Background/Objectives: Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer linked to asbestos exposure and with poor overall survival. In recent years, CT volumetric analysis has gained increasing interest as a more accurate method for assessing tumor burden. This study aims to evaluate the prognostic value of chest CT volumetric analysis in MPM, comparing tumor volume with tumor thickness measurements and survival outcomes. Methods: This is a retrospective, observational analysis of all patients undergoing diagnostic thoracoscopy between 2014 and 2021 at the University Hospital of Cattinara (Trieste, Italy). Inclusion criteria were as follows: age ≥ 18 years, histological diagnosis of MPM, and the availability of at least one contrast-enhanced chest CT scan at the time of diagnosis. For each patient, the tumor thickness was measured on the axial plane at three levels (upper, middle, and lower hemithorax). Tumor and effusion volumes were calculated with the RayStation® software version 11.7.174 (HealthMyne®, Madison, WI, USA). Results: A total of 81 patients were eligible for analysis. Maximum and mean tumor thickness were strongly associated with survival, with higher thicknesses correlating with an increased risk of death (adjusted hazard ratio per doubling (aHR) of 1.97 (95%CI: 1.40–2.77) and of 2.23 (95%CI: 1.56–3.20), p < 0.001)), respectively, while the effect of the tumor volume on survival was nevertheless significant but less impactful (aHR = 1.26 (1.10–1.45, p < 0.001)). The presence and volume of effusion did not correlate with survival (p = 0.48 and p = 0.64, respectively). Conclusions: This study supports the role of quantitative parameters for staging MPM, particularly given the frequent discrepancies between clinical and pathological staging when relying solely on qualitative measures.
