Growth Hormone-producing Pituitary Adenomas Research Articles

THU044 The Subcellular Localization Of β-Catenin Is Associated With Tumor Size And The Surgical Remission Rate In Growth Hormone-producing Pituitary Adenomas

Abstract Disclosure: S. Kuwabara: None. H. Kameda: None. H. Nomoto: None. K. Cho: None. A. Nakamura: None. Y. Ishi: None. H. Motegi: None. F. Miki: None. H. Miyoshi: None. T. Atsumi: None. The Wnt/β-catenin pathway is the best understood Wnt signaling pathway and controls cell proliferation. In the presence of Wnt, the translocation of β-catenin from the cytoplasm to the nucleus leads to pathway activation. It has been reported that the nuclear accumulation of β-catenin is associated with Ki-67 expression in pituitary adenomas and that the invasiveness of growth hormone (GH)-producing pituitary adenomas is associated with β-catenin expression. We aimed to clarify the effects of the Wnt/β-catenin pathway in GH-producing pituitary adenomas. We performed immunofluorescence staining using antibodies against GH and β-catenin in pathological samples of pituitary adenoma from 62 patients with acromegaly who underwent pituitary surgery at our hospital between January 2008 and December 2021. We also obtained clinical data for the patients, including the results of endocrine testing, and evaluated the relationships of key indices with the intracellular localization of β-catenin. Samples from 26 cases (42%) showed strong punctate expression of β-catenin in the nuclei (dot pattern (DP) group), and samples from 36 cases (58%) showed β-catenin expression in the cytoplasm or cell membrane (non-DP group). There were no differences in the sex, age, GH concentration, or insulin-like growth factor I (IGF-1) SD scores of the two groups, but the DP group had larger tumors (diameters 18±8 vs. 13±7 mm) and a higher prevalence of macroadenomas (77% vs. 53%). In the DP group, a paradoxical preoperative GH response (an increase of ≥30% of the basal concentration) to 75-g oral glucose tolerance testing was more frequent (46 vs. 22%, p<0.05) and postoperative remission was less frequent (23% vs. 50%, p<0.05). Accordingly, the Wnt/β-catenin pathway appears to be more active in the DP group. The larger tumors and lower postoperative remission rate of the DP group suggest that the Wnt/β-catenin pathway may influence tumor growth. Wnt/β-catenin pathway could play a major role in GH-producing pituitary tumor growth, therefore this pathway would be a potential therapeutic target in the affected patients. Presentation: Thursday, June 15, 2023

ODP328 Longitudinal Multidisciplinary Approach for Cabergoline-Resistant Aggressive Prolactinoma Complicated by Multiple Endocrine Neoplasia Type 1

Abstract Background Cabergoline-resistant prolactinomas comprise approximately 10% of all prolactinomas, and sometimes show aggressive features including invasion or higher proliferation profiles. The treatment for such cabergoline-resistant aggressive prolactinomas is challenging and requires a multidisciplinary approach. Clinical case: A 47-year-old woman was diagnosed with hyperprolactinemia after complaining of menstrual irregularities at 20 years old. No neoplastic lesion was identified in the suprasellar region, and 0.25 mg/week cabergoline was initiated. At 35 years’ old, an adenoma was suspected on the right side of the pituitary gland, though plasma prolactin values were sustained without any clinical symptoms. When the patient was 46 years old, her prolactin levels elevated to 202 ng/ml, and magnetic resonance imaging showed a tumor invaded bilateral cavernous sinuses. Because prolactin levels and tumor size continued to increase despite increasing the cabergoline dose to 1 mg/week, endoscopic transsphenoidal surgery was performed. The tumor nearly total removal, the postoperative prolactin levels decreased to 00, but started to increase again in a short period of time. Pathologic assessment revealed a high Ki-67 index (20%) and diffusely positive prolactin alongside negative expression of other anterior hormones. The tumor remained in the cavernous sinus and postoperative prolactin levels tended to increase over time. Cabergoline was restarted and increased to 7mg/week, although prolactin levels were not suppressed. Magnetic resonance imaging and computed tomography scanning showed no metastasis, and octreotide scintigraphy revealed no abnormal accumulation except for the tumor in the cavernous sinus. Radiation therapy was administered to the remaining tumor, and prolactin levels gradually decreased. Thereafter, hypercalcemia and high intact parathyroid hormone levels were found in the presence of left-inferior parathyroid enlargement, leading to a diagnosis of multiple endocrine neoplasia type 1 (MEN1). The patient had no family history of endocrine disease. MEN1 gene mutation was not detected by direct sequencing. Discussion Functional pituitary adenomas including prolactinomas and growth hormone-producing pituitary adenomas are usually benign with a Ki-67 index of approximately 1%, little mitosis, and slow progression 1) . However, pituitary adenomas in MEN1 patients have a higher rate of drug resistance and histological invasiveness than sporadic adenomas, which results in a higher postoperative recurrence rate and a lower normalization rate of approximately 40% 2) . For this case, close monitoring for tumor growth and metastasis was essential.

Clinicopathological Features of Growth Hormone-producing Pituitary Adenomas and Correlation With Preoperative Laboratory Findings.

The histopathological variability of each type of pituitary adenoma (PA) that causes growth hormone (GH) excess influences the phenotype, radiological characteristics and therapy response of acromegaly patients. We correlated the immunohistochemical (IHC) features of GH-secreting PAs with their clinical, laboratory and imaging data. We included 32 patients with documented acromegaly; tumour specimens were histologically and IHC examined: anterior pituitary hormones, pituitary-specific transcription factor-1 (PIT-1), Ki-67 labelling index were evaluated. Macroadenomas represented 93.75%. Post-surgery disease control negatively correlated with the maximum initial tumour diameter (p=0.04). Ki-67 did not predict remission. No correlation was found between GH serum levels and IHC expression (p=0.45). PIT-1 was positive in all specimens, two had a weak expression. Four were considered PIT-1 positive plurihormonal adenomas and several had unusual IHC combinations. PIT-1 accurately classifies GH-secreting PAs. The IHC classification as well as radiological dimensions and extent influence disease control, probably being the best prognosis factors.

Clinical, biological, radiological, and pathological comparison of sparsely and densely granulated somatotroph adenomas: a single center experience from a cohort of 131 patients with acromegaly.

Growth hormone-producing pituitary adenomas are divided into two clinically relevant histologic subtypes, densely (DG-A) and sparsely (SG-A) granulated. Histologic subtype was evaluated in a large cohort of patients with acromegaly, separating DG-A and SG-A, and correlated with clinicopathological characteristics. Patients with acromegaly undergoing surgery as initial therapy between 1995 and 2015 were identified. Histologic subtype was determined by keratin expression pattern with CAM5.2 and correlated with clinical and imaging parameters, somatostatin receptor subtype 2 (SST2) expression, post-surgical remission rate, and application of a prognostic scoring system incorporating proliferation and invasiveness. One hundred thirty-one patients were included. Tumors were classified as DG-A (75, 57.3%), SG-A (29, 22.1%), intermediate (I-A) (9, 6.9%), and unclassified (18, 13.7%) when CAM5.2 was negative. DG-A and I-A were combined for analysis (DG/I-A) and compared to SG-A. Age, gender, proliferation, and post-surgical remission did not differ. SG-A were larger [2 vs. 1.5cm (median), p = 0.03], more frequently invasive [65.5% vs. 32.9%, p = 0.004], associated with higher MRI T2-weighted signal ratio [1.01 vs. 0.82 (median), p = 0.01], showed lower SST2 expression (p < 0.0001), and scored higher in the prognostic classification (p = 0.004). Surgical remission occurred in 41.7% DG/I-A and 41.4% SG-A (p = 1.0). On multivariate analysis, absence of invasion (p = 0.009) and lower pre-operative IGF-1 index (p = 0.0002) were associated with post-surgical remission. CAM5.2 allowed distinction between DG/I-A and SG-A in most but not all cases. Histologic subtype did not predict surgical outcome. Absence of invasion and lower pre-operative IGF-1 index were the only significant predictors of post-surgical remission in this cohort.

The Impact of Insulin-Like Growth Factor Index and Biologically Effective Dose on Outcomes After Stereotactic Radiosurgery for Acromegaly: Cohort Study.

Stereotactic radiosurgery (SRS) is a safe and effective treatment for acromegaly. To improve understanding of clinical and dosimetric factors predicting biochemical remission. A single-institution cohort study of nonsyndromic, radiation-naïve patients with growth hormone-producing pituitary adenomas (GHA) having single-fraction SRS between 1990 and 2017. Exclusions were treatment with pituitary suppressive medications at the time of SRS, or <24 mo of follow-up. The primary outcome was biochemical remission-defined as normalization of insulin-like growth factor-1 index (IGF-1i) off suppression. Biochemical remission was assessed using Cox proportional hazards. Prior studies reporting IGF-1i were assessed via systematic literature review and meta-analysis using random-effect modeling. A total of 102 patients met study criteria. Of these, 46 patients (45%) were female. The median age was 49 yr (interquartile range [IQR]=37-59), and the median follow-up was 63 mo (IQR=29-100). The median pre-SRS IGF-1i was 1.66 (IQR=1.37-3.22). The median margin dose was 25 Gy (IQR=21-25); the median estimated biologically effective dose (BED) was 169.49 Gy (IQR=124.95-196.00). Biochemical remission was achieved in 58 patients (57%), whereas 22 patients (22%) had medication-controlled disease. Pre-SRS IGF-1i≥2.25 was the strongest predictor of treatment failure, with an unadjusted hazard ratio (HR) of 0.51 (95% CI=0.26-0.91, P=.02). Number of isocenters, margin dose, and BED predicted remission on univariate analysis, but after adjusting for sex and baseline IGF-1i, only BED remained significant-and was independently associated with outcome in continuous (HR=1.01, 95% CI=1.00-1.01, P=.02) and binary models (HR=2.27, 95% CI=1.39-5.22, P=.002). A total of 24 patients (29%) developed new post-SRS hypopituitarism. Pooled HR for biochemical remission given subthreshold IGF-1i was 2.25 (95% CI=1.33-3.16, P<.0001). IGF-1i is a reliable predictor of biochemical remission after SRS. BED appears to predict biochemical outcome more reliably than radiation dose, but confirmatory study is needed.

The Impact of Insulin-like Growth Factor Index and Biological Effective Dose on Outcomes After Stereotactic Radiosurgery for Acromegaly

Abstract INTRODUCTION Stereotactic radiosurgery (SRS) is a safe and effective adjuvant treatment for acromegaly. Clinical and dosimetric factors predicting biochemical remission are incompletely understood. METHODS A single-institution cohort study of non-syndromic, radiation-naïve patients with growth hormone producing pituitary adenomas (GHA) having single-fraction SRS between 1990 and 2017. Patients were excluded if they were receiving pituitary suppressive medications at the time of SRS or if they had &lt; 24 mo of follow-up. The primary outcome was biochemical remission defined as normalization of insulin-like growth factor-1 index (IGF-1i) off suppressive medications. Biochemical remission was assessed using Cox proportional hazards. RESULTS A total of 102 patients met study criteria. Forty-six (45%) were female, median age was 49 yr (IQR = 37–59), median follow-up was 63 mo (IQR = 29–100). Median pre-SRS IGF-1i was 1.66 (IQR = 1.37–3.22). Median margin dose was 25 Gy (IQR = 21–25); median estimated biological effective dose (BED) was 169.49 Gy (IQR = 124.95–196.00). Biochemical remission was achieved in 58 (57%) patients, whereas 22 patients (22%) had medication-controlled disease. IGF-1i was the strongest independent predictor of remission, with an unadjusted hazard ratio (HR) of 0.53 (95% CI = 0.36–0.75, P &lt; .0001). Number of isocenters, margin dose, and BED predicted remission on univariate analysis, but after adjusting for sex and baseline IGF-1i, only BED remained independently associated with outcome in both continuous (HR = 1.01, 95% CI = 1.00–1.01, P = .02) and binary models (HR = 2.27, 95% CI = 1.39–5.22, P = .002). Twenty-four (29%) developed new post-SRS hypopituitarism. CONCLUSION IGF-1i is a better predictor of biochemical remission after SRS than IGF-1 level. BED appears to predict biochemical outcome more reliably than radiation dose, but confirmatory study is needed.

Role of EGFL7/EGFR-signaling pathway in migration and invasion of growth hormone-producing pituitary adenomas.

Currently, the primary therapeutic strategy for most growth hormone-producing pituitary adenomas (GHPA) is surgery. Due to the invasiveness of GHPA, high recurrence has limited the benefit of complete adenoma removal surgery. Epidermal growth factor-like domain 7 (EGFL7) is a secreted factor implicated in tumor angiogenesis, growth, invasiveness and metastasis in GHPA. Herein, we observed that the expression level of EGFL7 and p-EGFR in invasive GHPA was much higher than that of non-invasive GHPA. The overexpression of EGFL7 was positively correlated with activation of EGFR (p-EGFR). Noticeably, EGFL7 knockdown significantly inhibited activation of EGFR signaling cascades, including p-ERGR, p-AKT and p-ERK. Further studies showed that EGFL7 knockdown or pharmacological inhibition of EGFR-pathway, using EGFR inhibitor Tyrphostin AG-1478, significantly suppressed migration and invasion of GH3 and GT1-1 cells. In summary, our findings suggest that EGFL7 is a key factor for regulation of EGFR signaling pathway and plays an important role in migration and invasion of invasive GHPA.

Attenuation of EGFL7 Expression Inhibits Growth Hormone-Producing Pituitary Adenomas Growth and Invasion.

Invasiveness of growth hormone-producing pituitary adenomas (GHPAs) causes difficulties in safe and complete adenoma removal during surgery and often leads to high recurrence. Epidermal growth factor-like domain 7 (EGFL7) has been shown to be able to promote tumor angiogenesis, growth, invasiveness, and metastasis through the Notch signaling pathway. It was previously demonstrated that EGFL7 was overexpressed in GHPAs. This study reports that EGFL7 and Notch2 (positive correlation with EGFL7) are overexpressed in invasive GHPA. A long-rank test (Kaplan-Meier method) shows that invasive GHPAs with EGFL7 strong expression results in reduced recurrence-free survival. Multivariate Cox regression analysis reveals that weak EGFL7 expression is an independent prognostic factor for recurrence-free survival. In addition, knockdown of EGFL7 expression suppresses proliferation and invasion of GH3 and GT1-1 cells in vitro. Moreover, attenuation of EGFL7 inhibits human GHPA growth in vivo. The data suggest that as a Notch agonist, EGFL7 may potentially be an appropriate novel molecular target for future development of GHPA medical therapy.

Growth hormone-producing pituitary adenomas in childhood and young adulthood: clinical features and outcomes.

Growth hormone (GH)-producing pituitary adenomas (PAs) in childhood or young adulthood are rare, and the details surrounding these tumors remain enigmatic. We present the clinical, pathological and genetic features of this disease. We identified 25 patients aged 20years or younger with GH-producing PAs who underwent surgery between 2003 and 2016 at Toranomon Hospital in Tokyo. We retrospectively reviewed the clinical data, treatment outcomes and pathological features of these patients to shed light on childhood acromegaly. The cohort comprised 14 male and 11 female patients whose average age at the time of surgery was 17.3years. Germline AIP mutations were present in 5 of 13 patients examined, and Carney complex was identified in 2 of 25 patients. The mean maximum tumor diameter was 26.7mm, and total resection assessed during surgery was achieved in 17 patients. Based on their respective pathological findings, patients were divided into the following 4 groups: sparsely granulated adenomas (5), densely granulated (DG) adenomas (6), plurihormonal adenomas (9), and silent subtype 3 (SS3) adenomas (5). During the mean follow-up period of 50.3 months, complete endocrinological remission was achieved in 14 of 25 patients (56%) by surgery alone and in 19 patients (76%) after postoperative adjuvant therapy. GH-producing PAs in young patients are intriguing and difficult to treat due to their distinct tumor characteristics, including a lower incidence of the DG subtype and a higher incidence of SS3 adenomas and genetic abnormalities. Therefore, multi-modal therapies are essential to achieve optimal clinical outcomes.

Correlation of Morphological and Functional Characteristics of Growth Hormone-Producing Pituitary Adenomas

Introduction. Previous studies demonstrated a relationship between T1- and T2-weighted signal intensity and tumor growth patterns and potential as well as hormonal activity in somatotropinomas. Further investigation of these findings could serve to define predictive diagnostic and treatment factors based on MRI characteristics.The aimof this retrospective study was to analyze the MRI characteristics of growth hormone-producing pituitary adenomas in newly diagnosed patients with acromegaly and to compare them with the corresponding morphological and biochemical characteristics.Methods. Seventy five patients with newly acromegaly were included in the study. Pre-treatment T1- and T2-weighted MR-images of all patients were analyzed, taking into account the intensity of the signals produced by the tumors, as well as their dimensions and growth direction. Growth hormone and IGF-1 levels were also recorded.Results. Out of 75 patients, 74.7% were macroadenomas. T1-weighted adenoma signal was hypointense in 45.3% of patients, hyperintense in 18.7% of patients and isointense in all other cases. T2-weighted adenoma signal was hypointense in 32.3% and hyperintense in 40.5% of patients. No statistically significant differences were found between GH and IGF1 levels as well as signal intensity in relation to patient age. Inferior tumor extension was present in 60.0% of patients overall and 33.3% more prevalent in patients with hyperintense T2 signal and 24.5% and 11.7% more prevalent in patients with hypointense and hyperintense T1 signal respectively. Superior extension was observed in 46.7% of patients and did not differ significantly from inferior extension in patients with hypointense T2 signal. The highest levels of IGF1 were associated with superior extension, while the highest levels of GH were associated with inferior extension. Mean adenoma volume was 8.45 times higher and GH levels were 3.8 times higher in patients with hyperintense T2-weighted signal and 2.3 and 1.3 times higher respectively in patients with hyperintense T1-weighted signal.Conclusion. Hyperintense T1- and T2-weighted MRI signal was associated with larger tumor dimensions, increased GH levels and more frequent inferior extension, all of which indicate higher proliferative potential of the adenomas.

Role of mTOR Inhibitors in Growth Hormone-Producing Pituitary Adenomas Harboring Different FGFR4 Genotypes.

Pituitary adenomas (PAs) are common intracranial lesions. Available medical therapies are limited in PAs, and therefore, it is essential to identify treatments that control PA growth when surgery is not an option. Fibroblast growth factor 4 is implicated in PA pathogenesis; therefore, in this study, we used an isogenic mammosomatotroph cell line (GH4C1) harboring different fibroblast growth factor receptor (FGFR)-4 genotypes to establish and characterize intracranial xenograft mouse models that can be used for preclinical drug testing. We show that proliferating GH4C1 tumors have an average latency of 3 weeks to form. Histological analysis revealed that prototypic FGFR4 (G388) tumors express increased prolactin and less GH, whereas tumors possessing the polymorphic variant of FGFR4 (R388) express increased GH relative to prolactin. All tumors show abundant mammalian target of rapamycin (mTOR) signaling as confirmed using phosphorylated (p)-S6 and p-4E-binding protein 1 as downstream regulators of this pathway. We subsequently demonstrate that the mTOR inhibitor RAD001 decreases tumor growth rate and reduces p-S6 but not p-4E-binding protein 1 activation, regardless of FGFR4 status. More importantly, GH activity was significantly reduced after mTOR inhibition in the R388 polymorphic variant tumors. This reduction was also associated with a concomitant reduction in serum IGF-1 levels in the R388 group. In summary, we demonstrate that the GH4C1 FGFR polymorphic xenograft is a useful model for examining PAs. Furthermore, we show that RAD001 can efficiently reduce tumor growth rate by a reduction in mTOR signaling and more importantly results in control of GH expression and IGF-1 secretion, providing further support for using mTOR inhibitors in PA patients, in particular GH-producing adenomas.

Aggressive transsphenoidal resection of tumors invading the cavernous sinus in patients with acromegaly: predictive factors, strategies, and outcomes.

Cavernous sinus (CS) invasion is the most important preoperative predictor of remission in the surgical treatment of growth hormone-producing pituitary adenomas. The purpose of this study was to evaluate the effectiveness of an aggressive technique for removal of tumors invading the CS in patients with acromegaly. The authors retrospectively reviewed the cases of 150 consecutive patients with acromegaly who underwent primary transsphenoidal surgery in 2010 and 2011. The authors reviewed preoperative Knosp grade, intraoperative findings, histology of the medial wall of the CS, and surgical outcome according to the current consensus criteria for acromegaly. Cavernous sinus invasion was identified in 55 patients (36.7%): definite CS involvement by the tumor was observed under direct vision in 41 patients (74.5%), while invasion was histologically verified in 39 patients (70.9%). Invasion increased in frequency with the higher Knosp grade but was observed in 14.4% (13 of 90) of Grade 0 and 1 tumors. Overall, the remission rate fulfilling stringent criteria was 84.7% (127 of 150). Although CS invasion was significantly associated with an unfavorable outcome (p < 0.0001), remission was achieved in 69.1% (38 of 55) of patients with invasion. No major complications occurred in this series. Cavernous sinus invasion is the most significant, independent predictor of unfavorable outcome. Confirmation of invasion requires direct observation within the CS regardless of the microscope or endoscope used. Particularly in cases in which only the medial wall is involved, histological verification is always necessary to detect the occult invasion. Direct removal of the invading tumor, by sharp excision of the medial wall of the CS, is effective and safe and increases the chance of remission.

Clinicopathological Features of Growth Hormone-Producing Pituitary Adenomas in 242 Acromegaly Patients: Classification according to Hormone Production and Cytokeratin Distribution

The aim of this study was to clarify the relationship between the histological features of GH-producing adenomas surgically resected at the Toranomon Hospital and the clinical features of the patients. Histological examinations, including immunohistochemistry for anterior pituitary hormones and cytokeratin (CK), were performed on 242 consecutively excised GH-producing pituitary adenomas. Immunohistochemistry showed 45% of the adenomas to be monohormonal and 55% to be plurihormonal, producing GH-PRL (77%), GH-TSH (13%), and GH-PRL-TSH (10%). One-fourth of the monohormonal GH adenomas had a dot-like pattern of CK immunoreactivity in the majority of the tumor cells (>80%); they were significantly more common in female or younger patients and usually tended to be larger and more invasive than monohormonal GH adenomas with perinuclear CK. Interestingly, CK-immunonegative adenomas were found in only 5% of the patients; they also showed a tendency to be larger, suggesting that they are a distinct type of GH adenoma with clinically aggressive features. Serum hormone levels correlated well with tumor size only in GH-producing adenomas with a perinuclear pattern of CK immunoreactivity. Each histological subtype of adenoma, classified according to the pattern of CK immunoreactivity, was associated with distinct clinical characteristics. This information is useful for understanding the pathophysiology of acromegaly-causing GH-producing adenomas.

Investigation of responsiveness to thyrotropin-releasing hormone in growth hormone-producing pituitary adenomas.

Objective. The aim of this study was to investigate how the paradoxical response of GH secretion to TRH changes according to tumor volumes. Methods. Patients with newly diagnosed acromegaly were classified as either TRH responders or nonresponders according to the results of a TRH stimulation test (TST), and their clinical characteristics were compared according to responsiveness to TRH and tumor volumes. Results. A total of 41 acromegalic patients who underwent the TST were included in this study. Between TRH responders and nonresponders, basal GH, IGF-I levels, peak GH levels, and tumor volume were not significantly different, but the between-group difference of GH levels remained near significant over the entire TST time. ΔGHmax-min during the TST were significantly different according to the responsiveness to TRH. Peak GH levels and ΔGHmax-min during the TST showed significantly positive correlations with tumor volume with higher levels in macroadenomas than in microadenomas. GH levels over the entire TST time also remained significantly higher in macroadenomas than in microadenomas. Conclusion. Our data demonstrated that the paradoxical response of GH secretion to TRH in GH-producing pituitary adenomas was not inversely correlated with tumor volumes.

Biological Characteristics of Growth Hormone-Producing Pituitary Adenomas Are Different According to Responsiveness to Thyrotropin-Releasing Hormone

The paradoxical response of GH to TRH in patients with acromegaly has been previously reported. However, few reports have focused on tumor characteristics reflected by this response. This study aimed to clarify the relationship between TRH-induced GH responsiveness and other tumor characteristics. Patients with acromegaly who underwent initial surgery between 2000 and 2012 were divided into TRH-responder and nonresponder groups. Clinical features were compared between the two groups with respect to tumor size, Knosp grade, endocrinological profiles, and histopathological findings revealed by cytokeratin staining. Tumor size was quantitatively evaluated with volumetry. Cytokeratin staining patterns were categorized into three groups: sparsely granulated type, densely granulated type, and intermediate type. Sixty-two patients were included in the study. TRH responders (n = 45) showed significantly smaller tumor size than nonresponders (n = 17) (2.78 ± 4.71 vs. 7.56 ± 9.00 ml, P < 0.005). In addition, TRH responders showed significantly higher preoperative basal GH per volume ratio than nonresponders (10.1 ± 8.4 vs. 7.72 ± 11.85 ng/ml(2), P < 0.05). Logarithmic regression modeling showed significant correlation between TRH responsiveness and tumor volume (r = -0.341; P < 0.01). The difference between cytokeratin staining patterns was also significant: sparsely granulated-type adenomas were found in only 13% of TRH responders but in 64% of nonresponders (P < 0.0005). TRH responders showed higher GH suppression rates in the octreotide test compared with nonresponders (86 vs. 68%, P < 0.01). The present data suggest that the responsiveness of serum GH level to TRH reflects significant tumor biological characteristics.

Tyrosine positron emission tomography and protein synthesis rate in pituitary adenoma: Different effects of surgery and radiation therapy

IntroductionPositron emission tomography (PET) using amino acid tracers is able to establish biochemical tumour characterization in vivo. The use of PET in the follow-up of non-functioning pituitary adenomas (NFA) and growth hormone producing pituitary adenomas (GHA) after surgery and radiation treatment is not yet clear. MethodsTo determine the value of PET before and after transsphenoidal neurosurgery in NFA and GHA, we investigated 12 patients with pituitary adenoma (9 NFA and 3 GHA) before and 4months after surgery with magnetic resonance imaging (MRI) and tyrosine PET (TYR-PET). Three years after radiation therapy TYR-PET was used to document residual activity in 6 of these patients (4 NFA- and 2 GHA). Tumour size was quantified by computerized MRI measurements. In TYR-PET, tumour activity was assessed by computerized measurements of the hot spot and by determination of protein synthesis rate (PSR). ResultsIn response to surgery, MRI showed a median tumour volume reduction of 58% (P<0.01). TYR-PET demonstrated 62% volume reduction (P<0.02), but no change in PSR (P>0.30). After radiation therapy the MRI-volumes of the residual pituitary adenomas did not change but the volume of the hot spot on TYR-PET-imaging was reduced by 58% (P=0.02), and PSR decreased in 5 of 6 patients (P=0.12). ConclusionAmino acid PET tumour activity is reduced parallel with MRI volume changes after surgery. The decrease in TYR-PET activity after radiation therapy, despite unaltered MRI tumour volume, supports the concept that it is possible to follow biological tumour activity with this technique. The diagnostic merit of this tracer technique, predicting pituitary adenoma re-growth, needs to be validated in a large prospective study.

Clinicopathological Features of Growth Hormone-producing Pituitary Adenomas: Difference among Various Types Defined by Cytokeratin Distribution Pattern Including a Transitional Form

Pituitary adenomas producing almost exclusively growth hormones (GH) have been ultrastructurally classified into two distinct types: densely granulated somatotroph (DG) adenomas and sparsely granulated (SG) adenomas. Fibrous body (FB), an intracytoplasmic globular aggregation of cytokeratin (CK) filaments, is a hallmark of SG adenomas. Under light microscope, FB could be identified by CK immunohistochemistry as a dot-pattern immunoreaction versus a perinuclear pattern for cells without FB. However, it has been noted that numerous adenomas contain mixed populations of the two patterns. To clarify clinicopathological characteristics of the adenomas with mixed populations ("intermediate type" adenomas) and to confirm clinicopathological differences between strictly defined DG-type and SG-type adenomas, we performed this study on 104 GH cell adenomas. Having segregated "intermediate-type" adenomas (26 cases), we found significant differences between typical DG-type (47 cases) and SG-type adenomas (31 cases); SG-type adenomas had younger ages (44 vs. 50), higher frequency of macroadenomas (86% vs. 58%), invasiveness (65% vs. 38%), advanced grades (3 or 4) in Knosp's classification (50% vs. 24%), and weaker immunoreaction for GH, beta-TSH, alpha-subunit, E-cadherin, and beta-catenin. Clinicopathological characteristics of "intermediate-type" adenomas were identical to those of DG-type adenomas. These findings confirm that SG-type adenoma is a distinct section of GH cell adenomas with special properties and biological behavior, and suggest that intermediate-phenotype adenomas are enrolled in DG-type adenomas. Special properties and biological behavior of SG-type adenomas may appear after the majority of tumor cells possess a fully developed fibrous body.

Significance of immunohistochemical expression of Rab3B and SNAP-25 in growth hormone-producing pituitary adenomas

Exocytosis proteins play an important role in the secretory activities of anterior pituitary cells and adenoma cells. An immunohistochemical study was conducted to elucidate the functional significance of these proteins in growth hormone (GH)-producing adenomas. We studied 40 GH-producing adenomas, 10 prolactinomas, and 10 clinically nonfunctioning (NF) adenomas immunohistochemically with antibodies specific for Rab3B and SNAP-25, both of which are considered essential in secretory activities of the pituitary, and keratin 8 (clone CAM5.2). The tumor volume (TV) was estimated with high-resolution magnetic resonance imaging. Immunoreactivity for Rab3B, which was granular in the cytoplasm, varied in GH adenomas, but was negative in prolactinomas and NF adenomas. Reactivity for SNAP-25, which was linear on the plasma membrane, varied in GH adenomas, and was intensely positive in prolactinomas, and negative in NF adenomas. In GH adenomas, an increased percentage of adenoma cells with dot-like immunoreactivity for keratin 8 was associated with decreased reactivities for Rab3B (R=0.739, P<0.0001) and SNAP-25 (R=0.840, P<0.0001). Increased reactivity for SNAP-25 correlated positively with plasma GH level per unit TV (R=0.685, P<0.0001). The immunoreactivities for Rab3B and SNAP-25 may reflect the number of secretory granules and exocytosis activity, respectively, in pituitary adenomas, including GH adenomas.

American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Acromegaly

growth hormone CorrectionEndocrine Practice Vol. 11Issue 2PreviewIn the American Association of Clinical Endocrinologists Acromegaly Guidelines, which were published in the May/June 2004 issue of Endocrine Practice (volume 10, pages 213-225), the algorithm for recommended management of growth hormone-producing pituitary adenomas (Fig. 1, page 219) should be adjusted slightly, as shown below. Full-Text PDF CorrectionsEndocrine Practice Vol. 14Issue 6PreviewIn an effort to give appropriate recognition to all authors of previous AACE clinical practice guidelines and ensure that all authors are indexed properly on MEDLINE, all previous guidelines and their respective authors are listed below. Full-Text PDF

Cavernous sinus invasion and tumor proliferative potential of growth hormone-producing pituitary tumors.

Surgical removal of growth hormone-producing pituitary adenomas (GHomas) becomes difficult when they invade the cavernous sinus (CS). We investigated the relation among tumor proliferative potential, tumor volume and invasion of GHomas to CS. 15 patients with GHoma aged 20-59 years were enrolled. The volumes of the adenomas were calculated from MR images and the extension to CS was classified into 5 grades according to Knosp's grading system. The immuno-histochemical staining for anti-Ki-67 monoclonal antibody (MIB-1) was performed and the proliferative potential of GHomas was determined as the percentage of MIB-1 labeled nuclei (MIB-1 index). The volume, MIB-1 index and pre-operative growth hormone (GH) level were compared with CS invasion by single and multiple regression analyses. With single regression analyses, CS invasion was significantly correlated with both the volume (r=0.69, p<0.01) and MIB-1 index (r=0.73, p<0.01), but not with the GH level (r=0.42, p=0.12). The volume and MIB-1 index showed a weak correlation but it was not significant (r=0.52, p=0.06). With multiple regression analysis, CS invasion was well explained by the volume and MIB-1 index of GHomas (r=0.82, p<0.01). About 66% of CS invasion was explained by these two factors. In view of these results, not only the volume but also the speed of growth are important for GHomas to invade CS. GHomas with a high MIB-1 index may, even if they are small, more readily invade CS and need closer post-operative hormonal and neuroimaging studies.