Neuroblastoma
Low, intermediate, and high-risk neuroblastoma
DefinitionClick to collapse
Neuroblastoma is a cancer originating from the developing sympathetic nervous system and is the most common extracranial solid tumor in children [1,2]. It is a primitive neoplasm of neuroectodermal origin composed of neuroblasts (immature nerve cells) arising from the embryonic neural crest [5,54]. These tumors may occur anywhere in the sympathoadrenal neuroendocrine system, including the adrenal gland, connective/soft tissue, retroperitoneum, and mediastinum [5,54]. Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma are collectively referred to as neuroblastic tumors, all with similar imaging appearance [1,2,54]. The tumor arises from the sympathetic nervous system and local extension mainly consists of vascular encasement, infiltration of adjacent soft tissues and organs (most commonly kidneys and liver), and infiltration of the foramina and epidural space of the spinal canal when the primary tumor arises from a paraspinal sympathetic chain [55]. Approximately 50% of patients present with localized or regional disease, and approximately 35% have regional lymph node spread at diagnosis [4,67]. The International Neuroblastoma Risk Group (INRG) Staging System (INRGSS) classifies tumors as L1 (localized, no image-defined risk factors [IDRFs]), L2 (locoregional with one or more IDRFs), M (distant metastatic disease except MS), and MS (metastatic disease in children <18 months confined to skin, liver, and/or bone marrow with <10% involvement) [55]. Risk classification is assigned based on age, INRG stage, MYCN amplification status, histopathology (favorable/unfavorable), segmental chromosomal aberrations (SCAs), and ploidy, with 5-year EFS rates of 90.7% for low-risk, 85.1% for intermediate-risk, and 51.2% for high-risk disease [47].
EpidemiologyClick to collapse
Neuroblastoma is the most common extracranial solid tumor in children, with an estimated 600 to 800 patients diagnosed annually in the United States [1,3]. The prevalence is approximately 1 per 7000 live births [2]. The average age at diagnosis is between 1 and 2 years, and the vast majority of individuals are <5 years of age at diagnosis [3,4]. Approximately 50% of patients present with localized or regional disease, and approximately 35% have regional lymph node spread at time of diagnosis [67]. Racial and ethnic disparities exist: a recent study found that 5-year survival was higher for white (80.7%) and Hispanic (80.8%) patients compared with Black patients (72.6%) [7,9]. Overall survival by risk group, based on the revised COG risk classification: low-risk 5-year OS 97.9% (±0.5%), intermediate-risk 5-year OS 95.8% (±0.8%), high-risk 5-year OS 62.5% (±1.3%) [47]. Five-year event-free survival rates are 90.7% for low-risk, 85.1% for intermediate-risk, and 51.2% for high-risk [47]. Outcomes have improved over time with increasingly intensive multimodal therapy, but high-risk disease remains challenging. Paraneoplastic syndromes occur in a small subgroup: opsoclonus-myoclonus-ataxia syndrome (OMAS) occurs in approximately 2% of patients, and vasoactive intestinal peptide tumor (VIPoma) syndrome occurs in <1% [29,24]. Familial neuroblastoma is rare, estimated at 1–2% of all cases [12]. The incidence of neuroblastoma is stable but outcomes vary by race/ethnicity and socioeconomic status [6,8].
SubtypesClick to collapse
Neuroblastoma (Schwannian stroma-poor)
The most common type of peripheral neuroblastic tumor, composed of neuroblasts with variable Schwannian stroma. Subtyped by degree of neuroblastic differentiation: undifferentiated, poorly differentiated, or differentiating. Further classified by mitosis-karyorrhexis index (MKI): low (<100/5000 cells), intermediate (100–200/5000), or high (≥200/5000).
Ganglioneuroblastoma, nodular (composite, Schwannian stroma-rich/stroma-dominant and stroma-poor)
Tumor composed of at least two distinct histologies: one is neuroblastoma (forming discrete nodules) and the other is ganglioneuroblastoma, intermixed or ganglioneuroma. The neuroblastoma component dictates clinical behavior. Prognostic group (FH/UH) determined by age-dependent morphologic features (grade of neuroblastic differentiation and MKI) applied to the neuroblastoma component.
Ganglioneuroblastoma, intermixed (Schwannian stroma-rich)
Tumor with abundant Schwannian stroma and scattered neuroblastic cells. Typically diagnosed in older children. Classified into FH group; expected excellent prognosis. Biopsy diagnosis should include comment 'Favorable histology based on review of limited material' due to risk of missing a neuroblastoma nodule.
Ganglioneuroma (Schwannian stroma-dominant)
Mature, benign tumor composed of ganglion cells and Schwannian stroma. Classified into FH group; excellent prognosis. Biopsy diagnosis with caution regarding sampling.
Molecular subtypes based on biomarker profiling
Risk stratification depends on MYCN amplification status, SCA status (segmental losses at 1p, 11q, 3p, 4p and gains at 17q, 1q, 2p), and ploidy (DNA index). MYCN amplification is the strongest independent prognostic factor. Favorable histology group includes poorly differentiated or differentiating subtype with low/intermediate MKI ≤547 days old, or differentiating with low MKI ≤1824 days old. Unfavorable histology includes undifferentiated at any age, high MKI at any age, poorly differentiated with any MKI ≥548 days old, differentiating with intermediate MKI ≥548 days, or differentiating with any MKI ≥1825 days.
Molecular PathogenesisClick to collapse
Neuroblastoma is driven by a combination of genomic events that influence prognosis and therapy. The strongest independent prognostic risk factor is amplification of the MYCN oncogene, which is associated with aggressive disease and is assessed in all neuroblastomas and ganglioneuroblastoma nodular tumors [57,58]. MYCN amplification is defined by FISH as >8 copies per cell or ≥4-fold increase, and can exceed 30-fold [9]. Segmental chromosomal aberrations (SCAs) are also prognostically important, with the most extensively studied including loss at 1p, 11q, 3p, and 4p, and gain at 17q, 1q, and 2p. The presence of SCAs in conjunction with other factors contributes to risk classification [10,11,59,81]. Ploidy status (DNA index) is another key factor: a DI of 1 (diploid) is less favorable than DI>1 (hyperdiploid), particularly in infants [60]. Germline alterations in ALK (gain-of-function mutations) and PHOX2B (loss-of-function mutations) are causative in familial neuroblastoma, which accounts for 1–2% of all cases [14,15,16]. Somatic ALK mutations and amplifications are also found in sporadic disease and predict response to ALK inhibitors in relapsed/refractory disease [63,64,65]. At relapse, tumors frequently acquire RAS-MAPK pathway mutations, which contribute to treatment resistance [51]. Additional germline variants in BARD1, SMARCA4, and RAS pathway genes (Costello syndrome, Noonan syndrome, neurofibromatosis) have been associated with neuroblastoma predisposition [13,17,18]. The genetic landscape also includes alterations in other neuroblastoma-associated genes identified through next-generation sequencing [62]. Overall, the genomic pattern (numerical vs. segmental alterations) is a predictor of outcome, with segmental patterns conferring worse prognosis [80]. These molecular features are integrated into the COG risk classification system to guide treatment [47].
Risk FactorsClick to collapse
Familial neuroblastoma and germline mutations
Familial neuroblastoma accounts for approximately 1–2% of all cases. Germline gain-of-function mutations in ALK and loss-of-function mutations in PHOX2B have been identified as causative factors [12,14,15,16]. Other germline pathogenic variants in BARD1, SMARCA4 are enriched and predict worse survival [17,18].
Associated genetic syndromes
Li-Fraumeni syndrome (TP53 mutations), Costello syndrome, Noonan syndrome, and neurofibromatosis (RAS pathway mutations) are associated with neuroblastoma [13].
Race/ethnicity and socioeconomic disparities
Limited data suggest health disparities exist. A recent study found 5-year survival was higher for white (80.7%) or Hispanic (80.8%) patients compared with Black patients (72.6%) [7,9]. Poverty has been associated with inferior survival in high-risk neuroblastoma clinical trials [8].
Other genetic susceptibility loci
Common genetic variants likely contribute to sporadic neuroblastoma predisposition, but additional validation studies are needed [12].
Clinical FeaturesClick to collapse
Typical Presentation
Neuroblastoma is a cancer of the developing sympathetic nervous system and the most common extracranial solid tumor in children, with an estimated 600–800 cases per year in the United States and a prevalence of approximately 1 per 7000 live births [1,2]. The average age at diagnosis is between 1 and 2 years, and the vast majority of patients are <5 years old [3,4]. Patients most commonly present with an abdominal mass or abdominal distension [2,5]. Other common presenting symptoms include loss of appetite, weight loss, irritability, constipation, fever, hypertension, anemia, and bone pain [5]. Paraneoplastic syndromes occur in a small subgroup and do not imply metastatic or incurable disease [6]. Opsoclonus-myoclonus-ataxia syndrome (OMAS) occurs in approximately 2% of patients, presenting with irregular multidirectional eye movements, myoclonic jerking of limbs, ataxia, and disordered mood/behavior [7,8]. Vasoactive intestinal peptide tumor (VIPoma) syndrome occurs in <1% of patients, causing chronic watery diarrhea, weight loss, and electrolyte abnormalities [9]. Lambert-Eaton myasthenic syndrome may rarely occur with proximal lower extremity weakness, loss of reflexes, and dysautonomia [10].
Symptoms
Abdominal mass/distension
Most common presenting feature; often found by caregiver or during routine exam
Bone pain
Often due to metastatic disease; may cause limping or refusal to bear weight
Periorbital ecchymosis (raccoon eyes)
Caused by orbital metastases; may be accompanied by proptosis
Fever, weight loss, irritability
Constitutional symptoms may indicate advanced disease
Opsoclonus-myoclonus-ataxia
Irregular eye movements, myoclonic jerking, ataxia, mood/behavior changes
Chronic watery diarrhea
Due to VIP secretion; associated with weight loss and electrolyte disturbances
Spinal cord compression symptoms
Back pain, weakness, bowel/bladder dysfunction
Hypertension
May result from renal artery compression or catecholamine secretion
Signs
Abdominal mass
Palpable, firm, often nontender; may cross midline
Hepatomegaly
Common in infants with stage MS disease; can cause respiratory compromise
Periorbital ecchymosis
Bilateral 'raccoon eyes' from metastatic deposits
Subcutaneous nodules
Bluish nodules on skin, especially in infants
Horner syndrome
Ptosis, miosis, anhidrosis; may be post-surgical or from thoracic tumor
Neurologic deficits
Motor or sensory deficits from spinal cord compression or paraspinal involvement
Red FlagsClick to collapse
Infants <2 months with existing or evolving hepatomegaly require urgent evaluation and possible therapy before biopsy [11].
Infants with coagulopathy, impending organ failure, or respiratory compromise from massive hepatomegaly need emergent treatment (score ≥2 per Hsu criteria) [12].
Patients with acute neurologic deterioration (e.g., rapid onset paraplegia, loss of bladder/bowel control) from spinal cord compression require urgent multidisciplinary evaluation and prompt therapy.
Proptosis, sudden vision loss, or progressive periorbital ecchymosis from orbital metastases warrants urgent ophthalmologic and oncologic assessment.
Progressive hypertension or signs of catecholamine crisis (e.g., tachycardia, flushing) may indicate tumor catecholamine secretion and require careful perioperative management.
Any child with refractory diarrhea, severe electrolyte disturbances, and weight loss should be evaluated for VIPoma syndrome.
Rapidly enlarging abdominal mass causing pain, respiratory distress, or lower extremity edema (suggestive of compartment syndrome) is a surgical emergency.
InvestigationsClick to collapse
Diagnostic
Tissue sampling (surgical resection or biopsy)
Definitive diagnosis requires tumor tissue for histology and molecular profiling
Hematoxylin and eosin (H&E) staining
Primary histologic diagnosis; determines tumor category and differentiation
Immunohistochemistry (IHC)
Aids diagnosis in small samples or undifferentiated tumors
Urine homovanillic acid (HVA) and vanillylmandelic acid (VMA)
Required for diagnosis if only diagnostic tissue is bone marrow
Bilateral bone marrow aspirates and trephine biopsies
Assess metastatic involvement; can be diagnostic if marrow is only source
Complete blood count (CBC) with differential
Baseline assessment; detect bone marrow suppression or blood loss
Comprehensive metabolic panel
Evaluate organ function, electrolytes, LDH
Lactate dehydrogenase (LDH)
Prognostic value; higher levels associated with worse outcome
Ferritin
Prognostic value; higher levels associated with worse outcome
Prothrombin time (PT)/INR
Useful if liver involved or concern for bleeding
Audiogram
Baseline if platinum-containing chemotherapy planned
Echocardiogram and ECG
Baseline if anthracycline-containing chemotherapy planned
Pregnancy test
For patients of childbearing potential
Fertility preservation referral
For patients likely to receive extensive alkylator therapy
Paraneoplastic syndrome testing
If clinical suspicion for OMAS (check anti-Hu/ANNA1, CSF studies) or VIPoma (serum VIP)
Staging
Cross-sectional imaging (CT with contrast or MRI with/without contrast)
Evaluate soft tissue disease; assess IDRFs for INRG staging
MRI of spine with/without contrast
Assess intraspinal extension, nerve root or spinal cord involvement
MRI of brain with/without contrast or CT skull/orbits with contrast
Evaluate intracranial extension, orbital metastases
I-123 MIBG scintigraphy with SPECT or SPECT/CT
Gold standard for detecting metastatic disease; identify MIBG-avid disease
FDG-PET/CT or PET/MRI
Alternative for MIBG non-avid or mixed-avidity tumors
Bilateral bone marrow aspirates and trephine biopsies
Assess marrow involvement; required for staging and risk classification
Ultrasound
Initial screening for abdominal/pelvic mass; low interobserver reproducibility
Biomarkers
MYCN amplification
Strong prognostic factor; associated with aggressive disease; determines risk group
Segmental chromosomal aberrations (SCAs)
Prognostic; presence of SCAs may be associated with aggressive disease depending on other factors
Ploidy (DNA index, DI)
DI=1 may be associated with aggressive disease depending on age and other factors
ALK amplification and sequence variants
Predict response to ALK inhibitors in relapsed/refractory disease
Next-generation sequencing (NGS)
Simultaneous evaluation of MYCN, SCAs, ALK, and other neuroblastoma-associated genes
Germline testing
Identify familial neuroblastoma (ALK, PHOX2B) or other predisposition syndromes (Li-Fraumeni, RASopathies)
StagingClick to collapse
International Neuroblastoma Risk Group (INRG) Staging System (INRGSS) [34]
T Categories
| Stage | Description |
|---|---|
| L1 (Localized) | Localized tumor not involving vital structures as defined by the list of image-defined risk factors (IDRFs) and confined to one body compartment [34]. |
| L2 (Locoregional) | Locoregional tumor with presence of one or more IDRFs [34]. |
N Categories
| Stage | Description |
|---|---|
| N (Regional lymph nodes) | The INRGSS does not include a separate N category. Regional lymph node involvement is integrated into L1/L2 staging: L1 implies no IDRFs; L2 includes IDRFs that may reflect nodal involvement (e.g., encasement of vessels) but not separately staged [34]. |
M Categories
| Stage | Description |
|---|---|
| M (Distant metastatic) | Distant metastatic disease (except stage MS) [34]. |
| MS (Metastatic special) | Metastatic disease in children younger than 18 months, with metastases confined to skin, liver, and/or bone marrow (<10% involvement) [34]. |
Stage Groupings
| Group | Criteria | Clinical Meaning | Five Yr Survival | Treatment Intent |
|---|---|---|---|---|
| L1 | Localized tumor with no IDRFs, confined to one body compartment. | Surgically resectable with low risk of complications; low to intermediate risk depending on age and biology. | Not reported by stage alone; survival by risk group: low risk 97.9%, intermediate 95.8%, high 62.5% [35]. | Curative; often surgery alone, observation (select infants), or surgery + chemotherapy for intermediate risk. |
| L2 | Locoregional tumor with one or more IDRFs. | Higher surgical risk; neoadjuvant chemotherapy often used; risk group depends on age, MYCN, histology, ploidy. | Variable by risk group, see above. | Curative; chemotherapy + surgery, with possible RT in high-risk cases. |
| M | Distant metastatic disease (excluding MS). | High-risk disease in most cases (≥18 months) or intermediate-risk in select infants <12 months with favorable biology. | High risk: 5-year OS 62.5% [35]. | Curative but intensive: induction chemo, surgery, high-dose chemo + stem cell rescue, RT, post-consolidation immunotherapy. |
| MS | Children <18 months, metastases confined to skin, liver, and/or bone marrow (<10% involvement). | Favorable biology often leads to spontaneous regression; requires close observation unless symptomatic. | Low risk: excellent (>95%); intermediate-risk: ~95% [35]. | Observation if asymptomatic with favorable biology; low-intensity chemotherapy if symptomatic or unfavorable biology; RT rarely needed. |
Staging Pearls
- The INRGSS replaced the older INSS to allow pretreatment staging based on imaging (IDRFs), not surgical findings [34].
- IDRFs are defined by consensus and include vascular encasement, tracheal compression, intraspinal extension, infiltration of adjacent organs, and others (see NEUROB-B 3 of 4) [36].
- MIBG avidity is present in up to 90% of tumors; MIBG scan is essential for M and MS staging [21].
- Bilateral bone marrow aspirates and biopsies are mandatory for detecting marrow involvement, which defines M or MS stage.
- MS stage is only applicable to children <18 months; patients ≥18 months with limited metastases are staged as M.
- The INRGSS stage is a key factor in the COG risk classification system, along with MYCN, histology, ploidy, SCAs, and age [35].
- FDG-PET is used as an alternative if MIBG non-avid; however, MIBG remains the preferred tracer for staging.
- Risk group assignment determines treatment intensity; not all patients with stage M are high-risk (e.g., infants <12 months with favorable biology).
Management PrinciplesClick to collapse
Neuroblastoma is a heterogeneous disease of the developing sympathetic nervous system, the most common extracranial solid tumor in children, with an estimated 600–800 new cases annually in the United States (prevalence ~1 per 7000 live births). The average age at diagnosis is between 1 and 2 years, with the vast majority of patients <5 years old. Treatment is multimodal and risk-adapted, stratified into low-, intermediate-, and high-risk groups based on age, INRG stage, MYCN amplification status, histopathology (International Neuroblastoma Pathology Classification [INPC] favorable or unfavorable), presence of segmental chromosomal aberrations (SCAs), and DNA index (DI). The goal for low- and intermediate-risk disease is cure with minimal toxicity, using surgery and moderate-intensity chemotherapy; for high-risk disease, intensive multimodality therapy divided into induction, consolidation, and post-consolidation phases has improved outcomes, with 5-year overall survival (OS) now approximately 62.5% ± 1.3% [Irwin 2021]. Treatment decisions must incorporate multidisciplinary evaluation including diagnostic and interventional radiology, nuclear medicine, surgery, pathology, radiation oncology, and pediatric oncology.
Curative with observation alone
Low-risk: infants <6 months with isolated adrenal masses ≤3.1 cm solid or ≤5 cm with ≥25% cystic component; also asymptomatic stage MS with favorable biology (<12 months, FH, DI>1, SCA-negative, MYCN non-amplified)
Observation with serial ultrasound; no biopsy or chemotherapy required.
Curative with surgery ± chemotherapy
Low-risk L1 tumors not meeting observation criteria; also some intermediate-risk localized tumors with favorable biology after chemotherapy
Surgical resection if safe; if incomplete resection and MYCN amplification is detected, reclassify as high-risk.
Curative with chemotherapy + surgery
Intermediate-risk: localized L2, stage M <18 months with favorable biology, stage MS symptomatic or with unfavorable biology
Response-adapted chemotherapy (2–8 cycles) based on age, stage, and biology; gross total resection may be performed after chemotherapy; surveillance after achieving target response.
Curative with intensive multimodality therapy
High-risk: all patients with MYCN amplification (except L1 completely resected), stage M ≥18 months, L2 ≥18 months with unfavorable histology or undifferentiated/poorly differentiated, and other subsets as defined by risk classification
Induction multiagent chemotherapy (5–6 cycles) + primary site resection; consolidation with high-dose chemotherapy and autologous stem cell rescue (tandem transplant preferred, category 1) + radiotherapy; post-consolidation with anti-GD2 antibody (dinutuximab) + sargramostim + isotretinoin (category 1); optional continuation therapy with eflornithine (category 2B).
Palliative or disease control
Relapsed/refractory high-risk neuroblastoma
Individualized, strongly encourage clinical trial; chemoimmunotherapy (e.g., irinotecan/temozolomide + anti-GD2 antibody) or I-131 MIBG or targeted agents (ALK inhibitors if ALK aberration).
A multidisciplinary team is essential for neuroblastoma management, including diagnostic radiologists, nuclear medicine physicians, interventional radiologists, surgeons (pediatric surgical oncologists), anatomic and molecular pathologists, radiation oncologists, and pediatric oncologists. Multidisciplinary discussion is required for optimal timing of surgery (at diagnosis vs. after neoadjuvant chemotherapy), assessment of image-defined risk factors (IDRFs), determination of resectability, and iterative decision-making during intermediate-risk therapy regarding additional chemotherapy vs. surgery. The Panel recommends coordinated diagnostic sampling including pathologists, oncologists, surgeons, and radiologists.
Management PathwaysClick to collapse
Branching: Age <6 months, Adrenal mass size (≤3.1 cm solid or ≤5 cm cystic), No IDRFs, Stage MS asymptomatic with favorable biology (<12 months, FH, DI>1, SCA-, MYCN non-amplified)
Branching: L1 stage, No MYCN amplification (or MYCN amplified but completely resected then low-risk), Presence of IDRFs (L1 vs. L2) – if L2, reassess risk group
Branching: Age, INPC histology (FH/UH), DI (diploid/hyperdiploid), SCA status, MYCN non-amplified
Branching: Age (<365 vs. 365–<547 days), Biologic features (FH, DI, SCA)
Branching: Age (<3 months), Symptoms (hepatomegaly, respiratory compromise), Biologic features (FH, DI, SCA, MYCN), Ability to biopsy
Branching: Risk classification (MYCN amplified, stage M ≥18 months, L2 ≥18 months UH, etc.), End-induction response (CR, PR, MR, SD, PD)
Branching: End-induction response: CR, PR, MR/SD, PD
Branching: Risk subgroup (common vs. special), End-induction residual disease
Branching: Disease status after consolidation (no progression vs. PD)
Branching: Timing of relapse, Extent of disease, MIBG avidity, Prior treatments, Organ function, Molecular features
Pretreatment EvaluationClick to collapse
Tissue Sampling
History and Physical
Laboratory Studies
Imaging
Pathology and Biomarker Testing
SurgeryClick to collapse
Surgery plays a critical role in diagnosis (biopsy), local control (resection of primary tumor and locoregional disease), and management of complications (e.g., silo placement for abdominal compartment syndrome). The extent and timing of surgery depend on risk group, presence of IDRFs, and response to neoadjuvant chemotherapy. Multidisciplinary discussion is essential to balance morbidity and oncologic outcomes.
Evaluate primary tumor resectability using cross-sectional imaging (CT or MRI) and IDRF assessment.
Multidisciplinary discussion of risks/benefits and optimal timing should include surgeons, diagnostic and interventional radiologists, medical oncologists, radiation oncologists, pathologists, and dieticians as needed.
For intermediate-risk disease, if more than minimal surgical risk, neoadjuvant chemotherapy should be given first.
For high-risk disease, neoadjuvant chemotherapy is nearly always indicated prior to resection.
Surgical approach should limit morbidity, avoid resection of vital structures, and preserve organ function.
Gross total resection is optimal for high-risk; subtotal resection if gross total would jeopardize vital organs, major nerves, or vessels.
Nephrectomy should be avoided. Resection of adjacent organs (kidney, pancreas, intestine) is not recommended.
Resection of nodal disease adherent to primary tumor is recommended; distant lymph node resection not required.
En bloc resection is not required; tumors may be resected in multiple segments.
Procedures
Biopsy
When upfront resection not possible or recommended (metastatic disease, L2 tumors, infants with MS disease at high risk for complications).
Resection – Low-Risk L1
L1 tumors not meeting observation criteria; completely resectable with minimal morbidity.
Resection – Intermediate-Risk Localized
Localized tumors after chemotherapy if target volume reduction not achieved; or if initial surgery safe without neoadjuvant therapy.
Resection – High-Risk Primary Tumor
All high-risk patients after initial cytoreductive chemotherapy.
Silo placement (laparotomy with silo)
Extreme situations: infants with abdominal compartment syndrome, severe respiratory compromise, or life-threatening hepatomegaly due to MS disease.
Cervical and cervicothoracic resection
Primary tumors in neck or cervicothoracic junction.
Thoracic cavity resection
Primary thoracic neuroblastoma.
Abdominal/adrenal/retroperitoneal/pelvic resection
Primary tumors in abdomen, adrenal, retroperitoneum, or pelvis.
Paraspinal tumor management
Intraspinal extension of paraspinal tumor.
Radiation TherapyClick to collapse
Radiation therapy (RT) is indicated for nearly all cases of high-risk neuroblastoma and in exceedingly rare circumstances for non-high-risk disease (e.g., symptomatic stage MS with inadequate response to chemotherapy). RT is delivered after recovery from high-dose chemotherapy with stem cell rescue unless emergent. The primary site is always irradiated; metastatic sites are irradiated if there is concern for active disease after induction chemotherapy (MIBG/FDG uptake and/or persistent soft tissue >1 cm³).
Principles
- RT is delivered after recovery from high-dose chemotherapy with stem cell rescue unless emergent indication.
- IMRT or proton therapy are recommended to reduce side effects.
- Primary site always irradiated. Metastatic sites only if active disease at end-induction.
- Metastatic sites should be irradiated concurrently with primary site if indicated.
- Repeat imaging after transplant and before RT is not routine but may aid decision-making in select cases.
- Simulation: supine with immobilization; 4D-CT recommended for targets subject to respiratory motion; consider MRI simulation for paraspinal sites.
- Target volume definitions: GTV includes postoperative tumor bed, residual disease, initially involved regional lymph nodes (based on post-induction/pre-surgery volume). CTV = GTV + 1 cm confined to anatomic borders. ITV if respiratory motion. PTV = CTV + 0.3–0.5 cm.
- If primary tumor resected prior to induction, GTV based on tumor volume at diagnosis.
- For metastatic sites: mGTV defined by post-induction volume; mCTV = mGTV + 1 cm; mPTV = mCTV + 0.3–0.5 cm.
Dose Frameworks
| Name | Total Dose | Dose Per Fraction | Fractions | Schedule | Indication |
|---|---|---|---|---|---|
| Standard dose to primary and metastatic sites | 21.6 Gy | 1.8 Gy | 12 | Daily fractions, typically 5 days per week. | Primary site and all sites of residual metastatic disease at end-induction. |
| Emergent RT | 4.5 Gy | 1.5 Gy | 3 | Daily or twice daily as needed for emergent decompression. | Hepatomegaly leading to respiratory distress; orbital/optic pathway disease leading to vision loss. |
Approaches
| Name | Dose Fractionation | Concurrent Chemotherapy | Indication | Key Trial | Toxicities |
|---|---|---|---|---|---|
| Post-consolidation RT to primary and metastatic sites | 21.6 Gy in 1.8 Gy fractions | None; delivered after recovery from transplant, before or concurrent with post-consolidation immunotherapy (but not concurrent with high-dose chemotherapy). | All high-risk patients after consolidation therapy. | COG ANBL0532: dose escalation to 36 Gy (boost of 14.4 Gy) did not improve local control or EFS [Liu 2020]. COG A3973: extended field to uninvolved nodal stations did not improve outcomes [Braunstein 2019]. | Renal (contralateral kidney V18 Gy <25%, mean ≤14.4 Gy; ipsilateral kidney V18 Gy <75%, mean ≤18 Gy), hepatic (mean <18 Gy), pulmonary (bilateral V20 Gy <30%, contralateral V20 Gy <10%), vertebral (minimum 18 Gy to prevent asymmetrical growth), ototoxicity, second malignancies. |
Systemic TherapyClick to collapse
Systemic therapy for neuroblastoma is risk-adapted and multimodal. For low-risk disease, treatment is primarily surgical, with observation for select infants. Intermediate-risk disease uses moderate-intensity multiagent chemotherapy (carboplatin, cyclophosphamide, doxorubicin, etoposide) with response-adapted duration (2–8 cycles). High-risk disease requires intensive induction chemotherapy (topotecan/cyclophosphamide, cisplatin/etoposide, and vincristine/doxorubicin/cyclophosphamide), consolidation with high-dose chemotherapy and autologous stem cell rescue, post-consolidation immunotherapy (anti-GD2 antibody + sargramostim + isotretinoin), and optional continuation therapy with eflornithine. For relapsed/refractory disease, chemoimmunotherapy (irinotecan/temozolomide + anti-GD2 antibody) or targeted radiopharmaceuticals (I-131 MIBG) or targeted agents (ALK inhibitors) are used, with clinical trial participation strongly encouraged.
Key Regimens
Treatment Response AssessmentClick to collapse
Title
Response Assessment
Timing
Response assessment is performed at protocol-specified timepoints that differ by risk group. For high-risk disease: full disease evaluation (anatomic imaging of primary site, I-123 MIBG scan [or FDG-PET if MIBG non-avid], bilateral bone marrow aspirates and biopsies) is recommended at end of induction, start of post-consolidation, and end of therapy. Midpoint I-123 MIBG scan recommended after first 3 cycles of post-consolidation. For intermediate-risk disease: evaluate after assigned number of chemotherapy cycles; if target response achieved, obtain MIBG as part of end-of-therapy evaluation.
Response Logic
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Primary site response: CR (<10 mm residual soft tissue, complete resolution of MIBG/FDG uptake), PR (≥30% decrease in longest diameter, MIBG/FDG stable/improved/resolved), SD (neither PR nor PD), PD (>20% increase and ≥5 mm absolute increase; note: fluctuating MIBG avidity alone is insufficient for PD).
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Metastatic bone/soft tissue response: CR (non-primary lesions <10 mm, lymph nodes short axis <10 mm, complete resolution of MIBG/FDG uptake), PR (≥30% decrease in sum of diameters, no new lesions, ≥50% reduction in MIBG absolute bone score [relative score 0.1-0.5] or ≥50% reduction in FDG-PET-avid bone lesions), SD, PD (any new soft tissue lesion MIBG-avid or histologically confirmed; new MIBG-avid bone site; FDG-PET-avid bone site with CT/MRI or histologic confirmation; >20% increase in sum of diameters; relative MIBG bone score ≥1.2).
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Bone marrow response: CR (no tumor infiltration), MD (≤5% tumor infiltration), SD (>5% tumor infiltration that does not meet CR/MD/PD), PD (marrow without infiltration becomes >5%; or >2-fold increase to >20%).
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Overall response: CR (all components CR), PR (PR in at least one component, all others CR/MD/PR or not involved), MR (PR or CR in at least one component but at least one other SD; no PD), SD (SD in one component, no better than SD in others; no PD), PD (any component PD).
Imaging Recommendations
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Primary site: RECIST 1.1 (single longest dimension) on CT or MRI; functional imaging (MIBG or FDG-PET) for assessment of avidity.
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Metastatic bone/soft tissue: MIBG scan with semiquantitative scoring (modified Curie score in North America or SIOPEN score). FDG-PET for MIBG non-avid tumors.
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Bone marrow: bilateral aspirates and trephine biopsies evaluated per Burchill criteria (immunocytology/immunohistochemistry for tumor cells; >5% viable tumor recommended as reliable level for detecting response).
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Urine catecholamines (HVA/VMA) and technetium-99m scintigraphy are no longer used for response assessment per revised INRC [Park 2017].
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Novel radiotracers are in development but insufficient data for routine incorporation into INRC.
Biopsy Or Salvage Logic
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For intermediate-risk patients who do not achieve target response after 8 cycles of chemotherapy, consider biopsy of residual mass to assess histologic differentiation; if differentiated, observation may be appropriate. If undifferentiated viable tumor remains, consider second-line chemotherapy (cyclophosphamide/topotecan) per Twist et al. [Twist 2019].
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For high-risk patients with less than PR at end of induction: bridging therapy may be offered to improve response before proceeding to consolidation [Desai 2022]. Patients with PD should receive non-myeloablative chemoimmunotherapy or enroll in clinical trial.
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For relapsed/refractory disease: repeat tumor biomarker profiling on a current sample is strongly recommended to identify actionable aberrations (e.g., ALK mutations) and guide therapy selection.