DNA topoisomerase II-alpha and cyclin A immunoexpression in meningiomas and its prognostic significance: an analysis of 263 cases

CONTEXT: Routine pathologic examination cannot distinctively predict the clinical course of meningiomas because even histologically benign tumors may recur after gross total resection. Therefore, numerous efforts have been made to evaluate the meningioma growth fraction and its prognostic value. However, a universally applicable proliferative marker for meningioma outcome is not yet a reality. OBJECTIVE: To investigate the prognostic utility of 3 proliferative markers, namely, Ki-67, DNA topoisomerase II-alpha (topoII), and cyclin A in a representative series of intracranial meningiomas. DESIGN: Two hundred sixty-three adult patients with intracranial meningiomas (208 benign, 42 atypical, and 13 anaplastic) were studied retrospectively. Tumor specimens were immunohistochemically examined with antibodies to Ki-67 (MM-1), topoII, and cyclin A. A computerized color image analyzer was used to count immunostained nuclei. RESULTS: The topoII and cyclin A scores exhibited a close correlation with Ki-67 immunostaining. Significant differences between the indices for all 3 markers were noted among the 3 grades of meningiomas. The scores for all 3 markers were significantly different between recurrent and nonrecurrent meningiomas, including benign tumors that were treated with gross total resection. Recurrence-free survival was significantly reduced for cases with a Ki-67 labeling index (LI) of 4.4% or greater, a topoII LI of 3.2% or greater, and a cyclin A LI of 3.1% or greater. Multivariate analysis revealed that the risk of recurrence for the entire meningioma cohort was significantly associated with tumor grade (hazard ratio = 2.7; P =.004), topoII LI of 3.2% or greater (hazard ratio = 5.5; P <.001), and a cyclin A LI of 3.1% or greater (hazard ratio = 2.4; P =.01). CONCLUSIONS: There is a close correlation in the expression of these 3 proliferative markers in meningiomas, and all of the markers showed a significant association with tumor grade, recurrence rate, and recurrence-free survival. Consequently, in addition to Ki-67, immunoexpression of topoII and cyclin A is available for predicting meningioma recurrence. Moreover, the topoII and cyclin A staining scores were found to be more sensitive predictors for meningioma progression than Ki-67 and, therefore, either of these 2 markers may prove to be clinically informative and useful.     

Immunohistochemical expression of SPARC is correlated with recurrence,survival and malignant potential in meningiomas

Meningioma is a common neoplasm that constitutes almost 30% of all primary central nervous system tumors and is associated with inconsistent clinical outcomes. The extracellular matrix proteins play a crucial role in meningioma cell biology and are important in tumor cell invasion and in progression to malignancy. SPARC (secreted protein, acidic and rich in cysteine) (osteonectin) is a matricellular glycoprotein that regulates cell function by interacting with different extracellular matrix proteins. The aim of this study was to evaluate the expression of SPARC with proliferation index, p53 reactivity in WHO grade 1 (benign), grade 2 (atypical) and grade 3 (anaplastic) meningiomas and correlate with clinical features of the patients, including location of the tumor, recurrence of the tumor and survival of patients. We studied 111 meningiomas, 69 being benign, 34 being atypical and eight being anaplastic meningiomas of various histological types. Using immunohistochemical analysis, we evaluated the expression of SPARC, Ki‐67 (MIB‐1) and p53 in meningiomas. Immunohistochemical scores of SPARC were determined as the sum of frequency (0–3) and intensity (0–3) of immunolabeling of the tumor cells. A high immunohistochemical score (4–6) for SPARC was more frequent in atypical and in anaplastic meningiomas than in benign meningiomas (p < 0.01). MIB‐1 proliferation index showed significant association between tumor grades in meningiomas (p < 0.01). At the end of a follow‐up period of 47.53 ± 25.04 months, 30 tumors recurred. A high SPARC expression was significantly associated with tumor recurrence (p = 0.02). The immunoreactivity of p53 protein and MIB‐1 score were significantly higher in recurrent meningiomas than in non‐recurrent meningiomas. The cumulative survival of patients with high SPARC expression was significantly lower than patients with low SPARC expression. The high SPARC expression scores were predominantly identified in meningothelial, fibrous and chordoid meningiomas; low SPARC expression scores were mostly spotted in secretory and psammomatous meningiomas. Evaluating SPARC expression might help assessing recurrence risk and survival estimation in meningiomas.     

Immunohistochemical study of Ki-67 (MIB-1), p53 protein, p21WAF1, and p27KIP1 expression in benign, atypical, and anaplastic meningiomas

Histologic grading of meningiomas has prognostic and clinical therapeutic implications. Meningiomas were histologically classified into 3 different World Health Organization grades. Grade II, an atypical meningioma, was defined by major and various minor histologic criteria. However, these histologic criteria sometimes are not fulfilled, and other criteria are necessary. We studied and analyzed the immunohistochemical expression of MIB-1, p53, p21WAF1, p27KIP1 proteins in 146 cases of meningiomas, including 109 benign, 27 atypical, and 10 anaplastic meningiomas. Most of the benign meningiomas expressed low MIB-1 labeling index (mean, 1.5%), and fewer cases had p53 protein expression. In contrast, the anaplastic meningiomas had a high labeling index of MIB-1 (mean, 19.5%) and always expressed p53 protein, with a mean labeling index of 6.3%. The atypical meningiomas had MIB-1 and p53 labeling indexes in the range between benign and anaplastic meningiomas, with mean labeling indexes of 8.1% and 3.5%, respectively. These expressions were statistically significant among benign, atypical, and anaplastic meningiomas (P <.001). We conclude that the immunohistochemistry of MIB-1 and p53 protein will be valuable in discriminating atypical meningiomas from benign or anaplastic meningiomas, at least in histologically borderline cases. In addition, we also found direct correlation of p21 and inverse correlation of p27 expressions in meningiomas with increasing histologic grade and proliferative index.     

The significance of immunohistochemical expression of Ki-67, p53, p21, and p16 in meningiomas tissue arrays

Although histologic grading of meningiomas has prognostic and clinical implications, it is difficult in some cases to predict the outcome of patients. There have been several efforts to evaluate the use of different immunohistochemical markers for predicting meningioma prognosis. We analyzed the immunohistochemical expression of Ki-67, p53, p21, p16, and PTEN proteins in 130 meningiomas (64 benign, 39 atypical, and 27 malignant meningiomas) using tissue microarray. The tumors were graded according to the World Health Organization classification. There was a statistically significant correlation between the expression of Ki-67, p53, p21, p16, and the grade of meningiomas (p0.001). By ordinal logistic regression, p53 and Ki-67 were significantly associated with grade, and an increase of 1% in the labeling index of these markers resulted in an increase in the risk of raising the grade by 2.17 and 1.49, respectively. Histological grade, p53, Ki-67 labeling indices, and overexpression of p16 were strongly associated with decreased event-free survival in univariate analysis. In contrast, multivariate analysis revealed that only tumor grade is an independent factor for predicting meningioma recurrence. We conclude that the Ki-67 and p53 labeling indices are useful additional tools in discriminating atypical from benign or anaplastic meningiomas, especially in histological borderline cases.     

Expression of cytokeratin by malignant meningiomas: diagnostic pitfall of cytokeratin to separate malignant meningiomas from metastatic carcinoma.

Based on clinical and histologic features, differentiating metastatic carcinomas from benign or malignant meningiomas usually is not difficult. Occasionally, however, in some patients without a clinical history of carcinoma, malignant meningiomas can morphologically simulate metastatic carcinoma, necessitating an immunohistochemical study for cytokeratin to make a correct diagnosis. However, the utility of immunohistochemical markers to separate malignant meningioma from metastatic carcinoma has not been investigated. The immunoperoxidase method with antigen retrieval was used to characterize the expression of three cytokeratins (AE1/AE3, CAM 5.2, and Pan cytokeratin), EMA, CEA, Ber-EP4, CD 15, and B72.3 in 12 previously diagnosed malignant meningiomas, 20 benign meningiomas, and 20 metastatic carcinomas. Cytokeratin expression was detected in 75% of malignant meningiomas, 0% of benign meningiomas, and 100% of metastatic carcinomas. While epithelial markers of Ber-EP4, CEA, B72.3 and CD-15 were positive in 90, 80, 70 and 65% of the metastatic carcinoma, respectively, they were negative in all 12 malignant meningioma examined. Vimentin immunoreactivity was seen in all benign and malignant meningiomas, and in 20% of metastatic carcinomas. Our results indicated that cytokeratin is not a reliable immunohistochemical marker to separate a malignant meningioma from metastatic carcinoma. A panel of epithelial markers including Ber-EP4, CEA, B72.3 and CD-15, and vimentin may be needed to separate malignant meningioma from metastatic carcinoma. Cytokeratin expression can be a potential pitfall for confusing a malignant meningioma with a metastatic carcinoma.     

Gene expression profiles of meningiomas are associated with tumor cytogenetics and patient outcome

Cytogenetic analysis is a powerful tool for predicting recurrence in meningiomas, even among histologically benign/grade I tumors. Despite this, no study has been reported in which the impact of tumor cytogenetics on the gene expression profiles (GEP) has been analyzed in meningiomas. Here, we analyzed the GEP of 47 tumors and correlated them with the most clinical relevant cytogenetic subgroups of meningiomas, as confirmed through the analysis of 172 patients. Additionally three normal meningeal samples were also studied.
Overall, our results show a clear association between the clinically relevant cytogenetic subgroups of meningiomas including diploid tumors (n = 18), isolated −22/22q− (n = 12), del(1p36) alone (n = 4) and complex karyotypes associated with del(1p36) and/or −14q (n = 13) and their GEP. Accordingly, based on the expression of 85 genes (40 of which were coded in the altered chromosomes used for patient stratification) the cytogenetic class of the tumor could be predicted with an error of <1%, a clear association being found between the GEP and patient outcome ( P  = 0.03) but not tumor histopathology.
In summary, we show a clear association between GEP of neoplastic cells and clinically relevant cytogenetic subgroups of meningiomas.     

A consistent region of deletion on 1p36 in meningiomas: identification and relation to malignant progression

We analyzed the genetic aberrations on chromosome arms 1p, 10q, and 14q, which are thought to be loci that include putative tumor suppressor genes in meningiomas. We initially conducted molecular genetic testing on a total of 72 tumors including 15 atypical and 8 anaplastic meningiomas using double-target fluorescence in situ hybridization. An incidence of deletion of 1p was observed in 16.3% of histologically benign, 86.7% of atypical, and 87.5% of anaplastic meningiomas. Microsatellite analysis for loss of heterozygosity on 1p, 10q, and 14q was performed in 15 tumors (6 benign, 6 atypical, and 3 anaplastic meningiomas). We detected a limited deleted region on 1p36 in two tumors and suggest a new consistent region of deletion at 1p36.21p23 distal to D1S507 and proximal to D1S214, which spans 8.21 megabases. In addition, loss of 10q was detected in two of three secondary atypical meningiomas, and loss of 14q in two of three primary anaplastic meningiomas. We suggest that one of the putative suppressor genes is located at 1p36.21p23, and that 10q loss may contribute to the malignant progression from benign to atypical meningiomas.     

Characterization of chromosome 14 abnormalities by interphase in situ hybridization and comparative genomic hybridization in 124 meningiomas: correlation with clinical, histopathologic, and prognostic features

We analyzed quantitative chromosome 14 abnormalities in 124 meningiomas by interphase fluorescence in situ hybridization (iFISH) and confirmed the nature of abnormalities by comparative genomic hybridization (CGH). We correlated the abnormalities with clinical, histopathologic, and prognostic factors. Of 124 cases, 50 (40.3%) showed loss (14.5%) or gain (25.8%) of the 14q32 chromosome region by iFISH. Most corresponded to numeric abnormalities: monosomy (12.9%), trisomy (1.6%), or tetrasomy (24.2%); in only 2 cases (1.6%), chromosome 14 loss did not involve the whole chromosome and was restricted to the 14q31-q32 region (confirmed by CGH). Cases with gain or monosomy corresponded more frequently to histologically malignant tumors (P = .009). Patients with monosomy 14/14q-, but not those with gain, more often were male (P = .04) and had a greater incidence of recurrence (P = .003) and shorter relapse-free survival (P = .03). The 2 patients with loss limited to 14q31-q32 had histologically benign tumors and no relapse after more than 5 years' follow-up. Most meningiomas with chromosome 14 abnormalities have numeric changes, with interstitial deletions of 14q31-q32 present in few cases. Of the abnormalities detected, only monosomy 14 showed an adverse prognostic impact.     

Evaluation of cyclin expression in testicular germ cell tumors: cyclin E correlates with tumor type, advanced clinical stage, and pulmonary metastasis.

The measurement of proliferative index has yielded promising yet conflicting results in the evaluation of testicular tumors. We have examined the role of Ki-67, along with the cyclins A and E in testicular tumorigenesis. We compared the immunoreactivity of 20 pure seminomas with 20 mixed germ cell tumors composed predominantly of embryonal carcinoma with a variety of proliferation markers, including Ki-67, cyclin A, and cyclin E. All 40 tumors stained for Ki-67, and 19 of 20 (95%) seminomas and 18 of 20 (90%) embryonal carcinomas stained positively for cyclin A. Cyclin E stained 14 of 19 (74%) of the embryonal carcinomas and only 4 of 20 (20%) of the seminomas (Fisher's exact two-tailed test, P = .0012). There was a trend toward larger tumor size for cyclin E-positive seminomas (median, 5.92 cm versus 3.96 cm; P = .08), although the same correlation was not significant in embryonal carcinomas. For both seminomas and embryonal carcinomas, staining with cyclin E did not correlate with the presence of lymphovascular invasion or capsular invasion. However, patients who had cyclin E-positive tumors presented with higher clinical stage (P = .0015). In addition, pulmonary spread in embryonal carcinomas (four patients) and seminomas (one patient) occurred only in patients whose tumors were cyclin E positive (P = .014). Although Ki-67 and cyclin A offer little prognostic information in testicular germ cell tumors, cyclin E immunoreactivity correlates with tumor type and is strongly predictive of distant tumor spread.     

Prognostic relevance of a novel proliferation marker, Ki-S11, for soft-tissue sarcoma. A multivariate study.

In 132 soft-tissue sarcomas and 52 benign soft-tissue tumors, cellular proliferation was examined by immunohistochemistry using monoclonal antibodies Ki-S11 (Ki-67 antigen) and Ki-S1 (topoisomerase II alpha) and by flow cytometric analysis of the S-phase fraction (SPF). Malignant tumors were graded histologically according to the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) system. Patient age, sex, tumor location, histological type, and DNA ploidy were considered as additional prognostic variables. Consistent immunoreactivity was seen in approximately 95% of the cases, and determination of SPF was possible in approximately 60% Ki-S11 and Ki-S1 immunolabeling indices correlated in a linear manner. All proliferation parameters yielded significant differences between benign and malignant tumors. Ki-S11 and Ki-S1 immunoreactive scores also co-varied significantly with SPF, mitotic count, and histopathological grade. In univariate analysis, immunohistochemical proliferation indices, histopathological grade, mitotic count, and SPF were predictive of overall survival and the development of metastases. In multivariate analysis, immunolabeling scores of proliferation markers, grade, and SPF emerged as independent predictors of global survival and systemic progression. We conclude that the immunohistochemical assessment of proliferation, being more readily performable and more easily assessable than the equally relevant S phase fraction, may add appreciable information to the current prognostic models for soft-tissue sarcoma.     

Allelic losses at 1p, 9q, 10q, 14q, and 22q in the progression of aggressive meningiomas and undifferentiated meningeal sarcomas

Meningiomas are usually benign tumors; however, they can recur after surgical resection and occasionally show histological progression to a higher malignancy grade. Five such rare cases of aggressively recurring meningiomas were present in our departmental cohort of 923 primary meningeal neoplasms operated over a 17-year period. Four other aggressively recurring meningeal tumors with a very similar clinical and histomorphological appearance (three undifferentiated meningeal sarcomas, one hemangiopericytoma) were also included in this study. We investigated whether disease progression can be traced by genetic alterations and whether a pattern of genetic alterations is specific for meningiomas. A total of 40 specimens from primary tumors and multiple recurrences of the nine patients were analyzed with 26 polymorphic allelic markers for deletions on 1p, 1q, 9q, 10q, 14q, and 22q. Loss of heterozygosity (LOH) at 22q was observed in all meningiomas cases at the earliest time point analyzed. Allelic loss at 1p was seen in the original tumor in two cases and upon meningioma recurrence in two others. Deletion on 10q occurred during tumor progression in two cases, and on 9q and 14q in one case. While allelic loss at 22q appears to be an early event in aggressive meningioma disease, there is a clear correlation of further deletions on chromosome arms 1p, 9q, 10q, and 14q with histopathological and clinical progression, as shown in these intraindividual trackings. None of these genetic findings were present in the non-meningiomatous meningeal tumors, indicating that meningothelial cells have their own lineage-specific genetic pathways towards clinical malignancy.     

The importance of cyclin D1 and Ki67 expression on the biological behavior of pancreatic adenocarcinomas

The aim of this study was to evaluate the role of cyclin D1 and Ki67 proteins involved in cell-cycle control as a prognostic factor in pancreatic carcinomas. We examined formalin-fixed, paraffin-embedded material from 59 pancreatic adenocarcinomas, for which appropriate clinical and prognostic data were available. The standard streptavidin biotin immunoperoxidase method was used for immunostaining with cyclin D1 and Ki67. The extent of positive nuclear and cytoplasmic cyclin D1 staining was graded semiquantitatively. Ki67 reactivity was quantified and expressed as the percentage of stained nuclei. Staining with cyclin D1 and Ki67 was compared with histopathological prognostic features, and their relation with survival was also tested statistically. Patients whose tumors were cyclin D1-positive showed perineural invasion significantly more frequently than did patients with cyclin D1-negative tumors at the immunohistochemical level. In addition, tumors with lymphatic vessel invasion and without showed a significant difference in terms of cytoplasmic cyclin D1 staining. Ki67 indices were statistically different in stage groups. There was a significant and direct correlation between Ki67 index and nuclear cyclin D1 staining scores. No relation with survival was found. Our results suggest that cell-cycle proteins do not directly affect the prognosis of patients with pancreatic adenocarcinoma. Conversely, cyclin D1-positive tumors tend to have perineural invasion more frequently. In addition, lymph vessel invasion is another factor related to cyclin D1 reactivity of the cells. Ki67 indices differ statistically in stage groups.     

Proliferating cell nuclear antigen (PCNA) in atypical and malignant meningiomas.

Because it is not easy to determine the tumor status of meningiomas by current diagnostic procedures, we investigated these tumors immunohistochemically using the monoclonal antibody PC 10. This antibody recognizes a fixation- and processing-resistant epitope of the proliferating cell nuclear antigen (PCNA), which is a 36-KD nuclear antigen associated with the cell cycle. We studied paraffin-embedded and formalin-fixed tissue specimens of a group of 21 atypical/malignant meningiomas together with 18 benign meningiomas. PCNA staining results were compared with the mean number of silver-stained nucleolar organizer region-associated proteins (AgNORs), tumor grading, and mitotic indices of these tumors. The percentage of PCNA-positive cells was found to range between 0.1% and 40%, irrespective of the tumor grade. When all tumors were collectively considered, no positive correlation was found between PCNA scores and histologic grading and only a weak one between PCNA score and mitotic index. A higher correlation was seen between AgNOR counts and tumor grading. Our results suggest that PCNA labeling and histologic grading seem to be independent parameters. The correlations found between AgNOR counts and tumor grading should be substantiated in further series.     

Meningeome

The prognosis of the generally benign meningiomas is mainly an issue of the likelihood of recurrence, which increases with WHO grade (7-20% in WHO grade I, 29-40% in WHO grade II, and 50-78% in WHO grade III meningiomas). Among clinical parameters the most important prognostic factor is the completeness of neurosurgical tumor resection. Among histopathological prognostic parameters the mitotic activity is the most important one. As the cutoffs of the mitotic index (MI) are defined for each grade by the WHO classification of brain tumors and because the MI can be applied as the sole grading criterion, the reliable and reproducible assessment of the MI is crucial for an appropriate risk stratification. This is provided by immunohistochemical mitosis markers, i.e., phospho-histone H3 (PHH3). The PHH3 method is superior to the conventional mitosis counting method and therefore allows a more reliable risk stratification. The Ki-67 labeling index provides additional prognostic information, especially in prognostically ambiguous meningiomas. Cytogenetically, the deletion of the short arm of one chromosome 1 (1p-) is an unfavorable prognostic parameter and is correlated with a high risk of recurrence. The enzyme reaction for alkaline phosphatase (ALPL) is a fast and efficient screening method, which strongly indicates an intact chromosome 1 in cases with a positive enzyme reaction.     

Characterization of complex chromosome aberrations in a recurrent meningioma combining standard cytogenetic and array comparative genomic hybridization techniques

Meningiomas were among the first solid tumors recognized as having cytogenetic alterations. The most consistent changes reported in grade I meningiomas were monosomy 22 or partial 22q deletion. The vast majority of meningiomas are histologically benign, but the prognosis is determined by risk of recurrence after surgical treatment. Despite important advances in the identification of prognostic factors in the past decade, the exact nature of tumor recurrence remains largely unknown. In the present study, a recurrent transitional meningioma deriving from the anterior portion of the falx cerebri was characterized by combining conventional cytogenetics and array comparative genomic hybridization (CGH). Cytogenetic analysis at diagnosis revealed the following complex numerical and structural aberrations: 42,XY,der(1)t(1;?)(p12;?),-6,der(12;15)(q10;q10),-18, -22. Additional clonal evolutions were further identified with disease relapse. Array CGH corroborated the cytogenetic findings. The presence of a complex cytogenetic profile and progression-associated chromosomal abnormalities in a benign meningioma suggests the existence of underlying molecular events.     

Pediatric adrenocortical tumors: morphological diagnostic criteria and immunohistochemical expression of matrix metalloproteinase type 2 and human leucocyte-associated antigen (HLA) class II antigens. Results from the Italian Pediatric Rare Tumor (TREP) Study project

Pediatric adrenocortical tumors are neoplasms that only rarely occur in pediatric patients. Their clinical behavior is often unpredictable, and the histologic criteria of malignancy used in adults are not always useful in children. The aim of this study was to validate the prognostic value of the pathologic criteria of Wieneke et al and to evaluate the potential prognostic expression of matrix metalloproteinase 2 and human leucocyte-associated antigen (HLA) class II antigens in a series of 20 pediatric patients affected by adrenocortical tumors, who were enrolled in the Italian Pediatric Rare Tumor (TREP) Study between 2000 and 2007. The age range was 0 to 17.5 years (mean, 7.28 years) with a male-female ratio of 1:2. The mean follow-up was 64.4 months. The histologic diagnoses were reviewed, and the cases were classified using the criteria for malignancy proposed by Wieneke et al. The immunohistochemical expression of matrix metalloproteinase 2 and HLA class II antigens was scored by semiquantitative analysis and compared with the clinicopathologic parameters and outcome. Based on the scoring system of Wieneke et al, 7 tumors were classified as malignant; 12 tumors, as benign; and only 1 tumor, with "unpredictable behavior." In all cases, the clinical behavior was consistent with the pathologic criteria of Wieneke et al. Notably, areas of regressive myxoid changes, not included among the criteria of Wieneke et al, were observed in all but 1 case of malignant tumors and only in 2 cases of benign tumors. Matrix metalloproteinase 2 was focally to diffusely expressed in all malignant and in most benign tumors. HLA class II antigens immunoreactivity was absent in all benign tumors and restricted to rare isolated cells in most malignant tumors. Our findings confirm that the pathologic scoring system of Wieneke et al is a simple and reproducible diagnostic tool to predict prognosis in pediatric adrenocortical tumors. Unlike in their adult counterpart, the expression of matrix metalloproteinase 2 or the loss of HLA class II antigens does not discriminate between benign and malignant tumors in children. Although pediatric adrenocortical tumors seem to be similar histologically to their adult counterparts, it is likely that they have distinctive molecular features.     

Correlation between histological grade, MIB-1, p53, and recurrence in 69 completely resected primary intracranial meningiomas with a 6 year mean follow-up

Sixty-nine intracranial, totally excised meningiomas were immunostained for MIB-1 and p53 protein expression. According to the 1993 WHO criteria, revised by Perry et al., the 69 meningiomas were classified into: grade I = 54 benign meningiomas, grade II = 10 atypical meningiomas, grade III = 5 malignant meningiomas. The patients were followed until death or for an average of 6.7 years. The 69 meningiomas were divided into two groups, according to the absence (n = 42) or presence (n = 27) of recurrences. In the last group we included 3 patients who died of meningioma recurrence. According to the percentage of MIB-1 positively stained cells, meningiomas were divided into three groups: <1% (n = 36), 1-10% (n = 28), >10% (n = 5). We found the MIB-1 labeling index (LI) <1% in 33 grade I (61%) and in 3 grade II (30%) meningiomas. On the other hand, 7 grade II (70%) and all grade III (100%) meningiomas presented a MIB-1 LI >1%. Correlation between histological grade and MIB-1 LI was statistically significant (p = 0.0006). The correlation between MIB-1 LI and follow-up was also highly significant (p < 0.001): the majority of meningiomas which did not recur (32/42 equal to 76%) were characterized by a low (<1%) MIB-1 LI. In the recurrence group MIB-1 LI was significantly higher than in the disease-free patients' group. Moreover, MIB-1 appeared to be a prognostic parameter not strongly related to the histological grade. In fact, it was significantly higher in recurrent histologically benign meningiomas, as compared with benign meningiomas without recurrence (p = 0.0006). Positive p53 protein expression (>1%) was shown in 26/45 meningiomas (57%), with an LI of 1-10% in 18 (40%) and an LI of >10% in 8 (17%) meningiomas. Although the p53 LI tended to be higher in atypical and malignant meningiomas, no significant correlation was found between the p53 expression and the recurrence (p = 0.05). The authors conclude that quantitative MIB-1 labeling is a useful technique in the routine diagnostic assessment of meningiomas, and helpful in obtaining more information about prognosis and thereby in planning the most suitable treatment.     

Correlation of histopathologic classification with proliferative activity and DNA ploidy in 120 intracranial meningiomas,with special reference to atypical meningioma.

Histologic classification of 120 meningiomas was correlated with their proliferative fraction and DNA ploidy using immunohistochemistry and flow cytometry to differentiate histologically atypical meningiomas from benign ones. Histologically, the 120 meningiomas included 101 benign (43 meningotheliomatous, 40 transitional, 11 fibroblastic, 2 secretory, 2 microcystic, 2 angiomatous, and 1 psammomatous), 15 atypical, and 4 malignant meningiomas. As a histologic spectrum between the benign and malignant meningiomas, atypical meningiomas were defined by the presence of two of the following criteria; high cellularity, focal necrosis, uninterrupted growth pattern, and certain cytologic findings i.e., high nuclear/cytoplasmic ratio, coarse chromatin, and prominent nucleoli. In 56 cases, immunostaining for proliferating cell nuclear antigen showed higher proliferating cell fraction in atypical and malignant meningiomas than that in benign meningiomas (p < 0.05). In the flow cytometric analysis, aneuploidy was more often seen in atypical meningiomas compared to benign meningiomas (p < 0.05). We found that benign, atypical, and malignant meningiomas could be histologically classified and correlated with proliferative activity and DNA ploidy pattern. Therefore, atypical meningiomas should be distinguished from benign meningiomas by histopathologic examination and confirmed by studies on their proliferation fractions and DNA ploidies.