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.

MIBG avidity correlates with clinical features, tumor biology, and outcomes in neuroblastoma: A report from the Children's Oncology Group

“…The presence of bone metastases was recorded at diagnosis based upon all available imaging data, with bone scan required at study entry on both A3961 and A3973 protocols. Biologic factors included MYCN status, ploidy, specific segmental chromosomal aberrations, histologic diagnosis, International Neuroblastoma Pathology Classification category, mitotic karyorrhectic index (MKI), and grade. EFS and overall survival (OS) rates were determined as described in the next section.…”

Association of MYCN copy number with clinical features, tumor biology, and outcomes in neuroblastoma: A report from the Children's Oncology Group

“…MNA is more common in patients with adrenal primary tumors and less common in those with thoracic primary tumors . There is a strong association between MNA and other tumor biologic and genomic features, such as unfavorable histology, diploidy, high mitotic karyorrhectic index (MKI), and loss of heterozygosity (LOH) at 1p …”

“…7 MNA is more common in patients with adrenal primary tumors and less common in those with thoracic primary tumors. 4,7 There is a strong association between MNA and other tumor biologic and genomic features, such as unfavorable histology, 9,10 diploidy, [11][12][13] high mitotic karyorrhectic index (MKI), 14 and loss of heterozygosity (LOH) at 1p. [15][16][17][18][19] MYCN copy number is a discrete variable, but groups have applied cutpoints that define specific tumors as amplified versus nonamplified.…”

Identification of patient subgroups with markedly disparate rates of MYCN amplification in neuroblastoma: A report from the International Neuroblastoma Risk Group project

“…MYCN status is also associated with other adverse prognostic factors. For example, MNA is associated with unfavorable histology, the mitosis‐karyorrhexis index (MKI), and diploid/tetraploid tumors . MNA is associated with the presence of a range of SCAs, especially 1p deletion, though 11q aberration shows a strong inverse relation .…”