Evidence-Based Management of Neuroblastoma: Staging, INRG Risk Grouping, and Molecular Stratification
The current standard for neuroblastoma management utilizes the International Neuroblastoma Risk Group (INRG) Staging System for pretreatment staging, combined with the Children's Oncology Group (COG) 2021 risk classification system that integrates multiple molecular and clinical factors to stratify patients into low-, intermediate-, and high-risk groups, which directly determines treatment intensity and impacts survival outcomes. 1
INRG Staging System
The INRG Staging System must be completed before treatment initiation, as it forms the foundation for risk classification and treatment decisions. 1
Stage Definitions
L1 (Localized): Tumor confined to one body compartment without involvement of vital structures, defined by absence of image-defined risk factors (IDRFs). 1
L2 (Locoregional): Tumor with presence of one or more IDRFs, indicating proximity to or involvement with vital structures. 1
M (Metastatic): Distant metastatic disease to any site. 1
MS (Metastatic Special): Unique category for children <18 months with metastases confined exclusively to skin, liver, and/or bone marrow (limited marrow involvement <10% tumor cells). 1
Critical Imaging Requirements
123I-MIBG scintigraphy is the primary imaging modality for metastatic disease assessment, with uptake demonstrated in up to 90% of neuroblastomas. 1 SPECT or SPECT/CT should be performed at sites of known or suspected disease to improve sensitivity. 1
FDG-PET imaging is mandatory for patients with MIBG-nonavid disease or suspected mixed-avidity disease (exception: patients <6 months with L1 adrenal tumors ≤3.1 cm if solid or ≤5 cm if ≥25% cystic). 1
Emergent therapy should not be delayed for imaging, but imaging must be obtained as soon as clinically feasible. 1
COG Risk Classification System (2021)
Risk classification must occur before therapy initiation and integrates six key prognostic factors: age at diagnosis, INRG stage, MYCN amplification status, histopathology (INPC classification), segmental chromosomal aberrations (SCAs), and tumor ploidy. 1
Low-Risk Group (5-year survival >95%)
Patients in this category require minimal or no treatment, with observation alone appropriate for select cases. 1
Any age with L1 disease and MYCN nonamplified tumors. 1
L1 disease with MYCN amplification only if complete surgical resection is achieved; incomplete resection automatically upgrades to high-risk. 1
Asymptomatic infants <12 months with MS disease meeting all of the following: favorable histology, MYCN nonamplified, hyperdiploid, and no SCAs. 1
Observation without biopsy is recommended for infants <6 months with isolated adrenal masses ≤3.1 cm (solid) or ≤5 cm (if ≥25% cystic). 1
High-Risk Group (5-year survival <50%)
MYCN amplification is the dominant factor that overrides most other prognostic variables, automatically assigning patients to high-risk regardless of age or stage (except completely resected L1 tumors). 1
All patients ≥18 months with M stage disease, regardless of any other features. 1
Patients 12-18 months with M or MS disease having any unfavorable factor: unfavorable histology, SCAs, or MYCN amplification. 1
L1 disease with MYCN amplification and incomplete resection. 1
Any age, any stage with MYCN amplification (except completely resected L1 tumors). 1
Intermediate-Risk Group (5-year survival 90-95%)
This category includes patients whose characteristics do not meet criteria for low-risk or high-risk groups. 1
Symptomatic infants with MS disease who are too unstable for biopsy (coagulopathy, impending organ failure, hepatomegaly with respiratory compromise) are presumptively assigned to intermediate-risk and started on therapy; reassignment to high-risk occurs if subsequent biopsy reveals MYCN amplification. 1
Treatment involves 2-8 cycles of chemotherapy based on age, stage, and biologic features. 1
Molecular Risk Stratification
MYCN Amplification
MYCN status is the single most powerful molecular prognostic factor and must be assessed in all cases. 1 Its presence drives high-risk classification independent of other factors (with the sole exception of completely resected L1 tumors). 1
Histopathology (International Neuroblastoma Pathology Classification)
Tumors are classified as favorable or unfavorable histology based on degree of differentiation and mitosis-karyorrhexis index, integrated with patient age. 1 Unfavorable histology contributes to high-risk assignment in specific age/stage combinations. 1
Segmental Chromosomal Aberrations (SCAs)
SCAs, particularly 11q deletion and 1p deletion, are independent adverse prognostic factors. 1 Presence of SCAs in young infants with MS disease excludes them from low-risk classification. 1
Tumor Ploidy
Hyperdiploid tumors in infants carry favorable prognosis, while diploid tumors are associated with worse outcomes. 1 This factor is particularly relevant for MS disease classification in infants <12 months. 1
Chromosome 11q Status
Loss of heterozygosity at chromosome 11q is an independent adverse prognostic marker, particularly in MYCN-nonamplified tumors. 2, 3
Critical Clinical Caveats
International differences exist in risk classification systems. 1 For example, patients with L2, MYCN-nonamplified disease who are >18 months with unfavorable histology are classified as high-risk by COG criteria but may be intermediate-risk by European cooperative groups. 1
Bone marrow assessment requires bilateral aspirates and core biopsies using conventional morphology for initial staging. 1 More sensitive methods (immunocytology, QRT-PCR) are reserved for minimal residual disease detection during or after therapy. 1
Multidisciplinary team involvement is mandatory, including diagnostic radiologists, nuclear medicine physicians, interventional radiologists, surgeons, anatomic and molecular pathologists, radiation oncologists, and pediatric oncologists. 1