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OBJECT The relationship between headaches, pituitary adenomas, and surgical treatment of pituitary adenomas remains unclear. The authors assessed the severity and predictors of self-reported headaches in patients referred for surgery of pituitary adenomas and evaluated the impact of endoscopic transsphenoidal surgery on headache severity and quality of life (QOL). METHODS In this prospective study, 79 patients with pituitary adenomas underwent endoscopic transsphenoidal resection and completed the Headache Impact Test (HIT-6) and the 36-Item Short Form Health Survey (SF-36) QOL questionnaire preoperatively and at 6 weeks and 6 months postoperatively. RESULTS Preoperatively, 49.4% of patients had mild headache severity, 13.9% had moderate severity, 13.9% had substantial severity, and 22.8% had intense severity. Younger age and hormone-producing tumors predisposed greater headache severity, while tumor volume, suprasellar extension, chiasmal compression, and cavernous sinus invasion of the pituitary tumors did not. Preoperative headache severity was found to be significantly associated with reduced scores across all SF-36 QOL dimensions and most significantly associated with mental health. By 6 months postoperatively, headache severity was reduced in a significant proportion of patients. Of the 40 patients with headaches causing an impact on daily living (moderate, substantial, or intense headache), 70% had improvement of at least 1 category on HIT-6 by 6 months postoperatively, while headache worsened in 7.6% of patients. The best predictors of headache response to surgery included younger age, poor preoperative SF-36 mental health score, and hormone-producing microadenoma. CONCLUSIONS The results of this study confirm that surgery can significantly improve headaches in patients with pituitary adenomas by 6 months postoperatively, particularly in younger patients whose preoperative QOL is impacted. A larger multicenter study is underway to evaluate the long-term effect of surgery on headaches in this patient group.

Background: O-6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that counteracts chemotherapeutic cytotoxicity of alkylating agents such as temozolomide. Low levels of MGMT expression have been shown to correlate with longer survival in glioma patients treated with temozolomide. The same is true in pituitary adenomas., Objective: We investigated the immunohistochemical expression of MGMT in a variety of corticotroph adenoma subtypes to determine the potential utility of temozolomide as a therapeutic agent., Methods: The tumors consisted of 40 cases of adrenocorticotropin-secreting pituitary tumors in Cushing disease, 12 Crooke cell adenomas, and 7 subtype I silent corticotroph adenomas. Staining for MGMT was assessed by light microscopy; nuclear reactivity was estimated semiquantitatively as present in < 10%, 10% to 25%, 25% to 50%, 50% to 75%, and > 75% of cells., Results: Immunoexpression showed no correlation with patient age, sex, tumor size, invasiveness, or recurrence in patients with Cushing disease. Among adrenocorticotropin-secreting adenomas associated with Cushing disease, most invasive (60%) and recurrent (86%) tumors showed low MGMT immunopositivity, defined as < 25%. Most (75%) Crooke cell adenomas exhibited an MGMT immunoreactivity of ≤ 50%. All subtype I silent corticotroph adenomas showed < 10% MGMT staining., Conclusion: Our descriptive findings of low MGMT expression in adrenocorticotropin-producing pituitary adenomas, particularly aggressive tumors, suggest that they may be suitable candidates for temozolomide therapy.

MGMT promoter hypermethylation of aggressive pituitary adenomas and pituitary carcinomas and low protein expression are implicated in improved response to treatment with temozolomide (TMZ). The aim of the present study was to investigate MGMT promoter methylation and immunoexpression in an aggressive subset of pituitary adenomas and carcinomas. Our material consisted of 12 silent subtype 3 (SS3) adenomas, 10 primary carcinomas, and 4 disseminated metastases. Two different tissue samples of 7 of the 12 SS3 adenomas and all carcinomas were analyzed for MGMT promoter methylation and immunohistochemical expression of MGMT. Immunoexpression was assessed semi-quantitatively as a percentage of immunoreactive nuclei. Overall 33% of carcinomas exhibited homogenous MGMT methylation in tumor and metastatic specimens. Low immunohistochemical MGMT expression was noted in 50% of carcinomas. Overall, 42% of the SS3 adenomas exhibited MGMT promoter methylation. MGMT immunostaining was predominantly negative (92%), with homogenous immunostaining results across different samples. Whereas all the methylated SS3 adenomas had low MGMT immunoreactivity, five unmethylated adenomas exhibited absent/low MGMT expression. There was no relationship between methylation status and MGMT immunoexpression was not apparent. MGMT methylation and low immunohistochemical expression seen in a subset of carcinomas and SS3 adenomas, suggesting that a subset of tumors may respond to treatment with TMZ. Heterogeneous MGMT methylation status in SS3 adenomas and the lack of concordance between methylation and immunohistochemical expression of MGMT suggest complex regulatory mechanisms, highlighting the need for improved methods in the research on a correlation between MGMT changes and response to TMZ.

MGMT expression in tumors has been correlated with response to treatment with temozolomide therapy. Few medical therapies are available for Nelson syndrome, and the efficacy of such therapeutics remains limited. The aim of the present study was to assess immunohistochemical expression of MGMT in ACTH-secreting pituitary adenomas of patients with Nelson syndrome. Our material consisted of eight specimens from ACTH-secreting pituitary adenomas of patients with Nelson syndrome. Immunohistochemical staining for MGMT was performed using the streptavidin-biotin-peroxidase complex method. MGMT immunoreactivity was assessed microscopically and recorded as an estimated percentage of nuclear MGMT immunostaining (0 = none, 1=<10%, 2=<25%, 3=<50%, 4=>50%). Five of the eight specimens (65%) exhibited no MGMT immunoreactivity, with two out of eight cases (25%) showing slight MGMT staining (<10%) and one out of eight cases (12%) demonstrating moderate MGMT positivity (<25%). Patient male/female ratio was 3:5, with average patient age being 62.4 (range 57–66). Our findings suggest that temozolomide therapy may be of potential use in patients with Nelson syndrome, as these tumors express absent/low levels of MGMT. Absent or low MGMT staining in brain and other neoplasms has been shown to correlate with successful treatment with temozolomide, and recent reports of aggressive pituitary adenomas suggest similar outcomes.

Objectives: The aim of this work was to investigate the immunohistochemical expression of nestin, a member of the intermediate filament family, in adenohypophysial vasculature during development and progression of pituitary infarction., Methods: Forty-five nontumorous adenohypophyses and 34 pituitary adenomas of various types, all exhibiting acute or healing infarcts, were examined immunohistochemically using the streptavidin-biotin-peroxidase complex method., Results: In both adenohypophyses and pituitary adenomas without infarction, nestin was expressed in only a few capillaries and endothelial cells. In acute infarcts without a vascular response, no nestin was demonstrable within necrotic capillaries (50 cases). In organizing infarcts, newly formed vessels spreading into necrotic zones showed nestin expression in all capillaries and practically every endothelial cell (25 cases). In the hypocellular, fibrotic scar phase, only a few vessels (4) were apparent, and immunoreactivity was focal and mild., Conclusions: Nestin is strongly expressed in newly formed capillaries and is downregulated when infarcts transform to fibrous tissue. Nestin expression may provide valuable insight into the process of pituitary angiogenesis.

Bihormonal or plurihormonal pituitary tumors produce two or more hormones different in chemical composition, immunoreactivity, and clinical significance. Immunohistochemical and electron microscopic investigations and more recently molecular-genetic studies have provided conclusive evidence of the production of multiple hormones by pituitary adenomas. Most frequently, they produce GH, PRL, TSH, and/or alpha-subunit of the glycoprotein hormones. Other uncommon combinations may also be apparent. We report the case of a 40-yr-old acromegalic man with a pituitary macroadenoma. The pituitary tumor was removed by transsphenoidal surgery. Histological, immunohistochemical, electron microscopic, and immunoelectron microscopic examinations revealed that the tumor contains multiple hormones (GH, LH, and alpha subunit) and transcription factors. The application of different reagents yielded different patterns of positivity indicating that the validity of some common immunohistochemical reagents must be re-evaluated.

Objective. We investigated the correlation between immunohistochemical expression of the pituitary tumor transforming gene (PTTG) and pituitary adenoma subtype. Methods. Pituitary adenomas (n = 89) were stained for PTTG using the streptavidin-biotin-peroxidase complex method and a monoclonal PTTG antibody. Results. PTTG staining was found to be cytoplasmic with a pronounced paranuclear expression pattern. Reactivity was highest in growth hormone (GH) adenomas as compared with other tumors, including prolactin (PRL), follicle-stimulating hormone/luteinizing hormone/a subunit, as well as adrenocorticotrophic hormone-secreting adenomas. PRL adenomas exhibited the lowest expression levels. Among GH adenomas, untreated tumors demonstrated significantly higher PTTG levels than octreotide-treated examples. Although dopamine agonist-treated PRL adenomas tended to show lower expression levels, statistical significance was not reached. Conclusions. Our finding that PTTG was differentially expressed in pituitary adenoma subtypes suggests a cellspecific function for PTTG. Moreover, treatment of GH adenomas with somatostatin analogues lowered PTTG expression. Further investigation into mechanisms mediating cell-specific expression of PTTG is warranted. [ABSTRACT FROM AUTHOR]