What is the latest system for neuroblastoma risk stratification and staging, according to the International Neuroblastoma Risk Group (INRG) and National Comprehensive Cancer Network (NCCN)?

Neuroblastoma Risk Stratification and Staging: INRG and NCCN Systems

The most current neuroblastoma risk stratification system is the Children's Oncology Group (COG) 2021 classification that incorporates the International Neuroblastoma Risk Group Staging System (INRGSS) and includes segmental chromosomal aberrations (SCAs) as a genomic biomarker. 1, 2

INRG Staging System

The INRGSS was developed to provide a pretreatment staging system that uses clinical and imaging data at diagnosis, replacing the older International Neuroblastoma Staging System (INSS) which was postsurgical 3. The INRGSS includes:

• Stage L1: Localized tumor confined to one body compartment without image-defined risk factors (IDRFs)
• Stage L2: Locoregional tumor with presence of one or more IDRFs
• Stage M: Distant metastatic disease (except MS)
• Stage MS: Metastatic disease in children <18 months with metastases confined to skin, liver, and/or bone marrow (limited marrow disease) 1, 3

Image-Defined Risk Factors (IDRFs)

IDRFs are radiological features that help determine surgical risk and are critical for distinguishing between L1 and L2 stages. The INRG has defined 20 specific IDRFs that should be assessed through standardized imaging protocols 4, 3.

Risk Classification System

The 2021 COG neuroblastoma risk classification system incorporates:

1. Age at diagnosis: Critical cutoffs at <12 months, 12-18 months, and ≥18 months
2. INRG stage: L1, L2, M, or MS
3. MYCN status: Amplified vs. non-amplified
4. Histopathology: Favorable vs. unfavorable based on International Neuroblastoma Pathology Classification (INPC)
5. Segmental chromosomal aberrations (SCAs): Particularly 1p and 11q status
6. Ploidy status: Diploid vs. hyperdiploid 1, 2

Risk Group Assignment

Based on these factors, patients are assigned to three risk groups:

Low-Risk Group

• Any age with L1 disease and MYCN non-amplified tumors
• L1 disease with MYCN amplification if complete resection is achieved
• Asymptomatic patients <12 months with MS disease, favorable histology, MYCN non-amplified, hyperdiploid, and without SCAs 1

Intermediate-Risk Group

• Patients whose disease characteristics don't meet criteria for either low-risk or high-risk groups 1

High-Risk Group

• Patients with L1 MYCN-amplified tumors with residual disease after resection
• Patients 12-18 months with M or MS stage disease with unfavorable prognostic factors (unfavorable histology, SCAs, or MYCN amplification)
• All patients ≥18 months with M stage disease regardless of other features
• Any patient with MYCN amplification (except completely resected L1 tumors) 1, 2

Diagnostic Evaluation for Risk Stratification

Proper risk stratification requires:

1. Imaging:

   • Cross-sectional imaging (MRI preferred or CT with contrast) of primary tumor site
   • 123I-MIBG scan for metastatic disease assessment (90% sensitivity)
   • 18F-FDG-PET for MIBG non-avid tumors 1, 5

2. Laboratory and Pathology:

   • Bilateral bone marrow aspirates and biopsies
   • Tumor tissue for histopathology and molecular studies
   • Next-generation sequencing to assess MYCN amplification, SCAs, ALK alterations, and ploidy status 1, 5

Clinical Implications

The risk classification directly determines treatment intensity:

• Low-risk: Often observation or surgical resection alone (>98% survival)
• Intermediate-risk: Moderate doses of chemotherapy with surgery (>90% survival)
• High-risk: Intensive multimodal therapy including chemotherapy, surgery, radiation, stem cell transplantation, and immunotherapy 6

Important Considerations

• Risk classification must be completed before treatment initiation, though emergent therapy should not be delayed for imaging if clinically indicated 1
• For symptomatic infants with stage MS disease too ill for initial biopsy, treatment starts with presumptive intermediate-risk assignment, with potential reassignment if MYCN amplification is later detected 1
• The INRG Task Force has established standardized methods for detecting minimal disease in bone marrow, blood, and stem cell preparations using immunocytology and RT-PCR 1

The 2021 COG risk classification system has demonstrated strong clinical validity with 5-year outcomes showing clear separation between risk groups: low-risk (90.7% EFS, 97.9% OS), intermediate-risk (85.1% EFS, 95.8% OS), and high-risk (51.2% EFS, 62.5% OS) 2.