Ki-67 Proliferation Index Is Associated With Tumor Grade and Survival in Pleural Epithelioid Mesotheliomas

Abstract

Pleural epithelioid mesothelioma (PEM) is divided into low and high grades based on nuclear atypia, mitoses, and necrosis in the tumor. Assessing mitoses and nuclear atypia tend to be labor-intensive with limited reproducibility. Ki-67 proliferation index was shown to be a prognostic factor in PEM, but its performance has not been directly correlated with tumor grade or mitotic score. This study evaluated the potential of Ki-67 index as a surrogate of tumor grade. We also compared the predictability of mitoses and Ki-67 index for overall survival (OS). Ninety-six PEM samples from 85 patients were identified from the surgical pathology file during 2000-2021 at our institution, and all glass slides were reviewed by 2 pulmonary pathologists to confirm the diagnosis and assign the tumor grade. Digital image analysis (DIA) was done for Ki-67 index. The agreement on tumor grading between 2 reviewers was moderate (kappa value = 0.47). The correlation between mitotic count (average count by 2 reviewers) and Ki-67 index was 0.65. The areas under the curve for predicting tumor grade by mitotic score and Ki-67 index were 0.84 and 0.74 (reviewer 1) and 0.85 and 0.81 (reviewer 2), respectively. High Ki-67 index and mitoses were significantly associated with poor OS ( P =0.03 and 0.0005, using 30% and 10/2 mm 2 as cutoffs, respectively). In conclusion, Ki-67 index by DIA was associated with tumor grade as well as mitotic count, and its predictability for OS was comparable to that of mitotic score, thus being a potential surrogate for tumor grade.

FIGURE 1

Interobserver Agreement for Mitotic Counts. Scatter plot demonstrating interobserver correlation (reviewer 2 x-axis, reviewer 1 y-axis) based on mitotic counts for 96 specimens. The red diagonal line (identity line) demonstrates perfect agreement between reviewers.

FIGURE 2

A, Correlation between mitotic count (reviewer averaged) with Ki-67%. Scatter plot demonstrating moderate correlation (0.645) between reviewer-averaged mitotic count (x-axis) and Ki-67% positivity (y-axis) for 96 specimens. B, ROC curves predicting tumor grade based on mitotic count or Ki-67%. ROC curve for tumor grade versus mitotic count for each reviewer (left). ROC curve for tumor grade versus Ki-67% for each reviewer (right). AUC indicates area under the curve; ROC, reviewer operating characteristic.

FIGURE 3

Overall survival by WHO tumor grade, mitotic count, and Ki-67 proliferation index. Kaplan-Meier plots illustrating overall survival for 85 patients with diffuse pleural epithelioid mesothelioma. Proposed mitotic count categorizations of 0 to 4, 5 to 9, and >10 mitoses show poorer survival probability with higher mitotic counts (lower left). Ki-67 proliferation index with a delineation of 30% positivity (lower right), showing similar performance to the tumor grade by reviewer 2.