Neuroblastoma of undifferentiated subtype, prognostic significance of prominent nucleolar formation, and MYC/MYCN protein expression: A report from the Children's Oncology Group

BACKGROUND This study sought to investigate biological/clinicopathological characteristics of neuroblastoma, undifferentiated subtype (NBUD). METHODS This study examined 157 NBUD cases filed at the Children's Oncology Group Neuroblastoma Pathology Reference Laboratory, and survival rates of the patients were analyzed with known prognostic factors. Immunostainings for MYCN and MYC protein were performed on 68 tumors. RESULTS NBUD cases had a poor prognosis (48.4% ± 5.0% 3‐year event‐free survival [EFS]; 56.5% ± 5.0% overall survival [OS]), and were often associated with high mitosis‐karyorrhexis index (MKI, 65%), prominent nucleoli (PN, 83%), ≥ 18 months of age (75%), MYCN amplification (MYCN‐A, 83%), diploid pattern (63%), and 1pLOH (loss of heterozygosity (72%). However, these prognostic indicators, except for MYCN status, had no significant impact on survival. Surprisingly, EFS for patients with MYCN‐A tumors (53.4% ± 5.6%) was significantly better (P = .0248) than for patients with MYCN‐nonamplified (MYCN‐NA) tumors (31.7% ± 11.7%), with MYCN‐NA and PN (+) tumors having the worst prognosis (9.3% ± 8.8%, P = .0045). Immunohistochemically, MYCN expression was found in 42 of 48 MYCN‐A tumors. In contrast, MYC expression was almost exclusively found in the MYCN‐NA tumors (9 of 20) especially when they had PN (8 of 11). Those patients with only MYC‐positive tumors had the worst EFS (N = 8, 12.5% ± 11.7%) compared with only MYCN‐positive (N = 39, 49.9% ± 17.7%) and both negative tumors (N = 15, 70.0% ± 17.1%) (P = .0029). High MKI was often found in only MYCN‐positive (30 of 38) but rarely in only MYC‐positive (2 of 8) tumors. CONCLUSIONS NBUD represents a unique subtype of neuroblastoma associated with a poor prognosis. In this subtype, MYC protein expression may be a new prognostic factor indicating more aggressive clinical behavior than MYCN amplification and subsequent MYCN protein expression. Cancer 2013;119:3718–3726. © 2013 American Cancer Society. Neuroblastoma, undifferentiated subtype, which is the histologically defined entity composed of neuroblasts often having prominent nucleoli, is frequently associated with poor prognostic factors. In this subtype, MYC protein expression could indicate more aggressive clinical behavior than MYCN amplification and subsequent MYCN protein expression.