High incidence of low O(6)-methylguanine DNA methyltransferase expression in invasive macroadenomas of Cushing's disease.
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.
Takeshita
Akira
A
Department of Endocrinology and Metabolism, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan. coactivator@mac.com
Inoshita
Naoko
N
Taguchi
Manabu
M
Okuda
Chikao
C
Fukuhara
Noriaki
N
Oyama
Kenichi
K
Ohashi
Kenichi
K
Sano
Toshiaki
T
Takeuchi
Yasuhiro
Y
Yamada
Shozo
S
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
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000324:Adrenocorticotropic Hormone; D019853:O(6)-Methylguanine-DNA Methyltransferase; D006854:Hydrocortisone; D000077204:Temozolomide