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Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy (2nd Edition)
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Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy (2nd Edition)

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 1 December 2024 | Viewed by 4956

Special Issue Editors

Dr. Kazunori Kageyama

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Guest Editor
Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
Interests: Cushing’s disease; hypopituitarism; pituitary tumor; proopiomelanocortin; stress
Special Issues, Collections and Topics in MDPI journals
Dr. Mitsuru Nishiyama

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Guest Editor
Health Care Center, Kochi University, 1-5-2 Akebono-cho, Kochi 780-8520, Japan
Interests: corticotropin-releasing hormone; Cushing’s disease; glucocorticoid; hypopituitarism; proopiomelanocortin
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the second edition of "Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy" (https://www.mdpi.com/journal/cancers/special_issues/PTMDT).

Pituitary tumors present a variety of hormonal activities and clinical features, from overt to subtle. Functioning pituitary tumors are defined by the autonomous/dysregulated secretion of pituitary hormones. In this Special Issue, we explore recent advances in the molecular insights, diagnosis, and targeted therapy of pituitary tumors. For example, Cushing’s disease is defined by the autonomous secretion of ACTH and excess cortisol production, with their obvious manifestation of the clinical features of Cushing’s disease. Mutations in the ubiquitin-specific protease (USP) 8 or USP48 genes have been detected in Cushing’s disease. Hormones produced from pituitary tumors sometimes induce severe complications such as hypertension, hyperglycemia, osteoporosis, infections, atherosclerosis, and mental disorders. The pathophysiological characteristics of hormone production and pituitary adenoma cells should be elucidated. In addition, the usefulness and accuracy of the recent diagnostic criteria for pituitary tumors also need to be evaluated. The primary treatment for some types of pituitary tumors may be surgical excision of the adenoma from the pituitary; however, curative surgery is still challenging, and additional therapies are required to treat the resulting hypersecretion of hormones and tumor growth. This Special Issue will include original basic/translational/clinical research articles and reviews on aspects related to the pathophysiology, diagnosis, and potential treatment of pituitary tumors.

We look forward to receiving your contributions.

Sincerely,

Dr. Kazunori Kageyama
Dr. Mitsuru Nishiyama
Guest Editors

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 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

  • acromegaly
  • adrenocorticotropic hormone
  • Cushing’s disease
  • diagnosis
  • growth hormone
  • pituitary tumor
  • proliferation
  • transcriptional factor
  • treatment

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Published Papers (5 papers)

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Research

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17 pages, 581 KiB  
Article
Associations of TRAF2 (rs867186), TAB2 (rs237025), IKBKB (rs13278372) Polymorphisms and TRAF2, TAB2, IKBKB Protein Levels with Clinical and Morphological Features of Pituitary Adenomas
by Balys Remigijus Zaliunas, Greta Gedvilaite-Vaicechauskiene, Loresa Kriauciuniene, Arimantas Tamasauskas and Rasa Liutkeviciene
Cancers 2024, 16(14), 2509; https://doi.org/10.3390/cancers16142509 - 10 Jul 2024
Viewed by 542
Abstract
Aim: The aim of this study was to determine associations of TRAF2 (rs867186), TAB2 (rs237025), IKBKB (rs13278372) gene polymorphisms and TRAF2, TAB2, IKBKB protein levels with clinical and morphological features of pituitary adenomas (PAs). Methods: This case–control study included 459 individuals [...] Read more.
Aim: The aim of this study was to determine associations of TRAF2 (rs867186), TAB2 (rs237025), IKBKB (rs13278372) gene polymorphisms and TRAF2, TAB2, IKBKB protein levels with clinical and morphological features of pituitary adenomas (PAs). Methods: This case–control study included 459 individuals divided into two groups: a control group (n = 320) and a group of individuals with PAs (n = 139). DNA from peripheral blood leukocytes was isolated using salt precipitation and column method. Real-time PCR was used for TRAF2 (rs867186), TAB2 (rs237025), and IKBKB (rs13278372) SNP genotyping, and TRAF2, TAB2, IKBKB protein concentration measurements were performed by immunoenzymatic analysis tests using a commercial ELISA kit according to the manufacturer’s recommendations. The labeling index Ki-67 was determined by immunohistochemical analysis using a monoclonal antibody (clone SP6; Spring Bioscience Corporation). Statistical data analysis was performed using the programs "IMB SPSS Statistics 29.0". Results: We found significant differences in TRAF2 (rs867186) genotypes (AA, AG, GG) between groups: 79.1%, 17.3%, 3.6% vs. 55.3%, 20.9%, 23.8% (p < 0.001). The G allele was less frequent in the PA group than in controls (12.2% vs. 34.2%, p < 0.001). The AG and GG genotypes reduced PA occurrence by 1.74-fold and 9.43-fold, respectively, compared to AA (p < 0.001). In the dominant model, GG and AG genotypes reduced PA odds by 3.07-fold, while in the recessive model, the GG genotype reduced PA odds by 8.33-fold (p < 0.001). Each G allele decreased PA odds by 2.49-fold in the additive model (p < 0.001). Microadenomas had significant genotype differences compared to controls: 81.3%, 18.8%, 0.0% vs. 55.3%, 20.9%, 23.8% (p < 0.001), with the G allele being less frequent (9.4% vs. 34.2%, p < 0.001). In macroadenomas, genotype differences were 78%, 16.5%, 5.5% vs. 55.3%, 20.9%, 23.8% (p < 0.001), and the G allele was less common (13.7% vs. 34.2%, p < 0.001). The dominant model showed that GG and AG genotypes reduced microadenoma odds by 3.5-fold (p = 0.001), and each G allele reduced microadenoma odds by 3.1-fold (p < 0.001). For macroadenomas, the GG genotype reduced odds by 6.1-fold in the codominant model (p < 0.001) and by 2.9-fold in GG and AG genotypes combined compared to AA (p < 0.001). The recessive model indicated the GG genotype reduced macroadenoma odds by 5.3-fold (p < 0.001), and each G allele reduced odds by 2.2-fold in the additive model (p < 0.001). Conclusions: The TRAF2 (rs867186) G allele and GG genotype are significantly associated with reduced odds of pituitary adenomas, including both microadenomas and macroadenomas, compared to the AA genotype. These findings suggest a protective role of the G allele against the occurrence of these tumors. Full article
(This article belongs to the Special Issue Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy (2nd Edition))
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14 pages, 2467 KiB  
Article
Genome-Wide DNA Methylation Profiling as a Prognostic Marker in Pituitary Adenomas—A Pilot Study
by Morten Winkler Møller, Marianne Skovsager Andersen, Bo Halle, Christian Bonde Pedersen, Henning Bünsow Boldt, Qihua Tan, Philipp Sebastian Jurmeister, Grayson A. Herrgott, Ana Valeria Castro, Jeanette K. Petersen and Frantz Rom Poulsen
Cancers 2024, 16(12), 2210; https://doi.org/10.3390/cancers16122210 - 13 Jun 2024
Viewed by 750
Abstract
Background: The prediction of the regrowth potential of pituitary adenomas after surgery is challenging. The genome-wide DNA methylation profiling of pituitary adenomas may separate adenomas into distinct methylation classes corresponding to histology-based subtypes. Specific genes and differentially methylated probes involving regrowth have been [...] Read more.
Background: The prediction of the regrowth potential of pituitary adenomas after surgery is challenging. The genome-wide DNA methylation profiling of pituitary adenomas may separate adenomas into distinct methylation classes corresponding to histology-based subtypes. Specific genes and differentially methylated probes involving regrowth have been proposed, but no study has linked this epigenetic variance with regrowth potential and the clinical heterogeneity of nonfunctioning pituitary adenomas. This study aimed to investigate whether DNA methylation profiling can be useful as a clinical prognostic marker. Methods: A DNA methylation analysis by Illumina’s MethylationEPIC array was performed on 54 pituitary macroadenomas from patients who underwent transsphenoidal surgery during 2007–2017. Twelve patients were excluded due to an incomplete postoperative follow-up, degenerated biobank-stored tissue, or low DNA methylation quality. For the quantitative measurement of the tumor regrowth rate, we conducted a 3D volumetric analysis of tumor remnant volume via annual magnetic resonance imaging. A linear mixed effects model was used to examine whether different DNA methylation clusters had different regrowth patterns. Results: The DNA methylation profiling of 42 tissue samples showed robust DNA methylation clusters, comparable with previous findings. The subgroup of 33 nonfunctioning pituitary adenomas of an SF1-lineage showed five subclusters with an approximately unbiased score of 86%. There were no overall statistically significant differences when comparing hazard ratios for regrowth of 100%, 50%, or 0%. Despite this, plots of correlated survival estimates suggested higher regrowth rates for some clusters. The mixed effects model of accumulated regrowth similarly showed tendencies toward an association between specific DNA methylation clusters and regrowth potential. Conclusion: The DNA methylation profiling of nonfunctioning pituitary adenomas may potentially identify adenomas with increased growth and recurrence potential. Larger validation studies are needed to confirm the findings from this explorative pilot study. Full article
(This article belongs to the Special Issue Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy (2nd Edition))
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13 pages, 1740 KiB  
Article
Alternations of Blood Pressure Following Surgical or Drug Therapy for Prolactinomas
by Yijun Cheng, Dapeng Wang, Hao Tang, Debing Tong, Weiguo Zhao, Shaojian Lin, Hong Yao, Wenwen Lv, Xun Zhang, Li Xue, Hanbing Shang and Zhe Bao Wu
Cancers 2024, 16(4), 726; https://doi.org/10.3390/cancers16040726 - 9 Feb 2024
Cited by 1 | Viewed by 1173
Abstract
Several subtypes of pituitary neuroendocrine tumors (PitNETs), such as acromegaly and Cushing’s disease, can result in hypertension. However, whether prolactinoma is associated with this complication remains unknown. Moreover, the effect of treatment with surgery or drugs on blood pressure (BP) is unknown. Herein, [...] Read more.
Several subtypes of pituitary neuroendocrine tumors (PitNETs), such as acromegaly and Cushing’s disease, can result in hypertension. However, whether prolactinoma is associated with this complication remains unknown. Moreover, the effect of treatment with surgery or drugs on blood pressure (BP) is unknown. Herein, a retrospective study reviewed 162 patients with prolactinoma who underwent transsphenoidal surgery between January 2005 and December 2022. BP measurements were performed 1 day before and 5 days after surgery. Accordingly, patients’ medical characteristics were recorded. In addition, in situ rat and xenograft nude-mice prolactinoma models have been used to mimic prolactinoma. In vivo BP and serum prolactin (PRL) levels were measured after cabergoline (CAB) administration in both rats and mice. Our data suggest that surgery can effectively decrease BP in prolactinoma patients with or without hypertension. The BP-lowering effect was significantly associated with several variables, including age, sex, disease duration, tumor size, invasion, dopamine agonists (DAs)-resistance, recurrence, and preoperative PRL levels. Moreover, in situ and xenograft prolactinomas induced BP elevation, which was alleviated by CAB treatment without and with a statistical difference in rats and mice, respectively. Thus, surgery or CAB can decrease BP in prolactinoma, indicating that pre- and postoperative BP management becomes essential. Full article
(This article belongs to the Special Issue Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy (2nd Edition))
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20 pages, 1425 KiB  
Article
The Influence of Telomere-Related Gene Variants, Serum Levels, and Relative Leukocyte Telomere Length in Pituitary Adenoma Occurrence and Recurrence
by Greta Gedvilaite, Loresa Kriauciuniene, Arimantas Tamasauskas and Rasa Liutkeviciene
Cancers 2024, 16(3), 643; https://doi.org/10.3390/cancers16030643 - 2 Feb 2024
Cited by 1 | Viewed by 923
Abstract
In this study, we examined 130 patients with pituitary adenomas (PAs) and 320 healthy subjects, using DNA samples from peripheral blood leukocytes purified through the DNA salting-out method. Real-time polymerase chain reaction (RT-PCR) was used to assess single nucleotide polymorphisms (SNPs) and relative [...] Read more.
In this study, we examined 130 patients with pituitary adenomas (PAs) and 320 healthy subjects, using DNA samples from peripheral blood leukocytes purified through the DNA salting-out method. Real-time polymerase chain reaction (RT-PCR) was used to assess single nucleotide polymorphisms (SNPs) and relative leukocyte telomere lengths (RLTLs), while enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of TERF1, TERF2, TNKS2, CTC1, and ZNF676 in blood serum. Our findings reveal several significant associations. Genetic associations with pituitary adenoma occurrence: the TERF1 rs1545827 CT + TT genotypes were linked to 2.9-fold decreased odds of PA occurrence. Conversely, the TNKS2 rs10509637 GG genotype showed 6.5-fold increased odds of PA occurrence. Gender-specific genetic associations with PA occurrence: in females, the TERF1 rs1545827 CC + TT genotypes indicated 3.1-fold decreased odds of PA occurrence, while the TNKS2 rs10509637 AA genotype was associated with 4.6-fold increased odds. In males, the presence of the TERF1 rs1545827 T allele was associated with 2.2-fold decreased odds of PA occurrence, while the TNKS2 rs10509637 AA genotype was linked to a substantial 10.6-fold increase in odds. Associations with pituitary adenoma recurrence: the TNKS2 rs10509637 AA genotype was associated with 4.2-fold increased odds of PA recurrence. On the other hand, the TERF1 rs1545827 CT + TT genotypes were linked to 3.5-fold decreased odds of PA without recurrence, while the TNKS2 rs10509637 AA genotype was associated with 6.4-fold increased odds of PA without recurrence. Serum TERF2 and TERF1 levels: patients with PA exhibited elevated serum TERF2 levels compared to the reference group. Conversely, patients with PA had decreased TERF1 serum levels compared to the reference group. Relative leukocyte telomere length (RLTL): a significant difference in RLTL between the PA group and the reference group was observed, with PA patients having longer telomeres. Genetic associations with telomere shortening: the TERF1 rs1545827 T allele was associated with 1.4-fold decreased odds of telomere shortening. In contrast, the CTC1 rs3027234 TT genotype was linked to 4.8-fold increased odds of telomere shortening. These findings suggest a complex interplay between genetic factors, telomere length, and pituitary adenoma occurrence and recurrence, with potential gender-specific effects. Furthermore, variations in TERF1 and TNKS2 genes may play crucial roles in telomere length regulation and disease susceptibility. Full article
(This article belongs to the Special Issue Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy (2nd Edition))
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Review

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26 pages, 3258 KiB  
Review
Topography and Radiological Variables as Ancillary Parameters for Evaluating Tissue Adherence, Hypothalamic–Pituitary Dysfunction, and Recurrence in Craniopharyngioma: An Integrated Multidisciplinary Overview
by Rosalinda Calandrelli, Gabriella D’Apolito, Matia Martucci, Carolina Giordano, Chiara Schiarelli, Giammaria Marziali, Giuseppe Varcasia, Luca Ausili Cefaro, Sabrina Chiloiro, Simone Antonio De Sanctis, Simona Serioli, Francesco Doglietto and Simona Gaudino
Cancers 2024, 16(14), 2532; https://doi.org/10.3390/cancers16142532 - 13 Jul 2024
Viewed by 825
Abstract
Craniopharyngiomas continue to present a challenge in clinical practice due to their heterogeneity and unpredictable adherence to vital neurovascular structures, particularly the hypothalamus. This results in different degrees of hypothalamus–pituitary axis dysfunction and a lack of uniform consensus and treatment guidelines regarding optimal [...] Read more.
Craniopharyngiomas continue to present a challenge in clinical practice due to their heterogeneity and unpredictable adherence to vital neurovascular structures, particularly the hypothalamus. This results in different degrees of hypothalamus–pituitary axis dysfunction and a lack of uniform consensus and treatment guidelines regarding optimal management. MRI and CT are complementary techniques in the preoperative diagnostic phase, enabling the precise definition of craniopharyngioma size, shape, and consistency, as well as guiding classification into histopathological subtypes and topographical categories. Meanwhile, MRI plays a crucial role in the immediate postoperative period and follow-up stages by identifying treatment-related changes and residual tumors. This pictorial essay aims to provide an overview of the role of imaging in identifying variables indicative of the adherence degree to the hypothalamus, hypothalamic–pituitary dysfunction, the extent of surgical excision, and prognosis. For a more comprehensive assessment, we choose to distinguish the following two scenarios: (1) the initial diagnosis phase, where we primarily discuss the role of radiological variables predictive of adhesions to the surrounding neurovascular structures and axis dysfunction which may influence the choice of surgical resection; (2) the early post-treatment follow-up phase, where we discuss the interpretation of treatment-related changes that impact outcomes. Full article
(This article belongs to the Special Issue Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy (2nd Edition))
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