Corticotroph macroadenomas are rare but difficult to manage
intracranial neoplasms. Mutations in the two
Cushing's disease mutational hotspots USP8 and USP48 are less frequent in corticotroph macroadenomas and invasive
tumors. There is evidence that TP53 mutations are not as rare as previously thought in these
tumors. The aim of this study was to determine the prevalence of TP53 mutations in corticotroph
tumors, with emphasis on macroadenomas, and their possible association with clinical and
tumor characteristics. To this end, the entire TP53 coding region was sequenced in 86 functional corticotroph
tumors (61 USP8 wild type; 66 macroadenomas) and the clinical characteristics of patients with TP53 mutant
tumors were compared with TP53/USP8 wild type and USP8 mutant
tumors. We found pathogenic TP53 variants in 9 corticotroph
tumors (all macroadenomas and USP8 wild type). TP53 mutant
tumors represented 14% of all functional corticotroph macroadenomas and 24% of all invasive
tumors, were significantly larger and invasive, and had higher Ki67 indices and Knosp grades compared to wild type
tumors. Patients with TP53 mutant
tumors had undergone more therapeutic interventions, including radiation and bilateral
adrenalectomy. In conclusion, pathogenic TP53 variants are more frequent than expected, representing a relevant amount of functional corticotroph macroadenomas and invasive
tumors. TP53 mutations associated with more aggressive
tumor features and difficult to manage disease.