Topoisomerase II alpha as a reliable proliferation marker in meningiomas

The value of DNA Topoisomerase IIalpha expression as a proliferation marker in meningiomas was investigated. The correlation to MIB-1 expression and tumor grade in 85 meningiomas (60 classical, 19 atypical and 6 anaplastic) was analysed by immunohistochemistry. MIB-1 labeling indices (LI) were 1.1% (+/- 0.85) for classical meningiomas, 1.9% (+/- 1.5) for atypical meningiomas and 5.6% (+/- 4.1) for anaplastic meningiomas, differences statistically significant (p = 0.03, < 0.0001, < 0.0001). Topoisomerase IIalpha LIs were 1.4% (+/- 1.2) for classical, 3.2% (+/- 2.4) for atypical and 9.7% (+/- 6.6) for anaplastic meningiomas, differences statistically significant (p = 0.003, < 0.0001, < 0.0001). Proliferation indices based on cells staining for MIB-1 and Topoisomerase IIalpha correlated highly with one another (r= 0.906, p <0.0001). Topoisomerase IIalpha exhibited a more distinct, less variable nuclear staining pattern compared to MIB-1 expression. DNA Topoisomerase IIalpha LI represents a reliable alternative to MIB-1 as a proliferation marker in human meningiomas, especially for computer assisted assessment, where a distinct uniform staining pattern is required.     

Proliferation and Dna fragmentation in meningioma subtypes

H. Maier, J. Wanschitz, R. Sedivy, K. Rössler, D. Öfner and H. Budka (1997) Neuropathology and Applied Neurobiology 23, 496–506 Proliferation and DNA fragmentation in meningioma subtypes Atypical meningioma has been introduced as tumour subtype of intermediate biological behaviour between classical and malignant meningiomas. To substantiate this three-step scale of malignancy, we assessed the proliferative activity reflected by Ki-67 (MIB1) labelling index (LI) in a series of 89 meningiomas, including 15 classical, 29 atypical, 35 anaplastic tumours, and 10 haemangiopericytomas and papillary meningiomas. The possible correlation of proliferation with the frequency of apoptosis and their relations to BCL-2 immunoexpression was investigated in seven classical, 10 atypical and 10 malignant meningiomas. Apoptosis was demonstrated by evaluation of the frequency of apoptotic figures, by the enzymatic technique of in situ tailing (IST) which stains apoptotic DNA fragments, and by DNA preparation and gel electrophoresis demonstrating DNA laddering in frozen tissues of five meningiomas. MIB1 LI revealed a highly significant increase from classical through atypical to anaplastic meningiomas (P 0.0001); haemangiopericytomas and papillary meningiomas were well within the range of atypical meningiomas. IST indices rose with increasing malignancy and correlated with MIB1 LI (P 0.0001); they showed a weak inverse correlation with BCL-2 immunoexpression (P= 0.05). BCL-2 expression tended to decrease with malignancy grade and was unrelated to MIB1 LI or frequency of apoptosis. Our data show that (i) apoptosis is a feature of meningiomas, significantly correlated with the malignancy scale, (ii) DNA fragmentation shows significant correlation with proliferation and inversely with BCL-2 expression; (iii) proliferation indices and frequencies of apoptosis/DNA fragmentation within meningioma subgroups corroborate the intermediate biological position of the atypical meningioma between classical and malignant meningiomas.     

Correlation of steroid receptors and growth factors expression with peritumoral edema accompanying cerebral neoplasms

The aetiology of peritumoral brain oedema still remains unclear, despite investigations, attempted to study the role of various clinical factors and histological features of the tumour. The aim of this investigation was to the evaluate correlation of peritumoral brain oedema with expression of progesterone (PR) and oestrogen (ER) receptors and vascular--endothelial growth factor (VEGF). Eighty nine samples of brain tumours were examined, among them 28 meningiomas, 43 gliomas and 18 metastatic tumours. Expression of steroid receptors was examined with the radioreceptor assay method and expression of VEGF by radioimmune assay. A statistically highly significant correlation was found of VEGF expression with the incidence of diffuse pattern of brain oedema around gliomas and metastatic tumours (p < 0.01). PR expression was associated significantly with the occurrence of localized type of oedema around meningiomas, but in gliomas the expression of this receptor correlated with a diffuse pattern of oedema. No correlation was found between ER expression and peritumoral brain oedema.     

The morphological analysis of vasculature and angiogenic potential in meningiomas: immunoexpression of CD31 and VEGF antibodies

Meningiomas, despite being the mostly well-differentiated tumours, are quite often characterised by invasive growth and recurrences. As this fact may be caused by proangiogenic factors, we have investigated immunoexpression of CD31 and vascular endothelial growth factor (VEGF) in these tumours. The materials included 10 atypical meningiomas (G2), and the following subtypes of benign meningiomas (G1): 21 transitional, 17 meningothelial and 13 fibrous. Paraffin sections were immunostained with CD31 (DAKO) and VEGF (Santa Cruz) antibodies. The highest number of blood vessels was revealed in atypical meningiomas and much lower (statistically significant difference) in benign ones. Diffuse or focal expression of VEGF of various intensity was shown both in atypical and benign types of tumours with no statistically significant differences between both groups of tumours and between subtypes of benign meningiomas.     

Morphometrical analysis of nucleolin immunohistochemistry in meningiomas

Nucleolin (110 kDa) is a major nucleolar protein in eukaryotic cells and one of the nucleolar organizer region (NOR)-associated proteins. We studied immunohistochemically 32 cases of meningioma, using specific antisera against nucleolin, and analyzed various nucleolin parameters, such as the number of regions and the total area of nucleolin staining per nucleus. The mean number and area of nucleolin stainings per nucleus were compared with the histological malignancy and Ki-67/MIB-1 proliferation index; the correlation with parameters of silver-stained NOR (AgNOR) was also studied. The results showed that there were statistically significant differences in the mean number and area of nucleolin stainings per nucleus between meningiomas and other two groups, atypical and anaplastic meningiomas (P < 0.05), although there was no difference between atypical and anaplastic meningiomas. The mean number and area of nucleolin stainings per nucleus were correlated with the incidence of Ki-67 positivity and AgNOR area. In view of the technical problems inherent in AgNOR staining, immunohistochemistry for nucleolin may represent a more specific and reproducible means for NOR visualization and be a promising technique for assessing cell proliferation. Received: 4 September 1995 / Revised, accepted: 20 December 1995     

DNA content is associated with malignancy of intracranial neoplasms

Objective

Flow cytometry has been applied to analyze the DNA-content distribution of tumors, in order to relate this to clinical and biological parameters of tumor behavior. Herewith, we investigated the value of cell cycle analysis in the characterization of intracranial lesions and its possible prognostic role.

Methods

DNA analysis was performed in tumor samples that were taken during surgery over a five year period. Diagnosed tumors were graded according to the World Health Organization 2007 classification scheme.

Results

Fifty-six patients were included in the study. There was a significant difference in G₀/G₁ phase and S-phase between low-grade and high-grade gliomas. There were 12 (57%) diploid and 9 (43%) aneuploid tumors. All aneuploid tumors were glioblastomas. Patients with G₀/G₁ value ≤69% and S phase value greater than 6% were associated with worse survival. As regards meningiomas, there was a significant difference in G₀/G₁ phase, S phase and mitoses fraction between benign and both atypical and anaplastic meningiomas. Aneuploidy was observed in the anaplastic tumors and in 2/4 atypical meningiomas.

Conclusion

The results of the present study, showed that cell cycle analysis could differentiate low from high grade gliomas and benign from atypical/anaplastic meningiomas. Furthermore, a prognostic significance was found in glioma patients. The role of cell cycle analysis in brain tumors thus warrants further investigation.     

Deletion mapping of the short arm of chromosome 1 identifies a common region of deletion distal to D1S496 in human meningiomas

We have studied a series of 63 meningiomas, including 47 benign meningiomas (World Health Organization, WHO, grade I), 13 atypical meningiomas (WHO grade II) and 3 anaplastic meningiomas (WHO grade III), using microsatellite and restriction fragment length polymorphism analysis for loss of heterozygosity (LOH) at 21 polymorphic loci on chromosome 1 (19 loci on 1p and 2 loci on 1q). LOH on 1p was found in 9 of 13 atypical meningiomas (70%) and in 3 of 3 (100%) anaplastic meningiomas, but only in 6 of 47 (13%) benign meningiomas. In 13 tumors allelic loss was observed at all informative loci on 1p. Terminal deletions with retention of heterozygosity at one or more proximal 1p loci were found in 5 tumors. The region commonly deleted in all tumors was located distally to the D1S496 locus, i.e., at cytogenetic bands 1p34 – 1pter, and included the chromosomal segment which is frequently deleted in neuroblastoma, malignant melanoma, and different types of carcinoma. Received: 11 February 1997 / Revised: 9 May 1997 / Accepted: 12 May 1997     

Anaplastic meningioma: Progression from atypical and chordoid morphotype with morphologic spectral variation at recurrence

The current WHO 2007 classification divides meningiomas into a 3‐grade prognostic hierarchy. Recent literature evokes two pathways to disease progression in meningiomas akin to a comparable paradigm in gliomas, but without similar prognostic connotation: de novo anaplastic meningioma (better prognosis), and transformed meningioma (worse prognosis). We present two adult cases of transformed meningiomas that display a spectrum of morphologic progression. Case 1 at presentation showed a random admixture of meningothelial, atypical and anaplastic meningioma. The tumor recurred as anaplastic meningioma. Case 2 presented as a chordoid meningioma, but recurred as anaplastic meningioma mainly at the invasive front in transition with residual chordoid pattern. Of interest, portions of tumor also showed papillary configuration. In accordance with the dire prognosis for anaplastic meningioma, both patients succumbed to their disease within 2 months of recurrence. The present study highlights two main points: First, that proper recognition of focal high‐grade areas in a heterogeneous low‐grade meningioma (case 1) provides critical morphologic clues to spatial histologic progression and predicts aggressive biologic behavior, as evidenced by progression to frankly anaplastic meningioma at recurrence. Second, the presence of papillary in addition to anaplastic areas, in the recurrence of a previously diagnosed chordoid meningioma supports the ostensibly heightened transforming potential of grade II meningiomas, but also reflects on the morphologic heterogeneity of high‐grade meningiomas, and their potentially diverse pathways of progression. We propose that grading of meningiomas as outlined by WHO is of more critical prognostic import than histologic sub‐typing, and must include a thorough survey of the tumor‐brain interface. Future molecular genetic correlates, akin to those characterized in gliomas, could help stratify prognostic subcategories to refine meningioma grading, and govern optimal therapeutic strategies.     

Vascular endothelial growth factor expression in cerebral neoplasms

Angiogenesis plays an important role in growth of neoplasm. Among a variety of proangiogenic agents, vascular endothelial growth factor (VEGF) is regarded as a crucial mediator of tumour angiogenesis. It acts in a paracrine way through the receptors localised in endothelial cells. Many authors maintain that rich vasculature of the neoplasm is associated with its malignant nature. The aim of this study was to examine the relations between expression of VEGF and features of malignancy of brain tumours. Sixty-seven samples of brain tumours were examined: 17 meningiomas, 34 gliomas and 16 metastases to the central nervous system. Expression of VEGF was estimated by radioimmune assay. The authors confirmed the presence of this factor in all types of tumours but the highest concentration of VEGF was found in high-grade gliomas.     

Characterisation of molecular alterations in microdissected archival gliomas

Classification of gliomas according to their molecular characteristics may be important in future histopathological diagnosis. However, gliomas frequently display heterogeneity at the histological, biological and molecular level. In this study of archival diagnostic gliomas, precision microdissection was used to enrich samples in the most malignant cells or to investigate intratumoural histological heterogeneity. Analysis of tumour samples microdissected from the most aggressive regions, representative of the histopathological diagnosis, revealed PTEN mutations in 4/14 anaplastic astrocytomas, 4/13 glioblastomas and 1 gliosarcoma, but not in 19 low-grade gliomas. Using a novel PCR procedure and direct sequence analysis of the entire coding sequence, TP53 mutations were detected in 1/3 pilocytic astrocytomas, 3/13 astrocytomas, 4/14 anaplastic astrocytomas, 5/13 glioblastomas and 1 gliosarcoma. All but one of the tumours with TP53 mutation showed p53 immunopositivity, but 5 low-grade and 10 high-grade gliomas had p53 protein nuclear accumulation in the absence of detectable mutation. p53 status was unrelated to p21 expression. Neither PTEN nor TP53 mutations influenced the proliferative index or microvessel density of high-grade astrocytomas. Unusual findings include: TP53 mutation in a juvenile pilocytic astrocytoma; TP53 and PTEN mutations in a de novo glioblastoma, a gliosarcoma with identical mutations in gliomatous and sarcomatous components, and an infratentorial anaplastic astrocytoma with an earlier supratentorial grade II astrocytoma bearing the same TP53 mutation but not the PTEN mutation or loss of heterozygosity (LOH) of 10q23. Similarly, the transition to high-grade histology was associated with acquisition of PTEN mutations and 10q23.3 LOH in two de novo high-grade tumours with regions of low-grade histology.     

端粒结合蛋白-1在脑胶质瘤中的表达及临床意义

目的探讨端粒结合蛋白-1(TRF-1)在不同级别脑胶质瘤及正常脑组织中的表达及其临床意义。方法选取58例脑胶质瘤和10例脑外伤内减压脑组织石蜡切片标本作为研究对象,应用免疫组化技术检测各组TRF1的表达水平,应用半定量法计算不同标本肿瘤细胞免疫标记的频率和强度积分。结果共58例不同级别胶质细胞瘤,其中低度恶性组(WHOⅠ、Ⅱ级)27例,高度恶性组(WHOⅢ、Ⅳ级)31例,10例脑外伤病人内减压脑组织作为正常对照。在所有胶质瘤组织及正常脑组织中均检测到TRF1表达,其中正常脑组织中TRF1表达高积分构成比90.00%,低度恶性胶质瘤组(WHOⅠ、Ⅱ级)的TRF1表达高积分构成比62.96%,高度恶性胶质瘤组(WHOⅢ、Ⅳ级)29.03%。统计分析发现,TRF1在不同级别胶质瘤中的表达与其恶性程度成负相关。结论在人脑胶质瘤和正常脑组织均有TRF1的广泛表达,其在不同级别脑胶质瘤中的表达水平与其恶性程度负相关,即随肿瘤的恶性程度的增高出现表达下调,TRF1可作为脑胶质瘤临床病理分级和恶性程度判断的参考指标。     

Flow-through fluorocytophotometry of different brain tumours

Summary The flow-through cytophotometric method was used to investigate the single-cell DNA content in 60 tumours of the CNS and allied structures (9 meningiomas, 5 ependymomas, 15 astrocytomas, 11 anaplastic astrocytomas, 8 glioblastomas, 7 medulloblastomas, 2 oligodendrogliomas, 1 anaplastic oligodendroglioma, and 2 neurinomas). The cytophotometric parameters were correlated with morphological and clinical data of the tumours. The results are summarised in Tables 1–7. With regard to the DNA content of their cell nuclei, the gliomas present a behaviour similar to tumours in other organs, but in the present study the cytophotometric signs of malignancy in gliomas are not so evident as in carcinomas or sarcomas. The information obtained by flow cytophotometric methods may be helpful in diagnosing the degree of malignancy in brain tumours.     

Atypical (anaplastic) meningioma: relationship between histologic features and recurrence--a clinicopathologic study

Two-hundred-and-eighty meningiomas of the surgical pathological files of the Taipei Veterans General Hospital from the period 1976-1986 were reviewed by the authors without prior knowledge of clinical circumstances or outcome. Thirty-four cases were regarded as atypical or anaplastic based on high cellularity, pleomorphism and the presence of mitotic figures with 6 cases showing only the above features and the remaining 28 displaying in addition one or more of the following "ominous" variables: papillary formation, necrosis and invasion of the underlying brain. With a median follow-up of three years after surgery the recurrence rate was 44% (15 cases) for this group of tumors whereas the remaining 246 histologically benign meningiomas had a 6% recurrence rate during the same period. This difference was statistically significant (p less than 0.0001). Once the atypical or anaplastic character of a meningioma was established, no difference in the recurrence rate was found related to the number of mitoses and whether the additional ominous variables were present, alone or in conjunction with others. Immunostaining for vimentin, S100, fibronectin and EMA showed variable results in the 34 atypical meningiomas but without significant difference between those that recurred within 3 years and the ones that did not.     

IL-17及IL-17R在人脑胶质瘤中的表达

目的探讨IL-17及IL-17R在人正常脑组织、低级别胶质瘤、高级别胶质瘤中的表达,及其与胶质瘤级别的关系。方法正常脑组织、低级别胶质瘤、高级别胶质瘤标本分别20、23、22例,采用PCR法检测IL-17mRNA,PCR法及原位杂交法检测IL-17RmRNA,免疫组化法检测IL-17蛋白在各组中的表达。结果 IL-17mRNA在各组中仅见微量表达;IL-17RmRNA在各组中的表达无明显差异(P0.05);蛋白IL-17的表达在正常脑组织、低级别胶质瘤、高级别胶质瘤中依次增高,各组间差异均具有统计学意义(P0.05)。结论蛋白IL-17可能在胶质瘤的发生、发展中起重要作用。     

Clinical Implications of the Mitotic Index as a Predictive Factor for Malignant Transformation of Atypical Meningiomas

ObjectiveIntracranial atypical meningiomas have a poor prognosis and high rates of recurrence. Moreover, up to one-third of the recurrences undergo high-grade transformation into malignant meningiomas. We aimed to investigate the clinical factors that can predict the propensity of malignant transformation from atypical to anaplastic meningiomas. MethodsBetween 2001 and 2018, all patients with atypical meningioma, in whom the tumors had undergone malignant transformation to anaplastic meningioma, were included. The patients’ medical records documenting the diagnosis of atypical meningioma prior to malignant transformation were reviewed to identify the predictors of transformation. The control group comprised 56 patients with atypical meningiomas who were first diagnosed between January 2017 and December 2018 and had no malignant transformation. ResultsNine patients in whom the atypical meningiomas underwent malignant transformation were included. The median time interval from diagnosis of atypical meningioma to malignant transformation was 19 months (range, 7–78). The study group showed a significant difference in heterogeneous enhancement (77.8% vs. 33.9%), bone invasion (55.6% vs. 12.5%), mitotic index (MI; 14.8±4.9 vs. 3.5±3.9), and Ki-67 index (20.7±13.9 vs. 9.5±7.1) compared with the control group. In multivariate analysis, increased MI (odds ratio, 1.436; 95% confidence interval, 1.127–1.900; p=0.004) was the only significant factor for predicting malignant transformation. ConclusionAn increased MI within atypical meningiomas might be used as a predictor of malignant transformation. Tumors at high risk for malignant transformation might require more attentive surveillance and management than other atypical meningiomas.     

Expression of prostaglandin H synthase-2 in human brain tumors

Numerous studies have demonstrated that prostaglandin H synthase-2 (PHS-2) is involved in gastrointestinal carcinogenesis, and that nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit PHS, can reduce the risk of colon cancer. In brain tumors, elevated prostaglandin production and its correlation to anaplastic grade of gliomas have been demonstrated. To determine whether the increased prostaglandin production is due to enhanced expression of PHS-2 and whether the up-regulation of PHS-2 has any correlation to histopathological findings in brain tumors, we evaluated the profile of PHS expression in several human glioma cell lines and surgical specimens from patients with various types of brain tumors. In glioma cell lines, five out of six cell lines showed constitutive expression of PHS-2, whereas PHS-1 was weakly expressed in all of them. All surgical specimens, except an ependymoma, which expressed both isozymes equally, expressed PHS-2 mRNA predominantly. Immunohistochemistry of various types of brain tumors, including six glioblastomas, nine astrocytomas, six meningiomas, five medulloblastomas, four craniopharyngiomas, three ependymomas, three neurinomas, two oligodendrogliomas, two malignant lymphomas, two dysembryoplastic neuroepitherial tumors and one metastatic brain tumor showed PHS-2 staining in most cases. In gliomas, astrocytomas (grade 2 and 3) were strongly stained, but the staining intensity of glioblastomas was relatively weak. Meningiomas and a metastatic brain tumor were also strongly stained. Our data thus suggest that most brain tumors express PHS-2, which may also play a role in tumorigenesis in the brain.     

脑肿瘤微卫星不稳定性和错配修复基因hMLH1,hMSH2蛋白表？…

目的 检测脑肿瘤微卫星不稳定性（ＭＩＮ）和错配修复（ＭＭＲ）基因蛋白表达的情况。方法 选取１２个微卫星多态性位点,以微卫星序列－ＰＣＲ法和免疫组化技术检测３７例胶质瘤、２４例脑膜瘤及６例神经鞘瘤中ＭＩＮ和ＭＭＲ基因ｈＭＬＨ１、ｈＭＳＨ２蛋白表达。结果 胶质瘤ＭＩＮ发生率为２７％（１０／３７）,脑膜瘤ＭＩＮ阳性率仅为４％（１／２４）,神经鞘瘤未见微卫生ＤＮＡ异常。ＡＢＣ免疫组化染色发现１０例ｈＭＬＨ     

Erythropoietin receptor is expressed in meningiomas and lower levels are associated with tumour recurrence

Aims: The Epo‐EpoR pathway plays a role in tumour growth, metastasis and treatment resistance and is a potential target in oncological treatment. As the EpoR status in human meningiomas is unknown, our aim was to characterize EpoR expression in these tumours. Methods: We examined 131 meningioma samples of all WHO grades from 116 patients by immunohistochemistry for EpoR. Among these, 25 meningiomas showed brain invasion and 29 patients had a further tumour recurrence. A group of 20 patients without tumour recurrence served as controls. In 12 cases we were able to compare both the primary and the following recurrent tumours. The presence of EpoR in meningiomas was confirmed by RT‐PCR and Western blot. Results: EpoR was expressed in all meningiomas. Statistical analysis revealed that the mean expression levels of EpoR were significantly lower in primary tumours with known recurrence compared with a recurrence‐free control group. Additional matched pair analysis in individual cases showed no significant differences between primary and recurrent tumours. No significant correlation between EpoR expression and WHO grade, age, sex or brain invasion was detected. Using specific primer pairs for RT‐PCR, we were able to detect all three known isoforms of EpoR: the full‐length isoform EpoR‐F, the truncated isoform EpoR‐T and the soluble isoform EpoR‐S. Conclusions: Our results demonstrate the expression of EpoR in meningiomas. Lower EpoR mean levels might be a useful marker for a higher recurrence risk, but further studies are needed to clarify the influence of EpoR on recurrences and the role of the different isoforms.