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1.
Vascular Endothelial Growth Factor (VEGF) Expression in Human Pituitary Adenomas and Carcinomas 总被引:4,自引:0,他引:4
Lloyd RV Scheithauer BW Kuroki T Vidal S Kovacs K Stefaneanu L 《Endocrine pathology》1999,10(3):229-235
Vascular endothelial growth factor (VEGF) is a key mediator of endothelial cell proliferation, angiogenesis, and vascular
permeability. Little is known about its expression in human pituitary adenomas.
We examined 148 human pituitary adenomas for VEGF protein expression by immunohistochemistry. The strongest immunoreactivity
was present in GH adenomas, corticotroph, silent corticotroph, silent subtype 3, and nononcocytic null cell adenomas. GH adenomas
treated with octreotide strained less intensely than did untreated tumors. Relatively weak staining was present in PRL, gonadotroph,
thyrotroph, and oncocytic null cell adenomas in the same sections showed evidence of down-regulation of VEGF protein expression
in adenomas. Pituitary carcinomas usually had stronger staining than adenomas.
In situ hybridization studies with oligonucleotide probes showed positive staining in all groups with stronger staining in
GH, ACTH, TSH, and gonadotroph adenomas and in pituitary carcinomas.
These results indicate that VEGF expression is more prominent in certain adenoma subtypes, that decreased expression occurs
in adenomas as compared to nontumorous pituitary and that carcinomas show increased VEGF expression relative to adenomas suggesting
up-regulation of VEGF during pituitary tumor progression. 相似文献
2.
Immunohistochemical analysis of tumor angiogenic factors in human pituitary adenomas 总被引:4,自引:0,他引:4
Microvessel density (MVD) has been studied in a number of neoplasias, and apparently, there is a relationship between angiogenesis and tumor progression, response to treatment, and outcome. In pituitary adenoma, the association between MVD and vascular endothelial growth factor (VEGF) with tumor behavior has been described, but correlation with other angiogenic factors such as fetal liver kinase 1 (Flk-1) or proliferative markers is unknown. We investigated MVD, VEGF, and its receptor Flk-1 expression in 60 human pituitary adenomas: 13 growth hormone cell adenomas, 7 prolactin cell adenomas, 5 corticotroph cell adenomas, 2 thyrotroph cell adenomas, and 33 nonfunctioning adenomas (30 gonadotroph cell adenomas and 3 null cell adenomas). We performed immunohistochemistry for CD34, Ki-67, VEGF, and Flk-1. To evaluate MVD, we used 2 methods: the number of vessels per square millimeter and the Chalkley method. Immunohistochemistry results were correlated, as well as with clinicopathologic factors. Adenomas with higher MVD were thyrotroph cell adenomas (299.9 +/- 87.5), and those with lower MVD were prolactin cell adenomas (168.6 +/- 63.3; P = .45, analysis of variance). We found a trend toward higher MVD in the adenomas of older patients (P = .142), but no difference was found regarding sex, extrasellar extension, or Ki-67 (P > .05). However, extrasellar extension was nearly significant when the Chalkley method score was high (P = .056). Low expression of VEGF was seen predominantly in prolactin cell adenomas, and high in nonfunctioning adenomas, or in cases of older patients (P < or = .032). Flk-1 score correlated with VEGF (P = .006). High expression was observed in nonfunctioning adenomas, cases presenting at older ages, and with extrasellar extension (P < or = .022). Our study shows that VEGF and Flk-1 are widely expressed in pituitary adenomas, predominantly in nonfunctioning adenomas and those presenting at older ages. Moreover, Flk-1 is associated with a more aggressive phenotype, and it may have potential therapeutic interest. 相似文献
3.
4.
Correlation between tumor vascularity and clinical findings in patients with pituitary adenomas 总被引:4,自引:0,他引:4
Angiogenesis generally plays an essential role in tumor growth and metastasis, and also influences the response to treatment
in human malignant solid tumors. Even in nonmalignant tumors, angiogenesis is essential for tumor growth and invasion. In
order to define the relationship between tumor vascularity and the clinical course in patients with pituitary adenomas, we
quantified the vascularity in 47 pituitary adenomas and in 6 normal anterior pituitary glands obtained at autopsy using a
computed image-analyzing system. We estimated two parameters, the vascular number and the area as the vascularity. Additionally,
we calculated mean individual vessel size using the above two parameters. The relationships of tumor vascularity to clinical,
endocrinological and histological findings was assessed. Factors considered included patient age and gender, preoperative
medication, histological type, concentration of each hypersecreted pituitary hormone, maximum tumor size, cavernous sinus
invasion, intratumoral hemorrhage, and immunohistological results of localization of vascular endothelial growth factor (VEGF).
Vascularity was significantly higher in normal glands than in pituitary adenomas. However, there were no significant correlations
between tumor vascularity and other clinical, endocrinological, or histological parameters, suggesting that increased angiogenesis
is not essential for pituitary adenoma growth or invasiveness. 相似文献
5.
Minematsu T Suzuki M Sanno N Takekoshi S Teramoto A Osamura RY 《Endocrine pathology》2006,17(2):143-153
6.
Takashi Yamamoto Yasuko Nishizawa Motomu Tsuji Youichi Saitoh Hiroko Funai Tatsuya Hirai Ayako Sugihara Tohru Tsujimura Yasuo Nakata Shingo Ishiguro Nobuyuki Terada 《Endocrine pathology》1999,10(2):157-164
Vascular endothelial growth factor (VEGF) induces endothelial cell proliferation and an increase in capillary permeability.
Because the anterior pituitary gland and pituitary adenomas are highly vascular, expression of VEGF was examined immunohistochemically.
Some normal pituitary cells stained positively for VEGF, and restaining for ACTH, prolactin, TSH, LH, FSH, and S-100 protein
after VEGF staining revealed that almost all cells staining positively for ACTH also stained for VEGF. Only adenomas staining
positively for ACTH stained for VEGF. These results suggest that VEGF is produced by normal pituitary cells and adenomas producing
ACTH. 相似文献
7.
Pituitary adenomas and granular cell tumors. Incidence, cell type, and location of tumor in 100 pituitary glands at autopsy. 总被引:2,自引:0,他引:2
Incidentally detected pituitary adenomas were investigated in 100 pituitary glands at autopsy to determine the number, cell type, and location of tumors, and the presence of coexisting granular cell tumors in the neurohypophysis. Pituitary glands were sagittally sectioned at 1.5-mm intervals in toto and embedded in 1 cassette to orient location of each tumor. Twenty-four pituitary glands harbored adenomas, most smaller than 3 mm and the largest 6 x 5 x 4 mm. Two pituitary glands contained double adenomas of immunocytochemically different cell types. Of the 26 adenomas, 10 had lactotrophs, 2 had mixed lactotrophs-somatotrophs, 1 had mixed lactotrophs-luteinizing hormone cells, and 12 were nonfunctioning. One adenoma with adenocorticotropic hormone cells was also detected. Thus 25 of 26 (96%) adenomas were either lactotrophic or nonfunctioning; this percentage is much higher than that of surgically resected tumors. Twenty-two tumors were contiguous with or adjacent to the capsule from which the adenomas originated. Nine granular cell tumors were noted in the neurohypophysis; 3 coexisted with pituitary adenomas. Fourteen additional cases revealed small granular cell nests. Thus the incidental finding of nonfunctioning pituitary adenomas is relatively common in adults (24% of cases in this study), and the coexistence of pituitary adenomas and granular cell tumors may suggest a possible histogenic connection between anterior and posterior pituitary tumorigenesis. 相似文献
8.
Microvessel density in pituitary adenomas and carcinomas 总被引:12,自引:0,他引:12
Vidal S Kovacs K Horvath E Scheithauer BW Kuroki T Lloyd RV 《Virchows Archiv : an international journal of pathology》2001,438(6):595-602
Tumor growth depends on several factors, including angiogenesis. Tumors cannot grow if new vessels are not formed to supply the cells with oxygen and other nutrients and to remove waste products. Increased angiogenesis can be correlated with tumor growth and metastatic potential in many tumor types, indicating that neoformation of vessels is a prognostic indicator of tumor behavior. We evaluated microvessel densities in 157 various pituitary adenoma types and seven pituitary carcinomas using immunocytochemistry for CD-34 antigen, a reliable marker of endothelial cells. The lowest percentage of microvessel density was found in growth hormone-producing adenomas, the highest level in pituitary carcinomas. In general, no major correlation was found between MIB-1 index (an indicator of cell proliferation) and microvessel density. The statistical study also demonstrated no gender-dependent changes in the microvessel density of pituitary tumors. Although the microvessel density was not significantly different in relation to invasiveness of pituitary tumors, our results demonstrate a tendency of invasive pituitary tumors to be more highly vascularized than non-invasive ones. Dopamine agonist and long-acting somatostatin analog treatment compared with untreated tumors did not significantly affect microvessel densities. Statistical differences were demonstrated in the microvessel density of macroadenomas between patients older and patients younger than 40 years. Significant differences were also apparent in the microvessel densities between microadenomas and macroadenomas diagnosed in young patients but not in the older age group. The strongly positive correlation observed between microvessel density and age is consistent with the view that age of the host may have an influence on the extent of neovascularization of pituitary adenomas. 相似文献
9.
Vasculature in Nontumorous Hypophyses,Pituitary Adenomas,and Carcinomas: A Quantitative Morphologic Study 总被引:3,自引:0,他引:3
Vascular supply is essential for tumor proliferation and metastasis formation. Correlation was noted between vascular density
and tumor size as well as metastases in several tumor types. The aim of the present study was to assess vascular density in
nontumorous hypophyses, pituitary adenomas, primary pituitary carcinomas, and carcinomas metastatic to the pituitary.
Twenty nontumorous hypophyses, 87 endocrinologically active or inactive pituitary adenomas, 8 primary pituitary carcinomas,
8 metastatic carcinomas, and 10 randomly selected noninvasive and 6 invasive adenomas were included in the study. Tissues
were fixed in formalin, embedded in paraffin, cut, stained with hematoxylin and eosin, PAS, and immunostained for adenohypophysial
hormones as well as Factor VIII-related antigen using the streptavidin-biotin-peroxidase complex method Four counts were performed:
percentage of capillary area, number of vessels per field, percentage of endothelial cells, and number of endothelial cells
per field. The results show that pituitary adenomas have significantly lower vascular densities as compared to nontumorous
adenohypophyses. Prolactin-producing adenomas removed from untreated patients have the highest counts and growth hormone-producing
adenomas the lowest counts. However, the observed differences among adenoma types are not of statistical significance. No
differences are noted between noninvasive and invasive tumors. Primary pituitary carcinomas show no significant increase in
vascular densities. Some metastatic tumors exhibit high vascularity. It can be concluded that pituitary adenomas have a limited
capacity to induce angiogenesis. Lack of significant angiogenesis may play a role in the slow pace of pituitary tumor growth
and rarity of metastases. 相似文献
10.
11.
Katharina H. Ruebel BS Long Jin MD Shuya Zhang BS Bernd W. Scheithauer MD Dr. Ricardo V. Lloyd MD PhD 《Endocrine pathology》2001,12(3):281-289
Recent studies have shown that methylation of the CpG island within the p16/CDKN2A/MTS1 (p16) gene is associated with loss
of expression of p16 protein in pituitary tumors. We analyzed a series of 21 pituitary adenomas and three normal pituitaries
along with a human pituitary cell line (HP75) for methylation of exon 1 by methylation-specific PCR, immunohistochemistry,
and Western blotting. PCR analysis showed that 5/7 (71%) of null cell adenomas, but only 2/7 (29%) gonadotroph tumors were
hypermethylated. In addition, 1 of 2 ACTH tumors but no GH (n=4) or PRL (n=1) adenoma examined were hypermethylated. Immunostaining and Western blot analysis of protein expression supported the methylation-specific
PCR analyses.
These results show that p16 gene silencing by hypermethylation is more common in null cell adenomas compared to other nonfunctioning
adenomas such as gonadotroph tumors and that the role of p16 in the pathogenesis of pituitary adenomas is restricted to specific
tumor subtypes.
Supported in part by NIH CA90249 and by a grant from the Jarislowsky Foundation. 相似文献
12.
Immunohistochemical analysis of p27 (Kip1) in human pituitary glands and in various types of pituitary adenomas 总被引:3,自引:0,他引:3
Komatsubara K Tahara S Umeoka K Sanno N Teramoto A Osamura RY 《Endocrine pathology》2001,12(2):181-188
p27 (Kip1) plays regulatory roles in the cell cycle by inhibiting the activity of cyclin dependent kinases (CDKs). This immunohistochemical
study is aimed at elucidating the expression of p27 in human pituitary and in various types of pituitary adenomas in order
to clarify its role in the regulation of proliferation.
Sixteen normal pituitary glands and 179 human pituitary adenomas were used for immunohistochemical studies. The tissues were
fixed in 10% formalin and embedded in paraffin. Indirect peroxidase method was performed after heat-induced antigen retrieval
using a monoclonal antibody against p27 protein. p27 protein was expressed in the nuclei of all 16 normal human pituitary
glands. p27 protein was also expressed in 128 of 179 cases of pituitary adenomas (71.5%).
A marked decrease of p27 expression was noted in ACTH-secreting adenomas, 8/20 (40.0%), compared with other types of pituitary
adenomas—GH-secreting adenomas, 35/46 (76.1%); PRL-secreting adenomas, 22/33 (66.7%); TSH-secreting adenomas, 8/11 (72.7%);
and nonfunctioning adenomas, 55/69 (79.7%).
These results suggest that p27 may play some role in the regulation of proliferation in all types of pituitary adenomas. The
lower levels of p27 in ACTH-secreting adenoma is of particular interest with respect to the intermediate lobe-derived pituitary
tumor developed in p27 knockout mice. 相似文献
13.
Shereen Ezzat 《Brain pathology (Zurich, Switzerland)》2001,11(3):356-370
Numerous factors have been shown to govern adenohypophysial cell proliferation. Human and animal models have documented that the hypothalamic trophic hormone growth hormone-releasing hormone stimulates cell proliferation, and prolonged stimulation leads to tumor formation. Similarly, lack of dopaminergic inhibition of lactotrophs and lack of feedback suppression by adrenal, gonadal or thyroid hormones are implicated, perhaps through hypothalamic stimulatory mechanisms, in pituitary adenoma formation superimposed on hyperplasia. However, most pituitary tumors are not associated with underlying hyperplasia. Overexpression of growth factors and their receptors, such as EGF, TGFalpha, EGF-R and VEGF has been identified in pituitary adenomas, and reduction of follistatin expression has been implicated in gonadotroph adenomas. Aberrant expression of members of the FGF family, an FGF antisense gene and FGF receptors have all been described in pituitary adenomas. The clonal composition of pituitary adenomas attests to the molecular basis of pituitary tumorigenesis, however, the evidence suggests that these various hypophysiotropic hormones and growth factors likely play a role as promoters of tumor cell growth in genetically transformed cells. 相似文献
14.
To investigate whether adenohypophysial hormone expression is heterogeneous within individual clinically nonfunctioning pituitary
adenomas, immunohistochemical examinations were performed on tissues obtained by multiple sampling of 11 adenomas. Stained
sections were assessed by morphometric image analysis as well as semiquantitative estimation under microscopy. All tumors
except one were immunopositive for one or more gonadotropins. Results were divided into five grades based on the proportion
of immunoreactive cells per section. Semiquantitative estimation showed only a one-grade difference among samples from the
same tumor in four cases for FSHβ and in two cases for LHβ. These qualitative similarities between multiple samples were confirmed
by morphometric image analysis.
From the practical standpoint of making a diagnosis of nonfunctioning pituitary adenoma, it is not necessary to take into
account immunohistochemical heterogeneity within an individual tumor, and immunohistochemical findings in a given sample obtained
at surgery can be regarded as representative of the entire adenoma. 相似文献
15.
Toshiko Sumi Lucia Stefaneanu Kalman Kovacs Sylvia L. Asa Guido Rindi 《Endocrine pathology》1993,4(2):95-99
In many human cancers, p53 gene mutations are frequently occurring genetic abnormalities, which may be detected by immunohistochemical
staining for p53 protein. In the present study, p53 immunoreactivity was investigated in formalin-fixed, paraffin-embedded
tissues from human and animal pituitary tumors, using the avidin-biotin-peroxidase complex technique. No p53 was detected
in 3 nontumorous human adenohypophyses or in 40 human pituitary tumors including 5 GH cell adenomas, 10 PRL cell adenomas,
2 mixed GH cell-PRL cell adenomas, 2 acidophil stem cell adenomas, 8 ACTH cell adenomas, 1 TSH cell adenoma, 1 FSH/LH cell
adenoma, 5 null cell adenomas, 5 oncocytomas, and 1 plurihormonal adenoma. Twenty nontumorous and hyperplastic pituitaries
of hGRH transgenic mice and 8 tumors in these transgenic animals were immunonegative for p53. All pituitary tumors found in
AVP/SV40 transgenic mice contained p53 immunoreactivity in the nuclei, while the nontumorous adenohypophysis of one such transgenic
mouse was negative. It can be concluded that p53 mutations are apparently not involved in the pathogenesis of human pituitary
adenomas or of the pituitary tumors which develop in hGRH transgenic mice. However, pituitary tumors in AVP/ SV40 transgenic
mice are accompanied by p53 expression. 相似文献
16.
Growth index is independent of microvessel density in non-small-cell lung carcinomas 总被引:10,自引:0,他引:10
Tsoli E Zacharatos P Dasiou-Plakida D Peros J Evangelou K Zavras AI Yannoukakos D Konstantopoulou I Asimacopoulos PJ Kittas C Gorgoulis VG 《Human pathology》2002,33(8):812-818
Induction of angiogenesis is essential for carcinogenesis and facilitates the processes of tumor development and metastasis. Vascular endothelial growth factor (VEGF) is an important angiogenic regulator under physiologic and pathologic conditions. To elucidate the role of angiogenesis in malignant growth, we evaluated angiogenesis and VEGF expression in a panel of 68 non-small-cell lung carcinomas (NSCLCs) and examined their relation with the kinetic parameters, ploidy, and p53 protein status, which have been analyzed previously. Angiogenesis was estimated as microvascular density (MVD) of the tumor area by CD31 immunodetection. Expression of VEGF was also immunohistochemically evaluated. All possible associations were assessed through a series of statistical methods. The mean MVD value was 39 microvessels/mm(2), and high VEGF immunoreactivity was observed in all specimens, with a mean percentage of positive cells of 73%. The relation between MVD and VEGF expression was not statistically significant (P = 0.065). No association was observed between MVD or VEGF levels with the proliferation index, apoptotic index, tumor ploidy status, p53 expression, and overall survival. We conclude that in a subset of NSCLCs, angiogenesis may be associated with VEGF, but other factors also participate in this process. Angiogenesis and growth (proliferation and apoptosis) are independent and probably differentially operated procedures, with only growth partially controlled by p53 protein expression. 相似文献
17.
Jin L Riss D Ruebel K Kajita S Scheithauer BW Horvath E Kovacs K Lloyd RV 《Endocrine pathology》2005,16(2):107-114
Galectin-3 (Gal-3), a β 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 folliculostellate (FS) cells and
tumors [1,2] and that Gal-3 had an important regulatory role in pituitary cell proliferation [1]. 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. 相似文献
18.
Rab proteins are low molecular weight GTP-binding proteins. Among these proteins, the Rab3 isoforms are considered to be involved in the exocytosis of synaptic vesicles and secretory granules in the central nervous system and anterior pituitary gland. In recent reports, the expression of Rab3 isoforms in anterior pituitary glands of mammalian species was extensively investigated. In the present study, we investigated the localization of Rab3 protein in 5 human nontumorous pituitaries and 114 human pituitary adenomas using immunohistochemical methods. In five human nontumorous pituitaries, Rab3 protein was expressed in the cytoplasm of anterior pituitary cells. Double staining for anterior pituitary hormones revealed the expression of Rab3 in growth hormone-secreting cells, but rare expression was observed in the other anterior pituitary hormone-secreting cells. Among the pituitary adenomas, 71 (62.3%) of 114 pituitary adenomas were positive for Rab3. Among the different pituitary adenoma types, the incidence of Rab3 immunopositivity was highest in growth hormone-secreting adenomas (100%), followed by adrenocorticotropic hormone-secreting adenomas (71.4%), thyroid-stimulating hormone-secreting adenomas (57.1%), nonfunctioning adenomas (56.0%), and prolactin-secreting adenomas (33.3%). After an embedding immunoelectron microscopic study, Rab3 was localized along the limiting membrane of secretory granules in the Rab3-positive pituitary adenomas. Western blotting showed the molecular weight of Rab3 to be 25 kDa in the pituitary adenomas, which were immunohistochemically positive for Rab3 protein. These results suggested that Rab3 might be involved in regulating the exocytosis of secretory granules of the anterior pituitary cells, especially growth hormone-secreting ones, which are particularly characterized by densely granulated cytologic features. 相似文献
19.
Mucha SA Meleń-Mucha G Godlewski A Stepień H 《Virchows Archiv : an international journal of pathology》2007,450(3):335-341
The development of estrogen-induced pituitary prolactinoma in Fischer 344 (F344) rats is associated with enhanced neovascularization. Based on the significance of matrix metalloproteinases (MMPs) for tumor growth and angiogenesis, we have studied the effect of batimastat (BB-94), a synthetic MMPs inhibitor (MMPI) on the progression of prolactin-secreting pituitary adenoma in rats. Pituitary tumors were induced in male F344 rats by s.c. implantation of Silastic tubes containing diethylstilbestrol (DES). The effects of chronic treatment with BB-94 (30 mg/kg b.w.) on pituitary weight, cell proliferation, apoptosis and vascular density were evaluated. We have stated that chronic treatment with batimastat caused a significant reduction in the pituitary weight. Batimastat has been found to decrease cell proliferation evaluated by a number of PCNA-positive stained cell nuclei. A marked increase in the apoptotic index within the pituitary was observed in the study group. Moreover, the density of microvessels identified by CD31 was reduced in the group treated with BB-94. The results of our study provide evidence for an inhibitory effect of batimastat, a synthetic MMPI, on the growth and angiogenesis in an experimental model of human prolactinoma. The ability of BB-94 to suppress established pituitary tumor growth suggests a possible application of MMPIs in the treatment of pituitary adenomas. 相似文献
20.
Sneha Arya M.A. Majaid S.D. Shwetha K. Sravani A. Arivazhagan S. Sampath V. Santosh 《Pathology, research and practice》2014