title: Enlarged and prominent nucleoli may be indicative of MYCN amplification: a study of neuroblastoma (Schwannian stroma-poor), undifferentiated/poorly differentiated subtype with high mitosis-karyorrhexis index.
abstract: BACKGROUND
  According to the International Neuroblastoma Pathology Classification, neuroblastomas exhibiting MYCN amplification (A-MYCN) have unique histologic features-namely, undifferentiated/poorly differentiated subtype with a high mitosis-karyorrhexis index (U/PD-H). Nonetheless, certain tumors possessing these histologic characteristics contain a nonamplified MYCN gene (NA-MYCN).
  
  
  METHODS
  The clinical characteristics of patients from the Children's Cancer Group (CCG) 3881 and 3891 studies who had neuroblastoma, U/PD-H, exhibiting A-MYCN (n=68) or NA-MYCN (n=33) were investigated. The histologic and cytologic features of tumors (A-MYCN, n=62; NA-MYCN, n=28) filed at the Pathology Reference Laboratory, Department of Pathology and Laboratory Medicine, Childrens Hospital Los Angeles, were reviewed, and nucleolar areas in undifferentiated neuroblastic cells were evaluated using image analysis methods.
  
  
  RESULTS
  All 68 patients whose tumors exhibited A-MYCN had disease that was in an advanced clinical stage (Stage III or IV); 89.7% of these patients were diagnosed between ages 0.5 and 3.5 years, and 67 of the 68 had been treated with the high-risk protocol in the CCG-3891 study. Children whose tumors exhibited NA-MYCN were evenly distributed across all age groups; 30 of these 33 children had advanced-stage disease, and 26 had been treated with a high-risk protocol. The prognosis associated with A-MYCN (event free survival [EFS], 15.7%; overall survival [OS], 22.2%) was significantly poorer than the prognosis associated with NA-MYCN (EFS, 56.1%; OS, 69.3%). The lone histologic/cytologic difference between tumors exhibiting A-MYCN and tumors exhibiting NA-MYCN involved nucleolar appearance. Neuroblastic cells in tumors exhibiting A-MYCN were characterized by the presence of 1 or more large, prominent nucleoli, and the mean nucleolar area was significantly greater in the 18 tumors exhibiting A-MYCN that were assessed (7.63 microm2) than in the 16 tumors exhibiting NA-MYCN that were assessed (5.53 microm2; P=0.004).
  
  
  CONCLUSIONS
  Neuroblastomas, U/PD-H, were found to vary in terms of molecular background and clinical behavior. The results of the current study indicate that nucleolar enlargement in neuroblastic cells may be a sign of MYCN amplification.
authors.affiliation: Department of Pathology and Laboratory Medicine, Childrens Hospital Los Angeles/Keck School of Medicine, University of Southern California, Los Angeles, California 90027, USA.
authors.forename: Chie
authors.initials: C
authors.lastname: Kobayashi
authors.forename: Hector L
authors.initials: HL
authors.lastname: Monforte-Munoz
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gerbing
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
authors.forename: John N
authors.initials: JN
authors.lastname: Lukens
authors.forename: Robert C
authors.initials: RC
authors.lastname: Seeger
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D002466:Cell Nucleolus; D002648:Child; D002675:Child, Preschool; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D000071447:N-Myc Proto-Oncogene Protein; D009367:Neoplasm Staging / Q000379:methods*; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology*; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics*; D015513:Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins