Ectopic sphenoidal ACTH-secreting adenoma revealed by 11C Methionine PET scan: case report.

BACKGROUND: Ectopic ACTH pituitary adenomas (EAPA), located outside the sella turcica and deriving from cellular remnants of Rathke's pouch are a very rare cause of Cushing's syndrome (CS). The diagnosis is often difficult and delayed, even after comprehensive work-up. To our knowledge, we report for the first time an ectopic corticotroph tumor of the posterior wall of the sphenoid sinus, leading to false positive results of bilateral inferior petrosal sinus sampling (BIPPS) and which was finally localized by a co-registered11 C Methionine PET/MR imaging. CASE PRESENTATION: A 48-year-old woman was referred for a high clinical suspicion of ACTH-dependent CS. Biological testing comprising low dose dexamethasone suppression and CRH stimulation tests were indicative of pituitary Cushing's disease, but comprehensive pituitary MRI did not reveal any pituitary adenoma. BIPSS confirmed however a central origin of ACTH secretion (central-to-peripheral ACTH ratio > 100) and revealed a significant right-to-left gradient (6.2), leading to a first right-sided exploratory hypophysectomy, that did not cure the patient. BIPSS images were reviewed and revealed preferential drainage of the left pituitary to the right petrosal sinus, leading us to a left sided exploratory hypophysectomy, which was again unsuccessful. A11 C Methionine PET/MRI was performed and revealed a hypermetabolic lesion adjacent to the posterior wall of the sphenoidal sinus. After surgical resection, this polypoid mass was identified as an ectopic ATCH-secreting pituitary adenoma expressing ACTH and T-Pit and complete remission of hypercortisolism was observed. CONCLUSIONS: In conclusion, we report a case of ACTH-dependent Cushing's syndrome, caused by an ectopic corticotroph adenoma located in the sphenoidal sinus, which perfectly mimicked the biological features of a classical pituitary ACTH adenoma on a comprehensive hormonal evaluation including BIPPS, and the features of a benign naso-sinusal polyp at MRI. We report for the first time a key role of11 C Methionine PET co-registered to high resolution MRI for localizing ectopic adenomas, efficiently guiding surgical removal and leading to complete remission of hypercortisolism.

Clinical Course and Unique Features of Silent Corticotroph Adenomas.

OBJECTIVE: Silent corticotroph adenomas (SCAs) behave more aggressively than other non-functioning adenomas (NFAs). This study aims to expand the body of knowledge of the behavior of SCAs. METHODS: Retrospective analysis of 196 non-corticotroph NFAs and 20 SCAs from 2012-2017 was completed. Demographics, clinical presentation, imaging, and biochemical data were gathered. The primary endpoint was to identify features of SCAs versus other NFAs that suggest aggressive disease, including pre-surgical comorbidities, postoperative complications, extent of tumor, and recurrence. Golden-angle radial sparse parallel (GRASP) magnetic resonance images were obtained from a subset of SCAs and NFAs. Permeability data were obtained to compare signal-to-time curve variation between the 2 groups. RESULTS: With multivariate regression analysis, SCAs showed higher rates of hemorrhage on preoperative imaging than NFAs (P = 0.017). SCAs presented more frequently with headache (P = 0.012), vision changes (P = 0.041), and fatigue (P = 0.028). SCAs exhibited greater extent of tumor burden with increased occurrence of stalk deviation (P = 0.008), suprasellar invasion (P = 0.021), optic chiasm compression (P = 0.022), and cavernous sinus invasion (P = 0.015). On GRASP imaging, SCAs had significantly lower permeability of contrast than NFAs (P = 0.001). Thirty percent of SCAs were noted to recur with a 14% recurrence rate in other NFAs, though this difference was not of statistical significance (P = 0.220). CONCLUSIONS: SCAs exhibit features of more aggressive disease. Interestingly, a significant increase in recurrence was not seen despite these features. The results of this study support the growing body of evidence that SCAs behave more aggressively than other NFPAs and was able to provide some insight into factors that may contribute to recurrence.

Development of 68Ga DOTA-CRH for PET/CT Imaging of ACTH-Dependent Cushing's Disease: Initial Study.

Purpose: Adrenocorticotropic hormone (ACTH)-dependent Cushing's disease accounts for 75% cases of the endogenous Cushing's syndrome. The size of lesion is usually very small, which results in false-negative magnetic resonance imaging (MRI) even after biochemical confirmation of the disease. Corticotrophin-releasing hormone (CRH) the key controller of hypothalamus-pituitary--adrenal axis binds to CRH receptor R1 and R2. CRH R1 is overexpressed in pituitary adenomas. The present study aims to target these overexpressed receptors with 68Ga-DOTA-CRH for noninvasive imaging of ACTH-dependent pituitary adenomas. Materials and Methods: Custom-synthesized 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-CRH peptide was purified by high performance liquid chromatography (HPLC) and characterized by mass spectra. Postradiolabeling optimization with 68Ga, quality control tests were carried out to ensure the suitability of 68Ga DOTA-CRH for intravenous administration. A pilot study consisting of 15 patients including 6 known cases of macroadenoma underwent 68Ga-DOTA-CRH regional brain positron emission tomography/computed tomography (PET/CT). The optimal imaging time and biodistribution studies were performed in five patients' whole-body and serial brain PET/CT imaging. Lesion activity was determined as SUVmax and correlated with CE-MRI and histopathology of excised tissue. Results: A retention time of 11.3 min and mass of 5145 Da was observed on HPLC and mass spectra. Radiolabeling yield of >98% was achieved under optimized conditions using 25-100 µg of conjugated peptide for 10-22 mCi of 68Ga. The quality control results were in agreement with acceptable criteria. 68Ga-DOTA-CRH was able to delineate ACTH secreting corticotropinoma in all 15 patients. Physiological uptake of radiotracer was observed in liver and spleen with diffused marrow activity. Excretion was noted by renal route. Imaging results were in correlation with CE-MRI and histopathology of excised tissue. Conclusion: 68Ga-DOTA-CRH PET/CT is a promising molecular imaging modality for detection of ACTH-dependent microadenoma.

A clinicoradiological analysis of silent corticotroph adenomas after the introduction of pituitary-specific transcription factors.

BACKGROUND: Silent corticotroph adenomas (SCAs) are a rare subtype of non-functional pituitary adenoma. While it has been suggested that they are more aggressive and recur more frequently following excision, there is limited literature on the optimum treatment strategy for these tumors, especially regarding the role of radiation therapy in incompletely resected tumors. METHOD: We assimilated data from 62 SCAs and 238 other non-functional adenomas (ONAs), defined according to the WHO 2017 criteria that incorporates transcription factor analysis. We compared their clinicoradiological characteristics, such as hormonal levels, tumor configuration, size, and invasiveness. For 52 SCAs and 205 ONAs with serial follow-up imaging, we studied outcomes for progression after subtotal resection with or without radiation therapy or recurrence after gross total resection. Kaplan Meier analysis for recurrence or progression was used to determine the need for a differential treatment strategy for SCAs compared with other non-functional adenomas specifically concerning the role of radiotherapy. RESULTS: Patients with SCAs present at a younger age than ONAs (43.9 years vs. 48.2 years, p = 0.014), with larger (14.9 cc vs. 9.7 cc, p = 0.006) and more invasive adenomas (61.2% vs. 45.8%, p = 0.021). Overall, SCAs are more likely to recur or progress (48.7 vs. 15.7%, p < 0.001) following excision than ONAs, with significantly poorer event-free survival (Log rank test p < 0.001). Early adjuvant radiotherapy provides favorable outcomes among SCAs with postoperative residual tumor, on par with ONAs. Multivariate analysis identified male gender (HR: 2.217; p = 0.017), MIB index ≥ 3% (HR: 2.116; p = 0.012), and SCA tumor pathology (HR: 3.787; p < 0.001) as factors predicting recurrence. CONCLUSIONS: Based on the results of this retrospective, single-center review of 300 non-functional adenomas, we conclude that silent corticotroph adenomas are an aggressive subtype of non-functional pituitary adenomas that are larger, more likely to be invasive, and tend to recur more frequently after a subtotal excision compared with other non-functional adenomas. A gross total resection must be attempted whenever possible and earlier adjuvant radiation is recommended when re-surgery for residual tumor is difficult.

Clinical, Biological, Radiological Pathological and Immediate Post-Operative Remission of Sparsely and Densely Granulated Corticotroph Pituitary Tumors: A Retrospective Study of a Cohort of 277 Patients With Cushing's Disease.

Purpose: Cushing's disease is the most common cause of endogenous hypercortisolemia due to a corticotroph pituitary tumor. Up-to-date there is no reliable biomarker of invasiveness among corticotroph tumors, while it is well established in the literature that sparsely granulated somatotroph tumors are characterized by poorer prognosis. The aim of the study was to correlate multiple data including clinical, biochemical, radiological, and pathological findings (including granulation pattern) as well as immediate post-operative remission status among patients operated on due to corticotroph tumors. Methods: We enrolled all patients consecutively operated on for planned transsphenoidal neurosurgery due to corticotroph PitNETs in years 2010-2018. We excluded from analysis silent corticotroph tumors, plurihormonal PitNETs, and the Crooke's cell adenomas. Results: We recorded 348 hormonally active corticotroph PitNETs. The results of the analysis showed the female predominance 79.88% (n = 278), with the mean age of Cushing's disease occurrence 43.27 years of age. The mean time from the first signs and symptoms to the operation was 2 years. The women were diagnosed earlier (20-40 years of age vs. 50-60 years of age among men). We performed a detailed analysis of 277 cases classified by granularity pattern as DG or SG corticotroph PitNETs. Densely granulated tumors (DG) occurred four times more frequently than sparsely granulated (SG) (n = 225 vs. n = 52), at similar age (mean 42.94; median 40 vs. mean 45.46; median 45.5; p = 0.3896), but were characterized by lower Knosp's scale grades (p = 0.0147*), smaller preoperative tumors' volumes measured at MRI, and more commonly exhibited lower Ki-67 labeling index (<3%) (p = 0.0168*). What is more, DG adenomas more frequently achieved an immediate remission status (measured as postoperative cortisol concentration <2 µg/dl; p = 0.0180*), and the mean postoperative cortisol concentration in DG group was lower than in SG group (mean 5.375 µg/dl vs. 10.47 µg/dl; median 2.49 µg/dl vs. 6.52 µg/dl; p = 0.0028**). Conclusions: Our study indicates that DG corticotroph adenomas occurred at younger age, more commonly were microadenomas as compared to SG tumors, less frequently had invasive features in comparison to SG corticotroph adenomas (p = 0.0019**), and more commonly achieved an immediate postsurgical hormonal remission (p = 0.0180*). We highlight the need for an accurate differentiation of DG and SG subtypes in the pathomorphological diagnosis of corticotropic tumors, especially in invasive PitNETs.

A challenging case of Cushing's disease complicated with multiple thrombotic phenomena following trans-sphenoidal surgery; a case report.

BACKGROUND: Cushing's syndrome occurs due to overproduction of cortisol from adrenal glands. Endogenous hypercortisolemia can occur secondary to adrenocorticotropic hormone (ACTH) dependent as well as independent causes. The presence of non-specific symptoms and signs contributes to a delay in diagnosis. Early identification and prompt definitive management is crucial. It is important to be alert about the post-operative complications including multiple thrombotic phenomena, which can add to the mortality. We report a case of Cushing's disease in a young female managed with trans-sphenoidal surgery, followed by a challenging post-operative period complicated with multiple thrombotic phenomena, ultimately succumbed. CASE PRESENTATION: A 32-year-old Sri Lankan female presented with overt features of Cushing's syndrome and diagnosed to have ACTH dependent Cushing's disease with pituitary microadenoma. She underwent trans-sphenoidal surgery, following which she developed fatal multiple complications including diverticular rupture and ischemic colitis, needing hemicolectomy, followed by a parieto-occipital infarction. CONCLUSION: This case highlights important and aggressive complications associated with Cushing's syndrome giving rise to a challenging post-operative course. Diverticular rupture had been described in association with hypercortisolemia and this case adds to the existing literature. Post-operative ischemic colitis and stroke which contributed to the death of this patient could have been due to the procoagulant state associated with Cushing's syndrome, with a high risk during the immediate post-operative period. This emphasizes the need to consider post-operative thromboprophylaxis in patients undergoing surgery for Cushing's syndrome.

Glucocorticoid Receptor Antagonism Upregulates Somatostatin Receptor Subtype 2 Expression in ACTH-Producing Neuroendocrine Tumors: New Insight Based on the Selective Glucocorticoid Receptor Modulator Relacorilant.

Somatostatin exhibits an inhibitory effect on pituitary hormone secretion, including inhibition of growth hormone and adrenocorticotropic hormone (ACTH), and it can have antisecretory and antitumor effects on neuroendocrine tumors (NETs) that express somatostatin receptors. Although the precise mechanism remains unclear, the finding that glucocorticoids downregulate somatostatin receptor subtype 2 (SSTR2) expression has been used to explain the lack of efficacy of traditional SSTR2-targeting analogs in patients with ACTH-secreting NETs. Glucocorticoid receptor (GR) antagonism with mifepristone has been shown to reverse the glucocorticoid-induced downregulation of SSTR2; however, the effects of GR modulation on SSTR2 expression in ACTH-secreting NETs, particularly corticotroph pituitary tumors, are not well known. The current study presents new insight from in vitro data using the highly selective GR modulator relacorilant, showing that GR modulation can overcome dexamethasone-induced suppression of SSTR2 in the murine At-T20 cell line. Additional data presented from clinical case observations in patients with ACTH-secreting NETs suggest that upregulation of SSTR2 via GR modulation may re-sensitize tumors to endogenous somatostatin and/or somatostatin analogs. Clinical, laboratory, and imaging findings from 4 patients [2 ACTH-secreting bronchial tumors and 2 ACTH-secreting pituitary tumors (Cushing disease)] who were treated with relacorilant as part of two clinical studies (NCT02804750 and NCT02762981) are described. In the patients with ectopic ACTH secretion, SSTR2-based imaging (Octreoscan and 68Ga-DOTATATE positron emission tomography) performed before and after treatment with relacorilant showed increased radiotracer uptake by the tumor following treatment with relacorilant without change in tumor size at computed tomography. In the patients with Cushing disease who received relacorilant prior to scheduled pituitary surgery, magnetic resonance imaging after a 3-month course of relacorilant showed a reduction in tumor size. Based on these findings, we propose that GR modulation in patients with ACTH-secreting NETs upregulates previously suppressed SSTR2s, resulting in tumor-specific antisecretory and anti-proliferative effects. The effect of relacorilant on pituitary corticotroph tumors is being investigated in an ongoing phase 3 study (NCT03697109; EudraCT 2018-003096-35).

Clinical, Laboratory, and Treatment Profiles of Silent Corticotroph Adenomas That Have Transformed to the Functional Type: A Case Series With a Literature Review.

Purpose: Silent corticotroph adenoma (SCA) is clinically non-functional pituitary adenoma with expression of corticotropin or Tpit. To further understand the characteristics of this rare type of SCA transforming to a functional SCA, we retrospectively reviewed SCAs that converted to typical Cushing's syndrome at a tertiary medical center and the relevant literature. Methods: Patients were identified based on the diagnosis of pituitary adenoma without symptoms of hypercortisolism at the initial visit with positive Immunohistochemical (IHC) staining for corticotropin or Tpit after surgery and subsequent transformation to functional SCAs during the follow-up period from March 1990 to January 2020 at Peking Union Medical College Hospital and in the literature. The characteristics of the clinical manifestations, biochemical results, imaging findings, pathology findings and outcome were analyzed. Results: Altogether, 16 patients were included in the study with an average age of 42.0 ± 12.48 (18-65) years at the first visit. Females were slightly predominant (F:M = 1.3:1). The median time of conversion from the nonfunctional to the functional type was 30 (13.0, 68.3) months. Once a functional SCA developed, the adrenocorticotropic hormone (ACTH) level and 24-h urine free cortisol were increased 3.8- (2.6, 12.9) and 5.3- (2.6, 19.3) fold, respectively, above the normal range. Approximately 50% of the patients had macrocystic changes on pituitary MRI. All 16 patients experienced 1-5 surgeries with a median of 2.5 (2.0, 4.0) surgeries. The proportion of patients with Ki-67 ≥ 3% increased from 22.2% (2/9) at the beginning to 50% (7/14) at the time of functional SCA diagnosis. Thirteen patients received radiotherapy, and 4 patients (30.8%) achieved remission. Four patients with refractory functional SCAs received temozolomide treatment with the normalization of cortisol in 4 cases and reduced tumor volume in 3 cases. Conclusion: In this study, all cases that transformed to functional SCAs were macroadenomas. Hypercortisolism was more severe in functional SCA patients. The tumors tended to have frequent recurrence and were highly invasive. Temozolomide could be a promising treatment for refractory functional SCA cases. Long-term follow-up is needed for nonfunctional SCAs since some cases have the potential to transform to clinical Cushing's syndrome.

[Obesity isn't always obesity: Cushing's disease - case report]. / Offita er ekki alltaf offita: Cushing-sjúkdómur, sjúkratilfelli

Woman in her thirties presented to the emergency room with a two-week history of worsening headache and diplopia. For eight years she had suffered from progressive weight gain, diabetes and hypertension that didn't improve with lifestyle modification. A lumbar puncture demonstrated increased intracranial pressure and MRI a pituitary adenoma. Physical examination was consistent with Cushing's syndrome and endocrine workup confirmed Cushing's disease. Treatment was complex, including unsuccessful pituitary surgery and gamma knife radiosurgery, and eventually bilateral adrenalectomy with subsequent development of Nelsons syndrome. This case illustrates the diagnostic delay that many patients with CD suffer from.

Cushing Syndrome Caused by Ectopic Adrenocorticotropic Hormone-Secreting Pituitary Adenomas: Case Report and Literature Review.

BACKGROUND: Ectopic adrenocorticotropic hormone-secreting pituitary adenomas (EAPAs) are rare adenomas causing Cushing syndrome, which are located in ectopic locations outside the sella turcica. No more than 100 cases of this entity have been reported. Because of its rarity and nonspecific clinical and biochemical features, EAPA is often misdiagnosed, leading to surgical failure and delayed treatment. In the article, the cases of 3 patients with suprasellar EAPAs treated at our institution are reported and a review of the literature is presented. CASE DESCRIPTION: All 3 patients with Cushing syndrome had ectopic pituitary adenomas located in the suprasellar region and identifiable on preoperative sellar magnetic resonance imaging. Preoperative laboratory evaluation in all patients showed identical results to those observed in Cushing disease. In 2 patients, craniotomies were performed directly to achieve total tumor resection and clinical remission. One patient, who underwent previous negative transsphenoidal exploration, achieved full remission through a second craniotomy despite pulmonary infection as a postoperative complication. CONCLUSIONS: Although EAPA is an extremely rare entity, it should be considered as a differential diagnosis of Cushing disease. Because of its similar clinical and biochemical behavior to intrasellar pituitary adrenocorticotropic hormone adenoma in Cushing disease, careful examination of the potential occurrence of EAPA on preoperative radiologic imaging is of considerable significance to avoid unnecessary surgery and achieve improved outcomes. Surgical resection EAPA remains the first choice of treatment, and the optimal surgical approach ought to be determined according to the adenoma features, the general condition of the patient, and the surgeon's experience.

Suprasellar pituitary adenomas: a 10-year experience in a single tertiary medical center and a literature review.

BACKGROUND: Suprasellar pituitary adenomas (SPAs) are a special type of pituitary adenoma. Although dozens of SPA cases have been reported, the exact definition and the characteristics of SPA have not been exhaustively discussed before. METHODS: In a retrospective electronic medical records review, 13 patients with SPA were identified in our hospital between January 2010 and December 2019. A literature review was performed by searching the online database PubMed, and 39 cases conformed to the criteria based on the previous literature. Data regarding clinical symptoms, imaging manifestations, surgical information and follow-ups were analyzed. RESULTS: The mean age at diagnosis of 52 patients with SPA was 36.73 years, and most of the patients were female (61.5%). The most common hormone-secreting subtypes of SPA were nonfunctioning (36.5%) and ACTH-secreting (34.6%) SPA. Macroadenomas (68.9%) were more common than microadenomas (31.1%). The origins of the SPAs included the intrasellar pituitary gland (type I), the subdiaphragmatic (type IIa) and supradiaphragmatic (type IIb) part of the pituitary stalk, and the suprasellar peri-infundibular region (type III). The most common anatomic subtype of SPA was type III, and type IIb was also common. The most common presentations of SPA were visual symptoms, especially for type III SPA. In addition, 64.7% and 73.1% of type IIb and III SPAs, respectively, were suspected to be of suprasellar origin based on presurgical imaging examination. Patients with tumors of suspected suprasellar origin were more likely to receive transcranial surgery (TCS) initially than those with tumors of suspected intrasellar origin (70.6% vs. 22.2%, p = 0.0013). The intact rate for the pituitary stalk after surgery for type II SPA was lower than that for type I and III SPA (52.6% vs. 92.6%, p = 0.0036). More patients with type II SPA experienced postoperative central diabetes insipidus (CDI) than those with type I and III SPA (57.9% vs. 11.1%, p = 0.0011). There was no significant difference in the incidence of postoperative CDI between transsphenoidal surgery (TSS) and TCS (p = 0.1304). Nine patients in our hospital received extended endoscopic TSS; only one experienced tumor recurrence, and no severe complications occurred after surgery. CONCLUSIONS: SPAs could be defined as pituitary adenomas completely or partially located in the suprasellar region. There were both similarities and differences among the different anatomic subtypes of SPA. For patients who were suspected of having SPAs, visual field tests, pituitary hormone evaluation and MRI were necessary. Because imaging examination is not a reliable method, surgery is the only way to confirm the tumor origin. Extended endoscopic TSS might be a safe and efficient approach to remove these tumors, but more studies are needed to verify this conclusion. For type II SPA, the pituitary stalk should be carefully protected during surgery, and postoperative CDI should be monitored.

Ultra-high field magnetic resonance imaging for localization of corticotropin-secreting pituitary adenomas.

Cushing's disease manifests as symptoms of glucocorticoid excess secondary to the increased secretion of corticotropin by a corticotroph adenoma in the pituitary gland. Unfortunately, magnetic resonance imaging (MRI) performed at conventional clinical field strengths of 1.5 or 3 Tesla has limited sensitivity for the detection of these pituitary tumors, and radiologic uncertainty often necessitates more invasive workup to confirm diagnosis and guide resection. It has been postulated that higher static magnetic field strengths may increase the adenoma detection rate and thus the utility of MRI for this clinical application. In this report, we describe our initial experience using ultra-high field 7 Tesla (7 T) MRI in patients with suspected Cushing's disease and negative or equivocal imaging at conventional field strengths. We performed contrast-enhanced 7 T pituitary MRI in 10 patients with up to three different T1-weighted sequences and correlated the imaging abnormalities identified with results of histologic evaluation in patients who subsequently underwent resection. We found that 7 T MRI enabled the identification of previously undetected areas of focal pituitary hypoenhancement in 9 patients (90%), of which 7 corresponded histologically to corticotroph adenomas. These early findings suggest an important adjunctive role for ultra-high field MR imaging in the noninvasive clinical workup of suspected Cushing's disease.

Aggressive Pituitary Tumor with Crooke's Cells and Invasion of the Posterior Fossa.

BACKGROUND: Pituitary adenomas are mostly benign in character and are managed via a transsphenoidal approach in most cases. Crooke's cell adenoma (CCA) is a particular variant accounting for less than 1% of the pituitary adenomas. They have a distinctive histopathologic pattern and behavior. CASE DESCRIPTION: We present a case of a 56-year-old man with recurrent pituitary adenoma and complicated neurosurgical history. Imaging follow-up showed a suprasellar mass with progressive growth into the posterior fossa. Surgical management via retrosigmoid craniectomy was performed, and histopathology elucidated Crooke's cells. CONCLUSIONS: CCA is recognized by its local aggressiveness and high recurrence rates. They tend to be locally invasive; however, posterior fossa invasion has not been reported to date. We aim to contribute to the arsenal of differential diagnosis of similar pituitary tumor cases.

Double Pituitary Adenomas with Synchronous Somatotroph and Corticotroph Clinical Presentation of Acromegaly and Cushing's Disease.

BACKGROUND: Double pituitary adenomas are a rare occurrence. Synchronous clinical manifestation is extremely rare. CASE DESCRIPTION: We report a case of a 51-year-old female with symptoms of both hypercortisolism and acromegaly during the past 2 years. Endocrine evaluation confirmed active acromegaly and revealed adrenocorticotropin hormone-dependent hypercortisolemia. Preoperative magnetic resonance imaging of the pituitary demonstrated separated double microadenomas with different intensity. Immunohistochemical analysis of each separate adenoma confirmed an exact diagnosis. The diagnosis of acromegaly and adrenocorticotropin hormone-dependent Cushing's disease was confirmed. CONCLUSIONS: This is the third reported case in the literature of synchronous clinical manifestation of acromegaly and Cushing's disease. Extensive surgical exploration of the sella must be performed to avoid surgical failures from residual tumor. Immunohistochemical analysis is required to confirm an exact diagnosis for each of the double pituitary adenomas.

Pediatric pituitary adenomas.

BACKGROUND: Pediatric pituitary adenomas are a rare medical entity that makes up a small portion of intracranial tumors in children and adolescents. Although benign, the majority of these lesions are secreting functional tumors with the potential for physiological sequela that can profoundly affect a child's development. FOCUS OF REVIEW: In this review, we discuss the medical and surgical management of these tumors with a focus on clinical presentation, diagnostic identification, surgical approach, and associated adjuvant therapies. We will also discuss our current treatment paradigm using endoscopic, open, and combined approaches to treat these tumors. The management of pituitary tumors requires a multidisciplinary team of surgeons, endocrinologists, and neuroanesthesiologists as well as neurocritical care specialists to deliver comprehensive care.

Improvement in cognitive impairment following the successful treatment of endogenous Cushing's syndrome-a case report and literature review.

BACKGROUND: Endogenous Cushing's syndrome, a rare endocrine disorder, characterised by chronic cortisol hypersecretion, results in neuropsychiatric disturbances and in cognitive deficits, which are only partially reversible after the biochemical remission of the disease. CASE PRESENTATION: We report a case of a woman with a profound cognitive deficit and a gradual functional decline caused by Cushing's disease of at least 10 years duration. The neurosurgical resection of her 2 mm adrenocorticotropic hormone (ACTH) secreting pituitary microadenoma resulted in a successful resolution of the patient's hypercortisolism and a significant recovery of her neurocognitive function. The patient's progress was evaluated using serial clinical observations, functional assessments, Mini-Mental Status exams and through the formal neuropsychological report. Furthermore, the patient's recovery of her neurocognitive function was reflected by a sustained improvement in the patient's specific structural brain abnormalities on radiological imaging. CONCLUSIONS: This report illustrates the importance of early detection and treatment of Cushing's syndrome in order to prevent neurocognitive impairment and neuropsychiatric disorders which are associated with an endogenous cortisol hypersecretion. The long term adverse effects of severe hypercortisolaemia on brain function and the pathophysiological mechanisms responsible for the structural and functional changes in brain anatomy due to glucocorticoid excess are reviewed.

Clinical Significance of Granulation Pattern in Corticotroph Pituitary Adenomas.

OBJECTIVE: The granulation pattern of pituitary tumors may be important to predict tumor behavior, treatment outcomes, and recurrences. Therefore, we compared densely granulated corticotroph tumor (DGCT) and sparsely granulated corticotroph tumor (SGCT) in terms of clinicopathologic findings. MATERIAL AND METHOD: A total of 41 patients (31 females/10 males) were assessed in the study. The granulation patterns were detected by Periodic Acid-Schiff (PAS) and adrenocorticotropic hormone (ACTH) immunoreactivity. Diffuse and strong staining by PAS and ACTH were identified as DGCT, whereas faint staining by PAS and focal, weak staining by ACTH were identified as SGCT. Perinuclear ring-like patterns with low molecular weight keratin were identified as Crooke's cell tumors. DGCTs and SGCTs were compared in terms of clinical findings and treatment outcomes. RESULTS: The majority of the patients (71%) had DGCTs (n=29); whereas 24% of the patients had SGCTs (n=10) and 5% of the patients had Crooke's cell tumors (n=2). DGCTs and SGCTs were similar in terms of age, sex, estimated duration of disease, baseline cortisol and ACTH levels. SGCTs were larger than DGCTs (p=0.034). The remissions with surgery rates were similar between the groups; however, hypothalamic-pituitaryadrenal axis recovery time was longer in SGCTs (p=0.033). Persistent disease after surgery was slightly higher in DGCTs and recurrences were frequent in SGCTs; however, the differences were not statistically significant. CONCLUSION: DGCTs are often small microadenomas, while SGCTs are larger. Recurrences were slightly more common in SGCTs; however, further studies including larger series are needed to be able to obtain more significant results.

Screening of AIP Gene Variations in a Cohort of Turkish Patients with Young-Onset Sporadic Hormone-Secreting Pituitary Adenomas.

Aims: Aryl hydrocarbon receptor-interacting protein (AIP) gene mutations have long been associated with apparently sporadic pituitary adenomas (PAs) with a prevalence range of 0-12%. The aim of this study was to evaluate the frequency of germline AIP variations in a large cohort of apparently sporadic PAs diagnosed before the age of 40 years, who did not exhibit hypercalcemia and/or MEN1 syndrome components during long-term follow-up. Materials and Methods: A total of 97 patients, diagnosed with functional PAs ≤40 years old, composed of somatotropinoma (n = 55), prolactinoma (n = 25), and corticotrophinoma (n = 17), were recruited for this study. Fifty-one of these patients [somatotropinoma (n = 30), prolactinoma (n = 15), and corticotrophinoma (n = 11)] were previously reported as AIP mutation-negative by Sanger sequencing. The entire coding sequence of the AIP gene, along with exon/intron boundaries and the untranslated regions of 41 newly recruited patients, were sequenced for germline variations. In addition, all patients were subjected to multiplex ligation-dependent probe amplification to detect copy number variations in the AIP gene. Results: The AIP c.911G>A: p.Arg304Gln (rs104894190) variant was detected in only two patients with functional PA: one with somatotropinoma [in 1/55 (1.8%)] and one with prolactinoma [in 1/25 (4%)]. None of the corticotrophinomas revealed AIP gene alterations. Thus, the overall prevalence of AIP variation was 2.1% in our cohort. Conclusions: Germline AIP gene variations among Turkish patients with apparently sporadic PAs are relatively rare among patients ≤40 years old. None of the patients in our cohort revealed any obviously pathogenic AIP variants.

Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab.

Context: Pituitary carcinoma is a rare and aggressive malignancy with a poor prognosis and few effective treatment options. Case: A 35-year-old woman presented with an aggressive ACTH-secreting pituitary adenoma that initially responded to concurrent temozolomide and capecitabine prior to metastasizing to the liver. Following treatment with ipilimumab and nivolumab, the tumor volume of the dominant liver metastasis reduced by 92%, and the recurrent intracranial disease regressed by 59%. Simultaneously, her plasma ACTH level decreased from 45,550 pg/mL to 66 pg/mL. Molecular Evaluation: Both prospective clinical sequencing with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and retrospective whole-exome sequencing were performed to characterize the molecular alterations in the chemotherapy-naive pituitary adenoma and the temozolomide-resistant liver metastasis. The liver metastasis harbored a somatic mutational burden consistent with alkylator-induced hypermutation that was absent from the treatment-naive tumor. Resistance to temozolomide treatment, acquisition of new oncogenic drivers, and subsequent sensitivity to immunotherapy may be attributed to hypermutation. Conclusion: Combination treatment with ipilimumab and nivolumab may be an effective treatment in pituitary carcinoma. Clinical sequencing of pituitary tumors that have relapsed following treatment with conventional chemotherapy may identify the development of therapy-induced somatic hypermutation, which may be associated with treatment response to immunotherapy.