Ki67 proliferation index augments two-tier tumour grade in prediction of survival and progression-free survival in epithelioid pleural mesothelioma

Background: Pleural mesothelioma (PM) is a fatal asbestos-related cancer with a poor and often uncertain prognosis. This study validates the histological proliferation marker Ki67 and evaluates whether its integration into the two-tier tumour grading system can improve prognostication in epithelioid PM. Methods: Patients with epithelioid PM were recruited from two longitudinal cohort studies from 2010-2023. Diagnostic biopsies were analysed by three pulmonary pathologists. Cox regression determined the relationship between covariables and outcomes. Pearson correlation assessed the association between Ki67 and two-tier grade. A prognostic model combining Ki67 and tumour grade was internally validated using bootstrapping. Results: 98 patients were recruited. Ki67 was strongly predictive of overall survival (OS) and progression-free survival (PFS) and correlated with two-tier tumour grade. 30% was the optimal cut-off, with Ki67 more strongly predictive of OS (hazard ratio (HR) 2.37, 95% CI 1.51-3.71) and PFS (HR 2.09, 1.35-3.23) than two-tier grade (HR 1.83, 1.13-2.97 and HR 1.70, 1.08-2.66, respectively). Combining Ki67 and two-tier grade improved prediction of OS and PFS compared with two-tier grade alone. Ki67 stratified patients within each tumour grade, with median survival in the lowest risk group (low Ki67, low grade) of 660.5 days (IQR 329-1297) and 300 days (IQR 124-366) in the highest risk group (high Ki67, high grade). Conclusion: Ki67 is a valid surrogate for tumour grade with an optimal cut-off at 30%. Integrating Ki67 into the two-tier grading system enhances prognostic accuracy, improves outcome prediction and would reduce uncertainty for patients and clinicians.