An Evaluation Into the Robustness of Grading of Pleural Mesothelioma Outside of Specialist Centres

Our plain-English summary of An Evaluation Into the Robustness of Grading of Pleural Mesothelioma Outside of Specialist Centres, by S. Prabhakaran, A.J. Hocking, Y. Irani, et al (APMIS, 2025).

The study

• Authors: S. Prabhakaran, A.J. Hocking, Y. Irani, M. Hussey, A. Alexeyenko, K. Dobra, T. Micsik, E. Duhig, A.E. Walts, L. Vanwalleghem, V. Chhut, A.C. Roden, V.L. Roggli, M. Hertoghs, F. Galateau-Salle, L. Brcic, D. Moffat, S. Klebe
• Journal: APMIS
• Published: 2025;133(3):e70006
• Read it: PubMed · Publisher · Free full text

Abstract

The 2021 WHO classification of thoracic tumours recommends grading pleural mesothelioma to aid prognostication. Robustness of grading and morphological characterisation is key to its clinical utility, though validation of this grading system has largely been conducted by expert thoracic pathologists. We conducted a survey inviting pathologists across a range of practices and expertise to grade digitised images of 50 epithelioid pleural mesotheliomas that had been graded by an expert in thoracic pathology. We included slides that were considered potentially problematic such as small biopsies, focal necrosis, and rare subtypes that may affect grading (small cell and deciduoid features). Using the Sectra Uniview web viewer, participants were asked to score atypia, mitotic count, and necrosis and choose from a list of cytological and architectural features. Seventy-four pathologists anonymously participated. There was 90% agreement of consensus scores with expert opinion using the WHO 2-tier grade and 72% for the 3-tier nuclear grade but only 70% for nuclear atypia, 56% for mitoses, and 84% for necrosis. Both 3-tier nuclear grade and WHO 2-tier grading systems were significantly associated with survival. Our study affirms the overall robustness and utility of grading for pleural mesothelioma, reveals variances, and suggests the need for dedicated training.

© 2025 The Author(s). APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.

In plain English

This study tested how consistently pathologists across a range of practices and levels of experience grade epithelioid pleural mesothelioma using the 2021 WHO system. Seventy-four pathologists took part anonymously, and their experience and specialist practice were not recorded. They viewed digitised slides from 50 patients diagnosed at Flinders Medical Centre, Australia, between 1991 and 2021, and scored nuclear atypia, mitotic count and necrosis. Their consensus scores were compared with an expert thoracic pathologist's scores. The consensus matched the expert on the WHO 2-tier grade in 45 of 50 cases, the 3-tier nuclear grade in 36, necrosis in 42, atypia in 35 and mitoses in 28. Among 48 patients analysed using the expert's 2-tier grades, median survival was 15 months for low grade (confidence interval 7.7 to 22) and 7 months for high grade (confidence interval 2.1 to 11.9), p = 0.002. Among the 17 patients whose tumours retained BAP1, the survival difference between grades was not statistically significant (p = 0.164). The authors concluded that the 2-tier grade is a robust prognostic tool but that training 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: Online survey study of agreement between pathologists grading digitised slides, with survival analysis of an archival patient cohort
• Who was studied: Archival tissue from 50 patients with epithelioid pleural mesothelioma diagnosed at Flinders Medical Centre, Adelaide, Australia, between 1991 and 2021 (2 resections, 48 pleural biopsies). The slides were graded by 74 pathologists who participated anonymously. The survey did not record their experience or specialist practice.
• Main results:
  • Participants' consensus scores agreed with the expert on the WHO 2-tier tumour grade in 45 of 50 cases (90%).
  • Consensus scores agreed with the expert on the 3-tier nuclear grade in 36 of 50 cases (72%).
  • Consensus agreement with the expert was 35 of 50 (70%) for nuclear atypia, 28 of 50 (56%) for mitoses and 42 of 50 (84%) for necrosis.
  • In pairwise comparisons between reviewers, agreement was modest but better than chance for all gradings except mitotic count. Agreement with the expert was better than agreement between reviewers.
  • Using the expert's 2-tier grades (survival analysis N = 48), median survival was 15 months for low grade (CI 7.7 to 22) and 7 months for high grade (CI 2.1 to 11.9), log rank p = 0.002. Using consensus scores (N = 46), it was 15 months (CI 7.6 to 22.3) for low grade and 6.5 months (CI 4.2 to 8.7) for high grade, p less than 0.001.
  • Using the expert's 3-tier nuclear grades, median survival was 22 months for Grade I (CI 0 to 56), 13 months for Grade II (CI 9.7 to 16.2) and 6.5 months for Grade III (CI 5.03 to 7.96), log rank p = 0.004. Consensus scores gave similar results, with p less than 0.001.
  • Consensus scores for nuclear atypia, mitotic counts and necrosis were each significantly associated with survival (p = 0.002, 0.027 and 0.002 respectively).
  • BAP1 was lost on IHC in 31 of 50 tumours and retained in 17. In the BAP1-loss group, median survival was 17.5 months for low grade (CI 4.8 to 30) and 6.5 months for high grade (CI 5.0 to 7.9), p = 0.003. In the BAP1-retained group the difference between grades was not statistically significant (p = 0.164).
• The authors' conclusion: The authors concluded that, despite some shortfalls in the reproducibility of individual features, the WHO 2-tier grade is a robust prognostic tool for survival. Because opinions on low versus high grade were evenly split for some cases, they concluded that training on grading mesothelioma is required.
• Limitations the authors state:
  • Sample size varied between cases, and some were small biopsies.
  • Participants' familiarity with digital platforms may have influenced their assessments compared with examining glass slides.
  • Agreement on architectural patterns and cytological features could not be compared in a statistically meaningful way because of incomplete data and high variability.
  • Because the survey was anonymous, it gave no information on participants' experience or specialist practice.
  • Some participants had technical difficulties, and some gave only a final 2-tier grade without atypia, mitosis or necrosis scores, so a 3-tier nuclear grade could not be determined for them.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, WHO Classification, Epithelioid, Pathology, Necrosis, Mitotic Count, Nuclear Grade, Nuclear Atypia.

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