Prognostic and survival-related factors in patients with well-differentiated oligodendrogliomas

Oligodendrogliomas are brain tumors with unpredictable biological and clinical behavior. Prognostic factors related to survival are still controversial. The present study reviews 50 patients with well-differentiated (WHO grade II) oligodendrogliomas, located in the cerebral hemispheres and operated upon between 1980 and 1998. Prognostic factors studied include patient's age and sex, tumor location and extent, preoperative KPS, and extent of the surgical resection. The Ki-67 and the proliferative cell nuclear antigen (PCNA) levels were studied in all patients and some growth factors (GFs), including vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and tenascine were examined in 20 patients. The long-term outcome and survival are not significantly correlated with the patient's age and sex, tumor location and extent, preoperative KPS and procedure for resection. Patients with lower Ki-67 and PCNA showed a significantly longer survival time (p < 0.001 and p < 0.019, respectively). Between 45 and 70 % of the tumors stained positive for one or more growth factors. Interestingly, cases with late recurrences (more than 4 years after surgery) and longer survival are significantly associated to negative GF expression or slight positivity, as compared with the variable and more often moderate immunoreactivity of cases with early anaplastic recurrences and shorter survival time. The presented data suggest that low proliferation indices and negative GF expression are associated with longer survival in well-differentiated oligodendrogliomas.     

Argyrophilic nucleolar organizer region proteins (Ag-NORs) in human brain tumors: relations with grade of malignany and proliferation indices

Summary Proliferation indices and mean number of silver-stained nucleolar organizer region-associated proteins (Ag-NORs) are compared in 65 brain tumors, including 34 gliomas, 8 meningiomas, 17 metastatic tumors, and 6 other tumors. Immunocytochemical investigations include labeling with the monoclonal antibody Ki-67 which identifies the whole growth fraction, and with a monoclonal antibody against bromodeoxyuridine (BrdUrd) which detects cells in the S phase of the cell cycle after in vitro incubation with BrdUrd. When all types of tumors are collectively considered, mean numbers of Ag-NORs did not correlate with Ki-67 and Brd-Urd labeling indices (LIs) and mitotic index. Among tumor subtypes, only meningiomas showed significant correlations between Ag-NOR counts, LIs, and malignancy. Mean number of Ag-NORs did not correlate with proliferation indices and tumor grade in low-grade and high-grade gliomas. However, recurrent high-grade gliomas showed a tendency to higher Ag-NOR counts than primary tumors. This study indicates that counting of Ag-NORs in paraffin sections is of limited value in tumor neuropathology. Correlations found in meningeal tumors should be substantiated in larger series.     

Immunohistochemical detection of progesterone receptors and the correlation with Ki-67 labeling indices in paraffin-embedded sections of meningiomas

Female sex steroids may play a role in the proliferation of meningiomas, which usually have a high level of progesterone receptors (PgRs). We aimed to investigate the presence of PgRs and the Ki-67 labeling index (Ki-67 LI) in meningioma cases (N = 110) in relation to the severity of the disease. We studied PgR immunoreactivities and the Ki-67 LI in paraffin-embedded sections from meningiomas. Immunodetection of PgRs was conducted with peroxidase-antiperoxidase complex. Immunodetection of Ki-67 antigen was achieved by streptavidin-biotinperoxidase complex. Of 110 meningiomas, in 57 (52%) the immunostaining for PgRs was moderately to strongly positive (Group 1), in 23 (20%) weakly positive (Group 2), and in 30 (28%) negative (Group 3). The positive immunostaining rate for the PgR in the benign meningiomas (76%) was significantly higher than that in nonbenign tumors. The positive immunostaining rate for the PgR was significantly higher in women (81%) than men (55%). The results suggested that progesterone may play a role in the growth of meningiomas. Our results confirmed that the immunodetection of the PgR and Ki-67 antigens on the paraffin sections of meningiomas provides a valuable tool for estimating the biological behavior of meningiomas.     

IMMUNOHISTOCHEMICAL DETECTION OF PROGESTERONE RECEPTORS AND THE CORRELATION WITH KI-67 LABELING INDICES IN PARAFFIN-EMBEDDED SECTIONS OF MENINGIOMAS

Female sex steroids may play a role in the proliferation of meningiomas, which usually have a high level of progesterone receptors (PgRs). We aimed to investigate the presence of PgRs and the Ki-67 labeling index (Ki-67 LI) in meningioma cases (N = 110) in relation to the severity of the disease. We studied PgR immunoreactivities and the Ki-67 LI in paraffin-embedded sections from meningiomas. Immunodetection of PgRs was conducted with peroxidase-antiperoxidase complex. Im muno detection of Ki-67 antigen was achieved by streptavidin-biotin-peroxidase complex. Of 110 meningiomas, in 57 (52%) the immunostaining for PgRs was moderately to strongly positive (Group 1), in 23 (20%) weakly positive (Group 2), and in 30 (28%) negative (Group 3). The positive immunostaining rate for the PgR in the benign meningiomas (76%) was significantly higher than that in nonbenign tumors. The positive immunostaining rate for the PgR was significantly higher in women (81%) than men (55%). The results suggested that progesterone may play a role in the growth of meningiomas. Our results confirmed that the immunodetection of the PgR and Ki-67 antigens on the paraffin sections of meningiomas provides a valuable tool for estimating the biological behavior of meningiomas.     

Invasive meningioma is associated with a low expression of E-cadherin and beta-catenin

Invasive meningioma shows benign histological features (WHO grade 1) and the brain expansion at the tumor-brain interface, and recurs more frequently than common meningiomas. To determine the mechanism of brain expansion, we studied the relationship between invasive meningioma and cell adhesion molecules. Immunostaining for E-cadherin (E-CH), N-cadherin (N-CH), beta-catenin, and Ki-67 was performed in 103 meningiomas that consisted of 61 meningothelial meningiomas, 25 fibrous meningiomas, 12 invasive meningiomas and 5 anaplastic meningiomas. All tumors were negative for N-CH. All the 61 meningothelial meningiomas, 10 of 12 invasive meningiomas, and 3 of 5 anaplastic meningiomas were positive for both E-CH and beta-catenin, while these were both negative in all of the fibrous meningiomas. In invasive meningiomas, the expansive part of the tumor showed a lower rate (4/12 tumors) of E-CH and beta-catenin positivity, while the central part showed a higher rate (10/12 tumors). The Ki-67 labeling index was higher in invasive and anaplastic meningiomas than in meningothelial meningiomas. These results suggest that a reduction in cell adhesion molecules and increased proliferative activity may be related, which may lead to a better understanding of the mechanism of meningioma expansion in the future.     

Spinal meningiomas: age-related features

Objectives

Spinal meningiomas mainly occur in old patients, with a remarkable female prevalence. This study investigates the different features between younger and older patients in an adult population (>18 years).

Materials and methods

A surgical series of 120 adult patients operated on for spinal meningiomas at the Neurosurgical Clinic of the “Federico II” University of Naples is reviewed.In this series 117 patients with a sporadic spinal meningioma were divided in two groups: group I including 30 patients (25.6%) younger than 50 years of age, group II including 87 patients (74.4%) older than 50 years. 3 patients had a spinal meningioma and neurofibromatosis.Several parameters, including sex, predisposing factors, tumor location and growth, histology, recurrences, proliferation index Ki-67 LI, and outcome, are considered and compared in the two age groups.

Results

Group I showed an incidence of high cervical spine (C1-C4) meningiomas higher than group II (23.3% vs 3.4%, p = 0.026) and lower rate of thoracic tumors (60% vs 82.7%, p = 0.04). No significant differences of histological type and Ki-67 LI were found. Group I had 2 cases of atypical meningiomas (6.6% vs 0%, ns). Recurrences occurred in 6.6% of group I and 2.6% of group II, with no significance. In recurrent meningiomas values of Ki-67 LI were significantly higher than values in not recurrent meningiomas (p = 0.0001), whereas no difference of estrogen and progesterone receptor expression was noted.

Conclusions

Younger adult patients with spinal meningiomas show not rare occurrence of NF (9%) and significantly higher incidence of high cervical and lower incidence of thoracic localizations with respect to the older patients. On the other hand, there are not significant differences of histology, Ki-67 LI and recurrence rate, excepting for a slight difference for atypical meningiomas.     

Ki-67在侵袭性脑膜瘤的表达与意义

目的探讨Ki-67表达水平与脑膜瘤侵袭性的关系。方法回顾性分析68例脑膜瘤病例资料,根据肿瘤侵袭性与否,分为侵袭组（n=18）和非侵袭组（n=50）,测定Ki-67的表达水平,并进行统计学分析。结果男性病人中侵袭性脑膜瘤的发生率（41.7%）明显高于女性（18.2%）（P〈0.05）。不同病理等级,侵袭性脑膜瘤的发生率有明显差别（P〈0.05）。不同年龄段及病理类型,侵袭性脑膜瘤发生率无明显差别（P〉0.05）。脑膜瘤侵袭性或性别,与Ki-67表达水平无明显相关性（P〉0.05）。病理等级和Ki-67表达水平有明显相关性（P〈0.05）。结论 Ki-67表达水平主要与病理等级有关。在相同病理等级脑膜瘤中,Ki-67表达水平与脑膜瘤侵袭性无明显相关性。     

Immunohistochemical expression of inducible nitric oxide synthase (iNOS) in human brain tumors: relationships of iNOS to superoxide dismutase (SOD) proteins (SOD1 and SOD2), Ki-67 antigen (MIB-1) and p53 protein

In this study, inducible nitric oxide synthase (iNOS) expression in a series of 158 human primary brain tumors was analyzed. To gain some insight into the biological significance of iNOS expression in tumor cells, comparative immunohistochemical analyses were employed to characterize the expression of iNOS, superoxide dismutase (SOD) proteins (SOD1 and SOD2), Ki-67 antigen (MIB-1) and p53 protein in these cells. Sixteen (39.0%) of the 41 glioblastoma multiforme (GBM) specimens showed iNOS immunoreactivity. Positive immunoreactions with iNOS were also detected in 2/8 anaplastic astrocytomas, 1/17 astrocytomas, 1/14 medulloblastomas and 1/11 primitive neuroectodermal tumors, but no positive reactions were observed in oligodendrogliomas (0/11), ependymomas (0/5), schwannomas (0/21), meningiomas (0/23) or pituitary adenomas (0/7). The MIB-1 labeling index of GBMs that expressed iNOS was significantly higher than that of GBMs that did not (0.025< P <0.05, Wilcoxon rank-sum test). Unlike iNOS-negative tumors, all iNOS-positive tumors coexpressed SOD1 or SOD2. In particular, there was a significant correlation between iNOS induction and SOD1 expression (P =1.65x10(-10), Fisher's exact test) in GBM specimens. There was no significant relationship between iNOS and p53 protein in any type of primary brain tumor (P >0.05, Fisher's exact test). No significant immunohistochemical reactions with iNOS, MIB-1 or p53 protein were observed in normal brain tissue sections. We conclude that primary brain tumors express iNOS, and that iNOS expression in brain tumor cells may depend, in part, on cellular proliferation potential. Based on the fact that SOD1 scavenges oxidative-stress species originating from large amounts of nitric oxide (NO) produced by iNOS, iNOS-expressing brain tumor cells may protect themselves against NO cytotoxicity by overinducing SOD1.     

Proliferative potential of meningiomas determined with the monoclonal antibody Ki-67

Summary In 30 meningiomas we investigated the proliferation rate of various subtypes with the monoclonal antibody Ki-67. Frozen sections were incubated with Ki-67 antibody using a modified Alkaline Phosphatase anti-Alkaline Phosphatase (APAAP)-technique and evaluation of proliferation rate was done by cell counting. Meningiomas of the meningiotheliomatous, fibrous and angioblastic subtype without atypical histological findings contained 1% or less proliferating cells. In recurent tumors, in transitional and in anaplastic meningiomas there is a marked increase of proliferating cells up to 20%. The distribution of marked cells varies in recurrent tumors and anaplastic meningiomas, and a focal proliferation of tumor cells was seen in meningiomas from transitional type. Immunohistological labelling of proliferating cells in meningiomas may allow a more precise prediction of the proliferation potential of each meningioma.     

The double immunostaining of CD133 and Ki-67 favours a significant co-localization pattern in fibroblastic subtype of meningiomas

BACKGROUND AND PURPOSE : A unique molecular and/or cellular marker for meningiomas, the most common intracranial tumours, has not been identified yet. MATERIAL AND METHODS: We investigated the co-localization fraction of CD133/Ki-67 in meningioma tissue array slide composed of 80 meningioma tissue samples of various histological variants. CD133 - a cell membrane stem cell marker - was previously proved to be associated with the initiation and progression of intracerebral gliomas and medulloblastomas. RESULTS : Immunohistochemical co-localization of CD133/Ki-67 was significantly higher in fibroblastic variant than in meningothelial and transitional subtypes. However, since there were only 3 atypical and 1 malignant meningioma spots in the tumour tissue array slide, it is difficult to draw a firm conclusion regarding the actual co-localization percentage and persistence of CD133/Ki-67 in atypical and malignant meningiomas. CONCLUSIONS : Far higher co-staining percentage of CD133/ Ki-67 in fibroblastic meningioma samples compared to meningothelial subtype, a histological meningioma variant, architectonically resembling the non-neoplastic meningeal cells, gave us the impression that CD133 may play a role in the formation and progression of fibroblastic meningioma variants. The persistency and the validity of this finding need to be verified by further histopathological and molecular research in order to clarify the possible role of CD133 in meningiogenesis.     

脑肿瘤干细胞的增殖活性与病理级别的相关性研究

目的检测增殖细胞核标记物Ki-67与脑肿瘤干细胞（BTSCs）标记物CD133、Nestin在60例脑胶质瘤组织中的表达,探讨BTSCs的增殖活性与病理级别的相关性。方法采用免疫组织化学SP法检测CD133、Nestin和Ki-67在60例胶质瘤组织中的表达;采用免疫荧光双染法检测Ki-67、CD133和Nestin之间的共表达情况。计算两种方法中CD133＋细胞、Nestin＋细胞和Ki-67＋细胞所占的百分率,并将Ki-67＋细胞与CD133＋细胞、Nestin＋细胞和肿瘤病理分级分别进行相关性分析。结果按照WHO 2000的神经系统肿瘤分类分级标准所有标本分为Ⅱ级18例,Ⅲ级23例,Ⅳ级19例,在不同的病理级别组中,CD133＋、Nestin＋和Ki-67＋细胞的表达有明显差异,并且免疫荧光双染相比免疫组化单染更能代表BTSCs的增殖活性研究。在免疫荧光共表达中,随着病理级别的升高,CD133＋/Ki-67＋细胞（F=30.668,P=0.000）或Nestin＋/Ki-67＋细胞（F=15.316,P=0.000）的百分比差异都有显著性,并且同时均与CD133＋/Nestin＋BTSCs的表达成正相关。结论Ki-67＋指标与肿瘤级别成正相关,可以作为预后判断的指标,同时与BTSCs标记物CD133、Nestin的表达之间也有明显的相关性,并且,免疫荧光双染得出的BTSCs的增殖活性与病理级别的相关性研究更有统计学意义。     

In situ analysis of cell kinetics in human brain tumors

Summary A newly developed in vitro labeling method with bromodeoxyuridine (BrdU) identifies S phase cells in situ in freshly obtained surgical tissue of human brain tumors which is subsequently fixed and embedded in paraffin for BrdU immunovisualization. For the first time, the BrdU labeling index (LI) is successfully compared here with the LI obtained by immunostaining of frozen sections of the same tumors with monoclonal antibody Ki-67 which identifies all proliferating cells, i.e., the growth fraction. LIs were counted in at least five different areas with high density of labeled cells; at least 1,000 cells were counted. In 13 metastatic tumors, Ki-67 LI was 8.3%–62.6%, and BrdU LI was 5.1%–28.0%. In 18 gliomas, Ki-67 LI was 1.4%–19.3%, and BrdU LI was 0.2%–11.6%. In 7 meningiomas, Ki-67 LI was 0.3%–3.0%, and BrdU LI was 0%–2.0%. Statistical comparison of Ki-67 and BrdU LIs by linear regression analysis revealed a highly significant correlation: BrdU LI=0.99+0.34 Ki-67 LI (r=0.92,P<0.001). A significant heterogeneity of proliferation patterns may occur within one sample from area to area, as well as between different samples of the same tumor, especially in gliomas; thus, some subjective influence on LIs by arbitrary sampling and selection could occur in quantitative evaluation of in situ cell kinetics of human brain tumors. This study indicates that our in vitro BrdU-labeling method allows the in situ identification of S phase cells in excellently preserved fixed tumor tissue which is well suited for further histological examination. This method compares favorably with Ki-67 labeling of frozen sections and might emerge as a powerful new tool for the routine study of cell proliferation in surgical specimens of human brain tumors.Supported by funds from the Commission for Cancer Research of the Medical Faculty of the University of Vienna     

星形细胞起源肿瘤Claudin-1、Ki-67、CD34表达水平与细胞增殖和侵袭的关系

目的 研究脑星形细胞起源肿瘤中紧密连接蛋白-1(Claudin-1)、Ki-67、CD34的表达及其与星形细胞起源肿瘤的侵袭、增殖和分级的关系.方法 应用免疫组织化学方法检测50例星形细胞起源肿瘤非肿瘤区、交界区和肿瘤区Claudin-1、细胞增殖标记抗体Ki-67、CD34的表达情况,分析其与肿瘤临床病理特征的关系.结果 组织学Ⅰ、Ⅱ级星形细胞起源肿瘤肿瘤区Claudin-1表达率(70.59%)高于Ⅲ、Ⅳ级的星形细胞起源肿瘤(9.09%)(P=0.000);Ⅲ、Ⅳ级星形细胞起源肿瘤肿瘤区、交界区和非肿瘤区Ki-67标记指数高于Ⅰ、Ⅱ级(P均=0.000);Ⅲ、Ⅳ级星形细胞起源肿瘤肿瘤区和交界区的微血管密度(MVD)高于Ⅰ、Ⅱ级(P=0.003,0.000);肿瘤区的Ki-67(12.74±6.93)高于交界区(7.42±3.93)和非肿瘤区(3.22±1.57)(P=0.000);肿瘤区的MVD(27.48±8.26)高于交界区(10.72±3.93)和非肿瘤区(6.48±1.45)(P=0.000).结论 Claudin-1、Ki-67、CD34的表达与星形细胞起源肿瘤的分级、增殖和侵袭有关,可作为判断肿瘤恶性度的重要指标.     

A clinicopathological and immunohistochemical study of central nervous system hemangiopericytomas

Hemangiopericytomas (HPC) of the central nervous system (CNS) are uncommon dural-based tumors that mimic meningiomas clinically and radiologically. Because there are few reports about these tumors from India, we aimed to study the clinico-pathological and immunohistochemical features of CNS HPC. During 2000 to 2008 all 23 patients diagnosed with HPC of CNS at our Institution were reviewed in the study (11 males and 12 females, mean age of 46 years). Clinical, radiological and histopathological features were reviewed. There were 14 patients with grade II and nine with grade III tumors. Immunohistochemistry with antibodies to epithelial membrane antigen (EMA), vimentin, S-100, CD34 and Ki-67 was done on routinely processed, paraffin-embedded sections of 20 tumors. All patients were EMA and S-100 negative, and vimentin positive. CD34 was positive in only five out of 20 patients. The mean Ki-67 labeling index was 4.25% in grade II tumors and 7.8% in grade III tumors. We concluded that HPC are distinct from meningiomas in morphology, immunohistochemistry and biologic behavior, although they resemble each other clinically and radiologically, HPCs need to be differentiated from meningiomas.     

Immunostaining for proliferating cell nuclear antigen: its role in determination of proliferation in routinely processed human brain tumor specimens

Alcohol- and formalin-fixed, paraffin-embedded samples of 71 brain tumors (35 gliomas, 22 metastatic carcinomas, 8 meningiomas and 6 other tumors) were investigated by immunocytochemistry with three different monoclonal antibodies against proliferating cell nuclear antigen (PCNA)/cyclin (19A2; 19F4; PC10). PC10 was found to work best; it is applicable to both alcohol- and formalin-fixed tumor samples. PCNA labeling indices (LIs) were compared in the same tumors with LIs obtained by Ki-67 immunostaining of frozen sections and by in vitro incubation with bromodeoxyuridine (BrdUrd); in the latter preparations, BrdUrd LIs could be compared with PCNA LIs in the very same areas of serial sections. In gliomas, PCNA LIs were 0.7–80.2% (mean 31.7%), in metastases 0–76.0% (mean 47.8%), and in meningiomas 0–53.0% (mean 19.3%). In general, PCNA LIs were highly significantly correlated with Ki-67 LIs (P=0.0002) and BrdUrd LIs (P=0.0001). However, when tumor subgroups are considered, only gliomas show a significant correlation with Ki-67 and BrdUrd LIs. Despite this statistical correlation, PCNA expression was out of proportion to proliferation indices as determined by both other methods in almost one third of all brain tumors. Immunocytochemistry for PCNA produces a broad spectrum of staining intensity of labeled nuclei, whose number is dependent upon the sensitivity of the immunocytochemical technique used. Thus, inter-oberserver and inter-laboratory variabilities in PCNA LI determination may occur. Overlapping of PCNA LIs between tumor subgroups of varying malignancy further limits the informational value for the individual case. In some classic meningiomas, high PCNA scores do not reflect the proliferative activity of the tumor, as Ki-67 and BrdUrd LIs are very low in these cases. We conclude that PCNA immunolabeling is of limited value in the individual tumor, mainly due to overexpression in many tumors, and at present cannot be recommended to replace Ki-67 and/or BrdUrd labeling methods for routine determination of proliferative activity in human tumor specimens.Supported in part by a grant from the Oncology Commission, Medical Faculty, University of Vienna     

Ganglioglioma: a detailed histopathological and immunohistochemical analysis of 61 cases

Gangliogliomas are tumors composed of intimately admixed neuronal and glial components and account for approximately 1% of all brain tumors. Here we report the histopathological findings in 61 gangliogliomas. Epilepsy was the most common presenting symptom. Most gangliogliomas were located in the temporal lobes (74%). Thirteen percent of the gangliogliomas were associated with glioneuronal hamartias. There was considerable variation in neuronal size and density, presence of binucleated neurons, calcifications, desmoplasia, lymphocytic infiltrate, pilocytic differentiation, Rosenthal fibers, location, or histological uniformity. Fifteen percent of the gangliogliomas contained areas of purely astrocytic differentiation. All tumors were examined immunohistochemically for an aberrant p53 tumor suppressor gene product and for the presence of nuclear antigens associated with cell proliferation (Ki-67, Ki-S1, proliferating cell nuclear antigen). In 45 of 61 cases (74%) labeling indices for Ki-67 were less than 1%. Nuclear labeling for Ki-67 was observed exclusively in the astrocytic component. Gangliogliomas with very large neurons had higher Ki-67 labeling indices and occurred in younger patients than gangliogliomas with small-or intermediate-sized neurons. None of the tumors had an aberrant expression of p53. The observations suggest that gangliogliomas may arise from glioneuronal hamartias through neoplastic transformation of the astrocytic component.Supported by a center grant from the University of Bonn Medical Center and the State of Nordrhein-Westfalen     

Recurrent meningiomas--the immunohistochemical analysis of angiogenesis and cellular proliferation. Preliminary study

Meningiomas exhibit a tendency to the local regrowth after their surgical resection, and some of those recurrent tumors show histological malignancy progression. The present study was performed on 10 cases of recurrent meningiomas chosen out of total 122 meningiomas diagnosed in our Department of Pathomorphology in the period 1993-1998. The tissue material from both operations was examined. One patient was operated three times. In three cases at the second operation there was progression from benign to atypical meningioma. The other tumors did not change their histological grade (four benign, one atypical and two anaplastic). The tumor tissue section were stained immunohistochemically with monoclonal antibodies raised against epithelial membrane antigen (EMA), Ki-67 and von Willebrand factor (vWf). The percentage of EMA-positive cells and Ki-67 immunoreactive cells (proliferation cell index--PCI) were counted. The vascular density (number of blood vessels/mm2) was assessed in the preparations stained with anti-vWf, as the measure of the intensity of angiogenesis. The values of the examined parameters were greatly differentiated within both the initial and the recurrent tumor groups. The values of vascular density ranged 12-96 vessels/mm2, the percentage of EMA-positive cells was 0.75%, PCI was from 0.3 to 9.3%. The values of the examined parameters did not differ significantly between initial and recurrent meningiomas groups. It is however worth to point out that PCI in the most recurrent tumors were higher than in their primary counterparts.     

The role of CD44 in glioblastoma multiforme

A transmembrane molecule with several isoforms, CD44 is overexpressed in many tumors and promotes tumor formation through interactions with the tumor microenvironment. CD44 has been implicated in malignant processes including cell motility, tumor growth, and angiogenesis. The role of CD44 has been examined in many cancer types. This paper provides, to our knowledge, the first focused review of the role of CD44 in glioblastoma multiforme (GBM), the most common and fatal of primary brain cancers. We summarize research that describes how CD44 promotes GBM aggressiveness by increasing tumor cell invasion, proliferation and resistance to standard chemoradiation therapy. Effects of CD44 inhibition in GBM are also explored. Clinical trials investigating CD44 targeting in CD44-positive solid tumors are underway, and the evidence presented here suggests that CD44 inhibition in GBM may be a promising therapy.     

Monoclonal antibody to stage-specific fetal brain 68-kDa glycoprotein (FGP68) revealed increased FGP68 expression in human primary brain tumors

We have produced a novel rat IgG(2a) monoclonal antibody against a stage-specific fetal brain glycoprotein of 68 kDa (FGP68), and succeeded in applying it to staining paraffin sections. To gain some insight into the pathobiological significance of this FGP68, this monoclonal antibody was used in immunohistochemical studies to compare the expression of FGP68 and Ki-67 antigen (MIB-1) in 235 primary brain tumors. Approximately half of the glioblastomas multiforme (GBMs) (44/75) and anaplastic astrocytomas (9/17) as well as some astrocytomas (5/30), medulloblastomas (2/14) and primitive neuroectodermal tumors (2/10) had tumor cells that expressed FGP68; however, pilocytic astrocytomas (0/7), oligodendrogliomas (0/15), ependymomas (0/6), schwannomas (0/21), meningiomas (0/22) and pituitary adenomas (0/18) did not express FGP68. The values of the MIB-1 labeling index were statistically higher in GBMs (0.005< P<0.01, Wilcoxon rank-sum test) and anaplastic astrocytomas (0.025< P<0.05) that expressed FGP68 than in those that did not. Normal brain tissue from 20 individuals aged 3-75 years was negative for FGP68 and MIB-1. We conclude that primary brain tumors express FGP68, one of the oncofetal proteins derived from fetal brain, and that FGP68 expression in certain brain tumor cells may depend, in part, on proliferation potential. Based on the possibility that the stage-specific FGP68 plays an important role in brain embryogenesis, some of FGP68-expressing tumor cells might phylogenetically revert to more primitive cells.     

Ki-67 immunoreactivity in human central nervous system tumors: a study with MIB 1 monoclonal antibody on archival material

Paraffin-embedded surgical specimens from 136 primary human central nervous system (CNS) tumors, including 50 meningiomas, 24 astrocytomas, 26 anaplastic astrocytomas, 9 glioblastomas, 8 oligoden-drogliomas, 4 ependymomas, 1 anaplastic ependymoma, 2 subependymomas, 9 medulloblastomas, and 3 paragangliomas, were immunostained, following microwave processing, using a streptavidin/peroxidase method and the MIB 1 monoclonal antibody (mAb) against the Ki-67 antigen. The following mean Ki-67 labeling index (LI) values ± SD were found: meningiomas, 2.47 ± 1.83; astrocytomas, 2.03 ± 2.03; anaplastic astrocytomas, 12.80 ± 6.29; glioblastomas, 14.57 ± 6.77; oligodendrogliomas, 5.06 ± 4.78; ependymomas, 2.63 ± 2.58; anaplastic ependymoma, 6.89; subependymomas, 1.79 ± 1.54; medulloblastomas, 18.77 ± 9.65; and paragangliomas, 2.19 ± 2.51. Our findings indicate that while malignant CNS tumors always exhibited high Ki-67 LI values, and benign CNS tumors generally displayed lower values, increased immunoreactivity for Ki-67 epitopes (Ki-67 LI higher than 4) was noted in a number of meningiomas, astrocytomas, ependymomas, oligodendrogliomas and paragangliomas, contrasting with their benign histological features. Further investigations of the Ki-67 immunoreactivity in CNS tumors and systematic correlation with the postoperative follow-up of patients are necessary to determine the value of Ki-67 LI in predicting the biological behavior of CNS neoplasms.Presented at the 69th Annual Meeting of the American Association of Neuropathologists, June 10–13, 1993, Salt Lake City, Utah, USA