非NF2突变型颅底脑膜瘤临床病理特点分析

目的 探讨非NF2基因突变AKT1(E17K)、SMO(L412F)、KLF4(K409Q)和TRAF7(G536S)型颅底脑膜瘤的临床病理特点。方法 收集92例颅底脑膜瘤患者的临床病理资料,并对所有脑膜瘤样本进行Sanger基因测序,检测4个非NF2点突变：AKT1(E17K)、SMO(L412F)、KLF4(K409Q)和TRAF7(G536S)。结果 92例颅底脑膜瘤中共检测出24例非NF2突变型脑膜瘤,1例为WHO 2级（非典型性）,23例为WHO 1级。其中,AKT1(E17K)突变7例,SMO(L412F)突变7例,KLF4(K409Q)突变8例,TRAF7(G536S)突变2例。AKT1(E17K)、SMO(L412F)和KLF4(K409Q)突变型多为脑膜上皮型和过渡型,KLF4(K409Q)和TRAF7(G536S)突变型主要为分泌型。KLF4(K409Q)突变型和TRAF7(G536S)突变型的肿瘤体积较小。较小的肿瘤体积对于预测KLF4(K409Q)和TRAF7(G536S)突变型脑膜瘤有一定特异性和敏感性（AUC分别为0.784和0.955）,差异有统计学意义（...     

Masked hypodiploidy in anaplastic meningiomas by duplication of the original clone found in atypical meningiomas: Illustration of the evolution of genetic alterations

Meningiomas are common, usually benign neoplasms of the central nervous system. Atypical and anaplastic meningiomas can be aggressive, show more rapid growth, and a greater propensity to recur following resection. General consensus believes that genetic abnormalities leading to anaplastic transformation are present at initial tumor presentation; however, this has not been demonstrated by array‐comparative genome hybridization. We confirm the hypothesis by showing the evolution of genetic alterations in the transformation of an atypical meningioma to an anaplastic meningioma. Additionally, we provide potential genes responsible for malignant transformation of meningiomas, which, with further research, may provide diagnostic and therapeutic implications.     

体外药敏试验及化疗耐药和敏感分子特征指导的恶性脑胶质瘤临床个体化化疗研究

目的 探讨恶性脑胶质瘤临床个体化化疗的策略.方法 恶性脑胶质瘤新鲜肿瘤组织用MTT法进行化疗药物体外药敏试验;用免疫组织化学方法 检测肿瘤组织O6-甲基鸟嘌呤-DNA甲基转移酶(O6-methylguanine-DNA methyltransferase,MGMT)蛋白表达,据MGMT测定结果选择化疗方案;经手术后病理确诊的MGMT表达阳性的恶性脑胶质瘤患者,接受3组化疗方案化疗:含亚硝脲类药物化疗组,含替莫唑胺化疗组,不含亚硝脲和替莫唑胺化疗组.评价3组化疗方案的近期疗效和不良反应;用FISH方法 检测间变性少突胶质细胞瘤组织1p/19q LOH,据检测结果选择化、放疗模式.结果体外药敏试验阴性符合率较高,为14/15.据MGMT表达情况选择化疗方案的客观有效率为34%,疾病控制率为72%.MGMT阳性表达的恶性脑胶质瘤,含亚硝脲类化疗组、含替莫唑胺化疗组、不含亚硝脲和替莫唑胺化疗组的客观有效率及疾病控制率分别为:0和2/11、3/18和11/18、7/22和17/22.不含亚硝脲和TMZ化疗组的客观有效率和疾病控制率均较含亚硝脲化疗组高,有统计学差异(P<0.05).结论 据体外药敏试验及MGMT测定选择化疗方案,可提高近期疗效;MGMT阳性表达的恶性胶质瘤病人,不含亚硝脲和替莫唑胺化疗方案有较好疗效;但含替莫唑胺化疗方案也可应用.     

High p‐mTOR expression is associated with recurrence and shorter disease‐free survival in atypical meningiomas

Due to their widely variable clinical behavior, the post‐surgical treatment of atypical meningiomas is controversial. Therefore, prognostic factors able to identify high‐risk cases, which may benefit from adjuvant treatments, are warranted. Mammalian target of rapamycin (mTOR) belongs to the PI3K‐AKT pathway. Its phosphorylated form (p‐mTOR Ser2448) is involved in cell growth, differentiation and tumorigenesis. The aim of this study was to evaluate p‐mTOR Ser2448 expression and its eventual correlation with clinicopathological features, recurrence, or disease‐free survival (DFS), in atypical meningiomas. p‐mTOR immunohistochemical expression was analyzed in 48 atypical meningiomas and correlated with clinicopathological parameters and with DFS. Eighty‐one percent of atypical meningiomas expressed p‐mTOR Ser2448. High immuno‐expression was significantly associated with recurrences (P = 0.01) and lower DFS (P = 0.01). The presence of brain invasion, high mitotic index plus sheeting, and Simpson grade were significant and independent prognostic variables at multivariate analysis. p‐mTOR Ser2448 is expressed in atypical meningiomas. High expression predicts development of recurrences and shorter DFS in patients affected by these tumors. Since p‐mTOR Ser2448 is a target of anti‐neoplastic drugs, evaluation of its expression may be used, not only to identify atypical meningiomas at higher risk of recurrence, but also to select those to submit to adjuvant targeted chemotherapy.     

Radiation-induced meningiomas: clinical, cytogenetic, and microarray features

Limited information exists about the clinical and biological features of radiation-induced meningiomas (RIMs), particularly those that follow high-dose therapeutic radiation. We report our experience with 20 patients with RIMs (16 following high-dose radiotherapy) treated at our institution from 1993-2006. Patients (14 female, 6 male) had intervals from first radiotherapy to RIM diagnosis of 11-63 years; 12 had at least one RIM occur at an interval of 30 years or more after initial radiotherapy. Multiple RIMs were seen in six patients, with one patient developing his six RIMs sequentially over a 22-year interval. Most RIMs could be managed surgically, either with a single extensive resection or additional resection(s). Adjuvant stereotactic radiosurgery, external beam radiation, or chemotherapy were required in a minority (n = 6). Most were WHO grade I meningiomas. Complex karyotypes were found in three of four cases and abnormalities of chromosome 1p and/or LOH 1p36 were identified in five of 11 informative cases. Gene-expression microarray analysis of RIMs (n = 5) compared to non-RIMs (MEN, n = 6) and a panel of other tumors (n = 62) showed that RIM gene-expression was similar to that seen in MEN, and by clustering analysis did not separate from them. However, microarray comparative gene-expression analysis did demonstrate a few genes with significant differences in the expression level in RIM versus MEN. Of note, NF2 was under-expressed in four of five RIMs (P = 0.0065), at a similar level as measured in MEN.     

脑膜瘤临床病理分析及应用新分类的临床意义

目的 探讨脑膜瘤临床病理诊断与鉴别诊断,及第4版WHO神经系统肿瘤分类标准对诊断的影响.方法 回顾性分析144例病理诊断为脑膜瘤病人的临床资料,分析其组织学分型和分级、免疫组化表型,并采用第4版WHO分类标准分析误诊的主要原因.结果 本组脑膜瘤包括15种组织学亚型;组织学分级:Ⅰ级136例,Ⅱ级4例,Ⅲ级4例.误诊8例(5.6％),其中分级错误7例,血管外皮瘤误诊为脑膜瘤1例.68例行免疫组化标记:波形蛋白阳性68例,上皮膜抗原(EMA)阳性62例,S-100蛋白阳性23例,角蛋白阳性15例.结论与第3版WHO神经系统肿瘤分类比较,第4版分类标准对脑膜瘤亚型的诊断标准没有变化,但分级标准明显不同,对病理医生规避医疗事故具有重要价值.     

Pediatric glioblastoma with oligodendroglioma component: Aggressive clinical phenotype with distinct molecular characteristics

The 2007 World Health Organization classification defined a new variant of glioblastoma (GBM) containing oligodendroglioma foci as GBM with an oligodendroglioma component (GBMO), which shows a favorable clinical outcome compared with “classic” GBM. However, all of the reported cases of GBMO have been adult cases, with no previous reports of pediatric cases. In this report, we demonstrated molecular characteristics of a pediatric GBMO case, showing aggressive clinical behavior with 8‐month overall survival. The case showed neither isocitrate dehydrogenase 1/2 genes (IDH1/2) mutation nor 1p/19q co‐deletion, a hallmark of oligodendroglioal tumors. In addition, microsatellite instability, leading to the putative mechanism of temozolomide (TMZ) resistance, was frequently detected. Molecular genetic analysis may provide critical prognostic and therapeutic insights, especially for the pediatric glioma containing oligodendroglioma components.     

Diagnostic,prognostic and predictive relevance of molecular markers in gliomas

The advances of genome‐wide ‘discovery platforms’ and the increasing affordability of the analysis of significant sample sizes have led to the identification of novel mutations in brain tumours that became diagnostically and prognostically relevant. The development of mutation‐specific antibodies has facilitated the introduction of these convenient biomarkers into most neuropathology laboratories and has changed our approach to brain tumour diagnostics. However, tissue diagnosis will remain an essential first step for the correct stratification for subsequent molecular tests, and the combined interpretation of the molecular and tissue diagnosis ideally remains with the neuropathologist. This overview will help our understanding of the pathobiology of common intrinsic brain tumours in adults and help guiding which molecular tests can supplement and refine the tissue diagnosis of the most common adult intrinsic brain tumours. This article will discuss the relevance of 1p/19q codeletions, IDH1/2 mutations, BRAF V600E and BRAF fusion mutations, more recently discovered mutations in ATRX, H3F3A, TERT, CIC and FUBP1, for diagnosis, prognostication and predictive testing. In a tumour‐specific topic, the role of mitogen‐activated protein kinase pathway mutations in the pathogenesis of pilocytic astrocytomas will be covered.     

Overexpression of mdm2 and p53 and association with progesterone receptor expression in benign meningiomas

The progesterone receptor is frequently found expressed in meningiomas at robust levels. As several studies of breast and endometrial tumors have shown an inverse correlation between progesterone receptor expression and p53 overexpression, we sought to determine if a similar relationship existed in meningiomas. As p53 may also be inactivated by the overexpression of mdm2, we examined a cohort of 90 benign meningiomas immunohistochemically for the presence of the progesterone receptor as well as overexpression of p53 and mdm2. The progesterone receptor was detected in 67% (61/90) of cases, while p53 and mdm2 overexpression were detected in 14% (13/90) and 46% (42/90) of cases, respectively. An absolute correlation was observed between the overexpression of nuclear mdm2 and overexpression of the progesterone receptor, with nuclear mdm2 overexpression being confined to progesterone receptor‐positive tumors (P = 0.001). While p53 overexpression was not associated with progesterone receptor expression, a combination of mdm2 overexpression and/or p53 overexpression was significantly associated with the presence of the progesterone receptor (P = 0.025). These results suggest the existence of a novel relationship between p53 (and its regulatory control) and the presence of the progesterone receptor and, as such, may have fundamental consequences in developing progesterone receptor‐targeted therapies for meningiomas.     

胶质瘤1p/19q联合缺失与临床病理因素的相关性分析

目的 本研究旨在筛选与胶质瘤组织1p/19q联合缺失相关的临床病理因素.方法 收集胶质瘤标本56例,采用荧光原位杂交(FISH)方法检测肿瘤组织标本中1p和19q的状态,并用免疫组化对9种肿瘤相关蛋白进行半定量分析,应用统计学方法筛选与1p/19q联合缺失相关的临床病理因素.结果 单因素分析证实病理类型、p53和O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)表达水平与1p/19q联合缺失相关,Logistic回归进一步证实病理类型和MGMT表达水平与1p/19q联合缺失相关,P值分别为0.001和0.004.结论 在胶质瘤中,通过病理类型和MGMT表达水平可以准确预测部分胶质瘤的1p/19q缺失状态,1p/19q联合缺失有可能通过p53和MGMT的低表达,增强烷化剂化疗疗效和延长存活期.

Abstract：

Objective This study aimed to select clinical and pathological aspects correlated with 1p/19q co- deletion in gliomas.Methods Samples of 56 glioma patients were collected.The status of chromosome 1p and 19q was detected by Fluorescence in Situ Hybridization (FISH) and the expression levels of nine tumor- associated proteins were analyzed semi- quantitatively by immunohistochemistry.Then the aspects correlated with 1p/19q co- deletion were chosen by univariate and logistic regression methods.Methods Pathology,expression levels of p53 and MGMT were the factors correlated with 1p/19q co-deletion by univariate analysis,while pathology and expression level of MGMT were further confirmed by logistic regression.Conclusion 1p/19q co- deletion could be predicted by pathology and expression level of MGMT exactly in part of gliomas.It is likely that 1p/19q co-deletion results in hypo-expression of p53 and MGMT in gliomas,which in turn lead to improved alkylator sensitivity and prolonged survival.     

A new der(1;7)(q10;p10) leading to a singular 1p loss in a case of glioblastoma with oligodendroglioma component

The combined 1p‐/19q‐ deletions in oligodendrogliomas originate from translocation between both chromosomes. In the few cases of oligoastrocytomas and glioblastomas with an oligodendroglioma component (GBMO) where only 1p deletion was described, the origin remains unknown. We report the first case of GBMO, in which a single 1p deletion was detected and was linked to a translocation between chromosomes 1 and 7. Fresh surgical specimens were collected during surgery and the samples were used for cell culture, touch preparation smear slides (TP slides) and DNA extraction. Peripheral venous blood was also collected from the patient. G‐banding using Trypsin and stained with Giemsa (GTG) banding and karyotyping were performed and 1p‐/19q‐, TP53, PTEN and c‐MYC were analyzed by fluorescent in situ hybridization (FISH). Multicolor FISH (mFISH) and microsatellites analyses were also performed to complete the investigation. Three‐dimensional quantitative FISH (3D‐QFISH) of telomeres was performed on nuclei from TP slides and analyzed using TeloView^TM to determine whether the 3D telomere profile as an assessment of telomere dysfunction and a characterization of genomic instability could predict the disease aggressiveness. An unbalanced chromosomal translocation was found in all metaphases and confirmed by mFISH. The karyotype of the case is: 50～99,XXX, +der(1;7)(q10;p10),inc[47] The derivative chromosome was found in all 47 analyzed cells, but the number of derivatives varied from one to four. There was neither imbalance in copy number for genes TP53 and PTEN, nor amplification of c‐MYC gene. We did not find loss of heterozygosity with analysis of microsatellite markers for chromosomes 1p and 19q in tumor cells. The 3D‐telomere profile predicted a very poor prognostic and short‐term survival of the patient and highlights the potential clinical power of telomere signatures as a solid biomarker of GBMO. Furthermore, this translocation between chromosomes 1 and 7 led to a singular 1p deletion in this GBMO and may generate the 1p and 7q deletions.     

胶质瘤1p/19q联合缺失特征分析

目的 研究胶质瘤中1p/19q联合缺失与患者临床特征及O6-甲基鸟嘌呤-DNA甲基转移酶(O6-methylguanine-DNA methyltransferase,MGMT)表达的关系.方法 使用荧光原位杂交技术,对中山大学附属肿瘤医院2009年3月至2011年3月的63例手术确诊胶质瘤标本进行1p/19q联合缺失检测,利用统计学方法分析1p/19q联合缺失患者与无联合缺失患者在性别、年龄、部位、病理类型及MGMT表达状态是否有差异.结果 全组63例患者,男38例,女25例,年龄(41.7 ± 15.3)岁.其中,16例(25.4%)存在1p/19q联合缺失.1p/19q联合缺失患者与无联合缺失患者在性别、年龄及肿瘤部位间的差异无统计学意义.各病理类型1p/19q联合缺失的比例从高到低依次为少突胶质细胞瘤(9/16)、间变性少突胶质细胞瘤(3/8)、星形细胞瘤(2/10)、间变性星形细胞瘤(1/6)及胶质母细胞瘤(1/21),其差异有统计学意义(P ＜ 0.01).在全组63例胶质瘤及25例含少突成分胶质瘤中,MGMT阳性肿瘤1p/19q联合缺失比例与MGMT阴性组间的差异皆无统计学意义.结论 1p/19q联合缺失主要与胶质瘤的病理类型有关,含少突成分胶质瘤中1p/19q联合缺失比例较高.1p/19q联合缺失可作为少突胶质细胞瘤病理诊断的重要参考指标.     

Losses of chromosomes 1p and 19q are rare in pediatric oligodendrogliomas

Pediatric oligodendrogliomas are rare neoplasms and have not been characterized extensively either pathologically or genetically. Given the recent interest in the significance of chromosomal losses in predicting the clinical course and in establishing uniform diagnoses of adult oligodendrogliomas, we reviewed the pathological and clinical features of a series of pediatric oligodendrogliomas and determined their 1p and 19q status using fluorescence in situ hybridization. Of 19 tumors originally diagnosed as oligodendroglioma, 7 were oligodendroglioma, 3 were anaplastic oligodendroglioma, 3 were oligoastrocytoma, and 6 were reclassified. Only one tumor, an anaplastic oligodendroglioma, had 1p loss; none had 19q loss. The single patient whose tumor had 1p loss did not have a particularly favorable clinical course. These results suggest that pediatric oligodendrogliomas arise by molecular alterations distinct from adult oligodendrogliomas, and such molecular alterations do not hold immediate promise as an adjunct to the diagnosis of pediatric oligodendrogliomas.     

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) and its receptor flt-1 in microcystic meningiomas

We investigated the immunohistochemical expression of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) and of its endothelial cell receptor flt-1 in relationship to microcyst formation in meningiomas. Expression of VPF/VEGF was studied in 60 meningiomas (6 microcystic, 38 partially microcystic and 16 with no microcystic areas) and 30 meningiomas from these three subgroups were evaluated for flt-1 expression. VPF/VEGF immunoreactivity was mainly observed in vessel endothelium. Positive vessels were present in 75% (33/44) of meningiomas with any amount of microcystic pattern and in 38% (6/16) of the solid meningiomas (P < 0.02). Densities and percentages of both VPF/VEGF-positive and flt-1-positive vessels were higher in meningiomas with microcystic areas than in solid meningiomas (P≤ 0.002). The 6 microcystic meningiomas showed the highest densities and percentages of both VPF/VEGF-positive (P≤ 0.0002) and flt-1-positive vessels (P≤ 0.01). Vessel expression of VPF/VEGF and flt-1 were positively correlated (r≥ 0.75, P < 0.0001). A strong positive correlation between VPF/VEGF-positive vessel density and proportion of microcystic pattern in all 60 specimens was found (r = 0.75, P < 0.0001). We conclude that accumulation of flt-1-bound VPF/VEGF on endothelial cells of meningiomas is associated with microcyst formation that leads to the histologic appearance of microcystic meningiomas. Received: 18 January 1999 / Revised, accepted: 31 March 1999     

Elevated p53 expression in benign meningiomas protects against recurrence and may be indicative of senescence

Prediction of recurrence after resection of benign meningiomas represents a significant clinical problem. A prospective study commenced in 1984 aimed to elucidate the molecular mechanisms involved in the development of abnormal karyotype and tumour recurrence in meningiomas. Expression of key cell cycle regulators p53, p21, mdm2 and proliferating cell nuclear antigen (PCNA) were studied by immunohistochemistry in 85 tumours for which follow-up data was available. It was found that most tumours expressed p53, p21 and PCNA, with significant correlations between expression of p53 and both p21 and PCNA. As PCNA fulfils a multifunctional role its expression may be an unreliable indicator of proliferation in benign tumours. The degree of tumour excision remains the best prognostic indicator while p53 is the main predictor of abnormal karyotype. Karyotype is not however, related to prognosis. Incompletely excised tumours which expressed high levels of p53 and p21 did not recur. It is suggested that this is indicative of a fully functional p53-mediated DNA damage response mechanism. Rather than contributing to tumour progression, p53 is fulfilling its role as guardian of the genome in benign meningiomas. This study shows that induction of senescence may be an important tumour suppressor mechanism in benign tumours.     

CENP-F过度表达与脑膜瘤生成及增殖活性的相关性

目的 探讨着丝粒／动粒复合体蛋白F（CENP—F）表达与脑膜瘤的生成及增殖活性之间的关系。方法 采用免疫组化方法检测65例脑膜瘤和10例正常脑组织石蜡标本的CENP—F表达，并采用逆转录聚合链反应（RT—PCR）方法检测11例新鲜脑膜瘤和10例新鲜正常脑组织标本中的CENP—F。结果 CENP—F在脑膜瘤中表达明显高于正常脑组织，随着肿瘤病理分级的增加．CENP—F表达的阳性率和表达水平也增高（P〈0．05）。结论 人类CENP-F的过度表达与脑膜瘤的生成及增殖活性之间存在着一定的关系。     

Gliosarcoma arising from oligodendroglioma,IDH mutant and 1p/19q codeleted

Herein, we present a rare case of gliosarcoma arising from oligodendroglioma, isocitrate dehydrogenase (IDH) mutant and 1p/19q codeleted. A 36‐year‐old man presented with a non‐enhanced calcified abnormal lesion on the right frontal lobe. The patient underwent subtotal surgical resection, PAV chemotherapy (procarbazine, nimustine (ACNU) and vincristine), and fractionated radiotherapy with 50 Gy. The pathological diagnosis was oligodendroglioma, IDH mutant and 1p/19q codeleted, World Health Organization 2016 grade II. Six years later, a new enhanced lesion appeared, and the recurrent tumor was surgically removed. Although the histopathological findings indicated gliosarcoma, the recurrent tumor still demonstrated the IDH mutation and 1p/19q codeleted. Thus, the recurrent tumor was considered to originate from oligodendroglioma, rather than being newly generated after chemoradiotherapy. Interestingly, the second recurrent tumor responded well to temozolomide chemotherapy. Based on the findings of this case, oligodendrogliomas have the potential for mesenchymal transformation on progression, while keeping their genotype.     

Correlations between molecular profile and tumor location in Chinese patients with oligodendroglial tumors

OBJECTIVE: To investigate possible correlations between molecular alterations and tumor location in Chinese patients with oligodendroglial tumors. METHODS: A series of 105 gliomas, including 42 oligoastrocytomas, and two control groups of 28 oligodendrogliomas and 35 astrocytomas, were retrospectively reviewed. In each case, the radiologic picture and loss of heterozygosity (LOH) on chromosome 1p and 19q detected by denaturing high-performance liquid chromatography (DHPLC) were analyzed. Correlations between molecular profile and tumor location were made by chi-square and Fisher's exact tests. RESULTS: Oligodendroglial tumors located in the nontemporal lobes were significantly more likely to have combination of LOH 1p and LOH 19q than tumors arising in the insula, temporal lobe, and temporal with another lobe (p=0.001). Subgroup analysis confirmed this finding in oligodendrogliomas (p=0.006), but the difference did not reach significance in the oligoastrocytoma group, although the trend was similar (p=0.067). In contrast to the oligodendroglial tumors, we detected no association between molecular alterations and location for diffuse astrocytomas. CONCLUSION: We conclude that molecular subsets of oligodendroglial tumors may arise preferentially in certain lobes of the brain, with tumors having LOH 1p and LOH 19q occurring most frequently in the nontemporal lobes. These findings suggest that molecular subsets of oligodendroglial tumors may arise from site-specific precursor cells, which has provided some information for the current management of these neoplasms in China.