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

Authors

  • Larry L. Wang MD, PhD,

    1. Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California
    Search for more papers by this author
  • Rie Suganuma MD, PhD,

    1. Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California
    Search for more papers by this author
  • Naohiko Ikegaki PhD,

    1. Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois
    Search for more papers by this author
  • Xao Tang PhD,

    1. Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois
    Search for more papers by this author
  • Arlene Naranjo PhD,

    1. Department of Biostatistics, Children's Oncology Group Statistics and Data Center, University of Florida, Gainesville, Florida
    Search for more papers by this author
  • Patrick McGrady MS,

    1. Department of Biostatistics, Children's Oncology Group Statistics and Data Center, University of Florida, Gainesville, Florida
    Search for more papers by this author
  • Wendy B. London PhD,

    1. Division of Hematology/Oncology, and Children's Oncology Group Statistics and Data Center, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
    Search for more papers by this author
  • Michael D. Hogarty MD,

    1. Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Julie M. Gastier-Foster PhD,

    1. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Ohio University College of Medicine, Columbus, Ohio
    Search for more papers by this author
  • A. Thomas Look MD,

    1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
    Search for more papers by this author
  • Julie R. Park MD,

    1. Department of Pediatrics, Seattle Children's Hospital, University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, Seattle, Washington
    Search for more papers by this author
  • John M. Maris MD,

    1. Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Susan L. Cohn MD,

    1. Department of Pediatrics, Division of Hematology/Oncology, University of Chicago, Chicago, Illinois
    Search for more papers by this author
  • Robert C. Seeger MD,

    1. Division of Hematology/Oncology, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California
    Search for more papers by this author
  • Hiroyuki Shimada MD, PhD

    Corresponding author
    1. Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California
    • Corresponding author: Hiroyuki Shimada, MD, PhD, Children's Hospital Los Angeles, 4650 Sunset Boulevard, MS 43, Los Angeles, CA 90027; Fax: (323) 361-8005; hshimada@chla.usc.edu

    Search for more papers by this author

Abstract

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.

Ancillary