Somatotroph Tumors Research Articles

The place of pasireotide in precision treatment of patients with acromegaly

Due to the syndromal nature of acromegaly, the effectiveness of its treatment depends on the consideration of age, clinical and pathomorphological features of the disease, which determine the logistics of the selection of personalized therapeutic measures. The disadvantage of the used empirical pharmacotherapy scheme with the help of the ‘trial and error’ method is the formal prescription of drugs without taking into account the peculiarities of the morphofunctional status of the supervised GH-secreting tumors and the targeting of drugs. The lack of differentiated approach to acromegaly treatment is accompanied by a high percentage of therapeutic failures, and also deliberately deprives a significant proportion of patients of the opportunity to achieve timely and safe control of the disease and improve the quality of life. The review presents a comparative analysis of modern drugs used in acromegaly with a focus on the clinical efficacy of the second-generation somatostatin receptor ligand – pasireotide. The mechanism of action and pharmacotherapeutic possibilities of pasireotide LAR are considered. The therapeutic niche for this drug is patients with the presence of sparsely granulated somatotrophic tumor (SGST), characterized by aggressive course, tendency to recurrence and refractoriness to therapy with first-generation somatostatin receptor ligands.Implementation of a precision approach using clinical, morphological, radiological and functional predictors allows not only to identify the specific morphotype of somatotrophic tumor, but also to predict the efficacy of the planned treatment. A table of multidirectional biomarkers of long-term sensitivity of tumor cells to first- and second-generation somatostatin receptor ligands is presented. When SGST, large size of the residual tumor and poor expression of the 2nd subtype of somatostatin receptors are detected, pasireotide LAR can be used as a 1st-line treatment, in both mono- and combination therapy with pegvisomant. Special caution is required when treating patients with diabetes mellitus or predisposition to its development. The paper discusses in detail the measures aimed at prevention, dynamic control and correction of pasireotide-associated hyperglycemia.

Comprehensive mapping of somatotroph pituitary neuroendocrine tumour heterogeneity using spatial and single-cell transcriptomics.

Pituitary neuroendocrine tumours (PitNETs) are common intracranial tumours that are highly heterogeneous with unpredictable growth patterns. The driver genes and mechanisms that are crucial for tumour progression in somatotroph PitNETs are poorly understood. In this study, we performed integrative spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq) analysis on somatotroph tumours and normal pituitary samples to comprehensively characterize the differences in cellular characteristics. By analyzing combined copy number variations (CNVs), tumour tissues were divided into two regions, which included the CNVhigh and CNVlow areas. The protumour genes DLK1 and RCN1 were highly expressed in the CNVhigh area, which might be related to tumour progression and could be targeted for precision therapy. We also found that the transforming growth factor beta signalling pathway participated in tumour progression and identified heterogeneity in the expression profiles of key genes. We assessed the intertumoral and intratumoral heterogeneity in somatotroph PitNETs and emphasized the importance of individualized treatment. In summary, we visualized the cellular distribution and transcriptional differences in normal pituitary and somatotroph PitNETs by ST and scRNA-seq for the first time. This study provides a strong theoretical foundation to comprehensively understand the crucial mechanisms involved in tumour progression and develop new strategies to treat somatotroph PitNETs. The first-ever visualization of cellular distributions in normal and tumor pituitary tissues. The inter- and intra-tumoral transcriptomic heterogeneity of somatotroph PitNETs was comprehensively revealed. Identification of potential protumor factors and critical signaling pathways, opening new avenues for therapeutic intervention.

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

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

12353 Differential Gene Expression And Pathway Analysis In Growth Hormone Secreting Pituitary Tumors According To Granulation Pattern

Abstract Disclosure: H. Shin: None. Differential gene expression and pathway analysis in growth hormone-secreting pituitary tumors according to granulation pattern. Hye Ju Shin [1], Kyung Won Kim[2], Chan Woo Kang[2], Eun Jig Lee[2], Cheol Ryong Ku[2]. [1]Department of Clinical Drug Discovery & Development, Yonsei University College of Medicine, Seoul, Republic of Korea, [2]Endocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea Objective: The purpose of this research is to explain clinical variations in patients with acromegaly by exploring gene expression differences according to granulation patterns in growth hormone (GH)-secreting pituitary tumors. Materials & methods: Transcriptome analysis was conducted on 6 normal pituitary tissues and 15 GH-secreting pituitary tumors, including 9 densely granulated somatotroph tumors (DGSTs) and 6 sparsely granulated somatotroph tumors (SGSTs). Results: The median age at diagnosis was 50 years, with a predominance of female patients (60%). We identified 3111 differentially expressed genes (DEGs) in tumors compared to normal pituitaries, with 1117 DEGs unique to a specific granulation within tumors. SGST showed enriched the pathways involved in neuronal development (axon development, axonogenesis, axon guidance, synapse and presynapse organization, gliogenesis, glial cell differentiation, nerve development, synaptic membrane adhesion, semaphorin-plexin signaling pathway involved in neuron projection guidance) and acute inflammatory response. No pathways were significantly downregulated in SGST compared with those in DGST. Three signaling pathways (JAK-STAT, phosphatidylinositol 3-kinase, and MAP cascade) and three neuronal development processes (generation of neurons, nerve development, and neurogenesis) were significantly enriched in both GO and GSEA analysis. The PPI networks constructed with the up- and downregulated DEGs consisted of 128 and 132 PPI pairs, respectively. There were 10 hub proteins, top highly connected DEGs: ANLN, TLE3, TLE2, DMD, ADRA1A, RBFOX1, MMP2, LMO1, RUNX1T1, and NPPA. Conclusion: The results indicate that granulation-specific gene expression may underpin diverse clinical characteristics in acromegaly. Overall, this study emphasizes the potential for further investigation into these transcriptomic variations and their roles in disease pathology, particularly the involvement of genes linked to neuronal development, inflammatory response, and JAK-STAT signaling in SGST. Presentation: 6/3/2024

Differential gene expression and pathway analysis in growth hormone-secreting pituitary tumors according to granulation pattern.

This study investigated differential gene expression between granulation patterns in growth hormone (GH)-secreting pituitary tumors, aiming to elucidate novel transcriptomes that explain clinical variances in patients with acromegaly. Transcriptome analysis was conducted on 6 normal pituitary tissues and 15 GH-secreting pituitary tumors, including 9 densely granulated somatotroph tumors (DGSTs) and 6 sparsely granulated somatotroph tumors (SGSTs). We identified 3111 differentially expressed genes (DEGs) in tumors compared to normal pituitaries, with 1117 DEGs unique to a specific granulation within tumors. SGST showed enrichment of neuronal development and acute inflammatory response pathways, along with a significant enhancement of JAK-STAT, phosphatidylinositol 3-kinase, and MAPK signaling. The results suggest that granulation-specific gene expression may underpin diverse clinical presentations in acromegaly, highlighting the potential for further investigation into these transcriptomic variations and their roles in disease pathology, particularly the involvement of genes linked to neuronal development, inflammatory response, and JAK-STAT signaling in SGST.

Granulation Patterns of Functional Corticotroph Tumors Correlate with Tumor Size, Proliferative Activity, T2 Intensity-to-White Matter Ratio, and Postsurgical Early Biochemical Remission

Unlike somatotroph tumors, the data on correlates of tumor granulation patterns in functional TPIT lineage pituitary neuroendocrine tumors (corticotroph tumors) have been less uniformly documented in most clinical series. This study evaluated characteristics of 41 well-characterized functional corticotroph tumors consisting of 28 densely granulated corticotroph tumors (DGCTs) and 13 sparsely granulated corticotroph tumors (SGCTs) with respect to preoperative clinical and radiological findings, tumor proliferative activity (including mitotic count and Ki-67 labeling index), and postoperative early biochemical remission rates. The median (interquartile range (IQR)) tumor size was significantly larger in the SGCT group [16.00 (16.00) mm in SGCT vs 8.5 (9.75) mm in DGCT, p = 0.049]. T2-weighted signal intensity and T2 intensity (quantitative) did not yield statistical significance based on tumor granulation; however, the T2 intensity-to-white matter ratio was significantly higher in SGCTs (p = 0.049). The median (IQR) Ki-67 labeling index was 2.00% (IQR 1.00%) in the DGCT group and 4.00% (IQR 7.00%) in the SGCT group (p = 0.043). The mitotic count per 2 mm2 was higher in the SGCT group (p = 0.001). In the multivariate analysis, the sparse granulation pattern (SGCT) remained an independent predictor of a lower probability of early biochemical remission irrespective of the tumor size and proliferative activity (p = 0.012). The current study further supports the impact of tumor granulation pattern as a biologic variable and warrants the detailed histological subtyping of functional corticotroph tumors as indicated in the WHO classification of pituitary neuroendocrine tumors. More importantly, the assessment of the quantitative T2 intensity-to-white matter ratio may serve as a preoperative radiological harbinger of SGCTs.

Growth hormone increase by luteinizing hormone-releasing hormone reflects gonadotroph-related characteristics in acromegaly

PurposeWe previously showed the clinical characteristics of acromegaly with a paradoxical growth hormone (GH) response to oral glucose or thyrotropin-releasing hormone. However, the clinical characteristics of acromegaly with an increased GH response to luteinizing hormone-releasing hormone (LHRH responders) remain unclear. The aim of the present study was to evaluate the clinical characteristics, especially gonadotroph-related characteristics of LHRH responders in acromegaly.MethodsThe clinical characteristics of 33 LHRH responders and 81 LHRH nonresponders were compared.ResultsNo differences in age, sex or basal serum levels of GH, insulin-like growth factor-1 (IGF-1), and gonadotropin were observed between the two groups. Steroidogenic factor 1 (SF-1), gonadotropin-releasing hormone receptor (GnRHR), and LH expression was more frequently observed in LHRH responders (P < 0.05). In addition, a greater increased rate of GH after LHRH loading, and the proportion of GnRHR and gonadotropin expression was observed in pituitary tumor with SF-1 expression than that without the expression (P < 0.01). LHRH responders showed a greater GH decrease in the octreotide test and a greater IGF-1 decrease after first-generation somatostatin ligand than LHRH nonresponders (P < 0.05). Furthermore, the proportion of hypointense pituitary tumors on T2-weighted magnetic resonance imaging and tumors with densely granulated type was higher in LHRH responders than in LHRH nonresponders, respectively (P < 0.05). No difference between the two groups was observed in either somatostatin receptor 2 or 5 expression.ConclusionsThe increased GH response to LHRH is associated with the gonadotroph-related characteristics. This response may reflect the biological characteristics of somatotroph tumors.

Three-dimensional chromatin landscapes in somatotroph tumour.

The three-dimensional (3D) genome architecture plays a critical role inregulating gene expression. However, the specific alterations in thisarchitecture within somatotroph tumors and their implications for gene expression remain largely unexplored. We employed Hi-C and RNA-seq analyses to compare the 3D genomic structures of somatotroph tumors with normal pituitary tissue. This comprehensive approachenabled the characterization of A/B compartments, topologically associateddomains (TADs), and chromatin loops, integrating these with gene expression patterns. We observed a decrease in both the frequency of chromosomal interactions andthe size of TADs in tumor tissue compared to normal tissue. Conversely, the number of TADs and chromatin loops was found to be increased in tumors. Integrated analysis of Hi-C and RNA-seq data demonstrated that changes inhigher-order chromat in structure were associated with alterations in gene expression. Specifically, genes in A compartments showed higher density and increased expression relative to those in B compartments. Moreover, the weakand enhanced insulation boundaries were identified, and the associated genes were enriched in the Wnt/β-Catenin signaling pathway. We identified the gainedand lost loops in tumor and integrated these differences with transcriptional changes to examine the functional relevance of the identified loops. Notably, we observed an enhanced insulation boundary and a greater number of loops in the TCF7L2 gene region within tumors, which was accompanied by an upregulation of TCF7L2 expression. Subsequently, TCF7L2 expression was confirmed through qRT-PCR, and upregulated TCF7L2 prompted cell proliferation and growth hormone (GH) secretion in vitro. Our results provide comprehensive 3D chromatin architecture maps of somatotroph tumors and offer a valuable resource for furthering the understanding of the underlying biology and mechanisms of gene expression regulation.

Real-world experience with 11C-methionine positron emission tomography in the management of acromegaly.

L-[methyl-11C]-methionine-positron emission tomography (Met-PET) is a potentially important imaging adjunct in the diagnostic workup of pituitary adenomas, including somatotroph tumors. Met-PET can identify residual or occult disease and make definitive therapies accessible to a subgroup of patients who would otherwise require lifelong medical therapy. However, existing data on its use are still limited to small case series. Here, we report the largest single-center experience (n = 61) in acromegaly. A total of 189 cases of acromegaly were referred to our national Met-PET service in the last 12 years. For this analysis, we have reviewed outcomes in those 61 patients managed exclusively by our multidisciplinary team (single center, single surgeon). Referral indications were as follows: indeterminate magnetic resonance imaging (MRI; n = 38, 62.3%), occult residual (n = 14, 23.0%), (radio-)surgical planning (n = 6, 9.8%), and occult de novo tumor (n = 3, 4.9%). A total of 33/61 patients (54.1%) underwent PET-guided surgery. Twenty-four of 33 patients (72.7%) achieved complete biochemical remission following (re-)surgery. Insulin-like growth factor 1 levels were reduced to <2 × upper limit of normal (ULN) in 6 of the remaining 9 cases, 3 of whom achieved levels of <1.1 × ULN compared with mean preoperative levels of 2.4 × ULN (SD 0.8) for n = 9. Only 3 patients developed single new hormonal deficits (gonadotropic/thyrotropic insufficiency). There were no neurovascular complications after surgery. In patients with persistent/recurrent acromegaly or occult tumors, Met-PET can facilitate further targeted intervention (surgery/radiosurgery). This led to complete remission in most cases (24/33) or significant improvement with comparatively low risk of complications. L-[methyl-11C]-methionine-positron emission tomography should therefore be considered in all patients who are potential candidates for further surgical intervention but present no clear target on MRI.

Usefulness of Opening the Diaphragma Sellae Before Transecting Interclinoidal Ligament for Endoscopic Endonasal Transoculomotor Triangle Approach: Technical Nuances and Surgical Outcomes

Opening the oculomotor triangle and removing the posterior fossa lesion by endoscopic endonasal approach (EEA) is challenging for even an experienced endoscopic neurosurgeon. We summarize the treatment experience and technical nuances with EEA for resection of pituitary neuroendocrine tumors and cavernous sinus (CS) meningiomas invading through the oculomotor triangle (OT). Between 2018 and 2022, eight cases, including five pituitary neuroendocrine tumors (PitNET) including three nonfunctioning and two somatotroph tumors with elevated growth hormone, and 3 CS meningiomas were treated using an endoscopic endonasal transoculomotor triangle approach. The critical surgical technique is continuously opening the diaphragma sellae from medial to lateral towards the interclinoidal ligament (ICL) and transecting it to enlarge the OT. We evaluated preoperative tumor size, previous surgical history, preoperative symptoms, extent of tumor resection, histopathology, and postoperative complications for all patients. The GTR(gross total resection)- defined as complete removal in 3 patients (38%), near-total resection(NTR) - defined as >95% removal in 4 patients (50%), and subtotal resection (STR)- defined as up to 90 % removal in one patient (12%)and gross-total resection of tumor invading through the OT was achieved in all patients through pure EEA. Two of three patients with visual deficit in Non-Functioning-PitNET improved, and the other remained stable postoperatively. One patient showed transient oculomotor nerve palsy. The Growth Hormone level of the two patients with somatotroph tumors declined to normal. For three patients with CS meningiomas, cranial nerve palsy improved in two patients, while the other patient developed increased facial numbness after surgery. Endoscopic endonasal transoculomotor triangle approach is an efficient surgical option for the tumor with CS invasion and OT penetration.

Clinicopathological Analysis of Densely and Sparsely Granulated Somatotroph Tumors of Pituitary

ObjectiveSomatotroph tumors are the second most common type of pituitary neuroendocrine tumors (PitNETs) that can be further classified into two subtypes, namely densely granulated somatotroph tumors (DGSTs) and sparsely granulated somatotroph tumors (SGSTs). The aim of this study is to investigate the clinical significance of the two subtypes by conducting a retrospective analysis. MethodsFrom the database of the Ningbo Clinical Pathology Diagnosis Center, we collected cases diagnosed with pituitary somatotroph tumors. We then compiled pertinent clinical and radiological data and proceeded with histopathological examination involving HE staining and immunohistochemical staining. Subsequent tumor analysis comparing the two subtypes used either the Chi-square test or Fisher's exact test. ResultsIn this study, we analyzed a total of forty cases of somatotroph tumors, with 18 cases classified as DGSTs and 22 cases as SGSTs. The male-to-female ratio was 5:4 for DGSTs and 4:7 for SGSTs. The mean age was 52.83 years for DGSTs and 47.18 years for SGSTs. Statistically significant differences were observed between the DGSTs and SGSTs groups concerning invasiveness (P=0.0267) and postoperative remission (P=0.007). Both DGSTs and SGSTs cells exhibited co-expression of PIT1, GH, and CAM5.2, although the patterns of CAM5.2 expression differed between the two subtypes. ConclusionsThe efficacy of CAM5.2 staining in distinguishing between DGSTs and SGSTs was demonstrated. SGSTs, with their increased invasiveness and lower remission rate, emerge as a high-risk subtype. The histological subtype of somatotroph tumors plays a crucial role in guiding treatment decisions and prognostic evaluation in affected patients.

Profiling of Unfolded Protein Response Markers and Effect of IRE1α-specific Inhibitor in Pituitary Neuroendocrine Tumor.

Inositol-requiring enzyme 1α (IRE1α) and PKR-like ER kinase (PERK), which are endoplasmic reticulum (ER) membrane proteins, regulate the unfolded protein response (UPR). These molecules have recently gained attention as a novel therapeutic target in secretory tumors. The roles of the UPR in pituitary neuroendocrine tumors (PitNETs) are unclear. To clarify UPR profiling of PitNETs and to investigate the effect of pharmacological modulation of UPR by KIRA8, a newly developed IRE1α-specific inhibitor. In 131 patients with PitNETs, we evaluated RNA expression of UPR markers in PitNETs and their clinical phenotypes. Using GH3 cells, we examined the effects of KIRA8 and its combination with octreotide on UPR profiling, cell growth, and apoptosis. Cytoprotective adaptive-UPR (A-UPR) markers were more increased in functioning PitNETs (FPitNETs, n = 112) than in nonfunctioning PitNETs (NFPitNETs, n = 19), while there was no difference in proapoptotic terminal-UPR (T-UPR) markers. Similarly, overt somatotroph tumors (STs, acromegaly, n = 11) increased A-UPR compared with silent STs (n = 10). In STs, serum IGF-1 levels were inversely correlated with Txnip mRNA expression, a representative T-UPR marker. KIRA8 inhibited cell growth and facilitated apoptosis in GH3 cells with increased expressions of T-UPR markers, which was enhanced by the combination with octreotide. Octreotide increased mRNA expression of Txnip and Chop, but decreased spliced Xbp1 under ER stress. Octreotide is suggested to inhibit activation of IRE1α but to reciprocally induce T-UPR under PERK. UPR markers in FPitNETs are implicated as dominant A-UPR but blunted T-UPR. KIRA8, enhanced with octreotide, unbalances the UPR, leading to antitumor effects. Targeting IRE1α may provide a novel strategy to treat PitNETs.

Development of an optimal imaging pathway for management of somatotroph tumors in acromegaly

Development of an optimal imaging pathway for management of somatotroph tumors in acromegaly

The role of hormonal status, morphological subtypes and proliferative marker Ki-67 labeling index on long-term outcomes in patients with acromegaly: a single tertiary center’s experience

Aims: Acromegaly is a rare disorder resulting from benign growth hormone secreting pituitary adenomas. Many factors affect long-term outcomes in acromegaly. In this study we aimed to investigate effects of hormonal status, morphological subtypes, immunohistochemical expression of pituitary hormones and Ki-67 labeling index on long-term outcomes in patients with acromegaly.&#x0D; Methods:. We collected the medical and pathological records of sixty-four patients who underwent surgery for growth hormone (GH) secreting somatotroph tumors between 2005-2017.&#x0D; Results: The remission rate after surgery was 48% (31/64) in all patients (33% for macroadenomas, 94% for microadenomas; p

THU023 Sparse Granulation In Growth Hormone Secreting Adenomas: Clinical Implications Of A Rare Histological Finding

Abstract Disclosure: A. Merrill: None. R. Varughese: None. G. Campbell: None. L. Belalcazar: None. Introduction: Acromegaly is an uncommon disease. Endocrinologists may be unfamiliar with the clinical implications of granularity findings on the histology of growth hormone (GH)-secreting adenomas. We present the case of a patient with acromegaly in whom a sparsely granulated (SG) histological subtype was identified post-operatively. We discuss the clinical presentation and therapeutic implications of this finding. Case Presentation: A 36-year-old man was admitted to the hospital with rectal bleeding and incidentally found to have features consistent with acromegaly. Patient reported that over 1 year he had noticed changes in his facial features, enlargement of his hands and had developed hand and knee arthralgias. During the 6 months prior to admission, he experienced worsening fatigue, but denied severe headaches or vision changes. Past medical history was significant for osteosarcoma as a young child treated with an above the knee amputation. Family history was negative for pituitary tumors or colon cancer. Physical exam revealed a blood pressure of 104/53 mmHg and an amputation-adjusted body mass index of 27.4 _kg/ m2 . He had mild frontal bossing, enlarged nose, macroglossia, swollen hands and foot. Rectal examination revealed hemorrhoids but no masses. Gross visual field deficits were identified at bedside. Laboratory findings were significant for an elevated IGF-1 at 975 ng/mL (83-240 ng/mL) and GH 45.2 ng/mL (0.3-9 ng/mL). Patient was also found to have panhypopituitarism: TSH 1.54 mIU/L (0.45-4.70 mIU/L), Free T4 0.62 ng/dl (0.78 - 2.20 ng/dL); ACTH 13.3 pg/ml (7.2 - 63.3 pg/mL), cortisol AM 3.6 ug/dL (4.5-23.0 ug/dL), peak cortisol after ACTH stimulation 16.0 ug/dL; testosterone 31.6 ng/dl (132-813 ng/dL), LH 1.75 mIU/ml (1.2-8.6 mIU/mL). His hemoglobin A1c was 5.7%. MRI of the brain revealed a large enhancing lobulated sellar/suprasellar lesion of 5.0 x 2.4 x 2.8 cm, with extension to the third ventricle and mass effect on the optic chiasm. Patient underwent partial surgical resection of the large tumor. Pathology identified a SG somatotroph tumor with most cells being negative or weakly positive for GH on immunohistochemical staining. TSH, prolactin, and ACTH stains were negative. There was evidence of residual tumor, which was located superiorly, not accessible through the transsphenoidal route.A colonoscopy and formal visual field testing are pending currently. Patient is waiting for a second surgery via craniotomy and, given the SG finding on histology, pasireotide therapy will be offered. Discussion: The sparsely granulated (SG) subtype is an uncommon variant of GH-producing. Our patient illustrates the aggressive nature of SG GH-producing adenomas. These tumors express more invasive growth and resistance to standard somatostatin analogue therapy. There is a growing recognition that adenoma granulation is an important consideration in the management of acromegaly. Presentation: Thursday, June 15, 2023

DNA Methylation Pattern in Somatotroph Pituitary Neuroendocrine Tumors

Introduction: Growth hormone secretion by sporadic somatotroph neuroendocrine pituitary tumors (PitNETs) is a major cause of acromegaly. These tumors are relatively heterogenous in terms of histopathological and molecular features. Our previous transcriptomic profiling of somatotroph tumors revealed three distinct molecular subtypes. This study aimed to investigate the difference in DNA methylation patterns in subtypes of somatotroph PitNETs and its role in distinctive gene expression. Methods: Genome-wide DNA methylation was investigated in 48 somatotroph PitNETs with EPIC microarrays. Gene expression was assessed with RNAseq. Bisulfite pyrosequencing and qRT-PCR were used for verifying the results of DNA methylation and gene expression. Results: Clustering tumor samples based on methylation data reflected the transcriptome-related classification. Subtype 1 tumors are densely granulated without GNAS mutation, characterized by high expression of NR5A1 (SF-1) and GIPR. The expression of both genes is correlated with specific methylation of the gene body and promoter. This subtype has a lower methylation level of 5′ gene regions and CpG islands than the remaining tumors. Subtype 2 PitNETs are densely granulated and frequently GNAS-mutated, while those in subtype 3 are mainly sparsely granulated. Methylation/expression analysis indicates that ∼50% genes located in differentially methylated regions are those differentially expressed between tumor subtypes. Correlation analysis revealed DNA methylation-controlled genes, including CDKN1B, CCND2, EBF3, CDH4, CDH12, MGMT, STAT5A, PLXND1, PTPRE, and MMP16, and genes encoding ion channels and semaphorins. Conclusion: DNA methylation profiling confirmed the existence of three molecular subtypes of somatotroph PitNETs. High expression of NR5A1 and GIPR in subtype 1 tumors is correlated with specific methylation of both genes.

PD-L1 Expression in Pituitary Neuroendocrine Tumors/Pituitary Adenomas.

About a third of Pituitary Neuroendocrine Tumors (PitNETs) may show aggressive behavior. Many efforts have been performed for identifying possible predictive factors to early determine the future behavior of PitNETs. Programmed cell death ligand 1 (PD-L1) expression was associated with a more aggressive biology in different solid tumors, but its role in PitNET is not well-established yet. Our study aims to analyze PD-L1 expression in a surgical cohort of PitNETs to determine its association with radiological invasion and pathology findings, as well as with long-term recurrence rates. We performed a retrospective analysis in a series of 86 PitNETs. Clinical presentation and radiological features of the preoperative period were collected, as well as pathological data and follow-up data. The rate of PD-L1 expression was immunohistochemically evaluated and expressed as a tumor proportion score (TPS). We assessed its relationship with cavernous sinus invasion and Trouillas' classification as primary outcomes. Secondary outcomes included the TPS' relationship with histopathological markers of proliferation, hormonal expression, tumor size and long-term recurrence rates. We calculated the optimal cut-point for the primary outcomes while maximizing the product of the sensitivity and specificity and then we evaluated the significance of secondary outcomes with logistic regression analysis. Eighty-six patients were included in the analysis; 50 cases were non-functional PitNETs. The TPS for PD-L1 showed a highly right-skewed distribution in our sample, as 30.2% of patients scored 0. Using Trouillas' classification, we found that "proliferative" cases have a significantly higher probability to express PD-L1 in more than 30% of tumor cells (OR: 5.78; CI 95%: 1.80-18.4). This same cut-point was also associated with p53 expression. A positive association was found between PD-L1 expression and GH expression (p = 0.001; OR: 5.44; CI 95%: 1.98-14.98), while an inverse relationship was found with FSH/LH expression (p = 0.014; OR = 0.27, CI 95%: 0.10-0.76). No association was found with CS invasion, tumor size, bone erosion or dura invasion. We could not find any association between PD-L1 expression and recurrence. PD-L1 expression was associated with proliferative grades of Trouillas' classification and p53 expression. We also confirmed a higher expression of PD-L1 in somatotroph tumors. Larger studies are necessary to investigate the relationship between PD-L1 expression and aggressive behaviors.

Outcomes of Endoscopic Transsphenoidal Approach for More Aggressive Pediatric Pituitary Adenomas: Early- and Late-Term Results from a Single Center Experience

Pediatric pituitary adenomas are rare lesions and account for approximately 3% of all supratentorial tumors in children.There is a paucity of reports on endoscopic transsphenoidal surgery in children. The aim of this study was to assess the early/late outcomes of endoscopic pediatric pituitary adenoma surgery at a high-volume tertiary center, as well as to characterize the factors associated with aggressive growth, including the histopathological features. Between August 1997-June 2022, a total of 3256 patients underwent endoscopic transsphenoidal surgery for pituitary adenoma at the Department of Neurosurgery and Pituitary Research Center of the Kocaeli University School of Medicine. Of these, 70(2.1%) pediatric patients (25 male,45 female)(age ≤18 years) with a pathological diagnosis of pituitary adenoma were retrospectively reviewed. The mean age of patients was 15.5±2.3 years.Among the hormone-secreting adenomas, 19(34.5%) were adrenocorticotrophic hormone (ACTH)-secreting, 13(23.6%) were growth hormone (GH)-secreting, 19(34.5%) were prolactin (PRL)-secreting, and 4(7.2%) were both GH- and PRL-secreting.Gross total resection was achieved in 93.3% of nonfunctional tumors.The early/late surgical remission rates for hormone-secreting adenomas were 61.5%/46.1%(mean follow-up:63.7±49.3 months) for acromegaly, 78.9%/68.4%(47.8±51.0 months) for Cushing's disease, 57.8%/31.5%(72.2±59.5 months) for prolactinoma, and 25%/25%(35.2±31.4 months) for GH+PRL-secreting adenomas.Five sparsely-granulated corticotroph tumors, 5 sparsely-granulated somatotroph tumors, and 11 densely-granulated lactotroph tumors were classified as aggressive histopathological subtypes. The unique characteristics of the pediatric population and the aggressiveness of the disease in this population pose considerable therapeutic challenges. To increase treatment success, current adjuvant therapies that are appropriate for the morphological and biological characteristics of the tumor are required in addition to surgical treatment.

CD68+ and CD8+ immune cells are associated with the growth pattern of somatotroph tumors and response to first generation somatostatin analogs.

Somatotropinomas are pituitary tumors with a heterogenous clinical behavior. The tumor microenvironment regulates the interaction between tumor cells and the host immune system, potentially modulating tumor behavior. Here, we aimed to investigate the tumor immune infiltration in a cohort of medically naïve acromegaly patients. A retrospective, monocenter study was designed to analyze the presence of CD3+, CD20+, CD138+, CD4+, CD8+, CD68+ immune cells in samples of somatotropinomas and their prognostic significance on tumor behavior and response to first generation somatostatin analogs (fg-SSA). Thirty-six patients (23 females) were included in the study. Macroadenomas were identified in 23 cases: 12 with cavernous sinus invasion. The number of CD8+ lymphocytes positively correlated with CD4+ lymphocytes (p = .05, r:0.245) and with CD68+ macrophages (p = .01, r = 0.291). The CD8+/CD4+ ratio inversely correlated with CD68+/CD8+ ratio (p < .001, r = -0.626). CD68+ macrophages positively correlated with tumor size (maximum diameter p = .003, r = 0.574; volume p = .009, r = 0.566) and were more numerous in somatotropinomas with Ki-67 > 3% (median 65/HPF, IQR:15), compared to cases with Ki67 < 3% (median 50/HPF, IQR:22, p < .001). CD8+ and CD138+ lymphocytes were more numerous in cases responsive to fg-SSA (respectively median 18/HPF IQR:18 and median 8/HPF IQR: 6.5) as compared to fg-SSA nonresponsive cases (median 14.5/HPF IQR:40 p = .03; median 3.5/HPF IQR: 14 p = .03). CD8+ lymphocytes act as single predictor of response to fg-SSA, independently from age, GH and IGF-I levels, tumor dimension and invasion. Our results support that lymphocytes and macrophages generate an immune network in somatotropinomas and the characteristic of the immune infiltrate may predict treatment outcome.

The effect of endoscopic transsphenoidal somatotroph tumors resection on pituitary hormones: systematic review and meta-analysis

PurposeCurrently, endoscopic transsphenoidal surgery is the main treatment for pituitary neuroendocrine tumors (PitNETs). Excision of the tumor may have positive or negative effects on pituitary endocrine function, and the pituitary function of somatotroph tumors is a point of particular concern after the operation. This study aimed to conduct a meta-analysis on the effect of endoscopic transsphenoidal somatotroph tumor resection on pituitary function.MethodsA systematic literature search was conducted for articles that included the evaluation of pituitary target gland before and after endoscopic transsphenoidal pituitary tumor resection and were published between 1992 and 2022 in PubMed, Cochrane, and Ovid MEDLINE.ResultsSixty-eight studies that included biochemical remission rates in 4524 somatotroph tumors were concluded. According to the 2000 consensus, the biochemical remission rate after transsphenoidal endoscopic surgery was 66.4% (95% CI, 0.622–0.703; P = 0.000), the biochemical remission rate was 56.2% according to the 2010 consensus (95% CI, 0.503–0.620; P = 0.041), and with the rate of biochemical remission ranging from 30.0 to 91.7% with investigator’s definition. After endoscopic resection, adrenal axis dysfunction was slightly higher than that before surgery, but the difference was not statistically significant. Hypothyroidism was 0.712 times higher risk than that before surgery (OR = 0.712; 95% CI, 0.527–0.961; P = 0.027). Hypogonadism was 0.541 times higher risk than that before surgery (OR = 0.541; 95% CI, 0.393–0.746; P = 0.000). Hyperprolactinemia was 0.131 times higher risk than that before surgery (OR = 0.131; 95% CI, 0.022–0.783; P = 0.026). The incidence of pituitary insufficiency was 1.344 times the risk before surgery after endoscopic resection of somatotroph tumors, but the difference was not statistically significant.ConclusionsIn patients with somatotroph tumors after undergoing endoscopic surgery, the risk of dysfunction and pituitary insufficiency tend to increase, while preoperative thyroid insufficiency, gonadal insufficiency, and hyperprolactinemia will be partially relieved.