Mediastinal epithelial neoplasms with recurrent molecular alterations

A wide variety of benign and malignant epithelial tumors arise in the mediastinum. This review sheds light on recurrent molecular genetic alterations of mediastinal epithelial tumors to help the surgical pathologist become aware of molecularly defined entities that one may encounter in practice and understand relevant genetic underpinnings, with an emphasis on diagnostically useful immunohistochemical targets. We discuss the molecular landscape of thymoma, including World Health Organization (WHO) types as well as micronodular and metaplastic thymoma, and introduce current concepts in the molecular subtyping of thymic carcinoma. We present an overview of proposed molecular classification schemes of thymic epithelial neoplasms that focuses on commonly occurring molecular alterations described in The Cancer Genome Atlas and original data sources, and relate them to longitudinal prognostic and therapeutic implications. Poorly differentiated epithelial neoplasms of the mediastinum defined by recurrent molecular alterations can display diagnostically challenging morphologic and immunohistochemical profiles and are critically important to recognize due to their aggressive behavior. We conclude with a discussion of NUT carcinoma and switch/sucrose non-fermentable (SWI/SNF) complex deficient tumors, including thoracic SMARCA4-deficient undifferentiated tumor, reviewing salient histopathologic and immunohistochemical features that allow their recognition from histologic mimics and tumors with overlapping immunoprofiles. We lastly outline the current understanding of genetic events that give rise to these destructive tumors.