sweating
- Stage 4S: Infants <12 months with localised primary + dissemination restricted to skin, liver, and/or bone marrow (excluding cortical bone), spontaneous regression typically occurs
International Neuroblastoma Staging System (INSS)
| Stage | Description |
|---|---|
| 1 | Localised tumour, complete resection, negative nodes |
| 2A | Localised, incomplete resection, ipsilateral nodes negative |
| 2B | Localised, ipsilateral nodes positive |
| 3 | Unresectable unilateral tumour crossing midline, or bilateral extension |
| 4 | Distant metastases (bone, bone marrow, liver, distant nodes) |
| 4S | Infant <12 months, localised primary + skin/liver/bone marrow (not cortical bone); spontaneous regression usual |
Note: The International Neuroblastoma Risk Group Staging System (INRGSS), based on image-defined risk factors (IDRFs) rather than surgical findings, is increasingly used in clinical trials alongside the INSS.
- Risk stratification integrates INSS stage, age at diagnosis, Shimada histological classification, ploidy (hyperdiploid = favourable), and MYCN amplification status.
- High-risk disease (stage 4, age >12 months; or any stage with MYCN amplification) has markedly inferior outcomes.
Wilms Tumour (Nephroblastoma)
Most common renal malignancy in children; peak age 3-4 years.
Clinical features:
- Smooth, non-tender unilateral abdominal mass (most common presentation)
- Haematuria (gross or microscopic), hypertension
- Associated anomalies: aniridia, hemihypertrophy, genitourinary anomalies
- Bilateral in 5-10% (higher in predisposition syndromes)
- Rhabdoid tumours of the kidney are histologically distinct, treated similarly, but carry considerably worse outcomes
- Histology: Triphasic, blastemal, stromal, and epithelial components.
- Anaplastic histology (diffuse > focal) is the main adverse histological feature.
COG surgical staging (post-nephrectomy):
| Stage | Description |
|---|---|
| I | Tumour limited to kidney, completely resected |
| II | Extension beyond kidney, completely resected |
| III | Residual non-haematogenous disease confined to abdomen |
| IV | Haematogenous metastases (lung, liver, bone, brain) |
| V | Bilateral renal involvement |
- Mesoblastic nephroma accounts for ~80% of solid renal masses in neonates.
- Although generally benign (capable of rare metastasis), it is treated by nephrectomy alone; chemotherapy is considered only for incomplete excision or rupture of the cellular/atypical histological type.
- Prognosis is excellent (~95% overall survival).
Wilms tumour surveillance: Abdominal ultrasound every 3 months until age 7 years is recommended for children with ≥5% risk, Beckwith-Wiedemann syndrome (4-10% risk), WT1-associated syndromes (WAGR, Denys-Drash), familial Wilms tumour, or offspring of a parent treated for bilateral disease.
Hepatoblastoma
Clinical features:
- Large right-sided abdominal mass, typically in children <3 years
- Markedly elevated alpha-fetoprotein (AFP), key diagnostic and response biomarker
- Association with Beckwith-Wiedemann syndrome, FAP, extreme prematurity
Rhabdomyosarcoma
Most common soft-tissue sarcoma in children. Histological subtypes: embryonal, alveolar (PAX-FOXO1 fusion, worse prognosis), and botryoid (a variant of embryonal; most common in neonatal period along with embryonal subtype).
| Primary Site | Clinical Presentation |
|---|---|
| Head and neck, orbit | Proptosis, periorbital swelling |
| Parameningeal (nasopharynx, middle ear) | Cranial nerve palsy, epistaxis, otorrhoea |
| Genitourinary (bladder, vagina) | Haematuria, urinary obstruction, grape-like polyps |
| Extremity | Painless soft-tissue mass |
| Paratesticular | Painless scrotal mass |
Infantile Fibrosarcoma
- Most common soft-tissue sarcoma in neonates/infants.
- Although histologically similar to adult fibrosarcoma, it has a much more favourable biology, metastases are rare, and spontaneous maturation can occur.
- Presents as a soft-tissue mass, most commonly in the head, neck, or extremities.
- ETV6-NTRK3 fusion is the defining cytogenetic abnormality.
- Treatment is surgical excision; chemotherapy (vincristine, actinomycin D, cyclophosphamide) is used when excision would be disfiguring or is incomplete.
- TRK inhibitors (larotrectinib, entrectinib) have excellent activity.
Osteosarcoma
- Adolescents; metaphysis of distal femur, proximal tibia, proximal humerus
- Persistent, worsening bone pain; soft-tissue swelling; pathological fracture
Ewing Sarcoma
- Diaphysis of long bones, pelvis, ribs, vertebrae
- Pain, swelling, systemic features (fever, elevated ESR/CRP), may mimic osteomyelitis
- "Onion-skin" periosteal reaction on plain radiograph
Retinoblastoma
- Leukocoria (white pupillary reflex), most common presentation
- Strabismus, red eye, decreased vision
- Bilateral in hereditary form (germline RB1 mutation, autosomal dominant); unilateral usually sporadic
- Age <5 years; earlier onset in hereditary form
- Germline RB1 carriers: high lifetime risk of second malignancies, particularly osteosarcoma in irradiated fields
Neonatal Brain Tumours
- CNS tumours are the most common solid malignancy in childhood but are rare in the neonatal period (0.5-1.5% of all childhood CNS neoplasms; incidence ~4.24 per million live births).
- Neonatal brain tumours are predominantly supratentorial.
- Teratomas account for one-third to one-half of all cases, frequently in the pineal or suprasellar region, often very large with calcification visible on CT, and carry high operative mortality.
- Astrocytomas account for 20-30%, with PNETs/medulloblastoma the next most common.
Investigations
Initial Assessment (All Solid Tumours)
| Investigation | Purpose |
|---|---|
| FBC, film, ESR, CRP | Baseline; evidence of marrow infiltration |
| UEC, LFTs, uric acid, LDH | Tumour bulk, hepatic involvement, TLS risk |
| Coagulation profile | Pre-operative; hepatic function |
| AFP, β-hCG | Germ cell tumour, hepatoblastoma |
| Urinary catecholamines (VMA, HVA) | Neuroblastoma |
| ^{123}I-MIBG scintigraphy | Neuroblastoma staging and response |
| Bone marrow aspirate + trephine | Neuroblastoma, Ewing, rhabdomyosarcoma staging |
Imaging
| Modality | Application |
|---|---|
| Ultrasound | First-line abdominal mass assessment |
| CT chest/abdomen/pelvis | Staging, lymph nodes, pulmonary metastases |
| MRI | Soft-tissue detail, spinal cord, brain, local extension |
| PET-CT (FDG) | Ewing, osteosarcoma; response assessment |
| ^{123}I-MIBG scintigraphy | Neuroblastoma-specific |
| Plain radiographs | Osteosarcoma, Ewing, bone lesion characterisation |
Molecular and Genetic Testing
- Tumour biopsy: Histology + molecular studies, FISH, NGS, RNA fusion panels
- Germline testing where predisposition suspected (RB1, TP53, WT1, BRCA2)
- MYCN amplification, segmental chromosomal aberrations (1p loss, 11q loss), neuroblastoma
- EWS-ETS fusion detection (PCR/FISH), Ewing sarcoma
- ETV6-NTRK3 fusion: infantile fibrosarcoma
- Ploidy/DNA index: neuroblastoma (hyperdiploid = favourable)
Diagnosis
- Diagnosis requires histopathological confirmation in virtually all cases.
- Core biopsy or excisional biopsy (depending on site and resectability) is standard.
- Molecular pathology is integral to WHO-based classification.
| Tumour | Diagnostic Hallmarks |
|---|---|
| Neuroblastoma | Catecholamine excess, MIBG avidity, Homer Wright rosettes |
| Wilms tumour | Triphasic histology (blastemal, stromal, epithelial) |
| Hepatoblastoma | Markedly elevated AFP, fetal/embryonal histology |
| Retinoblastoma | Clinical + imaging (Flexner-Wintersteiner rosettes on biopsy, rarely required) |
| Rhabdomyosarcoma | Myogenic markers (MyoD1, desmin, myogenin); PAX-FOXO1 in alveolar subtype |
| Osteosarcoma | Malignant osteoid production |
| Ewing sarcoma | EWS-ETS gene fusion; CD99 positivity |
| Infantile fibrosarcoma | ETV6-NTRK3 fusion |
| Germ cell tumour | AFP/β-hCG elevation; histological subtype |
Management
Principles of Multidisciplinary Care
- Management is conducted through an MDT including paediatric oncologists, surgeons, radiation oncologists, pathologists, radiologists, psychosocial support, and allied health.
- Australian and NZ centres operate within COG or SIOP clinical trial frameworks.
- Precision therapeutics guided by genomic profiling of driver mutations is now standard approach.
Surgery
| Tumour | Surgical Approach |
|---|---|
| Wilms tumour (unilateral) | Upfront nephrectomy (COG); pre-operative chemotherapy then surgery (SIOP bilateral or renal-sparing cases) |
| Wilms tumour (bilateral) | Pre-operative chemotherapy first; renal-sparing surgery attempted |
| Neuroblastoma (low/intermediate risk) | Upfront resection |
| Neuroblastoma (high risk) | Induction chemotherapy first, then resection |
| Hepatoblastoma | Resection ± liver transplantation; pre-operative cisplatin-based chemotherapy to downstage |
| Rhabdomyosarcoma | Wide local excision where feasible; organ preservation prioritised |
| Osteosarcoma/Ewing | Limb-salvage surgery standard; amputation reserved for selected cases |
| Mesoblastic nephroma | Nephrectomy alone; chemotherapy only for incomplete excision/rupture of cellular type |
| Infantile fibrosarcoma | Surgical excision; chemotherapy if excision disfiguring or incomplete |
Intraoperative tumour spillage in Wilms tumour significantly worsens staging and prognosis.
Chemotherapy
| Tumour | Common Agents |
|---|---|
| Neuroblastoma (high-risk induction) | Cyclophosphamide, cisplatin, etoposide, doxorubicin, topotecan → ASCT consolidation |
| Wilms tumour | Vincristine, actinomycin D ± doxorubicin (stage-dependent) |
| Hepatoblastoma | Cisplatin ± doxorubicin |
| Rhabdomyosarcoma | Vincristine, actinomycin D, cyclophosphamide (VAC) |
| Osteosarcoma | Cisplatin, doxorubicin, high-dose methotrexate (with leucovorin rescue) |
| Ewing sarcoma | Vincristine, doxorubicin, cyclophosphamide (VDC) alternating with ifosfamide + etoposide (IE) |
| Retinoblastoma | Carboplatin, vincristine, etoposide ± intravitreal/intraarterial chemotherapy |
| Infantile fibrosarcoma | Vincristine, actinomycin D, cyclophosphamide |
- Dosing is weight-based (mg/kg) in children <12 kg and BSA-based (mg/m²) in larger children.
- Dose modification required for neonates, infants, and organ dysfunction.
Radiation Therapy
- Used selectively given long-term sequelae in growing children
- Indications: residual/unresectable disease, specific histological types, whole-lung irradiation (pulmonary metastases in Wilms tumour), local control in Ewing sarcoma
- Avoided in infants where possible; proton beam therapy increasingly used to reduce scatter dose
Targeted and Biological Therapies
| Agent | Indication |
|---|---|
| Dinutuximab (anti-GD2 monoclonal antibody) | Maintenance in high-risk neuroblastoma post-ASCT; significantly improves event-free survival |
| Isotretinoin (13-cis retinoic acid) | Differentiation therapy in neuroblastoma maintenance post-ASCT |
| ALK inhibitors (crizotinib, lorlatinib) | ALK-mutant neuroblastoma (emerging) |
| Larotrectinib / entrectinib (TRK inhibitors) | ETV6-NTRK3-positive infantile fibrosarcoma and other NTRK-fusion tumours |
| Intraarterial ophthalmic artery chemotherapy | Retinoblastoma, eye preservation |
Haematopoietic Stem Cell Transplantation
- Tandem autologous SCT with consolidation is standard in high-risk neuroblastoma following induction chemotherapy
- Allogeneic SCT in selected relapsed/refractory haematological malignancies; role in solid tumours limited
- HSCT indications continue to evolve as frontline therapies improve
Complications
Acute Treatment Toxicities
| Toxicity | Associated Agents / Context |
|---|---|
| Tumour lysis syndrome | High-burden tumours at diagnosis |
| Nephrotoxicity | Cisplatin, ifosfamide (Fanconi syndrome) |
| Cardiotoxicity | Anthracyclines (doxorubicin), cumulative dose-dependent |
| Ototoxicity | Cisplatin, high-frequency sensorineural hearing loss |
| Peripheral neuropathy | Vincristine |
| Hepatic veno-occlusive disease | SCT conditioning regimens |
| Neutropenic sepsis | All cytotoxic regimens |
Late Effects of Treatment
| Domain | Complication |
|---|---|
| Cardiac | Cardiomyopathy (anthracyclines), pericarditis (XRT) |
| Renal | CKD (nephrectomy + nephrotoxic agents) |
| Endocrine | GH deficiency, hypothyroidism, gonadal failure, early/late puberty |
| Musculoskeletal | Scoliosis, limb length discrepancy, avascular necrosis |
| Neurocognitive | Learning difficulties, cranial XRT, high-dose methotrexate |
| Second malignancies | Secondary leukaemia, solid tumours (post-XRT); RB1 germline: very high risk of osteosarcoma |
| Hearing | Sensorineural hearing loss (cisplatin), impacts schooling |
| Fertility | Gonadotoxicity from alkylating agents; fertility preservation counselling in adolescents pre-treatment |
- Long-term follow-up uses the COG Long-Term Follow-Up Guidelines (survivorshipguidelines.org).
- In Australia/NZ, this framework is accessed through COG membership.
- UK centres utilise the National Cancer Survivorship Initiative (NCSI) care pathways.
Prognosis
Survival by Tumour Type
| Tumour | 5-Year Survival (Approximate) |
|---|---|
| Wilms tumour (overall) | >85-90% |
| Mesoblastic nephroma | ~95% |
| Neuroblastoma, low/intermediate risk | >90% |
| Neuroblastoma, high risk | 40-50% with modern therapy |
| Hepatoblastoma (resectable) | ~70-80% |
| Retinoblastoma (non-metastatic) | >95% |
| Rhabdomyosarcoma (localised) | ~70-80% |
| Osteosarcoma (localised) | ~65-70% |
| Ewing sarcoma (localised) | ~60-70% |
| Ewing/osteosarcoma (metastatic) | <30% |
| Rhabdoid tumour | Poor, usually fatal regardless of treatment |
Poor prognostic features in neuroblastoma: MYCN amplification, age >18 months, INSS stage 4, unfavourable Shimada histology, segmental chromosomal aberrations (1p, 11q loss), diploid tumour.
When to Refer / Admit
Urgent Referral to Paediatric Oncology
- Any child with an unexplained abdominal, retroperitoneal, or soft-tissue mass
- Leukocoria in any infant or young child, same-day ophthalmology and oncology referral
- Unexplained hypertension with abdominal mass
- Bone pain with systemic features (fever, weight loss, elevated inflammatory markers) unresponsive to analgesia
- Paraneoplastic features (opsoclonus-myoclonus, secretory diarrhoea, Horner syndrome)
- Mediastinal mass on chest X-ray
Oncological Emergencies Requiring Admission
| Emergency | Key Features |
|---|---|
| Tumour lysis syndrome | Hyperkalaemia, hyperphosphataemia, hyperuricaemia and hypocalcaemia with risk of acute kidney injury and arrhythmia; greatest risk with bulky, rapidly proliferating disease (e.g. stage 4 neuroblastoma, large germ cell tumours) at the start of treatment; managed with hyperhydration and urate-lowering therapy (rasburicase or allopurinol) |
| Superior mediastinal / SVC syndrome | Anterior mediastinal mass (lymphoma, germ cell tumour, metastatic disease) causing facial and upper-limb oedema, plethora, distended neck veins, cough, stridor and orthopnoea; high risk of airway and cardiovascular collapse with sedation or general anaesthesia, obtain a tissue diagnosis by the least invasive route |
| Malignant spinal cord compression | Epidural tumour extension (paravertebral neuroblastoma "dumbbell" tumours, Ewing sarcoma, rhabdomyosarcoma) presenting with back pain, limb weakness, a sensory level and bladder or bowel dysfunction; requires emergency whole-spine MRI, immediate dexamethasone and urgent oncology/neurosurgical input |
| Raised intracranial pressure | CNS primary or metastatic disease causing early-morning headache, vomiting, papilloedema, diplopia and declining conscious state, with the late Cushing triad (hypertension, bradycardia, irregular respiration); risk of herniation, urgent imaging, dexamethasone and neurosurgical referral |
| Febrile neutropenia | Fever ≥38.0°C with neutrophils <0.5 × 10⁹/L in a child receiving chemotherapy; may progress rapidly to septic shock; admit for blood cultures and empirical broad-spectrum IV antibiotics within one hour |
| Massive hepatomegaly (infant stage 4S neuroblastoma) | Rapid hepatic enlargement in infants causing respiratory compromise, abdominal compartment syndrome and coagulopathy; may require low-dose chemotherapy or hepatic irradiation despite the otherwise favourable tumour biology |