Variable anatomical features of acromegaly in the nasal cavity and paranasal sinuses: implications for endoscopic endonasal transsphenoidal surgery.

PURPOSE: Growth hormone (GH)-secreting pituitary neuroendocrine tumors (PitNETs) are the most common cause of acromegaly. The endoscopic endonasal transsphenoidal approach (EEA) is commonly employed to remove them. Although morphological differences in the nasal cavity exist between acromegaly patients and those with other types of PitNET, few quantitative studies have been performed. This study aimed to evaluate the anatomical features of the nasal cavity and paranasal sinuses in patients with acromegaly. METHODS: Preoperative computed tomography images of the nasal cavity and paranasal sinuses were compared between 20 patients with a GH-secreting PitNET (acromegaly group) and 22 with a non-functioning PitNET (control group). In the acromegaly group, the relationships between preoperative GH and/or insulin-like growth factor 1 (IGF-1) levels and anatomical characteristics were assessed. RESULTS: In the acromegaly group, the distance between the nostril and dorsum sellae was significantly longer and the distance between the parasellar internal carotid arteries was significantly shorter (p = 0.0022 and 0.0092, respectively). Pneumatization volume in the nasal cavity did not differ between the groups. Nasal mucosa and bony hypertrophy were observed in the acromegaly group. Preoperative GH level was correlated with the width of the piriform aperture (p = 0.0171). CONCLUSION: The nasal and paranasal changes associated with acromegaly can make EEA challenging to perform. Widening the surgical corridor anterior to the sphenoid sinus is important in these patients.

AB092. Imaging the histopathology subtypes of the growth hormone-secreting pituitary neuroendocrine tumor.

BACKGROUND: Sparsely granulated (SG) growth hormone-secreting pituitary neuroendocrine tumors (GH-PitNETs) often present with a more aggressive clinical course compared to densely granulated (DG) tumors. These subtypes exhibit distinct biological and imaging characteristics. Thus, this study aims to differentiate between the histopathological subtypes of GH-PitNETs using pre-operative magnetic resonance imaging (MRI). METHODS: A retrospective analysis was conducted on 83 acromegalic patients treated at our institution between 2000 and 2010. Tumor volumes were segmented from preoperative MRIs, including T1-weighted, T2-weighted, T1 with contrast, and T2 fluid attenuated inversion recovery (FLAIR) sequences. Reference regions of interest (ROIs) were delineated using gray and white matter from the same sequences. Two pathologists reviewed pathology specimens for anti-cytokeratin (CAM 5.2) and Pit-1 expression. Clinical and radiological biomarkers were compared between SG and DG patients. RESULTS: A total of 83 patients with complete histopathology and 51 patients with complete MRIs were included in the analysis. SG PitNETs exhibited higher rates of supra-sellar invasion (61.5%, P<0.001), larger tumor sizes, lower pre-operative GH levels, and increased post-operative residual tumor (65.4%, P<0.001) compared to DG PitNETs. Additionally, SG PitNETs showed greater hyperintensity on T2-weighted images and enhanced contrast, whereas DG PitNETs exhibited less contrast enhancement. Utilization of these imaging biomarkers demonstrated an 94.1% accuracy in T2 FLAIR and overall of 78.7% predicting the histopathological subtypes of GH-PitNETs. CONCLUSIONS: Distinct histopathological subtypes of GH-PitNETs represent crucial prognostic factors. Utilizing multimodal pre-operative MRIs, clinicians can accurately identify sparsely granulated GH-PitNETs, facilitating improved treatment planning strategies.

FTO-mediated DSP m6A demethylation promotes an aggressive subtype of growth hormone-secreting pituitary neuroendocrine tumors.

BACKGROUND: Growth hormone-secreting pituitary neuroendocrine tumors can be pathologically classified into densely granulated (DGGH) and sparsely granulated types (SGGH). SGGH is more aggressive and associated with a poorer prognosis. While epigenetic regulation is vital in tumorigenesis and progression, the role of N6-methyladenosine (m6A) in aggressive behavior has yet to be elucidated. METHODS: We performed m6A-sequencing on tumor samples from 8 DGGH and 8 SGGH patients, complemented by a suite of assays including ELISA, immuno-histochemistry, -blotting and -fluorescence, qPCR, MeRIP, RIP, and RNA stability experiments, aiming to delineate the influence of m6A on tumor behavior. We further assessed the therapeutic potential of targeted drugs using cell cultures, organoid models, and animal studies. RESULTS: We discovered a significant reduction of m6A levels in SGGH compared to DGGH, with an elevated expression of fat mass and obesity-associated protein (FTO), an m6A demethylase, in SGGH subtype. Series of in vivo and in vitro experiments demonstrated that FTO inhibition in tumor cells robustly diminishes hypoxia resistance, attenuates growth hormone secretion, and augments responsiveness to octreotide. Mechanically, FTO-mediated m6A demethylation destabilizes desmoplakin (DSP) mRNA, mediated by the m6A reader FMR1, leading to prohibited desmosome integrity and enhanced tumor hypoxia tolerance. Targeting the FTO-DSP-SSTR2 axis curtailed growth hormone secretion, therefor sensitizing tumors to octreotide therapy. CONCLUSION: Our study reveals the critical role of FTO in the aggressive growth hormone-secreting pituitary neuroendocrine tumors subtype and suggests FTO may represent a new therapeutic target for refractory/persistent SGGH.

Anatomical Differences in Sphenoid Sinus During Endoscopic Transsphenoidal Surgery: Comparison Between Nonfunctioning Pituitary Neuroendocrine Tumor (PiTNET) and Growth Hormone-Secreting PiTNET.

BACKGROUND: In surgical practice during endoscopic endonasal approach, growth hormone-secreting pituitary neuroendocrine tumor (GH-secreting PitNET) patients show morphologic differences in the nasal cavities and sinuses, leading to a narrower surgical field and a carotid prominence and potentially increasing the complexity of the surgical and the risk of complications. The aim of the study is to evaluate the anatomical differences of the sphenoid sinus between patients with GH-secreting PitNETs and patients with nonfunctioning pituitary neuroendocrine tumor (NF-PitNET) who underwent endoscopic endonasal approach. METHODS: This is a monocentric retrospective study conducted at the author's institution. The minimum intercarotid distance, the largest diameter of the sphenoid sinus (DSS), and the distance between vomer and clivus (VCD) were collected and compared. Presence, localization, and course of intersphenoid sinus septum were also evaluated. RESULTS: One hundred consecutive patients were identified: 57 males (57%) and 43 females (43%), with a mean age of 55 years. Sixty patients had NF-PitNET (60%) and 40 had GH-secreting PitNET (40%). GH-secreting PitNET group presented inferior values of intercarotid distance (16.8 ± 3.94 mm vs. 20.4 ± 3.94 mm, P < 0.001), DSS (32.5 ± 9.81 mm vs. 38.6 ± 11.03 mm, P = 0.006), and VCD (25.5 ± 6.96 mm vs. 29.6 ± 8.47 mm, P = 0.012) compared to NF-PitNET group. Intersphenoid sinus septum showed no differences between the 2 groups. CONCLUSIONS: Intercarotid distance, DSS, and VCD resulted smaller in acromegalic patients, confirming that patients with GH-secreting PitNETs have a narrower surgical field. A meticulous anatomical preoperative planning and neuronavigation are important to recognize the sphenoid anatomical landmarks in order to reduce the risk of complications, especially in acromegalic patients.

Diagnostic, therapeutic, and prognostic characteristics of patients with acromegaly according to tumor size at diagnosis.

PURPOSE: To evaluate clinical, laboratory, radiological, therapeutic, and prognostic characteristics of patients with acromegaly according to the size of the growth hormone (GH)-secreting pituitary adenoma at diagnosis. METHODS: Observational, retrospective, single-center study of patients with acromegaly followed at a tertiary center. Data were collected regarding clinical presentation, characteristics of the adenoma in the magnetic resonance imaging, GH and IGF-1 levels, and disease control after surgery or adjuvant treatment (normal IGF-1 levels). Patients were divided according to the adenoma size at diagnosis in: group I < 10 mm; II 10-19 mm; III 20-29 mm; IV 30-39 mm; and V ≥ 40 mm. Comparisons were made between the groups, and correlations of tumor size with disease parameters, ROC curves, and logistic regression analyses were performed to investigate tumor size and confounding factors that could impact the outcomes. RESULTS: 117 patients were studied [59 women, age at diagnosis 43 ± 13 years; group I = 11 patients (9%); group II 54 (46%); group III 34 (29%); group IV 10 (9%); group V 8 (7%)]. Hypopituitarism, cavernous sinus invasion, GH levels, and use of somatostatin receptor ligands had their prevalence increased according to the adenoma size. Age showed a negative correlation with tumor size. A tumor diameter around 20 mm was the best predictor for the presence of hypopituitarism, invasiveness, need of adjuvant therapies, and poorer disease control. CONCLUSION: Adenomas < 20 mm showed lower morbidity and better therapeutic response in acromegaly, while those ≥ 20 mm had similar clinical, therapeutic, and prognostic behavior.

Medical treatment of acromegaly - When the tumor size matters: A narrative review.

Medical treatment of acromegaly is generally positioned as a second line of treatment after pituitary adenoma surgery. With the rising availability and variety of medications for acromegaly increases our understanding of their effectiveness and safety. Volume of the published data on the impact of medical therapy on biochemical control of acromegaly, contrasts a relative lack of publications which comprehensively address pituitary tumor alterations under different drug modalities. Assessment of changes in GH-secreting adenoma volume is often overshadowed by clinicians' focus on GH and IGF-I levels during acromegaly treatment. Close analysis of studies published in the last two decades, reveals that both an increase and decrease in somatotropinoma volume are possible during treatment with any of available drugs for acromegaly. Changes in pituitary tumor size may arise from the biological nature of adenoma itself, independently of the administered medications. Therefore, an individual approach is necessary in the treatment of patients with acromegaly, based on repeated insight to their clinical, biochemical, pathological and imaging characteristics. In this review, we summarize and comment how pituitary tumor size is affected by the treatment with all currently available drugs in acromegaly: long-acting somatostatin receptor ligands of the first generation (octreotide LAR and lanreotide autogel) and the second generation (pasireotide-LAR), as well as pegvisomant (PEG) and cabergoline (CAB).

Suspected silent pituitary somatotroph neuroendocrine tumor associated with acromegaly-like bone disorders: a case report.

BACKGROUND: Growth hormone (GH) positive pituitary neuroendocrine tumors do not always cause acromegaly. Approximately one-third of GH-positive pituitary tumors are classified as non-functioning pituitary tumors in clinical practice. They typically have GH and serum insulin-like growth factor 1 (IGF-1) levels in the reference range and no acromegaly-like symptoms. However, normal hormone levels might not exclude the underlying hypersecretion of GH. This is a rare and paradoxical case of pituitary tumor causing acromegaly-associated symptoms despite normal GH and IGF-1 levels. CASE PRESENTATION: We report a case of a 35-year-old woman with suspicious acromegaly-associated presentations, including facial changes, headache, oligomenorrhea, and new-onset diabetes mellitus and dyslipidemia. Imaging found a 19 × 12 × 8 mm pituitary tumor, but her serum IGF-1 was within the reference, and nadir GH was 0.7ng/ml after glucose load at diagnosis. A thickened skull base, increased uptake in cranial bones in bone scan, and elevated bone turnover markers indicated abnormal bone metabolism. We considered the pituitary tumor, possibly a rare subtype in subtle or clinically silent GH pituitary tumor, likely contributed to her discomforts. After the transsphenoidal surgery, the IGF-1 and nadir GH decreased immediately. A GH and prolactin-positive pituitary neuroendocrine tumor was confirmed in the histopathologic study. No tumor remnant was observed three months after the operation, and her discomforts, glucose, and bone metabolism were partially relieved. CONCLUSIONS: GH-positive pituitary neuroendocrine tumors with hormonal tests that do not meet the diagnostic criteria for acromegaly may also cause GH hypersecretion presentations. Patients with pituitary tumors and suspicious acromegaly symptoms may require more proactive treatment than non-functioning tumors of similar size and invasiveness.

Aortic root dilation in acromegaly.

Previous studies have linked persistent elevations in growth hormone (GH) and insulin-like growth factor-1 (IGF-1) to cardiac abnormalities including aortic root dilation. Guidelines in the management of this dilation below the size recommended for surgery have not been well defined but follow-up and intervention when appropriate could be life-saving. We report the case of a man in his 60s who had been living with undiagnosed acromegaly for many years. His initial assessment through point-of-care ultrasound raised concerns about potential cardiac enlargement, prompting further investigation with a formal echocardiogram, which revealed a significant aortic root dilation measuring 4.5 cm. Subsequent blood tests confirmed elevated levels of IGF-1. Brain MRI showed a focal lesion in the pituitary gland, which was surgically resected, confirming the diagnosis of a GH-secreting pituitary adenoma. One year after surgery, a repeat CT angiogram of the chest demonstrated a stable size of the aortic root aneurysm.

The diverging role of O-GlcNAc transferase in corticotroph and somatotroph adenomas.

PURPOSE: Molecular mechanisms involved in the pathogenesis and tumor progression of pituitary adenomas (PA) remain incompletely understood. Corticotroph and somatotroph PA are associated with a high clinical burden, and despite improved surgical outcomes and medical treatment options, they sometimes require multiple surgeries and radiation. Preliminary data suggested a role for O-GlcNAc Transferase (OGT), the enzyme responsible for the O-GlcNAcylation of proteins. O-GlcNAcylation and OGT have been found elevated in other types of tumors. METHODS: We evaluated 60 functioning and nonfunctioning PA (NFPA) from operated patients and postmortem normal and tumoral pituitary tissue by immunohistochemistry. We performed transcriptomic analyses to explore the relevance of the O-GlcNAc Transferase (OGT) in PAs. We detected OGT in immunobiological analysis and define its level in PA tissue in patients. RESULTS: OGT was strongly associated with PA hormone secretory capacity in functioning PA and with tumor growth in NFPAs. In NFPAs, OGT was positively associated with tumor size but not with cavernous sinus invasion (Knosp grading). In GH-secreting PA, OGT expression was negatively correlated with circulating Insulin-like Growth Factor 1 level. In adrenocorticotropic hormone (ACTH)-secreting PA, OGT expression was positively associated with circulating ACTH levels. OGT did not correlate with tumor size in secreting PAs. OGT levels were higher in gonadotroph PA compared to normal glands. CONCLUSION: O-GlcNAcylation can be downregulated in non-cancerous tumors such as GH-secreting adenomas. Future studies are warranted to elucidate the role of OGT in the pathogenesis of PAs.

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

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

Oral octreotide capsules for acromegaly treatment: application of clinical trial insights to real-world use.

INTRODUCTION: Acromegaly is a rare endocrine disorder usually caused by a benign growth hormone‒secreting pituitary adenoma. Surgical adenoma resection is typically the first line of treatment, and medical therapy is used for patients with persistent disease following surgery, for adenoma recurrence, or for patients ineligible for, or declining, surgery. Approved somatostatin receptor ligands (SRLs) have been limited to injectable options, until recently. Oral octreotide capsules (OOC) are the first approved oral SRL for patients with acromegaly. AREAS COVERED: We review published reports and provide case study examples demonstrating practical considerations on the use of OOC. Using two hypothetical case scenarios, we discuss current treatment patterns, breakthrough symptoms and quality of life (QoL), efficacy of SRLs, OOC dose titration, evaluation of OOC treatment response, and incidence and management of adverse events. EXPERT OPINION: OOC are an option for patients with acromegaly including those who experience breakthrough symptoms, who have preference for oral therapies, or other reasons for declining injectable SRLs. OOC have been associated with improved patient-reported QoL measures compared with those reported for lanreotide and octreotide. Continued real-world experience will determine whether OOC, alone or in combination with other therapies, provides further advantages over current injectable acromegaly treatments.

GNAS mutations suppress cell invasion by activating MEG3 in growth hormone-secreting pituitary adenoma.

Approximately 30%-40% of growth hormone-secreting pituitary adenomas (GHPAs) harbor somatic activating mutations in GNAS (α subunit of stimulatory G protein). Mutations in GNAS are associated with clinical features of smaller and less invasive tumors. However, the role of GNAS mutations in the invasiveness of GHPAs is unclear. GNAS mutations were detected in GHPAs using a standard polymerase chain reaction (PCR) sequencing procedure. The expression of mutation-associated maternally expressed gene 3 (MEG3) was evaluated with RT-qPCR. MEG3 was manipulated in GH3 cells using a lentiviral expression system. Cell invasion ability was measured using a Transwell assay, and epithelial-mesenchymal transition (EMT)-associated proteins were quantified by immunofluorescence and western blotting. Finally, a tumor cell xenograft mouse model was used to verify the effect of MEG3 on tumor growth and invasiveness. The invasiveness of GHPAs was significantly decreased in mice with mutated GNAS compared with that in mice with wild-type GNAS. Consistently, the invasiveness of mutant GNAS-expressing GH3 cells decreased. MEG3 is uniquely expressed at high levels in GHPAs harboring mutated GNAS. Accordingly, MEG3 upregulation inhibited tumor cell invasion, and conversely, MEG3 downregulation increased tumor cell invasion. Mechanistically, GNAS mutations inhibit EMT in GHPAs. MEG3 in mutated GNAS cells prevented cell invasion through the inactivation of the Wnt/ß-catenin signaling pathway, which was further validated in vivo. Our data suggest that GNAS mutations may suppress cell invasion in GHPAs by regulating EMT through the activation of the MEG3/Wnt/ß-catenin signaling pathway.

Complete Shrinking of Mixed Growth Hormone and Prolactin-Secreting Pituitary Adenoma With Bromocriptine Therapy Alone.

A 40-year-old man presented with acromegaly, reduction of visual acuity and visual field, and elevated blood sugar. Imaging examinations demonstrated a large sellar adenoma with suprasellar extension that compresses the optic chiasma upward, spreads downward to the sphenoid sinus, and invades the cavernous sinus bilaterally. Random prolactin and growth hormone were beyond the scope of normal. The patient achieved complete shrinking of the adenoma by taking bromocriptine orally. For some kinds of giant mixed growth hormone-prolactin adenomas, surgical treatment is not necessary, and drug treatment can also achieve good results.

Integrative clinical, hormonal, and molecular data associate with invasiveness in acromegaly: REMAH study.

INTRODUCTION: Growth hormone (GH)-secreting pituitary tumors (GHomas) are the most common acromegaly cause. At diagnosis, most of them are macroadenomas, and up to 56% display cavernous sinus invasion. Biomarker assessment associated with tumor growth and invasion is important to optimize their management. OBJECTIVES: The study aims to identify clinical/hormonal/molecular biomarkers associated with tumor size and invasiveness in GHomas and to analyze the influence of pre-treatment with somatostatin analogs (SSAs) or dopamine agonists (DAs) in key molecular biomarker expression. METHODS: Clinical/analytical/radiological variables were evaluated in 192 patients from the REMAH study (ambispective multicenter post-surgery study of the Spanish Society of Endocrinology and Nutrition). The expression of somatostatin/ghrelin/dopamine system components and key pituitary/proliferation markers was evaluated in GHomas after the first surgery. Univariate/multivariate regression studies were performed to identify association between variables. RESULTS: Eighty percent of patients harbor macroadenomas (63.8% with extrasellar growth). Associations between larger and more invasive GHomas with younger age, visual abnormalities, higher IGF1 levels, extrasellar/suprasellar growth, and/or cavernous sinus invasion were found. Higher GH1 and lower PRL/POMC/CGA/AVPR1B/DRD2T/DRD2L expression levels (P < .05) were associated with tumor invasiveness. Least Absolute Shrinkage and Selection Operator's penalized regression identified combinations of clinical and molecular features with areas under the curve between 0.67 and 0.82. Pre-operative therapy with DA or SSAs did not alter the expression of any of the markers analyzed except for DRD1/AVPR1B (up-regulated with DA) and FSHB/CRHR1 (down-regulated with SSAs). CONCLUSIONS: A specific combination of clinical/analytical/molecular variables was found to be associated with tumor invasiveness and growth capacity in GHomas. Pre-treatment with first-line drugs for acromegaly did not significantly modify the expression of the most relevant biomarkers in our association model. These findings provide valuable insights for risk stratification and personalized management of GHomas.

Effectiveness of combined first-line medical treatment in acromegaly with prolactin cosecretion.

OBJECTIVE: The aim of this study is to compare the response to first-line medical treatment in treatment-naive acromegaly patients with pure growth hormone (GH)-secreting pituitary adenoma (GH-PA) and those with GH and prolactin cosecreting PA (GH&PRL-PA). DESIGN: This is a retrospective multicentric study of acromegaly patients followed from 2003 to 2023 in 33 tertiary Spanish hospitals with at least 6 months of first-line medical treatment. METHODS: Baseline characteristics, first-line medical treatment strategies, and outcomes were analyzed. We employed a multiple logistic regression full model to estimate the impact of some baseline characteristics on disease control after each treatment modality. RESULTS: Of the 144 patients included, 72.9% had a GH-PA, and 27.1% had a GH&PRL-PA. Patients with GH&PRL-PA were younger (43.9 ± 15.0 vs 51.9 ± 12.7 years, P < .01) and harboring more frequently macroadenomas (89.7% vs 72.1%, P = .03). First-generation somatostatin receptor ligand (fgSRL) as monotherapy was given to 106 (73.6%) and a combination treatment with fgSRL and cabergoline in the remaining 38 (26.4%). Patients with GH&PRL-PA received more frequently a combination therapy (56.4% vs 15.2%, P < .01). After 6 months of treatment, in the group of patients under fgSRL as monotherapy, those patients with GH&PRL-PA had worse control compared to GH-PAs (29.4% vs 55.1%, P = .04). However, these differences in the rate of disease control between both groups disappeared when both received combination treatment with fgSRL and cabergoline. CONCLUSION: In GH&PRL-PA, the biochemical control achieved with fgSRL as monotherapy is substantially worse than in patients harboring GH-PA, supporting the inclusion of cabergoline as first-line medical treatment in combination with fgSRLs in these subgroups of patients.

Efficacy and safety of radiosurgery in acromegaly.

Stereotactic radiosurgery (SRS) more and more frequently plays a crucial role in the treatment of acromegaly. We provide a systematic review of the literature and meta-analysis, according to PRISMA, on SRS for the management of growth hormone (GH)-secreting pituitary adenomas, including several radiosurgical techniques, with the aim of describing efficacy and safety of this treatment. A weighted random effects model was used to calculate pooled outcome estimates. From 346 abstract reviews, 27 retrospective studies were included. Despite the variability in hormonal remission criteria and the heterogeneity between treatment guidelines among included studies, most of them reported an endocrine remission rate between 40% and 60%. Random effects meta-analysis for overall endocrine remission and 5-year probability of remission estimate after SRS were 46% (95% CI: 39-53%) and of 48% (95% CI: 38-57%), respectively. Random effects meta-analysis for new hypopituitarism estimate after SRS was 23% (95% CI: 17-29%). Furthermore, incidence of radiation induced optic neuropathy after SRS ranged between 0% and 6% This meta-analysis confirms and quantifies safety and effectiveness of SRS to achieve endocrine remission after surgical management in acromegaly.

Histopathology of growth hormone-secreting pituitary tumors: State of the art and new perspectives.

Somatotroph (GH) adenomas/PitNETs typically arise from adenohypophysis and are biochemically active, leading to acromegaly and gigantism. More rarely, they present with ectopic origin and do not present overt biochemical or clinical features (silent variants). Histopathological examination should consider the clinical and radiological background, and include multiple steps assessing tumor morphology, pituitary transcription factors (PTFs), hormone secretion, proliferation markers, granulation, and somatostatin receptors (STRs), aimed at depicting as better as possible tumor origin (in case of non-functioning and/or metastatic tumor), and clinical behavior, including response to treatment. GH-secreting tumors are part of the Pit-1 family tumors and can secrete GH only (pure somatotrophs) or co-secrete prolactin (mixed tumors; in this case, various histological subtypes have been identified). Each subtype presents unique radiological, biochemical, and clinical characteristic. Therefore, the integration of biochemical, clinical, radiological, and histopathological elements is fundamental for proper diagnosis and management of pituitary adenomas/PitNETs, to be performed in referral Centers. In more recent times, the importance of genetic and epigenetic evaluation in the characterization of pituitary tumors (i.e., early identification of aggressive variants) has been outlined by some large studies, with the intention of improving targeted treatments.

Lysine Methyltransferase 5A Promotes the Progression of Growth Hormone Pituitary Neuroendocrine Tumors through the Wnt/ß-Catenin Signaling Pathway.

INTRODUCTION: Growth hormone (GH) secreting pituitary adenoma is considered one of the most harmful types of Pituitary Neuroendocrine Tumors (PitNETs). Our previous research has found that high expression of Lysine methyltransferase 5A (KMT5A) is closely related to the proliferation of PitNETs. The aim of this study was to investigate the role and molecular mechanism of KMT5A in the progression of GH PitNETs. METHODS: Immunohistochemistry, qRT-PCR, and Western blot (WB) were used to assess the expression levels of KMT5A in human normal pituitary and GH PitNETs, as well as in rat normal pituitary and GH3 cells. Additionally, we utilized RNA interference technology and treatment with a selective KMT5A inhibitor to decrease the expression of KMT5A in GH3 cells. CCK-8, EdU, flow cytometry (FCM), clone formation, and WB assay were further employed to evaluate the impact of KMT5A on the proliferation of GH3 cells in vitro. A xenograft model was established to evaluate the role of KMT5A in GH PitNETs progression in vivo. RESULTS: KMT5A was highly expressed in GH PitNETs and GH3 cells. Moreover, the reduction of KMT5A expression led to inhibited growth of GH PitNETs and increased apoptosis of tumor cells, as indicated by the findings from CCK-8, EdU, clone formation, and FCM assays. Additionally, WB analysis identified the Wnt/ß-catenin signaling pathway as a potential mechanism through which KMT5A promotes GH PitNETs progression. CONCLUSION: Our research suggests that KMT5A may facilitate the progression of GH PitNETs via the Wnt/ß-catenin signaling pathway. Therefore, KMT5A may serve as a potential therapeutic target and molecular biomarker for GH PitNETs.