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Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic...
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Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 64144

Special Issue Editor

Prof. Dr. Monica Fedele

E-Mail Website
Guest Editor
CNR—Institute of Experimental Endocrinology and Oncology, 80131 Naples, Italy
Interests: molecular mechanisms of cancer cell transformation; PATZ1 in development and cancer; animal models; tumor biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent progress in understanding the molecular features of pituitary tumors, one of the most frequent intracranial tumors and neuroendocrine neoplasms affecting 1 in 1000 in the general population, allowed us to improve their classification, with an impact on the diagnosis and the prediction of targeted treatments. Pituitary tumorigenesis is driven by diverse mechanisms, including gene amplification, mutation, overexpression, down-regulation and epigenetic silencing, microRNA misexpression, cell cycle dysregulation, endocrine dysfunction, and others.

A deep knowledge of each of these mechanisms, mainly achieved thanks to the use of animal models, is leading to the development of effective therapeutic strategies, even for the most aggressive subtypes, characterized by invasiveness, recurrence, and resistance to conventional treatment.

In this Special Issue, we will publish reviews and original research that provide new insights into signaling pathways and biomarkers driving pituitary tumorigenesis, diagnosis, and therapeutic perspectives. Articles about aggressive pituitary tumors will be particularly welcomed.

Prof. Dr. Monica Fedele
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Pituitary adenomas
  • Pituitary tumorigenesis
  • Prolactinomas
  • Non-functioning pituitary adenomas
  • Somatotropinomas
  • Adrenocorticotropinomas
  • Mammosomatotroph cell adenomas
  • Thyrotroph cell adenomas
  • Pituitary neuroendocrine tumors
  • Targeted treatment for pituitary adenomas
  • Pituitary adenoma biomarkers

Published Papers (15 papers)

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Editorial

Jump to: Research, Review

3 pages, 180 KiB  
Editorial
Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting
by Monica Fedele
Cancers 2021, 13(7), 1697; https://doi.org/10.3390/cancers13071697 - 03 Apr 2021
Viewed by 1367
Abstract
In this Special Issue, a series of eight original research articles and six reviews have been collected to highlight the latest knowledge into molecular features, diagnosis and therapeutic targeting of pituitary tumors, one of the most frequent intracranial tumors and neuroendocrine neoplasms [...] [...] Read more.
In this Special Issue, a series of eight original research articles and six reviews have been collected to highlight the latest knowledge into molecular features, diagnosis and therapeutic targeting of pituitary tumors, one of the most frequent intracranial tumors and neuroendocrine neoplasms [...] Full article
(This article belongs to the Special Issue Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting)

Research

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18 pages, 646 KiB  
Article
Sexual Dimorphism in Cellular and Molecular Features in Human ACTH-Secreting Pituitary Adenomas
by Francesca Pecori Giraldi, Maria Francesca Cassarino, Antonella Sesta, Mariarosa Terreni, Giovanni Lasio and Marco Losa
Cancers 2020, 12(3), 669; https://doi.org/10.3390/cancers12030669 - 13 Mar 2020
Cited by 11 | Viewed by 2798
Abstract
(1) Background. Cushing’s disease presents gender disparities in prevalence and clinical course. Little is known, however, about sexual dimorphism at the level of the corticotrope adenoma itself. The aim of the present study was to evaluate molecular features of ACTH-secreting pituitary adenomas collected [...] Read more.
(1) Background. Cushing’s disease presents gender disparities in prevalence and clinical course. Little is known, however, about sexual dimorphism at the level of the corticotrope adenoma itself. The aim of the present study was to evaluate molecular features of ACTH-secreting pituitary adenomas collected from female and male patients with Cushing’s disease. (2) Methods. We analyzed 153 ACTH-secreting adenomas collected from 31 men and 122 women. Adenomas were established in culture and ACTH synthesis and secretion assessed in basal conditions as well as during incubation with CRH or dexamethasone. Concurrently, microarray analysis was performed on formalin-fixed specimens and differences in the expression profiles between specimens from male and female patients identified. (3) Results. ACTH medium concentrations in adenomas obtained from male patients were significantly lower than those observed in adenomas from female patients. This could be observed for baseline as well as modulated secretion. Analysis of corticotrope transcriptomes revealed considerable similarities with few, selected differences in functional annotations. Differentially expressed genes comprised genes with known sexual dimorphism, genes involved in tumour development and genes relevant to pituitary pathophysiology. (4) Conclusions. Our study shows for the first time that human corticotrope adenomas present sexual dimorphism and underlines the need for a gender-dependent analysis of these tumours. Differentially expressed genes may represent the basis for gender-tailored target therapy. Full article
(This article belongs to the Special Issue Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting)
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12 pages, 7198 KiB  
Article
Proton Magnetic Resonance Spectroscopy Characterization of Rathke’s Cleft Cysts (RCCs): Relevance to the Differential Diagnosis of Pituitary Adenomas and RCCs
by Omkar B. Ijare, Martyn A. Sharpe, David S. Baskin and Kumar Pichumani
Cancers 2020, 12(2), 360; https://doi.org/10.3390/cancers12020360 - 04 Feb 2020
Cited by 1 | Viewed by 2673
Abstract
Background: Rathke’s Cleft Cysts (RCCs) are rare epithelial cysts arising from remnants of the Rathke pouch in the pituitary gland. A subset of these lesions enlarge and produce a mass effect with consequent hypopituitarism, and may result in visual loss. Moreover, some RCCs [...] Read more.
Background: Rathke’s Cleft Cysts (RCCs) are rare epithelial cysts arising from remnants of the Rathke pouch in the pituitary gland. A subset of these lesions enlarge and produce a mass effect with consequent hypopituitarism, and may result in visual loss. Moreover, some RCCs with a high intra-cystic protein content may mimic cystic pituitary adenoma, which makes their differential diagnosis ambiguous. Currently, medical professionals have no definitive way to distinguish RCCs from pituitary adenomas. Therefore, preoperative confirmation of RCCs would be of help to medical professionals for the management and proper surgical decision making. The goal of this study is to identify molecular markers in RCCs. Methods: We characterized aqueous and chloroform extracts of surgically resected RCCs and pituitary adenomas using ex vivo 1H NMR spectroscopy. Results: All RCCs exclusively showed the presence of mucopolysaccharides which are glycosaminoglycans (GAGs) made up of disaccharides of aminosugars and uronic sugars. Conclusion: GAGs can be used as metabolite marker for the detection of RCCs and this knowledge will lay the groundwork for the development of a non-invasive, in vivo magnetic resonance spectroscopy methodology for the differential diagnosis of RCCs and pituitary adenomas using clinical MRI scanners. Full article
(This article belongs to the Special Issue Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting)
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14 pages, 1163 KiB  
Article
How Valuable Is the RT-qPCR of Pituitary-Specific Transcription Factors for Identifying Pituitary Neuroendocrine Tumor Subtypes According to the New WHO 2017 Criteria?
by María Eugenia Torregrosa-Quesada, Araceli García-Martínez, Sandra Silva-Ortega, Sebastián Martínez-López, Rosa Cámara, Carmen Fajardo, Cristina Lamas, Ignacio Aranda and Antonio Picó
Cancers 2019, 11(12), 1990; https://doi.org/10.3390/cancers11121990 - 11 Dec 2019
Cited by 13 | Viewed by 2271
Abstract
The classification of pituitary neuroendocrine tumors (PitNETs) subtypes continues generating interest. In 2017, the World Health Organization (WHO) proposed considering the immunohistochemical (IHC) analysis of pituitary-specific transcription factors (TF) for their typification. The present study targeted the quantification of pituitary-specific TF (TPIT [...] Read more.
The classification of pituitary neuroendocrine tumors (PitNETs) subtypes continues generating interest. In 2017, the World Health Organization (WHO) proposed considering the immunohistochemical (IHC) analysis of pituitary-specific transcription factors (TF) for their typification. The present study targeted the quantification of pituitary-specific TF (TPIT, PIT-1, SF-1, GATA2, ESR1) gene expression by RT-qPCR to overcome the shortcomings of IHC and to complement it. We analyzed 251 tumors from our collection of PitNETs and performed additional IHC studies in a subset of 56 samples to analyze the concordance between gene and protein expression of the TF. The molecular and IHC studies allowed us to significantly reduce the percentage of null cell tumors in our series, most of which were reclassified as gonadotroph tumors. The concordance between the molecular and the immunohistochemical studies was good for tumors coming from the corticotroph and Pit-1 lineages but worsened for the rest of the tumors. Indeed, the RT-qPCR helped to improve the typification of plurihormonal Pit-1 and unusual tumors. Overall, our results suggest that the RT-qPCR of pituitary-specific TF and hormone genes could help pathologists, endocrinologists, and neurosurgeons to improve the management of patients with pituitary tumors. Full article
(This article belongs to the Special Issue Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting)
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14 pages, 481 KiB  
Article
Patient-Reported Outcome (PRO) as an Addition to Long-Term Results after High-Precision Stereotactic Radiotherapy in Patients with Secreting and Non-Secreting Pituitary Adenomas: A Retrospective Cohort Study up to 17-Years Follow-Up
by Kerstin A. Kessel, Christian D. Diehl, Markus Oechsner, Bernhard Meyer, Jens Gempt, Claus Zimmer, Friederike Schmidt-Graf and Stephanie E. Combs
Cancers 2019, 11(12), 1884; https://doi.org/10.3390/cancers11121884 - 27 Nov 2019
Cited by 5 | Viewed by 2091
Abstract
High-precision radiotherapy has been established as a valid and effective treatment option in patients with pituitary adenomas. We report on outcome after fractionated stereotactic radiotherapy (FSRT) in correlation with patient-reported outcomes (PROs). We analyzed 69 patients treated between 2000 and 2019. FSRT was [...] Read more.
High-precision radiotherapy has been established as a valid and effective treatment option in patients with pituitary adenomas. We report on outcome after fractionated stereotactic radiotherapy (FSRT) in correlation with patient-reported outcomes (PROs). We analyzed 69 patients treated between 2000 and 2019. FSRT was delivered with a median total dose of 54 Gy (single fraction: 1.8 Gy). PRO questionnaires were sent to 28 patients. Median overall survival was 17.2 years; mean local control was 15.6 years (median not reached). Median follow-up was 5.8 years. Twenty (71%) patients participated in the PRO assessment. Physicians reported symptoms grade ≥3 in 6 cases (9%). Of all, 35 (51%) patients suffered from hypopituitarism at baseline, and during follow-up, new or progressive hypopituitarism was observed in 11 cases (16%). Patients reported 10 cases of severe side effects. Most of these symptoms were already graded as CTCAE (Common Terminology Criteria for Adverse Events) grade 2 by a physician in a previous follow-up exam. PROs are an essential measure and only correlate to a certain extent with the physician-reported outcomes. For high-precision radiotherapy of pituitary adenomas, they confirm excellent overall outcomes and low toxicity. In the future, the integration of PROs paired with high-end treatment will further improve outcomes. Full article
(This article belongs to the Special Issue Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting)
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14 pages, 3272 KiB  
Article
The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the Spotlight
by Silviu Sbiera, Meik Kunz, Isabel Weigand, Timo Deutschbein, Thomas Dandekar and Martin Fassnacht
Cancers 2019, 11(11), 1761; https://doi.org/10.3390/cancers11111761 - 08 Nov 2019
Cited by 28 | Viewed by 4222
Abstract
Cushing’s disease (CD) is a rare condition caused by adrenocorticotropic hormone (ACTH)-producing adenomas of the pituitary, which lead to hypercortisolism that is associated with high morbidity and mortality. Treatment options in case of persistent or recurrent disease are limited, but new insights into [...] Read more.
Cushing’s disease (CD) is a rare condition caused by adrenocorticotropic hormone (ACTH)-producing adenomas of the pituitary, which lead to hypercortisolism that is associated with high morbidity and mortality. Treatment options in case of persistent or recurrent disease are limited, but new insights into the pathogenesis of CD are raising hope for new therapeutic avenues. Here, we have performed a meta-analysis of the available sequencing data in CD to create a comprehensive picture of CD’s genetics. Our analyses clearly indicate that somatic mutations in the deubiquitinases are the key drivers in CD, namely USP8 (36.5%) and USP48 (13.3%). While in USP48 only Met415 is affected by mutations, in USP8 there are 26 different mutations described. However, these different mutations are clustering in the same hotspot region (affecting in 94.5% of cases Ser718 and Pro720). In contrast, pathogenic variants classically associated with tumorigenesis in genes like TP53 and BRAF are also present in CD but with low incidence (12.5% and 7%). Importantly, several of these mutations might have therapeutic potential as there are drugs already investigated in preclinical and clinical setting for other diseases. Furthermore, network and pathway analyses of all somatic mutations in CD suggest a rather unified picture hinting towards converging oncogenic pathways. Full article
(This article belongs to the Special Issue Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting)
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13 pages, 236 KiB  
Article
Toxicity Profiles of Fractionated Radiotherapy, Contemporary Stereotactic Radiosurgery, and Transsphenoidal Surgery in Nonfunctioning Pituitary Macroadenomas
by Chia-Lun Chang, Kevin Sheng-Po Yuan, Alexander T.H. Wu and Szu-Yuan Wu
Cancers 2019, 11(11), 1658; https://doi.org/10.3390/cancers11111658 - 26 Oct 2019
Cited by 8 | Viewed by 2169
Abstract
Background: Here, we compared the toxicity profiles of contemporary stereotactic radiosurgery (SRS), modern fractionated radiotherapy (FRT), and transsphenoidal surgery used to treat nonfunctioning pituitary macroadenomas. Methods: We included the data of patients with nonfunctioning pituitary macroadenomas. To compare treatment outcomes, the patients were [...] Read more.
Background: Here, we compared the toxicity profiles of contemporary stereotactic radiosurgery (SRS), modern fractionated radiotherapy (FRT), and transsphenoidal surgery used to treat nonfunctioning pituitary macroadenomas. Methods: We included the data of patients with nonfunctioning pituitary macroadenomas. To compare treatment outcomes, the patients were categorized groups 1 (those receiving modern FRT), 2 (those receiving contemporary SRS), and 3 (those receiving transsphenoidal surgery). The multivariable Cox proportional hazards regression analysis was performed to yielded adjusted hazard ratios (aHRs) and their 95% CIs for local recurrence in groups 2 and 3 compared with group 1. Results: We included the data of 248 patients with nonfunctioning pituitary macroadenomas. The analytical results revealed no significant differences in second primary brain or head and neck cancer, hypopituitarism, or optic nerve injury between the three cohorts. The multivariable Cox proportional hazards regression analysis revealed that compared with group 1, the aHRs (95% CIs) for stroke risk in groups 2 and 3 were 0.37 (0.14–0.99) and 0.51 (0.31–0.84), respectively. Conclusion: Contemporary SRS and transsphenoidal surgery for nonfunctioning pituitary macroadenoma treatment have equivalent toxicity profiles. However, modern FRT for nonfunctioning pituitary macroadenoma treatment might considerably increase stroke risk. Full article
(This article belongs to the Special Issue Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting)
14 pages, 1833 KiB  
Article
The Role of Aberrant DNA Methylation in Misregulation of Gene Expression in Gonadotroph Nonfunctioning Pituitary Tumors
by Paulina Kober, Joanna Boresowicz, Natalia Rusetska, Maria Maksymowicz, Agnieszka Paziewska, Michalina Dąbrowska, Jacek Kunicki, Wiesław Bonicki, Jerzy Ostrowski, Janusz A. Siedlecki and Mateusz Bujko
Cancers 2019, 11(11), 1650; https://doi.org/10.3390/cancers11111650 - 25 Oct 2019
Cited by 11 | Viewed by 2878
Abstract
Gonadotroph nonfunctioning pituitary adenomas (NFPAs) are common intracranial tumors, but the role of aberrant epigenetic regulation in their development remains poorly understood. In this study, we investigated the effect of impaired CpG methylation in NFPAs. We determined DNA methylation and transcriptomic profiles in [...] Read more.
Gonadotroph nonfunctioning pituitary adenomas (NFPAs) are common intracranial tumors, but the role of aberrant epigenetic regulation in their development remains poorly understood. In this study, we investigated the effect of impaired CpG methylation in NFPAs. We determined DNA methylation and transcriptomic profiles in 32 NFPAs and normal pituitary sections using methylation arrays and sequencing, respectively. Ten percent of differentially methylated CpGs were correlated with gene expression, and the affected genes are involved in a variety of tumorigenesis-related pathways. Different proportions of gene body and promoter region localization were observed in CpGs with negative and positive correlations between methylation and gene expression, and different proportions of CpGs were located in ‘open sea’ and ‘shelf/shore’ regions. The expression of ~8% of genes differentially expressed in NFPAs was related to aberrant methylation. Methylation levels of seven CpGs located in the regulatory regions of FAM163A, HIF3A and PRSS8 were determined by pyrosequencing, and gene expression was measured by qRT-PCR and immunohistochemistry in 83 independent NFPAs. The results clearly confirmed the negative correlation between methylation and gene expression for these genes. By identifying which aberrantly methylated CpGs affect gene expression in gonadotrophinomas, our data confirm the role of aberrant methylation in pathogenesis of gonadotroph NFPAs. Full article
(This article belongs to the Special Issue Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting)
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23 pages, 4880 KiB  
Article
Splicing Machinery is Dysregulated in Pituitary Neuroendocrine Tumors and is Associated with Aggressiveness Features
by Mari C. Vázquez-Borrego, Antonio C. Fuentes-Fayos, Eva Venegas-Moreno, Esther Rivero-Cortés, Elena Dios, Paloma Moreno-Moreno, Ainara Madrazo-Atutxa, Pablo Remón, Juan Solivera, Luiz E. Wildemberg, Leandro Kasuki, Judith M. López-Fernández, Mônica R. Gadelha, María A. Gálvez-Moreno, Alfonso Soto-Moreno, Manuel D. Gahete, Justo P. Castaño and and Raúl M. Luque
Cancers 2019, 11(10), 1439; https://doi.org/10.3390/cancers11101439 - 26 Sep 2019
Cited by 25 | Viewed by 3471
Abstract
Pituitary neuroendocrine tumors (PitNETs) constitute approximately 15% of all brain tumors, and most have a sporadic origin. Recent studies suggest that altered alternative splicing and, consequently, appearance of aberrant splicing variants, is a common feature of most tumor pathologies. Moreover, spliceosome is considered [...] Read more.
Pituitary neuroendocrine tumors (PitNETs) constitute approximately 15% of all brain tumors, and most have a sporadic origin. Recent studies suggest that altered alternative splicing and, consequently, appearance of aberrant splicing variants, is a common feature of most tumor pathologies. Moreover, spliceosome is considered an attractive therapeutic target in tumor pathologies, and the inhibition of SF3B1 (e.g., using pladienolide-B) has been shown to exert antitumor effects. Therefore, we aimed to analyze the expression levels of selected splicing-machinery components in 261 PitNETs (somatotropinomas/non-functioning PitNETS/corticotropinomas/prolactinomas) and evaluated the direct effects of pladienolide-B in cell proliferation/viability/hormone secretion in human PitNETs cell cultures and pituitary cell lines (AtT-20/GH3). Results revealed a severe dysregulation of splicing-machinery components in all the PitNET subtypes compared to normal pituitaries and a unique fingerprint of splicing-machinery components that accurately discriminate between normal and tumor tissue in each PitNET subtype. Moreover, expression of specific components was associated with key clinical parameters. Interestingly, certain components were commonly dysregulated throughout all PitNET subtypes. Finally, pladienolide-B reduced cell proliferation/viability/hormone secretion in PitNET cell cultures and cell lines. Altogether, our data demonstrate a drastic dysregulation of the splicing-machinery in PitNETs that might be associated to their tumorigenesis, paving the way to explore the use of specific splicing-machinery components as novel diagnostic/prognostic and therapeutic targets in PitNETs. Full article
(This article belongs to the Special Issue Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting)
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Review

Jump to: Editorial, Research

17 pages, 512 KiB  
Review
How to Classify Pituitary Neuroendocrine Tumors (PitNET)s in 2020
by Jacqueline Trouillas, Marie-Lise Jaffrain-Rea, Alexandre Vasiljevic, Gérald Raverot, Federico Roncaroli and Chiara Villa
Cancers 2020, 12(2), 514; https://doi.org/10.3390/cancers12020514 - 22 Feb 2020
Cited by 121 | Viewed by 12838
Abstract
Adenohypophyseal tumors, which were recently renamed pituitary neuroendocrine tumors (PitNET), are mostly benign, but may present various behaviors: invasive, “aggressive” and malignant with metastases. They are classified into seven morphofunctional types and three lineages: lactotroph, somatotroph and thyrotroph (PIT1 lineage), corticotroph (TPIT lineage) [...] Read more.
Adenohypophyseal tumors, which were recently renamed pituitary neuroendocrine tumors (PitNET), are mostly benign, but may present various behaviors: invasive, “aggressive” and malignant with metastases. They are classified into seven morphofunctional types and three lineages: lactotroph, somatotroph and thyrotroph (PIT1 lineage), corticotroph (TPIT lineage) or gonadotroph (SF1 lineage), null cell or immunonegative tumor and plurihormonal tumors. The WHO 2017 classification suggested that subtypes, such as male lactotroph, silent corticotroph and Crooke cell, sparsely granulated somatotroph, and silent plurihormonal PIT1 positive tumors, should be considered as “high risk” tumors. However, the prognostic impact of these subtypes and of each morphologic type remains controversial. In contrast, the French five-tiered classification, taking into account the invasion, the immuno-histochemical (IHC) type, and the proliferative markers (Ki-67 index, mitotic count, p53 positivity), has a prognostic value validated by statistical analysis in 4 independent cohorts. A standardized report for the diagnosis of pituitary tumors, integrating all these parameters, has been proposed by the European Pituitary Pathology Group (EPPG). In 2020, the pituitary pathologist must be considered as a member of the multidisciplinary pituitary team. The pathological diagnosis may help the clinician to adapt the post-operative management, including appropriate follow-up and early recognition and treatment of potentially aggressive forms. Full article
(This article belongs to the Special Issue Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting)
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25 pages, 1249 KiB  
Review
Exploring the Role of Novel Medical Therapies for Aggressive Pituitary Tumors: A Review of the Literature—“Are We There Yet?”
by Lydia S. Lamb, Hao-Wen Sim and Ann I. McCormack
Cancers 2020, 12(2), 308; https://doi.org/10.3390/cancers12020308 - 28 Jan 2020
Cited by 27 | Viewed by 3328
Abstract
Aggressive pituitary tumors account for up to 10% of pituitary tumors and are characterized by resistance to medical treatment and multiple recurrences despite standard therapies, including surgery, radiotherapy, and chemotherapy. They are associated with increased morbidity and mortality, particularly pituitary carcinomas, which have [...] Read more.
Aggressive pituitary tumors account for up to 10% of pituitary tumors and are characterized by resistance to medical treatment and multiple recurrences despite standard therapies, including surgery, radiotherapy, and chemotherapy. They are associated with increased morbidity and mortality, particularly pituitary carcinomas, which have mortality rates of up to 66% at 1 year after diagnosis. Novel targeted therapies under investigation include mammalian target of rapamycin (mTOR), tyrosine kinase, and vascular endothelial growth factor (VEGF) inhibitors. More recently, immune checkpoint inhibitors have been proposed as a potential treatment option for pituitary tumors. An increased understanding of the molecular pathogenesis of aggressive pituitary tumors is required to identify potential biomarkers and therapeutic targets. This review discusses novel approaches to the management of aggressive pituitary tumors and the role of molecular profiling. Full article
(This article belongs to the Special Issue Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting)
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14 pages, 889 KiB  
Review
The Role of Single-Nucleotide Polymorphisms in Pituitary Adenomas Tumorigenesis
by Sumedh S. Shah and Manish K. Aghi
Cancers 2019, 11(12), 1977; https://doi.org/10.3390/cancers11121977 - 09 Dec 2019
Cited by 4 | Viewed by 3197
Abstract
Pituitary adenomas (PAs) are among the most common intracranial neoplasms, but despite their histologically benign nature, these tumors sometimes grow large enough to cause symptoms of mass effect such as vision loss, headaches, or hypopituitarism. When they get this large, surgery will unfortunately [...] Read more.
Pituitary adenomas (PAs) are among the most common intracranial neoplasms, but despite their histologically benign nature, these tumors sometimes grow large enough to cause symptoms of mass effect such as vision loss, headaches, or hypopituitarism. When they get this large, surgery will unfortunately not be curative and, other than prolactinomas, medical options are limited, and radiation has variable efficacy in controlling growth. Understanding the genetic perturbations, such as single nucleotide polymorphisms (SNPs), that promote the formation or growth of functional and nonfunctional PAs is important because such genetic insights could improve the diagnosis and subsequent classification of PAs as well as unlock potential therapeutic targets outside contemporary standard of care. While there have been great strides in the research of SNPs as drivers of PA formation and maintenance, a comprehensive discussion of these genetic mutations has not been undertaken. In the present article, and with the goal of providing scientists and clinicians a central review, we sought to summarize the current literature on SNPs and their relationship to PA formation. Across multiple tumor types, such as nonfunctioning PAs, prolactinomas, corticotroph adenomas, somatotroph adenomas, thyrotropic adenomas, and gonadotroph adenomas, SNPs in cell surface receptors implicated in proliferation can be appreciated. Polymorphisms found in tumor suppressors and cell cycle regulators have also been identified, such as p53 SNPs in nonfunctioning PAs or cyclin D1 in prolactinomas. While the translational relevance of SNPs in the formation of PAs is still in the early stages, the use of wide-scale genomic analysis to identify patients at risk for developing PAs could yield therapeutic benefit in the future. Full article
(This article belongs to the Special Issue Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting)
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21 pages, 2761 KiB  
Review
Pituitary Adenomas and Invasiveness from Anatomo-Surgical, Radiological, and Histological Perspectives: A Systematic Literature Review
by Simona Serioli, Francesco Doglietto, Alessandro Fiorindi, Antonio Biroli, Davide Mattavelli, Barbara Buffoli, Marco Ferrari, Claudio Cornali, Luigi Rodella, Roberto Maroldi, Roberto Gasparotti, Piero Nicolai, Marco Maria Fontanella and Pietro Luigi Poliani
Cancers 2019, 11(12), 1936; https://doi.org/10.3390/cancers11121936 - 04 Dec 2019
Cited by 43 | Viewed by 11920
Abstract
Invasiveness in pituitary adenomas has been defined and investigated from multiple perspectives, with varying results when its predictive value is considered. A systematic literature review, following PRISMA guidelines, was performed, searching PubMed and Scopus databases with terms that included molecular markers, histological, radiological, [...] Read more.
Invasiveness in pituitary adenomas has been defined and investigated from multiple perspectives, with varying results when its predictive value is considered. A systematic literature review, following PRISMA guidelines, was performed, searching PubMed and Scopus databases with terms that included molecular markers, histological, radiological, anatomical and surgical data on invasiveness of pituitary adenomas. The results showed that differing views are still present for anatomical aspects of the sellar region that are relevant to the concept of invasiveness; radiological and histological diagnoses are still limited, but might improve in the future, especially if they are related to surgical findings, which have become more accurate thanks to the introduction of the endoscope. The aim is to achieve a correct distinction between truly invasive pituitary adenomas from those that, in contrast, present with extension in the parasellar area through natural pathways. At present, diagnosis of invasiveness should be based on a comprehensive analysis of radiological, intra-operative and histological findings. Full article
(This article belongs to the Special Issue Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting)
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22 pages, 312 KiB  
Review
The Microenvironment of Pituitary Tumors—Biological and Therapeutic Implications
by Mirela Diana Ilie, Alexandre Vasiljevic, Gérald Raverot and Philippe Bertolino
Cancers 2019, 11(10), 1605; https://doi.org/10.3390/cancers11101605 - 21 Oct 2019
Cited by 46 | Viewed by 4091
Abstract
The tumor microenvironment (TME) includes resident and infiltrative non-tumor cells, as well as blood and lymph vessels, extracellular matrix molecules, and numerous soluble factors, such as cytokines and chemokines. While the TME is now considered to be a prognostic tool and a therapeutic [...] Read more.
The tumor microenvironment (TME) includes resident and infiltrative non-tumor cells, as well as blood and lymph vessels, extracellular matrix molecules, and numerous soluble factors, such as cytokines and chemokines. While the TME is now considered to be a prognostic tool and a therapeutic target for many cancers, little is known about its composition in pituitary tumors. This review summarizes our current knowledge of the TME within pituitary tumors and the strong interest in TME as a therapeutic target. While we cover the importance of angiogenesis and immune infiltrating cells, we also address the role of the elusive folliculostellate cells, the emerging literature on pituitary tumor-associated fibroblasts, and the contribution of extracellular matrix components in these tumors. The cases of human pituitary tumors treated with TME-targeting therapies are reviewed and emerging concepts of vascular normalization and combined therapies are presented. Together, this snapshot overview of the current literature pinpoints not only the underestimated role of TME components in pituitary tumor biology, but also the major promise it may offer for both prognosis and targeted therapeutics. Full article
(This article belongs to the Special Issue Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting)
19 pages, 2315 KiB  
Review
Emerging Role of USP8, HMGA, and Non-Coding RNAs in Pituitary Tumorigenesis
by Daniela D’Angelo, Marco De Martino, Claudio Arra and Alfredo Fusco
Cancers 2019, 11(9), 1302; https://doi.org/10.3390/cancers11091302 - 04 Sep 2019
Cited by 6 | Viewed by 3841
Abstract
Two novel molecular mechanisms with a driver role in pituitary tumorigenesis have been recently identified. They are (a) mutations in the Ubiquitin-Specific Protease 8 (USP8) gene in corticotroph tumors and (b) overexpression of the HMGA1 and HMGA2 genes in most of the pituitary [...] Read more.
Two novel molecular mechanisms with a driver role in pituitary tumorigenesis have been recently identified. They are (a) mutations in the Ubiquitin-Specific Protease 8 (USP8) gene in corticotroph tumors and (b) overexpression of the HMGA1 and HMGA2 genes in most of the pituitary tumors. Moreover, deregulated expression of the non-coding RNAs has been very frequently observed in this neoplasia. The aim of this review is to better elucidate the role, the mechanisms, and the possible clinical impact of these novel alterations in the development of pituitary neoplasia. Full article
(This article belongs to the Special Issue Pituitary Tumors: New Insights into Molecular Features, Diagnosis and Therapeutic Targeting)
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