Mesothelioma in situ-spectrum pleural lesions: Diagnostic challenges and longitudinal follow-up in a case series.

Mesothelioma in situ (MIS) is a recognized preinvasive mesothelial lesion included in the 2021 World Health Organization classification as a potential precursor of diffuse pleural mesothelioma. It is defined by a single layer of atypical mesothelial cells lining the pleural surface, molecular alterations such as BRCA1-associated protein 1 (BAP1) or methylthioadenosine phosphorylase (MTAP) loss of expression, and absence of stromal invasion. All cases diagnosed as MIS were retrospectively retrieved from institutional archives. Cases were assessed through an integrated multidisciplinary review including clinical data, imaging findings, thoracoscopic multi-site pleural biopsies, histomorphology, and ancillary immunohistochemistry. All cases presented with unexplained, unilateral pleural effusion and lacked significant findings on ^18F-FDG PET/CT. Diagnosis was confirmed via thoracoscopic biopsy and immunohistochemistry, with BAP1 loss in all cases. Three patients fulfilled diagnostic criteria for confirmed MIS. In one patient, initial biopsy showed a superficial proliferation compatible with MIS, but subsequent surgical sampling demonstrated invasive pleural mesothelioma with an associated MIS-like surface component. Concurrent loss of BAP1 and MTAP expression was observed only in this latter case. MIS is a challenging diagnosis that requires close integration of clinical, radiological, and pathological data. Recognition of this entity may allow earlier identification of patients at risk of invasive mesothelioma. Our findings primarily illustrate the heterogeneity of MIS-spectrum lesions and the importance of adequate tissue sampling and longitudinal follow-up. Larger prospective studies are needed to clarify its natural history, validate prognostic molecular markers, and define optimal surveillance and treatment approaches.