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Abstract Context Few data exist about the clinical course of acromegaly, surgical and medical outcomes in patients with GH- and prolactin cosecreting pituitary adenomas (GH&PRL-PAs). Nevertheless, some series described a more aggressive clinic-radiological behavior than in growth hormone–secreting pituitary adenomas (GH-PAs). Objective This work aims to evaluate differences in clinical presentation and in surgical outcomes between GH-PAs and GH&PRL-PAs. Methods A multicenter retrospective study was conducted of 604 patients with acromegaly who underwent pituitary surgery. Patients were classified into 2 groups according to serum PRL levels at diagnosis and immunohistochemistry (IHC) for PRL: a) GH&PRL-PAs when PRL levels were above the upper limit of normal (ULN) and IHC for GH and PRL was positive or PRL levels were greater than 100 ng/dL and PRL IHC was not available (n = 130) and b) GH-PA patients who did not meet the previously mentioned criteria (n = 474). Results GH&PRL-PAs represented 21.5% (n = 130) of patients with acromegaly. The mean age at diagnosis was lower in GH&PRL-PAs than in GH-PAs (P < .001). GH&PRL-PAs were more frequently macroadenomas (90.6% vs 77.4%; P = .001) and tended to be more invasive (33.6% vs 24.7%; P = .057) than GH-PAs. Furthermore, they had presurgical hypopituitarism more frequently (odds ratio 2.8; 95% CI, 1.83-4.38). Insulin-like growth factor ULN levels at diagnosis were lower in patients with GH&PRL-PAs (median 2.4 [interquartile range (IQR) 1.73-3.29] vs 2.7 [IQR 1.91-3.67]; P = .023). There were no differences in the immediate (41.1% vs 43.3%; P = .659) or long-term postsurgical acromegaly biochemical cure rate (53.5% vs 53.1%; P = .936) between groups. However, there was a higher incidence of permanent arginine-vasopressin deficiency (AVP-D) (7.3% vs 2.4%; P = .011) in GH&PRL-PA patients. Conclusion GH&PRL-PAs are responsible for 20% of acromegaly cases. These tumors are more invasive, larger, and cause hypopituitarism more frequently than GH-PAs and are diagnosed at an earlier age. The biochemical cure rate is similar between both groups, but patients with GH&PRL-PAs tend to develop permanent postsurgical AVP-D more frequently.

Abstract Context Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. Objective To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. Design We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. Results Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. Conclusion ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.

ContextSomatic mutations in the ubiquitin-specific protease 8 (USP8) gene have been recently identified as the most common genetic alteration in patients with Cushing disease (CD). However, the frequency of these mutations in the pediatric population has not been extensively assessed.ObjectiveWe investigated the status of the USP8 gene at the somatic level in a cohort of pediatric patients with corticotroph adenomas.Design and MethodsThe USP8 gene was fully sequenced in both germline and tumor DNA samples from 42 pediatric patients with CD. Clinical, biochemical, and imaging data were compared between patients with and without somatic USP8 mutations.ResultsFive different USP8 mutations (three missense, one frameshift, and one in-frame deletion) were identified in 13 patients (31%), all of them located in exon 14 at the previously described mutational hotspot, affecting the 14-3-3 binding motif of the protein. Patients with somatic mutations were older at disease presentation [mean 5.1 ± 2.1 standard deviation (SD) vs 13.1 ± 3.6 years, P = 0.03]. Levels of urinary free cortisol, midnight serum cortisol, and adrenocorticotropic hormone, as well as tumor size and frequency of invasion of the cavernous sinus, were not significantly different between the two groups. However, patients harboring somatic USP8 mutations had a higher likelihood of recurrence compared with patients without mutations (46.2% vs 10.3%, P = 0.009).ConclusionSomatic USP8 gene mutations are a common cause of pediatric CD. Patients harboring a somatic mutation had a higher likelihood of tumor recurrence, highlighting the potential importance of this molecular defect for the disease prognosis and the development of targeted therapeutic options.Mutations in the USP8 gene have been identified in one third of patients from a cohort of 42 pediatric patients with Cushing disease, in association with increased likelihood of disease recurrence.

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.

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. This article reviews the major biological characteristics of somatostatin receptors (SST2 and SST5) in anterior pituitary tumors, and the immunohistochemical evaluation of their expression as predictors of response to pharmacological therapy with SST ligands.

Drivers of sporadic benign pituitary adenoma growth are largely unknown. Whole-exome sequencing of 159 prospectively resected pituitary adenomas showed that somatic copy number alteration (SCNA) rather than mutation is a hallmark of hormone-secreting adenomas and that SCNAs correlate with adenoma phenotype. Using single-gene SCNA pathway analysis, we observed that both cAMP and Fanconi anemia DNA damage repair pathways were affected by SCNAs in growth hormone-secreting (GH-secreting) somatotroph adenomas. As somatotroph differentiation and GH secretion are dependent on cAMP activation and we previously showed DNA damage, aneuploidy, and senescence in somatotroph adenomas, we studied links between cAMP signaling and DNA damage. Stimulation of cAMP in C57BL/6 mouse primary pituitary cultures using forskolin or a long-acting GH-releasing hormone (GHRH) analog increased GH production and DNA damage measured by H2AX phosphorylation and a comet assay. Octreotide, a somatostatin receptor ligand that targets somatotroph adenoma GH secretion in patients with acromegaly, inhibited cAMP and GH and reversed DNA damage induction. In vivo long-acting GHRH treatment also induced pituitary DNA damage in mice. We conclude that cAMP, which induces somatotroph proliferation and GH secretion, may concomitantly induce DNA damage, potentially linking hormone hypersecretion to SCNA and genome instability. These results elucidating somatotroph adenoma pathophysiology identify pathways for targeted treatment.

Abstract Context Cushing disease (CD) is a life-threatening disorder. Therapeutic goals include symptom relief, biochemical control, and tumor growth inhibition. Current medical therapies for CD by and large exert no action on tumor growth. Objective To identify drugs that inhibit corticotroph tumor adrenocorticotropic hormone (ACTH) secretion and growth. Design High throughput screen employing a novel “gain of signal” ACTH AlphaLISA assay. Setting Academic medical center. Patients Corticotroph tumor tissues from patients with CD. Interventions None. Main outcome measures Potent inhibitors of corticotroph tumor ACTH secretion and growth. Results From a kinase inhibitor library, we identified the dual PI3K/HDAC inhibitor CUDC-907 as a potent inhibitor of murine and human corticotroph tumor ACTH secretion (median effective concentration 1-5 nM), and cell proliferation (median inhibitory concentration 5 nM). In an in vivo murine corticotroph tumor xenograft model, orally administered CUDC-907 (300 mg/kg) reduced corticotroph tumor volume (TV [cm3], control 0.17 ± 0.05 vs CUDC-907 0.07 ± 0.02, P < .05) by 65% and suppressed plasma ACTH (ACTH [pg/mL] control 206 ± 27 vs CUDC-907 47 ± 7, P < .05) and corticosterone (corticosterone [ng/mL] control 180 ± 87 vs CUDC-907 27 ± 5, P < .05) levels by 77% and 85% respectively compared with controls. We also demonstrated that CUDC-907 acts through HDAC1/2 inhibition at the proopiomelanocortin transcriptional level combined with its PI3K-mediated inhibition of corticotroph cell viability to reduce ACTH secretion. Conclusions Given its potent efficacy in in vitro and in vivo models of CD, combined with proven safety and tolerance in clinical trials, we propose CUDC-907 may be a promising therapy for CD.

Abstract Purpose The molecular pathogenesis of growth hormone-secreting pituitary adenomas is not fully understood. Cytogenetic alterations might serve as alternative driver events in GNAS mutation–negative somatotroph tumors. Experimental Design We performed cytogenetic profiling of pituitary adenomas obtained from 39 patients with acromegaly and four patients with sporadic gigantism by using array comparative genomic hybridization analysis. We explored intratumor DNA copy-number heterogeneity in two tumor samples by using DNA fluorescence in situ hybridization (FISH). Results Based on copy-number profiles, we found two groups of adenomas: a low–copy-number alteration (CNA) group (<12% of genomic disruption, 63% of tumors) and a high-CNA group (24% to 45% of genomic disruption, 37% of tumors). Arm-level CNAs were the most common abnormalities. GNAS mutation–positive adenomas belonged exclusively to the low-CNA group, whereas a subgroup of GNAS mutation–negative adenomas had a high degree of genomic disruption. We detected chromothripsis-related CNA profiles in two adenoma samples from an AIP mutation–positive patient with acromegaly and a patient with sporadic gigantism. RNA sequencing of these two samples identified 17 fusion transcripts, most of which resulted from chromothripsis-related chromosomal rearrangements. DNA FISH analysis of these samples demonstrated a subclonal architecture with up to six distinct cell populations in each tumor. Conclusion Somatotroph pituitary adenomas display substantial intertumor and intratumor DNA copy-number heterogeneity, as revealed by variable CNA profiles and complex subclonal architecture. The extensive cytogenetic burden in a subgroup of GNAS mutation–negative somatotroph adenomas points to an alternative tumorigenic pathway linked to genomic instability. Using cytogenetic profiling and DNA FISH analysis, we identified extensive intertumor and intratumor DNA copy-number heterogeneity reflecting a complex clonal architecture in somatotroph adenomas.

BackgroundSuprasellar pituitary adenomas (SPAs) are a special type of pituitary adenoma. Although dozens of SPA cases have been reported, the exact definition and the characteristics of SPA have not been exhaustively discussed before.MethodsIn a retrospective electronic medical records review, 13 patients with SPA were identified in our hospital between January 2010 and December 2019. A literature review was performed by searching the online database PubMed, and 39 cases conformed to the criteria based on the previous literature. Data regarding clinical symptoms, imaging manifestations, surgical information and follow-ups were analyzed.ResultsThe mean age at diagnosis of 52 patients with SPA was 36.73 years, and most of the patients were female (61.5%). The most common hormone-secreting subtypes of SPA were nonfunctioning (36.5%) and ACTH-secreting (34.6%) SPA. Macroadenomas (68.9%) were more common than microadenomas (31.1%). The origins of the SPAs included the intrasellar pituitary gland (type I), the subdiaphragmatic (type IIa) and supradiaphragmatic (type IIb) part of the pituitary stalk, and the suprasellar peri-infundibular region (type III). The most common anatomic subtype of SPA was type III, and type IIb was also common. The most common presentations of SPA were visual symptoms, especially for type III SPA. In addition, 64.7% and 73.1% of type IIb and III SPAs, respectively, were suspected to be of suprasellar origin based on presurgical imaging examination. Patients with tumors of suspected suprasellar origin were more likely to receive transcranial surgery (TCS) initially than those with tumors of suspected intrasellar origin (70.6% vs. 22.2%, p = 0.0013). The intact rate for the pituitary stalk after surgery for type II SPA was lower than that for type I and III SPA (52.6% vs. 92.6%, p = 0.0036). More patients with type II SPA experienced postoperative central diabetes insipidus (CDI) than those with type I and III SPA (57.9% vs. 11.1%, p = 0.0011). There was no significant difference in the incidence of postoperative CDI between transsphenoidal surgery (TSS) and TCS (p = 0.1304). Nine patients in our hospital received extended endoscopic TSS; only one experienced tumor recurrence, and no severe complications occurred after surgery.ConclusionsSPAs could be defined as pituitary adenomas completely or partially located in the suprasellar region. There were both similarities and differences among the different anatomic subtypes of SPA. For patients who were suspected of having SPAs, visual field tests, pituitary hormone evaluation and MRI were necessary. Because imaging examination is not a reliable method, surgery is the only way to confirm the tumor origin. Extended endoscopic TSS might be a safe and efficient approach to remove these tumors, but more studies are needed to verify this conclusion. For type II SPA, the pituitary stalk should be carefully protected during surgery, and postoperative CDI should be monitored.