Outcomes of therapy for Cushing's disease due to adrenocorticotropin-secreting pituitary macroadenomas.

We reviewed our experience with 21 patients who had Cushing's disease due to ACTH-secreting macroadenomas to clarify the natural history of this disease. All patients had typical clinical and biochemical features of ACTH-dependent hypercortisolism. Their mean maximal tumor diameter was 1.6 +/- 0.1 cm, and the range was 1.0-2.7 cm. Six patients had cavernous sinus invasion, three had invasion of the floor of their sella, and nine had suprasellar extension. The observed remission rate was significantly lower in macroadenoma patients than in microadenoma patients (67% vs. 91%; chi 2 = 5.7; P < 0.02). Cavernous sinus invasion (odds ratio, 35; 95% confidence interval, 2.6-475; P < 0.008) and presence of a maximum tumor diameter 2.0 cm or more (odds ratio, 12.9; 95% confidence interval, 1.4-124; P < 0.02) emerged as the only predictors of residual disease after surgery. The observed recurrence rate was significantly higher in macroadenoma patients than in microadenoma patients (36% vs. 12%; chi 2 = 4.2; P < 0.05). Macroadenoma patients tended to suffer from recurrences earlier than did microadenoma patients (16 vs. 49 months). Stepwise multiple logistic regression did not identify any predictors of disease recurrence in macroadenoma patients. Eight macroadenoma patients underwent a total of nine repeat surgical procedures, but none of these resulted in clinical remissions. Only four of seven (57%) patients followed for a sufficient period of time achieved normal urinary free cortisol levels after conventional radiotherapy. Three (75%) of these four patients had re-recurrent hypercortisolism after brief periods of eucortisolism. Pharmacological agents and adrenalectomy were effective in the management of hypercortisolism in patients with residual and recurrent disease. Our results indicate that ACTH-secreting macroadenomas are more refractory to conventional treatments than are ACTH-secreting microadenomas.

Pituitary adenomas: screening for G alpha q mutations.

Mutant, guanosine triphosphatase-deficient, alpha-subunits of the G protein, Gs, gsp ocogene have been discovered in 40% of GH-secreting pituitary adenomas. Therefore, we hypothesized that a novel G protein class, G alpha q, involved in pituitary signal transduction, might be involved in pituitary tumorigenesis. Recombinant mutations of G alpha q result in constitutive activation of phospholipase C and have transforming activity. Therefore, we screened tumor samples from 37 pituitary adenomas for the presence of activating mutations of the G alpha q gene. Importantly, our sample contains 8 FSH and LH adenomas. In the pituitary gland, FSH and LH are linked to the GnRH-G alpha q signaling cascade, making these tumors a logical choice for screening for G alpha q mutations. Complementary DNA (cDNA) was synthesized by RT-PCR with G alpha q specific primers to exclude pseudogene transcripts. Fragments of G alpha q cDNA-encompassing residues (Arg183, Gln209) were screened by single-strand conformation polymorphism and then sequenced in both directions. No mutations were detected. We conclude that mutations in these regions of the G alpha q cDNA occur infrequently, if at all, in human pituitary adenomas. Alternative mechanisms underlying pituitary tumorigenesis should be explored.

Human pituitary adenomas express endogenous inhibin subunit and follistatin messenger ribonucleic acids.

Specific factors involved in the pathogenesis of tumors that stimulate clonal human pituitary adenoma cell proliferation remain unknown. An important question regarding the pathogenesis of human pituitary tumors is whether they synthesize autocrine regulatory factors that regulate both hormone biosynthesis and neoplastic growth. Activin and inhibin are both comprised of inhibin subunits and have diverse regulatory roles as growth and differentiation factors in normal and neoplastic tissue. Activin stimulates FSH beta messenger ribonucleic acid (mRNA) biosynthesis and FSH secretion, and these effects are down-regulated in normal gonadotrophs by the endogenous glycoprotein follistatin. In addition to its effects on gonadotrophs, activin modulates hormone secretion by somatotroph and corticotroph cell lines. It is not known whether human neoplastic pituitary tissue synthesizes inhibin subunits or follistatin or whether their expression is cell type specific. We investigated whether alpha-, beta A-, and beta B-inhibin subunit and follistatin mRNAs could be detected in 27 human pituitary adenomas [clinically nonfunctioning (n = 11), somatotroph (n = 5), corticotroph (n = 5), and lactotroph (n = 6)] using reverse transcriptase-polymerase chain reaction techniques. Twenty-six of the tumors contained mRNAs encoding one or more inhibin subunits. beta B-Inhibin mRNA was the most prevalent (81% of tumors), followed by beta A-inhibin (59% of tumors) and alpha-inhibin (52% of tumors). Endogenous alpha-, beta A-, and beta B-inhibin subunit mRNA synthesis was also examined in normal human pituitary and testicular complementary DNA libraries, and all subunit mRNAs were detected. In contrast to the widespread expression of inhibin subunits in pituitary tumors, follistatin mRNA was detected in a subset of nonfunctioning tumors (54%) as well as in control normal human pituitary and testicular complementary DNA libraries. Tumor-specific follistatin biosynthesis was not observed in other pituitary tumor subtypes. These data are the first to demonstrate that 1) endogenous inhibin subunits are synthesized in human pituitary adenomas of all known secretory phenotypes as well as normal pituitary tissue; and 2) follistatin gene expression in pituitary adenomas is specific to clinically nonfunctioning or gonadotropin subunit-producing tumors. The characterization of inhibin subunit and follistatin biosynthesis by human pituitary tumors will be important in investigating their potential roles in regulating both tumor phenotype and cell proliferation.

Transsphenoidal adenomectomy for growth hormone-secreting pituitary adenomas in acromegaly: outcome analysis and determinants of failure.

The results of transsphenoidal adenomectomy for growth hormone (GH)-secreting pituitary adenomas in acromegaly performed over a 17-year period were analyzed retrospectively to determine which preoperative factors significantly influenced the long-term surgical outcome. These variables were then used to develop a logistic regression model to determine the probability of surgical failure. The series consisted of 103 patients. Long-term follow-up study (mean duration 102 +/- 64 months) was performed to derive outcome analysis and determinants of failure. Surgical control was defined as a long-term postoperative serum basal GH level of less than 5 micrograms/liter, a long-term postoperative serum somatomedin C (SM-C) level of less than 2.2 U/ml, and a favorable clinical response. Eighteen (17.5%) patients did not meet these criteria. The overall control rate by the GH criteria was 81.3% and by the SM-C criteria 76.2%. By multivariate logistic regression analysis, tumor stage was the strongest predictor of outcome (p < 0.05). The preoperative GH level, tumor grade, and preoperative SM-C level were significant univariate predictors (p < 0.05). There were statistically significant differences in mean preoperative GH and SM-C levels (p < 0.05, t-test) and tumor stage (p < 0.05, chi-squared test) between patients whose acromegaly was controlled by surgery and those whose acromegaly was not. Furthermore, estimates were derived of the probability of surgical failure based on preoperative GH level, preoperative SM-C level, and tumor grade and stage. The authors believe these findings will enhance clinical decision-making for neurosurgeons considering transsphenoidal microsurgery in patients with acromegaly.

Pituitary adenoma: correlation of half-dose gadolinium-enhanced MR imaging with surgical findings in 26 patients.

Sellar magnetic resonance imaging studies obtained with half doses of gadopentetate dimeglumine (0.05 mmol/kg) were prospectively interpreted and retrospectively rated in 26 patients who subsequently underwent transsphenoidal sellar surgery for suspected pituitary adenoma. Studies included a sagittal scout view followed by a non-contrast-material-enhanced, an immediate postcontrast, and a delayed postcontrast T1-weighted image (obtained at 1.0 or 1.5 T). Ten of 11 confirmed microadenomas were identified prospectively; all were identifiable in retrospect. Macroadenomas (12 cases) were well demonstrated. The high signal intensity of the posterior pituitary and of intrasellar hemorrhage was obscured on postcontrast studies. Delayed images proved unnecessary. This prospective evaluation suggests that a half-dose study is comparable to retrospective studies in which full-dose techniques were used for detection of micro- and macroadenomas. Imaging times are reasonably short, and cost of contrast material is potentially reduced. Confirmation with larger studies is required, and careful endocrinologic and clinical follow-up of nonsurgical patients is necessary.

Clinical aspects of lumbar intervertebral disc disease.

The diagnosis and management of lumbar disc disease has undergone significant changes in recent years. This is especially true for diagnostic imaging studies (MRI and CT). Currently, CT/myelography or unenhanced MRI may be used to confirm the diagnosis and the level of involvement of lumbar disc disease. The indications for lumbar disc surgery include patients with neurologic deficits and/or those in whom intractable pain does not respond to conservative measures. Conventional disc surgery and/or microdiscectomy are both good operative procedures for lumbar disc disease, and each yields excellent results when criteria for diagnosis and surgery are strictly followed.

Loss of vision after transsphenoidal surgery.

Eleven patients who experienced significant loss of vision after transsphenoidal surgery are reported on. The mechanisms involved in these visual complications include direct injury or devascularization of the optic apparatus, fracture of the orbit, postoperative hematoma, cerebral vasospasm, and prolapse of the optic chiasm into an empty sella. Factors that may increase the risk of visual complications include the presence of a pituitary macroadenoma, previous visual impairment, a "bottleneck" or dumbbell-shaped tumor, previous surgery and/or radiation therapy, and, possibly, use of a lumbar subarachnoid catheter during operation. A practical approach to the management and avoidance of these complications is presented.

Cushing's disease: results of transsphenoidal microsurgery with emphasis on surgical failures.

From 1977 to 1988, 56 patients with a preoperative diagnosis of Cushing's disease were treated by transsphenoidal microsurgical exploration of the pituitary gland. In 42 patients, a discrete tumor was found and a selective adenomectomy was performed. Total hypophysectomy was performed in nine patients. In an attempt to preserve pituitary function, a technique of subtotal hypophysectomy was utilized in the remaining five patients. Regular and adequate follow-up results were obtained in 53 patients. A sustained remission was obtained in 45 of these 53 patients for a remission rate of 84.9%. Eight patients were classified as therapeutic failures. The causes for failure included: 1) invasive tumor; 2) hyperplasia mistaken for an adenoma; 3) a presumed ectopic source of adrenocorticotropic hormone; 4) misdiagnosis; 5) atypical tumor; and 6) recurrence of disease after remission. In cases of therapeutic failure, the original diagnosis of Cushing's disease must be reevaluated and treatment continued until sustained remission is achieved. Necessary measures to help avoid surgical failures and an approach for further diagnostic and therapeutic maneuvers in these cases are discussed.

Trends in neurosurgery. The 1989 AANS presidential address.

This overview of neurosurgical practice examines patterns of case management, using several areas such as head injury, brain tumors, and the delivery of health care to illustrate the changes that have taken place over the past 40 years and the changes that might be expected in the next 40 years. The rapid pace of progress has indicated further exciting growth of this specialty into the 21st century; however, what remains constant is the dynamic character of the neurosurgeon. This view of the past and the possibilities for future innovation enables neurosurgeons of all generations to have a sense of pride in the achievements generated by their peers.

Management of prolactinomas associated with very high serum prolactin levels.

The authors have reviewed the results of transsphenoidal microsurgical management in 69 patients with prolactin-secreting pituitary adenomas who had preoperative serum prolactin levels over 200 ng/ml. The patients were divided into three groups based on their preoperative serum prolactin levels: over 200 to 500 ng/ml (Group A); over 500 to 1000 ng/ml (Group B); and over 1000 ng/ml (Group C). The percentage of successful treatment ("control rate") was 68%, 30%, and 14%, respectively, in these three groups of patients. Based on these results, the authors offer guidelines for the management of patients with prolactin-secreting pituitary adenomas associated with exceptionally high serum prolactin levels. The surgical control rate of 68% in Group A seems to justify surgery for these patients, while primary medical care with bromocriptine is recommended for most patients with serum prolactin levels over 500 ng/ml.

Rapid assessment of corticotropin reserve after pituitary surgery.

Corticotropin deficiency may occur after pituitary surgery, and, if unrecognized and untreated, it can be fatal. In this study the insulin tolerance test was used to assess hypothalamic-pituitary-adrenal reserve five to seven days after pituitary surgery, and postoperative morning serum cortisol concentration was compared with the insulin tolerance test for predicting corticotropin deficiency. In 35 patients with pituitary tumors studied prospectively, 27 had normal insulin tolerance test results five to seven days after pituitary surgery; in these patients, the morning serum cortisol concentration two to three days after surgery was 250 nmol/L (9 micrograms/dL) or greater. Eight patients had subnormal insulin tolerance test results or clinical evidence of adrenal insufficiency; the morning serum cortisol concentration in these patients was 80 nmol/L (3 micrograms/dL) or less. Postoperative adrenal insufficiency was transient (one to three months) in five of these eight patients. We retrospectively identified 45 patients whose postoperative morning serum cortisol values were 200 nmol/L (7 micrograms/dL) or greater; none of these patients had clinical evidence of adrenal insufficiency. We conclude that a morning serum cortisol level obtained two to three days after surgery and 24 hours after the discontinuation of hydrocortisone accurately predicts postoperative corticotropin reserve.

Isolated histiocytosis X of the pituitary gland: case report.

The authors describe a case of a granuloma of histiocytosis X localized in the pituitary gland. The patient presented with diabetes insipidus and hyperprolactinemia. The diagnosis was established by surgical removal of the pituitary lesion through a transsphenoidal approach. The clinical and pathological aspects of the case are discussed.

Ganglioglioma of the cerebellum: case report.

The authors report a rare case of a cerebellar ganglioglioma. A review of 12 previously reported cases and our case suggest that surgical removal of this neoplasm carries a good prognosis.

Pituitary tumors composed of adenohypophysial adenoma and Rathke's cleft cyst elements: a clinicopathological study.

Nine cases of pituitary tumors composed of mixed tissue elements of adenohypophysial adenoma and Rathke's cleft cyst are reported. All cases were associated with hyperprolactinemia and were managed by transsphenoidal adenomectomy with good results. The clinical and pathological features are presented, and embryological pathogenesis for the occurrence of this unique association is discussed in connection with the high incidence of immunoreactive S-100 protein cells identified in tumor tissues. Patients with this kind of pituitary tumor can be managed in the same fashion as patients with other types of pituitary adenoma.

Gadolinium-DTPA and MR imaging of pituitary adenoma: a preliminary report.

Gadolinium-DTPA MR imaging (Gd-MR), unenhanced MR imaging, and contrast-enhanced CT studies were compared prospectively in six patients with surgically confirmed pituitary adenomas and three patients without sellar pathology to determine the utility of Gd-MR in the diagnosis of pituitary adenoma. In normal patients, the pituitary gland, cavernous sinus, and infundibulum enhanced by T1 shortening after gadolinium. In adenoma patients, two of four focal lesions identified with contrast-enhanced CT were identified with Gd-MR, and one was identified with unenhanced MR. The earliest short repetition-time sequence performed after gadolinium injection was best for focal lesion detection. Normal cavernous sinus enhancement by gadolinium made identification of cavernous sinus extension of adenoma difficult. Infundibulum displacement was better seen with contrast-enhanced CT (two vs one); however, unenhanced and Gd-MR were better than contrast-enhanced CT for demonstrating chiasmal compression (four vs three). Contrast-enhanced CT, Gd-MR, and plain MR were equally able to identify gland enlargement, sellar floor erosion, and abnormalities of the diaphragma sellae. In this preliminary series, we found Gd-MR to be promising for imaging adenomas; however, modifications in Gd-MR technique including thinner slices and immediate scanning after gadolinium injection are necessary for the best detection of focal lesions.

MR imaging of pituitary adenoma: CT, clinical, and surgical correlation.

Twenty-five patients with suspected pituitary adenoma were evaluated prospectively with CT and MR. Nine patients underwent transsphenoidal surgery, and three of these showed a documented decrease in size of mass on bromocriptine therapy. CT was more sensitive than MR for detecting focal lesions (seven vs three) and sellar-floor erosion (12 vs six). MR was superior to CT in identifying infundibular abnormalities (seven vs six), focal abnormalities of the diaphragma sellae (10 vs seven), cavernous sinus invasion (four vs two), and optic chiasm compression (six vs zero). Thus, MR may be the procedure of choice for optimal identification and localization of macroadenoma. For patients with suspected microadenoma, however, this preliminary series indicates that CT remains the radiographic procedure of choice.

[A recurrent case of TSH-PRL secreting microadenoma following hypothyroidism].

A thirty-seven-year-old housewife whose chief complaints were recurrence of galactorrhea and amenorrhea three years after having a selective adenomectomy. Hormonal examination done as a result of the continuation of the endocrinism revealed a hyperprolactinemia and high level of TRH due to hypothyroidism. Serum prolactin responded to neither TSH stimulation nor L-Dopa suppression tests. In addition, serum TSH did not react to TRH test. Contrast enhancement CT showed an intrasellar enhancing mass the size of which was less than 1 cm in diameter. A unilateral septal transsphenoidal operation was performed; and a soft white-yellowish mass 7 X 5 X 5 mm in size was found in the left inferolateral aspect of the pituitary gland. Histological studies of frozen sections of this revealed it to be a pituitary adenoma, with the border between tumor and normal tissue being quite distinct. Immunocytochemical diagnosis further confirmed it to be both PRL and TSH producing adenoma. Electron microscopy showed more than three different hormone-producing cells. The PRL cells contained large, and the TSH cells had small hormone granules; but some tumor cells contained secretory granules of both sizes suggesting production of both PRL and TSH in the cytoplasm. It is necessary in the management of patients like this, during the post-operative period, to adequately institute a thyroid hormone replacement therapy so as to prevent recurrence.