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.

Keywords: International Neuroblastoma Pathology Classification; age cut-off; mitosis-karyorrhexis index; neuroblastoma; prognosis.

Figure 1

Mitotic and karyorrhectic activities in neuroblastoma tumors. Left: Low-MKI (<100/5000 cells) tumors; middle: intermediate-MKI (100–200/5000 cells) tumor typically showing markedly different areas of activity, from lower (upper) to higher (lower); and right: high-MKI (≥200/5000 cells) tumor. MKI indicates mitosis-karyorrhexis index. Hematoxylineosin, original magnification ×400. A color version of this figure is available online.

Figure 2

Upper bar graphs: Distribution of MKI classes in MYCN nonamplified neuroblastomas (left) and in MYCN amplified neuroblastomas (right). Lower pie graphs: Distribution of MYCN nonamplified and MYCN amplified neuroblastomas in each MKI class. There is a significant association between increasing MKI class and MYCN amplification (P < 0.0001). L-MKI indicates low-MKI tumors; I-MKI, intermediate-MKI tumors; H-MKI, high-MKI tumors; MKI, mitosis-karyorrhexis index.

Figure 3

Cox proportional hazards model for event-free survival with age ≥ cut-off (in months) for patients with low-MKI (A, n = 2365), intermediate-MKI (B, n = 1068), and high-MKI (C, n = 849) tumors. The hazard ratio (with 95% confidence intervals) is the increased risk of event in the group of patients with age ≥ cut-off in comparison to the group with age < cut-off. Shaded areas (between 28 and 60 months for low MKI, 12 and 18 months for intermediate MKI, and 3 and 4 months for high MKI) indicate age cut-off points, effectively differentiating 2 groups of patients in terms of increased risk of event for older children in each MKI class. MKI indicates mitosis-karyorrhexis index.

Figure 4

Event-free survival for patients with different MKI tumors based on the age cut-offs incorporated in the standard International Neuroblastoma Pathology Classification system. Patients with L-MKI tumors diagnosed at < 60 months and with I-MKI tumors diagnosed at <18 months had a significantly better prognosis than patients with L-MKI tumor diagnosed at ≥60 months, with I-MKI tumor diagnosed at ≥18 months, and with H-MKI tumor diagnosed at any age (P < 0.0001). L-MKI indicates low-MKI tumors; I-MKI, intermediate-MKI tumors; H-MKI, high-MKI tumors; MKI, mitosis-karyorrhexis index.