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5 pages, 218 KiB

Open AccessEditorial

Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy

by Kazunori Kageyama and Mitsuru Nishiyama

Cancers 2023, 15(23), 5526; https://doi.org/10.3390/cancers15235526 - 22 Nov 2023

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Abstract

The anterior pituitary gland comprises a heterogeneous population of pituitary cells [...] Full article

(This article belongs to the Special Issue Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy)

Research

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14 pages, 715 KiB

Open AccessArticle

The Prognostic-Based Approach in Growth Hormone-Secreting Pituitary Neuroendocrine Tumors (PitNET): Tertiary Reference Center, Single Senior Surgeon, and Long-Term Follow-Up

by Abel Ferrés, Luís Reyes, Alberto Di Somma, Thomaz Topczewski, Alejandra Mosteiro, Giulia Guizzardi, Andrea De Rosa, Irene Halperin, Felicia Hanzu, Mireia Mora, Isam Alobid, Iban Aldecoa, Núria Bargalló and Joaquim Enseñat

Cancers 2023, 15(1), 267; https://doi.org/10.3390/cancers15010267 - 30 Dec 2022

Cited by 5 | Viewed by 1325

Abstract

Postoperative deserved outcomes in acromegalic patients are to normalize serum insulin-like growth factor (IGF-1), reduce the tumoral mass effect, improve systemic comorbidities, and reverse metabolic alterations. Pituitary neuroendocrine tumors (PitNET) are characterized to present a heterogeneous behavior, and growth hormone (GH)-secreting PitNET is [...] Read more.

Postoperative deserved outcomes in acromegalic patients are to normalize serum insulin-like growth factor (IGF-1), reduce the tumoral mass effect, improve systemic comorbidities, and reverse metabolic alterations. Pituitary neuroendocrine tumors (PitNET) are characterized to present a heterogeneous behavior, and growth hormone (GH)-secreting PitNET is not an exception. Promptly determining which patients are affected by more aggressive tumors is essential to guide the optimal postoperative decision-making process [prognostic-based approach]. From 2006 to 2019, 394 patients affected by PitNET were intervened via endoscopic endonasal transsphenoidal approach by the same senior surgeon. A total of 44 patients that met the criteria to be diagnosed as acromegalic and were followed up at least for 24 months (median of 66 months (26–156) were included in the present study. Multiple predictive variables [age, gender, preoperative GH and IGF-1 levels, maximal tumor diameter, Hardy’s and Knosp’s grade, MRI. T2-weighted tumor intensity, cytokeratin expression pattern, and clinicopathological classification] were evaluated through uni- and multivariate statistical analysis. Sparse probability of long-term remission was related to younger age, higher preoperative GH and- or IGF-1, group 2b of the clinicopathological classification, and sparsely granulated cytokeratin expression pattern. Augmented recurrence risk was related to elevated preoperative GH levels, tumor MRI T2-weighted hyperintensity, and sparsely granulated cytokeratin expression pattern. Finally, elevated risk for reintervention was related to group 2b of the clinicopathological classification, Knosp’s grade IV, and tumor MRI T2-weighted hyperintensity. In this study, the authors determined younger age, higher preoperative GH and- or IGF-1 levels, group 2b of the clinicopathological classification, Knosp’s grade IV, MRI T2-weighted tumor hyperintensity and sparsely granulated cytokeratin expression pattern are related to worse postoperative outcomes in long-term follow-up patients affected with GH-secreting PitNET. Full article

(This article belongs to the Special Issue Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy)

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Review

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17 pages, 1430 KiB

Open AccessReview

Advances in Molecular Pathophysiology and Targeted Therapy for Cushing’s Disease

by Shinobu Takayasu, Kazunori Kageyama and Makoto Daimon

Cancers 2023, 15(2), 496; https://doi.org/10.3390/cancers15020496 - 13 Jan 2023

Cited by 2 | Viewed by 2496

Abstract

Cushing’s disease is caused by autonomous secretion of adrenocorticotropic hormone (ACTH) from corticotroph pituitary neuroendocrine tumors. As a result, excess cortisol production leads to the overt manifestation of the clinical features of Cushing’s syndrome. Severe complications have been reported in patients with Cushing’s [...] Read more.

Cushing’s disease is caused by autonomous secretion of adrenocorticotropic hormone (ACTH) from corticotroph pituitary neuroendocrine tumors. As a result, excess cortisol production leads to the overt manifestation of the clinical features of Cushing’s syndrome. Severe complications have been reported in patients with Cushing’s disease, including hypertension, menstrual disorders, hyperglycemia, osteoporosis, atherosclerosis, infections, and mental disorders. Cushing’s disease presents with a variety of clinical features, ranging from overt to subtle. In this review, we explain recent advances in molecular insights and targeted therapy for Cushing’s disease. The pathophysiological characteristics of hormone production and pituitary tumor cells are also explained. Therapies to treat the tumor growth in the pituitary gland and the autonomous hypersecretion of ACTH are discussed. Drugs that target corticotroph pituitary neuroendocrine tumors have been effective, including cabergoline, a dopamine receptor type 2 agonist, and pasireotide, a multi-receptor-targeted somatostatin analog. Some of the drugs that target adrenal hormones have shown potential therapeutic benefits. Advances in potential novel therapies for Cushing’s disease are also introduced. Full article

(This article belongs to the Special Issue Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy)

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16 pages, 1166 KiB

Open AccessReview

Transcriptomic Profiles of Normal Pituitary Cells and Pituitary Neuroendocrine Tumor Cells

by Jun Y. Oh, Robert C. Osorio, Jangham Jung, Luis Carrete, Nikita Choudhary, Meeki Lad, Atul Saha and Manish K. Aghi

Cancers 2023, 15(1), 110; https://doi.org/10.3390/cancers15010110 - 24 Dec 2022

Cited by 3 | Viewed by 2962

Abstract

The pituitary gland is one of the most cellularly diverse regions of the brain. Recent advancements in transcriptomic biology, such as single-cell RNA sequencing, bring an unprecedented glimpse into the molecular composition of the pituitary, both in its normal physiological state and in [...] Read more.

The pituitary gland is one of the most cellularly diverse regions of the brain. Recent advancements in transcriptomic biology, such as single-cell RNA sequencing, bring an unprecedented glimpse into the molecular composition of the pituitary, both in its normal physiological state and in disease. Deciphering the normal pituitary transcriptomic signatures provides a better insight into the ontological origin and development of five types of endocrine cells, a process involving complex cascades of transcription factors that are still being established. In parallel with these observations about normal pituitary development, recent transcriptomic findings on pituitary neuroendocrine tumors (PitNETs) demonstrate both preservations and changes in transcription factor expression patterns compared to those seen during gland development. Furthermore, recent studies also identify differentially expressed genes that drive various tumor behaviors, including hormone hypersecretion and tumor aggression. Understanding the comprehensive multiomic profiles of PitNETs is essential in developing molecular profile-based therapies for PitNETs not curable with current treatment modalities and could eventually help align PitNETs with the breakthroughs being made in applying precision medicine to other tumors. Full article

(This article belongs to the Special Issue Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy)

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14 pages, 686 KiB

Open AccessReview

An Overview of Pituitary Incidentalomas: Diagnosis, Clinical Features, and Management

by Shigeyuki Tahara, Yujiro Hattori, Koji Suzuki, Eitaro Ishisaka, Shinichiro Teramoto and Akio Morita

Cancers 2022, 14(17), 4324; https://doi.org/10.3390/cancers14174324 - 03 Sep 2022

Cited by 3 | Viewed by 2224

Abstract

Pituitary incidentalomas are tumors or mass lesions of the pituitary gland. These are incidentally discovered during imaging studies for symptoms that are not causally related to pituitary diseases. The most common symptom that triggers an examination is headache, and the most common type [...] Read more.

Pituitary incidentalomas are tumors or mass lesions of the pituitary gland. These are incidentally discovered during imaging studies for symptoms that are not causally related to pituitary diseases. The most common symptom that triggers an examination is headache, and the most common type of pituitary incidentalomas are pituitary neuroendocrine tumors (PitNETs) and Rathke cleft cysts. The existing treatment strategy is controversial; however, surgical resection is recommended in cases of clinically non-functioning PitNETs with optic chiasm compression. In contrast, cystic lesions, such as Rathke cleft cysts, should be followed if the patients are asymptomatic. In this case, MRI and pituitary function tests are recommended every six months to one year; if there is no change, the follow-up period should be extended. The natural history of PitNET is partially known, and the management of pituitary incidentalomas is determined by this history. However, the pathogenesis of PitNET has significantly changed with the new World Health Organization classification, and follow-up is important based on this new classification. Therefore, a high level of evidence-based research is needed to consider treatment guidelines for pituitary incidentalomas in the future. Full article

(This article belongs to the Special Issue Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy)

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13 pages, 310 KiB

Open AccessReview

Genetic and Epigenetic Pathogenesis of Acromegaly

by Masaaki Yamamoto and Yutaka Takahashi

Cancers 2022, 14(16), 3861; https://doi.org/10.3390/cancers14163861 - 10 Aug 2022

Cited by 6 | Viewed by 1858

Abstract

Acromegaly is caused by excessive secretion of GH and IGF-I mostly from somatotroph tumors. Various genetic and epigenetic factors are involved in the pathogenesis of somatotroph tumors. While somatic mutations of GNAS are the most prevalent cause of somatotroph tumors, germline mutations in [...] Read more.

Acromegaly is caused by excessive secretion of GH and IGF-I mostly from somatotroph tumors. Various genetic and epigenetic factors are involved in the pathogenesis of somatotroph tumors. While somatic mutations of GNAS are the most prevalent cause of somatotroph tumors, germline mutations in various genes (AIP, PRKAR1A, GPR101, GNAS, MEN1, CDKN1B, SDHx, MAX) are also known as the cause of somatotroph tumors. Moreover, recent findings based on multiple perspectives of the pangenomic approach including genome, transcriptome, and methylome analyses, histological characterization, genomic instability, and possible involvement of miRNAs have gradually unveiled the whole landscape of the underlying mechanisms of somatotroph tumors. In this review, we will focus on the recent advances in genetic and epigenetic pathogenesis of somatotroph tumors. Full article

(This article belongs to the Special Issue Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy)

15 pages, 1835 KiB

Open AccessReview

Disease Modeling of Pituitary Adenoma Using Human Pluripotent Stem Cells

by Ryusaku Matsumoto, Hidetaka Suga, Hiroshi Arima and Takuya Yamamoto

Cancers 2022, 14(15), 3660; https://doi.org/10.3390/cancers14153660 - 27 Jul 2022

Cited by 3 | Viewed by 2474

Abstract

Pituitary adenomas are characterized by abnormal growth in the pituitary gland. Surgical excision is the first-line treatment for functional (hormone-producing) pituitary adenomas, except for prolactin-producing adenomas; however, complete excision is technically challenging, and many patients require long-term medication after the treatment. In addition, [...] Read more.

Pituitary adenomas are characterized by abnormal growth in the pituitary gland. Surgical excision is the first-line treatment for functional (hormone-producing) pituitary adenomas, except for prolactin-producing adenomas; however, complete excision is technically challenging, and many patients require long-term medication after the treatment. In addition, the pathophysiology of pituitary adenomas, such as tumorigenesis, has not been fully understood. Pituitary adenoma pathophysiology has mainly been studied using animal models and animal tumor-derived cell lines. Nevertheless, experimental studies on human pituitary adenomas are difficult because of the significant differences among species and the lack of reliable cell lines. Recently, several methods have been established to differentiate pituitary cells from human pluripotent stem cells (hPSCs). The induced pituitary hormone-producing cells retain the physiological properties already lost in tumor-derived cell lines. Moreover, CRISPR/Cas9 systems have expedited the introduction of causative gene mutations in various malignant tumors into hPSCs. Therefore, hPSC-derived pituitary cells have great potential as a novel platform for studying the pathophysiology of human-specific pituitary adenomas and developing novel drugs. This review presents an overview of the recent progresses in hPSC applications for pituitary research, functional pituitary adenoma pathogenesis, and genome-editing techniques for introducing causative mutations. We also discuss future applications of hPSCs for studying pituitary adenomas. Full article

(This article belongs to the Special Issue Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy)

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13 pages, 1431 KiB

Open AccessReview

Update in Pathogenesis, Diagnosis, and Therapy of Prolactinoma

by Noriaki Fukuhara, Mitsuru Nishiyama and Yasumasa Iwasaki

Cancers 2022, 14(15), 3604; https://doi.org/10.3390/cancers14153604 - 24 Jul 2022

Cited by 10 | Viewed by 6371

Abstract

Prolactinomas comprise 30–50% of all pituitary neuroendocrine tumors, frequently occur in females aged 20 to 50, and cause hypogonadism and infertility. In typical cases, female patients exhibit galactorrhea and amenorrhea due to serum prolactin (PRL) elevation, and patients during pregnancy should be carefully [...] Read more.

Prolactinomas comprise 30–50% of all pituitary neuroendocrine tumors, frequently occur in females aged 20 to 50, and cause hypogonadism and infertility. In typical cases, female patients exhibit galactorrhea and amenorrhea due to serum prolactin (PRL) elevation, and patients during pregnancy should be carefully treated. During diagnosis, other causes of hyperprolactinemia must be excluded, and an MRI is useful for detecting pituitary neuroendocrine tumors. For treating prolactinoma, dopamine agonists (DAs) are effective for decreasing PRL levels and shrinking tumor size in most patients. Some DA-resistant cases and the molecular mechanisms of resistance to a DA are partially clarified. The side effects of a DA include cardiac valve alterations and impulse control disorders. Although surgical therapies are invasive, recent analysis shows that long-term remission rates are higher than from medical therapies. The treatments for giant or malignant prolactinomas are challenging, and the combination of medication, surgery, and radiation therapy should be considered. Regarding pathogenesis, somatic SF3B1 mutations were recently identified even though molecular mechanisms in most cases of prolactinoma have not been elucidated. To understand the pathogenesis of prolactinomas, the development of new therapeutic approaches for treatment-resistant patients is expected. This review updates the recent advances in understanding the pathogenesis, diagnosis, and therapy of prolactinoma. Full article

(This article belongs to the Special Issue Pituitary Tumors: Molecular Insights, Diagnosis, and Targeted Therapy)

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