G. Blaauw

Presence of progesterone receptors and absence of oestrogen receptors in human intracranial meningioma cytosols.

The occurrence of oestrogen and progestin receptors in cytosols from human intracranial meningiomas was studied with a dextran-coated charcoal assay and Scatchard plot analysis. [3H]-Oestradiol and [3H]-promegestone (17 alpha, 21-dimethyl-19-norpregna-4,9-diene-3,20-dione, R-5020) were used as tracers. Using this method, no high-affinity binding sites for oestradiol were observed, whereas progestin binding was identified in 18 out of 20 meningioma cytosols. The number of progestin binding sites was identical in meningioma cytosols obtained from female patients (192 +/- 57 fmol/mg protein, mean +/- S.E.M., n = 12) and those obtained from male patients (230 +/- 57 fmol/mg protein, n = 6), as was the dissociation constant of the complex (1.5 +/- 0.3 vs 1.4 +/- 0.3 nmol/l respectively). Only progestins (progesterone, R-5020 and megestrol acetate) competed successfully with tritiated R-5020. Oestrogens, androgens and cortisol showed no appreciable cross-reaction. It was concluded that the cytosols from human intracranial meningiomas contain progesterone receptors in the absence of oestrogen receptors. The presence of these progesterone receptors may indicate that (anti)-progestational treatment could be of potential value in cases which cannot be treated by surgery alone.

Sex steroid receptors in human meningiomas

SummaryResults of experiments on the presence of steroid receptors in a series of 67 meningioma tissues, which were derived from 64 patients are presented. All tissues were studied using dextran-coated charcoal adsorption and Scatchard plot analysis. Progestin receptors were present in a high concentration in more than 80% of the specimens. Very low concentrations of an oestrogen binding agent were found in a limited number of samples. Thus, most meningiomas contain high levels of progestin receptors in the virtual absence of oestrogen receptors. Relations were not observed between progestin receptor-content and the age and sex of the patients, or the location and the histological type of the tumour. The role and action of progestin on meningiomas is still unknown. The presence of progestin receptors, however, suggests that meningioma may be regarded as a true target tissue for progestins.

Progestin and Estrogen Receptors in Human Meningioma

Progestin receptors (PR) were detected with a dextran-coated charcoal assay and Scatchard plot analysis in 40 of 45 cytosols from human meningioma. The mean PR level in samples from female patients (297 ± 104 fmol/mg protein; mean SEM; n = 28) was not different from that in samples from male patients (190 ± 76; n = 12), No differences were observed in the PR content of meningiomas resected from different locations. In the three cases studied, nuclear progestin binding was also detected. An estrogen-binding component was detected in the cytosol of 7 of 44 samples, but the binding capacity was relatively low (13 ± 13 fmol/mg protein; mean ± SD). During isoelectric focusing only part of this binding component behaved as might be expected from a true estrogen receptor. Nuclear estrogen binding was not observed in two samples with detectable cytoplasmic estrogen binding. The presence of both cytoplasmic and nuclear PR suggests that in meningioma a functionally active progestin-receptor system comparable with that in other progestin target tissues is operating. In contrast to these other tissues, however, the synthesis of PR in meningioma may not be influenced by estrogens. Further research should focus on evaluating whether the growth rate of meningiomas can be modulated by antiprogestins.

Oestrogen receptor independent expression of progestin receptors in human meningioma—a review

Human meningiomas are rich in progestin receptors (PR), which are expressed in this tissue in an oestrogen independent fashion. In the search for an explanation of this observation, the existence of a protein in human meningioma cytosol which is capable of binding to a synthetic oestrogen responsive element (ERE) has been demonstrated. Using reverse transcriptase, PCR mRNA encoding for the wild-type oestrogen receptor (ER) was found. In addition, several splice variants of ER mRNA have been identified in human meningioma tissue, including variants lacking exons 4, 5 and 7. We found the ER delta 4 protein to have no transcriptional activity and the ER delta 7 protein reportedly is dominant negative. These mutants therefore probably are not responsible for the autonomous PR synthesis in human meningioma. The ER delta 5 protein, by contrast, has been reported to have oestrogen independent transcriptional activity and it is tempting to speculate that this protein is similar or identical to the ERE binding protein we have found in human meningioma. The role of wild type ER mRNA is presently unclear. Activation of other signal transduction pathways in meningioma does not lead to an increased PR concentration. The promoter area of the meningioma PR gene should be investigated for the possible sensitivity to other transcription factors.

Progesterone Receptor, Bcl-2 and Bax Expression in Meningiomas

Meningiomas are generally benign central nervous system neoplasms, which frequently express progesterone receptor (PR) and only rarely express the estrogen receptor (ER). For breast cancer, a relation between steroid hormone receptors and proteins involved in the apoptotic process has been described. For meningiomas, the exact relation between PR and these proteins is not known. In this study, ER, PR, bcl-2 and bcl-2-associated × protein (Bax) expression levels were determined in meningioma cytosols. As a reference for our experimental conditions, we also determined these proteins in breast cancer cytosols.PR and ER were determined with a ligand-binding assay and scatchard-plot analysis. The expression levels of the anti- and pro-apoptotic proteins, bcl-2 and Bax, respectively, were determined by immunoblotting.In 65% of the meningioma, bcl-2 expression was found in variable amounts. In contrast to breast cancer, a significant negative association between PR and bcl-2 was found (P < 0.01). Bax expression appeared nobreak constitutive, not related to PR, and 2.6 times higher than breast cancer.As both PR and bcl-2 appear positively associated with prognosis, the negative relationship between bcl-2 and PR found in this study might have some biological and clinical significance.

TP53 mutations in human meningiomas

Overexpression of p53 has been reported to play a role in the development of neoplasms of the central nervous system. Meningiomas are generally benign intracranial tumors originating from the meninges. Overexpression of the p53 protein in meningiomas and an association with histological type and recurrence has been reported. Mutation of the TP53 gene leads to a more stable p53 protein in quantities high enough for detection by immunohistochemistry. In the search for these mutations the core domain of the TP53 gene of meningiomas has been analyzed. Only a very low incidence of mutations was reported. The apparent discordance between overexpression of p53 protein and TP53 gene mutations may be explained by mutations located outside the core domain. This issue was addressed in the present study. All 11 exons of 17 meningiomas were analyzed for DNA alterations by PCR single-strand conformation polymorphism (PCR-SSCP) analysis with subsequent sequencing. PCR-SSCP analysis showed a various number of band shifts and nucleotide alterations, caused either by alterations in the flanking introns or common polymorphisms (codon 36 and 72). The allele frequencies of the polymorphisms found in this small population of tumors resemble the frequencies reported in the literature. In addition, three nucleotide changes located in introns 2, 3 and 7 were found in 11, 3 and 4, respectively, of 17 specimens. Based on this study and on reports by others we conclude that it is not very likely that TP53 mutations are involved in the etiology of meningiomas.

Influence of transsphenoidal hypophysectomy on visual deficit due to a pituitary tumour.

SummaryThe effect of transsphenoidal hypophysectomy is presented in 60 patients with visual impairment due to a pituitary adenoma, derived from a total series of 194 patients. The preoperative visual acuity and visual fields were compared with those one year after operation.The visual field loss was estimated using a semi-quantitative method. Seventy-two eyes had diminished visual acuity, and this improved in 45 eyes (63%). Visual field loss was present in 102 eyes and this improved in 71 eyes (70%). Improvement of either visual acuity and/or visual field was found in 84 eyes (78%). In 16 patients (27%) vision became normal after operation. Improvement of the visual acuity was usually accompanied by an improvement in the visual fields.

Histogenesis of intracranial haemangiopericytoma and haemangioblastoma

SummaryAn immunohistochemical study was performed on three meningeal haemangiopericytomas and four cerebellar haemangioblastomas (paraffin embedded) in an attempt to elucidate the uncertain histogenesis of these tumours. The tumour cells of all meningeal haemangiopericytomas show no expression of α-smooth muscle actin and, thus, no immunohistochemical proof of their true pericytic nature can be obtained. The stromal cells of cerebellar haemangioblastomas show foci of positive staining for S-100 protein, neuron-specific enolase and synaptophysin, thereby clearly indicating their neuroectodermal origin. These results allow the conclusion that the present nomenclature of these tumours is at least arguable and probably incorrect.

Progesterone receptor synthesis in human meningiomas: relation to the estrogen-induced proteins pS2 and cathepsin-D and influence of epidermal growth factor, Forskolin and phorbol ester in vitro.

Autonomous expression of progesterone receptors (PR) in human meningiomas is well established. To evaluate whether, similar to progesterone receptors, other estrogen-inducible proteins are also autonomously expressed in meningiomas, concentrations of pS2 and cathepsin-D (Cath-D) were measured in 52 meningiomas. No pS2 protein was detectable in 52/52 tested meningiomas. The Cath-D protein was measurable in all 52 meningiomas, but the mean concentration of Cath-D in meningioma cytosols was 2.4-fold lower than that of a group of 54 breast tumors (p < 0.001). These results indicate that autonomous expression is a PR-related rather than an estrogen receptor-related phenomenon and, consequently, that estradiol is probably not responsible for PR synthesis in human meningiomas. To evaluate the role of other, non-estradiol-dependent signalling pathways in PR synthesis, the effects of EGF, Forskolin and phorbol ester on PR synthesis were tested in vitro. No PR was detectable after the addition of EGF to six different primary cultures. Forskolin and TPA addition caused a morphological change in meningioma cells, but did not induce PR or pS2 synthesis in two different primary meningioma cultures. We conclude that PR synthesis in human meningiomas cannot be triggered by switching on the signalling pathways activated by these growth factors.

Cranial extradural cyst

SummaryA large skull defect due to an extradural collection of clear and colourless fluid in a 59-years-old man is described. Hesitantly, we consider this to be the consequence of skull erosion due to Pacchionian granulations.