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The pituitary gland is a small gland in the brain located behind the nose. Pituitary tumors are abnormal growths that develop in the pituitary gland. Most pituitary tumors are noncancerous (benign) growths, but they cause the pituitary gland to produce too little or too much hormones, thus causing the body to appear different symptoms from each specifically related hormone. Many pituitary tumors can also compress the nearby optic nerve, causing vision problems.
Fig 1. Pituitary gland tumor
People with pituitary gland tumors may experience the following symptoms or signs. such as fatigue, nausea, headaches, vision problems, unexplained tiredness, mood changes, irritability, unexplained changes in menstrual cycles, erectile dysfunction, which is caused by hormone changes, infertility, unexpected breast growth or production of breast milk, Cushing’s syndrome, acromegaly, etc.
The cause of the pituitary gland tumor has not been determined yet. However, people with a family history of multiple endocrine neoplasia, type 1 (MEN 1), have an increased risk of pituitary tumors.
Various signaling pathways are misregulated in the pituitary gland, which leads to pituitary carcinogenesis. Studies in the pathogenesis and functional regulation of pituitary gland tumors are mainly focused on the following two topics: (a) the origin of pituitary gland tumors and abnormal physical adjustment due to the activation of oncogenes and loss of function for tumour-suppressor genes; and (b) the mechanistic anomalies of the intracellular signal transduction. Among these, the Raf/MEK/ERK signaling has been considered to be one of the major and central pathways in disease etiology. Raf/MEK/ERK signaling controls cellular growth, differentiation and survival. Other signaling pathways include pituitary organogenesis (Notch, Wnt and Hedgehog), regulation of basic cellular processes ((PI3K)/AKT), tumorigenesis (cAMP, pRb/E2F), etc. In addition, numerous oncogenes, tumor suppressor genes, and cell cycle mediators have been identified as functionally involved in pituitary tumor initiation and progression, including oncogenes (PTTG), cell cycle regulators (Rb1, p16, p21, p27, cyclin D1, and cyclin E), tumor suppressor (GADD45β, AIP, Menin), cell proliferation (GNAS), matrix metalloproteinase 2/9 (MMP-2/9) and hypoxia-inducible factor (HIF). In addition, dysregulation of miRNAs has also been found in pituitary tumors, and the relevantly verified targets include AIP (miR-107), HMGA2 (miR-326, miR-432 and miR-570), E2F1 (miR-326 and miR-603), PTEN (miR-26b), BMI1 (miR-128).
Fig. 2 Tumorigenic mechanisms in somatotroph cells
Accurate pituitary tumor diagnosis usually involves blood/urine hormone tests (GH, ACTH, and PRL, etc.) and an MRI or CT of the brain. Pituitary tumors are clinically categorized by their hormone-secreting characteristics, with over-secretion of growth hormone (GH), prolactin, adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) or clinically nonfunctioning tumors. Histological characterization has been based on immunohistochemical staining of pituitary hormones, with more recently transcription factors (PIT1 for GH, prolactin and TSH lineages, SF1 for gonadotroph lineages and TPIT for ACTH lineage) being applied to the classification. In addition, there is a wide range of biomarkers applicable to evaluating the aggressiveness of pituitary adenomas and prognosis, such as proliferation marker (Ki-67), proliferating cell nuclear antigen (PNCA), tumor suppressor (p53 protein), epithelial-mesenchymal transition related cell adhesion (cadherin), oncogenes (PTTG), extracellular matrix regulation (MMP-9), angiogenesis and cell proliferation (VEGF, FGFRs, FGFs, and COX-2), etc.
Treatment for pituitary tumors depends on their size, and the status it has grown in the brain. Age and overall health of patients are also factors. Surgery, radiation therapy, and medications are usually used alone or in combination to treat pituitary tumors and restore hormone production to normal levels.
Surgery mainly includes two methods: endoscopic transnasal transsphenoidal approach or transcranial approach.
Fig. 3 Endoscopic transnasal transsphenoidal surgery
Radiation therapy can be used after surgery or alone if surgery isn't an option. Methods of radiation therapy include Stereotactic radiosurgery, External beam radiation, Intensity-modulated radiation therapy (IMRT), Proton beam therapy.
Treatment with medications may help to block excess hormone secretion and sometimes shrink certain types of pituitary tumors: prolactinomas (cabergoline and bromocriptine), Cushing syndrome (ketoconazole, mitotane and metyrapone), Growth hormone-secreting tumors (pegvisomant, octreotide and lanreotide), Chemotherapy medication (TMZ).
Targeted therapy and immunotherapy can also be used for the treatment of pituitary tumors, such as mTOR inhibitors (Afinitor), multi-kinase inhibitors (sunitinib, Sutent), targeting VEGF (Bevacizumab), immune Checkpoint Inhibitors (nivolumab: anti- PD-1, ipilimumab: anti-CTLA-4). The research of targeting other pathways that are abnormal in pituitary tumors, such as histone deacetylases, heat shock proteins, proteasomes, and topoisomerases, will provide additional therapeutic options for pituitary cancer.
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