Factors distinguishing thymomas from thymic squamous cell carcinoma: a proposal for diagnosis emphasizing the immunophenotype.

Thymic epithelial tumors (TETs) are rare but represent the most common neoplasms in the adult mediastinum. They are primarily classified into thymomas and thymic carcinomas, with thymic squamous cell carcinoma (SCC) being the most prevalent subtype of thymic carcinoma. Distinguishing thymomas from thymic carcinoma is critical, as it directly influences treatment strategies. However, considerable interobserver variability remains, and differentiating type A and type B3 thymomas-characterized by scattered or absent immature T cells-from thymic SCC continues to pose a diagnostic challenge. Notably, thymomas and thymic carcinomas are biologically distinct entities. Typical thymic SCC more prominently exhibits phenotypes of medullary thymic epithelial cells (mTECs) than thymomas. For example, we have demonstrated that thymic SCC frequently shows characteristics resembling tuft cells, a subset of mTECs. Moreover, these tuft cell-like phenotypes are strongly associated with KIT expression, a well-established marker of thymic SCC, which likely activates signaling pathways characteristic of this carcinoma subtype. The mTEC-like properties of thymic SCC may support the notion that it can partially mimic the cytoarchitecture of the thymus, a feature generally associated with thymoma. Therefore, immunophenotypic profiling may enhance diagnostic accuracy in distinguishing thymomas from thymic SCC. This review presents this perspective through discussion of various TET cases, focusing on type A thymoma, type B3 thymoma, and thymic SCC. Rather than asserting a definitive viewpoint, we aim to encourage constructive discussion toward a diagnostic consensus for TETs.