Intratumour, anatomical and temporal heterogeneity in mesothelioma

Pleural mesothelioma (PM) is characterised by marked heterogeneity, both clinically in terms of survival and response to treatment, and in terms of histology and molecular status. Development of novel therapies, stratified treatment pathways and a better understanding of resistance mechanisms are urgently needed. This requires an in-depth understanding of the multiple sources of heterogeneity affecting tumour cells and the tumour microenvironment.

This review, which synthesises the key studies available in the literature, provides a detailed description of the current state of the art regarding heterogeneity in PM. After an overview of the general molecular landscape and a summary of heterogeneity between patients (intertumour heterogeneity), we review sources of variation within an individual patient's tumour (intratumour heterogeneity). This section covers both the local heterogeneity classically reported in other tumours and the anatomical heterogeneity, which is more profound in PM given the large pleural surface area over which the disease develops and progresses. We also synthesise the available data on changes that develop over time (temporal heterogeneity). The various cellular and molecular sources of heterogeneity are also highlighted throughout each section, including histological variations, genomic and non-genomic molecular changes and variations in tumour, stromal and immune compartments.

The solid understanding of intertumour heterogeneity recently achieved has highlighted diverse molecular and cellular landscapes. However, this knowledge has yet to be effectively translated into clinical practice (eg, diagnostic classification, treatment allocation, trial design). Further research is needed for a better comprehension of intratumour heterogeneity, including characterisation of local tumour-immune-stromal interactions, including those based on anatomical position on the pleural surface. Efforts should also include dissection of intratumour heterogeneity in patients treated by immunotherapy, development of preclinical models that adequately capture heterogeneity and the investigation of clonality and tumour evolution over time.