Pituitary Adenoma Subtypes Research Articles

Outcomes in surgical management of microprolactinomas: an international multi-institutional series.

Prolactinomas represent the most common pituitary adenoma subtype, the majority of which are microprolactinomas. Dopamine agonists (DAs) remain the first-line intervention for microprolactinomas, however, many patients either cannot tolerate DAs or require lifelong therapy to maintain hormonal control. As endoscopic endonasal surgery (EES) continues to revolutionize the surgical management of sellar lesions, we sought to reassess the feasibility and efficacy of early surgical resection for microprolactinoma. Retrospective chart review from 2010 to 2021 of adults who underwent EES for microprolactinoma was performed across three medical centers. Surgical failure was defined as a need to restart DAs, a serum prolactin level greater than 30ng/mL at last follow-up, tumor recurrence, or a need for reoperation. A total of 56 patients were identified with a mean age of 32.9 years and an average of 26.4 months of follow-up. The majority had been on DAs preoperatively (98.2%). The most common surgical indications were DA intolerance (73.2%), tumor unresponsiveness (19.6%), and desire for pregnancy (7.1%). Gross total resection was achieved in 51 (91.1%) cases. The overall surgical remission rate was approximately 70% with failures observed in 17 (30.4%) patients. Multivariate logistic regression identified subtotal resection as the only independent predictor of surgical failure (p = 0.038*). The most common postoperative complication was transient arginine vasopressin deficiency (AVP-D) (21.4%). There were no cases of permanent AVP-D, new visual deficits, or cerebrospinal fluid leak. With a surgical remission rate of nearly 70%, EES represents a safe and viable alternative strategy to long-term DA treatment for microprolactinomas.

Comparative mortality in pituitary adenomas subtypes: a tertiary referral center study.

Mortality in pituitary adenomas (PAs) has been extensively compared to general population. However, direct comparisons between PA subtypes are scarce. We aimed to compare mortality in various subtypes of PA (acromegaly, Cushing's disease (CD), macroprolactinomas and non-functioning pituitary macroadenomas (MacroNFPA)), within a single referral center. We retrospectively analyzed mortality and survival time in all 962 PAs admitted in our department between 2011 and 2023: acromegaly (n = 306), CD (n = 69), macroprolactinoma (n = 168) and MacroNFPA (n = 419). Median follow-up was 10.2 (5.2, 15.2) years. The overall survival probability was 90.9% and 78.1% after 10 and 20 years respectively with age at diagnosis as the only significant predictor. There were no significant differences in survival probability between various PA subtypes in the whole cohort. In patients over 45 years of age at diagnosis there was a significant difference in survival probability between the four groups (p = 0.01) in the first 15 years of follow-up. In head-to-head comparisons CD had a significantly higher mortality risk than patients with acromegaly (HR 3.38 [CI 95% 1.07 to 10.60]) even after adjusting for age and sex. Patients diagnosed with CD after 45 years of age have a significantly lower survival probability than other PA subtypes in the first 15 years of follow-up. All other PA subtypes had a similar survival probability after adjusting for age and sex. Due to advances in medical treatment of hormone secreting tumors, mortality in patients with PAs might increasingly depend more on tumor mass than on hormonal hypersecretion.

Comprehensive transcriptomic analysis identifies three distinct subtypes of pituitary adenomas: insights into tumor behavior, prognosis, and stem cell characteristics

BackgroundPituitary adenomas (PAs) are the second most common intracranial tumor. While current diagnostic practices rely primarily on histological testing, they often fail to capture the molecular complexities of pituitary adenomas, underscoring the need for a molecular-based classification to refine therapeutic strategies and prognostic assessments. This study aims to provide a molecularly unbiased classification of pituitary adenomas and explore their unique gene expression patterns and clinical features.MethodsWe performed unsupervised hierarchical clustering of the gene expression profiles of 117 PA samples to identify three distinct molecular subtypes. Subsequently, we analyzed the compiled transcriptomic profiles of each individual subtype for pathway enrichment. We also validated the new classification with a validation set containing 158 PAs and 24 pituitary adenoma stem cells (PASCs).ResultsConsensus clustering of transcriptomic data from 117 pituitary adenoma (PA) samples identified three distinct molecular subtypes, each showing unique gene expression patterns and associated biological processes: Group I is enriched in signaling pathways, such as the cAMP signaling pathway and the calcium signaling pathway. Group II is primarily related to metabolic processes, including nitrogen metabolism and arginine biosynthesis in cancer. Group III predominantly shows enrichment in immune responses and potential malignant transformation of the disease, especially through cancer-related pathways such as the JAK–STAT signaling pathway and the PI3K–Akt signaling pathway. The immune profiling revealed distinct patterns for each subtype: Group I had higher dendritic cells and fewer CD8+ T cells, Group II had more monocytes and macrophages, and Group III had elevated levels of T cells. Additionally, there were differences in clinical characteristics and prognosis among the subtypes, with Group III having a worse prognosis, despite the smaller tumor size compared to other groups. Notably, differences in PASCs correlated with the molecular subtypes, with Group III stem cells being enriched in tumorigenesis pathways, PI3K–Akt signaling pathway and Ras signaling pathway.ConclusionOur study introduces a novel molecular classification for pituitary adenomas, independent of traditional histological methods. Each subtype features distinct genetic, molecular, and immunological profiles. We have isolated pituitary adenoma stem-like cells (PASCs), pairing them with tumor tissues for detailed transcriptomic analysis. These PASCs exhibit diverse molecular traits consistent with the new classification.

Diagnosis and management of pituitary adenomas in children and adolescents.

Pituitary adenomas (PAs)-also now called pituitary neuroendocrine tumours or Pit-NETS-are rare in children and adolescents and exceptional below the age of 10. Most evidence-based high-quality data are derived from larger studies in adult patients. We will review recent knowledge on the epidemiology, clinical features, diagnosis, and treatment modalities of the different types of pituitary adenomas diagnosed in children and adolescents, emphasizing the many reasons why these cases should be discussed within pituitary-specific multidisciplinary teams with experts from both paediatric and adult practice. Paediatric PA presents multiple peculiarities that may challenge their adequate management. They are overall proportionally larger and more aggressive than in adults, with potential mass effects including hypopituitarism. Hormonal hypersecretion is frequent, resulting in clinical syndromes affecting normal growth and pubertal development. Prolactinomas represent the most frequent subtype of PA found during childhood, followed by adrenocorticotropin (ACTH) and growth hormone (GH)-secreting adenomas, while clinically non-functioning adenomas are exceptionally diagnosed before the age of 16. The occurrence of a pituitary tumour in a young individual should also prompt genetic testing in each case, searching for either germline mutations in one of the known genes that may drive inherited/familial PA (such as the multiple endocrine neoplasia type 1 or MEN1 gene, or the aryl hydrocarbon receptor interacting protein or AIP gene), or for a mosaic activating mutation of GNAS as found in the McCune-Albright syndrome.

Induction of apoptosis by oridonin in nonfunctioning pituitary adenoma cells.

Nonfunctioning pituitary adenoma (NFPA) is one of the major subtypes of pituitary adenomas (PA) and its primary treatment is surgical resection. However, normal surgery fails to remove lesions completely and there remains in lack of frontline treatment, so the development of new drugs for NFPA is no doubt urgent. Oridonin (ORI) has been reported to have antitumor effects on a variety of tumors, but whether it could exhibit the same effect on NFPA requires to be further investigated. The effects of ORI on pituitary-derived folliculostellate cell line (PDFS) cell viability, colony formation, proliferation ability, migration, and invasion were examined by Cell Counting Kit-8, colony formation assay,5‑Ethynyl‑2'‑deoxyuridine proliferation assay, wound-healing assay, and Transwell assay. The differentially expressed genes in the control and ORI-treated groups were screened by transcriptome sequencing analysis and analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment. Cell cycle analysis was performed to detect changes in cell cycle. Annexin V-fluorescein isothiocyanate/propidium iodide staining was performed to detect apoptosis in ORI-treated cells. Western blot assay was performed to detect Bax, Bcl-2, and cleaved Caspase-3 protein expression. ORI inhibited PDFS cell viability and significantly suppressed cell proliferation, migration, and invasion. GO and KEGG results showed that ORI was associated with signaling pathways such as cell cycle and apoptosis in PDFS cells. In addition, ORI blocked cells in G2/M phase and induced apoptosis in PDFS cells. ORI can trigger cell cycle disruption and apoptosis collaboratively in PDFS cells, making it a promising and effective agent for NFPA therapy.

Differential expression of cancer-related lncRNAs in different subtypes of pituitary adenomas

Recent investigations have demonstrated abnormal expression of non-coding RNAs in pituitary adenomas. Cntribution of many lncRNAs to the pathogenesis of these tumors has not been evaluated yet. HOTTIP, ANRIL, PANDAR, PCGEM1 and HOTAIR are among lncRNAs with established roles in the pathogenesis of human cancers, particularly those originated from endocrine organs. The current study aims at assessment of expression of these lncRNAs in pituitary adenomas in comparison with the adjacent non-cancerous pituitary tissues. HOTAIR expression was absent from the majority of adenoma and non-tumoral samples. Expression of HOTTIP was significantly higher in non-functioning pituitary adenoma (NFPA) samples compared with paired normal samples (expression ratio (95 % CI)= 2.1 (1.13–2.1), P value=0.03). Expression of PANDAR was higher in total adenoma samples compared with paired normal samples (expression ratio (95 % CI)= 1.91 (1.16–3.13), P value=0.02). Expression of ANRIL was higher in NFPA samples compared with paired normal samples (expression ratio (95 % CI)= 1.94 (1.05–3.6), P value=0.048) and in total adenoma samples compared with paired normal samples (expression ratio (95 % CI)= 1.82 (1.11–2.98), P value=0.025). The current study raises the possibility of contribution of lncRNAs in the pathogenesis of at least some subtypes of pituitary adenomas and warrant further functional studies in this field.

Immunohistochemical and Clinicopathologic Profiling of Pituitary Adenomas at a Nigerian Tertiary Hospital

Background: Pituitary adenoma is the most common pituitary tumour and the third most common intracranial tumour worldwide. Only a few studies have been done in Africa on the immunohistochemical expression pattern and clinicopathologic presentations of the different hormonal subtypes of pituitary adenomas. Objective: To evaluate the immunohistochemical hormonal profiles and clinicopathologic behaviour of pituitary adenomas diagnosed within ten years at the Lagos University Teaching Hospital, Lagos, Nigeria. Methods: In this 10-year retrospective, cross-sectional study, all cases of pituitary adenomas diagnosed at the hospital mentioned above between 1 January 2009 and 31 December 2018 were analysed. Their paraffin-embedded tissue blocks were stained with haematoxylin and eosin and then with immunostains for growth hormome (GH), adrenocorticotrophic hormone (ACTH), thyroid stimulating hormone (TSH), follicular stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL), using their standard immunohistochemistry protocols. Results: Seventy pituitary adenoma cases were studied. The male-to-female ratio of the patients was 1.6:1. The median age was 45 years, and the peak age of occurrence was the fifth decade for both sexes. Most were null cell adenomas (44.7%) and FSH-beta gonadotrophs (22.9%). The least diagnosed were thyrotroph (1.4%) and corticotroph adenomas (1.4%). Most of the adenomas were macroadenomas, and the most common presenting symptom was visual impairment. Conclusion: Pituitary adenoma is commoner in males in their 5th decade of life at the Lagos University Teaching Hospital, Lagos, Nigeria. The null cell adenoma is the commonest type of pituitary adenoma diagnosed in the center, and the majority of the patient diagnosed with pituitary adenoma present late with complications of visual impairment.

Elevated risk of recurrence and retreatment for silent pituitary adenomas.

Pituitary adenomas are the most common tumor of the pituitary gland and comprise nearly 15% of all intracranial masses. These tumors are stratified into functional or silent categories based on their pattern of hormone expression and secretion. Preliminary evidence supports differential clinical outcomes between some functional pituitary adenoma (FPA) subtypes and silent pituitary adenoma (SPA) subtypes. We collected and analyzed the medical records of all patients undergoing resection of SPAs or FPAs from a single high-volume neurosurgeon between 2007 and 2018 at Brigham and Women's Hospital. Descriptive statistics and the Mantel-Cox log-rank test were used to identify differences in outcomes between these cohorts, and multivariate logistic regression was used to identify predictors of radiographic recurrence for SPAs. Our cohort included 88 SPAs and 200 FPAs. The majority of patients in both cohorts were female (48.9% of SPAs and 63.5% of FPAs). SPAs were larger in median diameter than FPAs (2.1cm vs. 1.2cm, p < 0.001). The most frequent subtypes of SPA were gonadotrophs (55.7%) and corticotrophs (30.7%). Gross total resection (GTR) was achieved in 70.1% of SPA resections and 86.0% of FPA resections (p < 0.001). SPAs had a higher likelihood of recurring (hazard ratio [HR] 3.2, 95% confidence interval [95%CI] 1.6-7.2) and a higher likelihood of requiring retreatment for recurrence (HR 2.5; 95%CI 1.0-6.1). Subset analyses revealed that recurrence and retreatment were more both likely for subtotally resected SPAs than subtotally resected FPAs, but this pattern was not observed in SPAs and FPAs after GTR. Among SPAs, recurrence was associated with STR (odds ratio [OR] 9.3; 95%CI 1.4-64.0) and younger age (OR 0.92 per year; 95%CI 0.88-0.98) in multivariable analysis. Of SPAs that recurred, 12 of 19 (63.2%) were retreated with repeat surgery (n = 11) or radiosurgery (n = 1), while the remainder were observed (n = 7).There were similar rates of recurrence across different SPA subtypes. Patients undergoing resection of SPAs should be closely monitored for disease recurrence through more frequent clinical follow-up and diagnostic imaging than other adenomas, particularly among patients with STR and younger patients. Several patients can be observed after radiographic recurrence, and the decision to retreat should be individualized. Longitudinal clinical follow-up of SPAs, including an assessment of symptoms, endocrine function, and imaging remains critical.

From Genes to Therapy: Pituitary Adenomas in the Era of Precision Medicine.

This review presents a comprehensive analysis of pituitary adenomas, a type of brain tumor with diverse behaviors and complexities. We cover various treatment approaches, including surgery, radiotherapy, chemotherapy, and their integration with newer treatments. Key to the discussion is the role of biomarkers in oncology for risk assessment, diagnosis, prognosis, and the monitoring of pituitary adenomas. We highlight advances in genomic, epigenomic, and transcriptomic analyses and their contributions to understanding the pathogenesis and molecular pathology of these tumors. Special attention is given to the molecular mechanisms, including the impact of epigenetic factors like histone modifications, DNA methylation, and transcriptomic changes on different subtypes of pituitary adenomas. The importance of the tumor immune microenvironment in tumor behavior and treatment response is thoroughly analyzed. We highlight potential breakthroughs and innovations for a more effective management and treatment of pituitary adenomas, while shedding light on the ongoing need for research and development in this field to translate scientific knowledge into clinical advancements, aiming to improve patient outcomes.

OR20-04 Genetic Profiling Using A Gene Panel Identifies Pathogenic Variants And Copy Number Variations In Pituitary Adenomas

Abstract Disclosure: T. Silva: None. D. Mohan: None. J. Mebarak: None. D. Meredith: None. W. Bi: Speaker; Self; Stryker. R. Carroll: None. U.B. Kaiser: None. A. Marcondes Lerario: None. A. Abreu: None. Introduction: Pituitary adenomas (PA) are the second most common central nervous system neoplasm and arise from different cell lineages. PA are benign tumors, although a subset of them may present with aggressive behavior, resulting in significant morbidity. Several genetic alterations have been implicated in PA tumorigenesis, such as USP8 mutations in Cushing disease (CD) and GNAS mutations in somatotroph adenomas (SA). However, the genetic profiles of PA are not completely understood. The aim of this study was to identify genetic alterations associated with PA using a gene panel. Methods: Targeted next generation exome sequencing (OncoPanel) was performed to identify single nucleotide variants (SNV) and copy number variations (CNV) associated with PA. OncoPanel version 1 included 275 genes, version 2 had 300 genes, and the third, current version 447 genes. USP8 was included only in the most recent version. Patients undergoing surgery at our institution between 2013-2020, who agreed to participate in the OncoPanel initiative and who had samples with good quality DNA were enrolled. Classification of PA into subtypes was performed by combining clinical and histopathological data. A strict algorithm was used to assess SNV pathogenicity. Chi-square, Mann Whitney and Kruskal-Wallis tests were used for statistical analyses. Results: Our cohort included 171 patients with following PA subtypes: TPIT lineage - 18 CD, 14 silent ACTH; PIT-1 lineage - 29 SA, 21 lactotroph and 4 silent poorly differentiated PIT-1 adenomas; SF-1 lineage - 77 gonadotroph and 8 null cell adenomas (negative immunostaining for hormones and TF). GNAS mutations were found in 28% of SA and USP8 mutations in 50% of CD screened for USP8. Pathogenic variants in MECOM were associated with silent ACTH, in FGFR4 and NF2 with CD, and in NOTCH2 with lactotroph adenomas, whereas pathogenic variants in TP53, EGFR, MEN1, BRCA1, FH, ATR, BLM, and XPC were identified in multiple PA subtypes. The number of CNV varied significantly between different subtypes of adenomas and were higher in lactotroph (median, 46), poorly differentiated PIT-1 (41), SA (26) and silent ACTH (17) compared to CD (3), gonadotroph (1) and null cell (0.5) (p&amp;lt; 0.001). MIB-1 proliferation index &amp;gt;3% was associated with higher CNV burden (p=0.022). Interestingly, copy number loss of chromosome 16 and 1q combined were exclusively identified in SA without GNAS mutations. Conclusion: OncoPanel analyses identified pathogenic variants in PA, some well recognized variants such as USP8 and GNAS, and some rare events such as NF2 in CD. In addition, our findings highlight subtype-specific patterns of genomic instability. The association between high CNV burden and the MIB-1 proliferation index may help to predict adenoma behavior. Genomic profile using a gene panel has the potential to better classify PA and contribute to clinical management. Presentation: Saturday, June 17, 2023

THU098 Gonadotropin Secreting Pituitary Tumor Presenting As Primary Hypogonadism

Abstract Disclosure: J.N. Shapiro: None. T.X. Lu: None. J. Eapen: None. J.G. Karam: None. Gonadotroph adenomas are the most common subtype of nonfunctional pituitary adenomas, with 35 percent secreting enough LH or FSH to raise serum gonadotropin levels, but clinical syndromes due to hypersecretion of gonadotropins are rare. A low testosterone level with high FSH or LH can mislead to a diagnosis of concomitant primary hypogonadism rather than a secreting pituitary adenoma. We present a case of a patient with an FSH-secreting pituitary macroadenoma presenting with low testosterone levels. The patient is a 67-year-old man incidentally found to have a pituitary macroadenoma measuring 12 x 13 x 12 millimeters, impinging upon the optic chiasm on MRI of the brain obtained for headaches. Visual field tests revealed abnormalities compatible with glaucoma, but not chiasm compression. He has no symptoms of hormonal excess or deficit, although his wife reported decreased erectile function. Physical examination was unremarkable except for an atrophic left testicle. Pituitary hormone function tests (ACTH, AM cortisol, IGF-1, prolactin, thyroid function tests, and 24-hour urine free cortisol) were within normal range, except for an elevated FSH 14.8-18.1 mIU/mL and decreased testosterone in range of 185-256 ng/dL, with normal LH at 7.0 mIU/mL, for which he was referred for urology for evaluation of primary hypogonadism. The patient underwent transsphenoidal resection of the pituitary adenoma. Postoperative pathology revealed a pituitary adenoma, gonadotroph cell type, with immunohistochemical staining scattered positive FSH, and rare positive LH. Postoperative MRI showed post-surgical changes with no residual nodular enhancement. Following surgery, the patient suffered from severe clinical hypogonadism with episodes of profuse diaphoresis and extreme fatigue. Postoperative laboratory values revealed panhypopituitarism with undetectable testosterone level, and low LH and FSH levels. The patient was successfully treated with hydrocortisone, levothyroxine, and testosterone, with resolution of his symptoms. Our patient presented with a pituitary macroadenoma, low testosterone, and high FSH suggestive initially of primary hypogonadism, but found ultimately to have an FSH-secreting adenoma. He likely had underlying hypogonadism, primary or secondary, and although his adenoma secreted FSH, it was not enough to maintain testosterone level in normal range, possibly in part due to biologically inactive FSH molecules or to primary testicular failure. The extremely low testosterone levels postoperatively suggest that his testicular function was mostly stimulated by the adenoma secreted FSH and was therefore drastically lost after surgery. This case increases awareness to consider a gonadotropin-secreting tumor in the differential diagnosis of a pituitary adenoma with high FSH or LH, even when testosterone level is unexpectedly low. Presentation: Thursday, June 15, 2023

Pituitary adenomas with multiple cell lineage combinations: clinicopathological features and short-term prognosis.

There are few published data concerning pituitary adenomas (PAs) derived from multiple lineages. In this study the authors aimed to determine the clinicopathological characteristics and prognostic profiles of PAs with multiple cell lineage combinations (PAwMCs). The authors reviewed data on 723 patients with PAs who had undergone surgery between 2018 and 2021 and identified 93 cases (12.9%) of PAwMC. They collected detailed data on these cases, including clinical information, pathological features, and prognosis. From among 589 cases of PAs with only one cell lineage (PAwOCs), they randomly selected 100 cases to investigate differences between the two tumors. To enable investigation of the characteristics of different subgroups, they further subclassified PAwMCs into 4 groups according to the following specified combinations of pituitary-associated transcription factors: group A, immunopositive for pituitary-specific positive transcription factor 1 (Pit1) and steroidogenic factor 1 (SF1); group B, immunopositive for Pit1 and T-box transcription factor (Tpit); group C, immunopositive for SF1 and Tpit; and group D, immunopositive for Pit1, SF1, and Tpit. Compared with PAwOC, PAwMC was more often associated with hormone hypersecretion (31.0% vs 50.0%, p = 0.037) and had worse short-term prognoses with lower complete response rates (58.7% vs 30.0%, p = 0.026) and more postoperative complications (19.4% vs 35.9%, p = 0.041). Each of the 4 PAwMC subgroups had its own clinical features. Overall, PAwMCs displayed more neurological manifestations than evidence of hypersecretion, which may be attributable to a disparity between pituitary-associated transcription factors and endocrine-related manifestations. Moreover, multiple cell lineages, tumor size (p = 0.011), and Knosp grade (p = 0.013) were all found to be critical predictors of the prognosis of PAwMC. The authors described a special subtype of PAs, which derived from multiple lineages. They found a unique effect of the combination of distinct cell lineages on PAs and present detailed clinicopathological and prognostic profiles of these special PAs. These data will contribute to a more comprehensive view of PAs and assist in the selection of treatment.

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

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. 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. 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. 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. 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.

Pituitary adenomas and cerebrovascular disease: A review on pathophysiology, prevalence, and treatment.

Pituitary adenomas (PAs) have been shown to cause excess cardiovascular disease comorbidity and mortality. Cerebrovascular disease (CeVD) is a small subset of cardiovascular disease with high morbidity, and its risk in patients with pituitary adenomas has been sparingly explored. In this review, we examine what is known about the prevalence of cerebrovascular disease in patients with PAs, from its initial discovery in 1970 to present. An abundance of literature describes increased cerebrovascular mortality in patients with acromegaly, while research on other PA subtypes is less frequent but shows a similarly elevated CeVD mortality relative to healthy populations. We also review how cerebrovascular risk changes after PAs are treated, with PA treatment appearing to prevent further accumulation of cerebrovascular risk without reversing prior elevations. While acromegaly-associated CeVD appears to becaused by elevated growth hormone (GH) levels and Cushing disease's elevated glucocorticoids similarly cause durable alterations in cerebrovascular structure and function, less is known about the mechanisms behind CeVD in other PA subpopulations. Proposed pathophysiologies include growth hormone deficiency inducing vessel wall damage or other hormone deficits causing increased atherosclerotic disease. Early diagnosis and treatment of PAs may be the key to minimizing lifetime CeVD risk elevations. More research is needed to better understand the mechanisms behind the increased CeVD seen in patients with PAs. Physicians caring for PA patients must remain vigilant for signs and symptoms of cerebrovascular disease in this patient population.

The Integrated Stress Response Is Tumorigenic and Constitutes a Therapeutic Liability in Somatotroph Adenomas.

Somatotroph adenomas are the leading cause of acromegaly, with the nearly sparsely granulated somatotroph subtype belonging to high-risk adenomas, and they are less responsive to medical treatment. The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. In this study, we identified the characteristic profiling of the integrated stress response in translocation and translation initiation factor activity in somatotroph adenomas, normal pituitary, or other adenoma subtypes through proteomics. Immunohistochemistry exhibited the differential significance and the priority of eukaryotic translation initiation factor 2β (EIF2β) in somatotroph adenomas compared with gonadotroph and corticotroph adenomas. Differentially expressed genes based on the level of EIF2β in somatotroph adenomas were revealed. MetaSape pathways showed that EIF2β was involved in regulating growth and cell activation, immune system, and extracellular matrix organization processes. The correlation analysis showed Spearman correlation coefficients of r = 0.611 (p &lt; 0.001) for EIF2β and eukaryotic translation initiation factor 2 alpha kinase 1 (HRI), r = 0.765 (p &lt; 0.001) for eukaryotic translation initiation factor 2 alpha kinase 2 (PKR), r = 0.813 (p &lt; 0.001) for eukaryotic translation initiation factor 2 alpha kinase 3 (PERK), r = 0.728 (p &lt; 0.001) for GCN2, and r = 0.732 (p &lt; 0.001) for signal transducer and activator of transcription 3 (STAT3). Furthermore, the invasive potential in patients with a high EIF2β was greater than that in patients with a low EIF2β (7/10 vs. 4/18, p = 0.038), with a lower immune-cell infiltration probability (p &lt; 0.05). The ESTIMATE algorithm showed that the levels of activation of the EIF2 pathway were negatively correlated with the immune score in somatotroph adenomas (p &lt; 0.001). In in vitro experiments, the knockdown of EIF2β changed the phenotype of somatotroph adenomas, including cell proliferation, migration, and the secretion ability of growth hormone/insulin-like growth factor-1. In this study, we demonstrate that the ISR is pivotal in somatotroph adenomas and provide a rationale for implementing ISR-based regimens in future treatment strategies.

Emerging Roles of miRNA, lncRNA, circRNA, and Their Cross-Talk in Pituitary Adenoma

Pituitary adenoma (PA) is a common intracranial tumor without specific biomarkers for diagnosis and treatment. Non-coding RNAs (ncRNAs), including microRNAs (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA), regulate a variety of cellular processes, such as cell proliferation, differentiation, and apoptosis. Increasing studies have shown that the dysregulation of ncRNAs, especially the cross-talk between lncRNA/circRNA and miRNA, is related to the pathogenesis, diagnosis, and prognosis of PA. Therefore, ncRNAs can be considered as promising biomarkers for PA. In this review, we summarize the roles of ncRNAs from different specimens (i.e., tissues, biofluids, cells, and exosomes) in multiple subtypes of PA and highlight important advances in understanding the contribution of the cross-talk between ncRNAs (e.g., competing endogenous RNAs) to PA disease.

The Endoscopic Endonasal Transsphenoidal Approach for Thyrotropin-Secreting Pituitary Adenomas: Single-Center Experience and Clinical Outcomes of 49 Patients

To analyze surgical outcomes and tumor characteristics of 49 patients with thyrotropin-secreting pituitary adenoma, a rare functional pituitary adenoma subtype with challenging surgery, who underwent endoscopic endonasal transsphenoidal surgery. In this single-center study, clinical, radiological, surgical, and endocrinological data of 49 patients diagnosed with thyrotropin-secreting pituitary adenoma were retrospectively reviewed. Mean tumor size was 21.12 mm (6 microadenomas, 41 macroadenomas, 2 giant adenomas). Cavernous sinus invasion was present in 12 (24.48%) patients. Tumor consistency was firm in 23 (46.93%) patients. Plurihormonal secretion characteristics were present in 9 patients (5 growth hormone+ thyrotropin and 4 growth hormone+ prolactin+ thyrotropin). Mean follow-up duration was 51.73 months. Of the cases with firm tumors, 14 patients had a history of antithyroid drug use; there was no statistically significant correlation between the antithyroid medication and the firmness of the tumor. Gross total resection was achieved in 32 (65.30%) cases, near-total resection was achieved in 14 (28.57%) cases, and subtotal resection was achieved in 3 (6.12%) cases. The analysis showed that the negative effect of >2 cm tumor size and cavernous sinus invasion on resection rate was statistically significant (P < 0.001). Although early remission was achieved in 33 (67.34%) patients, 44 (89.79%) patients were in euthyroid state at >3 months' follow-up. Complications were 4 new-onset pituitary deficiencies, 3 cases of permanent diabetes insipidus, 1 thyrotoxic crisis, and 1 cerebrospinal fluid leak. Endoscopic endonasal transsphenoidal surgery is the first-line treatment in thyrotropin-secreting pituitary adenoma and should be performed in a tertiary center. Gross total resection is the goal, and early diagnosis is essential for surgical success.

Prospective intraoperative and histologic evaluation of cavernous sinus medial wall invasion by pituitary adenomas and its implications for acromegaly remission outcomes

Recurrence and biochemical remission rates vary widely among different histological subtypes of pituitary adenoma. In this prospective study, we evaluated 107 consecutive primary pituitary adenomas operated on by a single neurosurgeon including 28 corticotroph, 27 gonadotroph, 24 somatotroph, 17 lactotroph, 5 null-cell and 6 plurihormonal. In each case, we performed direct endoscopic intraoperative inspection of the medial wall of the cavernous sinus, which was surgically removed when invasion was visualized. This was performed irrespective of tumor functional status. Medial wall resection was performed in 47% of pituitary adenomas, and 39/50 walls confirmed pathologic evidence of invasion, rendering a positive predictive value of intraoperative evaluation of medial wall invasion of 78%. We show for the first-time dramatic disparities in the frequency of medial wall invasion among pathological subtypes. Somatotroph tumors invaded the medial wall much more often than other adenoma subtypes, 81% intraoperatively and 69% histologically, followed by plurihormonal tumors (40%) and gonadotroph cell tumors (33%), both with intraoperative positive predictive value of 100%. The least likely to invade were corticotroph adenomas, at a rate of 32% intraoperatively and 21% histologically, and null-cell adenomas at 0%. Removal of the cavernous sinus medial wall was not associated with permanent cranial nerve morbidity nor carotid artery injury, although 4 patients (all Knosp 3-4) experienced transient diplopia. Medial wall resection in acromegaly resulted in the highest potential for biochemical remission ever reported, with an average postoperative day 1 GH levels of 0.96 ug/L and surgical remission rates of 92% based on normalization of IGF-1 levels after surgery (mean = 15.56 months; range 3–30 months). Our findings suggest that tumor invasion of the medial wall of the cavernous sinus may explain the relatively low biochemical remission rates currently seen for acromegaly and illustrate the relevance of advanced intradural surgical approaches for successful and durable outcomes in endonasal pituitary surgery for functional adenomas.

ACT001 inhibits pituitary tumor growth by inducing autophagic cell death via MEK4/MAPK pathway.

ACT001, derived from traditional herbal medicine, is a novel compound with effective anticancer activity in clinical trials. However, little is known regarding its role in pituitary adenomas. Here, we demonstrated that ACT001 suppressed cell proliferation and induced cell death of pituitary tumor cells in vitro and in vivo. ACT001 was also effective in suppressing the growth of different subtypes of human pituitary adenomas. The cytotoxic mechanism ACT001 employed was mainly related to autophagic cell death(ACD), indicated by autophagosome formation and LC3-II accumulation. In addition, ACT001-mediated inhibitory effect decreased when either ATG7 was downregulated or cells were cotreated with autophagy inhibitor 3-methyladenine (3-MA). RNA-seq analysis showed that mitogen-activated protein kinase (MAPK) pathway was a putative target of ACT001. Specifically, ACT001 treatment promoted the phosphorylation of JNK and P38 by binding to mitogen-activated protein kinase kinase 4 (MEK4). Our study indicated that ACT001-induced ACD of pituitary tumor cells via activating JNK and P38 phosphorylation by binding with MEK4, and it might be a novel and effective anticancer drug for pituitary adenomas.

Exosomal miRNA Profiling is a Potential Screening Route for Non-Functional Pituitary Adenoma.

Non-functional pituitary adenomas (NFPAs) are one of the most prevalent pituitary adenoma subtypes. The lack of reliable screening approach for NFPAs for the insidious clinical course usually leads to delays in medical therapy and consequently worse prognosis. Hence, we employed a sequence cohort (patient: control, 6:2) and a validation cohort (patient: control, 22:8) to develop a serum exosomal miRNA profile-based method for NFPA screening and prognosis prediction. We found that a total of 1,395 kinds of human miRNA were detected. Compared with healthy donors, 18 up-regulated and 36 down-regulated miRNAs showed significant expression alterations in NFPA patients. Target genes of differentially expressed miRNAs are mainly enriched in axonogenesis and cancer-associated terms. After validation, hsa-miR-486-5p, hsa-miR-151a-5p, hsa-miR-652-3p_R+1, and hsa-miR-1180-3p were promising biomarkers for NFPA, in which miR-486-5p was the most competent one. After a median of 33 months of prospective follow-up, exosomal hsa-miR-486-5p also was an efficient predictive biomarker for progression or relapse of NFPAs. By protein-protein interaction network construction of hsa-miR-486-5p targeted genes, the core modules revealed a high possibility that exosomal hsa-miR-486-5p regulated tumor progression by epigenetic regulation of MAPK signaling pathways. In conclusion, exosomal hsa-miR-486-5p, hsa-miR-151a-5p, hsa-miR-652-3p_R+1, and hsa-miR-1180-3p are candidate biomarkers for diagnosis and screening of NFPAs. More importantly, prospective follow-up reveals that hsa-miR-486-5p can be regarded as a significant predictor for prognosis of NFPAs.