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Purpose: Diabetes insipidus (DI) following transsphenoidal surgery (TSS) is a common complication. Although postoperative DI often occurs in patients with craniopharyngioma and Rathke's cleft cyst, postoperative DI in patients with non-functioning pituitary adenoma (NFPA) has not been fully examined. We clarified the clinical characteristics and magnetic resonance imaging (MRI) findings predicting postoperative DI in NFPAs., Methods: A total of 333 patients undergoing initial TSS for NFPA were included in this retrospective study. Hyperintensity (HI) in the posterior pituitary lobe was evaluated on preoperative T1-weighted MRI. Based on the findings of HI patients were divided into three groups as follows: HI was not detected (Disappearance group), HI located intrasellarly (Intrasellar group), and HI located suprasellarly (Suprasellar group)., Results: The overall rate of DI was 21.9%, including permanent DI in 0.6%. DI occurred at postoperative day 1 (72.6%) or day 2 (19.2%) and improved within 7 days in most cases (87.7%). Univariable and multivariable analyses showed that the predictive factors of DI were a younger age (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.95-0.99, P = 0.0037) and larger tumor diameter (OR 1.04, 95% CI 1.01-1.08, P = 0.0155). The rate of DI was highest in the Disappearance group (43.8%) followed by the Intrasellar group (26.0%). The OR was 2.17 in the Intrasellar group compared with the Suprasellar group (95% CI 1.17-4.02, P = 0.0141)., Conclusions: Factors predicting DI following TSS for NFPA were a younger age, larger tumor size, and the location of intrasellar HI on preoperative T1-weighted MRI., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The safety of transsphenoidal surgery (TSS) for pituitary adenoma in elderly populations is becoming a new topic in our aging society. However, previous studies did not focus on the surgical procedures in elderly patients. We attempted to clarify the safety of TSS and the influence of pseudocapsular resection in elderly patients with non-functioning pituitary adenoma (NFPA)., Methods: A total of 284 patients undergoing initial TSS for NFPA were categorized into two groups as follows: 1) Elderly group (n = 69; age ≥ 70 years); and 2) Younger group (n = 215; age < 70 years). Furthermore, all patients were newly divided into the two following categories: 1) Resected group (n = 121, with total pseudocapsule resection); and 2) Non-Resected group (n = 163, without total pseudocapsule resection). The main outcome measure was the incidence of perioperative complications and the rate of severe growth hormone deficiency (sGHD) after TSS., Results: There were no significant differences in the rates of perioperative complication between the Elderly and Younger groups. Furthermore, pseudocapsular resection did not increase the surgical risks in either group. On the other hand, sGHD only showed a significant improvement in the Younger group. The only factor predicting the new development of sGHD following TSS was an older age, not pseudocapsule resection., Conclusions: Aging does not increase the perioperative complications of TSS for NFPA; however, aging has a negative influence on the postoperative function of GH secretion. In contrast, pseudocapsular resection does not have any negative influence on the perioperative complications or postoperative function of GH secretion, even in elderly patients, based on the authors' experience and surgical technique., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Recently, several reports have revealed new aspects regarding transsphenoidal surgery (TSS) for pituitary lesions in elderly patients., Objective: The aim of present study is to provide an updated review of the recent literature, which we hope will contribute to the management of nonfunctioning pituitary adenoma (NFPA) in elderly patients., Methods: We searched PubMed and Web of Science for reports on TSS for NFPAs in elderly patients and reviewed the literature., Results: NFPAs, which cause the symptoms of tumor mass effect, are the most common form of pituitary adenoma in elderly individuals. The rates of tumor resection and postoperative visual improvement in elderly patients are similar to those in younger patients; however, elderly patients have greater difficulty in recovering from preoperative hypopituitarism. TSS is associated with low rates of morbidity and mortality in elderly patients. However, there is a possibility that the risks of morbidity and mortality increase with advancing age. TSS is not considered for elderly patients who show hypopituitarism alone, but who either have or are predicted to experience a tumor mass effect. Prospective MRI follow-up without surgery can be also proposed for elderly patients with a high American Society of Anesthesiologists (ASA) grade or those in whom there is no evidence of tumor growth towards the optic pathway., Conclusions: TSS is considered a safe procedure for the treatment of NFPA and is even tolerated by elderly patients; however, the surgical indications, which are based on the patient's clinical condition and the results of radiological examinations, should be strict., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: The glomerular filtration rate (GFR) is increased in patients with active acromegaly. The aim of this study is to elucidate whether renal function deteriorates in patients with acromegaly and whether this deterioration is reversible after surgical remission., Design/methods: A case-control study of 48 acromegalic patients who were surgically cured (cases) and 48 patients with nonfunctioning pituitary adenomas (NFomas, controls) was conducted. We performed clinical and biochemical examinations before surgery and 3months post-surgery. The GFR of each patient was estimated (estimated GFR, eGFR) using their serum creatinine, age, sex, and body surface area, and postoperative changes in the eGFR were assessed., Results: The preoperative eGFR was significantly higher in patients with acromegaly than in those with NFoma (99.8 vs 75.1mL/min respectively, P<0.01). In acromegalic patients, surgical remission was accompanied by a significant decline in the eGFR (from 99.8 to 86.2mL/min, P<0.01). Conversely, in patients with NFoma, the postoperative eGFR did not change significantly (from 75.1 to 81.9mL/min, P=0.12). Among the acromegalic patients, the postoperative decreases in the eGFR were more prominent in patients with a preoperatively high or normal vs low eGFR., Conclusions: Our data demonstrated a significant post-surgical eGFR decrease in patients with acromegaly, but not in patients with NFomas. This change in the eGFR was reversible in acromegalic patients with a high/normal preoperative eGFR, but not in those with a low preoperative eGFR. This suggests that the reversible pathophysiological change in some patients is functional but not organic., (© 2016 European Society of Endocrinology.)

Objective: Pseudocapsular resection is a useful surgical technique for removing functioning pituitary adenomas; however, the significance of this procedure in nonfunctioning pituitary adenomas (NFPAs) had not been discussed in detail. We clarify the safety of pseudocapsular resection in NFPAs based on the incidence of surgical complications and evaluation of pituitary function., Methods: In 143 patients, initial surgery for NFPAs was performed with preoperative and postoperative pituitary provocation tests. Patients were categorized into 3 groups: total group (n = 65), in which the pseudocapsule was totally removed; partial group (n = 11), in which the pseudocapsule was partially removed; and nonremoval group (n = 67), in which the pseudocapsule was not removed or did not exist. The main outcome measure was the incidence of surgical complications and postoperative pituitary functions., Results: Intraoperative cerebrospinal fluid leakage and temporary diabetes insipidus occurred more frequently in the total group than in the nonremoval group; however, the differences were not statistically significant. There was no difference in the incidence of any other complications, including postoperative cerebrospinal fluid leakage and permanent diabetes insipidus, between the total and nonremoval groups. Postoperative anterior pituitary function improved to the same degree in both the total and the nonremoval groups. Univariate and multivariate analyses revealed that pseudocapsular resection was not a factor in the postoperative deterioration of pituitary function., Conclusions: Pseudocapsular resection in NFPAs does not increase the risk of surgical complications or aggravate postoperative pituitary function., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Apart from the radiologic features regarding size and invasiveness, we had noticed some differences in morphology among types of pituitary adenomas. We conducted this study to verify the differences in radiologic morphology between growth hormone producing pituitary adenomas (GHoma) and nonfunctioning pituitary adenomas (NFoma). Pre-surgical magnetic resonance images (MRIs) were assessed in 50 cases of GHoma and 50 cases of NFoma. Geometric parameters on MRI were set in accordance with sellar anatomy. Intensity of T1-weighted image was not different between the two groups, but hypo-intensity of T2-weighted image was more frequently seen in GHoma. Predominant inferior extension of tumor was seen mostly in GHoma (88 vs. 38%). Extension of the tumor to the superior compartment of cavernous sinus was more frequent in NFoma. Pituitary gland was generally located superior to GHoma and postero-superior to NFoma. Growth characteristics of pituitary adenoma were confirmed to differ between GHoma and NFoma.

To know the clinical characteristics of pituitary adenomas in the elderly patients aged 80 years or older who were surgically treated. From 1995 through 2012, 907 patients underwent surgery for the pituitary adenomas at Kagoshima- and Hiroshima University hospitals in Japan. Ten (1.1%) patients were aged 80 years or older. We retrospectively assessed the clinical characteristics including preoperative comorbidities, manifestations, neuroimaging findings, and endocrinologic features of these ten patients. The subjects included eight males and two females. Their ages ranged from 80 to 86 with mean of 83.1 years. Of these, besides one case of growth hormone-producing adenoma, others were clinically nonfunctioning adenoma. Six patients had modest comorbidities such as hypertension, cardiovascular diseases, diabetes mellitus, or chronic kidney dysfunction, and all patients were classified into grade 2-3 on American Society of Anesthesiologists' Physical Status grading. Transsphenoidal surgery was performed in all due to visual disturbance in eight, diabetes mellitus as an intercurrent illness of acromegaly in one, and for the purpose of preventing visual disturbance in one patient who had an adenoma impinging optic chiasm but still had normal visual field. The surgeries provided sufficient decompression of the optic pathways and improved visual disorder in all. In an acromegalic male, his comorbidities considerably improved. No permanent surgical morbidity ensued. More than three axes of anterior pituitary hormones were preoperatively impaired in all, which were rarely recovered. Transsphenoidal surgery is safe and efficient treatment way for patients aged 80 years or older with pituitary adenomas with chiasmatic symptoms when the patients' general condition is well preserved and pituitary hormonal deficiency is adequately replaced.

Pituitary adenomas in childhood and adolescence are relatively rare. In the present study we investigated intratumoral hemorrhage in pituitary adenomas and examined cases of intratumoral hemorrhage using adult patients for comparison. From 1975 to 2012, 38 consecutive patients operated for pituitary adenoma and one patient treated with medication alone, were enrolled in this study. Their ages were less than 18 years old at the initial diagnosis (mean age 15.3 ± 2.9 years). The comparison group consisted of 209 consecutive adult patients (>18 years old). The incidence and characteristics of intratumoral hemorrhage in pituitary adenomas were evaluated, based on magnetic resonance imaging (MRI) findings (28 cases) and on operative findings. The incidence of pituitary adenomas in childhood and adolescence was 38/1,073 (3.5 %) patients operated. Functioning pituitary adenomas (82.1 %) were common and non-functioning pituitary adenomas (17.9 %) were rare. Although no significant difference in tumor size was found and Knosp grade did not differ between young (≤18 years old) and adult (>18 years old) patients, indications of intratumoral hemorrhage on MRI was common in young patients (42.9 %). Based on both MRI and operative findings, intratumoral hemorrhage was significantly more likely to occur in young patients, compared with adult patients.

Thyroid stimulating hormone-secreting pituitary adenomas (TSHomas) are uncommon tumors of the anterior pituitary gland. Patients with TSHomas may present with hyperthyroidism, but the incidence of thyroid storm due to TSHomas has yet to be determined. We report a rare case of thyroid storm caused by TSHoma in a 54-year-old woman. Preoperatively she had symptoms of excessive sweating and palpitation. Blood tests showed inappropriate secretion of TSH with blood TSH 6.86 μ U/mL, fT3 19.8 pg/mL, and fT4 5.95 ng/dL. Magnetic resonance imaging (MRI) revealed a pituitary tumor with maximum diameter of 13 mm that was extirpated through transsphenoidal route. After operation the patient was stuporous and thyroid storm occurred presenting with hyperthermia, hypertension, and tachycardia. It was well managed with nicardipine, midazolam, steroids, and potassium iodide. Immunohistochemical staining of tumor specimen was positive for TSH and growth hormone (GH). One year after operation, fT3 and fT4 levels were still high. As her tumor was diagnosed to be GH- and TSH-producing adenoma, octreotide injection therapy was started, which normalized thyroid hormone levels. This is the second reported case with thyroid storm due to TSHoma and emphasizes the importance of strategies with interdisciplinary cooperation for prevention of such emergency conditions.

Context: Temozolomide (TMZ) is an alkylating agent and was a first-line chemotherapeutic agent for malignant gliomas. Recently, TMZ has been documented to be effective against atypical pituitary adenomas (APAs) and pituitary carcinomas (PCs)., Objective: The clinical and pathological characteristics of APAs and PCs treated with TMZ in Japan were surveyed and analyzed retrospectively., Design: Members of the Japan Society of Hypothalamic and Pituitary Tumors were surveyed regarding the clinical characteristics of APAs and PCs treated with TMZ. Stored tumor samples were gathered from the responders and were assessed by the immunohistochemistry of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, p53, MSH6, and anterior pituitary hormones. Responses to TMZ treatment were defined as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) according to RECIST (Response Evaluation Criteria in Solid Tumors) version 2.0., Subjects: Three samples from 3 subjects with APA and 11 samples from 10 subjects with PC were available., Results: The 13 subjects had APAs and PCs consisting of 5 prolactin-producing tumors, 5 ACTH-producing tumors, and 3 null cell adenomas. The clinical response to TMZ treatment was as follows: 4 cases of CR and PR (31%), 2 cases of SD (15%), 6 cases of recurrence after CR and PR (46%), and 1 case of PD (8%). However, considerable subjects had recurrent disease after a response to TMZ. The immunohistochemical findings of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, and p53 did not show any significant correlation with the efficacy of TMZ. However, the immunopositivity of MSH6 was positively correlated with TMZ response (P = .015, Fisher's exact test)., Conclusions: This study showed that preserving MSH6 function was contributory to the effectiveness of TMZ in malignant pituitary neoplasms. It is necessary to survey more cases and evaluate multifactor analyses.

A 59-year-old woman presented with a rare supra-diaphragmatic pituitary adenoma manifesting as a mass lesion. Her baseline data and the response of anterior pituitary hormones to the provocation test were within the normal range. Magnetic resonance imaging showed a homogeneously enhanced tumor located on the diaphragma sellae. The tumor was totally removed by the endonasal trans-tuberculum sellae approach under combined microscopic and endoscopic observation. Her postoperative course was uneventful and the histological diagnosis was pituitary adenoma located in the suprasellar region. The trans-tuberculum sellae approach is a less invasive method to remove pituitary adenoma located in the suprasellar region.

Tumor-induced secondary hyperprolactinemia in patients with non-prolactin (PRL)-secreting pituitary tumors has traditionally been ascribed to pituitary stalk damage. We conducted a retrospective analysis of secondary hyperprolactinemia in 106 patients who underwent surgery for non-PRL-secreting pituitary adenoma. The incidence of hyperprolactinemia was evaluated, and pituitary-stalk damage was assessed radiographically using MRI (size of tumor and extension type) and endocrinologically by monitoring hormonal function using a provocation test. The effect of a tumor-derived intrasellar factor, leukemia inhibitory factor (LIF), on hyperprolactinemia was also investigated. Hyperprolactinemia was observed in 31 of the 106 (29.2%) patients. It was not correlated with either physical stalk compression or endocrinological dysfunction. However, LIF expression was negatively correlated with the incidence of secondary hyperprolactinemia (p<0.01). Although secondary hyperprolactinemia might be caused by pituitary stalk damage, it is possible that LIF masks the effect., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: The relationship between tumor consistency and apparent diffusion coefficient (ADC) values is controversial. We evaluated the role of the ADC using an advanced diffusion-weighted imaging (DWI) technique. We employed periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) DWI acquired on a 3-T magnetic resonance imaging (MRI) scanner to assess the consistency of pituitary adenomas and examined the relationship between the ADC and the hormone secretion status of the tumors and their MIB-1 labeling index (MIB-1 LI)., Materials and Methods: The study protocol was approved by our institutional review board. We retrospectively studied 24 operated patients with pituitary adenomas who had undergone PROPELLER DWI on a 3-T MRI scanner. Conventional MRI findings were expressed as the ratio of the signal intensity (SI) in the lesions to the SI of the normal white matter and the degree of contrast enhancement. Minimum-, mean-, and maximum ADC (ADCmin, ADCmean, ADCmax) values were calculated. The consistency of the tumors was determined by neurosurgeons. All surgical specimens were submitted for histological study to calculate the MIB-1 LI and the percent collagen content. Preoperative MRI-, intraoperative-, and histological findings were analyzed by a statistician., Results: Our study included 15 soft-, 5 fibrous-, and 4 hard tumors. Tumor consistency was strongly associated with the percent collagen content. However, neither the tumor consistency nor the percent collagen content was correlated with MRI findings or ADC values. The SI of growth hormone-producing adenomas on T2-WI was lower than of the other pituitary adenomas studied (p<0.01); no other significant difference was found in the ADC or on conventional MRI between pituitary adenomas with different secretory functions. The MIB-1 LI of pituitary adenomas was not correlated with their appearance on conventional MRI or their ADC values., Conclusion: Using the PROPELLER DWI technique we confirmed that the ADC was not correlated with the consistency of pituitary adenomas. We also demonstrate that the ADC was not associated with the hormone-secreting status or the MIB-1 LI of pituitary adenomas., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

To know the longitudinal shift of blood IGF-1 of cured acromegaly, we conducted retrospective survey of changes in blood IGF-1 over two years, which has not been previously investigated. Blood IGF-1 levels were measured for longer than 2 years after TSS in 37 patients whose nadir GH during postoperative oral glucose tolerance test (OGTt) was under 1 ng/mL. Blood IGF-1 very gradually declined after three months; 230.6 (mean) ng/mL at 3-12 months, 202.3 ng/mL at 12-24 months, and 198.6 ng/mL at 24-36 months. Their SD values, calculated based on standard IGF-1 values of age- and sex-matched Japanese population, also slowly decreased after three months; 1.69 (mean) at 3-12 months, 1.23 at 12-24 months, and 1.12 at 24-36 months. Very slow decrease of the IGF-1 levels continued beyond the first several months and even the first year after TSS. The declination of values is greater than that associated with aging. This declination may be at least partially a reflection of the slow decrease and late normalization of GH secretion.

This study is a retrospective analysis of hyponatremia after transsphenoidal surgery in patients with pituitary adenoma. We evaluated (i) the incidence of post-operative hyponatremia (serum Na levels ≤ 135 mEq/L) and the emergence of hyponatremic symptoms, and assessed (ii) the risk factors under a uniform protocol of i.v. infusion with steroid and electrolyte fluid. We examined 88 consecutive operated patients (female: 60; male: 28) with pituitary adenoma. Apart from reconfirming the effects of the purported risk factors, we focused on the degree of serum Na decline on post-operative hyponatremia. Although remained stable during early post-operative period (4 days after surgery), the serum Na levels subsequently decreased after post-operative day 4 in 81 of 88 cases (92.0%). Of 88 patients, 27 (30.7%) and 9 (10.2%) cases suffered from hyponatremia, and developed hyponatremic symptoms. Interestingly, the degree of serum Na levels decline (from pre-operative levels) indicated a useful independent risk factor for monitoring hyponatremic symptoms (p = 0.006) and the degree of decline tended to be greater in elder patients (> 60 years) (p = 0.0346). Serum Na levels should be monitored from, at least, post-operative day 7 to detect early development of hyponatremia. Special attention and recovery effort should be given to elder patients with marked serum Na level decline after surgery.

Stem-like cells in tumors are capable of self-renewal and pluri-differentiation; they are thought to play important roles in tumor initiation and maintenance. Stem-like cells in malignant glioma express CD133. We examined samples from human pituitary adenoma, a generally benign neoplasm, for CD133 expression using routine immunohistochemical and biochemical methods. Our study of 70 pituitary adenomas (clinically nonfunctioning adenomas and growth hormone-, prolactin-, adrenocorticotropic hormone-, and thyroid-stimulating hormone-producing adenomas) showed that 18 (25.7%) expressed CD133. This rate was higher in clinically nonfunctioning (33.3%) than functioning adenomas (12.0%) (p = 0.085). Real-time PCR assay revealed the expression of CD133 mRNA in samples immunohistochemically positive for CD133. Neither the patient age and gender, nor the tumor size or postoperative recurrence rate correlated with CD133 positivity. CD133+ cells ubiquitously coexpressed CD34, nestin, and VEGFR2 (KDL1). S-100 and GFAP were not coexpressed with CD133. Chromogranin A, Pit-1, SF-1, and NeuroD1 were immune-negative, indicating that CD133+ cells did not have the potential to differentiate into functional endocrine cells. Our data suggest that the expression of CD133 in pituitary adenomas is related to immature endothelial progenitor cells that may play a role in the neovascularization of pituitary adenomas. Further studies are needed to elucidate the significance of CD133+ cells with respect to neovascularization and their sustainable growth in pituitary adenomas., (Copyright © 2011 S. Karger AG, Basel.)

Object: The increase in the incidental detection of asymptomatic pituitary adenomas, known as "pituitary incidentalomas," led the authors to conduct a survey of the natural course of these lesions., Methods: Forty-two patients with clinically nonfunctioning pituitary adenomas who had manifested no neurological or endocrinological disorders were monitored with magnetic resonance imaging studies. The follow-up period ranged from 10.8 to 168.2 months (mean +/- standard deviation, 61.9 +/- 38.2 months). The mean initial tumor size was 18.3 +/- 7 mm. In 21 patients, the tumor increased by at least 10% of its measured size on detection. This increase was first detected between 8.4 and 58.8 months (mean 31.8 +/- 17.6 months) after diagnosis. There was no correlation between the original tumor size, patient age, or the presence of intratumoral cysts and tumor growth. Symptoms were noted in 10 patients during follow up; in four, extensive tumor necrosis accompanied hemorrhage, leading to severe headache, acute ophthalmological symptoms, and panhypopituitarism, which was indicative of pituitary apoplexy. Transsphenoidal surgery was performed in 12 patients with enlarged tumors, including three with apoplexy. With the exception of one apoplectic patient, visual function was recovered in all who underwent surgery. All apoplectic patients continue to manifest hypopituitarism., Conclusions: In the course of 4 years, the size of the incidentalomas increased in 40% of 42 patients and became symptomatic in 20%. During the 5-year follow up, pituitary apoplexy developed in 9.5%. These findings may justify early intervention, especially in young individuals with incidentally found macroadenoma.

The authors investigated the relationship between hemorrhage and the expression of vascular endothelial growth factor (VEGF) in pituitary adenomas. The subjects were 39 patients with pituitary adenomas. Surgically obtained tumor tissue was immunohistochemically stained using antibodies against VEGF, CD-34, Ki-67, and anterior pituitary hormones. The expression of VEGF was graded as 0, 1+, and 2+. The relationship between intratumoral hemorrhage and factors such as tumor size, Ki-67 labeling indices, number of CD-34 positive vessels, and VEGF expression was examined by multivariate analysis. High-grade VEGF expression was the sole independent factor correlated with intratumoral hemorrhage. The number of CD-34 positive vessels had no effect on the incidence of hemorrhage in patients with pituitary adenomas. In conclusion, a positive relationship between VEGF expression and hemorrhage in pituitary adenoma was observed. The patho-mechanical significance of this correlation is under investigation.

To determine the clinical significance of dynamic magnetic resonance imaging (MRI) for pituitary adenomas, we analyzed sequential enhancement patterns of pituitary adenomas and factors contributing to these sequential patterns. Dynamic MRI was performed in 67 patients with pituitary adenomas and compared to conventional imaging. Subjects were classified into four categories according to the sequential enhancement patterns of the adenomas. Factors supposed to correlate with enhancement pattern, such as secreting hormone, tumor size, microscopically examined vascularity and arterial involvement, and intraoperatively observed texture of the adenomas, were examined among the groups. Adenomas inclined to have late enhancement patterns were relatively small compared to those with early patterns. Tumors with very early enhancement patterns were significantly more fibrous than those with the other three patterns. The factors that contribute to sequential enhancement patterns remain unclear. None the less, scrutinizing the dynamic sequential pattern may provide useful information about the probable texture of the tumor., (Copyright 2002 Elsevier Science Ltd.)

Background: Telomerase activity responsible for cellular immortality may participate the development of human cancers. Telomerase is a multisubunit ribonucleoprotein composed of at least three components: hTERT, hTERC, and TEP1. This is the first report showing telomerase activity and telomerase component expression in pituitary adenoma with histological malignant transformation., Description: A 16-year-old male with a prolactin-producing pituitary adenoma with metastasis is presented. The patient underwent three partial resections of an intra- and suprasellar lesion over a 2-year period and received focal irradiation. Eight years after the first admission, a metastatic lesion to the subarachnoid space around the medulla oblongata was detected and the lesion was resected as the fourth operation. Furthermore, the suprasellar lesion showed regrowth and partial resection was performed as the fifth operation. The last two specimens were diagnosed as pituitary carcinoma. Radiotherapy with gamma knife was performed for the residual suprasellar lesion and a new lesion in the left temporal lobe after the fifth operation. Telomerase activity was examined by TRAP/TRAP-HPA methods, qualitatively and quantitatively. Telomere length was examined by Southern blot analysis, and the expression of telomerase components (hTERT, hTERC, and TEP1) was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). The MIB1 index, telomerase activity, and hTERT expression increased according to histologic malignancy chronologically in this patient. None of the specimens showed immunoreactivity for p53, EGFR, or bc12. No telomerase activity was detected in pituitary adenomas without malignant transformation, other benign brain tumors, or normal brain tissues., Conclusion: We report a patient with pituitary adenoma transforming to carcinoma. The tumor cells acquired immortality and revealed malignant transformation during the course of the disease, that was proved by an increase of telomerase activity and hTERT expression.

Background: The purpose of this study was to evaluate the usefulness of an oblique "cross court" transsphenoidal approach using a speculum with slightly modified projections for pituitary adenomas showing lateral extension., Method: The projection of the speculum on the side of the cavernous lesion was shortened by 5 mm. The tip of the longer projection was placed in the sphenoid sinus, while the end of the shorter projection was placed on the concha sphenoidalis. An oblique transsphenoidal view was then easily obtained by opening the speculum. The contralateral nasal incisura had to be widened in some cases to achieve a more oblique view., Findings: Twenty-eight patients diagnosed with pituitary adenoma showing lateral growth underwent adenomectomy under direct observation of the medial portion of the cavernous sinus using this approach. Postoperative normalization of hyperendocrinopathy or gross total removal of the tumour was achieved in the majority of patients., Interpretation: An oblique transsphenoidal approach using this speculum and contralateral minor maxillary osteotomy afforded a direct view of the medial cavernous sinus, sufficient for the removal of adenomas showing minor to moderate lateral growth.

The purpose of the present study was to investigate postsurgical change in body composition in patients who have undergone surgery for acromegaly. Eight patients with acromegaly had determination of serum GH, insulin-like growth factor-I (IGF-I), height, body weight, and bioelectric impedance before surgery and at 2 weeks, 1 month, 3 months, and 6 months after surgery. Body composition was analyzed by bioelectric impedance analysis (BIA). We analyzed body fat (BF), body lean mass (BLM), body cell mass (BCM), total body water (TBW), intracellular water (ICW) and extracellular water (ECW). The serum GH concentration and IGF-I had decreased significantly 2 weeks after surgery. Body weight had decreased significantly 1 month after surgery and recovered 3 months after surgery. BIA showed that TBW and BCM had decreased significantly 2 weeks after surgery. BF gradually increased up to 1 month after surgery and was increased significantly at 3 months after surgery. The percent ratio of TBW/body weight decreased and the percent ratio of BF/body weight increased during the 6 months after surgery. The percent ratio of ECW/TBW did not change during the 6 months following surgery. In conclusion, the rapid body weight loss which occurred within 2 weeks after surgery was caused by decreases in TBW and BCM. The recovery of body weight, which was seen later than 1 month after surgery, was caused by an increase in BF. The postoperative change in body composition in acromegaly ceased 3 months after surgery.

Objective: To improve the safety and efficacy of transsphenoidal pituitary adenoma surgery, we investigated transsphenoidal intraoperative color Doppler ultrasonography using a biplane transducer system., Methods: We studied 23 patients with pituitary adenomas (18 patients with macroadenomas and 5 patients with microadenomas) who underwent transsphenoidal surgery. The Hitachi EUB555 color Doppler ultrasound system (Hitachi Medical, Tokyo, Japan) was used with a pediatric biplane transesophageal echo cardiography probe (EUP-ES533, 7.5 MHz, biplane phased array sector probe, 9.8-mm tip). The probe was inserted into the saline-filled sphenoid sinus after the sellar floor was opened. Intra- and suprasellar images were obtained just before dural incision and after the tumor removal was thought to have been accomplished., Results: In all patients, the tumor was depicted as a slightly hyperechoic mass, as compared with the cerebrum. Using color Doppler imaging, major cerebral arteries were depicted clearly in 74% of patients. The pituitary glands, pituitary stalks, and optic chiasms were observed in patients with small adenomas, but not when large adenomas were present. Cavernous sinus invasion, concomitant aneurysm, and residual tumor were clearly visualized. In patients with large adenomas, the end point of surgery was decided when there was an ultrasonographically demonstrated collapsed tumor capsule, subcapsular total vacancy, and reappearance of the optic chiasm., Conclusion: Trans-sellar color Doppler ultrasonography seems to be a useful intraoperative guiding system that may improve the safety and efficacy of transsphenoidal surgery.

Pituitary adenomas generally are regarded as benign tumors, although some invade the cavernous sinus and recur. We examined the epithelial cadherin (E-CD) expression in 30 pituitary adenomas (6 with cavernous sinus invasion and 24 without). Immunoreactivity of E-CD were found in all pituitary adenomas but they were very various. The presence of an association between E-CD expression and cavernous sinus invasion was assessed. There were no significant differences in E-CD expression between invasive and noninvasive adenomas. These results suggest that E-CD expression is not associated with cavernous sinus invasion in pituitary adenomas.

The incidence of intracranial aneurysm associated with pituitary adenoma is not definitely established although reported higher than in general population. This study was designed to find the existence of such association in a large series of pituitary adenoma cases. A retrospective study of 467 cases of pituitary adenoma (mean age: 41 +/- 15 years) was done. All patients underwent cerebral angiography at least of anterior circulation, detailed hormonal study, and 155 cases had additional magnetic resonance (MR) angiography. Twenty-five cases (5.4%) of pituitary adenoma (mean age 52 years) had intracranial aneurysm, 97% on anterior circulation, and 12% had multiple aneurysms. Two cases presented with aneurysmal rupture and the rest were incidental. Aneurysm was more frequently seen with increasing age (p < 0.001) and the age distribution resembled that of aneurysm among general population. Although the combination was most frequent among nonfunctioning adenoma (8.8%), and least frequent among prolactinoma (2.4%), this association was again due to age factor. There was no association between hormone secretion, size and invasive nature of the tumor. The results showed no association between intracranial aneurysm and pituitary adenoma. Our speculation is that such occurrence is merely a chance factor and the risk is no greater than that among general population.

Pituitary adenomas are generally regarded as benign tumours, but they may recur. We identified eight patients with pituitary adenomas that showed rapid regrowth within 2 years of initial surgery. We estimated the percentage of cells in each specimen that showed positive immunostaining for MIB1 (a novel anti-Ki-67) and compared the values to those of 40 adenomas that showed no regrowth. The mean MIB1 index for 40 adenomas that showed no evidence of regrowth was 0.19 +/- 0.06%. This was significantly (p < 0.0001) lower than that for adenomas that showed rapid regrowth (1.27 +/- 0.31%), based on the initial resected specimens. Immediately after detection of rapid regrowth and in adenomas that were resistant to bromocriptine or irradiation, the MIB1 index was always greater than 1.0%. Most patients with rapidly regrowing adenomas were well controlled by radiation therapy. Our results suggest that a MIB1 index greater than 1.0% may be a useful predictor of rapid regrowth of pituitary adenomas and may be useful for planning of therapy.

The purpose of this study was to assess the effect of surgery on gonadal function in 42 male patients with pituitary adenomas Gonadal functions were evaluated by measuring total serum testosterone concentrations pre- and postoperatively. The subjects of the study were 20 patients with GH secreting adenoma, 7 patients with prolactinoma and 15 patients with nonfunctioning (NF) adenoma. Their ages ranged from 18 to 60 years (mean +/- SEM, 41 +/- 1.9). The serum testosterone concentration was low at less than 300 ng/dl preoperatively in 14 of 20 patients (70%) with GH producing adenoma, 6 of 7 patients (86%) with prolactinoma, and 7 of 15 patients (47%) with NF adenoma. Postoperatively, the total serum testosterone concentration was normalized in 9 of 14 patients (64%) with GH producing adenoma, one of 6 patients (17%) with prolactinoma, and 5 of 7 patients (71%) with NF adenoma. The normalization of serum GH and prolactin concentrations is indispensable for the restoration of gonadal function. It is very important to preserve the normal preoperative gonadotropin secretion by means of gentle surgery.

The effects of surgery on pituitary-gonadal function were investigated in women with pituitary adenomas other than prolactinomas. The subjects were 46 women of premenopausal age with a pituitary adenoma. Twenty tumors were GH producing, 19 were nonfunctioning, and 7 were adrenocorticotropin producing adenomas. The surgery was performed mainly via the transsphenoidal route, with the aim of eradicating the tumor and preserving pituitary function. The menstrual cycle was preserved postoperatively in 9 out of 10 (90%) patients with regular preoperative menstruation. Menstrual disturbance was seen in 36 (78.3%) cases preoperatively. The causative factors for menstrual disturbance were gonadotropin impairment and hyperprolactinemia in GH producing and nonfunctioning adenoma. Excessive hormonal secretion itself is a major causative factor for menstrual disturbance in GH and ACTH producing adenoma. Regular menstruation was restored following surgery in 20 out of 36 (55.6%) patients with menstrual problems. The predicting factors for postoperative recovery of menstruation are: size of adenoma less than 40 mm, period of amenorrhea less than 5 years, and preoperatively preserved gonadotropin secretion. In addition, preoperative hyperprolactinemia was also a predicting factor in women with nonfunctioning adenoma. Thus, even in patients with pituitary adenomas other than prolactinoma, the restoration of menstruation is highly achievable when surgery is performed with attention to preserving pituitary function.

Pituitary adenomas are regarded generally as benign tumours, but some of them can invade the cavernous sinus. On the other hand, matrix metalloproteinase-9 (MMP-9), which is a type IV collagenase, recently has been found to be expressed in matastases and to be related to the invasiveness of various malignant tumours including brain tumours. In order to investigate some characteristic features of pituitary adenomas which invade the cavernous sinus, we examined immunohistological studies for MMP-9 in seven pituitary adenomas for type IV collagen in a dura mater and assayed for type IV collagenase activity in seven adenomas using type IV collagen labelled with fluorescein isothiocyaniate (FITC). We found immunopositive adenoma cells for MMP-9 in all invasive adenoma and immunopositive spindle like cells for type IV collagen in the dura mater. All three invasive adenomas had high levels of type IV collagenase activity (0.57-0.72 U/ml), but the four adenomas which did not invade the cavernous sinus had low levels of type IV collagenase activity (0.0-0.10 U/ml). These results suggest that the level of type IV collagenase activity in a pituitary adenoma may be related to its ability to invade the cavernous sinus.

Twenty-two pituitary adenomas were examined on the secretion of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) using a cell immunoblot assay, and discussed regarding an association between cavernous sinus invasion and the secretion of these proteins. The cell immunoblot assay, a kind of immunoblot procedure, is able to detect proteins at the single cell level and to detect the incidence of tumour cells secreting the target proteins in the total tumour cell population. The incidence of tumour cells secreting MMP-9 was significantly higher in invasive adenomas than in noninvasive ones. On the other hand, TIMP-1 secretion was not detected in any adenomas in this study. This result suggested that MMP-9 secretion, and especially the number of MMP-9-secreting cells, may be associated with cavernous sinus invasion of pituitary adenomas.

Studies of anterior pituitary function in patients treated for nonfunctioning pituitary adenomas have been limited by their short duration. The purpose of the present study was to examine pituitary function longitudinally among three types of patients: those with complete tumor removal (group A); those with subtotal or partial adenomectomy (group B); and those in group B who underwent additional radiation therapy (group C). The subjects were 33 patients whose anterior pituitary function was evaluated by provocative tests such as insulin induced hypoglycemia, thyrotropin releasing hormone administration test and luteinizing hormone releasing hormone administration test. They underwent preoperative evaluation and postoperative reevaluations at 2 weeks, 3 months, 6 months and annually thereafter, for over 10 years. Anterior pituitary function was restored within a year after surgery, if at all. No additional function was restored after one year from treatment. In group A, no one developed impairment of anterior pituitary function after one year from surgery. In group B, however, new impairment was noted at intervals, due to tumor regrowth. In Group C, deficiencies developed after one year, irrespective of tumor regrowth. In conclusion, lifelong endocrinological follow-up is recommended for patients receiving postoperative irradiation, and for patients with potential for tumor regrowth. On the other hand, patients with total adenomectomy may be exempted from periodic endocrinological follow-up if they do not need postoperative hormonal replacement therapy.

To detect growth hormone-releasing hormone (GHRH) secreted by monodispersed human GH-producing pituitary adenoma cells, the cell immunoblot assay was performed. GHRH-secreting cells were observed in 3 cases of GH-producing pituitary adenomas. The incidence of GHRH-secreting cells in the total cell populations was 0.24-3.42%. By contrast, no GHRH-secreting cells were observed in 2 cases of clinically nonfunctioning pituitary adenomas. The findings obtained by immunohistochemical studies for adenohypophysial hormones and for nuclear antigens of proliferative activity revealed that the incidence of GHRH-secreting cells is more related to the frequency of GH cells than to the proliferative activity in GH-producing pituitary adenomas.

Pituitary adenomas generally are regarded as benign tumours, but a part of them can invade the cavernous sinus and recur. We examined 43 pituitary adenomas for the following factors: tumour volume, endocrinological function, cavernous sinus invasion, and growth rates examined by using anti-proliferating cell nuclear antigen (PCNA) and MIB1 (a novel anti-Ki-67) as markers. There was significant correlation between PCNA- and MIB1-positive cell rates and PCNA- and MIB1-positive cell rates were higher in the three cases with rapid regrowth than in the other cases. Staining was stronger and more distinct for MIB1 than for anti-PCNA; thus, MIB1-positive cells were easily distinguished by their intense immunoreactivity. MIB1 may be useful for detecting those rare cases with rapid regrowth even when initially regarded as benign tumours. Adenomas with cavernous sinus invasion were significantly larger than those demonstrating no invasion. However, no significant difference was found in the frequency of PCNA- or MIB1-positive cells between adenomas with and without cavernous sinus invasion. These findings suggest that cavernous sinus invasion and growth rate are independent biological factors. Therefore, cavernous sinus invasion may be due to chemical factors produced by the tumour itself rather than as a result of rapid tumour growth.

A 42-year-old man presented with classical symptoms of Cushing's disease. Endocrinological examinations indicated the presence of a adrenocorticotropin-(ACTH) producing pituitary adenoma. Magnetic resonance imaging showed a cystic sellar lesion, which had features of a Rathke's cleft cyst, whereas the adenoma was not depicted. The ratio of blood ACTH concentration between cubital vein, left, and right cavernous sinus was 1: 1.4: 20. During transsphenoidal surgery, in addition to the Rathke's left cyst, a tiny adenoma was detected beneath the left pituitary lobe. Cavernous sinus sampling is a useful auxiliary in the localization of an ACTH-producing adenoma, as in this case.

The position of the normal pituitary gland, assessed using gadolinium - enhanced MRI was compared with the position found at surgery for pituitary adenoma in 25 patients. The tumours were five microadenomas and 20 macroadenomas. Using T1-weighted imaging, the anterior lobe could be differentiated on the sagittal image in five patients (20%) and on the coronal image in four (16%). The high intensity of the posterior lobe could be differentiated using T1-weighted sagittal imaging in 13 patients (52%). The normal pituitary gland, which enhanced more strongly than tumour, could be differentiated using Gd-DTPA-enhanced MRI on the sagittal images in 22 cases (88%) and on the coronal image in 17 (68%). In seven patients, the normal pituitary gland surrounded the tumour; it was displaced superiorly in 14 cases and superioposterorly in two but in no case was it displaced anteriorly or downwards.

Purpose: To describe the gadolinium-enhanced MR findings of Rathke cleft cyst correlate them with the surgical findings, and define those preoperative findings that differentiate this lesion from other sellar and juxtasellar tumors., Methods: We studied 18 patients who were diagnosed as having Rathke cleft cyst pathologically. These patients were imaged with T1- and T2-weighted coronal and sagittal spin-echo sequences. Fifteen of these patients received gadopentetate dimeglumine., Results: In eight patients, the cyst showed low intensity on T1-weighted images and high intensity on T2-weighted images. At surgery, the cyst fluid was cerebrospinal fluid-like or light brown in five patients, motor oil-like in one patient, and milky in two patients. In 10 patients, cysts showed isointensity to high intensity on T1-weighted images and had various intensity on T2-weighted images. All 10 contained milky fluid. In three patients the intensity of fluid was heterogeneous. A waxy nodule was found in two patients. The position of the normal pituitary gland confirmed by surgery in all cases coincided with enhancement on MR imaging. The variable position of the normal pituitary gland was clearly identified in the sagittal images. The cyst walls showed no enhancement by gadopentetate dimeglumine., Conclusions: Because Rathke cleft cysts show variable intensities on MR, the diagnosis is often difficult when based on MR signal intensity values alone. MR imaging with gadopentetate dimeglumine does assist in the diagnosis of Rathke cleft cysts. Diagnostic clues include the lack of cyst wall enhancement and displacement of the normal pituitary gland.

In order to know the exact incidence of oral complications due to the sublabial transsphenoidal approach, the authors meticulously heard the complaints of 46 patients, who had undergone the approach more than 3 months before. The incidence of the patients who had one or more complaints concerning the oral region was 52.2%. Dysesthesia of the upper lip was most frequent (37%), followed by upper lip pain (17.4%). These complaints were more marked in two patients who had undergone operations using the sublabial approach twice. Among the nine patients with dentures, the dentures had to be remade in three patients because of gigival atrophy several months after the use of the sublabial approach. With a view to overcoming these complications, the authors adapted the endonasal transsphenoidal approach in 13 patients. There was no inconvenience during surgery while this approach was being used, and there were no postoperative oral complications. Among three patients using dentures, there were none who needed remodeling of their dentures. In nine patients, the tension reducing incision was made in the bottom of the columella, which caused no cosmetic problem. Furthermore, the time consumed for approaching the sphenoid sinus was less than that required when using the sublabial approach. In conclusion, the following type of patient is believed to be an appropriate candidate for endonasal approach. A patient who has a relatively smaller sellar lesion and 1) An acromegalic patient whose nostril is relatively large, 2) An elderly patient using dentures, 3) A patient who has undergone previous transsphenoidal surgery, or 4) A patient whose columellar crease is hidden.(ABSTRACT TRUNCATED AT 250 WORDS)

With large pituitary adenomas, the optic nerves and chiasm usually lie on the tumour capsule and are displaced superiorly. We report a large invasive pituitary adenoma, with complete involvement of both optic nerves. Review of the preoperative MR images demonstrated the optic nerves, with signal intensity close to that of cerebral white matter, and different from the flow void of the basal cerebral arteries. Correlation of this observation with intraoperative findings is discussed.

There has been a dramatic development in the treatment of pituitary adenomas during the last two decades. The main factors which led to this development were the introduction of transsphenoidal surgery, the development of new imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) and the introduction of newer dopaminergic agents. Present status of the treatment of pituitary adenoma is reported here. This report is based on the experiences of 381 cases of pituitary adenomas treated at the Department of Neurosurgery, Hiroshima University School of Medicine within the last 16 years. There are some problems which have to be solved in order to achieve further development in the treatment of pituitary adenomas. Our experience in this field and a need for future development are listed below. 1) The transsphenoidal adenomectomy gives high cure rates in cases of micro and expansive prolactinomas and growth hormone secreting adenomas. 2) Results of the transsphenoidal surgery in cases of ACTH secreting adenomas is not satisfactory. In order to get higher cure rate, a more elaborate operative techniques and an introduction of more effective drug therapy are needed. 3) Further safety and curability in pituitary surgery will be achieved by the exploitation of new imaging modalities such as MRI.

The effect of long-term somatostatin analogue (SMS 201-995) treatment in two acromegalic patients is reported. Continuous tumor shrinkage was observed even after 129 and 139 weeks of treatment with 600 micrograms of SMS 201-995 daily. A huge and firm adenoma underwent shrinkage during treatment with SMS 201-995. No serious side effect appeared during 160 weeks of treatment. SMS 201-995 has a longterm tumor shrinkage effect and improves endocrinopathies.

The authors reported a rare case of sellar germinoma which was misdiagnosed as nonfunctioning pituitary adenoma. A 32-year-old woman was admitted to our hospital because of amenorrhea and disturbance of left visual acuity. She had become amenorrhagic after her second delivery two years before. Neurological examination revealed she was normal except for diminished left visual acuity (Rt. = 1.2, Lt. = 0.5). The general condition was good. Urine volume and its specific gravity were within normal range. Endocrinological examination showed hyperprolactinemia (PRL 72 ng/ml) accompanied with impairment of GH, TSH, LH and FSH's reserve. Basal levels and reserve of the blood cortisol were normal. AFP and hCG were within normal range. CT scan revealed a homogenously enhanced intrasellar tumor which had a suprasellar portion (vertical length: 15 mm). T1 weighted MRI revealed low intensity tumor, and T2 weighted image revealed high intensity tumor. Sagittal MR image with gadolinium enhancement showed the pituitary gland anterior to the tumor. Transsphenoidal removal was performed. The histological diagnosis was pure germinoma. After the operation, the intracranial and spinal disseminations were disclosed. Complete neuraxis irradiation resulted in the complete remission of the tumor. Sellar germinoma without diabetes insipidus is considered to be very difficult to diagnose preoperatively. However, the authors proposed that anterior shift of the pituitary gland in sagittal MR image may be a clue to the diagnosis of sellar germinoma.

The authors report a very rare case of pituitary adenoma producing both GH and ACTH. A 29-year-old female was admitted with obesity, amenorrhea, acromegaly, hirsutism, excessive pigmentation, acne, and diabetes mellitus. Computed tomography revealed an intrasellar tumor 16 mm in height, with a destroyed sellar floor. The blood concentrations of GH, ACTH and cortisol were increased (GH: 92 ng/ml, ACTH: 94 pg/ml, cortisol: 18.3 micrograms/dl). No diurnal variation in the amount of cortisol was observed. The urinary 17-OHCS was suppressed by 8 mg but not by 2 mg of dexamethasone. A subtotal adenomectomy was then performed through the transsphenoidal approach, which led to a sufficient reduction of both blood GH and ACTH (cortisol). Histologically the tumor was an acidophilic pituitary adenoma. Immunoperoxidase staining showed diffuse GH and sporadic ACTH producing cells, but failed to show any cells producing both hormones. The electron micrograms of neoplastic cells showed the ultrastructural characteristics of respective GH and ACTH cells. Another increase in both GH and cortisol, which occurred 19 months after the operation, has been controlled by bromocriptine administration. This case may be the first reported case of a pituitary adenoma producing both GH and ACTH, not accompanied by prolactin (PRL) hypersecretion, which has been fully confirmed endocrinologically and histopathologically.