Pleural Mesothelioma Diagnosis for the Pulmonologist: Steps Along the Way

Background/Objectives: Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor with a poor prognosis and complex diagnostic pathways. Pulmonologists often play a central role in its initial recognition and investigation. This narrative review synthesizes the current evidence on the diagnostic approach to MPM, with emphasis on imaging, tissue sampling, histopathology, and emerging diagnostic innovations relevant to clinical pulmonology. Methods: English-language studies published between January 2005 and June 2025 were identified from PubMed and Scopus. International guidelines and consensus documents were also reviewed to provide an updated overview of diagnostic strategies. Results: Diagnosis of MPM relies on a stepwise integration of clinical, radiological, and pathological information. Thoracic ultrasound, computed tomography, positron emission computed tomography and magnetic resonance imaging complement each other across different stages of the diagnostic pathway. Image-guided pleural biopsy and medical thoracoscopy remain the gold standard for tissue confirmation, supported by immunohistochemistry and molecular testing. The 2021 World Health Organization classification of pleural tumors and the International Association Study of Lung Cancer 9th Edition Tumour-Node-Mestastatis system have refined histologic and staging criteria, thereby improving reproducibility and prognostic accuracy. Emerging tools, including liquid biopsy, novel serum and molecular biomarkers, artificial-intelligence-based radiomics, and breathomics, offer promise for earlier and less invasive diagnosis but require prospective validation. Conclusions: Current advances are redefining MPM diagnosis toward integrated, multidisciplinary, and precision-based models. Future priorities include standardizing diagnostic algorithms, validating minimally invasive biomarkers, and integrating AI and molecular profiling into clinical workflows to enhance patient stratification.