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Biomedical subjects

Eva Horvath

Publications and source records attributed to Eva Horvath.

At least 19 recordsLinked to original sources
PubMed2006

Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: Morphological findings.

Administration of temozolomide to a 46-year-old man with an invasive aggressive prolactin (PRL)-secreting pituitary neoplasm resulted in improvement of the clinical condition and significant decrease of blood PRL levels. Histologic, immunohistochemical, and electron microscopic study demonstrated marked morphological differences in the tumor exposed to temozolomide compared with the unexposed tumor. Necrosis, hemorrhagic areas, accumulation of connective tissue, focal inflammatory infiltration, and neuronal transformation were seen. Immunohistochemical prognostic indicators showed a reduction in growth potential. Based on the clinical, laboratory, and morphological findings, we recommend temozolomide therapy in patients with pituitary tumors not responding adequately to other treatment options.

Antineoplastic Agents, Alkylating↗
PubMed2006

Pathology of acromegaly.

This review summarizes current knowledge on pituitary changes in patients with acromegaly. The histologic, immunohistochemical and electron microscopic study provided conclusive evidence that a marked diversity exists between the tumors which secrete growth hormone (GH) in excess, such as densely and sparsely granulated GH cell adenoma, the mixed GH prolactin cell adenoma and the mammosomatotrope adenoma. The latter two tumors produce GH and prolactin simultaneously. Densely granulated GH cell tumors may produce thyrotropin and alpha subunit as well. Somatotrope carcinomas are extremely rare. GH cell hyperplasia can also be associated with acromegaly in patients with extrapituitary GH-releasing hormone secreting tumors. The medical therapy of acromegaly is reviewed briefly, including long-acting somatostatin analogs and pegvisomant, a GH receptor blocker.

Acromegaly↗
PubMed2006

Pituitary tumor transforming gene overexpression facilitates pituitary tumor development.

Intrinsic and extrinsic stimuli result in profound pituitary growth changes ranging from hypoplasia to hyperplasia. Pituitary tumor transforming gene (PTTG) abundance correlates with pituitary trophic status. Mice with Pttg inactivation exhibit pituitary hypoplasia, whereas targeted pituitary PTTG overexpression driven by alpha-subunit glycoprotein (alphaGSU) promoter results in focal pituitary hyperplasia. To test the impact of pituitary hyperplasia on tumor development, we crossbred alphaGSU.PTTG with Rb+/- mice, which develop pituitary tumors with high penetrance. Pituitary glands of resulting bitransgenic alphaGSU.PTTGxRb+/- mice were compared with monotransgenic alphaGSU.PTTG, Rb+/-, and wild-type mice. Confocal microscopy showed that PTTG-overexpressing cells have enlarged nuclei and marked redistribution of chromatin, and electron microscopy of alphaGSU.PTTG pituitaries showed enlarged gonadotrophs with prominent Golgi complexes and numerous secretory granules. These morphological findings were even more remarkable in alphaGSU.PTTGxRb+/- pituitaries. Mice from all four genotypes were sequentially imaged by magnetic resonance imaging to evaluate pituitary volume, and glands from alphaGSU.PTTGxRb+/- mice were the largest as early as 2 months of age (P = 0.0003). Cumulative incidence of pituitary tumors visualized by magnetic resonance imaging did not differ between Rb+/- and alphaGSU.PTTGxRb+/- mice. However, anterior lobe tumors determined after necropsy were 3.5 times more frequent in alphaGSU.PTTGxRb+/- than in Rb+/- mice (P = 0.0036), whereas the frequency of intermediate lobe tumors was similar. In summary, alphaGSU.PTTGxRb+/- pituitary glands exhibit enhanced cellular activity, increased volume, and higher prevalence of anterior pituitary tumors, indicating that changes in pituitary PTTG content directly relate to both pituitary trophic status and tumorigenic potential.

Animals↗
PubMed2006

Immunohistochemical expression of nestin in the non-tumorous hypophysis and in pituitary neoplasms.

The aim of the present work was to investigate whether nestin, a member of the intermediate filament family, is immunohistochemically expressed in the non-tumoral human hypophysis and pituitary neoplasms. Twenty-three normal pituitaries and 125 pituitary neoplasms were included. The tissues were formalin-fixed and paraffin embedded. The neoplasms were identified on hematoxylin-eosin stained sections and were classified by immunohistochemistry as well as electron microscopy. For immunohistochemistry, the streptavidin-biotin-peroxidase complex method was applied using appropriate controls. Several corticotrophs in the autopsy obtained pituitaries showed cytoplasmic nestin immunopositivity. No nestin immunoreactivity was found in other cell types in non-tumorous adenohypophyses and in the cells of various pituitary adenomas. Nestin was, however, expressed in a small proportion of endothelial cells in both anterior and posterior lobes. Staining was also noted in several pituicytes, neurohypophysial nerve fibers, and Herring bodies. In contrast to CD-34 and Factor-8 immunostaining which demonstrated immunopositivity in practically all endothelial cells of every capillary, nestin expression was only focally seen suggesting that the functional status of the immunoreactive and non-staining endothelial cells was not the same. No statistically significant correlation was apparent between nestin immunoreactivity and patient age, gender, tumor size, mitotic index, Ki-67, labeling nuclear index, hormonal immunoprofile, and tumor type. In conclusion, nestin expression in adenomas cannot be viewed as a biologically relevant marker of cell proliferation and as a prognostic indicator. The patchy expression of nestin in endothelial cells remains unexplained and its significance requires further studies.

Adenoma↗
PubMed2006

Vascularization of rat pituitary autografts.

Pituitary autotransplantation eliminates direct vascular contact between the hypothalamus and the adenohypophysis, and enables us to study the role of the hypothalamus in regulating adenohypophysial endocrine activity. The aim of this study was to investigate vascularization of the pituitary autografts. Three-month-old male Wistar rats were hypophysectomized, and their adenohypophyses were autotransplanted under the renal capsule. The animals were killed 3 weeks after autotransplantation. The grafts were removed and studied by using histology, immunohistochemistry and transmission electron microscopy. In the central portion of the grafts, organizing necrosis was apparent. The peripheral portion of the graft contained all adenohypophysial cell types, with a predominance of lactotrophs. Vascular endothelial growth factor and hypoxia-inducible factor were expressed in the graft mainly in the perinecrotic areas. Several capillaries inside the grafts were lined by continuous unfenestrated epithelium, while others were lined by fenestrated endothelium, suggesting that neovascularization is the result of two processes: ingrowths of capillaries from the renal capsule to the graft, and neoformation of capillaries from pre-existing adenohypophysial vessels. In conclusion, hypoxia seems to be an important factor in the vascularization of pituitary autografts. Mediated via hypoxia-inducible factor, hypoxia stimulates vascular endothelial growth factor secretion, which plays a crucial role in angiogenesis.

Animals↗
PubMed2006

Pathobiology of pituitary adenomas and carcinomas.

OBJECTIVE: To examine relationships between pituitary tumors and lesion size, invasiveness, resectability, deoxyribonucleic acid ploidy, cell cycle profile, mitotic activity, and immunoreactivity for MIB-1, proliferating cell nuclear antigen (PCNA), p27Kip1, and p53. PATIENTS AND METHODS: One hundred fifty-three adenomas of most pathological subtypes, including 20 medically treated and prolactin and growth hormone-containing tumors, as well as 10 premetastatic tumors and 13 pituitary carcinomas, were studied. RESULTS: Significant (P < 0.05) differences were noted between functional versus nonfunctional adenomas (percent aneuploidy, percent S phase, p27Kip1 labeling indices [LI], male sex, tumor size, and frequency of visual disturbance); Cushing's versus silent adrenocorticotropin adenomas (percent hypertetraploidy, p53 LI, tumor size, visual disturbance, and resectability); untreated versus medically treated prolactin cell adenomas (MIB-1 LI, p53 LI, and resectability); untreated versus medically treated growth hormone-containing adenomas (percent diploidy, percent S phase, MIB-1 LI, p53 LI, and p27 LI); untreated prolactin cell adenomas versus premetastatic tumors (percent hypertetraploidy, PCNA LI, p53 LI, invasiveness, and resectability); untreated growth hormone-containing adenomas versus premetastatic tumors (percent diploidy, percent S phase, PCNA LI, p53 LI, invasiveness, and resectability); Cushing's adenomas versus premetastatic tumors (percent diploidy, percent hypertetraploidy, percent S phase, MIB-1 LI, p53 LI, tumor size, invasiveness, visual disturbance, and resectability); Nelson's adenomas versus premetastatic tumors (p53 LI, tumor size, invasiveness, and resectability); silent adenomas as a whole versus nonfunctional adenomas (percent nondiploid, percent S phase, invasiveness, and respectability); silent adrenocorticotropin adenomas I and II versus silent adenoma Subtype III (invasiveness); silent adrenocorticotropin adenoma Subtypes I and II versus premetastatic tumors (MIB-1 LI and invasiveness); silent adenoma Subtype III versus premetastatic tumors (PCNA and p53 LI); and premetastatic tumors versus metastatic pituitary carcinomas (MIB-1 LI). CONCLUSION: Only trends toward differences were noted between Cushing's versus Nelson's adenomas and between prolactinomas of reproductive female patients versus those of menopausal female patients and male patients. Too few "atypical adenomas" were encountered to permit their comparison with premetastatic tumors, but our results suggest that most pituitary carcinomas arise by malignant transformation from adenomas.

Adolescent↗
PubMed2006

Diversity of ACTH-immunoreactive cells in the human adenohypophysis: an immunohistochemical study with special reference to cluster formation and follicular cell association.

Horvath et al. called relatively small ACTH-immunoreactive (ACTH-IR) cells observed in basophil invasion "proopiomelanocortin (POMC) cells," and these cells were supposed to be different from larger ACTH-IR cells in human adenohypophysis. To clarify the existence of "anterior POMC cells," we examined 21 autopsy cases taking note of follicular cells (FCs). We found that smaller ACTH-IR cells were clustered forming small areas without FC association, clustered small cell island (CSCI). CSCI was found in all the specimens we examined using immunohistochemical staining for ACTH and cytokeratin (AE1/AE3) in serial sections. ACTH-IR cells outside CSCI were of various sizes, mainly consisting of larger ACTH-IR cells that were diffusely scattered among other hormone-secreting cells and closely associated with FCs. By immunohistochemistry, ACTH-IR cells within CSCI and basophil invasion showed uniformly weak reactivity and common patterns for cytokeratins (CAM5.2 and 35 beta H11), carboxypeptidase D, and LeuM1, whereas those outside CSCI showed a great variety of immunoreactivity. The similarity in the immunoreactivity of ACTH-IR cells between CSCI and basophil invasion suggests that ACTH-IR cells in these two areas have common characteristics and ACTH-IR cells in CSCI are most likely "POMC cells." The clustered "anterior POMC cells" may be distinguishable by light microscopic immunohistochemistry.

Adrenocorticotropic Hormone↗
PubMed2005

Morphologic changes of prolactin-producing pituitary adenomas after short treatment with dopamine agonists.

Treatment of patients with prolactin (PRL)-producing pituitary adenomas with dopamine agonists has proved successful for most cases. Dopamine agonists inhibit PRL secretion, suppress cell proliferation, and may induce apoptosis to adenoma cells. Dopamine agonists induce striking morphologic changes in the majority of treated PRL-producing adenomas. To date, these morphologic effects have been primarily described only after long-term treatment. To the best of our knowledge, no similar studies have investigated apoptotic alterations induced after short-term therapy. The purpose of this report is to describe the morphologic changes seen in PRL-producing adenomas after short-term dopamine agonist treatment. We present two cases of PRL-producing macroadenomas, both from male patients who received treatment with dopamine agonists, the first for 5 and the second for 8 days. In contrast to long-term treatment, no striking reduction of PRL immunoreactivity was noted. Slight stromal fibrosis was noted in case 1, which contained several cells all in late phase of apoptosis. In addition to typical apoptotic cells, numerous "dark" cells representing another common form of cell death were also noted. These novel findings represent characteristic features of short-term dopamine agonist treatment, which are not seen in long-term treatment.

Adult↗
PubMed2005

Immunohistochemical study on so-called follicular cells and folliculostellate cells in the human adenohypophysis.

Non-hormone-secreting cells in human adenohypophysis have been designated as either follicular cells (FC) or folliculostellate cells (FSC). They have similarly long cytoplasmic processes, and the difference between FC and FSC remains unclear. An immunohistochemical study for S-100 protein, cytokeratin (CK, detected by AE1/AE3) and glial fibrillary acidic protein (GFAP) was performed in autopsy pituitaries. Double immunohistochemistry for S-100 protein and CK revealed that there were numerous coexpressed cells. The most frequent type ('CK-type cell') was cells weakly positive for S-100 protein in the nucleus and for CK-immunoreactivity in the cytoplasm. The next numerous type ('S-100 protein cell') was cells strongly positive for S-100 protein and weakly positive or negative for CK. The CK-type cells were frequently observed in the vicinity of follicular structures and in neighborhood of adrenocorticotropic hormone -immunoreactive cells, and were most likely the cells termed FC. They were often observed around necrotic areas. The S-100 protein cells were individually found in the circumference of endocrine cell nest, and seemed to be the so-called stellate cells. GFAP-positive cells were rare. It is implied that S-100 protein-positive FSC could be divided into at least two main subtypes: FC (CK-type cells) and stellate cells (S-100 protein cells).

Adrenocorticotropic Hormone↗
PubMed2005

Galectin-3 Expression in Functioning and Silent ACTH-Producing Adenomas.

Galectin-3 (Gal-3), a beta galactoside-binding protein, has been implicated in a variety of biological functions including cell growth, differentiation, tumor cell adhesion, angiogenesis, tumor progression, and metastasis. We recently reported that Gal-3 was expressed in a subset of normal pituitary cells and tumors including PRL, ACTH, and in folliculo-stellate (FS) cells and tumors and that Gal-3 had an important regulatory role in pituitary cell proliferation. We further investigated the expression of Gal-3 protein in ACTH- and PRL-producing tumors and the expression of various galectin mRNAs by RT-PCR in pituitary adenomas and normal pituitary. Most silent ACTH subtypes 1 and 2 adenomas were negative or only focally positive for Gal-3 expression compared to functioning ACTH tumors from patients with Cushing's disease and Nelson's syndrome. In the normal pituitary, Gal-3 was expressed in less than 1% of the basophil-invading cells (ACTH cells present in the posterior pituitary) and in a subset of the anterior lobe ACTH-positive cells. RT-PCR analyses showed that many members of the galectin family including galectins 1, 2, 3, 4, 5, 6, 7, 8, and 9 were expressed in normal pituitary and in functioning ACTH- and PRL-producing tumors. These results indicate that Gal-3 is associated with functioning ACTH and PRL tumors and is expressed infrequently in silent ACTH adenomas, suggesting that Gal-3 protein and/or gene is altered in non-functioning ACTH tumors. The use of ACTH and Gal-3 immunostaining should help in the diagnosis of silent ACTH adenomas.

ACTH-Secreting Pituitary Adenoma↗
PubMed2004

Prolactin-producing pituitary adenoma with incomplete neuronal transformation: an intermediate adenoma-neuronal tumor.

We present a unique case of a prolactin (PRL)-producing pituitary adenoma showing incomplete neuronal differentiation without ganglion cells. A 27-year-old man presented with nausea, headaches, and instability over the last 2 months. Clinical examination revealed obesity with no other endocrinological signs. His serum PRL levels were slightly elevated (38 ng/ml), whereas concentrations of the other adenohypophysial hormones were within normal range. Histology revealed an unusual pituitary adenoma containing many hypocellular areas with fibrillar appearance. The sizable tumor cells were polyhedral or elongated harboring an ovoid, vesicular nucleus with prominent nucleolus, lacking, however, the typical features of ganglion cells. By immunohistochemistry, many adenoma cells were positive for PRL. Immunostain for neurofilament protein revealed variable amounts of fibrils dispersed throughout the stroma, mostly in the hypocellular areas. In addition, neurofilament protein and chromogranin were strongly reactive in approximately 15% of the tumor cell population, whereas reactivity for synaptophysin was uniform throughout the tumor. These findings led to the conclusion that part of the tumor-cell population expressed a hybrid immunoprofile of adenoma-neuronal cell. Our case is the first PRL-producing pituitary adenoma showing incomplete neuronal differentiation lacking mature ganglion cells.

Adenoma↗
PubMed2004

Increased zinc content in transplastomic tobacco plants expressing a polyhistidine-tagged Rubisco large subunit.

Rubisco is a hexadecameric enzyme composed of two subunits: a small subunit (SSU) encoded by a nuclear gene (rbcS), and a large subunit (LSU) encoded by a plastid gene (rbcL). Due to its high abundance, Rubisco represents an interesting target to express peptides or small proteins as fusion products at high levels. In an attempt to modify the plant metal content, a polyhistidine sequence was fused to Rubisco, the most abundant protein of plants. Plastid transformation was used to express a polyhistidine (6x) fused to the C-terminal extremity of the tobacco LSU. Transplastomic tobacco plants were generated by cotransformation of polyethylene glycol-treated protoplasts using two vectors: one containing the 16SrDNA marker gene, conferring spectinomycin resistance, and the other the polyhistidine-tagged rbcL gene. Homoplasmic plants containing L8-(His)6S8 as a single enzyme species were obtained. These plants contained normal Rubisco amounts and activity and displayed normal photosynthetic properties and growth. Interestingly, transplastomic plants accumulated higher zinc amounts than the wild-type when grown on zinc-enriched media. The highest zinc increase observed exceeded the estimated chelating ability of the polyhistidine sequence, indicating a perturbation in intracellular zinc homeostasis. We discuss the possibility of using Rubisco to express foreign peptides as fusion products and to confer new properties to higher plants.

Journal Article↗
PubMed2004

Morphology, molecular regulation and significance of apoptosis in pituitary adenomas.

Apoptosis represents energy-requiring spontaneous single cell death, with specific morphologic and biochemical features. It is a rapidly processed sequence of events resulting in elimination of damaged cells. Apoptosis occurs in physiological remodeling and proliferative conditions, and also in neoplastic lesions. Several molecules and molecular systems such as bcl-2/bax, Fas/FasL and caspases regulate the apoptotic process. Apoptosis is characterized by a stereotypic pattern of morphologic features, which can be illustrated mostly by electron microscopy. DNA and biochemical assays, based on the specific pattern of nucleosomal fragmentation can detect apoptosis. The in situ labeling techniques are currently used to demonstrate apoptosis in paraffin sections. Several studies of pituitary animal models, cell lines and human pituitaries have been performed during the last 6 years. By electron microscopy, pituitary adenoma cells undergoing apoptosis exhibit a common prototypical pathway of changes. Although the results by the situ labeling techniques are not uniform, apoptosis occurs with low frequency in a subset of pituitary adenomas, in carcinomas and in pituitary hyperplasia. Alternative techniques based on remodeling of cytoskeleton by caspase activity can identify early apoptotic stages. This review presents the principles of apoptosis and summarizes the morphologic and functional changes of apoptosis in pituitary.

Adenoma↗
PubMed2004

Pituitary pathology in Erdheim-Chester disease.

Pituitary morphologic changes in patients with Erdheim-Chester disease have not been described in detail. We report here the histologic and immunohistochemical findings in the autopsy obtained pituitary of a 35-yr-old woman with extensively disseminated Erdheim-Chester disease. The posterior lobe was completely replaced by xanthogranulomatous infiltrates, providing an explanation for the patient's diabetes insipidus. The anterior lobe was intact and immunohistochemistry demonstrated expression of GH, TSH, FSH, LH, and alpha subunit within the normal range. A clinically observed decrease of anterior pituitary function was interpreted as hypothalamic in origin due to massive destruction of the hypophysial stalk and compression of the hypothalamus. Prolactin immunoreactive cells were numerous, consistent with the view that prolactin cell hyperplasia resulted from the loss of hypothalamic dopaminergic inhibition. Massive Crooke's hyalinization in the ACTH-producing cells was considered unrelated to Erdheim-Chester disease and was the consequence of treatment with pharmacologic doses of glucocorticoid hormones. It can be concluded that prolactin cell hyperplasia may be the only finding in the adenohypophysis of patients with disseminated Erdheim-Chester disease. It appears that in our patient the clinically apparent anterior hypopituitarism was not due to the lack of storage but rather to insufficient release of adenohypophysial hormones caused by the defect in hypothalamic regulation.

Adult↗
PubMed2004

Expression of caveolin-1 and caveolin-2 in the human pituitary: an immunohistochemical study.

Caveolins are coat proteins of caveolae, the plasmalemmal transport vesicles. To our knowledge their presence in the human pituitary and various types of hypophysial adenomas has not been investigated. In the present work, expression of caveolin-1 and caveolin-2 was studied by immunohistochemistry using the streptavidin-biotin-peroxidase complex method. The material included 7 autopsy obtained, 5 surgically removed non-tumorous pituitaries, and 97 hypophysial adenomas classified on the basis of histologic immunohistochemical and ultrastructural features. No immunoreactivity was seen for caveolin-1 and caveolin-2 in non-tumorous adenohypophysial and neurohypophysial cells and in the tumor cells, indicating that caveolins are not involved in the initiation and progression of pituitary adenomas. The expression of caveolin-1 and caveolin-2 in the endothelial cells did not depend on age, gender, endocrine status of the patients, morphologic features, and type of pituitary tumors. Scattered endothelial cells were immunopositive for both caveolins showing similar cytoplasmic localization. Evidence that the two caveolins were indeed localized to the same endothelial cell was demonstrated on consecutive sections using Factor-8 and CD-34, two reliable endothelial cell markers. Not every endothelial cell was immunoreactive for the two caveolins, suggesting that the functional status of endothelial cells is not the same within the adenomas, not even in the same capillary.

Adenoma↗
PubMed2003

Cyclooxygenase-2 expression in human pituitary tumors.

BACKGROUND: Cyclooxygenase-2 (COX-2) plays a role in progression of colon, breast, pancreas, and lung carcinomas. The authors investigated COX-2 expression in pituitary tumors. METHODS: Expression of COX-2 was evaluated in 164 surgically removed human pituitary tumors. Correlation of COX-2 with MIB-1, a cell proliferation marker, as well as angiogenesis, patient age, gender, tumor type, size, invasiveness, and metastatic potential was investigated. RESULTS: Cyclooxygenase-2 immunoreactivity was confined to the cytoplasm of tumor cells, whereas the nuclei were unlabeled. Few normal peritumoral adenohypophysial cells showed slight COX-2 cytoplasmic immunoreactivity. The staining intensity and the percentage of immunopositive cells were higher in tumors. Most pituitary tumors (96%) were COX-2-immunopositive. Expression was strong in 60 (44%), moderate in 39 (28%), and weak in 32 (24%). Male gonadotroph adenomas and null cell adenomas showed a high level of COX-2 expression. Growth hormone-producing adenomas, prolactin-producing adenomas, thyrotropic hormone-producing adenomas, female gonadotroph adenomas, silent adrenocorticotropic hormone-producing adenomas, and silent subtype 3 adenomas had a low level of COX-2 expression. Significant correlation was demonstrated with patient age, but not with tumor size, invasiveness, and MIB-1 labeling indices. Expression was medium to high in 76% of macroadenomas and in only 45% of microadenomas. Strong correlations were noted with angiogenesis markers, such as microvessel density and surface density. CONCLUSIONS: Correlation with angiogenesis suggests that COX-2 may be involved in the regulation of angiogenesis in pituitary tumors. Phamacologic inhibition of COX-2 activity might suppress angiogenesis in pituitary tumors and may provide a novel approach for medical therapy.

Adenoma↗
PubMed2003

Angiogenesis in normal and neoplastic pituitary tissues.

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.

Angiogenesis Inhibitors↗