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This Article Full Text Full Text (PDF) All Versions of this Article: EJE-09-0414v1 161/4/553    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Takeshita, A. Articles by Yamada, S. PubMed PubMed Citation Articles by Takeshita, A. Articles by Yamada, S.

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

¹ Department of Endocrinology and Metabolism, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan, Departments of² Pathology, ³ Gastroenterology and ⁴ Hypothalamic and Pituitary Surgery, Toranomon Hospital, Tokyo 105-8470, Japan⁵ Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan⁶ Department of Pathology, The University of Tokushima Graduate School of Medicine, Tokushima 770-8503, Tokyo, Japan

(Correspondence should be addressed to A Takeshita at Department of Endocrinology and Metabolism, Toranomon Hospital and Okinaka Memorial Institute for Medical Research; Email: coactivator{at}mac.com)

Context: 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.

Objective: 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 O⁶-methylguanine DNA methyltransferase (MGMT) expression is associated with epigenetic gene silencing and predicts a better response to temozolomide.

Methods: 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.

Results: 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.

Conclusion: 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.