[Effect of gonadotropin releasing hormone on pituitary gonadotropin function in the presence of neoplasms of the pituitary gland].
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OBJECTIVE AND IMPORTANCE: Pituitary carcinomas are extremely rare. Cases reported in the medical literature in the 20th century included tumors that produced adrenocorticotropic hormone, prolactin, growth hormone, and/or thyrotropin. CLINICAL PRESENTATION: Here we present a 22-year-old woman with a pituitary carcinoma that was immunohistochemically positive for luteinizing hormone and follicle-stimulating hormone at both the primary and metastatic sites. The patient exhibited elevated serum levels of alpha-subunit. INTERVENTION: The patient had experienced failure of previous treatments, including standard surgery and radiotherapy, and presented to us for radical resection of the tumor, with exenteration of the involved cavernous sinus. She was pretreated with cytotoxic chemotherapy and continued to receive this therapy after surgery. CONCLUSION: This is the only documented case of a gonadotropin-staining pituitary carcinoma for which hormone production was proven in both the primary and metastatic tumors. Many benign "nonsecreting" pituitary adenomas actually produce subclinical amounts of gonadotropins, and malignant nonfunctional pituitary neoplasms may do the same.
Mice bearing retinoblastoma susceptibility gene (RB) germ-line mutations almost invariably develop pituitary neoplasms. We therefore tested 17 patients with pituitary tumors for loss of heterozygosity (LOH) using an RB sequence polymorphism and 5 polymorphic microsatellite markers surrounding the RB gene on the long arm of chromosome 13. In all of the 13 malignant or highly invasive pituitary tumor cases, and in 4 of their respective metastases, a RB allele was lost. In contrast, no LOH at the RB locus was detected in 4 benign pituitary adenoma cases. Three invasive tumors also lost a portion of 13q, which included D13s137, D13s133, and D13s118 telomeric and centromeric to RB, respectively. Immunohistochemical analysis, however, revealed the presence of RB protein in tumors with LOH and the RB locus. Therefore, although inactivation of RB may play a role in the development of invasive pituitary adenomas and carcinomas in mice, another tumor suppressor gene on 13q is likely involved in human pituitary tumor progression. LOH of 13q markers may also be of predictive value in determining the biological behavior of pituitary macroadenomas and their progression to invasiveness and frank malignancy.
Angiogenesis, or the formation of new blood vessels, is a dynamic process needed for embryogenesis, post-natal growth, morphogenesis, tumorigenesis, and for other biological processes. Angiogenesis is very important for tumor development and progression. This review examines the activators and inhibitors of angiogenesis with emphasis on the pituitary gland and pituitary neoplasms. Some of the proteins regulating angiogenesis in pituitary tumors such as vascular endothelial growth factor (VEGF) and VEGF receptors, fibroblasts growth factors (FGF), transforming growth factor beta (TGFB), interleukins, interferons, and matrix metalloproteinases (MMPs) and inhibitors of MMPs have been examined in animal and human pituitary tumor models. However, many other significant regulators of angiogenesis including angiopoietins, angiostatin, and thrombospondins have not been studied extensively in pituitary tumors to date. Newer concepts and developments in angiogenesis such as vasculogenic mimicry and gene therapy approaches to angiogenesis in cancer treatment are also discussed.
Pituitary neoplasm was identified in 43 dogs with pituitary-dependent hyperadrenocorticism via necropsy (n = 33), diagnostic imaging with computerized tomography or magnetic resonance imaging (n = 5), or diagnostic imaging and necropsy (n = 5). All dogs had clinical signs and clinicopathologic test results typical of hyperadrenocorticism. Thirty-seven dogs had grossly visible pituitary tumors, and 6 dogs had microscopic pituitary tumors. Fifteen dogs had developed neurologic signs typical of those resulting from an enlarging pituitary mass. Twenty-three dogs had pituitary tumors greater than or equal to 1 cm in diameter. Provocative testing of the pituitary-adrenocortical axis was performed on all dogs. Dogs with grossly visible pituitary tumors and dogs with neurologic signs had significantly (P less than 0.05) higher mean plasma endogenous ACTH concentrations, compared with values from dogs with microscopic tumors and dogs without neurologic signs, respectively. Dogs with grossly visible pituitary tumors and dogs with tumors greater than or equal to 1 cm in diameter had significantly (P less than 0.05) lower adrenocortical responsiveness to exogenous ACTH, compared with dogs with microscopic pituitary tumors and dogs with tumors less than 1 cm in diameter, respectively. Despite these differences, there was overlap between test results among dogs. On the basis of endocrine test results, it would appear difficult to distinguish dogs with pituitary-dependent hyperadrenocorticism and large pituitary tumors from those with pituitary-dependent hyperadrenocorticism and microscopic pituitary tumors prior to onset of neurologic signs.
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Explore the source record for details and available documents.
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Only 1% of all pituitary surgeries are performed to treat tumors that have metastasized to the pituitary gland; however, in certain cases of malignant neoplasms pituitary metastases do occur. Breast and lung cancers are the most common diseases that metastasize to the pituitary. Breast cancer metastasizes to the pituitary especially frequently, with reported rates ranging between 6 and 8% of cases. Most pituitary metastases are asymptomatic, with only 7% reported to be symptomatic. Diabetes insipidus, anterior pituitary dysfunction, visual field defects, headache/pain, and ophthalmoplegia are the most commonly reported symptoms. Diabetes insipidus is especially common in this population, occurring in between 29 and 71% of patients who experience symptoms. Differentiation of pituitary metastasis from other pituitary tumors based on neuroimaging alone can be difficult, although certain features, such as thickening of the pituitary stalk, invasion of the cavernous sinus, and sclerosis of the surrounding sella turcica, can indicate metastasis to the pituitary gland. Overall, neurohypophysial involvement seems to be most prevalent, but breast metastases appear to have an affinity for the adenohypophysis. Differentiating metastasis to the pituitary gland from bone metastasis to the skull base, which invades the sella turcica, can also be difficult. In metastasis to the pituitary gland, surrounding sclerosis in the sella turcica is usually minimal compared with metastasis to the skull base. Treatment for these tumors is often multimodal and includes surgery, radiation therapy, and chemotherapy. Tumor invasiveness can make resection difficult. Although surgical series have not shown any significant survival benefits given by tumor resection, the patient's quality of life may be improved. Survival among these patients is poor with mean survival rates reported to range between 6 and 22 months.
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A case of pituitary carcinoma is here presented, together with a review of the 25 cases so far reported in the literature. After a long-standing history of Cushing's disease, treated with interstitial pituitary irradiation and total adrenalectomy, Nelson's syndrome developed due to a pituitary neoplasm that finally spread through the subarachnoidal space, bringing the patient to death. The possible long-term role of surgery and radiotherapy in switching an aggressive behavior is also discussed.
A large invasive pituitary neoplasm, surgically resected by left frontotemporal craniotomy, and thought to represent "chromophobe" adenoma by light microscopy, exhibited ultrastructural features characteristic of oncocytoma. Electron microscopic and immunocytochemical studies showed that the tumor did not possess enhanced secretory activity. The indispensable role of electron microscopy in the identification of this rare neoplasm and especially in the classification of all pituitary tumors is emphasized.
Transforming growth factor (TGF)-beta has been implicated in the regulation of normal and neoplastic anterior pituitary cell function. TGF-beta regulates the expression of various proteins, including p27Kip1 (p27), a cell cycle inhibitory protein. We examined TGF-beta, TGF-beta type II receptor (TGF-beta-RII), and p27 expression in normal pituitaries, pituitary adenomas, and carcinomas to analyze the possible roles of these proteins in pituitary tumorigenesis. Normal pituitary, pituitary adenomas, and pituitary carcinomas all expressed TGF-beta and TGF-beta-RII immunoreactivity. Reverse transcription polymerase chain reaction analysis showed TGF-beta 1, -beta 2, and -beta 3 isoforms and TGF-beta-RII in normal pituitaries and pituitary adenomas. Pituitary adenomas cells cultured for 7 days in defined media showed a biphasic response to TGF-beta with significant inhibition of follicle-stimulating hormone secretion at higher concentrations (10(-9) mol/L) and stimulation of follicle-stimulating hormone secretion at lower concentrations (10(-13) mol/L) of TGF-beta 1 in gonadotroph adenomas. Immunohistochemical analysis for p27 protein expression showed the highest levels in nontumorous pituitaries with decreased immunoreactivity in adenomas and carcinomas. When nontumorous pituitaries and various adenomas were analyzed for p27 and specific hormone production, growth hormone, luteinizing hormone, and thyroid-stimulating hormone cells and tumors had the highest percentages of cells expressing p27, whereas adrenocorticotrophic hormone cells and tumors had the lowest percentages. Immunoblotting analysis showed that adrenocorticotrophic hormone adenomas also had the lowest levels of p27 protein. Semiquantitative reverse transcription polymerase chain reaction and Northern hybridization analysis did not show significant differences in p27 mRNA expression in the various types of adenomas or in nontumorous pituitaries. In situ hybridization for p27 mRNA showed similar distributions of the gene product in nontumorous pituitaries, pituitary adenomas, and carcinomas. These results indicate that TGF-beta and TGF-beta-RII are widely expressed in nontumorous pituitaries and in pituitary neoplasms and that TGF-beta 1 regulates pituitary hormone secretion. The levels of the TGF-beta-regulated protein p27 decreases in the progression of normal to neoplastic pituitaries. In contrast, the mRNA levels of p27 remained relatively constant in nontumorous pituitaries, pituitary adenomas, and carcinomas, indicating that p27 protein levels in adenomas and carcinomas are regulated by translational and post-translational mechanisms.
Analyses of apoptosis and of the apoptosis regulatory proteins Bcl-2, Bax, Bcl-X, and Bad were done in 95 nontumorous and neoplastic pituitary tissues by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL), immunohistochemistry, and Western blotting. The apoptotic index was relatively low in all groups but was at least fourfold higher in pituitary carcinomas compared with any other groups. Pituitaries from pregnant and postpartum women had a fivefold higher apoptotic index compared with matched controls from nonpregnant females. Preoperative treatment of adenomas with octreotide or dopamine agonists did not change the apoptotic index significantly. The lowest levels of Bcl-2, Bax, and Bcl-X expression were in pituitary carcinomas as detected by immunostaining. An immortalized human pituitary adenoma cell line, HP75, developed in our laboratory using a replication-defective recombinant human adenovirus with an early large T-antigen, had a much higher level of apoptosis than nontumorous and neoplastic pituitaries. Treatment with transforming growth factor (TGF)-beta1 and protein kinase C (PKC) inhibitors increased apoptosis in this cell line. Analysis of the Bcl-2 family of proteins after treatment with TGF-beta1 and PKC inhibitors showed a 20% to 30% decrease in Bcl-X in the treated groups compared with controls. These results, which represent the first study of apoptosis in pituitaries from pregnant and postpartum cases and in pituitary carcinomas, indicate that 1) the apoptotic rate is low in nontumorous and neoplastic pituitary tissues but is relatively higher in pituitary carcinomas, 2) there are alterations in the expression of the Bcl-2 family of proteins in pituitary neoplasms with a decrease in Bcl-2 expression in pituitary carcinomas that may contribute to pituitary tumor pathogenesis and/or proliferation, and 3) cultured pituitary tumor cells respond to TGF-beta1 and PKC inhibitors by undergoing apoptotic cell death.