title: Age-dependent prognostic effect by Mitosis-Karyorrhexis Index in neuroblastoma: a report from the Children's Oncology Group.
abstract: Prognostic effects of Mitosis-Karyorrhexis Index (MKI) used in the International Neuroblastoma Pathology Classification (INPC) are age-dependent. A total of 4,282 neuroblastomas reviewed at the Children's Oncology Group Neuroblastoma Pathology Reference Laboratory (8/1/2001-3/31/2012) included 2,365 low-MKI (L-MKI), 1,068 intermediate-MKI (I-MKI), and 849 high-MKI (H-MKI) tumors. Cox proportional hazards models were fit to determine age cut-offs at which the relative risk of event/death was maximized in each MKI class. Backward-selected Cox models were fit to determine the prognostic strength of the age cut-offs for survival in the presence of other prognostic factors. The age cut-offs used in the INPC for L-MKI tumors (<60 months, n  =  2,710, 84.0% ± 1.0% event-free survival [EFS], 93.8 ± 0.7% overall survival [OS] vs ≥60 months, n  =  195, 49.8% ± 4.6% EFS, 71.7% ± 4.1% OS; P < 0.0001) and I-MKI tumors (<18 months, n  =  568, 83.8% ± 2% EFS, 93.7% ± 1.3% OS vs ≥18 months, n  =  500, 51.4% ± 2.9% EFS, 66.7% ± 2.7% OS; P < 0.0001) were within the effective range for distinguishing prognostic groups. As for H-MKI tumors (no cut-off age in the INPC, 51.0% ± 2.2% EFS, 64.4% ± 2.1% OS), a new cut-off of 3-4 months was suggested (<4 months, n  =  38, 82.3% ± 8.4% EFS, 81.8% ± 8.5% OS vs ≥4 months, n  =  811, 49.6% ± 2.2% EFS, 63.7% ± 2.1% OS, P  =  0.0034 and 0.0437, respectively). Multivariate analyses revealed that cut-offs of 60 and 18 months for L-MKI and I-MKI tumors, respectively, were independently prognostic. However, the cut-off of 4 months for H-MKI tumors did not reach statistical significance in the presence of other factors. The age cut-offs for MKI classes (60 months for L-MKI, 18 months for I-MKI, no cut-off for H-MKI) in the current INPC are reasonable and effective for distinguishing prognostic groups with increased risk of event/death for older patients.
authors.affiliation: 1 Department of Pathology & Laboratory Medicine, Children's Hospital Los Angeles, and University of Southern California Keck School of Medicine, 4650 Sunset Boulevard, MS #43, Los Angeles, CA 90027, USA.
authors.forename: Risa
authors.initials: R
authors.lastname: Teshiba
authors.forename: Shinya
authors.initials: S
authors.lastname: Kawano
authors.forename: Larry L
authors.initials: LL
authors.lastname: Wang
authors.forename: Lejian
authors.initials: L
authors.lastname: He
authors.forename: Arlene
authors.initials: A
authors.lastname: Naranjo
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.forename: Robert C
authors.initials: RC
authors.lastname: Seeger
authors.forename: Julie M
authors.initials: JM
authors.lastname: Gastier-Foster
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hogarty
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cohn
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Julie R
authors.initials: JR
authors.lastname: Park
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
mesh_terms: D000367:Age Factors; D001706:Biopsy; D016009:Chi-Square Distribution; D002675:Child, Preschool; D018450:Disease Progression; D018572:Disease-Free Survival; D005784:Gene Amplification; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D007621:Karyotyping; D008938:Mitosis; D008940:Mitotic Index; D015999:Multivariate Analysis; D000071447:N-Myc Proto-Oncogene Protein; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D010524:Peripheral Nervous System Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012307:Risk Factors; D013997:Time Factors
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins
keywords: International Neuroblastoma Pathology Classification; age cut-off; mitosis-karyorrhexis index; neuroblastoma; prognosis