E-cadherin expression and gene expression profiles in corticotroph pituitary neuroendocrine tumor subtypes.

Corticotroph adenomas/pituitary neuroendocrine tumors (PitNETs) are associated with significant morbidity and mortality. Predictors of tumor behavior have not shown high prognostic accuracy. For somatotroph adenomas/PitNETs, E-cadherin expression correlates strongly with prognosis. E-cadherin expression has not been investigated in other PitNETs. A retrospective chart review of adults with corticotroph adenomas/PitNETs was conducted to assess correlation between E-cadherin expression and tumor characteristics. In addition, gene expression microarray was performed in subset of tumors (n = 16). Seventy-seven patients were identified; 71% were female, with median age of cohort 45.2 years. Seventy-five percent had macroadenomas, of which 22% were hormonally active. Ninety-five percent of microadenomas were hormonally active. Adrenocorticotropic hormone granulation pattern by IHC identified 63% as densely granulated (DG) and 34% as sparsely granulated (SG). All microadenomas were DG (p < .001); 50% of macroadenomas were DG associated with increased tumor invasion compared to SG. E-cadherin IHC was positive in 80%, diminished in 17%, and absent in 20% and did not correlate with corticotroph PitNETs subtype, size, or prognosis. In contrast to the distinct transcriptomes of corticotroph PitNETs and normal pituitaries, a comparison of clinically active and silent corticotroph PitNETs demonstrated similar molecular signatures indicating their common origin, but with unique differences related to their secretory status.

Medical Costs Associated with High/Moderate/Low Likelihood of Adult Growth Hormone Deficiency: A Healthcare Claims Database Analysis.

Purpose: Adult growth hormone deficiency (AGHD) is often underdiagnosed and undertreated, leading to costly comorbidities. Previously, we developed an algorithm to identify individuals in a commercially insured US population with high, moderate, or low likelihood of having AGHD. Here, we estimate and compare direct medical costs by likelihood level. Patients and Methods: Retrospective, observational analysis using the Truven Health MarketScan database to analyze direct medical costs relating to inpatient and outpatient claims, outpatient prescription claims, medication usage, clinical utilization records, and healthcare expenditures. Patients were categorized into groups based on algorithmically determined likelihoods of AGHD. Likelihood groups were further stratified by age and sex. Trajectories of annual costs (USD) by likelihood level were also investigated. Results: The study cohort comprised 135 million US adults (aged ≥18 years). Individuals ranked as high-likelihood AGHD had a greater burden of comorbid illness, including cardiovascular disease and diabetes, than those ranked moderate- or low-likelihood. Those in the high-likelihood group had greater mean total direct medical monthly costs ($1844.51 [95% confidence interval (CI): 1841.24;1847.78]) than those in the moderate- ($945.65 [95% CI: 945.26;946.04]) and low-likelihood groups ($459.10 [95% CI: 458.95;459.25]). Outpatient visits accounted for the majority of costs overall, although cost per visit was substantially lower than for inpatient services. Costs tended to increase with age and peaked around the time that individuals were assigned a level of AGHD likelihood. Total direct medical costs in individuals with a high likelihood of AGHD exceeded those for individuals with moderate or low likelihood. Conclusion: Understanding the trajectory of healthcare costs in AGHD may help rationalize allocation of healthcare resources.

Growth hormone is an important substance found in the body. Adult growth hormone deficiency (AGHD) is the reduced production of growth hormone unrelated to the normal reduction seen with aging. Untreated AGHD can result in the development of other conditions, known as comorbidities, which can be expensive to manage. Previously, 135 million privately insured people in the US, aged 18­64 years, were categorized into groups by their likelihood (high, medium, or low) of having AGHD. This study compared the estimated direct medical costs (eg hospital care and medication) across the different likelihood levels. People with a high likelihood of AGHD had more comorbidities than people with a medium/low likelihood, and an average total direct medical monthly cost of $1844.51, nearly twice as much as those with a medium likelihood ($945.65), and four times as much as those with a low likelihood ($459.10). These costs tended to increase with age, with the highest costs associated with people aged 50­59 years and 60­64 years. Outpatient costs (for treatments not requiring an overnight hospital stay) accounted for the greatest proportion of total medical costs, ahead of inpatient costs (for treatments requiring an overnight hospital stay) and medication costs. These findings suggest that diagnosing and treating AGHD earlier may help to reduce medical costs over time. Increased testing and treatment will cause an initial increase in the use of healthcare resources, but could improve overall cost effectiveness by reducing the long-term impact of the disease and avoiding unnecessary healthcare use.

Development of a Novel Algorithm to Identify People with High Likelihood of Adult Growth Hormone Deficiency in a US Healthcare Claims Database.

Objective: Adult growth hormone deficiency (AGHD) is an underdiagnosed disease associated with increased morbidity and mortality. Identifying people who may benefit from growth hormone (GH) therapy can be challenging, as many AGHD symptoms resemble those of aging. We developed an algorithm to potentially help providers stratify people by their likelihood of having AGHD. Design: The algorithm was developed with, and applied to, data in the anonymized Truven Health MarketScan® claims database. Patients. A total of 135 million adults in the US aged ≥18 years with ≥6 months of data in the Truven database. Measurements. Proportion of people with high, moderate, or low likelihood of having AGHD, and differences in demographic and clinical characteristics among these groups. Results: Overall, 0.5%, 6.0%, and 93.6% of people were categorized into groups with high, moderate, or low likelihood of having AGHD, respectively. The proportions of females were 59.3%, 71.6%, and 50.4%, respectively. People in the high- and moderate-likelihood groups tended to be older than those in the low-likelihood group, with 58.3%, 49.0%, and 37.6% aged >50 years, respectively. Only 2.2% of people in the high-likelihood group received GH therapy as adults. The high-likelihood group had a higher incidence of comorbidities than the low-likelihood group, notably malignant neoplastic disease (standardized difference -0.42), malignant breast tumor (-0.27), hyperlipidemia (-0.26), hypertensive disorder (-0.25), osteoarthritis (-0.23), and heart disease (-0.22). Conclusions: This algorithm may represent a cost-effective approach to improve AGHD detection rates by identifying appropriate patients for further diagnostic testing and potential GH replacement treatment.

Corrigendum: Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study.

[This corrects the article DOI: 10.3389/fendo.2021.662865.].

Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study.

Introduction/Purpose: Relacorilant is a selective glucocorticoid receptor modulator (SGRM) with no progesterone receptor activity. We evaluated the efficacy and safety of relacorilant in patients with endogenous Cushing syndrome (CS). Materials and Methods: A single-arm, open-label, phase 2, dose-finding study with 2 dose groups (NCT02804750, https://clinicaltrials.gov/ct2/show/NCT02804750) was conducted at 19 sites in the U.S. and Europe. Low-dose relacorilant (100-200 mg/d; n = 17) was administered for 12 weeks or high-dose relacorilant (250-400 mg/d; n = 18) for 16 weeks; doses were up-titrated by 50 mg every 4 weeks. Outcome measures included proportion of patients with clinically meaningful changes in hypertension and/or hyperglycemia from baseline to last observed visit. For patients with hypertension, clinical response was defined as a ≥5-mmHg decrease in mean systolic or diastolic blood pressure, measured by a standardized and validated 24-h ABPM. For patients with hyperglycemia, clinical response was defined ad-hoc as ≥0.5% decrease in HbA1c, normalization or ≥50-mg/dL decrease in 2-h plasma glucose value on oral glucose tolerance test, or decrease in daily insulin (≥25%) or sulfonylurea dose (≥50%). Results: 35 adults with CS and hypertension and/or hyperglycemia (impaired glucose tolerance or type 2 diabetes mellitus) were enrolled, of which 34 (24 women/10 men) received treatment and had postbaseline data. In the low-dose group, 5/12 patients (41.7%) with hypertension and 2/13 patients (15.4%) with hyperglycemia achieved response. In the high-dose group, 7/11 patients (63.6%) with hypertension and 6/12 patients (50%) with hyperglycemia achieved response. Common (≥20%) adverse events included back pain, headache, peripheral edema, nausea, pain at extremities, diarrhea, and dizziness. No drug-induced vaginal bleeding or hypokalemia occurred. Conclusions: The SGRM relacorilant provided clinical benefit to patients with CS without undesirable antiprogesterone effects or drug-induced hypokalemia.

Cystic sellar salivary gland-like lesions.

INTRODUCTION: Cystic sellar salivary gland-like lesions (CSSLs) are exceedingly rare, with fewer than a dozen case reports. They contain amorphous colloid identical to Rathke cleft cyst contents, but the cyst wall additionally shows cohesive aggregates of benign salivary glands. We report three new examples. MATERIALS AND METHODS: Two cases were seen at University of Colorado Denver and one at Memorial Sloan Kettering (MSK). Molecular testing was attempted on two of three. RESULTS: Case 1 is a 20-year-old female who presented with panhypopituitarism and was found to have a suprasellar mass that proved to be a CSSL. She received no postoperative adjuvant therapy, but recurrence of headaches and blurred vision 2 years later prompted return to medical attention. A much smaller local cyst recurrence was now accompanied by a thickened, bulbous infundibular stalk. Second resection yielded a gliotic infundibular stalk and amorphous mucin, but no residual salivary-like glands. She is without further recurrence on 6-year follow-up. Case 2 is a 29-year-old female with headache; while seen initially at a tertiary care center, diagnosis was only made after consultation at MSK. Case 3 is 68-year-old female who had originally presented with apoplexy to an outside hospital 7 years prior to surgery and diagnosis. Molecular testing was uninformative on case 1 and negative for mutations or fusions on case 3. CONCLUSION: Few pathologists or neuropathologists have encountered CSSLs in their practices; case 1 produced recurrence and significant infundibular stalk damage, and case 3 originally manifested apoplexy, features not previously reported.

Surgical management considerations in cystic prolactinomas-a single center case series.

PURPOSE: The optimal treatment of prolactinomas with a predominantly cystic component remains poorly defined. The cystic tumor component is considered to respond less favorably to medical treatment, thereby advocating surgical management. The purpose of this study was to assess remission rates in surgically treated cystic prolactinomas, and to compare outcomes to similarly treated solid micro- and macroprolactinomas. METHODS: Clinical and imaging data were retrospectively compiled from 56 patients who underwent transsphenoidal resection, for symptomatic prolactinomas, from 2004 to 2018, at a single academic institution. Pituitary adenomas were subdivided according to tumor size and tumor consistency: cystic prolactinomas (>50% cystic tumor component) n = 17; solid microprolactinomas (<10 mm) n = 10; and solid macroprolactinomas (≥10 mm) n = 29. Remission was defined as a prolactin level of <10 ng/dl either immediately postoperative or at a later time point. RESULTS: Median tumor size was 15 mm for cystic prolactinomas, 7 mm for solid microprolactinomas, and 25.5 mm for solid macroprolactinomas. Remission was achieved in 76% (n = 13/17) of surgically treated cystic prolactinomas, 100% (n = 10/10) of solid microprolactinomas, and 24% (n = 7/29) of solid macroprolactinomas. More than 44% of solid macroprolactinomas had a Knosp grade > 3, while most cystic prolactinomas (93.8%) and all solid microprolactinomas (100%) had a Knosp grade ≤ 2. CONCLUSIONS: Despite their large tumor size (≥10 mm), high remission rates can be expected with surgically treated cystic prolactinomas. This case series of cystic prolactinomas demonstrates the successful use of transsphenoidal surgery as a favorable, and a potentially curative alternative to dopaminergic therapy in this patient population.

Very Unusual Sellar/Suprasellar Region Masses: A Review.

The cause of sellar region masses in large retrospective series is overwhelmingly pituitary adenomas (84.6%), followed by craniopharyngiomas (3.2%), cystic nonneoplastic lesions (2.8%), inflammatory lesions (1.1%), meningiomas (0.94%), metastases (0.6%), and chordomas (0.5%) (1). While other rare lesions were also identified (collectively 6.0%), single unusual entities in the above-cited series numbered <1-2 examples each out of the 4122 cases, underscoring their rarity. We searched our joint files for rare, often singular, sellar/suprasellar masses that we had encountered over the past several decades in our own specialty, tertiary care specialty pituitary center practices. Cases for this review were subjectively selected for their challenging clinical and/or histological features as well as teaching value based on the senior authors' (MBSL, BKD) collective experience with over 7000 examples. We excluded entities deemed to be already well-appreciated by neuropathologists such as mixed adenoma-gangliocytoma, posterior pituitary tumors, metastases, and hypophysitis. We identified examples that, in our judgment, were sufficiently unusual enough to warrant further reporting. Herein, we present 3 diffuse large cell B cell pituitary lymphomas confined to the sellar region with first presentation at that site, 2 sarcomas primary to sella in nonirradiated patients, and 1 case each of granulomatosis with polyangiitis and neurosarcoidosis with first presentations as a sellar/suprasellar mass. Other cases included 1 of chronic lymphocytic leukemia within a gonadotroph adenoma and 1 of ectopic nerve fascicles embedded within a somatotroph adenoma, neither of which impacted patient care. Our objective was to share these examples and review the relevant literature.

Strategies to reduce readmissions for hyponatremia after transsphenoidal surgery for pituitary adenomas.

PURPOSE: Disorders of water balance, particularly hyponatremia from altered antidiuretic hormone (ADH) secretion, are a common post-operative complication of transsphenoidal surgery (TSS). We present our results from implementation of a 2-week 1.5 liter/daily fluid restriction on readmission rates for hyponatremia. METHODS: A retrospective chart review was performed on 295 patients that underwent TSS for pituitary adenomas at the University of Colorado, between March 2014 and March 2017. Groups were divided into those before and after the implementation of a two-week, 1.5 liter daily fluid restriction and measurement of a serum sodium level 7 days (+/- 2 days) after discharge. A standard-of-care approach for variable degrees of hyponatremia was also utilized to guide hyponatremia management. Patient demographics, hospital course, post-operative complication rates, and rates of hospital admissions for hyponatremia were then evaluated. RESULTS: Readmissions for symptomatic hyponatremia within 30 days of TSS occurred in 9 of 118 (7.6%) of patients prior to fluid restriction implementation and in four of 169 (2.4%) of patients in the post-implementation, fluid-restricted group (p-value = 0.04): a 70% reduction in hospitalizations. The two groups were similarly matched for pituitary tumor sub-type, age and gender. None of these factors were predictive for hyponatremia. Importantly, the mild fluid restriction did not result in any hospital readmissions for hypernatremia. CONCLUSIONS: Mild fluid restriction (to 1.5 liters daily), in addition to a single post-operative serum sodium level, is an effective approach to preventing readmission for hyponatremia after TSS for pituitary adenomas.

Negative surgical exploration in patients with Cushing's disease: benefit of two-thirds gland resection on remission rate and a review of the literature.

OBJECTIVEThe authors report their single-institution experience with the pathological findings, rates of remission, and complications in patients with presumed Cushing's disease (CD) who underwent a two-thirds pituitary gland resection when no adenoma was identified at the time of transsphenoidal surgery (TSS). The authors also review the literature on patients with CD, negative surgical exploration, and histological findings.METHODSThis study is a retrospective analysis of cases found in neurosurgery and pathology department databases between 1989 and 2011. In all cases, patients had been operated on by the same neurosurgeon (K.O.L.). Twenty-two (13.6%) of 161 patients who underwent TSS for CD had no adenoma identified intraoperatively after systematic exploration of the entire gland; these patients all underwent a two-thirds pituitary gland resection. A chart review was performed to assess treatment data points as well as clinical and biochemical remission status.RESULTSOf the 22 patients who underwent two-thirds gland resection, 6 (27.3%) ultimately had lesions found on final pathology. All 6 patients were found to have a distinct adrenocorticotropic hormone (ACTH) cell adenoma. Sixteen (72.7%) of the patients had no tumor identified, with 3 of these patients suspected of having ACTH cell hyperplasia. The follow-up duration for the entire group was between 14 and 315 months (mean 98.9 months, median 77 months). Remission rates were 100% (6/6 patients) for the ACTH cell adenoma group and 75% (12/16) for the group without adenoma. Overall, 18 (81.8%) of the 22 patients had no evidence of hypercortisolism at last follow-up, and 4 patients (18%) had persistent hypercortisolism, defined as a postoperative cortisol level > 5 µg/dl. Of these 4 patients, 1 was suspected of harboring a cavernous sinus adenoma, 2 were found to have lung tumors secreting ACTH, and 1 remained with an undiagnosed etiology. Rates of postoperative complications were low.CONCLUSIONSThe diagnosis and treatment of CD can be challenging for neurosurgeons, endocrinologists, and pathologists alike. Failure to find a discrete adenoma at the time of surgery occurs in at least 10%-15% of cases, even in experienced centers. The current literature provides little guidance regarding rational intraoperative approaches in such cases. The authors' experience with 161 patients with CD, when no intraoperative tumor was localized, demonstrates the utility of a two-thirds pituitary gland resection with a novel and effective surgical strategy, as suggested by a high initial remission rate and a low operative morbidity.

Differential somatostatin receptor (SSTR) 1-5 expression and downstream effectors in histologic subtypes of growth hormone pituitary tumors.

PURPOSE: The aim of this study was to examine whether differential expression of somatostatin receptors (SSTR) 1-5 and downstream effectors are different in densely (DG) and sparsely (SG) granulated histological growth hormone (GH) pituitary tumor subtypes. METHODS: The study included 33 acromegalic patients with 23 DG and 10 SG tumors. SSTR1-5 were measured by qPCR and immunoblotting. Signaling candidates downstream of SSTR2 were also assessed. RESULTS: SSTR2 mRNA and protein levels were significantly higher in DG compared to SG tumors. Downstream of SSTR2, p27(kip1) was decreased (2.6-fold) in SG compared to DG tumors, suggesting a potential mechanism of SSA resistance in SG tumors with intact SSTR2 expression. Re-expression of E-cadherin in GH pituitary cell increased p27(kip1) levels. CONCLUSIONS: Histological subtyping correlated with SSTR2, E cadherin and p27(kip) protein levels and these may serve as useful biomarkers in GH tumors to predict behavior and response to therapy with SSA.

Growth hormone tumor histological subtypes predict response to surgical and medical therapy.

Growth hormone (GH) pituitary tumors are associated with significant morbidity and mortality. Current treatments, including surgery and medical therapy with somatostatin analogs (SSA), dopamine agonists and/or a GH receptor antagonist, result in disease remission in approximately half of patients. Predictors of GH tumor response to different therapies have been incompletely defined based on histologic subtype, particularly densely (DG) versus sparsely (SG) granulated adenomas. The aim of this study was to examine our own institutional experience with GH adenomas and correlate how subtype related to clinical parameters as well as response to surgery and medical therapies. A retrospective chart review of 101 acromegalic patients operated by a single neurosurgeon was performed. Clinical data were correlated with histologic subtype and disease control, as defined by IGF-1 levels, and random growth hormone levels in response to surgery and/or medical therapies. SG tumors, compared to DG, occurred in younger patients (p = 0.0010), were 3-fold larger (p = 0.0030) but showed no differences in tumor-invasion characteristics (p = 0.12). DG tumors had a higher rate of remission in response to surgery compared to SG, 65.7 vs. 14.3 % (p < 0.0001), as well as to medical therapy with SSAs (68.8 % for DG vs. 28.6 % for SG tumors; p = 0.028). SG tumors not controlled with SSAs consistently responded to a switch to, or addition of, a GH receptor antagonist. Histological GH tumor subtyping implicates a different clinical phenotype and biologic behavior, and provides prognostic significance for surgical success and response to medical therapies.

Cushing's disease due to mixed pituitary adenoma-gangliocytoma of the posterior pituitary gland presenting with Aspergillus sp. sinus infection.

Gangliocytic lesions of the pituitary gland producing Cushing's disease are extremely rare entities that may exist with or without a pituitary adenoma. The latter have been designated mixed pituitary adenoma-gangliocytomas, the majority of which produce growth hormone, not adrenocorticotropin (ACTH), and are localized to the anterior gland. We now report an immunocompetent woman with hypercortisolism who presented with an intranasal aspergilloma eroding the bony sellar floor. The fungal ball was contiguous with, and extended into, a large neurohypophyseal-centered mass. Transsphenoidal resection revealed a gangliocytic lesion of the posterior gland with small clusters of intimately admixed ACTH-immunoreactive adenoma cells as the cause of her Cushing's disease. Rare transitional sizes and shapes of cells coupled with immunohistochemical findings supported interpretation as advanced neuronal metaplasia within an ACTH adenoma. This mixed ACTH adenoma-gangliocytoma is the first example to present clinically with an opportunistic infection.

Clinical implications of growth hormone-secreting tumor subtypes.

Growth hormone (GH) pituitary tumors are almost always benign adenomas, yet are associated with significant morbidity and mortality. Surgical and medical responses of GH tumors are often incomplete, and therefore predictors of residual or recurrent disease are needed. Clinical features, including patient gender, age or size of adenoma, have proven to be unreliable predictors of recurrence. Differing clinical behavior between the two GH tumor subtypes, sparsely granulated (SG) versus densely granulated (DG), has been reported, but has not been used routinely in clinical management. SG tumors are more common in younger patients (<50 years), and are usually larger tumors. SG tumors have been reported to be less responsive to somatostatin analogs (SSA) than DG tumors. The mechanisms underlying these potential differences in tumor behavior, however, are poorly defined. Subsets (up to 50 %) of DG adenomas harbor a gsp mutation that can activate cAMP that provides a theoretical intracellular target for somatostatin therapy. In contrast, some SG tumors have reduced somatostatin receptor expression and mutations in the extracellular domain of the GH receptor that may contribute to SSA resistance. While DG versus SG growth hormone adenomas are readily distinguished by immunohistochemistry, other less common GH adenoma variants still require electron microscopy (EM) for confident subclassification. Whether these less common variants possess unique clinical features is unknown. Research is needed to identify clinically relevant biomarkers of GH pituitary tumors that predict risk of recurrence and response to medical therapy.

McCune-Albright syndrome: surgical and therapeutic challenges in GH-secreting pituitary adenomas.

McCune-Albright syndrome (MAS) is a postzygotic (non-germline) disorder characterized by polyostotic fibrous dysplasia, cafe-au-lait macules and hypersecretory endocrinopathies. A significant percentage of MAS patients have pituitary adenomas that are either growth hormone (GH) or mixed GH/prolactin (PRL)-producing. Surgical excision may be challenging-or even impossible-due to the associated severe fibrous dysplasia of the skull base. Treatment relies on an interdisciplinary, multi-modal approach from endocrinologists, neurosurgeons and radiation oncologists. We present two cases of women with MAS and GH-secreting pituitary adenomas, encountered in our 30-year experience with pituitary diseases. The first patient successfully underwent transsphenoidal surgical resection for a pituitary microadenoma in 1997 (at age 18) and again in 2009 for recurrent disease, with a significant reduction in IGF-1 level. Immunohistochemistry (IHC) and electron microscopy (EM), performed on both specimens, showed a mammosomatotroph adenoma with GH, PRL, alpha subunit (+) IHC, with increased fibrous bodies developing over the 13-year interval. Focal hyperplasia could be discerned. EM in 1997 showed an admixture of mammosomatotrophs, mature lactotrophs and somatotrophs, with a bimodal population identified in 2009. The second MAS patient had long-standing polyostotic fibrous dysplasia, but was only recently diagnosed with GH excess and a pituitary adenoma, at the age of 29 years. Surgical resection was not advised in this patient because of the massive obstructive skull-base fibrous dysplasia. Medical therapy was initiated with somatostatin analogues, although responses in both patients have been suboptimal to date. We review the literature on GH excess in MAS to highlight its surgical and medical challenges.

Transsphenoidal resection of 82 Rathke cleft cysts: limited value of alcohol cauterization in reducing recurrence rates.

OBJECT: The aim of this study was to report the results of a large clinical series of patients with symptomatic Rathke cleft cysts (RCCs) who underwent resection by a single neurosurgeon using intraoperative alcohol cauterization, and to review any possible differences in recurrence rates in those treated with this chemically ablative technique. METHODS: The authors performed a retrospective database review of 82 patients (age range 10-74 years) with symptomatic RCCs who underwent surgery between 1993 and 2009. RESULTS: Preoperative symptoms of headaches, vision disturbances, and hormone dysfunction were observed in 68%, 35%, and 56% of patients, respectively. All 82 patients underwent treatment by a single surgeon. Surgery consisting of simple cyst drainage followed by cyst wall biopsy without vigorous cyst wall removal was performed. A subset of these patients (62) received intraoperative alcohol instillation. Perioperative complication rates were low: CSF leakage, symptomatic hyponatremia, and permanent diabetes insipidus (DI) in 2%, 5%, and 0% of patients, respectively. Headaches and vision problems improved or resolved in 71% and 83% of patients, respectively. In addition, hyperprolactinemia, hypothyroidism, panhypopituitarism, DI, and adrenal insufficiency improved or resolved in 94%, 90%, 50%, 33%, and 67% of patients, respectively. Recurrence, as defined by enlargement of the cyst as compared with its appearance on baseline 3-month postoperative MR imaging, was noted in 10.7% of the primary surgery group. There was a trend toward increased recurrence rates in the alcohol-treated (12.9%) versus no-alcohol treatment groups (0%), although not statistically significant (p = 0.20). CONCLUSIONS: This large, single-surgeon/single-institution series of patients with symptomatic RCCs confirms that significant postoperative improvement in headaches, vision, and pituitary hormone dysfunction can be achieved via a conservative surgical approach, with low complication and recurrence rates. The data also demonstrate a limited role for alcohol cauterization in the treatment of symptomatic RCCs.

The proliferative status of thyrotropes is dependent on modulation of specific cell cycle regulators by thyroid hormone.

In this report we have examined changes in cell growth parameters, cell cycle effectors, and signaling pathways that accompany thyrotrope growth arrest by thyroid hormone (TH) and growth resumption after its withdrawal. Flow cytometry and immunohistochemistry of proliferation markers demonstrated that TH treatment of thyrotrope tumors resulted in a reduction in the fraction of cells in S-phase that is restored upon TH withdrawal. This is accompanied by dephosphorylation and rephosphorylation of retinoblastoma (Rb) protein. The expression levels of cyclin-dependent kinase 2 and cyclin A, as well as cyclin-dependent kinase 1 and cyclin B, were decreased by TH, and after withdrawal not only did these regulators of Rb phosphorylation and mitosis increase in their expression but so too did the D1 and D3 cyclins. We also noted a rapid induction and subsequent disappearance of the type 5 receptor for the growth inhibitor somatostatin with TH treatment and withdrawal, respectively. Because somatostatin can arrest growth by activating MAPK pathways, we examined these pathways in TtT-97 tumors and found that the ERK pathway and several of its upstream and downstream effectors, including cAMP response element binding protein, were activated with TH treatment and deactivated after its withdrawal. This led to the hypothesis that TH, acting through increased type 5 somatostatin receptor, could activate the ERK pathway leading to cAMP response element binding protein-dependent decreased expression of critical cell cycle proteins, specifically cyclin A, resulting in hypophosphorylation of Rb and its subsequent arrest of S-phase progression. These processes are reversed when TH is withdrawn, resulting in an increase in the fraction of S-phase cells.

Growth arrest of thyrotropic tumors by thyroid hormone is correlated with novel changes in Wnt-10A.

The molecular mechanism underlying thyroid hormone inhibition of thyrotrope cell growth is poorly understood. A comprehensive screen for T3-regulated genes involved in thyrotrope cell regulation was performed by Affymetrix MGU74A Genechip microarray analyses, which compared total RNA from hypothyroid versus 24 h T3-treated TtT-97 tumors. Of the 13,000 genes screened, a number of novel, T3-responsive candidate genes were identified. Within the Wnt family of growth factors, only Wnt-10A transcripts were abundantly expressed in hypothyroid TtT-97 tumors, and were down-regulated with T3 by 6 h of treatment. In addition, nuclear beta-catenin, which is a downstream mediator of canonical Wnt signaling, was decreased at the protein and functional levels. TtT-97 growth suppression was associated with decreased cyclin A transcript levels. We conclude that treatment of thyrotropic TtT-97 tumors with T3 resulted in the decreased expression of Wnt-10A, and that thyroid hormone may inhibit growth via cyclin A regulation.