Relevance of mutations in protein deubiquitinases genes and TP53 in corticotroph pituitary tumors.

Introduction: Corticotroph pituitary neuroendocrine tumors (PitNETs) develop from ACTH-producing cells. They commonly cause Cushing's disease (CD), however, some remain clinically silent. Recurrent USP8, USP48, BRAF and TP53 mutations occur in corticotroph PitNETs. The aim of our study was to determine frequency and relevance of these mutations in a possibly large series of corticotroph PitNETs. Methods: Study included 147 patients (100 CD and 47 silent tumors) that were screened for hot-spot mutations in USP8, USP48 and BRAF with Sanger sequencing, while 128 of these patients were screened for TP53 mutations with next generation sequencing and immunohistochemistry. Results: USP8 mutations were found in 41% CD and 8,5% silent tumors, while USP48 mutations were found in 6% CD patients only. Both were more prevalent in women. They were related to higher rate of biochemical remission, non-invasive tumor growth, its smaller size and densely granulated histology, suggesting that these mutation may be favorable clinical features. Multivariate survival analyses did not confirm possible prognostic value of mutation in protein deubiquitinases. No BRAF mutations were found. Four TP53 mutations were identified (2 in CD, 2 in silent tumors) in tumors with size >10mm including 3 invasive ones. They were found in Crooke's cell and sparsely granulated tumors. Tumors with missense TP53 mutations had higher TP53 immunoreactivity score than wild-type tumors. Tumor with frameshift TP53 variant had low protein expression. TP53 mutation was a poor prognostic factor in CD according to uni- and multivariate survival analyses in spite of low mutations frequency. Conclusions: We confirmed high prevalence of USP8 mutations and low incidence of USP48 and TP53 mutations. Changes in protein deubiquitinases genes appear to be favorable prognostic factors in CD. TP53 mutations are rare, occur in both functioning and silent tumors and are related to poor clinical outcome in CD.

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

BACKGROUND: 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. OBJECTIVE: The aim of this study was to delineate the spectrum of PA based on WHO 2017 classification of endocrine tumors. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Effects of the Cortisol Milieu on Tumor-Infiltrating Immune Cells in Corticotroph Tumors.

CONTEXT: Corticotrophs are susceptible to lymphocyte cytotoxicity, as seen in hypophysitis, suggesting that an immunological approach may be a potential strategy for corticotroph-derived tumors. OBJECTIVE: We aimed to clarify whether corticotroph tumors that induce hypercortisolemia (ACTHomas) could be targets for immunotherapy. METHODS: Tumor-infiltrating immune cells were immunohistochemically analyzed. ACTHomas were compared with other pituitary tumors, and further divided into 3 different cortisol-exposed milieus: Naïve (ACTHomas without preoperative treatment), Met (ACTHomas with preoperative metyrapone), and SCA (silent corticotroph adenomas). A 3-dimensional cell culture of resected tumors was used to analyze the effects of immune checkpoint inhibitors. RESULTS: The number of tumor-infiltrating lymphocytes (TILs) was low in ACTHomas. Among these, the number of CD8+ cells was lower in ACTHomas than in both somatotroph and gonadotroph tumors (both P < .01). Then we compared the differences in TILs among Naïve, Met, and SCA. The number of CD4+ cells, but not CD8+ cells, was higher in both Met and SCA than in Naïve. Next, we investigated tumor-associated macrophages, which could negatively affect T cell infiltration. The numbers of CD163+ and CD204+ cells were positively associated with cortisol levels. Moreover, tumor size was positively correlated with the number of CD204+ cells. CONCLUSION: We found the possibility that ACTHomas were immunologically cold in a cortisol-independent manner. In contrast, the tumor infiltration of CD4+ cells and M2-macrophages were associated with the cortisol milieu. Future studies are needed to validate these results and develop effective immunotherapy while considering the cortisol milieu.

Metformin inhibits cell proliferation and ACTH secretion in AtT20 cells via regulating the MAPK pathway.

We investigated the impact of metformin on ACTH secretion and tumorigenesis in pituitary corticotroph tumors. The mouse pituitary tumor AtT20 cell line was treated with varying concentrations of metformin. Cell viability was assessed using the CCK-8 assay, ACTH secretion was measured using an ELISA kit, changes in the cell cycle were analyzed using flow cytometry, and the expression of related proteins was evaluated using western blotting. RNA sequencing was performed on metformin-treated cells. Additionally, an in vivo BALB/c nude xenograft tumor model was established in nude mice, and immunohistochemical staining was conducted for further verification. Following metformin treatment, cell proliferation was inhibited, ACTH secretion decreased, and G1/S phase arrest occurred. Analysis of differentially expressed genes revealed cancer-related pathways, including the MAPK pathway. Western blotting confirmed a decrease in phosphorylated ERK1/2 and phosphorylated JNK. Combining metformin with the ERK1/2 inhibitor Ulixertinib resulted in a stronger inhibitory effect on cell proliferation and POMC (Precursors of ACTH) expression. In vivo studies confirmed that metformin inhibited tumor growth and reduced ACTH secretion. In conclusion, metformin inhibits tumor progression and ACTH secretion, potentially through suppression of the MAPK pathway in AtT20 cell lines. These findings suggest metformin as a potential drug for the treatment of Cushing's disease.

PAM variants in patients with thyrotrophinomas, cyclical Cushing's disease and prolactinomas.

Introduction: Germline loss-of-function variants in PAM, encoding peptidylglycine α-amidating monooxygenase (PAM), were recently discovered to be enriched in conditions of pathological pituitary hypersecretion, specifically: somatotrophinoma, corticotrophinoma, and prolactinoma. PAM is the sole enzyme responsible for C-terminal amidation of peptides, and plays a role in the biosynthesis and regulation of multiple hormones, including proopiomelanocortin (POMC). Methods: We performed exome sequencing of germline and tumour DNA from 29 individuals with functioning pituitary adenomas (12 prolactinomas, 10 thyrotrophinomas, 7 cyclical Cushing's disease). An unfiltered analysis was undertaken of all PAM variants with population prevalence <5%. Results: We identified five coding, non-synonymous PAM variants of interest amongst seven individuals (six germline, one somatic). The five variants comprised four missense variants and one truncating variant, all heterozygous. Each variant had some evidence of pathogenicity based on population prevalence, conservation scores, in silico predictions and/or prior functional studies. The yield of predicted deleterious PAM variants was thus 7/29 (24%). The variants predominated in individuals with thyrotrophinomas (4/10, 40%) and cyclical Cushing's disease (2/7, 29%), compared to prolactinomas (1/12, 8%). Conclusion: This is the second study to demonstrate a high yield of suspected loss-of-function, predominantly germline, PAM variants in individuals with pathological pituitary hypersecretion. We have extended the association with corticotrophinoma to include the specific clinical entity of cyclical Cushing's disease and demonstrated a novel association between PAM variants and thyrotrophinoma. PAM variants might act as risk alleles for pituitary adenoma formation, with a possible genotype-phenotype relationship between truncating variants and altered temporal secretion of cortisol.

Clinical Spectrum of USP8 Pathogenic Variants in Cushing's Disease.

Cushing's disease (CD) is a life-threatening condition with a challenging diagnostic process and scarce treatment options. CD is caused by usually benign adrenocorticotrophic hormone (ACTH)-secreting pituitary neuroendocrine tumors (PitNETs), known as corticotropinomas. These tumors are predominantly of sporadic origin, and usually derive from the monoclonal expansion of a mutated cell. Somatic activating variants located within a hotspot of the USP8 gene are present in 11-62% of corticotropinomas, making USP8 the most frequent genetic driver of corticotroph neoplasia. In contrast, other somatic defects such as those affecting the glucocorticoid receptor gene (NR3C1), the BRAF oncogene, the deubiquitinase-encoding gene USP48, and TP53 are infrequent. Moreover, patients with familial tumor syndromes, such as multiple endocrine neoplasia, familial isolated pituitary adenoma, and DICER1 rarely develop corticotropinomas. One of the main molecular alterations in USP8-driven tumors is an overactivation of the epidermal growth factor receptor (EGFR) signaling pathway, which induces ACTH production. Hotspot USP8 variants lead to persistent EGFR overexpression, thereby perpetuating the hyper-synthesis of ACTH. More importantly, they condition a characteristic transcriptomic signature that might be useful for the clinical prognosis of patients with CD. Nevertheless, the clinical phenotype associated with USP8 variants is less well defined. Hereby we discuss the current knowledge on the molecular pathogenesis and clinical picture associated with USP8 hotspot variants. We focus on the potential significance of the USP8 mutational status for the design of tailored clinical strategies in CD.

Crooke Cell Adenoma Confers Poorer Endocrinological Outcomes Compared with Corticotroph Adenoma: Results of a Multicenter, International Analysis.

BACKGROUND: Crooke cell adenomas (CCAs) are a rare, aggressive subset of secretory pituitary corticotroph adenomas (sCTAs) found in 5%-10% of patients with Cushing disease. Multiple studies support worse outcomes in CCAs but are limited by small sample size and single-institution databases. We compared outcomes in CCA and sCTA using a multicenter, international retrospective database of high-volume skull base centers. METHODS: Patients surgically treated for pituitary adenoma from January 2017 through December 2020 were included. RESULTS: Among 2826 patients from 12 international centers, 20 patients with CCA and 480 patients with sCTA were identified. No difference in baseline demographics, tumor characteristics, or postoperative complications was seen. Microsurgical approaches (60% CCA vs. 62.3% sCTA) were most common. Gross total resection was higher in CCA patients (100% vs. 83%, P = 0.05). Among patients with gross total resection according to intraoperative findings, fewer CCA patients had postoperative hormone normalization of pituitary function (50% vs. 77.8%, P < 0.01) and remission of hypersecretion by 3-6 months (75% vs. 84.3%, P < 0.01). This was the case despite CCA having better local control rates (100% vs. 96%, P < 0.01) and fewer patients with remnant on magnetic resonance imaging (0% vs. 7.2%, P < 0.01). A systematic literature review of 35 studies reporting on various treatment strategies reiterated the high rate of residual tumor, persistent hypercortisolism, and tumor-related mortality in CCA patients. CONCLUSIONS: This modern, multicenter series of patients with CCA reflects their poor prognosis and reduced postsurgical hormonal normalization. Further work is necessary to better understand the pathophysiology of CCA to devise more targeted treatment approaches.

[Correlation analysis of anterior pituitary hormone and tumor size in patients with pituitary adenomas].

Objective: To summarize the correlation between anterior pituitary function and tumor size in patients with different hormone-secreting pituitary adenomas. Methods: This was a retrospective case series study. The clinical data of 1 946 patients with pituitary adenoma hospitalized in the First Medical Center of Chinese PLA General Hospital from January 1, 2005, to December 31, 2020, were collected. The correlation between tumor size and anterior pituitary hormone levels was analyzed using Spearman rank correlation analysis in different types of pituitary adenomas. Results: The median age of the 1 946 patients was 45.1 years, of which 857 (44.0%) were men. The maximum tumor diameter of the patients [M (Q1, Q3)] was 22 (14, 30) mm. Tumor size in nonfunctioning adenomas (n=1 191) was negatively correlated with adrenocorticotropic hormone (ACTH) (r=-0.11, P<0.001), growth hormone (r=-0.13, P<0.001), and luteinizing hormone (men: r=-0.26, P<0.001, women: r=-0.31, all P<0.001). The tumor size of somatotropic adenomas (n=297) was positively correlated with growth hormone (r=0.46, P<0.001), but negatively correlated with male testosterone (r=-0.41, P<0.001). The tumor size of ACTH-secreting pituitary adenomas (n=155) was positively correlated with the ACTH level at 8∶00 AM (r=0.25, P<0.001); however, no correlation was found with cortisol at 8∶00 AM (P>0.05). The tumor size of prolactinomas (n=303) was positively correlated with the prolactin level (men: r=0.34, P=0.001; women: r=0.13, P=0.070). Conclusions: The correlation between the function of the anterior pituitary and size of the tumor depends on the cellular origin of the pituitary adenoma and specific type of hormone secretion. In somatotroph adenomas, ACTH-secreting pituitary adenomas, and prolactinomas, there is a positive correlation between tumor size and level of hormones secreted by the corresponding tumors. In patients with nonfunctioning adenomas, the tumor size was negatively correlated with the hormone levels of the pituitary-adrenal and pituitary-growth hormone axes.

Neuromedin B receptor as a potential therapeutic target for corticotroph adenomas.

PURPOSE: Cushing's disease (CD) results from autonomous adrenocorticotropic hormone (ACTH) secretion by corticotroph adenomas, leading to excessive cortisol production, ultimately affecting morbidity and mortality. Pasireotide is the only FDA approved tumor directed treatment for CD, but it is effective in only about 25% of patients, and is associated with a high rate of hyperglycemia. Neuromedin B (NMB), a member of the bombesin-like peptide family, regulates endocrine secretion and cell proliferation. Here, we assessed NMB and NMB receptor (NMBR) expression in human corticotroph adenomas and the effects of NMBR antagonist PD168368 on murine and human corticotroph tumors. METHODS: To investigate NMB and NMBR expression, real-time qPCR and immunostaining on human pathological specimens of corticotroph, non-functional and somatotroph adenomas were performed. The effects of PD168368 on hormone secretion and cell proliferation were studied in vitro, in vivo and in seven patient-derived corticotroph adenoma cells. NMB and NMBR were expressed in higher extent in human corticotroph adenomas compared with non-functional or somatotroph adenomas. RESULTS: In murine AtT-20 cells, PD168368 reduced proopiomelanocortin (Pomc) mRNA/protein expression and ACTH secretion as well as cell proliferation. In mice with tumor xenografts, tumor growth, ACTH and corticosterone were downregulated by PD168368. In patient-derived adenoma cells, PD168368 reduced POMC mRNA expression in four out of seven cases and ACTH secretion in two out of five cases. A PD168368-mediated cyclin E suppression was also identified in AtT-20 and patient-derived cells. CONCLUSION: NMBR antagonist represents a potential treatment for CD and its effect may be mediated by cyclin E suppression.

An individualized approach to the management of Cushing disease.

Cushing disease caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary corticotroph adenoma leads to hypercortisolaemia with high mortality due to metabolic, cardiovascular, immunological, neurocognitive, haematological and infectious conditions. The disorder is challenging to diagnose because of its common and heterogenous presenting features and the biochemical pitfalls of testing levels of hormones in the hypothalamic-pituitary-adrenal axis. Several late-night salivary cortisol and 24-h urinary free cortisol tests are usually required as well as serum levels of cortisol after a dexamethasone suppression test. MRI might only identify an adenoma in 60-75% of patients and many adenomas are small. Therefore, inferior petrosal sinus sampling remains the gold standard for confirmation of ACTH secretion from a pituitary source. Initial treatment is usually transsphenoidal adenoma resection, but preoperative medical therapy is increasingly being used in some countries and regions. Other management approaches are required if Cushing disease persists or recurs following surgery, including medications to modulate ACTH or block cortisol secretion or actions, pituitary radiation, and/or bilateral adrenalectomy. All patients require lifelong surveillance for persistent comorbidities, clinical and biochemical recurrence, and treatment-related adverse effects (including development of treatment-associated hypopituitarism). In this Review, we discuss challenges in the management of Cushing disease in adults and provide information to guide clinicians when planning an integrated and individualized approach for each patient.

Metastatic pituitary tumors: an institutional case series.

PURPOSE: Pituitary carcinomas are a rare entity that respond poorly to multimodal therapy. Patients follow a variable disease course that remains ill-defined. METHODS: We present an institutional case series of patients treated for pituitary carcinomas over a 30-year period from 1992 to 2022. A systematic review was conducted to identify prior case series of patients with pituitary carcinomas. RESULTS: Fourteen patients with a mean age at pituitary carcinoma diagnosis of 52.5 years (standard deviation [SD] 19.4) met inclusion criteria. All 14 patients had tumor subtypes confirmed by immunohistochemistry and hormone testing, with the most common being ACTH-producing pituitary adenomas (n = 12). Patients had a median progression-free survival (PFS) of 1.4 years (range 0.7-10.0) and a median overall survival (OS) of 8.4 years (range 2.3-24.0) from pituitary adenoma diagnosis. Median PFS and OS were 0.6 years (range 0.0-2.2) and 1.5 years (range 0.1-9.6) respectively upon development of metastases. Most patients (n = 12) had locally invasive disease to the cavernous sinus, dorsum sellae dura, or sphenoid sinus prior to metastasis. Common sites of metastasis included the central nervous system, liver, lung, and bone. In a pooled analysis including additional cases from the literature, treatment of metastases with chemotherapy or a combination of radiation therapy and chemotherapy significantly prolonged PFS (p = 0.02), while failing to significantly improve OS (p = 0.14). CONCLUSION: Pituitary carcinomas are highly recurrent, heterogenous tumors with variable responses to treatment. Multidisciplinary management with an experienced neuro-endocrine and neuro-oncology team is needed given the unrelenting nature of this disease.

The clinicopathological features and prognosis of silent corticotroph tumors: an updated systematic review and meta-analysis.

INTRODUCTION: Data on silent corticotroph tumor (SCT) are still heterogeneous and controversial. In this study, we aimed to compare the demographic, clinicopathological manifestations, postoperative complications, and patient outcomes of SCTs with other non-functioning pituitary neuroendocrine tumor (NFT) and functioning corticotroph tumor (FCT) or so-called Cushing disease adenoma. METHODS: We searched PubMed and Web of Science for data of interest. Odds ratio (OR), mean difference (MD), hazard ratio (HR), and their 95% confidence intervals (CI) were pooled using the random-effect model. RESULTS: Twenty-nine studies with 985 SCTs were included in meta-analyses. In comparison to other NFTs, SCTs were more commonly associated with female gender, younger age, cavernous sinus invasion, apoplexy, and radiotherapy administration. Postoperatively, SCT patients were more likely to experience hypocortisolism, new-onset visual disturbances, and a higher risk for tumor progression than other NFTs. We did not find any significant differences between SCT type I and type II. Compared to FCTs, SCTs were more likely male, older age, and had larger tumor sizes. The prevalence of a USP8 mutation was significantly higher in FCT than in SCT. CONCLUSION: SCT was demographically, clinicopathologically, and prognostically distinct from other NFTs and FCTs. These tumors should be considered high-risk; appropriate treatment decisions and more stringent follow-up should be tailored to improve patient outcomes.

Cushing syndrome caused by an ectopic ACTH-producing pituitary adenoma of the clivus region: A rare case report and literature review.

RATIONALE: Ectopic ACTH-producing pituitary adenoma (EAPA) of the clivus region is extraordinarily infrequent condition and merely a few reports have been reported to date. PATIENT CONCERNS: The patient was a 53-year-old woman who presented with Cushing-like appearances and a soft tissue mass in the clivus region. DIAGNOSES: The final diagnosis of clivus region EAPA was established by clinical, radiological and histopathological findings. INTERVENTIONS: The patient underwent gross total clivus tumor resection via transsphenoidal endoscopy. OUTCOMES: Half a year after surgery, the patient Cushing-like clinical manifestations improved significantly, and urinary free cortisol and serum adrenocorticotropin (ACTH) returned to normal. LESSONS: Given the extreme scarcity of these tumors and their unique clinical presentations, it may be possible to misdiagnose and delayed treatment. Accordingly, it is especially crucial to summarize such lesions through our present case and review the literature for their precise diagnosis and the selection of optimal treatment strategies.

Postoperative Serum Cortisol and Cushing Disease Recurrence in Patients With Corticotroph Adenomas.

CONTEXT: In Cushing disease, the association between the rate of serum cortisol decline and recurrent disease after corticotroph adenoma removal has not been adequately characterized. OBJECTIVE: To analyze postoperative serum cortisol and recurrence rates in Cushing disease. METHODS: Patients with Cushing disease and pathology-confirmed corticotroph adenoma were retrospectively studied. Cortisol halving time was estimated using exponential decay modeling. Halving time, first postoperative cortisol, and nadir cortisol values were collected using immediate postoperative inpatient laboratory data. Recurrence and time-to-recurrence were estimated and compared among cortisol variables. RESULTS: A total of 320 patients met inclusion/exclusion criteria for final analysis, and 26 of those patients developed recurrent disease. Median follow-up time was 25 months (95% CI, 19-28 months), and 62 patients had ≥ 5 years follow-up time. Higher first postoperative cortisol and higher nadir were associated with increased risk of recurrence. Patients who had a first postoperative cortisol ≥ 50 µg/dL were 4.1 times more likely to recur than those with a first postoperative cortisol < 50 µg/dL (HR 4.1, 1.8-9.2; P = .0003). Halving time was not associated with recurrence (HR 1.7, 0.8-3.8, P = .18). Patients with a nadir cortisol ≥2 µg/dL were 6.6 times more likely to recur than those with a nadir cortisol of < 2 µg/dL (HR 6.6, 2.6-16.6, P < .0001). CONCLUSION: Postoperative nadir serum cortisol is the most important cortisol variable associated with recurrence and time-to-recurrence. Compared to first postoperative cortisol and cortisol halving time, a nadir < 2 µg/dL showed the strongest association with long-term remission and typically occurs within the first 24 to 48 hours after surgery.

Differentiation of silent corticotroph pituitary neuroendocrine tumors (PitNETs) from non-functioning PitNETs using kinetic analysis of dynamic MRI.

PURPOSE: Silent corticotroph pituitary adenomas (SCAs)/pituitary neuroendocrine tumors (PitNETs) are common non-functioning pituitary adenomas (NFAs)/PitNETs with a clinically aggressive course. This study aimed to investigate the ability of time-intensity analysis of dynamic magnetic resonance imaging (MRI) for distinguishing adrenocorticotropic hormone (ACTH)-positive SCAs and ACTH-negative SCAs from other NFAs. MATERIALS AND METHODS: We retrospectively evaluated the dynamic MRI findings of patients with NFAs. The initial slope of the kinetic curve (slopeini) obtained by dynamic MRI for each tumor was analyzed using a modified empirical mathematical model. The maximum slope of the kinetic curve (slopemax) was obtained by geometric calculation. RESULTS: A total of 106 patients with NFAs (11 ACTH-positive SCAs, 5 ACTH-negative SCAs, and 90 other NFAs) were evaluated. The kinetic curves of ACTH-positive SCAs had significantly lesser slopeini and slopemax compared with ACTH-negative SCAs (P = 0.040 and P = 0.001, respectively) and other NFAs (P = 0.018 and P = 0.035, respectively). Conversely, the slopeini and slopemax were significantly greater in ACTH-negative SCAs than in NFAs other than ACTH-negative SCAs (P = 0.033 and P = 0.044, respectively). In receiver operating characteristic analysis of ACTH-positive SCAs and other NFAs, the area under the curve (AUC) values for slopeini and slopemax were 0.762 and 0748, respectively. In predicting ACTH-negative SCAs, the AUC values for slopeini and slopemax were 0.784 and 0.846, respectively. CONCLUSIONS: Dynamic MRI can distinguish ACTH-positive SCAs and ACTH-negative SCAs from other NFAs.

Radiomics model and clinical scale for the preoperative diagnosis of silent corticotroph adenomas.

OBJECTIVE: Silent corticotroph adenomas (SCAs) are a subtype of nonfunctioning pituitary adenomas that exhibit more aggressive behavior. However, rapid and accurate preoperative diagnostic methods are currently lacking. DESIGN: The purpose of this study was to examine the differences between SCA and non-SCA features and to establish radiomics models and a clinical scale for rapid and accurate prediction. METHODS: A total of 260 patients (72 SCAs vs. 188 NSCAs) with nonfunctioning adenomas from Peking Union Medical College Hospital were enrolled in the study as the internal dataset. Thirty-five patients (6 SCAs vs. 29 NSCAs) from Fuzhou General Hospital were enrolled as the external dataset. Radiomics models and an SCA scale to preoperatively diagnose SCAs were established based on MR images and clinical features. RESULTS: There were more female patients (internal dataset: p < 0.001; external dataset: p = 0.028) and more multiple microcystic changes (internal dataset: p < 0.001; external dataset: p = 0.012) in the SCA group. MRI showed more invasiveness (higher Knosp grades, p ≤ 0.001). The radiomics model achieved AUCs of 0.931 and 0.937 in the internal and external datasets, respectively. The clinical scale achieved an AUC of 0.877 and a sensitivity of 0.952 in the internal dataset and an AUC of 0.899 and a sensitivity of 1.0 in the external dataset. CONCLUSIONS: Based on clinical information and imaging characteristics, the constructed radiomics model achieved high preoperative diagnostic ability. The SCA scale achieved the purpose of rapidity and practicality while ensuring sensitivity, which is conducive to simplifying clinical work.

Molecular characterization of epithelial-mesenchymal transition and medical treatment related-genes in non-functioning pituitary neuroendocrine tumors.

Introduction: Different medical therapies have been developed for pituitary adenomas. However, Non-Functioning Pituitary Neuroendocrine Tumors (NF-PitNET) have shown little response to them. Furthermore, epithelial-mesenchymal transition (EMT) has been linked to resistance to medical treatment in a significant number of tumors, including pituitary adenomas. Methods: We aimed to evaluate the expression of EMT-related markers in 72 NF-PitNET and 16 non-tumoral pituitaries. To further explore the potential usefulness of medical treatment for NF-PitNET we assessed the expression of somatostatin receptors and dopamine-associated genes. Results: We found that SNAI1, SNAI2, Vimentin, KLK10, PEBP1, Ki-67 and SSTR2 were associated with invasive NF-PitNET. Furthermore, we found that the EMT phenomenon was more common in NF-PitNET than in GH-secreting pituitary tumors. Interestingly, PEBP1 was overexpressed in recurrent NF-PitNET, and could predict growth recurrence with 100% sensitivity but only 43% specificity. In parallel with previously reported studies, SSTR3 is highly expressed in our NF-PitNET cohort. However, SSTR3 expression is highly heterogeneous among the different histological variants of NF-PitNET with very low levels in silent corticotroph adenomas. Conclusion: NF-PitNET showed an enhanced EMT phenomenon. SSTR3 targeting could be a good therapeutic candidate in NF-PitNET except for silent corticotroph adenomas, which express very low levels of this receptor. In addition, PEBP1 could be an informative biomarker of tumor regrowth, useful for predictive medicine in NF-PitNET.

Feasibility analysis of ACTH adenoma model in USP8-/- mice.

INTRODUCTION: Patients with adrenocorticotropic hormone (ACTH)-secreting pituitary tumours (35% to 60%) present with somatic mutations in the USP8 gene. USP8 mutations lead to enhanced deubiquitination of the epidermal growth factor receptor (EGFR) and result in an imbalance in EGFR signalling, accompanied by excessive activation of ACTH production and cell growth. USP8 emerged as a novel and exciting candidate gene for Cushing's disease. MATERIAL AND METHODS: In this study, USP8 mutant mouse models (USP8+/- and USP8-/-) were established, their phenotypes were analysed and identified, biochemical indexes were detected, pituitary and adrenal tissue specimens were taken for HE staining and immunohistochemical identification of hormones, and the differences between the 2 groups of mutant mice and wild type mice were analysed and compared. RESULTS: Compared with the control group (wild type), immunofluorescence assay results for USP8+/- mice and USP8-/- mice showed increased pituitary ACTH expression, which was statistically different (p < 0.05), and there were no significant differences in body weight, plasma ACTH, 24-hour urinary free cortisol, and immunohistochemical results. Higher blood glucose in USP8-/- mice than in USP8+/+ mice was observed. The heart rates of USP8-/- mice were higher than those of USP8+/- mice and USP8+/+ mice. HE staining and tissue fibre staining were done, and no significant pathological changes were seen in the 3 groups of pituitary and adrenal tissues. CONCLUSION: USP8 knockout mice have the potential to form an animal model of ACTH adenoma.

Refractory corticotroph adenomas.

The majority of corticotroph adenomas are benign but some are locally invasive, demonstrate high rates of recurrence, and exhibit a relatively poor response to often repeated surgical, medical, and radiation treatment. Herein, we summarize the currently known somatic and genetic mutations and other molecular factors that influence the pathogenesis of these tumors and discuss currently available therapies. Although recent molecular studies have advanced our understanding of the pathogenesis and behavior of these refractory corticotroph adenomas, these insights do not reliably guide treatment choices at present. Development of additional diagnostic tools and novel tumor-directed therapies that offer efficacious treatment choices for patients with refractory corticotroph adenomas are needed.

Clinical presentation and recurrence of pituitary neuroendocrine tumors: results from a single referral center in Colombia.

INTRODUCTION: Pituitary neuroendocrine tumors (PitNETs) represent 15-18.2% of all intracranial tumors. Their clinical presentation can range from chronic headache, visual defects, hypopituitarism to hormone excess syndromes. PitNETS are commonly classified as functioning neuroendocrine tumors (F-PitNETs) and non-functioning neuroendocrine tumors (NF-PitNETs). At the moment, new classification has emerged based on cell lineages. Almost 50% of all patients with PitNETs require surgical intervention, and about 25% of these have residual and persistent disease that may require additional management. SUBJECTS AND METHODS: A retrospective cohort of medical records of patients with PitNETs, aiming to describe the incidence of recurrence of patients who received surgical treatment over a 12 month follow up period at San Jose Hospital (SJH) in Bogotá, Colombia, over an observation period of 10 years. Furthermore, clinical presentation, biochemical characteristics and immunohistochemistry, postoperative complications are detailed. RESULTS: Eight hundred and eighty-seven patients with pituitary tumors were included in the cohort; 83% (737/887) had a diagnosis of PitNET. Of these, 18.9% (140) received surgical management. The majority 58% (98/140) had nonfunctional-PitNETs (NF-PitNETs), followed by growth-hormone-secreting pituitary adenoma (22.1%; 33/140), adrenocorticotropic- hormone-secreting pituitary adenoma (9.3%; 13/140), and prolactinomas (9.3%; 13/140). A recurrence was found in 45.71% (64/140), subclassified as biochemical in 15.71% (22/140), controlled with medications in 20% (28/140), and remission occurred in 18.57% (26/140). CONCLUSION: Clinical presentation and incidence of recurrence in patients with PitNETs in a referral center in Colombia are similar to other surgical cohorts with low cure rates and high recurrence.