International Neuroblastoma Risk Group Staging System
The INRG Staging System (INRGSS) is a pretreatment classification system that stages neuroblastoma into four categories—L1, L2, M, and MS—based on image-defined risk factors (IDRFs) assessed before any therapy, and this staging directly determines risk classification and treatment intensity. 1
INRGSS Stage Definitions
The staging system was specifically designed to enable uniform disease classification before treatment initiation, replacing the older postsurgical International Neuroblastoma Staging System (INSS). 2
Localized Disease Stages
L1 (Localized): A tumor confined to one body compartment without involvement of vital structures as defined by the absence of any IDRFs. 1
L2 (Locoregional): A tumor with the presence of one or more IDRFs, indicating locoregional disease with potential involvement of vital structures. 1
IDRFs include 20 specific imaging criteria such as vascular encasement, organ infiltration, and spinal canal involvement that serve as proxies for tumor biologic features and surgical risk. 1, 2
Metastatic Disease Stages
M (Metastatic): Distant metastatic disease to any site including bone, distant lymph nodes, or other organs. 1
MS (Metastatic Special): A unique category diagnosed only in children <18 months of age with metastases confined exclusively to skin, liver, and/or bone marrow (with limited marrow involvement defined as <10% tumor cell infiltration). 1
Risk Classification Integration
The INRGSS stage is one of six critical prognostic factors used in the 2021 Children's Oncology Group (COG) risk classification system. 1, 3
Key Prognostic Factors
Risk assignment integrates:
- Age at diagnosis (cutoffs at <12 months, 12-18 months, ≥18 months) 1
- INRG stage (L1, L2, M, MS) 1
- MYCN amplification status (the single most powerful prognostic factor) 1
- Histopathology (favorable vs. unfavorable by International Neuroblastoma Pathology Classification) 1
- Segmental chromosomal aberrations (SCAs including 1p, 11q deletions) 1, 3
- Tumor ploidy (diploid vs. hyperdiploid) 1
Low-Risk Assignment
Any age with L1 disease and MYCN nonamplified tumors automatically qualify as low-risk. 1
L1 disease with MYCN amplification is low-risk only if complete resection is achieved; residual tumor after resection mandates high-risk classification. 1
Asymptomatic infants <12 months with MS disease, favorable histology, MYCN nonamplified, hyperdiploid tumors without SCAs are low-risk. 1
High-Risk Assignment
MYCN amplification overrides all other prognostic factors and automatically assigns high-risk status regardless of age or stage, with the sole exception of completely resected L1 tumors. 1
All patients ≥18 months with M stage disease are high-risk regardless of any other biologic features. 1
Patients 12-18 months with M or MS disease who have unfavorable histology, SCAs, or MYCN amplification are high-risk. 1
L2 disease in patients ≥18 months with MYCN nonamplified tumors but unfavorable histology or undifferentiated/poorly differentiated tumors are high-risk by COG criteria (though may be intermediate-risk by European cooperative groups). 1
Intermediate-Risk Assignment
Patients whose disease characteristics do not meet criteria for either low-risk or high-risk groups are classified as intermediate-risk. 1
Symptomatic infants with MS disease who are too unstable for biopsy (e.g., coagulopathy, respiratory compromise from hepatomegaly) receive presumptive intermediate-risk therapy, with reassignment to high-risk if MYCN amplification is later identified. 1
Critical Imaging Requirements
Mandatory Pretreatment Imaging
Cross-sectional imaging (MRI with/without contrast or CT with contrast) to evaluate soft tissue disease and assess IDRFs. 1
123I-MIBG scintigraphy is the primary modality for metastatic disease assessment, with uptake in up to 90% of neuroblastomas, interpreted using the modified Curie score in North America. 1, 4
FDG-PET imaging is mandatory for patients with MIBG-nonavid disease or suspected mixed-avidity disease, except for patients <6 months with L1 adrenal tumors ≤3.1 cm if solid or ≤5 cm if ≥25% cystic. 1, 4
MRI of spine with/without contrast for paraspinal disease or concerns about nerve root/spinal cord involvement. 1
Timing Considerations
Staging must be completed before treatment initiation when possible, as risk classification guides therapy selection. 1
Emergent therapy should not be delayed for imaging in critically ill patients, but imaging should be obtained as soon as clinically feasible. 1
Common Pitfalls and Caveats
IDRF Assessment Challenges
Concordance in IDRF assessment between local and central reviewers is poor (51.9% agreement), indicating significant variability in interpretation. 5
Even among experienced pediatric surgeons and radiologists, concordance is only moderate (81.7% agreement), with radiologists more likely to identify IDRFs than surgeons. 5
Individual IDRFs may differ in their prognostic value and impact on resectability; L2 classification does not automatically equate to unresectability. 6
International Classification Differences
COG criteria differ from European cooperative groups, particularly for L2 MYCN-nonamplified disease in patients >18 months with unfavorable histology (high-risk by COG, may be intermediate-risk elsewhere). 1
Clinicians treating patients who may transfer care internationally should be aware of these classification differences. 1
Molecular Testing Requirements
All patients require comprehensive molecular testing before treatment, including MYCN status, SCAs, ploidy, ALK alterations, and histopathology. 4, 7
Next-generation sequencing can simultaneously evaluate multiple prognostic factors and identify actionable mutations, which is particularly valuable when tissue is limited. 7