title: Evolution of mesothelioma from benign asbestos pleural inflammation
Creators: name: Ferguson, Katie
Publisher: name: University of Glasgow
Year: 2025

description: Pleural Mesothelioma (PM) is an incurable disease with a poor life expectancy. It is most commonly associated with asbestos exposure and the latency period from exposure to PM presentation is usually 20-50years. PM can present after a period of benign pleural inflammation, but the true rate of PM evolution in such cases, and factors promoting evolution, remain unclear. There has been an increase in mesothelioma research in recent years, leading to improved understanding of mesothelioma biology and subsequent treatment advances, but the prognosis remains poor. There have been improvements in PM diagnostics with the addition of ancillary testing including BRCA1-associated protein 1 (BAP1), Methylthioadenosine Phosphorylase (MTAP) and Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A), but their use in prognostication of PM is not fully understood.

The aim of this thesis is to further our knowledge of benign asbestos pleural inflammation and early mesothelioma. The introduction of this thesis outlines the current knowledge of the pathophysiology, clinical characteristics and diagnostics of benign pleural inflammation and PM.

Chapter 2 describes the Meso-ORIGINS Feasibility Study which includes a prospective study to explore the feasibility of a surveillance protocol for patients with asbestos associated pleural inflammation (AAPI), including repeat pleural sampling. This chapter also describes a retrospective study carried out to determine more precisely the rate of evolution of AAPI to PM, and to identify baseline predictors of PM evolution. 296 AAPI patients (39 prospective, 257 retrospective) were recruited/selected. 21/39 prospective recruits were histologically diagnosed (target n=27). Repeat LAT was technically feasible and acceptable in 13/28(46%) and 24/36(67%) cases with complete follow-up data. Mesothelioma evolution was confirmed histologically in 36/257 retrospective cases (14%(95%CI 10.3-18.8) and associated with malignant CT features (OR 4.78(95% CI 2.36-9.86) and age (OR 1.06(95% CI 1.02-1.12).

Chapter 3 describes a systematic review and meta-analysis which aims to define the true rate of PM evolution from benign pleural inflammation, and identify any characteristics that may give rise to a higher risk of PM evolution. 17/265 identified studies were included, describing 2607 NSP cases and 146 PM evolutions. The summary point estimate of PM evolution was 5.44%(95% CI 3.37- 7.51), with significant heterogeneity (p&lt;0.001, I² 82.7%). Higher PM evolution rate was associated with ≥50% asbestos exposure by cohort and high PM incidence settings. Lower evolution rate was associated with surgical NSP biopsies.

Chapter 4 describes a retrospective cohort study performed to evaluate the prognostic utility of CDKN2A and BAP1 testing in PM and benign AAPI. 155 PM cases were included and CDKN2A and BAP1 loss were observed in in 63.2% and 57.4%, respectively. Stage I prevalence was high (60.7%). PM median OS was 12.4 months (95% CI: 11.2-15.9). Adverse OS was associated with non-epithelioid histology, higher performance status and later stage. CKDN2A/BAP1 status was not associated with OS, including by histological subtype or when both genes were lost. Among 42 eligible AAPI cases, CDKN2A and BAP1 loss were observed in 1/42 (2%) and 2/39 (5%), respectively. 28/42 cases died during follow-up; 7/28 (25%) had post-mortem examinations. No PM evolutions were observed.

The findings in these chapters have been essential in the development and delivery of the Meso-ORIGINS study, which forms a major part of the PREDICTMeso International Accelerator. We have emphasised the importance of longitudinal tissue sampling spanning the period preceding PM development and the use of multi-omic testing to define the biological processes driving PM evolution and survival once PM is established.