title: High incidence of low O(6)-methylguanine DNA methyltransferase expression in invasive macroadenomas of Cushing's disease.
abstract: BACKGROUND
  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 O(6)-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.
  
  
  CONCLUSIONS
  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.
authors: Department of Endocrinology and Metabolism, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan. coactivator@mac.com
authors: Akira
authors: A
authors: Takeshita
authors: Naoko
authors: N
authors: Inoshita
authors: Manabu
authors: M
authors: Taguchi
authors: Chikao
authors: C
authors: Okuda
authors: Noriaki
authors: N
authors: Fukuhara
authors: Kenichi
authors: K
authors: Oyama
authors: Kenichi
authors: K
authors: Ohashi
authors: Toshiaki
authors: T
authors: Sano
authors: Yasuhiro
authors: Y
authors: Takeuchi
authors: Shozo
authors: S
authors: Yamada
mesh_terms: D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D047748:Pituitary ACTH Hypersecretion / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D010911:Pituitary Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D000077204:Temozolomide; D014057:Tomography, X-Ray Computed; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000324:Adrenocorticotropic Hormone; D019853:O(6)-Methylguanine-DNA Methyltransferase; D006854:Hydrocortisone; D000077204:Temozolomide