Neuroblastoma Management Guidelines

Introduction to Risk Classification

The International Neuroblastoma Risk Group (INRG) Staging System and the Children's Oncology Group (COG) 2021 risk classification system are used for pretreatment staging and risk stratification, which determines treatment intensity and impacts survival outcomes 1.

The INRG Staging System must be completed before treatment initiation and forms the foundation for risk classification and treatment decisions 1, 2.
Tumors are classified into four stages: L1 (Localized), L2 (Locoregional), M (Metastatic), and MS (Metastatic Special) 1, 2, 3, 4.

123I-MIBG scintigraphy is the primary imaging modality for metastatic disease assessment, with uptake demonstrated in up to 90% of neuroblastomas 2.
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 2, 4.

Risk classification must occur before therapy initiation and integrates six key prognostic factors: age at diagnosis, INRG stage, MYCN amplification status, histopathology, segmental chromosomal aberrations, and tumor ploidy 1, 2, 5.
Patients are classified into low-risk, intermediate-risk, and high-risk groups, with 5-year survival rates of >95%, 90-95%, and <50%, respectively 1, 5, 6.

Patients in this category require minimal or no treatment, with observation alone appropriate for select cases, such as any age with L1 disease and MYCN nonamplified tumors 1, 3, 6.

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, 3, 5.
All patients ≥18 months with M stage disease, regardless of any other features, are classified as high-risk 1, 4, 5.

This category includes patients whose characteristics do not meet criteria for low-risk or high-risk groups, with treatment involving 2-8 cycles of chemotherapy based on age, stage, and biologic features 1, 6, 7.

MYCN status is the single most powerful molecular prognostic factor and must be assessed in all cases, with its presence driving high-risk classification independent of other factors 1, 2, 5.
Histopathology, segmental chromosomal aberrations, and tumor ploidy are also important prognostic factors, with unfavorable histology, SCAs, and diploid tumors associated with worse outcomes 1, 2, 3, 5.

International differences exist in risk classification systems, with patients with L2, MYCN-nonamplified disease who are >18 months with unfavorable histology classified as high-risk by COG criteria but may be intermediate-risk by European cooperative groups 5, 6, 7.
Bone marrow assessment requires bilateral aspirates and core biopsies using conventional morphology for initial staging, with more sensitive methods reserved for minimal residual disease detection during or after therapy 8, 9, 10.
Multidisciplinary team involvement is mandatory, including diagnostic radiologists, nuclear medicine physicians, interventional radiologists, surgeons, anatomic and molecular pathologists, radiation oncologists, and pediatric oncologists 5, 7.