Deciphering the biology of thymic epithelial tumors

Thymic cancers arise from epithelial cells of the thymus and have a predilection for intrathoracic spread. Clinical behavior varies from relatively indolent to highly aggressive with a capacity to metastasize widely and adversely affect survival. Paraneoplastic autoimmune disorders are frequently observed in association with thymoma and have a significant impact on quality of life. Underlying immune deficits associated with thymic epithelial tumors (TETs) increase the risk for development of opportunistic infections and emergence of extrathymic malignancies. Advances in the molecular characterization of thymic tumors have revealed the lowest tumor mutation burden among all adult cancers and the occurrence of distinct molecular subtypes of these diseases. Mutations in general transcription factor IIi (GTF2I) are unique to TETs and are rarely observed in other malignancies. The infrequency of actionable mutations has created obstacles for the development of biologic therapies and has spurred research to uncover druggable genomic targets. Persistence of autoreactive T cells due to altered thymic function increases the risk for development of severe immune-related toxicity and limits opportunities for use of immune-based therapies, especially in patients with thymoma. In this paper we review emerging data on the molecular characterization and immunobiology of thymic tumors and highlight clinical implications of these discoveries.