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Object: Intraoperative MRI (iMRI) provides updated information for neuronavigational purposes and assessments on the status of resection during transsphenoidal surgery (TSS). The high-field technique additionally provides information about vascular structures at risk and precise information about extrasellar residual tumor, making it readily available during the procedure. The imaging, however, extends the duration of surgery. To evaluate the benefit of this technique, the authors conducted a retrospective study to compare postoperative outcome and residual tumor in patients who underwent conventional microsurgical TSS with and without iMRI., Methods: A total of 143 patients were assessed. A cohort of 67 patients who had undergone surgery before introduction of iMRI was compared with 76 patients who had undergone surgery since iMRI became routine in TSS at the authors' institution. Residual tumor, complications, hormone dependency, biochemical remission rates, and improvement of vision were assessed at 6-month follow-up. A volumetric evaluation of residual tumor was performed in cases of parasellar tumor extension., Results: The majority of patients in both groups suffered from nonfunctioning pituitary adenomas. At the 6-month follow-up assessment, vision improved in 31% of patients who underwent iMRI-assisted surgery versus 23% in the conventional group. One instance of postoperative intrasellar bleeding was found in the conventional group. No major complications were found in the iMRI group. Minor complications were seen in 9% of patients in the iMRI group and in 5% of those in the conventional group. No differences between groups were found for hormone dependency and biochemical remission rates. Time of surgery was significantly lower in the conventional treatment group. Overall a residual tumor was found after surgery in 35% of the iMRI group, and 41% of the conventional surgery group harbored a residual tumor. Total resection was achieved as intended significantly more often in the iMRI group (91%) than in the conventional group (73%) (p < 0.034). Patients with a planned subtotal resection showed higher mean volumes of residual tumor in the conventional group. There was a significantly lower incidence of intrasellar tumor remnants in the iMRI group than in the conventional group. Progression-free survival after 30 months was higher according to Kaplan-Meier analysis with the use of iMRI, but a statistically significant difference could not be shown., Conclusions: The use of high-field iMRI leads to a significantly higher rate of complete resection. In parasellar tumors a lower residual volume and a significantly lower rate of intrasellar tumor remnants were shown with the technique. So far, long-term follow-up is limited for iMRI. However, after 2 years Kaplan-Meier analyses show a distinctly higher progression-free survival in the iMRI group. No significant benefit of iMRI was found for biochemical remission rates and improvement of vision. Even though the surgical time was longer with the adjunct use of iMRI, it did not increase the complication rate significantly. The authors therefore recommend routine use of high-field iMRI for pituitary surgery, if this technique is available at the particular center.

The authors' object in this paper was to review the definition, epidemiology, biology, resistance mechanisms, and treatment options for dopamine agonist-resistant prolactinomas (DARPs). Prolactinomas are relatively unique among primary brain tumors in that medical treatment alone using dopamine agonists carries a high probability of disease control or even radiographic and endocrine remission, and thus has replaced surgery as the first line of therapy. Unfortunately, slightly less than 10% of patients with prolactinomas do not experience normalization of their prolactin levels in response to dopamine agonists, and harbor tumors that are resistant to dopamine agonist therapy. A literature review underscores that in male patients these DARPs are more likely to be invasive macroadenomas than dopamine agonist-responsive prolactinomas and that they are also more angiogenic, more proliferative, and more likely to exhibit cellular atypia. Estrogen receptor antagonists and temozolomide are the most commonly applied medical therapies in cases in which resection and radiosurgery have not induced remission of the hyperprolactinemia. Dopamine agonist-resistant prolactinomas exhibit aggressive behavior and tend to be large, invasive, hyperangiogenic tumors with high mitotic indices, which makes their management via surgery, radiosurgery, or alternative medical therapies challenging, thus underscoring the need for novel medical therapies or treatment regimens that target these lesions.

Object: The aim of this study was to correlate proton MR (1H-MR) spectroscopy data with histopathological and surgical findings of proliferation and hemorrhage in pituitary macroadenomas., Methods: Quantitative 1H-MR spectroscopy was performed on a 1.5-T unit in 37 patients with pituitary macroadenomas. A point-resolved spectroscopy sequence (TR 2000 msec, TE 135 msec) with 128 averages and chemical shift selective pulses for water suppression was used. Voxel dimensions were adapted to ensure that the volume of interest was fully located within the lesion and to obtain optimal homogeneity of the magnetic field. In addition, water-unsuppressed spectra (16 averages) were acquired from the same volume of interest for eddy current correction, absolute quantification of metabolite signals, and determination of full width at half maximum of the unsuppressed water peak (FWHM water). Metabolite concentrations of choline-containing compounds (Cho) were computed using the LCModel program and correlated with MIB-1 as a proliferative cell index from a tissue specimen., Results: In 16 patients harboring macroadenomas without hemorrhage, there was a strong positive linear correlation between metabolite concentrations of Cho and the MIB-1 proliferative cell index (R = 0.819, p < 0.001). The metabolite concentrations of Cho ranged from 1.8 to 5.2 mM, and the FWHM water was 4.4-11.7 Hz. Eleven patients had a hemorrhagic adenoma and showed no assignable metabolite concentration of Cho, and the FWHM water was 13.4-24.4 Hz. In 10 patients the size of the lesion was too small (< 20 mm in 2 directions) for the acquisition of MR spectroscopy data., Conclusions: Quantitative 1H-MR spectroscopy provided important information on the proliferative potential and hemorrhaging of pituitary macroadenomas. These data may be useful for noninvasive structural monitoring of pituitary macroadenomas. Differences in the FWHM water could be explained by iron ions of hemosiderin, which lead to worsened homogeneity of the magnetic field.

Object: The authors conducted a study to determine the long-term results of gamma knife surgery for residual or recurrent growth hormine (GH)-producing pituitary adenomas and to compare the results with those after treatment of other pituitary adenomas., Methods: The series consisted of 67 patients. The mean tumor diameter was 19.2 mm and volume was 5.4 cm3. The mean maximum dose was 35.3 Gy and the mean margin dose was 18.9 Gy. The mean follow-up duration was 63.3 months (range 13-142 months). The tumor resolution rate was 2%, the response rate 68.3%, and the control rate 100%. Growth hormone normalization (GH < 1.0 ng/ml) was found in 4.8%, nearly normal (< 2.0 ng/ml) in 11.9%, significantly decreased (< 5.0 ng/ml) in 23.8%, decreased in 21.4%, unchanged in 21.4%, and increased in 16.7%. Serum insulin-like growth factor (IGF)-1 was significantly decreased (IGF-1 < 400 ng/ml) in 40.7%, decreased in 29.6%, unchanged in 18.5%, and increased in 11.1%, which was almost parallel to the GH changes., Conclusions: Gamma knife surgery was effective and safe for the control of tumors; however, normalization of GH and IGF-1 secretion was difficult to achieve in cases with large tumors and low-dose radiation. Gamma knife radiosurgery is thus indicated for small tumors after surgery or medication therapy when a relatively high-dose radiation is required.

Object: The cell cycle-dependent nuclear antigen Ki-67 is related to growth potential in a variety of tumors. Elevated expression of Ki-67 was previously shown in recurrent pituitary adenomas; however, it has remained unclear whether this expression is related to the growth velocity or invasive behavior of these tumors. The aim of this study was to determine the correlation of Ki-67 antigen expression, growth velocity, and invasiveness in nonfunctioning pituitary adenomas., Methods: Between April 1998 and April 2002, 23 patients with nonfunctioning pituitary adenomas who had participated in an observation period in which multiple computerized tomography and magnetic resonance imaging studies had been performed were surgically treated in our department. Tumor volumes were assessed using a stereological method based on the Cavalieri principle. The growth rate was calculated for each patient. Expression of Ki-67 antigen was examined using the monoclonal antibody MIB-1. The assessed growth velocity of the adenomas was best described by a linear growth model. The correlation between Ki-67 expression and growth rate was highly significant. Rapidly growing adenomas (> 0.07% daily increase in size) were found to have a Ki-67 labeling index (LI) exceeding 1.5%, whereas all five adenomas with a very slow growth rate (< 0.02% daily increase in size) had a Ki-67 LI lower than 1.5%. No correlation was found between the growth rate and the invasive character of the adenomas., Conclusions: Expression of Ki-67 antigen is significantly correlated to the growth velocity of pituitary adenomas. Invasive behavior is a feature independent of proliferative activity. The extent of Ki-67 expression is helpful for clinical decision making and routine assessment of Ki-67 is recommended during the histopathological workup of pituitary adenomas.

Object: Prolactin-secreting pituitary adenomas may be managed by surgery, medication, radiotherapy, or observation. The authors reviewed a consecutive series of patients who were followed for at least 5 years after surgery to assess the prognostic significance of preoperative factors (tumor size and prolactin level) and an immediate postoperative factor (prolactin level obtained the morning after surgery) on long-term hormonal outcome, thereby clarifying the indications for surgical removal of tumor, the definition of successful treatment outcomes, and the nature of "recurrent" tumors., Methods: Between 1979 and 1991, 241 patients with prolactinomas underwent transsphenoidal resection. Nineteen patients were lost to follow-up review, whereas the remaining 222 patients underwent measurement of their prolactin levels on postoperative Day 1 (POD 1), at 6 and 12 weeks, and every 6 months thereafter for a minimum of 5 years. On POD 1, prolactin levels in 133 patients (Group 1) were lower than 10 ng/ml, in 43 patients (Group 2) between 10 and 20 ng/ml, and in 46 patients (Group 3) higher than 20 ng/ml. At 6 and 12 weeks, normal prolactin levels (< or = 20 ng/ml) were measured in 132 (99%) of the 133 patients in Group 1 but only in 32 (74%) of the 43 patients in Group 2. By 5 years postoperatively, normal levels of prolactin were still measured in 130 patients (98%) in Group 1 compared with only five patients (12%) in Group 2. No patient with a prolactin level lower than 3 ng/ml on POD 1 was found to have an elevated hormone level at 5 years. The likelihood of a long-term chemical cure was greater for patients with microadenomas (91% cure rate) than for those with macroadenomas (33%). Preoperative prolactin levels also correlated with hormonal outcome., Conclusions: Prolactin levels lower than 10 ng/ml on POD 1 predict a long-term chemical cure in patients with microadenomas (100% cure rate) and those with macroadenomas (93% cure rate). In contrast, a cure is not likely to be obtained in patients with normal levels ranging between 10 and 20 ng/ml on POD 1 if they harbor macroadenomas (0% cure rate). A recurrence reported several years after surgery probably represents the presence of persistent tumor that was not originally removed. If the initial operation was performed by an experienced surgeon, however, reoperation is not likely to yield a chemical cure.

Object: Giant prolactinomas are rare tumors whose treatment and outcome has only been addressed in isolated case reports. The authors document the long-term follow-up findings and clinical outcome in a group of patients with giant prolactinomas., Methods: This study is a retrospective chart and clinical review of more than 2000 cases of pituitary tumors treated at the authors' institution, of which 10 met the criteria for inclusion (prolactin level > 1000 ng/ml, diameter > 4 cm on neuroimaging studies, and clinical signs of hyperprolactinemia/mass effect). The average follow-up duration was 6.7 years after initial treatment with either bromocriptine or transsphenoidal resection. In more than 90% of the patients in this series the disease was controlled by medical treatment with bromocriptine alone; the other 10% required early surgery via transsphenoidal resection. All patients had improvement in visual symptoms. All tumors had extrasellar components, five of which exhibited frank invasion of the cavernous sinus. Tumor volume on magnetic resonance imaging was decreased on average by 69%; this occurred at a faster rate and in larger amounts when treated with bromocriptine than has been reported in the literature for macroprolactinomas., Conclusions: According to long-term follow-up findings, giant prolactinomas are exquisitely responsive to dopamine agonist therapy. In giant prolactinomas the prolactin level does not correlate with size. The main indication for early surgery is intratumoral hematoma, whereas our main indications for late surgery are cerebrospinal fluid leakage caused by medical treatment, or an increasing prolactin level despite medical therapy. Checking prolactin levels in suspicious sellar and/or suprasellar lesions may be diagnostic and prevent unnecessary surgery.

The authors report the case of a 37-year-old woman who presented with amenorrhea and an increased level of serum prolactin. Magnetic resonance images of the pituitary revealed a lesion with characteristics consistent with those of a microadenoma. Transsphenoidal exploration was performed, but a prolactinoma was not found. After endocrinological review, the patient's hyperprolactinemia was found to be caused by the presence of macroprolactin and her amenorrhea was due to intense exercise and low body weight. Macroprolactin is an isoform of prolactin that is variably reactive in assays for prolactin, but displays minimum bioactivity in vivo. Patients with macroprolactin are mostly asymptomatic. This phenomenon may cause elevated prolactin values, which the authors view as apparent hyperprolactinemia. The presence of macroprolactin is an underrecognized problem, occurring in as many as 15 to 20% of patients with elevated prolactin values and often leading to unnecessary, expensive diagnostic procedures and inappropriate treatment. The presence of macroprolactin should always be suspected when the patient's clinical history or clinical or radiological data are incompatible with the prolactin value. Physicians dealing with diagnosis and treatment of hyperprolactinemia (general practitioners, gynecologists, neurosurgeons, endocrinologists, and biochemists) should be aware of the potentially misleading nature of macroprolactin.

Object: Clinically evident multiple pituitary adenomas rarely occur. The authors assess the incidence and clinical relevance of multiple adenomas in Cushing's disease., Methods: A prospective clinical database of 660 pituitary surgeries was analyzed to assess the incidence of multiple pituitary adenomas in Cushing's disease. Relevant radiographic scans, medical records, and histopathological reports were reviewed. Thirteen patients with at least two separate histopathologically confirmed pituitary adenomas were identified. Prolactinomas (nine patients) were the most common incidental tumors. Other incidental tumors included secretors of growth hormone ([GH], one patient) and GH and prolactin (two patients), and a null-cell tumor (one patient). In two patients, early repeated surgery was performed because the initial operation failed to correct hypercortisolism, in one instance because the tumor excised at the initial surgery was a prolactinoma, not an adrenocorticotropic hormone-secreting tumor. One patient had three distinct tumors., Conclusions: Multiple pituitary adenomas are rare, but may complicate management of patients with pituitary disease.

A transmaxillosphenoidal approach was used to remove sellar tumors invading the cavernous sinus. This procedure, a widening of the standard transsphenoidal approach to the sella turcica, uses the sublabial or transnasal route in which the medial wall of the maxillary sinus is laterally dislocated. This method provides good exposure of the prominences of bone above the carotid artery which lies on the posterolateral wall of the sphenoid sinus. This bone area is the key to opening the cavernous sinus inferomedially and removing lesions within its medial compartment. The inferomedial approach takes an entirely extracerebral route so that tumors invading the cavernous sinus through its medial wall are approached inferomedially following the direction of tumor growth. It also allows direct visualization of the intracavernous carotid artery during tumor removal, thus sparing the cranial nerves, which run on the opposite side. Adequate surgical exposure of a pituitary adenoma is achieved with a custom-made sphenoidal retractor with asymmetric blades, the shorter blade holding aside the thin medial wall of the maxillary sinus. Between October, 1989, and July, 1993, 11 patients with tumors invading the cavernous sinus underwent surgery via this approach; 10 had pituitary adenomas and one had a craniopharyngioma. Eight tumors were treated by primary operation: four tumors were totally and four subtotally (> 80%) removed; one tumor already operated on elsewhere was totally removed; and of two tumors already operated on and irradiated, one was subtotally removed and the other only partially (approximately 40%) removed owing to marked postirradiation scarring. None of the patients suffered permanent cranial nerve deficit and all but one showed marked clinical improvement.

The factors responsible for the production of prolactin-secreting tumors are obscure. One hypothesis, that chronic loss of dopamine control from the hypothalamus may be associated with prolactinoma formation, was tested. Female adult Fischer 344 rats were subjected to ovariectomy and were then given subcutaneous implants of diethylstilbestrol (DES) Silastic capsules to produce lactotrophic hyperplasia. Sequential studies assessed the neuronal activity of the tuberoinfundibular dopaminergic neurons of the arcuate nucleus of the hypothalamus (A12) during and after this estrogen-induced pituitary growth. Immunocytochemical staining for tyrosine hydroxylase was used as a marker for dopamine synthesis, plasma radioimmunoassay provided plasma prolactin levels, and magnetic resonance imaging and histological studies were performed to examine the structural changes occurring in the pituitary gland. Animals were sacrificed from 3 to 67 days after DES implantation. To determine the reversibility of the estrogen-induced changes, rats were also sacrificed at different time intervals after the removal of 30-, 40-, or 60-day DES implants. After 30 days of DES treatment, plasma prolactin levels increased 40-fold and pituitary weight increased more than threefold. Tyrosine hydroxylase immunoreactivity diminished gradually and was almost completely depleted at 30 days. Pituitary histology revealed marked prolactin cell hyperplasia. These changes were completely reversible; removal of the capsule after 30 days resulted in eventual normalization of plasma prolactin levels and pituitary size and in restoration of tyrosine hydroxylase immunoreactivity in the A12 region. Sixty days of DES treatment produced large hemorrhagic tumors with sustained high plasma prolactin levels and an irreversibly distorted A12 area. These observations suggest that in these animals loss of dopamine regulation secondary to estrogen stimulation initially produces prolactin hyperplasia but that prolonged loss leads to adenoma formation.