Revised Neuroblastoma Risk Classification System: A Report From the Children's Oncology Group

Abstract

PURPOSE Treatment planning for children with neuroblastoma requires accurate assessment of prognosis. The most recent Children's Oncology Group (COG) risk classification system used tumor stage as defined by the International Neuroblastoma Staging System. Here, we validate a revised classifier using the International Neuroblastoma Risk Group Staging System (INRGSS) and incorporate segmental chromosome aberrations (SCA) as an additional genomic biomarker. METHODS Newly diagnosed patients enrolled on the COG neuroblastoma biology study ANBL00B1 between 2007 and 2017 with known age, International Neuroblastoma Staging System, and INRGSS stage were identified (N = 4,832). Tumor MYCN status, ploidy, SCA status (1p and 11q), and International Neuroblastoma Pathology Classification histology were determined centrally. Survival analyses were performed for combinations of prognostic factors used in COG risk classification according to the prior version 1, and to validate a revised algorithm (version 2). RESULTS Most patients with locoregional tumors had excellent outcomes except for those with image-defined risk factors (INRGSS L2) with MYCN amplification (5-year event-free survival and overall survival: 76.3% ± 5.8% and 79.9% ± 5.5%, respectively) or patients age ≥ 18 months with L2 MYCN nonamplified tumors with unfavorable International Neuroblastoma Pathology Classification histology (72.7% ± 5.4% and 82.4% ± 4.6%), which includes the majority of L2 patients with SCA. For patients with stage M (metastatic) and MS (metastatic, special) disease, genomic biomarkers affected risk group assignment for those < 12 months ( MYCN) or 12-18 months ( MYCN, histology, ploidy, and SCA) of age. In a retrospective analysis of patient outcome, the 5-year event-free survival and overall survival using COG version 1 were low-risk: 89.4% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 86.1% ± 1.3% and 94.9% ± 0.8%; high-risk: 50.8% ± 1.4% and 61.9% ± 1.3%; and using COG version 2 were low-risk: 90.7% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 85.1% ± 1.4% and 95.8% ± 0.8%; high-risk: 51.2% ± 1.4% and 62.5% ± 1.3%, respectively. CONCLUSION A revised 2021 COG neuroblastoma risk classifier (version 2) that uses the INRGSS and incorporates SCAs has been adopted to prospectively define COG clinical trial eligibility and treatment assignment.

MYCN in Neuroblastoma: “Old Wine into New Wineskins”

“…Yet, there are several factors that can modify the decision for surgical intervention. All recent reports agree on the fact that disease staging is crucial for the treatment of the disease [ 47 , 216 ]. It has been reported that surgical treatment and its success is linked to the image defined risk factors (IDRF), which include the crossing and extending of the tumor, the engulfment of vessels, the compression of other organs and the encasing of nerves [ 217 ].…”

“…A recent study highlighted that exportin-T overexpression, is an independent poor prognosis factor in MYCN amplified neuroblastoma [ 46 ]. Further on, the most recent neuroblastoma risk classification system indicated that the presence of image defined risk factors (IDRF), MYCN amplification and age are important prognostic factors related to poor prognosis [ 47 ]. Another prognostic factor recently mentioned was the overexpression of c-myc, which was confirmed to be linked to poor prognosis independently of MYCN amplification [ 48 ].…”

Genetic and Histopathological Heterogeneity of Neuroblastoma and Precision Therapeutic Approaches for Extremely Unfavorable Histology Subgroups

“…Prognostic factors utilized in the latest and revised COG system include clinical staging, according to the INRG Staging System (INRGSS; Stages L1, L2, M and MS); age at diagnosis (new cut-off points at 365 days, 548 days and 5 years); histopathology, according to the INPC (favorable histology (FH) vs. unfavorable histology (UH)); MYCN oncogene status (non-amplified vs. amplified); DNA index (hyperdiploid vs. diploid); and segmental chromosomal aberrations (1p − , 11q − , 17q + ; No vs. Yes) [ 8 ]. The hazard ratio by each prognostic factor is shown in the Figure 1 and the recent and revised COG neuroblastoma risk classification system is summarized in Figure 2 [ 8 ].…”

“…Yes) [ 8 ]. The hazard ratio by each prognostic factor is shown in the Figure 1 and the recent and revised COG neuroblastoma risk classification system is summarized in Figure 2 [ 8 ]. Treatment of patients in the low-risk group is often followed by observation (with no chemotherapy or radiation) after surgery or even biopsy alone.…”

“…High-risk patients are treated with intensive chemotherapy, surgery, radiation therapy, bone marrow/hematopoietic stem cell transplantation and biological-based therapies. The reported 5-year survival rates for non-high-risk and high-risk patients are around 90% and 50%, respectively [ 8 ].…”