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

Our plain-English summary of Ki67 proliferation index augments two-tier tumour grade in prediction of survival and progression-free survival in epithelioid pleural mesothelioma, by G.A. Lynch, Y.Z. Zhang, N. Bhatt, et al (ERJ Open Research, 2026).

The study

• Authors: G.A. Lynch, Y.Z. Zhang, N. Bhatt, P. Charters, A. Aujayeb, S. Walker, J. Symonds, A.O. Clive, R. Bhatnagar, A. Morley, P. White, A.G. Nicholson, N.A. Maskell, A. Bibby
• Journal: ERJ Open Research
• Published: 2026;12(3)
• Read it: PubMed · Publisher · Free full text

Abstract

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.

Copyright ©The authors 2026.

In plain English

This study tested whether Ki67, a laboratory stain that marks multiplying tumour cells, helps predict outcomes in epithelioid pleural mesothelioma. The authors used diagnostic biopsies from 98 patients in two prospective UK cohort studies (2010 to 2023). Three pathologists who did not know the patients' survival reviewed them. Patients whose Ki67 was 30% or more had a median survival of 310 days, compared with 649.5 days for those below 30% (hazard ratio 2.37, 95% CI 1.51 to 3.71). Ki67 also predicted progression-free survival. The current two-tier tumour grade was linked to survival, but not after adjustment for age, sex, performance status and tumour stage. Adding Ki67 to tumour grade predicted survival better than grade alone. Median survival was 660.5 days with low Ki67 and low grade, and 300 days with high Ki67 and high grade. The authors concluded that tumour grade plus Ki67 at 30% should be considered as a new reporting standard. They noted that the 30% cut-off was chosen and tested in the same data, and that external validation is needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Prognostic study using patients from two prospective cohort studies, with biopsies reviewed by three pathologists blinded to survival
• Who was studied: 98 patients with epithelioid pleural mesothelioma (46 from the Pleural Investigation Study, 52 from ASSESS-Meso), from Bristol and Northumbria, UK, January 2010 to November 2023; 97 had Ki67 results
• Exposure: Asbestos exposure was not studied. The factors examined were the Ki67 proliferation index and two-tier tumour grade in diagnostic biopsies, plus other pre-specified markers (albumin, neutrophil-lymphocyte ratio, host response, nuclear atypia, mitotic activity, necrosis, tertiary lymphoid structures, nuclear grade)
• Main results:
  • Ki67 of 30% or more predicted overall survival (crude HR 2.37, 95% CI 1.51 to 3.71; adjusted HR 2.63, 1.53 to 4.49) and progression-free survival (crude HR 2.09, 1.35 to 3.23; adjusted HR 1.94, 1.17 to 3.20)
  • Median overall survival was 649.5 days (IQR 322 to 1263.5) for Ki67 below 30% and 310 days (IQR 158 to 416) for Ki67 of 30% or more
  • Two-tier tumour grade was associated with overall survival (crude HR 1.83, 1.13 to 2.97; adjusted 1.55, 0.89 to 2.70) and progression-free survival (crude HR 1.70, 1.08 to 2.66; adjusted HR 1.66, 1.00 to 2.78); it did not remain predictive after adjustment
  • Combining tumour grade with Ki67 gave a c-statistic for overall survival of 0.65 (95% CI 0.58 to 0.72), compared with 0.56 (0.50 to 0.62) for tumour grade alone, a significant improvement (p=0.0021)
  • Median survival in the four Ki67 and grade groups: 660.5 days for low Ki67 and low grade, 507.5 days for low Ki67 and high grade, 332 days for high Ki67 and low grade, and 300 days for high Ki67 and high grade
  • Agreement between pathologists for Ki67 split at 30% had a kappa of 0.71
• The authors' conclusion: The authors concluded that tumour grade plus Ki67 split at 30% should be considered as a new reporting standard in epithelioid pleural mesothelioma
• Limitations the authors state:
  • Treatment status was left out of the prediction models
  • The 30% cut-off was chosen and tested in the same dataset, which may overstate its performance
  • Among patients with low Ki67, survival did not separate by tumour grade, possibly because the low-Ki67, high-grade group was small
  • When analysed by treatment status, the ability to predict progression-free survival was weaker
  • The combined Ki67 and grade approach needs external validation before clinical use

Topics

Medical terms in this study, explained in our Lexicon: Progression-Free Survival, Epithelioid, Pleural Mesothelioma, Prognosis, Overall Survival, Hazard Ratio, Median Overall Survival.

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• Preoperative Circulating Tumor DNA in Patients with Peritoneal Carcinomatosis is an Independent Predictor of Progression-Free Survival — J.M. Baumgartner, V.M. Raymond, et al. (2018)
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• Prognostic factors for progression-free and overall survival in malignant pleural mesothelioma — J. Guzmán-Casta, S. Carrasco-CaraChards, et al. (2021)

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