Abstract
Mediastinum is a Pandora's Box containing many different structures that can give origin to several cancer types. Our aims are to provide a general framework to make a diagnosis of an undifferentiated pleomorphic sarcoma and to highlight relevant immunohistochemical and molecular techniques that can help in the differential diagnosis. We, therefore, provide a simple three-step algorithmic approach to diagnose pleomorphic sarcoma, emphasizing the role of clinicopathological correlations and advocating for a "relative frequency" method, especially when the material for the diagnosis is scarce, as in small biopsies. In the first place, if clinical and/or radiological features make a non-sarcoma diagnosis more likely, it should be ruled in. Next, even if no specific non-sarcomatous diagnoses are suspected, they should always be ruled out. Lastly, since many sarcomas can have a pleomorphic appearance, specific entities should also be ruled out because their identification might affect prognosis and treatment. We then cover selected immunohistochemical and molecular ancillary tests that can come at hand in the diagnosis, highlighting the pros and cons; in particular the use and the limitations of H3K27me3 immunohistochemistry, the meaning of MDM2 amplification in the mediastinum and the implication of muscle differentiation-either smooth or skeletal-in sarcomas. The main take home messages are to always rule-out more frequent lesion first and always include clinical and radiological information in the diagnostic process.