Navigating the Foggy Landscape of Epithelioid Peritoneal Mesothelioma: A Proposed Standardized Institutional Algorithm for Multimodal Management

Purpose: Diffuse malignant peritoneal mesothelioma is a rare disease requiring management in specialized referral centers. We report our institutional experience with epithelioid diffuse malignant peritoneal mesothelioma, focusing on a standardized treatment algorithm and on pre-operative cisplatin–pemetrexed as a bridge to cytoreductive surgery and HIPEC. Methods: Consecutive patients treated between 2016 and 2024 were retrospectively reviewed. Treatment allocation was based on diagnostic laparoscopy, PCI assessment, and multidisciplinary evaluation. Patients with technically resectable disease underwent upfront CRS–HIPEC, whereas borderline or unresectable patients received cisplatin–pemetrexed followed by systematic reassessment. Results: Forty-three patients were included; 19 underwent CRS–HIPEC, including 8 after pre-operative chemotherapy, and 24 received medical management alone. Curative-intent cytoreduction (CC-0/1) was achieved in all operated patients, with no 30-day mortality. No statistically significant difference in overall survival was detected between upfront and conversion surgery patients in this small cohort. Higher PCI and Ki-67 were independently associated with worse overall survival. Conclusions: A structured multidisciplinary pathway may support tailored treatment selection in epithelioid diffuse malignant peritoneal mesothelioma. In selected responders, cisplatin–pemetrexed may act as a bridge to surgery, although larger studies are required to validate this strategy.