Co-expression of intermediate filaments glial fibrillary acidic protein and cytokeratin in pituitary adenoma

Abstract Purpose To analyze the co-expression of the intermediate filaments GFAP and cytokeratin in 326 pituitary adenomas with regard to the distribution pattern, the subtype of the adenoma and clinical prognostic data. Methods Tissue from 326 pituitary adenomas and 13 normal anterior pituitaries collected in the Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, between 2006 and 2009 was investigated by immunohistochemistry, immunofluorescence and electron microscopy. Results Co-expression of intermediate filaments GFAP and cytokeratin was associated with hormone expression in 62/278 cases (22%), but only found in 2/48 (4%) of null cell adenomas (p < 0.01). Simultaneous co-expression of GFAP and cytokeratin in the same cells was demonstrated in 26 out of 326 pituitary adenomas and in all 13 pituitaries. In pituitary intermediate filaments were demonstrated in a larger area of the cytoplasm than in adenoma (p < 0.01), however, overlapping expression was seen in 2.6% of the total area in both, pituitary and adenoma. Congenially, cells with overlapping expression were found near vessels and in follicles. Furthermore, adenomas with cellular co-expression of GFAP and cytokeratin were associated with a lower recurrence rate (7.7%) compared to adenomas without co-expression of intermediate filaments (17.8%). Conclusions Cellular co-expression of the intermediate filaments GFAP and cytokeratin in pituitary adenomas and the pituitary was demonstrated and shown to be associated with hormone expression and low recurrence rate. The results are discussed with regard to the biology of folliculostellate cells, neural transformation and tumor stem cells. This study may complement the understanding of pituitary adenoma biology.

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Ki-67/MIB-1 and Recurrence in Pituitary Adenoma

Journal of Neurological Surgery Part B Skull Base ◽

10.1055/s-0041-1735874 ◽

2021 ◽

Author(s):

Kent Tadokoro ◽

Colten Wolf ◽

Joseph Toth ◽

Cara Joyce ◽

Meharvan Singh ◽

...

Keyword(s):

Systematic Review ◽

Pituitary Adenoma ◽

Recurrence Rate ◽

Pituitary Adenomas ◽

Cellular Proliferation ◽

Published Data ◽

Ki 67 ◽

Institutional Data ◽

Mib 1

Abstract Objectives Ki-67/MIB-1 is a marker of cellular proliferation used as a pathological parameter in the clinical assessment of pituitary adenomas, where its expression has shown utility in predicting the invasiveness of these tumors. However, studies have shown variable results when using Ki-67/MIB-1 association with recurrence. The purpose of this study is to determine if a high Ki-67/MIB-1 labeling index (LI) is predictive of recurrence in pituitary adenomas. Methods A retrospective chart review was performed for patients undergoing pituitary adenoma resection with at least 1 year of follow-up. Additionally, systematic data searches were performed and included studies that correlated recurrence rate to Ki-67/MIB-1 LI. Our institutional data were included in a synthesis with previously published data. Results Our institutional review included 79 patients with a recurrence rate of 26.6%. We found that 8.8% of our patients had a high Ki-67/MIB-1 LI (>3%); however, high Ki-67/MIB-1 was not associated with recurrence. The systematic review identified 244 articles and 49 full-text articles that were assessed for eligibility. Quantitative analysis was performed on 30 articles including our institutional data and 18 studies reported recurrence by level of Ki-67/MIB-1 LI. Among studies that compared Ki-67/MIB-1 ≥3 vs. <3%, 10 studies reported odds ratios (OR) greater than 1 of which 6 were statistically significant. A high Ki-67/MIB-1 had higher odds of recurrence via the pooled odds ratio (OR = 4.15, 95% confidence interval [CI]: 2.31–7.42). Conclusion This systematic review suggests that a high Ki-67/MIB-1 should prompt an increased duration of follow-up due to the higher odds of recurrence of pituitary adenoma.

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Folate receptor overexpression can be visualized in real time during pituitary adenoma endoscopic transsphenoidal surgery with near-infrared imaging

Journal of Neurosurgery ◽

10.3171/2017.2.jns163191 ◽

2018 ◽

Vol 129 (2) ◽

pp. 390-403 ◽

Cited By ~ 16

Author(s):

John Y. K. Lee ◽

Steve S. Cho ◽

Ryan Zeh ◽

John T. Pierce ◽

Maria Martinez-Lage ◽

...

Keyword(s):

Pituitary Adenoma ◽

Real Time ◽

Pituitary Adenomas ◽

Near Infrared ◽

Folate Receptor ◽

Mri Findings ◽

Null Cell ◽

Postoperative Mri ◽

Visual Contrast ◽

Nir Imaging

OBJECTIVEPituitary adenomas account for approximately 10% of intracranial tumors and have an estimated prevalence of 15%–20% in the general US population. Resection is the primary treatment for pituitary adenomas, and the transsphenoidal approach remains the most common. The greatest challenge with pituitary adenomas is that 20% of patients develop tumor recurrence. Current approaches to reduce recurrence, such as intraoperative MRI, are costly, associated with high false-positive rates, and not recommended. Pituitary adenomas are known to overexpress folate receptor alpha (FRα), and it was hypothesized that OTL38, a folate analog conjugated to a near-infrared (NIR) fluorescent dye, could provide real-time intraoperative visual contrast of the tumor versus the surrounding nonneoplastic tissues. The preliminary results of this novel clinical trial are presented.METHODSNineteen adult patients who presented with pituitary adenoma were enrolled. Patients were infused with OTL38 2–4 hours prior to surgery. A 4-mm endoscope with both visible and NIR light capabilities was used to visualize the pituitary adenoma and its margins in real time during surgery. The signal-to-background ratio (SBR) was recorded for each tumor and surrounding tissues at various endoscope-to-sella distances. Immunohistochemical analysis was performed to assess the FRα expression levels in all specimens and classify patients as having either high or low FRα expression.RESULTSData from 15 patients (4 with null cell adenomas, 1 clinically silent gonadotroph, 1 totally silent somatotroph, 5 with a corticotroph, 3 with somatotrophs, and 1 somatocorticotroph) were analyzed in this preliminary analysis. Four patients were excluded for technical considerations. Intraoperative NIR imaging delineated the main tumors in all 15 patients with an average SBR of 1.9 ± 0.70. The FRα expression level of the adenomas and endoscope-to-sella distance had statistically significant impacts on the fluorescent SBRs. Additional considerations included adenoma functional status and time from OTL38 injection. SBRs were 3.0 ± 0.29 for tumors with high FRα expression (n = 3) and 1.6 ± 0.43 for tumors with low FRα expression (n = 12; p < 0.05). In 3 patients with immunohistochemistry-confirmed FRα overexpression (2 patients with null cell adenoma and 1 patient with clinically silent gonadotroph), intraoperative NIR imaging demonstrated perfect classification of the tumor margins with 100% sensitivity and 100% specificity. In addition, for these 3 patients, intraoperative residual fluorescence predicted postoperative MRI results with perfect concordance.CONCLUSIONSPituitary adenomas and their margins can be intraoperatively visualized with the preoperative injection of OTL38, a folate analog conjugated to NIR dye. Tumor-to-background contrast is most pronounced in adenomas that overexpress FRα. Intraoperative SBR at the appropriate endoscope-to-sella distance can predict adenoma FRα expression status in real time. This work suggests that for adenomas with high FRα expression, it may be possible to identify margins and to predict postoperative MRI findings.

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PTTG has a Dual Role of Promotion-Inhibition in the Development of Pituitary Adenomas

Protein and Peptide Letters ◽

10.2174/0929866526666190722145449 ◽

2019 ◽

Vol 26 (11) ◽

pp. 800-818

Author(s):

Zujian Xiong ◽

Xuejun Li ◽

Qi Yang

Keyword(s):

Cell Cycle ◽

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Cell Cycle Progression ◽

Key Factors ◽

Cycle Progression ◽

Sister Chromatids ◽

Regulation Of Cell Cycle ◽

Late Stages

Pituitary Tumor Transforming Gene (PTTG) of human is known as a checkpoint gene in the middle and late stages of mitosis, and is also a proto-oncogene that promotes cell cycle progression. In the nucleus, PTTG works as securin in controlling the mid-term segregation of sister chromatids. Overexpression of PTTG, entering the nucleus with the help of PBF in pituitary adenomas, participates in the regulation of cell cycle, interferes with DNA repair, induces genetic instability, transactivates FGF-2 and VEGF and promotes angiogenesis and tumor invasion. Simultaneously, overexpression of PTTG induces tumor cell senescence through the DNA damage pathway, making pituitary adenoma possessing the potential self-limiting ability. To elucidate the mechanism of PTTG in the regulation of pituitary adenomas, we focus on both the positive and negative function of PTTG and find out key factors interacted with PTTG in pituitary adenomas. Furthermore, we discuss other possible mechanisms correlate with PTTG in pituitary adenoma initiation and development and the potential value of PTTG in clinical treatment.

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Successful pregnancy after operation in an infertile woman caused by luteinizing hormone-secreting pituitary adenoma: case report and literature review

BMC Endocrine Disorders ◽

10.1186/s12902-020-00677-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yi Zhang ◽

Cheng Chen ◽

Min Lin ◽

Kan Deng ◽

Huijuan Zhu ◽

...

Keyword(s):

Case Report ◽

Pituitary Adenoma ◽

Literature Review ◽

Pituitary Adenomas ◽

Sella Turcica ◽

Infertile Woman ◽

Mass Treatment ◽

Successful Pregnancy ◽

Case Presentation ◽

Transsphenoidal Resection

Abstract Background Functional gonadotroph adenomas (FGAs) are rare adenomas that most commonly secrete FSH. However, solitary LH-secreting pituitary adenomas are unusual. Case presentation A 30-year-old woman with elevated LH and normal FSH presented with inability to conceive. An MRI revealed an enlarged sella turcica and an intrasellar mass. Treatment with transsphenoidal resection led to normalization of LH and estradiol, as well as successful pregnancy. And we reviewed 6 cases of LH-secreting pituitary adenomas from 1981 to 2020. Conclusions Our case is unique because of the LH-secreting pituitary adenoma without FSH hypersecretion. This case indicates that pituitary adenoma should be considered when other diseases causing infertility have been excluded.

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HIF-1α Inhibition Sensitized Pituitary Adenoma Cells to Temozolomide by Regulating Presenilin 1 Expression and Autophagy

Technology in Cancer Research & Treatment ◽

10.1177/1533034615618834 ◽

2016 ◽

Vol 15 (6) ◽

pp. NP95-NP104 ◽

Cited By ~ 6

Author(s):

Zhang kun ◽

Yang yuling ◽

Wang dongchun ◽

Xie bingbing ◽

Li xiaoli ◽

...

Keyword(s):

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Ph Value ◽

Hypoxia Inducible Factor ◽

Presenilin 1 ◽

Gh3 Cells ◽

Lysosomal Ph ◽

Hypoxia Inducible Factor 1Α ◽

Anticancer Effects ◽

Autophagy Induction

Pituitary adenomas usually develop temozolomide resistance, which could compromise the anticancer effects of temozolomide. Suppression of hypoxia-inducible factor 1α has been shown to sensitize glioblastoma cells to temozolomide treatment according to previous reports. However, whether and how the suppression of hypoxia-inducible factor 1α could sensitize pituitary adenomas to temozolomide treatment are still poorly understood. In the present study, using hypoxia-inducible factor 1α knockdown strategy, we demonstrated for the first time that hypoxia-inducible factor 1α knockdown could inhibit temozolomide-induced autophagy in rat pituitary adenoma GH3 cells and thus increase antitumor efficacy of temozolomide. Furthermore, we found hypoxia-inducible factor 1α knockdown could block autophagy process through neutralizing lysosomal pH value but not inhibiting autophagy induction. Finally, we found hypoxia-inducible factor 1α could regulate lysosomal pH value through regulating full length presenilin 1 expression, and exogenous reexpression of presenilin 1could restore lysosome acidic levels. Our data indicated hypoxia-inducible factor 1α knockdown could be a potential approach to improve the efficacy of temozolomide therapy for pituitary adenomas.

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MICROSURGICAL ANATOMY OF THE DIAPHRAGMA SELLAE AND ITS ROLE IN DIRECTING THE PATTERN OF GROWTH OF PITUITARY ADENOMAS

Neurosurgery ◽

10.1227/01.neu.0000317321.79106.37 ◽

2008 ◽

Vol 62 (3) ◽

pp. 717-723 ◽

Cited By ~ 39

Author(s):

Alvaro Campero ◽

Carolina Martins ◽

Alexandre Yasuda ◽

Albert L. Rhoton

Keyword(s):

Pituitary Adenoma ◽

Cavernous Sinus ◽

Dura Mater ◽

Pituitary Adenomas ◽

Potential Role ◽

Pituitary Tumors ◽

Microsurgical Anatomy ◽

Suprasellar Region ◽

Lateral Distance ◽

Diaphragma Sellae

Abstract OBJECTIVE To evaluate the anatomic aspects of the diaphragma sellae and its potential role in directing the growth of a pituitary adenoma. METHODS Twenty cadaveric heads were dissected and measurements were taken at the level of the diaphragma sellae. RESULTS The diaphragma sellae is composed of two layers of dura mater. There is a remarkable variation in the morphology of the diaphragm opening. The average anteroposterior distance of the opening was 7.26 mm (range, 3.4–10.7 mm) and the average lateral-to-lateral distance was 7.33 mm (range, 2.8–14.1 mm). CONCLUSION The variability in the diameter of the opening of the diaphragma sellae could explain the growth of pituitary tumors toward the cavernous sinus or toward the suprasellar region.

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Pediatric Pituitary Adenoma: Case Series, Review of the Literature, and a Skull Base Treatment Paradigm

Journal of Neurological Surgery Part B Skull Base ◽

10.1055/s-0038-1625984 ◽

2018 ◽

Vol 79 (01) ◽

pp. 091-114 ◽

Cited By ~ 19

Author(s):

Avital Perry ◽

Christopher Graffeo ◽

Christopher Marcellino ◽

Bruce Pollock ◽

Nicholas Wetjen ◽

...

Keyword(s):

Systematic Review ◽

Pituitary Adenoma ◽

Skull Base ◽

Pituitary Adenomas ◽

Pediatric Population ◽

Csf Leak ◽

Persistent Disease ◽

Treatment Paradigm ◽

Surgical Cure

Background Pediatric pituitary adenoma is a rare skull base neoplasm, accounting for 3% of all intracranial neoplasms in children and 5% of pituitary adenomas. Compared with pituitary tumors in adults, secreting tumors predominate and longer disease trajectories are expected due to the patient age resulting in a natural history and treatment paradigm that is complex and controversial. Objectives The aims of this study were to describe a large, single-institution series of pediatric pituitary adenomas with extensive long-term follow-up and to conduct a systematic review examining outcomes after pituitary adenoma surgery in the pediatric population. Methods The study cohort was compiled by searching institutional pathology and operative reports using diagnosis and site codes for pituitary and sellar pathology, from 1956 to 2016. Systematic review of the English language literature since 1970 was conducted using PubMed, MEDLINE, Embase, and Google Scholar. Results Thirty-nine surgically managed pediatric pituitary adenomas were identified, including 15 prolactinomas, 14 corticotrophs, 7 somatotrophs, and 4 non-secreting adenomas. All patients underwent transsphenoidal resection (TSR) as the initial surgical treatment. Surgical cure was achieved in 18 (46%); 21 experienced recurrent/persistent disease, with secondary treatments including repeat surgery in 10, radiation in 14, adjuvant pharmacotherapy in 11, and bilateral adrenalectomy in 3. At the last follow-up (median 87 months, range 3–581), nine remained with recurrent/persistent disease (23%).Thirty-seven publications reporting surgical series of pediatric pituitary adenomas were included, containing 1,284 patients. Adrenocorticotropic hormone (ACTH)-secreting tumors were most prevalent (43%), followed by prolactin (PRL)-secreting (37%), growth hormone (GH)-secreting (12%), and nonsecreting (7%). Surgical cure was reported in 65%. Complications included pituitary insufficiency (23%), permanent visual dysfunction (6%), chronic diabetes insipidus (DI) (3%), and postoperative cerebrospinal fluid (CSF) leak (4%). Mean follow-up was 63 months (range 0–240), with recurrent/persistent disease reported in 18% at the time of last follow-up. Conclusion Pediatric pituitary adenomas are diverse and challenging tumors with complexities far beyond those encountered in the management of routine adult pituitary disease, including nuanced decision-making, a technically demanding operative environment, high propensity for recurrence, and the potentially serious consequences of hypopituitarism with respect to fertility and growth potential in a pediatric population. Optimal treatment requires a high degree of individualization, and patients are most likely to benefit from consolidated, multidisciplinary care in highly experienced centers.

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miR-26a Plays an Important Role in Cell Cycle Regulation in ACTH-Secreting Pituitary Adenomas by Modulating Protein Kinase Cδ

Endocrinology ◽

10.1210/en.2012-2070 ◽

2013 ◽

Vol 154 (5) ◽

pp. 1690-1700 ◽

Cited By ~ 44

Author(s):

Erica Gentilin ◽

Federico Tagliati ◽

Carlo Filieri ◽

Daniela Molè ◽

Mariella Minoia ◽

...

Keyword(s):

Cell Cycle ◽

Pituitary Adenoma ◽

Protein Kinase ◽

Pituitary Adenomas ◽

Viable Cell Number ◽

Pituitary Cells ◽

Human Pituitary ◽

Human Pituitary Adenoma ◽

Acth Secreting ◽

Protein Kinase Cδ

Abstract The functional aftermath of microRNA (miRNA) dysregulation in ACTH-secreting pituitary adenomas has not been demonstrated. miRNAs represent diagnostic and prognostic biomarkers as well as putative therapeutic targets; their investigation may shed light on the mechanisms that underpin pituitary adenoma development and progression. Drugs interacting with such pathways may help in achieving disease control also in the settings of ACTH-secreting pituitary adenomas. We investigated the expression of 10 miRNAs among those that were found as most dysregulated in human pituitary adenoma tissues in the settings of a murine ACTH-secreting pituitary adenoma cell line, AtT20/D16v-F2. The selected miRNAs to be submitted to further investigation in AtT20/D16v-F2 cells represent an expression panel including 5 up-regulated and 5 down-regulated miRNAs. Among these, we selected the most dysregulated mouse miRNA and searched for miRNA targets and their biological function. We found that AtT20/D16v-F2 cells have a specific miRNA expression profile and that miR-26a is the most dysregulated miRNA. The latter is overexpressed in human pituitary adenomas and can control viable cell number in the in vitro model without involving caspase 3/7-mediated apoptosis. We demonstrated that protein kinase Cδ (PRKCD) is a direct target of miR-26a and that miR26a inhibition delays the cell cycle in G1 phase. This effect involves down-regulation of cyclin E and cyclin A expression via PRKCD modulation. miR-26a and related pathways, such as PRKCD, play an important role in cell cycle control of ACTH pituitary cells, opening new therapeutic possibilities for the treatment of persistent/recurrent Cushing's disease.

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Benserazide and nomifensine in the diagnosis of prolactin-secreting pituitary adenomas

Acta Endocrinologica ◽

10.1530/acta.0.1010171 ◽

1982 ◽

Vol 101 (2) ◽

pp. 171-179 ◽

Cited By ~ 3

Author(s):

A. E. Pontiroli ◽

G. Loda ◽

A. Roggia ◽

P. Scagliola ◽

L. Falsetti

Keyword(s):

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Dopa Decarboxylase ◽

Dopaminergic Drug ◽

Normal Women ◽

Synaptic Level

Abstract. Benserazide, an inhibitor of dopa-decarboxylase, stimulates prolactin (Prl) release in normal women and in puerperae; nomifensine, a dopaminergic drug able to release dopamine and to inhibit its re-uptake at the post-synaptic level, inhibits Prl release in the same subjects. Similar modifications of Prl release are evident in selected cases of non-tumoural hyperprolactinaemia, while neither drug modifies Prl release in patients with a Prl-secreting pituitary adenoma. The aim of our study was to compare the effect of these drugs in patients with a Prl-secreting pituitary adenoma, in patients with 'functional' hyperprolactinaemia and in patients with minor abnormalities of sellar tomography. Neither drug modified Prl release in patients with macro- or microadenomas; several patients in the remaining groups failed to respond to one or both tests, the concordance between the two tests averaging 75%. Patients responding to both tests, to one test or to neither test showed progressively higher basal Prl levels. Since benserazide and nomifensine can indicate the presence of a pituitary adenoma earlier than sellar tomography, our results indicate that patients with no Prl response to one or to both tests probably harbour a pituitary adenoma which cannot yet be revealed by sellar tomography.

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Modern views on the genetic determinism of GH-secreting pituitary adenomas (literature review and own data)

INTERNATIONAL JOURNAL OF ENDOCRINOLOGY ◽

10.22141/2224-0721.17.1.2021.226425 ◽

2021 ◽

Vol 17 (1) ◽

pp. 11-19

Author(s):

R. Nikolaiev ◽

L. Rostomyan ◽

A. Beckers ◽

O. Khyzhnyak ◽

M. Mykytyuk ◽

...

Keyword(s):

Pituitary Adenoma ◽

Genetic Analysis ◽

Pituitary Adenomas ◽

Young Age ◽

Mccune Albright Syndrome ◽

Men1 Gene ◽

Men 1 ◽

Albright Syndrome ◽

Aip Gene ◽

Mccune Albright

Background. This article presents a review of the current literature on the role of the genetic component in the etiology and pathogenesis of hormone-active pituitary adenomas secreting growth hormone (GH) and clinically manifesting by acromegaly and/or gigantism (multiple endocrine neoplasia 1 (MEN-1), McCune-Albright syndrome, Carney complex, X-linked acrogigantism (X-LAG), familial isolated pituitary adenoma — FIPA). Materials and methods. To identify mutations in the AIP gene and to verify FIPA, 26 patients of the Ukrainian population (19 women and 7 men) were examined in whom acromegaly was diagnosed in adolescence or young age, and genetic analysis was performed. To determine the genetic determinism in the development of GH-secreting pituitary adenoma and differential diagnosis of FIPA and MEN-1 syndromes by sequencing method (MLPA — ligation-dependent probe amplification), the genes MLPA, P244-C1 were studied involving exons 1–6 MEN1 gene, (MLPA, P017-D1) AIP gene. Results. Among those examined, only two patients had AIP gene mutations. In one patient, genetic screening for MEN1 gene mutation was negative and no clinical symptoms suggestive of McCune-Albright syndrome were detected. A variant heterozygous missense c.714C>G (p.Cys238Trp) was found in the AIP gene. This AIP gene assay is compatible with a genetic predisposition to develop pituitary adenoma. The offspring of this patient has a 50% chance of inheriting this variant, acromegaly, hypersomatotropinemia, MEN-1 syndrome, familial isolated pituitary adenoma. Another patient was diagnosed with MEN syndrome type 1 (Wermer syndrome): insulinoma, parathyroid gland adenomas (2), primary hyperparathyroidism with a heterozygous c.134A>G variant (p.Glu45Gly) found in the MEN1 gene. The presence of the c.l34A>G (p.Glu45Gly) class variant 4 is likely to be pathogenic. The prevalence of this variant in the general population is unknown, so it is very rare. Conclusions. The genetic analysis is appropriate in pediatric and young patients or those with GH-secreting macro/giant pituitary adenoma diagnosed at a young age (under 35), regardless of family history. In patients with a history of a disease, genetic analysis is recommended in any case to identify FIPA and to predict the further course of the disease and the effectiveness of treatment with somatostatin analogues.

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