[Pituitary metastases: a diagnostic and therapeutic challenge]. / Metástasis hipofisarias: un desafío diagnóstico y terapéutico.

INTRODUCTION: Sellar metastases (SM) are rare manifestations of malignancy. Breast and lung cancer are the most common primary tumors. Most cases are diagnosed in patients with advanced malignant disease; however, symptoms of pituitary involvement can precede the diagnosis of the primary tumor. METHODS: Retrospective analysis of symptoms at presentation, hormonal, radiological and histological findings, management, and outcome of patients with SM from 2009 to 2020. RESULTS: Eighteen patients'cases were included, 11 with histological confirmation. Median (m) age was 53 years (range 35-75), 53% male. Primary malignant tumors: 8 lungs, 6 breast, 1 follicular thyroid carcinoma, 1 Hodgkin lymphoma, and 2 clear cell renal carcinomas. The m time between the diagnosis of the primary neoplasm and the occurrence of the SM was 108 months (range: 11-180). In 8 patients the diagnosis of the primary neoplasm was made after the finding of the symptomatic sellar mass. Insipidus diabetes, adenohypophysis deficit, visual disorders, headache, and cranial nerve deficits were evident in 78, 77, 61, 39 and 39% of the cases, respectively. Fifteen patients harbored supra / parasellar masses, in three a lesion was limited to the pituitary gland, and stalk. Eleven out of 18 (61.1%) of the patients were operated on by the trans-sphenoidal approach, for diagnostic and / or decompressive purposes. Eighteen died, with a median survival time of 6 months (1-36). DISCUSSION: In the presence of a pituitary lesion with diffuse gadolinium uptake, associated with insipidus diabetes and / or visual disorder SM should be suspected even in patients without a history of oncological disease.

Introducción: La región selar es un sitio infrecuente de metástasis, encontrándose en el 1% de las cirugías hipofisarias. Los tumores primarios más habituales son mama y pulmón. En general son diagnosticadas en pacientes con enfermedad avanzada, aunque pueden ser el debut de la enfermedad oncológica. Métodos: Análisis retrospectivo de las características clínicas, bioquímicas, radiológicas de pacientes con metástasis selares o hipofisarias (MS) durante el periodo 2009-2020. Resultados: Se reportaron 18 casos de pacientes, 11 de ellos con confirmación histológica. La mediana de edad fue 53 años (rango: 35-75), 53% hombres. La localización del tumor primario fue: 8 pulmón, 6 mama, 1 carcinoma folicular de tiroides, 1 linfoma Hodgkin y 2 carcinomas renales de células claras. La media de tiempo entre el diagnóstico del tumor primario y la aparición de la MS -en los casos de presentación metacrónica- fue 108 meses (rango: 11-180). En 8 pacientes (44.4%), el diagnóstico de la neoplasia primaria se hizo a partir del hallazgo de la masa selar. Diabetes insípida, hipopituitarismo, trastornos visuales, oftalmoplejía y cefalea se presentaron en el 78, 77, 61, 39 y 39%, respectivamente. Quince pacientes presentaron masas con extensión supra/paraselar; y 3 lesión limitada a la hipófisis y tallo. Fueron operados 11/18 por vía transesfenoidal, para diagnóstico y/o descompresión. Fallecieron 17, con una mediana de sobrevida de 6 meses (1- 36). Discusión: La sospecha de MS debe estar presente ante una masa selar y supraselar con captación difusa del gadolinio, diabetes insípida, hipopituitarismo y/o disfunción visual, aun en pacientes sin antecedentes oncológicos.

The Immune Microenvironment Landscape of Pituitary NeuroEndocrine Tumors, a Transcriptomic Approach.

Pituitary neuroendocrine tumors (PitNET) are known to be variably infiltrated by different immune cells. Nonetheless, their role in pituitary oncogenesis has only begun to be unveiled. The immune microenvironment could determine the biological and clinical behavior of a neoplasm and may have prognostic implications. To evaluate the expression of immune-related genes and to correlate such expression with the presence of infiltrating immune cells in forty-two PitNETs of different lineages, we performed whole transcriptome analysis and RT-qPCR. Deconvolution analysis was carried out to infer the immune cell types present in each tumor and the presence of immune cells was confirmed by immunofluorescence. We found characteristic expression profiles of immune-related genes including those encoding interleukins and chemokines for each tumor lineage. Genes such as IL4-I1, IL-36A, TIRAP, IL-17REL, and CCL5 were upregulated in all PitNETS, whereas IL34, IL20RA, and IL-2RB characterize the NR5A1-, TBX19-, and POU1F1-derived tumors, respectively. Transcriptome deconvolution analysis showed that M2 macrophages, CD4+ T cells, CD8+ T cells, NK cells, and neutrophils can potentially infiltrate PitNET. Furthermore, CD4+ and CD8+ T cells and NK cells infiltration was validated by immunofluorescence. Expression of CCL18, IL-5RA, and HLA-B as well as macrophage tumor infiltration could identify patients who can potentially benefit from treatment with immune checkpoint inhibitors.

Mesenchymal stem cells induce an immunosuppressive microenvironment in pituitary tumors.

BACKGROUND: The tumor microenvironment (TME) includes diverse cellular components such as mesenchymal stem cells (MSC) and immune cells among others. MSC have been isolated from different tumors and they favor tumor cell growth, however, their role in pituitary tumors (PT) remains unknown. Herein we report the presence of MSCs in 2 ACTH-secreting PT causing Cushing disease (MCU), 2 nonfunctioning adenomas of gonadotrope differentiation (MNF) and 2 non tumoral pituitary glands (MS). METHODS: We have analyzed their transcriptomic profiles by RNAseq and compared MSC in terms of their immunosuppressive effects against lymphoid T cell and macrophage populations by means of co-cultures and flow cytometry. RESULTS: Our transcriptomic analysis revealed molecular differences between MSC derived from non-tumoral pituitaries and MSC derived from PT. Two distinct subpopulations of MSC, one displaying immunosuppressive properties and the other with increased pro-proliferative capabilities, regardless of their origin. MSC derived from ACTH- and nonfunctioning PT, but not those derived from non-tumoral glands significantly inhibited the proliferation of activated T cells, favored the generation of Tregs and promote M2 macrophage polarization. Such immunosuppressive effects were correlated with an upregulation of programmed death ligand 1 and intracellular expression of macrophage colony stimulating factor (M-CSF) and IL-10. Importantly, MSC derived from ACTH-PT showed a higher immunosuppressive potential than MSC isolated from nonfunctioning tumors. CONCLUSION: This study demonstrates the presence of at least two MSC subpopulations in the pituitary gland and suggests that immunosuppressive effects of MSC may have important implications in PT growth.

Genomics, Transcriptomics, and Epigenetics of Sporadic Pituitary Tumors.

Pituitary tumors (PT) are highly heterogeneous neoplasms, comprising functioning and nonfunctioning lesions. Functioning PT include prolactinomas, causing amenorrhea-galactorrhea in women and sexual dysfunction in men; GH-secreting adenomas causing acromegaly-gigantism; ACTH-secreting corticotrophinomas causing Cushing disease (CD); and the rare TSH-secreting thyrotrophinomas that result in central hyperthyroidism. Nonfunctioning PT do not result in a hormonal hypersecretion syndrome and most of them are of gonadotrope differentiation; other non-functioning PT include null cell adenomas and silent ACTH-, GH- and PRL-adenomas. Less than 5% of PT occur in a familial or syndromic context whereby germline mutations of specific genes account for their molecular pathogenesis. In contrast, the more common sporadic PT do not result from a single molecular abnormality but rather emerge from several oncogenic events that culminate in an increased proliferation of pituitary cells, and in the case of functioning tumors, in a non-regulated hormonal hypersecretion. In recent years, important advances in the understanding of the molecular pathogenesis of PT have been made, including the genomic, transcriptomic, epigenetic, and proteomic characterization of these neoplasms. In this review, we summarize the available molecular information pertaining the oncogenesis of PT.

Regulatory mechanisms of microRNAs in endocrine disorders and their therapeutic potential.

MicroRNAs (miRNAs) are small endogenous non-coding RNA molecules capable of regulating gene expression at the post-transcriptional level either by translational inhibition or mRNA degradation and have recently been importantly related to the diagnosis and prognosis of the most relevant endocrine disorders. The endocrine system comprises various highly vascularized ductless organs regulating metabolism, growth and development, and sexual function. Endocrine disorders constitute the fifth principal cause of death worldwide, and they are considered a significant public health problem due to their long-term effects and negative impact on the patient's quality of life. Over the last few years, miRNAs have been discovered to regulate various biological processes associated with endocrine disorders, which could be advantageous in developing new diagnostic and therapeutic tools. The present review aims to provide an overview of the most recent and significant information regarding the regulatory mechanism of miRNAs during the development of the most relevant endocrine disorders, including diabetes mellitus, thyroid diseases, osteoporosis, pituitary tumors, Cushing's syndrome, adrenal insufficiency and multiple endocrine neoplasia, and their potential implications as disease biomarkers.

miR-383-5p, miR-181a-5p, and miR-181b-5p as Predictors of Response to First-Generation Somatostatin Receptor Ligands in Acromegaly.

Acromegaly is a chronic systemic disease caused in the vast majority of cases by growth hormone (GH)-secreting adenoma, with surgery being the first-line treatment. When a cure is not attained with surgery, first-generation somatostatin receptor ligands (fg-SRLs) are the most common medication prescribed. Predictors of response to fg-SRLs have been studied; however, they cannot fully predict the response to fg-SRL. MicroRNAs are small RNAs, the main role of which is messenger RNA (mRNA) post-transcriptional regulation. This study aimed to identify the microRNAs involved in resistance to treatment with fg-SRLs in acromegaly. Ten patients with acromegaly undergoing treatment with fg-SRLs were selected to undergo miRNA sequencing: five controlled and five uncontrolled with treatment. Bioinformatic analysis was performed to detect differentially expressed miRNAs. Then, the same 10 samples were used for validation by qPCR and an additional 22 samples were analyzed, totaling 32 samples. e We found 59 differentially expressed miRNAs in the first analysis. miR-181a-5p and miR-181b-5p were downregulated, and miR-383-5p was upregulated in the uncontrolled group. Receiver operating characteristic (ROC) curve analysis of miR-383-5p showed an NPV of 84.3% and a PPV of 84.5%. In summary, miR-181a-5p, miR-181b-5p, and miR-383-5p are biomarkers of response to fg-SRLs, and they can be used individually or included in prediction models as tools to guide clinical decisions.

Integrating Methylome and Transcriptome Signatures Expands the Molecular Classification of the Pituitary Tumors.

OBJECTIVE: To explore pituitary tumors by methylome and transcriptome signatures in a heterogeneous ethnic population. METHODS: In this retrospective cross-sectional study, clinicopathological features, methylome, and transcriptome were evaluated in pituitary tumors from 77 patients (61% women, age 12-72 years) followed due to functioning (FPT: GH-secreting n = 18, ACTH-secreting n = 14) and nonfunctioning pituitary tumors (NFPT, n = 45) at Ribeirao Preto Medical School, University of São Paulo. RESULTS: Unsupervised hierarchical clustering analysis (UHCA) of methylome (n = 77) and transcriptome (n = 65 out of 77) revealed 3 clusters each: one enriched by FPT, one by NFPT, and a third by ACTH-secreting and NFPT. Comparison between each omics-derived clusters identified 3568 and 5994 differentially methylated and expressed genes, respectively, which were associated with each other, with tumor clinical presentation, and with 2017 and 2022 WHO classifications. UHCA considering 11 transcripts related to pituitary development/differentiation also supported 3 clusters: POU1F1-driven somatotroph, TBX19-driven corticotroph, and NR5A1-driven gonadotroph adenomas, with rare exceptions (NR5A1 expressed in few GH-secreting and corticotroph silent adenomas; POU1F1 in few ACTH-secreting adenomas; and TBX19 in few NFPTs). CONCLUSION: This large heterogenic ethnic Brazilian cohort confirms that integrated methylome and transcriptome signatures classify FPT and NFPT, which are associated with clinical presentation and tumor invasiveness. Moreover, the cluster NFPT/ACTH-secreting adenomas raises interest regarding tumor heterogeneity, supporting the challenge raised by the 2017 and 2022 WHO definition regarding the discrepancy, in rare cases, between clinical presentation and pituitary lineage markers. Finally, making our data publicly available enables further studies to validate genes/pathways involved in pituitary tumor pathogenesis and prognosis.

ß-Catenin is reduced in membranes of human prolactinoma cells and it is inhibited by temozolomide in prolactin secreting tumor models.

INTRODUCTION: Prolactinomas are the most frequent pituitary tumor subtype. Despite most of them respond to medical treatment, a proportion are resistant and become a challenge in clinical management. Wnt/ß-Catenin pathway has been implicated in several cancers including pituitary tumors and other sellar region malignancies. Interestingly, Wnt/ß-Catenin inhibition augments the cytotoxicity of the chemotherapeutic agent Temozolomide (TMZ) in different cancers. TMZ is now being implemented as rescue therapy for aggressive pituitary adenoma treatment. However, the molecular mechanisms associated with TMZ action in pituitary tumors remain unclear. OBJECTIVES: Our aims in the present study were to evaluate differential ß-Catenin expression in human resistant prolactinomas and Wnt/ß-Catenin signaling activation and involvement in Prolactin (PRL) secreting experimental models treated with TMZ. RESULTS: We first evaluated by immunohistochemistry ß-Catenin localization in human resistant prolactinomas in which we demonstrated reduced membrane ß-Catenin in prolactinoma cells compared to normal pituitaries, independently of the Ki-67 proliferation indexes. In turn, in vivo 15 mg/kg of orally administered TMZ markedly reduced PRL production and increased prolactinoma cell apoptosis in mice bearing xenografted prolactinomas. Intratumoral ß-Catenin strongly correlated with Prl and Cyclin D1, and importantly, TMZ downregulated both ß-Catenin and Cyclin D1, supporting their significance in prolactinoma growth and as candidates of therapeutic targets. When tested in vitro, TMZ directly reduced MMQ cell viability, increased apoptosis and produced G2/M cell cycle arrest. Remarkably, ß-Catenin activation and VEGF secretion were inhibited by TMZ in vitro. CONCLUSIONS: We concluded that dopamine resistant prolactinomas undergo a ß-Catenin relocalization in relation to normal pituitaries and that TMZ restrains experimental prolactinoma tumorigenicity by reducing PRL production and ß-Catenin activation. Together, our findings contribute to the understanding of Wnt/ß-Catenin implication in prolactinoma maintenance and TMZ therapy, opening the opportunity of new treatment strategies for aggressive and resistant pituitary tumors.

The kinome, cyclins and cyclin-dependent kinases of pituitary adenomas, a look into the gene expression profile among tumors from different lineages.

BACKGROUND: Pituitary adenomas (PA) are the second most common intracranial tumors and are classified according to hormone they produce, and the transcription factors they express. The majority of PA occur sporadically, and their molecular pathogenesis is incompletely understood. METHODS: Here we performed transcriptome and proteome analysis of tumors derived from POU1F1 (GH-, TSH-, and PRL-tumors, N = 16), NR5A1 (gonadotropes and null cells adenomas, n = 17) and TBX19 (ACTH-tumors, n = 6) lineages as well as from silent ACTH-tumors (n = 3) to determine expression of kinases, cyclins, CDKs and CDK inhibitors. RESULTS: The expression profiles of genes encoding kinases were distinctive for each of the three PA lineage: NR5A1-derived tumors showed upregulation of ETNK2 and PIK3C2G and alterations in MAPK, ErbB and RAS signaling, POU1F1-derived adenomas showed upregulation of PIP5K1B and NEK10 and alterations in phosphatidylinositol, insulin and phospholipase D signaling pathways and TBX19-derived adenomas showed upregulation of MERTK and STK17B and alterations in VEGFA-VEGFR, EGF-EGFR and Insulin signaling pathways. In contrast, the expression of the different genes encoding cyclins, CDK and CDK inhibitors among NR5A1-, POU1F1- and TBX19-adenomas showed only subtle differences. CDK9 and CDK18 were upregulated in NR5A1-adenomas, whereas CDK4 and CDK7 were upregulated in POUF1-adenomas. CONCLUSIONS: The kinome of PA clusters these lesions into three distinct groups according to the transcription factor that drives their terminal differentiation. And these complexes could be harnessed as molecular therapy targets.

Pituitary carcinoma in a bitch: clinical, tomographic, histopathological and immunohistochemistry findings

Background: Primary pituitary carcinoma is rarely reported in dogs and only few reports describe its malignancy. In veterinary literature, primary pituitary carcinomas correspond up to 2.4% to 3.4% of intracranial neoplasms found in dogs andinformation regarding its biological behavior is quite limited. In humans, primary pituitary carcinomas represent less than1.0% of all tumors found in the pituitary gland. The proposed classification for pituitary carcinoma in humans and dogsdetermines that the tumor must have its origin in adenohypophyseal region and disseminated metastasis by cerebrospinalfluid or systemically to other organs must be observed. In dogs, a few reports have described primary pituitary carcinoma.The goal of this report was to describe clinical, tomographic, histopathological and immunohistochemistry features of abitch with primary pituitary carcinoma with adjacent invasion.Case: A 7-year-old female spayed Golden Retriever dog was assessed by general practice due progressive weight loss,muscular atrophy, lethargy, blindness, head pressing, and hyporexia for 21 days. Computed tomography (CT) showeda cerebral parenchyma with expansive extra-axial base formation, originating from sella turcica topography, measuringabout 2.0 cm dorsally, displacing the third ventricle, suggesting the diagnosis of pituitary neoplasia. The hormones thyroidstimulating hormone (TSH) and total thyroxine (T4) as well as stimulation ACTH test were unremarkable. After 7 days,neurological clinical signs progressed and unfortunately the patient died ten days later after hospitalization. A necropsyexam revealed pituitary gland with increased dimensions (2.5 x 2.0 cm). Histopathological fi ndings revealed tumor proliferation in pituitary gland. The neoplasm showed invasion to the nervous parenchyma and metastatic foci between the brainlobes. Immunohistochemistry was positive for keratin and neuron-specifi c enolase...

GnRH agonist-associated pituitary apoplexy: a case series and review of the literature.

PURPOSE: To examine the clinical presentation and longitudinal outcome of Pituitary Apoplexy (PA) after gonadotropin-releasing hormone agonist (GnRHa) in a series of patients and compare to prior reports. METHODS: A retrospective chart review was performed on seven patients receiving GnRHa who developed PA. Prior reported cases were analyzed. RESULTS: Six men (median age 72 years) with prostate cancer and one woman (aged 22 years) undergoing oocyte donation presented with PA between 1990 and 2020. Most presented with within 24 h of the first dose, but two developed PA 1 to 5 months after GnRHa initiation. The main clinical manifestations were headache (100%), nausea and vomiting (86%). While no patients had a previously known pituitary tumor, all had imaging demonstrating sellar mass and/or hemorrhage at presentation. Among those surgically treated (5/7), 80% (4/5) of patients had pathologic specimens that stained positive for gonadotropins; the remaining patient's pathologic specimen was necrotic. At the time of PA, the most common pituitary dysfunction was hypocortisolism. Central adrenal insufficiency and central hypothyroidism were reversible in a subset. Pituitary imaging remained stable. CONCLUSIONS: This is the first report of a case series with PA after GnRHa administration with longitudinal follow-up. Although infrequent, PA can be life-threatening and should be suspected among patients receiving GnRHa, with or without a known pituitary adenoma, who develop acute headache, nausea and/or vomiting. Since hypopituitarism was reversible in a subset, ongoing pituitary function testing may be indicated.

Rathke's cleft cyst infections and pituitary abscesses: case series and review of the literature.

PURPOSE: Pituitary abscesses (PAs) are a rare clinical entity which may arise from normal pituitary tissue or underlying lesions within the gland. Rathke's cleft cysts (RCCs) are not commonly associated with the development of PA. METHODS: Retrospective chart review of three patients with PAs within RCCs at a single university center and review of the literature. RESULTS: Three cases are reported. The first case presented with fever and headache and a history of prior surgery due to RCC and a recent respiratory tract infection. The second case had a history of recent skin infections and presented with sudden onset headache and hypopituitarism. In the third case, chronic visual field impairment prompted an ophthalmologic evaluation resulting in a diagnosis of an adenoma and an infected RCC. In all three cases, an endoscopic endonasal approach was performed to drain infected tissue and allowed microbiological identification of gram-positive cocci, followed by treatment with antibiotics for at least three weeks. Cases in the literature are scarce and the diagnosis is usually made intraoperatively due to non-specific manifestations and imaging. PAs arising from underlying pituitary lesions are less common than primary PAs. Differential diagnosis should include pituitary apoplexy, hypophysitis and other cystic lesions. CONCLUSION: PAs occurring in RCCs are infrequent. Clinical manifestations are commonly subacute, without septic symptoms. Imaging is usually non-specific. Preoperative diagnosis is infrequent and a broad differential diagnosis should be considered. Empirical antimicrobial therapy should be initiated and adjusted after obtaining cultures to reduce the rate of recurrence and improve clinical outcomes.

Pituitary neuroendocrine tumors and differentiated thyroid cancer: do metabolic and inflammatory risk factors play roles?

PURPOSE: It is postulated that patients with different types of pituitary neuroendocrine tumors (PitNETs) may present a higher incidence of cancer. Factors underlying individuals becoming overweight, such as insulin resistance, hyperleptinemia, and low-grade inflammation, may play a role in the risk of differentiated thyroid carcinoma (DTC) in such patients. This study aimed to investigate the frequency of and obesity-related risk factors associated with DTC in patients with PitNETs. METHODS: This cross-sectional study involved 149 patients with nonacromegalic PitNETs (AG group), 71 patients with acromegaly (ACRO group), and 156 controls (CG group). All participants underwent insulin and blood glucose measurements with the determination of the homeostatic model assessment-insulin resistance (HOMA-IR) index, leptin, and high-sensitivity C-reactive protein (hsCRP), and they also underwent thyroid ultrasound. Clinically significant nodules were biopsied for subsequent cytopathological evaluation, and participants were operated on when indicated. RESULTS: Patients in the AG group had high levels of insulin resistance and significantly higher levels of leptin and hsCRP compared with those of patients in the ACRO group. There were no cases of DTC in the AG group; two findings, one incidental, of DTC occurred in the CG group, and three cases of DTC were present in the ACRO group. Acromegaly was associated with DTC after adjusted analysis. CONCLUSIONS: Our findings in patients with nonacromegalic PitNETs do not indicate a high risk for DTC despite the presence of metabolic and inflammatory risk factors for neoplastic events. In contrast, acromegaly promotes a greater risk of DTC.

Granular cell tumors of the sellar region: what should be done after subtotal resection? A systematic review.

PURPOSE: Granular cell tumors (GCT) are highly vascularized and adherent to adjacent structures, and so, complete resection represents a challenge. Adjuvant therapy decisions for residual GCTs currently relies on individual clinician decisions due to a paucity of systematic literature data. We present a comprehensive analysis about the impact of adjuvant therapy in reported cases of patients with incomplete GCT resection. METHODS: One database (PubMed) and crossed references were queried for GCT with incomplete resection or biopsy from 1962 to 2020. Literature review was performed according to the PRISMA guidelines. Also, two patients with residual GCT from our institutions are added to the analysis. Data regarding clinical presentation, surgical approach, use of adjuvant therapy, Ki-67 labeling, and follow up assessments were extracted and analyzed from selected publications. RESULTS: Thirty-three studies met the predetermined inclusion criteria and 53 patients were selected (including our two reported cases). The median of age was 49 [IQR, 39-60 years], with a slight male predominance (1.2:1). Among the surgical procedures, seven (13%) were biopsies alone. Adjuvant therapy was used in 18 patients (radiotherapy, 94.5%; chemotherapy, 5.5%) but there is no statistical correlation with adjuvant therapy and the progression of the remnant tumor (p = 0.33). Our institutions' patients did not receive adjuvant therapy and did not show tumor progression on MRI. CONCLUSION: Our systematic literature review suggests there is a limited role for chemo and/or radiotherapy in the management of incomplete GCT resection. It may be reasonable recommending close clinical follow up in patients with incomplete resection.

Protein stabilization by RSUME accounts for PTTG pituitary tumor abundance and oncogenicity.

Increased levels of the proto-oncogene pituitary tumor-transforming gene 1 (PTTG) have been repeatedly reported in several human solid tumors, especially in endocrine-related tumors such as pituitary adenomas. Securin PTTG has a critical role in pituitary tumorigenesis. However, the cause of upregulation has not been found yet, despite analyses made at the gene, promoter and mRNA level that show that no mutations, epigenetic modifications or other mechanisms that deregulate its expression may explain its overexpression and action as an oncogene. We describe that high PTTG protein levels are induced by the RWD-containing sumoylation enhancer (RWDD3 or RSUME), a protein originally identified in the same pituitary tumor cell line in which PTTG was also cloned. We demonstrate that PTTG and RSUME have a positive expression correlation in human pituitary adenomas. RSUME increases PTTG protein in pituitary tumor cell lines, prolongs the half-life of PTTG protein and regulates the PTTG induction by estradiol. As a consequence, RSUME enhances PTTG transcription factor and securin activities. PTTG hyperactivity on the cell cycle resulted in recurrent and unequal divisions without cytokinesis, and the consequential appearance of aneuploidies and multinucleated cells in the tumor. RSUME knockdown diminishes securin PTTG and reduces its tumorigenic potential in a xenograft mouse model. Taken together, our findings show that PTTG high protein steady state levels account for PTTG tumor abundance and demonstrate a critical role of RSUME in this process in pituitary tumor cells.

Acromegaly: A rare disease?

Acromegaly is generally considered a benign and uncommon disease. However, some recent data bring support to the idea that it is more frequent than previously thought. Besides, acromegaly can significantly shorten the length of life due to its cardiovascular and metabolic complications. Since its clinical signs are insidiously progressive for many years, there is a considerable delay in its detection. Usually, many different specialists have been consulted before reaching diagnosis of acromegaly. Those specialists include cardiologists, pulmonologists, dentists, rheumatologists, and diabetes specialists. Possible means to achieve earlier detection are based on increasing awareness of doctors and the public in general. In this paper, the author analyzes the factors related to delayed diagnosis and the potential ways to ameliorate awareness of the disease with particular attention to screening procedures.

Acromegaly: a rare disease?

Acromegaly is generally considered a benign and uncommon disease. However, some recent data bring support to the idea that it is more frequent than previously thought. Besides, acromegaly can significantly shorten the length of life due to its cardiovascular and metabolic complications. Since its clinical signs are insidiously progressive for many years, there is a considerable delay in its detection. Usually, many different specialists have been consulted before reaching diagnosis of acromegaly. Those specialists include cardiologists, pulmonologists, dentists, rheumatologists, and diabetes specialists. Possible means to achieve earlier detection are based on increasing awareness of doctors and the public in general. In this paper, the author analyzes the factors related to delayed diagnosis and the potential ways to ameliorate awareness of the disease with particular attention to screening procedures.

Existe la idea generalizada de que la acromegalia es una enfermedad benigna e infrecuente. Sin embargo, el paciente acromegálico ve comprometida su vida a causa de complicaciones cardiovasculares y metabólicas. Por otra parte, trabajos recientes muestran que su frecuencia parece mucho mayor que lo supuesto previamente. Dado que los signos y síntomas de la enfermedad se instalan lenta e insidiosamente, existe una demora considerable en su diagnóstico. Habitualmente, los pacientes han consultado diversos especialistas antes de que el trastorno sea detectado. Los mismos incluyen cardiólogos, neumonólogos, odontólogos, reumatólogos y diabetólogos. Un camino posible para lograr una detección temprana es el incremento del grado de concientización de los médicos y de la comunidad. En este artículo se analizan los factores vinculados al retraso diagnóstico y los medios posibles para mejorar el conocimiento y detección precoz de la enfermedad.

Diagnosis and treatment of TSH-secreting adenomas: review of a longtime experience in a reference center.

PURPOSE: TSH-secreting pituitary adenomas are among the less prevalent pituitary tumors, corresponding to 0.9-1.5% of all pituitary adenomas in surgical series. METHODS: A series of 11 patients with TSH-secreting and cosecreting adenomas diagnosed and treated in the last 25 years in a single center is described. RESULTS: The mean age at diagnosis was 37 years (range 18-80 years; median 23 years); the ratio of male-to-female patients was similar (6M:5F). Only three patients was the correct diagnosis established shortly after the initial medical evaluation. Other four patients were initially diagnosed with other pituitary adenomas (prolactinoma, acromegaly, and non-secreting pituitary tumor) and another four diagnosed with primary hyperthyroidism. There was a mean diagnostic delay of 6.0 years (range 0.5-25 years; median 2 years). Nine patients had macroadenomas and two patients had microadenomas. Seven patients underwent pituitary surgery which controlled the disease in only two (one micro- and one noninvasive macroadenoma). The other treatments were directed to the thyroid gland (surgery or 131I radiotherapy), pituitary radiotherapy, and somatostatin analog. CONCLUSION: In spite of its relatively straightforward diagnosis, which includes clinical/subclinical hyperthyroidism with or without goiter, increased free thyroxine and nonsuppressed TSH levels, and pituitary mass, the diagnosis of TSH-secreting and cosecreting adenomas was frequently unrecognized and thus much delayed. Serum alpha-subunit levels were high in nearly all patients with TSH-secreting adenomas and useful in excluding other conditions in the differential diagnosis. Proper indication and interpretation of simple laboratory tests should be emphasized in medical education to improve diagnostic accuracy.

Molecular Mechanisms Underlying Pituitary Pathogenesis.

During the last years, progress has been made on the identification of mechanisms involved in anterior pituitary cell transformation and tumorigenesis. Oncogene activation, tumor suppressor gene inactivation, epigenetic changes, and microRNAs deregulation contribute to the initiation of pituitary tumors. Despite the high prevalence of pituitary adenomas, they are mostly benign, indicating that intrinsic mechanisms may regulate pituitary cell expansion. Senescence is characterized by an irreversible cell cycle arrest and represents an important protective mechanism against malignancy. Pituitary tumor transforming gene (PTTG) is an oncogene involved in early stages of pituitary tumor development, and also triggers a senescence response by activating DNA-damage signaling pathway. Cytokines, as well as many other factors, play an important role in pituitary physiology, affecting not only cell proliferation but also hormone secretion. Special interest is focused on interleukin-6 (IL-6) because its dual function of stimulating pituitary tumor cell growth but inhibiting normal pituitary cells proliferation. It has been demonstrated that IL-6 has a key role in promoting and maintenance of the senescence program in tumors. Senescence, triggered by PTTG activation and mediated by IL-6, may be a mechanism for explaining the benign nature of pituitary tumors.

Endoscopic Endonasal Transsphenoidal Pituitary Tumors Approach: Nuances of Neurosurgical Technique / Abordagem endoscópica endonasal transesfenoidal para tumores hipofisários: detalhes da técnica neurocirúrgica

Pituitary tumors are responsible for 7 to 17% of all intracranial lesions. Over the past decade, advances in endoscopic microsurgical techniques have resulted in an increasingly aggressive endonasal approach to tumors of the midline skull base. We present our series emphasizing technical nuances of endoscopic endonasal transsphenoidal approach to treat pituitary adenomas.

Tumores hipofisários são responsáveis por 7 a 17% de todas as lesões intracranianas. Durante a última década, avanços nas técnicas microcirúrgicas endoscópicas resultaram no aumento de acessos endonasais agressivos para tumores de base de crânio de linha média. Apresentamos nossa série de casos, com ênfase nos detalhes técnicos do acesso endoscópico endonasal transesfenoidal para o tratamento de tumores da hipófise.