A New WHO Entity of SMARCB1/INI1-Deficient Undifferentiated Thoracic Tumors: Rare, Aggressive, and Overlooked

SMARCB1/INI1-deficient undifferentiated tumors of the thorax represent a very rare and highly aggressive group of malignancies characterized by rapid progression and considerable diagnostic challenges. Their clinical and radiological features are often nonspecific, while their histological appearance - frequently rhabdoid or undifferentiated - overlaps with several other high-grade thoracic neoplasms. Because these tumors generally lack lineage-defining immunohistochemical markers, diagnosis requires an integrated approach combining morphological assessment, broad immunohistochemical profiling, and confirmation of complete SMARCB1/INI1 loss. In this report, we describe a rare mediastinal case that illustrates the stepwise diagnostic process required to identify this entity. Key aspects of the differential diagnosis are discussed, along with relevant therapeutic implications. Early recognition of such tumors is crucial, as accurate diagnosis can significantly influence treatment strategies and facilitate enrollment in emerging clinical trials targeting SWI/SNF-deficient cancers. Recognition of this recently highlighted yet still unclassified entity within the 2021 WHO classification of thoracic tumors is essential, since timely and precise diagnosis - as demonstrated in our case - directly impacts therapeutic decision-making and enables access to novel targeted therapeutic options.