Silent Corticotroph Pituitary Adenomas Research Articles

Difference in miRNA Expression in Functioning and Silent Corticotroph Pituitary Adenomas Indicates the Role of miRNA in the Regulation of Corticosteroid Receptors.

Corticotroph pituitary adenomas commonly cause Cushing’s disease (CD), but some of them are clinically silent. The reason why they do not cause endocrinological symptoms remains unclear. We used data from small RNA sequencing in adenomas causing CD (n = 28) and silent ones (n = 20) to explore the role of miRNA in hormone secretion and clinical status of the tumors. By comparing miRNA profiles, we identified 19 miRNAs differentially expressed in clinically functioning and silent corticotroph adenomas. The analysis of their putative target genes indicates a role of miRNAs in regulation of the corticosteroid receptors expression. Adenomas causing CD have higher expression of hsa-miR-124-3p and hsa-miR-135-5p and lower expression of their target genes NR3C1 and NR3C2. The role of hsa-miR-124-3p in the regulation of NR3C1 was further validated in vitro using AtT-20/D16v-F2 cells. The cells transfected with miR-124-3p mimics showed lower levels of glucocorticoid receptor expression than control cells while the interaction between miR-124-3p and NR3C1 3′ UTR was confirmed using luciferase reporter assay. The results indicate a relatively small difference in miRNA expression between clinically functioning and silent corticotroph pituitary adenomas. High expression of hsa-miR-124-3p in adenomas causing CD plays a role in the regulation of glucocorticoid receptor level and probably in reducing the effect of negative feedback mediated by corticosteroids.

Increased PCSK1N in silent corticotroph pituitary adenomas may explain their “silence”

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Silent corticotroph pituitary adenomas: clinical characteristics, long-term outcomes, and management of disease recurrence.

Silent corticotroph adenomas (SCAs) are a distinct subtype of nonfunctioning pituitary adenomas (NFAs) that demonstrate positive immunohistochemistry for adrenocorticotropic hormone (ACTH) without causing Cushing's disease. SCAs are hypothesized to exhibit more aggressive behavior than standard NFAs. The authors analyzed their institution's surgical experience with SCAs in an effort to characterize rates of invasion, postoperative clinical outcomes, and patterns of disease recurrence and progression. The secondary objectives were to define the best treatment strategies in the event of tumor recurrence and progression. A retrospective analysis of patients treated at the authors' institution identified 100 patients with SCAs and 841 patients with NFAs of other subtypes who were treated surgically from 2000 to 2019. Patient demographics, tumor characteristics, surgical and neuroimaging data, rates of endocrinopathy, and neurological outcomes were recorded. Cohorts of patients with SCAs and patients with standard NFAs were compared with regard to these characteristics and outcomes. The SCA cohort presented with cranial neuropathy (13% vs 5.7%, p = 0.0051) and headache (53% vs 42.3%, p = 0.042) compared to the NFA cohort, despite similar rates of apoplexy. The SCA cohort included a higher proportion of women (SCA 60% vs NFA 45.8%, p = 0.0071) and younger age at presentation (SCA 50.5 ± 13.3 vs NFA 54.6 ± 14.9 years of age, p = 0.0082). Reoperations were comparable between the cohorts (SCA 16% vs NFA 15.7%, p = 0.98). Preoperative pituitary function was comparable between the cohorts with the exception of higher rates of preoperative panhypopituitarism in NFA patients (2% vs 6.1%, respectively; p = 0.0033). The mean tumor diameter in SCA patients was 24 ± 10.8 mm compared to 26 ± 11.3 mm in NFA patients (p = 0.05). Rates of cavernous sinus invasion were higher in the SCA group (56% vs 49.7%), although this result did not reach statistical significance. There were no significant differences in extent of resection, intraoperative CSF leak rates, endocrine or neurological outcomes, or postoperative complications. Ki-67 rates were significantly increased in the SCA cohort (2.88 ± 2.79) compared to the NFA cohort (1.94 ± 1.99) (p = 0.015). Although no differences in overall rates of progression or recurrence were noted, SCAs had a significantly lower progression-free survival (24.5 vs 51.1 months, p = 0.0011). Among the SCA cohort, progression was noted despite the use of adjuvant radiosurgery in 33% (n = 4/12) of treated tumors. Adequate tumor control was not achieved in half (n = 6) of the SCA progression cohort despite radiosurgery or multiple resections. In this study, to the authors' knowledge the largest surgical series to assess outcomes in SCAs to date, the findings suggest that SCAs are more biologically aggressive tumors than standard NFAs. The progression-free survival duration of patients with SCAs is only about half that of patients with other NFAs. Therefore, close neuroimaging and clinical follow-up are warranted in patients with SCAs, and residual disease should be considered for early postoperative adjuvant radiosurgery, particularly in younger patients.

Distinct Pattern of Endoplasmic Reticulum Protein Processing and Extracellular Matrix Proteins in Functioning and Silent Corticotroph Pituitary Adenomas

Simple SummaryCorticotroph pituitary adenomas present a spectrum of functionality regarding hormonal production, ranging from functioning to silent tumors. Moreover, they show different invasiveness and recurrent behavior profiles, the silent being considered an aggressive type of adenomas. Through analyses of global transcriptome and proteome, we show that both groups expressed genes and protein related to protein synthesis and vesicular transport, and present a distinct pattern of collagen/ extracellular matrix proteins. Endoplasmic reticulum protein processing is a key factor for hormone production in functioning corticotroph adenomas. Furthermore, a distinct cell adhesion profile in silent corticotroph adenomas may explain the aggressive behavior. Together, our findings shed light on the different repertoires of activated signaling pathways in corticotroph pituitary adenomas and may reveal new potential medical targets.Functioning (FCA) and silent corticotroph (SCA) pituitary adenomas act differently from a clinical perspective, despite both subtypes showing positive TBX19 (TPIT) and/or adrenocorticotropic hormone (ACTH) staining by immunohistochemistry. They are challenging to treat, the former due to functional ACTH production and consequently hypercortisolemia, and the latter due to invasive and recurrent behavior. Moreover, the molecular mechanisms behind their distinct behavior are not clear. We investigated global transcriptome and proteome changes in order to identify signaling pathways that can explain FCA and SCA differences (e.g., hormone production vs. aggressive growth). In the transcriptomic study, cluster analyses of differentially expressed genes revealed two distinct groups in accordance with clinical and histological classification. However, in the proteomic study, a greater degree of heterogeneity within the SCA group was found. Genes and proteins related to protein synthesis and vesicular transport were expressed by both adenoma groups, although different types and a distinct pattern of collagen/extracellular matrix proteins were presented by each group. Moreover, several genes related to endoplasmic reticulum protein processing were overexpressed in the FCA group. Together, our findings shed light on the different repertoires of activated signaling pathways in corticotroph adenomas, namely, the increased protein processing capacity of FCA and a specific pattern of adhesion molecules that may play a role in the aggressiveness of SCA.

Neuroimaging of aggressive pituitary tumors.

Aggresssive pituitary tumors are defined as radiologically invasive, exhibiting a rapid growth and a poor response to the medical and surgical treatment options. The role of magnetic resonance imaging (MRI) is fundamental to assess tumor aggressiveness before surgical exploration. Distinction between cavernous sinus invasion and cavernous sinus compression is often challenging and cannot be solved always by using the Knosp criteria. Ideally, T2W images demonstrating the ruptured internal dural wall of cavernous sinus is the ultimate proof of cavernous sinus invasion. Subtle tumor volume increase in a short time can be shown when sequential MR images are rigorously replicable. A microcystic pattern observed on T2W images frequently reflects a potentially aggressive tumor as observed in silent corticotroph pituitary adenomas.

Pathway enrichment analysis in functioning and silent corticotroph pituitary adenomas reveals mechanisms to explain their distinct clinical behaviour

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Advances in Gamma Knife radiosurgery for pituitary tumors.

For the residual/recurrent pituitary adenomas, stereotactic radiosurgery (SRS) plays an important role in long-term tumor control and, for secretory adenomas, endocrine remission. The purpose of this review is to address the advances in SRS technique and detail the latest treatment strategies for various types of pituitary adenomas with a focus on recently published literature. From recent publications, SRS may be considered as an upfront treatment in patients with an adenoma that resides largely in the cavernous sinus and for whom resection is unlikely to produce substantial reduction in the overall tumor volume. Early treatment (<6 months after prior resection) with SRS appears to decrease the rate of tumor progression of subtotally resected nonfunctioning pituitary macroadenomas. Some types of adenomas may appear more aggressive with a high recurrence rate, for example, silent corticotroph pituitary adenomas, or sparsely granulated somatotroph-cell adenomas, may be indicated for a high-radiation dose. Finally, whole-sellar radiation and fractionated SRS are the alternative strategies, and may be indicated for challenging cases. The role of SRS for the pituitary adenoma is well established, and the treatment strategy is increasingly individualized based upon tumor histology, location, and volume. Hypopituitarism is the most complicated and can occur even years after SRS.

The aggressive clinical course of silent corticotroph pituitary adenomas: a case series

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Génétique de la maladie de Cushing

Cushing's disease is caused by corticotroph adenomas of the pituitary. To explore molecular mechanisms of endocrine autonomy, we recently performed exome sequencing of 10 corticotroph adenomas [1] identifying somatic mutations in the USP8 deubiquitinase gene in 4 of 10 adenomas. The mutations clustered in the 14-3-3 protein-binding motif enhancing proteolytic cleavage and catalytic activity of USP8. Cleaved USP8 led to increased EGF receptor deubiquitination impairing its downregulation and sustaining EGF signaling. USP8 mutants enhanced promoter activity of the gene for proopiomelanocortin. Our data show that dominant mutations in USP8 cause Cushing's disease via activation of EGF receptor signaling. In a follow-up study, we performed a retrospective, multicentric, genetic analysis of 134 functioning and 11 silent corticotroph pituitary adenomas using Sanger sequencing. Clinical data from these patients have been collected and examined within the context of the mutational status of USP8. New mutations were characterized by functional studies. Somatic mutations in USP8 were found in 48 (36%) adenomas from patients with Cushing's disease, but in none of the 11 silent corticotropinomas. The prevalence was higher in adults than in pediatric cases and in females than in males. Adults having USP8-mutated adenomas were diagnosed at an earlier age (36 vs. 44 years) than those with wild-type adenomas. Future research will be directed towards therapeutic targeting of USP8 in corticotroph adenomas.

Neurocysticercosis, Meningioma, and Silent Corticotroph Pituitary Adenoma in a 61-Year-Old Woman

We report here the case of a 61-year-old woman who presented with hydrocephalus and cystic and solid lesions in sella turcica, suprasellar areas, and third ventricle. After ventriculoperitoneal shunt she developed cognitive changes and the cystic lesions enlarged. Magnetic resonance imaging (MRI) demonstrated multiple cysts and a solid lesion in the sella and around the anterior clinoid process. With diagnosis of neurocysticercosis she underwent craniotomy. Pathologic examination documented two different lesions: viable and dead cysticerci with inflaming infiltration and a left anterior clinoidal meningioma. At the second surgery, six weeks later via transnasal transsphenoidal approach a silent corticotroph pituitary adenoma was removed which was studied by histology, immunohistochemistry, and electron microscopy. To our knowledge, the occurrence of these three different lesions in the sellar area was not described before.

Silent corticotroph adenomas

Silent corticotroph pituitary adenomas (SCA) are defined as pituitary adenomas showing positive staining for adrenocorticotrophic hormone in immunohistochemical studies, but not associated with perioperative clinical or laboratory features of hypercortisolaemia. They account for 1.1-6% of surgically removed pituitary adenomas. Currently, two distinct pathologic subtypes of SCA are recognised. Their pathogenesis remains unclear. They present with local mass effects (headache, visual deterioration, cranial nerve palsies, endocrine dysfunction). The lack of manifestations of cortisol excess has not been conclusively explained. In surgical series, most tumours are macroadenomas with suprasellar extension present in 87-100% of the cases; this is in contrast to Cushing's disease, which is mostly attributed to microadenomas. Surgery remains the main therapeutic approach. Attempts to identify predictors of recurrence have not been successful. Management and follow-up protocols should be planned taking into account their potential aggressive behaviour, particularly upon recurrence. The development of florid pituitary Cushing's syndrome and local recurrence followed by metastatic disease (occasionally outside the central nervous system) have been rarely reported.

Atypical pituitary adenoma (silent corticotroph pituitary adenoma)

Introduction: Pituitary adenomas are benign neoplasms with clinical behaviour and recurrence depending on the size of the tumour, therefore it is more common in nonfunctioning macroadenoma adenomas.Material and methods: Patient 1: A 40‐year female presented originally with visual field disturbance and underwent transphenoidal resection of pituitary macroadenoma in 1995. The tumour recurred in 1997 and 1998. Despite aggressive radiotherapy, the tumour metastasized to the vertebra in 1999. Patient 2: A 46‐year female presented with clinically nonfunctioning pituitary macroadenoma. She required two transphenoidal operations in 1998 and 1999, and underwent radiotherapy.Results: Patient 1: The initial biopsy shows silent corticotroph pituitary adenoma with occasional mitotic figures and Ki67 labelling index 2%. The recurrences in 1997 and 1998 showed increased nuclear pleomorphism, mitotic activity and Ki67 labelling (5% and 8%). The p53 was positive. The metastatic deposit in the vertebra showed similar histology but with Ki67 labelling of 15% and p53 immunoreactivity of 10%. Patient 2: The initial biopsy in 1998 showed silent corticotroph adenoma with Ki67 of 1%. The recurrence in 1999 showed increased mitotic figure, Ki67 labelling of 5% and p53 immunoreactivity.Conclusion: Silent corticotroph adenoma could be regarded as atypical pituitary adenoma with aggressive behaviour and high recurrence rate.