Micronodular thymoma with lymphoid stroma is a rare thymic neoplasm characterized by discrete nodules of epithelial tumor cells separated by abundant lymphoid stroma. The genetic features of micronodular thymoma with lymphoid stroma remain largely unexplored. Owing to the interference of abundant intra-tumoral non-neoplastic lymphoid cells, a highly sensitive approach is necessary to study the genetic changes in these tumors. In this study, we applied a highly sensitive next-generation sequencing assay using molecular barcoding Ion AmpliSeq HD technology to study the most commonly mutated genes in thymomas, including GTF2I, HRAS, NRAS, KRAS, and TP53. A total of 12 cases of micronodular thymomas with lymphoid stroma were tested, and 2 cases also had areas of type A thymoma in their tumor bed. Two micronodular thymic carcinomas with lymphoid stroma, a histological mimic of micronodular thymoma, were also included for comparison. Recurrent GTF2I p.L424H mutations were found in all cases of micronodular thymoma with lymphoid stroma but not in micronodular thymic carcinomas. In addition, 3 cases of micronodular thymoma with lymphoid stroma also had concomitant HRAS and/or KRAS mutations. Our study shows that GTF2I p.L424H mutation is a constant genetic feature in micronodular thymoma with lymphoid stroma. This finding strongly suggests micronodular thymoma with lymphoid stroma is closely related to type A and type AB thymomas as they all share GTF2I p.L424H mutations.

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