High incidence of low O6-methylguanine DNA methyltransferase expression in invasive macroadenomas of Cushing's disease

Abstract

Crooke's cell adenoma (CCA), characterized by massive Crooke's hyaline change in corticotroph adenoma, causes a rare subtype of Cushing's disease. In contrast to ordinary corticotroph adenomas, CCAs are generally aggressive and present as invasive macroadenomas, which are refractory to both surgery and radiotherapy and have a high-recurrence rate. Moreover, some patients with CCA present with distant or craniospinal metastases. Currently, there are no effective standard therapies for CCA. We report a patient with Crooke's cell carcinoma who presented with local invasion and liver metastases, which was refractory to conventional therapeutic modalities including transsphenoidal surgery, radiosurgery, medications, and hepatic transcatheter arterial embolization. After all these treatments failed, the patient had monthly temozolomide administrations, resulting in gradual clinical improvement and biochemical data that were consistent with tumor shrinkage. In glioblastoma, low O(6)-methylguanine DNA methyltransferase (MGMT) expression is associated with epigenetic gene silencing and predicts a better response to temozolomide. We thus investigated MGMT expression, immunohistochemically, in seven CCAs (five invasive macroadenomas and two invasive microadenomas) and 17 ordinary-type adenomas (OTAs; three noninvasive macroadenomas, 12 noninvasive microadenomas, and two invasive microadenomas) from patients with Cushing's disease. In seven CCAs, all five invasive macroadenomas exhibited low MGMT expression, defined as <5% nuclear MGMT staining. In 17 OTAs, only one adenoma showed low MGMT expression. In Cushing's disease, invasive macroadenomas including CCA usually have low-MGMT expression. Temozolomide thus may be a new therapeutic option for invasive macroadenomas such as CCA particularly when conventional treatments are ineffective.