Nonfunctioning Pituitary Adenomas Research Articles

Pre-and post-surgical non-functional pituitary adenomas and their relationship with high levels of serum glucose

Objectives This clinical, analytical, retro-prospective, auto-controlled, not randomized, and not blinded study, aimed to investigate the association of changes in the serum glucose levels with the pre-and-post changes in the size tumor in mm3 in the Non-Functional pituitary adenomas. Methods Pre-and post-surgical MRI, as well as the measurements in the serum glucose levels and immunohistochemical techniques were performed in all the patients in the study, with a mean followed-up until 208.57 days. A comparison was made between the reductions in tumor size of hormonally active pituitary adenomas (HSPAs) vs NFPAs. Results Seventy-four patients were included in this study, of whom, 46 were NFPAs. The decrease in the NFPAs tumor size after surgery was statistically significant (P ≤ 0.0001). The Mean of the differences of both type of tumors in mm3 were −9552 ± 10287. Pre-surgery, the mean of the HSPAs were 8.923 ± 2.078; and the NFPAs were 14.161 ± 1.912. The differences in the tumor size were statistically significant (p = 0.039). Post-surgical, the mean of the HSPAs were 2.079 ± 971, with a (p = 0.14): and the NFPAs were 4.609 ± 1.205. After surgery of the NFPAs, most of the patients-maintained serum levels ≤ 100 mg/dL, with a statistical significance (P ≤ 0.0003). Conclusion This study demonstrates for the first time the correlation between the presence of pre-and post- surgical changes in the NFPAs, with modifications in the levels of serum glucose, and the comparison, pre- and post-surgical between the tumor size of HSPAs and NFPAs.

Hypogonadotropic hypogonadism in patients with non-functioning pituitary adenomas before and after transsphenoidal surgery - A prospective study

Hypogonadotropic hypogonadism in patients with non-functioning pituitary adenomas before and after transsphenoidal surgery - A prospective study

Oral health-related quality of life in patients with acromegaly vs patients with non-functioning pituitary adenomas

Oral health-related quality of life in patients with acromegaly vs patients with non-functioning pituitary adenomas

Longterm-outcomes in patients with cushing's disease vs non-functioning pituitary adenoma after pituitary surgery: an active-comparator cohort study

Longterm-outcomes in patients with cushing's disease vs non-functioning pituitary adenoma after pituitary surgery: an active-comparator cohort study

Expression pattern of select cell proliferation and apoptotic markers in non-functioning pituitary adenomas predictive of tumour growth/recurrence: a pilot project

Expression pattern of select cell proliferation and apoptotic markers in non-functioning pituitary adenomas predictive of tumour growth/recurrence: a pilot project

A retrospective evaluation of operated non-functional pituitary adenomas over four decades in the maltese population

A retrospective evaluation of operated non-functional pituitary adenomas over four decades in the maltese population

Immunohistochemical staining patterns of non-functioning pituitary adenomas and presentation of secondary hormonal deficiencies

Immunohistochemical staining patterns of non-functioning pituitary adenomas and presentation of secondary hormonal deficiencies

Cell lineage specific differences in clinical behavior of clinically non-functioning pituitary adenomas according to the 2017 WHO classification - a systematic review and meta-analysis

Cell lineage specific differences in clinical behavior of clinically non-functioning pituitary adenomas according to the 2017 WHO classification - a systematic review and meta-analysis

Expression analysis of necroptosis related genes and lncRNAs in patients with pituitary neuroendocrine tumors

Necroptosis can either be the cause of tumorigenesis or it can impede its process. Recently, it has been proved that long non-coding RNAs (lncRNAs) have different crucial roles at cellular level, especially on cell death. Regarding the important role of necroptosis and lncRNAs in the pathogenesis of different cancers, especially pituitary adenomas (PAs), we assessed expression levels of two necroptosis related genes, namely TRADD and BIRC2, in addition to three related lncRNAs, namely FLVCR1-DT, MAGI2-AS3, and NEAT1 in PAs compared with adjacent normal tissues (ANTs). TRADD had no significant difference between two groups; however, BIRC2, FLVCR1-DT, MAGI2-AS3, and NEAT1 were upregulated in PAs compared to ANTs (Expression ratios [95% CI] = 2.3 [1.47–3.6], 2.13 [1.02–4.44], 3.01 [1.76–5.16] and 2.47 [1.37–4.45], respectively). When taking into account different types of PAs, significant upregulation of BIRC2, MAGI2-AS3 and NEAT1 was recorded in non-functioning PAs compared with corresponding ANTs (Expression ratios [95% CI] =1.9 [1.04–3.43], 2.69 [1.26–5.72] and 2.22 [0.98–5.01], respectively). Additionally, higher levels of BIRC2 were associated with higher flow of CSF (P value=0.048). Moreover, higher Knosp classified tumors had lower levels of BIRC2 (P value=0.001). Finally, lower levels of MAGI2-AS3 were associated with larger tumor size (P value=0.006). NEAT1 expression was correlated with FLVCR1-DT and TRADD. TRADD expression was correlated with FLVCR1-DT. Additional correlation was observed between expression of BIRC2 and MAGI2-AS3. In sum, this study provides evidence that dysregulated levels of studied genes could contribute to the pathogenesis of pituitary tumors.

Clinical and radiographic characteristics of patients with non-functioning pituitary adenomas categorized according to their serum prolactin concentration: novel predictors of postoperative transient diabetes insipidus following surgery.

Non-functioning pituitary adenomas (NFPAs) are often associated with hyperprolactinemia, which is known as the "stalk effect". However, the relationships between hyperprolactinemia and the radiographic characteristics of the tumor that affects the pituitary stalk have not been well characterized. We aimed to identify the differences in the clinical and radiographic characteristics of patients with NFPA, with and without hyperprolactinemia. We enrolled 107 patients with NFPA and allocated them to hyperprolactinemia and non-hyperprolactinemia groups using two different cut-off values: (1) the upper limit of the normal reference range, adjusted for sex and menopausal status, and (2) the upper quartile across the cohort, and compared their clinical and radiographic characteristics. These analyses were conducted to clarify the relationship between the "stalk effect" and the postoperative change in antidiuretic hormone secretion. The specific radiographic characteristics of the patients included the presence of a cystic or hemorrhagic tumor and the presence of pituitary stalk deviation, which were more frequent in the patients with hyperprolactinemia. Interestingly, the incidence of postoperative transient diabetes insipidus was statistically significantly higher in the hyperprolactinemia group (≥40 ng/mL) and in the group with radiologic evidence of stalk deviation, which were shown to be independent risk factors on multivariate analysis. The presence of a "stalk effect" was associated with a higher risk of postoperative transient diabetes insipidus, reflecting perioperative pituitary stalk dysfunction following NFPA surgery, especially in patients with serum prolactin concentrations ≥40 ng/mL and radiologic evidence of stalk deviation.

Magnetic Resonance Imaging Features of the Sphenoid Sinus in Patients with Non-Functioning Pituitary Adenoma.

Background and Objectives: A magnetic resonance imaging (MRI) scan is part of the diagnostic protocol in pituitary adenoma patients. The goal of the present study is to present and analyse the MRI appearances of the sphenoid sinus (SS) in patients with non-functioning pituitary adenoma (NFPA). Materials and Methods: This is a retrospective case-control study conducted between January 2015 and December 2023 in a tertiary referral hospital. Forty NFPA patients were included in the study group, while the control group consisted of 30 age- and gender-matched cases. Results: The sellar type of SS pneumatization was the most frequently encountered pattern among both groups. The presence of the lateral recess of the SS, mucosal cysts, and sphenoethmoidal cells was similar in both patient groups. The proportion of patients with SS mucosal thickness greater than 3 mm was 42.5% in NFPA group and 3% in the control group, and this difference was statistically significant (p < 0.001). The space between the two optic nerves was significantly larger in the NFPA group as compared to the control group (p < 0.001). Conclusions: Our study was able to establish a statistically significant association between the presence of NFPA and both the thickening of the SS mucosa and increased space between optic nerves.

Increased Prevalence of Germline Pathogenic CHEK2 Variants in Individuals With Pituitary Adenomas.

CHEK2 is a cell cycle checkpoint regulator gene with a long-established role as a clinically relevant, moderate risk breast cancer predisposition gene, with greater risk ascribed to truncating variants than missense variants. To assess the rate and pathogenicity of CHEK2 variants amongst individuals with pituitary adenomas (PAs). We assessed 165 individuals with PAs for CHEK2 variants. The study population comprised a primary cohort of 29 individuals who underwent germline and tumor whole-exome sequencing, and a second, independent cohort of 136 individuals who had a targeted next-generation sequencing panel performed on both germline and tumor DNA (n = 52) or germline DNA alone (n = 84). We identified rare, coding, nonsynonymous germline CHEK2 variants amongst 3 of 29 (10.3%) patients in our primary cohort, and in 5 of 165 (3.0%) patients overall, with affected patients having a range of PA types (prolactinoma, thyrotropinoma, somatotropinoma, and nonfunctioning PA). No somatic variants were identified. Two variants were definitive null variants (c.1100delC, c.444 + 1G > A), classified as pathogenic. Two variants were missense variants (p.Asn186His, p.Thr476Met), classified as likely pathogenic. Even when considering the null variants only, the rate of CHEK2 variants was higher in our cohort compared to national control data (1.8% vs 0.5%; P = .049). This is the first study to suggest a role for the breast cancer predisposition gene, CHEK2, in pituitary tumorigenesis, with pathogenic/likely pathogenic variants found in 3% of patients with PAs. As PAs are relatively common and typically lack classic autosomal dominant family histories, risk alleles-such as these variants found in CHEK2-might be a significant contributor to PA risk in the general population.

Germline Variants in Sporadic Pituitary Adenomas.

Data on germline genetics of pituitary adenomas (PAs) using whole-exome sequencing (WES) are limited. This study investigated the germline genetic variants in patients with PAs using WES. We studied 134 consecutive functioning (80.6%) and nonfunctioning (19.4%) PAs in 61 female (45.5%) and 73 male patients (54.5%). Their median age was 34 years (range, 11-85 years) and 31 patients had microadenomas (23.0%) and 103 macroadenomas (77%). None of these patients had family history of PA or a known PA-associated syndrome. Peripheral blood DNA was isolated and whole-exome sequenced. We used American College of Medical Genetics and Genomics (ACMG) criteria and a number of in silico analysis tools to characterize genetic variant pathogenicity levels and focused on previously reported PA-associated genes. We identified 35 variants of unknown significance (VUS) in 17 PA-associated genes occurring in 40 patients (29.8%). Although designated VUS by the strict ACGM criteria, they are predicted to be pathogenic by in silico analyses and their extremely low frequencies in 1000 genome, gnomAD, and the Saudi Genome Project databases. Further analysis of these variants by the Alpha Missense analysis tool yielded 8 likely pathogenic variants in 9 patients in the following genes: AIP:c.767C>T (p.S256F), CDH23:c.906G>C (p.E302D), CDH23:c.1096G>A (p.A366T), DICER1:c.620C>T (p.A207V), MLH1:c.955G>A (p.E319K), MSH2:c.148G>A (p.A50T), SDHA:c.869T>C (p.L290P) and USP48 (2 patients): c.2233G>A (p.V745M). This study suggests that about 6.7% of patients with apparently sporadic PAs carry likely pathogenic variants in PA-associated genes. These findings need further studies to confirm them.

Association between Intracellular Calcium Signaling and Tumor Recurrence in Human Non-Functioning Pituitary Adenomas.

Clinically non-functioning pituitary adenomas (CNFPAs) are the second most frequent sellar tumor among studies on community-dwelling adults. They are characterized by the absence of hormonal hypersecretion syndrome, and patients present with compressive symptoms, such as a headache and visual field defects. Immunohistochemically, most CNFPAs are of gonadotrope differentiation, with only a few of them being truly null cell adenomas. Although these tumors express receptors for one or more hypothalamic releasing hormones, to what extent this has an impact on the biological and clinical behavior of these neoplasms remains to be defined. In this research, we evaluated the basal and hypothalamic secretagogue-stimulated intracellular calcium mobilization in 13 CNFPAs, trying to correlate this response to the phenotypic features of the patients. Our results indicate that the recurrence of a CNFPA correlates positively with cellular responsiveness, as measured by spontaneous intracellular calcium activity and the ability to respond to multiple hypothalamic secretagogues. We conclude that this finding may be a useful tool for predicting the clinicopathologic behavior of CNFPAs, by testing the variation of cellular responsiveness to hypothalamic secretagogues.

Correlation of older age with better progression-free survival despite less aggressive resection in nonfunctioning pituitary adenomas.

Nonfunctioning pituitary adenomas (NFPAs) present at a wide range of ages; it is possible that variable outcomes are based on patient age at presentation. This study aimed to explore long-term outcomes of patients with NFPAs following endonasal transsphenoidal surgery (ETS), considering age stratification. This retrospective study included 228 patients with NFPAs who underwent ETS, with a median follow-up period of 63 months. The outcomes included progression-free survival (PFS) rates and neurological and endocrinological outcomes. Age-stratified Kaplan-Meier and Cox proportional hazards analyses were performed. Patients were classified into four age groups: ≤ 49, 50-59, 60-69, and ≥ 70 years. Age-stratified analysis showed a significant correlation between age and PFS in NFPAs (5-year PFS rates: 63.0% in those ≤ 49 years, 76.7% in those 50-59 years, 85.0% in those 60-69 years, and 88.1% in those ≥ 70 years; p = 0.001, log-rank test). Bivariate (HR 1.03, 95% CI 1.01-1.05; p = 0.001) and multivariable (HR 1.03, 95% CI 1.02-1.05; p = 0.001) analyses demonstrated that older age was significantly associated with longer PFS. Multivariable analysis also demonstrated that smaller maximum tumor diameter (HR 0.77, 95% CI 0.60-0.99; p = 0.036) and gross-total resection (HR 8.55, 95% CI 3.90-18.75; p = 0.001) were significantly associated with longer PFS. Multivariable logistic regression analysis demonstrated that only younger age was associated with postoperative improvement of male hypogonadism (HR 0.91, 95% CI 0.84-0.99; p = 0.019). Other postoperative neurological and endocrinological outcomes were not significantly associated with age. Older patients with NFPAs treated with ETS demonstrated a longer PFS. Of endocrinological outcomes studied, only male hypogonadism improvement was associated with younger patient age.

Emotional disorders in the structure of psychoorganic pathology in tumors of the diencephalon

IntroductionThe tumors of the diencephalon region (thalamic-hypothalamic-pituitary system) include a large group: pituitary adenomas, craniopharyngiomas, gliomas, and others. Tumors differ in the histological structure, and manifestations of the clinical symptoms; by hormonal data; by approaches and methods in treatment.Psychic symptoms are revealed in disease in addition to cerebral, neuroendocrine symptoms, neurological disorders. Psychoorganic syndrome is represented by emotional, motivational, personal, cognitive impairments, inversion of the sleep-wake cycle, seizures.Disorders of mental activity are detected in all tumors of this localization in varying degrees, according to the different authors from 20 to 100%; affective pathology varies from 2 to 80% by the literature.ObjectivesTo study the emotional disorders in the structure of psychoorganic pathology in tumors of diencephalon regionMethods290 patients (18-78 years old, mean age 38+2): pituitary adenomas (PA), as the most common – 170 (58,6%), craniopharyngiomas (CG), as with the most varied manifestation of mental symptoms – 120 (41,4%). Methods: psychopathological, data from endocrinological, neurological, neuroimaging methods.ResultsEmotional disorders were detected in patients from 30 to 68% of cases, depending on the histology of the tumours: PA with excessive secretion of growth hormone - emotional disorders are in 60%; PA with excessive secretion of adrenocorticotropic hormone - in 50%; PA with excessive secretion of prolactin - in 30%; with excessive secretion of thyroid-stimulating hormone - in 40%; non-functioning PA - in 16%; CG - in 68%.Emotional disorders were more often represented by changeable mood, depression, apathy, sleep disturbance, and visceral symptoms. Symptoms differed depending on the histology of the tumor (type and level of hormones), the volume of the lesion and direction of growth, and concomitant hypertensive-hydrocephalic symptoms. Emotional disturbances often include memory impairment, personality and behavior changes.ConclusionsEmotional disorders are detected in patients in 30-68% of cases in the structure of psychoorganic pathology with damage to the diencephalon region (in particular, with pituitary adenomas and craniopharyngiomas); are determined by the topography of the tumor and histology with the involvement of the corresponding structures and nuclei in the pathological process.Disclosure of InterestNone Declared

Long-term radiographic and endocrinological outcomes of stereotactic radiosurgery for recurrent or residual nonfunctioning pituitary adenomas.

Stereotactic radiosurgery (SRS) is used for the treatment of residual/recurrent nonfunctional pituitary adenoma (NFPA). The aim of this study was to evaluate the factors related to long-term tumor control and delayed endocrinopathies following SRS. This retrospective, multicenter study included patients with recurrent/residual NFPA treated with single-fraction SRS; they were then divided into two arms. The first arm included patients with at least 5 years of radiographic follow-up and all patients with local tumor progression. The second arm included patients with at least 5 years of endocrinological follow-up and all patients who developed endocrinopathy. Study endpoints were tumor control and new or worsening hypopituitarism after SRS and were analyzed using Cox regression and Kaplan-Meier methodology. There were 360 patients in the tumor control arm (median age 52.7 [IQR 42.9-61] years, 193 [53.6%] males) and 351 patients in the hypopituitarism arm (median age 52.5 [IQR 43-61] years, 186 [53.0%] males). The median follow-up in the tumor control evaluation group was 7.95 (IQR 5.7-10.5) years. Tumor control rates at 5, 8, 10, and 15 years were 93% (95% CI 90%-95%), 87% (95% CI 83%-91%), 86% (95% CI 82%-90%), and 69% (95% CI 59%-81%), respectively. The median follow-up in the endocrinopathy evaluation group was 8 (IQR 5.9-10.7) years. Pituitary function preservation rates at 5, 8, 10, and 15 years were 83% (95% CI 80%-87%), 81% (95% CI 77%-85%), 78% (95% CI 74%-83%), and 71% (95% CI 63%-79%), respectively. A margin dose > 15 Gy (HR 0.8, 95% CI 0.7-0.9; p < 0.001) and a delay from last resection to SRS > 1 year (HR 0.9, 95% CI 0.7-0.9; p = 0.04) were significant factors related to tumor control in multivariable analysis. A maximum dose to the pituitary stalk ≤ 10 Gy (HR 1.1, 95% CI 1.09-1.2; p < 0.001) was associated with pituitary function preservation. New visual deficits after SRS occurred in 7 (1.94%) patients in the tumor control group and 8 (2.3%) patients in the endocrinopathy group. Other new cranial nerve deficits post-SRS occurred in 4 of 160 patients with data in the tumor control group and 3 of 140 patients with data in the endocrinopathy group. SRS affords favorable and durable tumor control for the vast majority of NFPAs. Post-SRS hypopituitarism occurs in a minority of patients, but this risk increases with time and warrants long-term follow-up.

Autoimmune Disorders Associated With Surgical Remission of Cushing's Disease : A Cohort Study.

Glucocorticoids suppress inflammation. Autoimmune disease may occur after remission of Cushing's disease (CD). However, the development of autoimmune disease in this context is not well described. To determine 1) the incidence of autoimmune disease in patients with CD after surgical remission compared with patients with nonfunctioning pituitary adenomas (NFPAs) and 2) the clinical presentation of and risk factors for development of autoimmune disease in CD after remission. Retrospective matched cohort analysis. Academic medical center/pituitary center. Patients with CD with surgical remission and surgically treated NFPA. Cumulative incidence of new-onset autoimmune disease at 3 years after surgery. Assessment for hypercortisolemia included late-night salivary cortisol levels, 24-hour urine free cortisol (UFC) ratio (UFC value divided by the upper limit of the normal range for the assay), and dexamethasone suppression tests. Cumulative incidence of new-onset autoimmune disease at 3 years after surgery was higher in patients with CD (10.4% [95% CI, 5.7% to 15.1%]) than in those with NFPAs (1.6% [CI, 0% to 4.6%]) (hazard ratio, 7.80 [CI, 2.88 to 21.10]). Patients with CD showed higher prevalence of postoperative adrenal insufficiency (93.8% vs. 16.5%) and lower postoperative nadir serum cortisol levels (63.8 vs. 282.3 nmol/L) than patients with NFPAs. Compared with patients with CD without autoimmune disease, those who developed autoimmune disease had a lower preoperative 24-hour UFC ratio (2.7 vs. 6.3) and a higher prevalence of family history of autoimmune disease (41.2% vs. 20.9%). The small sample of patients with autoimmune disease limited identification of independent risk factors. Patients achieving surgical remission of CD have higher incidence of autoimmune disease than age- and sex-matched patients with NFPAs. Family history of autoimmune disease is a potential risk factor. Adrenal insufficiency may be a trigger. Recordati Rare Diseases Inc.

Single Versus Fractionated Gamma Knife Radiosurgery for Nonfunctioning Pituitary Adenomas Close to the Optic Pathway: A Multicenter Propensity Score Matched Study.

Gamma Knife radiosurgery (GKRS), typically administered in a single session (S-GKRS), is an effective treatment for nonfunctioning pituitary adenoma (NFPA). For lesions close to the optic pathway, the use of hypofractionated radiosurgery is growing. This study seeks to compare the results of S-GKRS vs fractionated-GKRS (F-GKRS) for NFPAs adjacent to the optic pathway. Two cohorts of patients with residual or recurrent NFPAs in contact to the optic pathway were retrospectively included in this study: (1) a group of patients who underwent a 3-day course of F-GKRS in Europe and (2) a group of patients treated with S-GKRS in the United States. A propensity score matching (ratio 1:1) was carried out to obtain and compare 2 homogeneous groups of patients with NFPA. A total of 84 patients were included for analysis (42 in the S-GKRS cohort and 42 in the F-GKRS group). The 2 cohorts did not differ for age, sex, number of previous surgical procedure, tumor volume, and follow-up. The mean follow-up was 60.2 ± 37.0 months and 62.4 ± 37.4 months for F-GKRS and S-GKRS cohort, respectively ( P = .38). The overall tumor control at last follow-up was achieved in 95.2% and 92.9% of patients in F-GKRS and S-GKRS, respectively ( P = .64). The 1-year, 3-year, 5-year, and 7-year progression-free survival rate after F-GKRS was 100%, 97.1%, 97.1%, and 91%, respectively. In the S-GKRS sample, progression-free survival rates were 100%, 100%, 92.5%, and 92.5% at 1, 3, 5, and 7 years after treatment, respectively. Two patients (4.7%) from the F-GKRS cohort and 2 (4.7%) from the S-GKRS cohort sustained visual worsening after radiosurgery ( P = 1.0). In the management of NFPAs adjacent to the optic pathway both F-GKRS and S-GKRS had comparable outcomes and risks at 7 years. Future prospective studies including larger cohorts with longer follow-up are needed to confirm our results.

Comparing redo surgery and stereotactic radiosurgery for recurrent, residual, and/or tumors showing progression in nonfunctioning pituitary adenomas: A systematic review and meta-analysis.

Non-functioning pituitary adenomas (NFPAs) are well-differentiated benign tumors originating from the adenohypophyseal cells of the pituitary gland. They present with headaches, visual disorders, or cranial nerve deficits. NFPAs can recur, progress, or present as residual tumors. We, therefore, conducted this review to compare the effects of both revision surgery and stereotactic surgery on tumor size, visual status, endocrine status, and complications. A systematic review of published literature on recurrent, residual, or progressing NFPAs that underwent redo surgery or stereotactic radiosurgery from the inception till June 2020 was conducted as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Thirteen records (1209 patients) were included, and risk ratio (RR) and 95% confidence intervals (CIs) estimated from each study were pooled using a random-effects meta-analysis model. Redo surgery was the preferred intervention in patients presenting with larger tumor sizes and was more effective in reducing the tumor size as compared to stereotactic radiosurgery (SRS) (risk ratio [RR] 56.14; 95% CI, 16.45-191.58). There was more visual loss with revision surgery as compared to SRS (risk ratio [RR] 0.08; 95% CI, 0.03-0.20). However, SRS was associated with fewer complications, such as new diabetes insipidus, as compared to the redo surgery (risk ratio [RR] 0.01; 95% CI 0.01-0.03). Redo surgery is the superior choice in the treatment of recurrent/residual or progressing NFPAs if the tumor size is large and an immediate reduction in tumor burden through debulking is warranted. However, redo surgery is associated with a higher risk of visual loss, new endocrinopathies, and other complications, in contrast to SRS.