title: Neuroblastoma of undifferentiated subtype, prognostic significance of prominent nucleolar formation, and MYC/MYCN protein expression: a report from the Children's Oncology Group.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California.
authors.forename: Larry L
authors.initials: LL
authors.lastname: Wang
authors.forename: Rie
authors.initials: R
authors.lastname: Suganuma
authors.forename: Naohiko
authors.initials: N
authors.lastname: Ikegaki
authors.forename: Xao
authors.initials: X
authors.lastname: Tang
authors.forename: Arlene
authors.initials: A
authors.lastname: Naranjo
authors.forename: Patrick
authors.initials: P
authors.lastname: McGrady
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hogarty
authors.forename: Julie M
authors.initials: JM
authors.lastname: Gastier-Foster
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.forename: Julie R
authors.initials: JR
authors.lastname: Park
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cohn
authors.forename: Robert C
authors.initials: RC
authors.lastname: Seeger
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
mesh_terms: D002454:Cell Differentiation; D002466:Cell Nucleolus / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D005500:Follow-Up Studies; D005784:Gene Amplification; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D019656:Loss of Heterozygosity; D000071447:N-Myc Proto-Oncogene Protein; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc
keywords: MYC/MYCN expression; MYCN amplification; neuroblastoma, undifferentiated subtype; prognostic factors
references.citation: Cancer. 1987 Jun 1;59(11):1853-9
references.pmid: 3567848
references.citation: Int J Cancer. 2000 Sep 20;89(5):395-402
references.pmid: 11008200
references.citation: Science. 1984 Jun 8;224(4653):1121-4
references.pmid: 6719137
references.citation: Cancer Res. 1990 Mar 1;50(5):1459-63
references.pmid: 2302711
references.citation: Cancer. 2004 Jan 15;100(2):390-7
references.pmid: 14716776
references.citation: J Cell Sci. 2003 May 1;116(Pt 9):1707-17
references.pmid: 12665552
references.citation: Clin Cancer Res. 2001 Aug;7(8):2425-33
references.pmid: 11489822
references.citation: Pediatr Blood Cancer. 2013 Mar;60(3):363-70
references.pmid: 22744966
references.citation: Pathol Oncol Res. 2007;13(4):269-75
references.pmid: 18158560
references.citation: Cancer Res. 1987 Oct 1;47(19):5207-12
references.pmid: 3040240
references.citation: Med Pediatr Oncol. 2001 Jan;36(1):169-76
references.pmid: 11464876
references.citation: Br J Cancer. 1977 Jan;35(1):1-39
references.pmid: 831755
references.citation: J Clin Oncol. 1998 Jul;16(7):2478-85
references.pmid: 9667267
references.citation: Genome Biol. 2008 Oct 13;9(10):R150
references.pmid: 18851746
references.citation: J Neurooncol. 2011 Mar;102(1):25-33
references.pmid: 20607354
references.citation: N Engl J Med. 1985 Oct 31;313(18):1111-6
references.pmid: 4047115
references.citation: Cancer. 2002 Mar 1;94(5):1574-83
references.pmid: 11920516
references.citation: Cancer. 2005 Jan 1;103(1):174-80
references.pmid: 15549714
references.citation: Cancer. 2001 Nov 15;92(10):2699-708
references.pmid: 11745206
references.citation: J Pediatr Hematol Oncol. 1998 Jan-Feb;20(1):18-25
references.pmid: 9482408
references.citation: FASEB J. 2011 Dec;25(12):4138-49
references.pmid: 21856782
references.citation: Oncologist. 2003;8(3):278-92
references.pmid: 12773750
references.citation: J Neurosci Res. 1989 Sep;24(1):21-8
references.pmid: 2810395
references.citation: Nat Rev Mol Cell Biol. 2005 Aug;6(8):635-45
references.pmid: 16064138
references.citation: Clin Cancer Res. 2007 May 1;13(9):2651-7
references.pmid: 17473196
references.citation: Cancer. 1999 Jul 15;86(2):364-72
references.pmid: 10421273
references.citation: Mol Cell Biol. 1999 Jan;19(1):1-11
references.pmid: 9858526
references.citation: J Clin Oncol. 2000 Jan;18(1):18-26
references.pmid: 10623689
references.citation: Cancer Res. 2006 Jan 15;66(2):673-81
references.pmid: 16423996
references.citation: J Clin Oncol. 1998 Apr;16(4):1256-64
references.pmid: 9552023
references.citation: N Engl J Med. 1999 Oct 14;341(16):1165-73
references.pmid: 10519894
references.citation: Cancer. 1999 Jul 15;86(2):349-63
references.pmid: 10421272