Endocrine Abstracts

Background: O-6-Methylguanine-DNA-methyltransferase (MGMT) is a DNA repair enzyme. It has been demonstrated that its higher expression counteracts cytotoxicity of alkylating agents used in the treatment of glioblastoma or invasive pituitary tumors. Little is known on the relationships between MGMT expression and invasiveness of corticotroph adenomas in Cushing disease (CD).

The Aim: To evaluate MGMT expression and its associations with clinical, neuropathological and ultrastructural features of surgically treated corticotroph tumors.

Study population and methods: This cohort study included 72 consecutive patients (60 females) aged 44.15 ± 15.15 yr operated via transsphenoidal approach (TSS) according to the same surgical protocol. Clinical, pathological and ultrastructural parameters were evaluated in light of surgical outcomes. MGMT expression was graded in four categories (<25%, 25–50%, 50–75%, >75%), Ki-67 labeling index in 3 categories (<3%; 3–10%; and >10% positive nuclei), p53 expression in 3 categories (<5%; 5–50%and >50% possitive cells) and mitotic index (MI) in 2 categories (≤ 2 vs >2 mitoses per 10 high power fields). Early remission was recognised on the basis of hormonal assessement 6 months after TSS.

Results: The proportions of patients in each MGMT expression category (<25%, 25–50%, 50–75%, >75%) were as follows: 19.4, 15.3, 15.3, 50.0%, respectively.

Tumors with lower MGMT expression had significantly larger maximal diameter (medians: 15 mm for <25% vs 6 mm for >75%, P _trend = 0.001), higher plasma ACTH (medians: 119.45 pg/ml for <25% vs 59.45 pg/ml for >75% MGMT expression, P _trend = 0.002), higher mitotic index (21.4% patients with MI > 2 for <25% MGMT expression vs 2.8% patients with MI > 2 mitoses for >75% MGMT expression, P_trend = 0.026) and higher expression of P 53 protein (14.3% patients with P 53 > 50% for <25% MGMT expression vs 0.0% patients with P 53 >50% for >75% MGMT expression, P_trend = 0.007). There was a borderline relationship between higher Ki-67 and lower MGMT expression (P = 0.099). We confirmed an association between sparsely granulated ultrastructure of corticotroph adenomas (SGCA) and lower MGMT expression: 64.3% SGCA for <25% vs 22.2% SGCA for >75% MGMT expression category, P_trend = 0.005). Moreover, men presented with lower MGMT expression (35.7% men in <25% MGMT category vs 2.8% with MGMT expression >75%, P = 0.004). Six months after TSS lower MGMT expression predicted lower early remission rate in CD. Early biochemical remission rates in each MGMT categories (<25%, 25–50%, 50–75%, >75%) were: 35.7%, 54.5%, 72.7% and 77.8%, respectively (P = 0.036).

Conclusion: The lower MGMT expression is characteristic for more invasive corticotroph tumors that may be associated with a lower effectiveness of surgical treatment of CD.