Monoamine Oxidase A Expression Marks Aged Progenitor Signatures in Thymic Epithelial Cells and Thymomas

The biological basis distinguishing thymomas from thymic carcinomas (TCs) remains incompletely defined, despite longstanding efforts to interpret thymic epithelial tumors (TETs) in relation to thymic epithelial cell (TEC) differentiation. We integrated single-cell transcriptomic, immunohistochemical, and bulk transcriptomic analyses to define TEC programs associated with TET subtypes.

We reanalyzed a publicly available human thymus single-cell RNA-seq dataset to define signature genes of TEC subclusters. Immunohistochemistry was performed on non-neoplastic thymus across developmental stages and on 83 TETs. Transcriptomic analyses were conducted using the TCGA-THYM cohort comprising 117 TETs.

We identified an adult-enriched TEC subset with an aged progenitor-like program, marked by monoamine oxidase A (MAOA). Strikingly, MAOA immunohistochemistry highlighted spindle-shaped epithelial cells in the involuted adult thymus and in type A/AB thymomas. Most type B3 thymomas also exhibited broad MAOA reactivity, whereas TCs were negative or showed only scattered tumor-cell staining. Furthermore, MAOA immunostaining complemented KIT in the distinction between thymomas and TCs. In the TCGA-THYM cohort, MAOA expression reproduced these subtype-associated patterns and correlated with aged progenitor signatures. TEC signature scoring further revealed enrichment of aged progenitor-like programs in type A/AB thymomas, while type B3 thymomas concomitantly exhibited aged progenitor-like and cortical TEC-like signatures. In marked contrast, TCs showed low levels of aged progenitor scores but prominent mature medullary TEC signatures.

Our findings refine the biological framework of TETs by linking thymomas to an aged progenitor-like TEC state. MAOA also offers practical diagnostic utility, particularly for distinguishing thymomas from TCs.