Update on Pleural Epithelioid Mesothelioma: New Insights for Diagnosis and Patient Management

Diffuse mesothelioma is typically diagnosed through histopathologic evaluation. Recent advances in therapeutic strategies have heightened the importance of accurate diagnosis and subtyping. In addition to the three well-established histologic subtypes of mesothelioma (epithelioid, biphasic, and sarcomatoid), the 2021 WHO classification of diffuse pleural mesothelioma emphasizes the importance of subtyping patterns and cytologic features to improve clinical diagnosis and patient management. Notably, the presence of a solid component or pleomorphic cytologic features observed within the epithelioid subtype is associated with a worse prognosis, approaching that of sarcomatoid mesothelioma. Conversely, cases with abundant myxoid stroma and a solid component comprising less than 50% are associated with improved survival. In addition, a two-tiered grading system (low versus high grade) is now recommended for epithelioid mesothelioma. On behalf of the International Association for the Study of Lung Cancer Mesothelioma Sub-Committee of the Rare Tumor Group, we here outline new, essential elements to assist clinicians in optimizing the management of patients with mesothelioma. This includes practical questions on immunohistochemical and molecular markers BAP1, methylthioadenosine phosphorylase, NF2, and fusion genes that are relevant to the diagnosis, prognosis, and application of emerging therapeutic strategies in diffuse pleural mesothelioma. This discussion also addresses frequently asked questions by clinicians regarding sampling modalities aimed at optimizing diagnostic accuracy. The impact of epigenetics, DNA methylation, and biomarker discovery is highlighted, with an emphasis on its limitations in distinguishing mesothelioma from reactive mesothelial proliferations and other neoplastic mimics. The emerging role of artificial intelligence in subtyping, grading, and prediction of biomarkers for genomic subtyping is also discussed.