Somatotroph Adenomas Research Articles

TMOD-06. ESTABLISHMENT OF PITUITARY NEUROENDOCRINE TUMOR (PITNET) ORGANOID MODELS

Abstract Pituitary neuroendocrine tumors (PitNETs) are tumors that originate from the anterior pituitary gland. While they are mostly benign, they can cause various clinical symptoms due to hormonal secretion abnormalities. PitNET can be broadly categorized into three lineages, each of which has its differentiation controlled by specific transcription factors. Treatment options for PitNET include surgical resection and pharmacotherapy, but available drugs are limited, and their efficacy markers remain unclear. To develop novel drugs for PitNET and identify their efficacy markers, it is necessary to develop new research models. In recent years, organoid models have garnered attention as novel research models for various cancer types. In this study, we established novel organoid models derived from PitNET patients and analyzed their histological and endocrinological characteristics. Surgical specimens from 4 cases of somatotroph adenoma, 1 case of double adenoma, 1 case of gonadotroph adenoma, and 1 case of corticotroph adenoma were minced in dissection medium and embedded in Matrigel basement membrane matrix respectively. The organoids were cultured under 5% CO2 at 37°C using media supplemented with various growth factors. After 28 days of culture, formalin-fixed paraffin-embedded sections were prepared to examine histological homology with patient tumors. Hematoxylin and eosin staining results showed that all organoids maintained cell morphology and tissue structure similar to the original tumors. Immunohistochemical staining for markers specific to each PitNET revealed similar staining patterns between the organoids and the original tumors. Furthermore, analysis of hormone levels in the culture medium showed that hormone production capabilities, such as growth hormone and follicle stimulating hormone, were maintained even after long-term culture. In this study, we successfully established PitNET organoid models that retain histological and endocrinological characteristics. These models are expected to serve as useful research tools for elucidating the molecular mechanisms of PitNET and developing novel therapies targeting critical molecular abnormalities.

Preoperative predictors of biochemical remission in somatotroph adenoma resections: a single-institution retrospective review.

There is persistent debate in the literature surrounding the true predictors of biochemical remission after resection of somatotroph adenoma. A multimodal analysis of a large number of patients is needed to better understand which patients may be at higher or lower risk for remission failure after surgery. A retrospective review was performed on patients undergoing somatotroph adenoma resection. Biochemical remission was defined as age- and sex-adjusted normalization of serum insulin growth factor-1 (IGF-1) levels at least 6 months after surgery. Patient case characteristics and clinicopathologic variables were tested for statistical associations with remission and were included in a random forest machine learning model to assess for their importance in determining remission status. Preoperative variables found to be significant remission predictors on statistical testing and important in the random forest model were subsequently assessed via receiver operating characteristic (ROC) analysis to determine numeric thresholds that optimally predicted preoperative likelihood of remission success or failure. Eighty patients were identified with somatotroph adenoma who underwent transsphenoidal resection, with 60 patients (75%) achieving biochemical remission. Statistical testing found that patients with failed remission were more likely to have larger tumors (1.9 vs 1.6 cm by the largest axis, p = 0.014; and 3.61 vs 2.66 cm3 by 3D volume, p = 0.013) that invaded the cavernous sinus more frequently (70% vs 22% of patients, p < 0.001) and have higher preoperative IGF-1 level (860 vs 660 ng/ml, p = 0.044). An optimized random forest machine learning model with 10,000 iterations found that tumor size, preoperative growth hormone and IGF-1 levels, and cavernous sinus invasion were important preoperative predictors of remission status. ROC analysis revealed that 96% of patients with preoperative 3D tumor volume less than 1.51 cm3 (area under the curve [AUC] 0.691, p = 0.003) and 100% with nonadjusted preoperative IGF-1 level less than 718.5 ng/ml (AUC 0.736, p = 0.002) achieved remission. Important preoperative predictors of postoperative remission for somatotroph adenoma resection include serum IGF-1 level, cavernous sinus invasion, and tumor size. Ninety-five percent of patients who achieved postoperative remission had preoperative 3D tumor volume less than 1.51 cm3.

Somatostatin receptors in pituitary somatotroph adenomas as predictors of response to somatostatin receptor ligands: A pathologist's perspective.

There are five subtypes of somatostatin receptors (SST1-5), which are expressed in several types of solid neoplasms, neuroendocrine tumors, and pituitary adenomas. Most commonly, SST2 and SST5, are of interest regarding diagnostic, treatment, and prognostic purposes. In this article the basic biological characteristics of SST are briefly reviewed, and focus given to the immunohistochemical evaluation of SST2 and SST5 in growth hormone (GH)-secreting pituitary tumors, and their quantification as predictors of response to treatment with somatostatin receptor ligands (SRL), the mainstay of the pharmacological therapy available for these tumors. Although many different scoring systems for SST2 immunohistochemistry showing correlation with SRL response have been reported, among which the immunoreactivity score (IRS) has been the most consistently used, a universally validated immunohistochemical technique and scoring scheme is lacking. Efforts should be made on collaborative multicenter studies aiming at validating homogeneous immunostaining protocols and a scoring system for SST2 and SST5 expression, to help clinicians to define the optimal therapeutic strategy for the patients with somatotroph tumors.

Mixed Gangliocytoma-Pituitary Adenoma: Incidental Discovery During Eye Injury Evaluation: A Case Study

Abstract Introduction/Objective Mixed gangliocytoma-adenoma is exceedingly rare, representing less than 0.5% of sellar tumors. We present a unique case of mixed gangliocytoma-pituitary adenoma incidentally diagnosed during the evaluation of traumatic eye injury. We aim to clarify the diagnostic process using real clinical data, stressing how such cases might be missed without careful histopathological examination Methods/Case Report A 32-year-old male presented for elective transsphenoidal resection (TSR) due to a suspected growth hormone (GH) secreting pituitary tumor. Surprisingly, the adenoma was discovered incidentally during an eye injury evaluation. Referred from an ophthalmology clinic, initial concerns were a possible blood clot or foreign body in the left eye, following a forceful encounter with a tree branch Results (if a Case Study enter NA) Imaging incidentally identified a 2 cm pituitary mass. Further evaluation showed elevated levels of insulin-like growth factor 1 (IGF1) at 1162 ng/ml and GH at 10.2 ng/ml. Remarkably, the patient had not observed signs of acromegaly, until photographic comparison between past and present appearances was made. TSR of the pituitary mass was done. Microscopic examination revealed monomorphic cells with round nuclei with the typical speckled chromatin pattern of neuroendocrine cells with cytoplasm ranging from chromophobic to eosinophilic, consistent with pituitary adenoma. An additional unexpected finding was the presence of large gangliocytic cells (large neurons), dispersed throughout the tumor as single or clustered cells. In some regions, distinct patches of fine neuropil stroma were associated with the clustered ganglion cells. IHC staining with synaptophysin and neurofilament highlighted the gangliocytic component. CAM 5.2 IHC stain showed perinuclear dot-like expression in the adenoma cells, GH IHC showed patchy expression, and prolactin IHC was expressed in scattered cells. Ki67 index was ~ 2%. There was no evidence of necrosis nor mitosis. The coexistence of sellar gangliocytoma with pituitary adenoma, as observed in this case, represents a rare entity known as mixed gangliocytoma-pituitary adenoma Conclusion The adenomatous component of mixed gangliocytoma-pituitary adenoma often secrete GH, leading to its classification as pituitary somatotroph adenoma. This poses a diagnostic challenge due to the lack of specific symptoms or unique brain imaging features, necessitating thorough histological evaluation for precise diagnosis and to ensure the gangliocytoma component is not overlooked

7248 Spliceosome component TCERG1 regulates the aggressiveness of somatotroph adenoma

Abstract Disclosure: K. Kim: None. The role of the spliceosome in the development of pituitary tumors is not well understood, despite preliminary studies indicating abnormal expression of oncogenic splicing variants in these neuroendocrine tumors. We aimed to identify differentially expressed spliceosome components in growth hormone (GH)-secreting pituitary tumors and investigate their roles in pathogenesis.We performed transcriptome analysis of 20 somatotroph adenomas and 6 normal pituitary tissues to select dysregulated spliceosome components. Clinical characteristics were analyzed based on gene expression in 64 patients with acromegaly. GH secreting pituitary adenomas were confirmed by 75 g oral glucose tolerance and immunohistochemical staining. Proliferation, invasion, and hormonal activity of GH secreting pituitary adenoma cells were investigated after modulating gene expression.TCERG1 expression was significantly higher in somatotroph adenomas than in normal cells (log2 fold change 0.59, adjusted P=0.0002*). Genotype-phenotype analysis revealed that patients with higher TCERG1 expression had lower surgical remission rates than those with lower expression (63.64% vs. 95.45%, P=0.009*). TCERG1 expression was significantly higher in groups with cavernous sinus (CS) invasion or Ki67 index over 1.5 (2.06 vs. 1.65, P=0.011*; 2.02 vs. 1.66, P=0.043*). TCERG1 overexpression led to a 16.91% increase in proliferation after 72 h (P&amp;lt;0.001*) and a 249.47% increase in invasion after 48 h in GH3 cells (P=0.026*). Conversely, TCERG1 silencing significantly decreased cell proliferation (10.15% at 72 h, P&amp;lt;0.001*) and invasion (96.87% at 48 h, P=0.029*). Vimentin was increased, but E-cadherin was decreased in both TCERG1 overexpressed GH3 cells and somatotroph adenomas. And TCERG1 silence reversed the expression of the genes (CDH2, SNAI1, ZEB2, and VIM) in GH3 cells. Additionally, GH secretion increased when TCERG1 was overexpressed in GH3 cells. Spliceosome machinery provide novel insights into the pathogenesis of GH-secreting pituitary tumor and highlight the potential role of TCERG1 as a therapeutic target. Presentation: 6/2/2024

12562 Extraocular Muscle Enlargement With Proptosis In A Patient With Non Thyroidal Disease

Abstract Disclosure: S.S. Bantu: None. P.N. Kabir: None. A. Gondhi: None. T.B. Vaughan: None. Extraocular muscle enlargement with proptosis in a patient with Nonthyroidal disease Introduction: Majority of cases with extraocular muscle enlargement (EOME) is due to Graves’ disease, commonly in about 95% cases and another 5% make up other causes including inflammatory, neoplastic, vascular, infectious and acromegaly. We present a patient with sudden loss of vision, retroorbital pain with visual field deficits found to have EOME and subsequently a pituitary macroadenoma on imaging. Case: We present a 54-year-old male with history of hypertension, obstructive sleep apnea and morbid obesity who presented to us with complains of left sided vision loss. Patient was evaluated by ophthalmology and noted to have unilateral, left-sided, change in visual acuity. Physical exam was notable for macrognathia, skin tags, enlarged hands, excessive sweating. MRI brain revealed bilateral EOME with proptosis and a pituitary macroadenoma measuring 1.5x1.7x1.3cm, abutting the pre-chiasmatic left optic nerve. On biochemical evaluation he was noted to have elevated IGF1 of 979 confirming the diagnosis of acromegaly. ((hemoglobin A1C of 5.5%, prolactin 5.1, FT4 0.89, TSH 0.692, total testosterone 61, IGF1 level was 979)). He underwent transsphenoidal resection of the pituitary macroadenoma. Pathology showed sparsely granulated somatotroph adenoma. Discussion: Acromegaly has an incidence of 3-4 cases per million per year. The characteristics of the disease are due to chronic growth hormone hypersecretion resulting in the excessive growth of tissue due to the stimulation of insulin-like growth factor 1 (IGF-1). EOME with proptosis in acromegaly is seen rarely. Visual symptoms may manifest as visual field deficits due to compression of the optic pathway in 18-25% cases, increased intraocular pressure, increase in corneal thickness and a diffuse symmetrical enlargement of the extraocular muscles which cannot be distinguished from thyroid orbitopathy on imaging. The degree of enlargement appears to correlate with the duration of the disease rather than the levels of IGF1. EOME improves with the treatment of acromegaly. Although visual symptoms may be a rare presentation of acromegaly, if the clinical suspicion exists, one may consider obtaining an IGF-1 level to complete the evaluation of EOME if the thyroid levels are normal. Presentation: 6/3/2024

8209 Silent Somatotroph Adenoma Unmasked as Pituitary Apoplexy, Disguised as Subarachnoid Hemorrhage

Abstract Disclosure: P. Vemparala: None. S. Challagulla: None. Introduction - Pituitary apoplexy is a rare and potentially life-threatening complication associated with pituitary adenomas, particularly in cases of nonfunctioning macroadenomas. Silent somatotroph adenomas, characterized by the presence of growth hormone (GH) immunoreactivity without manifesting signs and symptoms of acromegaly, are uncommon. This case report presents a distinctive instance where pituitary apoplexy served as the initial manifestation of a GH-immunoreactive tumor. CASE PRESENTATION- A 45-year-old male with a medical history of hypertension, sleep apnea, and hypogonadism sought emergency medical attention following a syncopal episode. Post-syncope, he reported severe headache and neck pain, with no other associated symptoms. Imaging revealed a subarachnoid hemorrhage and a sellar/suprasellar mass measuring approximately 2.8 x 3.6 x 4.2 cm. CT angiography ruled out an aneurysm or vascular malformation. The subarachnoid hemorrhage was attributed to hemorrhage within the sellar mass. Treatment with Nimodipine and levetiracetam was initiated. Laboratory investigations indicated normal insulin-like growth factor 1 (IGF-1) levels. Brain MRI revealed a 4.2 x 2.3 x 2.6 cm heterogeneous enhancing cystic sellar/suprasellar lesion causing mass effect on the hypothalamus and third ventricle. The patient underwent endoscopic transsphenoidal hypophysectomy, revealing a tumor that was diffusely positive for GH and synaptophysin immunostaining and negative for prolactin and ACTH. Ki67 was less than 5%, with no apparent mitotic activity, atypia, or tumor necrosis. The postoperative course was uneventful, and the patient was discharged on oral steroids. Conclusion- Silent somatotroph adenomas constitute a small percentage (2-4.2%) of pituitary adenomas. In contrast to silent gonadotroph adenomas, these tumors are more prevalent in women, tend to present earlier and exhibit higher recurrence rates. This case emphasizes the potential of silent somatotroph adenomas to manifest initially as pituitary apoplexy. It underscores the importance of vigilant post-surgical follow-up due to the possibility of recurrence. Additionally, recognizing pituitary apoplexy as subarachnoid hemorrhage is crucial for timely intervention and appropriate management. Presentation: 6/2/2024

9234 A Case of Gigantism Due to An AIP Gene Mutation: Implications for Genetic Counseling and Preimplantation Genetic Diagnosis

Abstract Disclosure: M. Serebro: None. M. Yacobi Bach: None. N. Even Zohar: None. A. Reches: None. Y. Greenman: None. From the age of 17 the patient experienced accelerated growth, facial changes, and enlargement of hands and feet. Despite having a sister already diagnosed with acromegaly, the patient did not undergo endocrine evaluation until the age of 25, when he was diagnosed with gigantism. Magnetic resonance imaging (MRI) revealed the presence of a macroadenoma with suprasellar extension reaching the optic chiasm. The patient underwent transsphenoidal surgery and excision of a sparsely granulated somatotroph adenoma that was Pit1 positive and exhibited weak immunostaining for growth hormone (GH). Insulin-like growth factor 1 (IGF1) levels normalized after surgery, and a fasting GH level was 0.6 ng/ml. Given the family history and the early onset of the disease, genetic counseling was recommended. Genetic testing revealed a heterozygote likely pathogenic variant in the AIP gene (c.713G&amp;gt;A). This finding prompted the recommendation for genetic testing of all first-degree relatives. The patient and his wife, who desired to have children, were referred to obstetrics and gynecology for pregestational diagnosis. Family segregation testing indicated that the patient's mother also carried the same AIP variant. Preimplantation genetic diagnosis (PGD) was conducted, revealing that 11 out of 20 embryos were carriers of the AIP variant. The non-carrier embryos were selected for implantation, and pregnancy was achieved. Efforts to inform first-degree relatives about the importance of genetic testing were undertaken, and one sister was tested and found to be healthy. Other siblings have not yet been tested. The patient's mother, identified as an AIP variant carrier, underwent endocrine laboratory tests that showed GH, IGF1, and prolactin levels within the normal range. Brain MRI did not reveal a pituitary lesion.This case highlights the significance of genetic counseling and testing in patients with familial endocrine disorders, the potential implications of a molecular diagnosis of a pathogenic AIP variant, and the challenges faced in reproductive decision-making for affected individuals and their families. Presentation: 6/3/2024

Spliceosome component TCERG1 regulates the aggressiveness of somatotroph adenoma.

We aimed to identify differentially expressed spliceosome components in growth hormone (GH)-secreting pituitary tumors and investigate their roles in pathogenesis. We performed transcriptome analysis of 20 somatotroph adenomas and 6 normal pituitary tissues to select dysregulated spliceosome components. Clinical characteristics were analyzed based on gene expression in 64 patients with acromegaly. Proliferation, invasion, and hormonal activity of GH secreting pituitary adenoma cells were investigated. TCERG1 expression was significantly higher in somatotroph adenomas than in normal pituitaries (log2 fold change 0.59, adjusted P = 0.0002*). Genotype-phenotype analysis revealed that patients with higher TCERG1 expression had lower surgical remission rates than those with lower expression (63.64% vs. 95.45%, P = 0.009*). TCERG1 expression was significantly higher in groups with cavernous sinus (CS) invasion or Ki67 index over 3 (all P>0.05*). TCERG1 overexpression led to a 29.60% increase in proliferation (P<0.001*) and a 249.47% increase in invasion after 48h in GH3 cells (P = 0.026*). Conversely, TCERG1 silencing significantly decreased cell proliferation (25.76% at 72h, P<0.001*) and invasion (96.87% at 48h, P = 0.029*). E-cadherin was decreased, but vimentin was increased in both TCERG1 overexpressed GH3 cells and somatotroph adenomas. And TCERG1 silence reversed the expression of the genes (CDH2, SNAI1, ZEB2, and VIM) in GH3 cells. Spliceosome machinery provide novel insights into the pathogenesis of GH-secreting pituitary tumor and highlight the potential role of TCERG1 as a biomarker for tumor aggressiveness.

Typical morphological characteristics of the immunohistochemical subtypes of pituitary microadenomas: a dual center study.

This study aimed to investigate the relationship between magnetic resonance image (MRI) features and the immunohistochemical subtypes of pituitary microadenomas (PMAs) characterized by location and growth pattern. A double-center, retrospective review of MRI characteristics was conducted in 57 PMA cases recorded from February 2014 to September 2023, identified based on the 2017 World Health Organization classification of pituitary gland tumors. The geometric center of the tumor was defined, and the possibility of PMA vertical or lateral growth patterns was evaluated according to the ratio of maximum diameter between the X and Y axes. Among the PMAs, somatotroph adenomas (STAs) significantly frequented the lateral-anteroinferior portion of the pituitary gland (P = 0.036). Lactotroph adenomas (LTAs) showed a significant locational preference for the lateral-posteroinferior portion (P = 0.037), and gonadotroph adenomas (GTAs) were predominantly located in the central-anteroinferior portion (P = 0.022). Furthermore, PMAs in the suprasellar portion exhibited vertical extension with statistical significance (P = 0.0). In our cohort, micro-STAs were predominantly located in the lateral-anteroinferior portion of the pituitary gland, micro-LTAs in the lateral-posteroinferior portion, and micro-GTAs in the central-anteroinferior portion. The growth pattern of PMAs was highly correlated with their vertical position instead of their immunohistochemical subtypes. Therefore, MRI shows potential in differentiating partial PMA subgroups, especially cases within the silent groups.

GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly.

About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion. We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas. 25 treatment-naïve patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches. The effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement. In four of seven patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = 0.0003). Somatotrophs were available from three of four of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion. Of 25 patients with acromegaly, seven had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in four. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist.

Activated AMP-protein kinase (pAMPK) is overexpressed in human somatotroph pituitary adenomas

IntroductionAMPK (AMP-activated protein kinase) is an enzyme that acts as a metabolic sensor and regulates multiple pathways via phosphorylating proteins in metabolic and proliferative pathways. The aim of this work was to study the activated cellular AMPK (phosphorylated-AMPK at Thr172, pAMPK) levels in pituitary tumor samples from patients with sporadic and familial acromegaly, as well as in samples from normal human pituitary gland. MethodsWe studied pituitary adenoma tissue from patients with sporadic somatotroph adenomas, familial acromegaly with heterozygote germline variants in the aryl hydrocarbon receptor interacting protein (AIP) gene (p.Q164*, p.R304* and p.F269_H275dup) and autopsy from normal pituitary glands without structural alterations. ResultsCellular levels of pAMPK were significantly higher in patients with sporadic acromegaly compared to normal pituitary glands (p < 0.0001). Tissues samples from patients with germline AIP mutations also showed higher cellular levels of pAMPK compared to normal pituitary glands. We did not observe a significant difference in cellular levels of pAMPK according to the cytokeratin (CAM5.2) pattern (sparsely or densely granulated) for tumor samples of sporadic acromegaly. ConclusionOur data show, for the first time in human cells, an increase of cellular levels of pAMPK in sporadic somatotropinomas, regardless of cytokeratin pattern, as well as in GH-secreting adenomas from patients with germline AIP mutations.

Comparative analysis of intraoperative and imaging features of invasive growth in pituitary adenomas.

Most pituitary adenomas (PAs), also termed pituitary neuroendocrine tumors, are benign in nature and can be treated effectively by surgical resection, medical treatment, and in special cases by radiotherapy. However, invasive growth can be an important feature of a more aggressive behavior and adverse prognosis. The extension of PAs into the cavernous sinus can be categorized according to the Knosp criteria on magnetic resonance imaging (MRI). Comparative analyses of MRI features and intraoperative findings of invasive growth regarding different clinical factors are still scarce. We performed a retrospective single-center analysis of 764 PAs that were surgically treated between October 2004 and April 2018. Invasive growth was assessed according to the surgical reports and preoperative MRI (Knosp criteria). Clinical data, such as patient age at diagnosis and gender, histopathological adenoma type, and extent of resection, were collected. Invasive features on MRI were seen in 24.4% (Knosp grades 3A-4, 186/764) of the cases. Intraoperatively, invasion was present in 42.4% (324/764). Complete resection was achieved in 80.0% of adenomas and subtotal resection, in 20.1%. By multivariate analysis, invasion according to intraoperative findings was associated with the sparsely granulated corticotroph (SGCA, P = .0026) and sparsely granulated somatotroph (SGSA, P = .0103) adenoma type as well as age (P = .0287). Radiographic invasion according to Knosp grades 3A-4 correlated with age (P = .0098), SGCAs (P = .0005), SGSAs (P = .0351), and gonadotroph adenomas (P = .0478). Both criteria of invasion correlated with subtotal resection (P = .0001, respectively). Both intraoperative and radiographic signs of invasive growth are high-risk lesions for incomplete extent of resection and occur more frequently in older patients. A particularly high prevalence of invasion can be found in the SGCA and SGSA types. Cavernous sinus invasion is also more common in gonadotroph adenomas. Usage of the Knosp classification is a valuable preoperative estimation tool.

Medical treatment of functional pituitary adenomas, trials and tribulations.

Functioning pituitary adenomas (FPAs) include most frequently prolactinomas, somatotroph or corticotroph adenomas, while thyrotroph and gonadotroph adenomas are very rare. Despite their benign histological nature (aggressive tumors are rare and malignant ones exceptional), FPAs could cause significant morbidity and increased mortality due to complications associated with hormonal excess syndromes and/or mass effect leading to compression of adjacent structures. This mini review will focus on the increasing role of medical therapy in the multimodal treatment, which also includes transsphenoidal surgery (TSS) and radiotherapy. Most patients with prolactinomas are treated only with medications, but surgery could be considered for some patients in a specialized pituitary center, if higher chances of cure. Dopamine agonists, especially cabergoline, are efficient in reducing tumor size and normalizing prolactin. TSS is the first-line treatment for all other FPAs, but most patients require complex adjuvant treatment, including a combination of therapeutic approaches. Medical therapy is the cornerstone of treatment in all patients after unsuccessful surgery or when surgery cannot be offered and includes somatostatin receptor ligands and dopamine agonists (almost all FPAs), growth hormone receptor antagonists (acromegaly), adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers (Cushing's disease). Novel medical treatments, especially for acromegaly and Cushing's disease are under research. An enlarged panel of effective drugs available with increased knowledge of predictive factors for response and/or adverse effects will enhance the possibility to offer a more individualized treatment. This would not only improve disease control and prognosis, but also quality of life.

A low-grade somatotroph adenoma presenting as a giant pituitary macro-adenoma

A low-grade somatotroph adenoma presenting as a giant pituitary macro-adenoma

Empty sella in somatotropic pituitary adenomas; a series of 23 cases.

We aimed to investigate empty sella syndrome in somatotrophic pituitary adenoma for possible etiology, complications, and treatment options. Among over 2,000 skull base masses that have been managed in our center since 2013, we searched for growth hormone-producing adenomas. Clinical, surgical, and imaging data were retrospectively collected from hospital records to check for sella that lacked pituitary tissue on routine imaging. In 220 somatotrophic adenomas, 23 patients had an empty sella with surgical and follow-up data. The mean age of the sample was 46 years with the same male-to-female ratio. Five cases had partial empty sella and the rest were complete empty sellas. The most common simultaneous hormonal disturbance was high prolactin levels. Six had adenoma invasion into the clivus or sphenoid sinus and 10 had cavernous sinus intrusion. Peri-operative low-flow and high-flow cerebrospinal fluid (CSF) leaks were encountered in one and two patients, respectively, which were successfully sealed by abdominal fat. The majority of cases required growth hormone replacement therapy while it was controlled without any replacement therapy in nine patients. No pituitary hormonal disturbance occurred after transsphenoidal surgery except for hypothyroidism in one patient. An empty sella filled with fluid can be detected frequently in pituitary adenomas, especially in the setting of acromegaly. The pituitary gland may be pushed to the roof of the sella and might be visible as a narrow rim on imaging or may be detected in unusual places out of the sella. The pathophysiology behind such finding originates from soft and hard tissue changes and CSF pressure alternations during abundant growth hormone production.

KDM1A genotyping and expression in 146 sporadic somatotroph pituitary adenomas.

A paradoxical increase of growth hormone (GH) following oral glucose load has been described in ∼30% of patients with acromegaly and has been related to the ectopic expression of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in somatotropinomas. Recently, we identified germline pathogenic variants and somatic loss of heterozygosity of lysine demethylase 1A (KDM1A) in patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. The ectopic expression of GIPR in both adrenal and pituitary lesions suggests a common molecular mechanism. We aimed to analyze KDM1A gene sequence and KDM1A and GIPR expressions in somatotroph pituitary adenomas. We conducted a cohort study at university hospitals in France and in Italy. We collected pituitary adenoma specimens from acromegalic patients who had undergone pituitary surgery. We performed targeted exome sequencing (gene panel analysis) and array-comparative genomic hybridization on somatic DNA derived from adenomas and performed droplet digital PCR on adenoma samples to quantify KDM1A and GIPR expressions. One hundred and forty-six patients with sporadic acromegaly were studied; 72.6% presented unsuppressed classical GH response, whereas 27.4% displayed a paradoxical rise in GH after oral glucose load. We did not identify any pathogenic variant in the KDM1A gene in the adenomas of these patients. However, we identified a recurrent 1p deletion encompassing the KDM1A locus in 29 adenomas and observed a higher prevalence of paradoxical GH rise (P = .0166), lower KDM1A expression (4.47 ± 2.49 vs 8.56 ± 5.62, P < .0001), and higher GIPR expression (1.09 ± 0.92 vs 0.43 ± 0.51, P = .0012) in adenomas from patients with KDM1A haploinsufficiency compared with those with 2 KDM1A copies. Unlike in GIP-dependent primary bilateral macronodular adrenal hyperplasia, KDM1A genetic variations are not the cause of GIPR expression in somatotroph pituitary adenomas. Recurrent KDM1A haploinsufficiency, more frequently observed in GIPR-expressing adenomas, could be responsible for decreased KDM1A function resulting in transcriptional derepression on the GIPR locus.

Prognostic indicators in pituitary adenoma surgery: a comprehensive analysis of surgical outcomes and complications.

The primary aim of this study was to identify predictive factors associated with onset of de-novo clinically significant pituitary insufficiencies following endoscopic endonasal surgery (EES) for pituitary adenomas. The secondary objective explored the predictive factors of surgical success. A retrospective analysis was conducted on 211 patients who underwent EES. Logistic regression models were employed for the primary and secondary objectives. Patients were stratified into specific groups based on surgical indications and prolactin levels for nuanced analysis. Significant predictors for de-novo pituitary insufficiencies included male sex (OR 3.3, CI95% 1.3-8.1, p=0.01), immediate postoperative insufficiencies (OR 5.6, CI95% 2.8-11.1, p<0.001), and HYPRONOS criteria (OR 5.7, CI95% 1.6-20.9, p=0.008). For surgical success, preoperative insufficiencies (OR 0.7, CI95% 0.5-0.9, p=0.008), repeat surgeries (OR 0.1, CI95% 0-0.4, p=0.001), and gonadotroph or somatotroph adenomas were significant. Age and adenoma size were not predictive in multivariate analysis. Furthermore, we observed a "dip and recover" effect of prolactin after surgery and lower prolactin levels at follow-up (< 3 ng/ml) are correlated with more anterior pituitary insufficiencies than normoprolactinemic patients (p = 0.004). This study identifies key predictors for outcomes in pituitary surgery. Our research is the first to employ individualized success criteria for EES, challenging existing perceptions about the role of age and adenoma size. These findings open avenues for nuanced, individualized preoperative risk assessment and postoperative management.

Delineating the Spectrum of Pituitary Adenoma Based on the WHO 2017 Classification.

The WHO 2017 classification of endocrine tumors incorporates lineage-specific transcription factors (TF) and hormone expression for the classification of pituitary adenoma (PA). There is paucity of reports describing the spectrum of PA based on this classification. The aim of this study was to delineate the spectrum of PA based on WHO 2017 classification of endocrine tumors. PA diagnosed in the year 2018 were studied. H and E and hormonal immunohistochemistry (IHC) for GH, PRL, ACTH, TSH, FSH, LH, CK, T-Pit and MIB-1 were performed and the results were analyzed. The cohort included 88 cases. M: F ratio was 2:1. Clinically, 22 (25%) were functional and 66 (75%) were non-functional adenomas. Amongst the clinically functional adenomas, GH secreting adenomas were the commonest (68%). Majority (83%) of non-functional adenomas were hormone positive with gonadotroph adenomas being the commonest (72.7%). Eleven (12.5%) PA were clinically and hormonally silent. Three of these showed intense nuclear T-Pit positivity, classifying them under silent corticotroph adenoma. Lineage of the remaining eight adenomas remained undetermined, since, IHC for Pit-1 and SF-1 was not performed. The aggressive adenomas identified by IHC included sparsely granulated somatotroph adenoma, Crooke cell adenoma, silent corticotroph adenoma, densely granulated lactotroph adenoma in men and constituted 17% of the PA. Four (4/88) cases were clinically invasive. A large majority of PA including aggressive adenomas can be identified by IHC. Addition of T-Pit helped to identify silent corticotroph adenoma. Pit -1 and SF-1 TF would help identify plurihormonal Pit-1 PA and null cell adenomas.

Importance of Intraoperative Factors in Postoperative Arginine Vasopressin Deficiency After Pituitary Adenoma Surgery

ObjectivePituitary adenoma (PA) is the most frequent tumor in the sellar region. Arginine vasopressin deficiency (AVP-D), formerly known as central diabetes insipidus, is a common complication after pituitary surgeries. In this study, we reviewed patients with PAs after endoscopic transsphenoidal surgery, evaluated the incidence of postoperative AVP-D, and determined associated risk factors. MethodsWe retrospectively studied 520 patients who underwent endoscopic transsphenoidal surgery for PAs and evaluated perioperative risk factors and their associations with postoperative AVP-D. Patients who developed AVP-D were categorized in 3 groups: (1) early AVP-D, (2) transient AVP-D, and (3) permanent AVP-D. ResultsOf the 520 patients, 24.8% experienced early AVP-D, and 1.9% (n = 10) had transient AVP-D. Permanent AVP-D was observed in only 6 patients (1.1%). Gross total resection, hormonal remission, pituitary stalk manipulation, and intraoperative cerebrospinal fluid leak were significantly associated with a higher incidence of AVP-D (P = .027, P = .002, P < .001 and P < .001, respectively). All patients who developed permanent AVP-D had somatotroph adenomas. AVP-D was not found to be related with tumor size. The length of hospital stay was prolonged by AVP-D on average by 1.5 days (P = .018). ConclusionThe reported incidence of AVP-D has a considerably wide range. A consistent definition and grading for AVP-D will increase consistency and comparability among studies. Nonetheless, most patients experience AVP-D on a temporary basis, and only a few require long-term treatment. Cerebrospinal fluid leak, gross total resection, and hormonal remission were identified as risk factors for postoperative AVP-D. We believe that the intraoperative risk factors play the main role in postoperative AVP-D. The course of surgery and operative findings help us plan selective postoperative patient monitoring and care.