Moving Beyond Morphology: Toward a Morpho-Molecular Classification of Pleural Mesothelioma

Despite recent advances in the treatment of pleural mesothelioma, it remains a challenging and heterogeneous disease, with limited options for patients. Survival rates have only marginally improved in the past years, highlighting the need for a better biological understanding of the disease for the translation into clinical practice. Although recent years have seen substantial progress in genomics and molecular pathology, much of the existing literature has focused on morphology-correlated changes, with molecular, immunohistochemical, clinical, and blood biomarkers largely studied in a correlative framework. Despite these efforts, TNM classification remains the most powerful predictor of survival and one of the most important parameters to guide therapy in clinical practice. However, emerging evidence reveals that histology alone fails to capture the full heterogeneity of the disease, leading to suboptimal diagnostic, prognostic, and therapeutic approaches. This review summarizes recent major molecular findings relating not only to histology but also ploidy, tumor microenvironment, and methylation-which together offer a more comprehensive understanding of interpatient heterogeneity. In light of these results, we discuss the potential for a new morpho-molecular classification based on these molecular findings to overcome the current clinical challenges. Future directions for the field are also proposed, including the potential for emerging technologies such as single-cell, spatial omics, and artificial intelligence to fill in the gaps of bulk studies and unveil clinically relevant information about pleural mesothelioma tumor heterogeneity.