Background: Diffuse pleural mesothelioma is a thoracic malignancy associated with aggressive clinical behaviour and a lack of treatment options. It is hypothesised that the diverse spectrum of observed clinical and biological characteristics in the literature could be explained by inter-tumoural and intra-tumoural heterogeneity. Consequently there is scope to improve the contemporary classification of these tumours, especially a subset of those representing minimally or superficially invasive pleural mesothelioma, allowing the disease to be diagnosed earlier in its natural history.
Materials and methods: Using a number of databases (including an institutional mesothelioma database that I retrospectively curated and prospectively maintained) and datasets linked to the diagnostic practice at an academic centre over a period of 30 years, the clinical, histopathological and molecular characteristics of pleural mesothelioma were interrogated via a multidisciplinary approach. The emphasis of the approach was on the outcomes following multimodality therapy including radical surgery, histological heterogeneity of epithelioid pleural mesothelioma and proposal of a minimal sampling requirement, histology-molecular correlation of key genomic alterations, and the development of a risk stratification system for atypical mesothelial proliferation of the pleura.
Results: The histological subtype of mesothelioma predicted outcome following multimodality therapy and influenced key surgical and oncological parameters. It was also determined that the epithelioid subtype, the most common subtype of mesothelioma, can be classified using a nuclear grading system based on the morphology of tumour cell nucleus, mitotic activity and the presence of tumour necrosis. This can be reliably performed on biopsies provided the minimum sampling requirement is met. Epithelioid mesothelioma exhibits extensive heterogeneity in architectural growth patterns and cytological features, although most of which is a function of nuclear grade. A morphology-based classification stratified atypical mesothelial proliferation into high risk and low risk categories, the latter demonstrating significantly superior survival outcomes and supports the hypothesised existence of a minimally invasive stage of pleural mesothelioma.
Conclusions: This thesis expands the evidence base in several aspects central to the future iterations of mesothelioma classification and highlights the importance of accurate and informative histopathological diagnosis in its multidisciplinary management. Furthermore, the findings lay a cornerstone to the establishment of future academic-clinical partnerships, of multi-dimensional and multi-parametric nature, integrating the expertise of fundamental science, clinical specialities and histopathology in the research of this disease.