TERT promoter mutations in primary and secondary WHO grade III meningioma

Purpose: TERT promoter mutation (TERTp^Mut) has a strong association to recurrence and has been suggested to act as a driver mutation for malignant transformation of WHO grade I and II meningiomas. TERTp^Mut has been investigated in selected high‐grade meningioma samples. The existence of TERTp^Mut across recurrent tumors in a population‐based cohort needs to be investigated in order to identify when TERTp^Mut emerges across recurrent samples and to validate prognostic impact among WHO grade III tumors. Methods: We gathered material from a consecutive single‐center cohort of 40 patients with malignant meningioma (WHO grade III) treated between 2000 and 2018, including specimens from primary and secondary malignant meningiomas with the corresponding earlier benign specimens and later malignant recurrences. In total 107 tumor samples were studied by Sanger sequencing for TERT promoter mutational status. Results: Seven of 40 patients (17.5%) harbored TERTp^Mut thus validating the incidence of TERTp^Mut in previous non‐population‐based cohorts. In 6/7 patients, the TERTp^Mut was present at initial surgery (WHO grade I–III) while in one patient the TERTp^Mut was found de novo when the meningioma became malignant. The incidences were 2/1.000.000/year for TERTp^Mut WHO grade III meningioma and 8/1.000.000/year for TERTp^wt WHO grade III meningioma in our catchment area. We found a 1.7 times higher recurrence rate (CI 95% 0.65–4.44) and a 2.5 higher mortality rate per 10 person‐years (CI 95% 1.01–6.19) for TERTp^Mut compared to TERTp^wt. Conclusion: TERTp^Mut can occur independently of malignant progression in meningioma and was most often present from the first tumor sample across recurring tumors. TERTp^Mut in WHO grade III may represent a marker of an aggressive subset of tumors.     

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.     

Mitotic Index is an Independent Predictor of Recurrence‐Free Survival in Meningioma

While World Health Organization (WHO) grading of meningioma stratifies patients according to recurrence risk overall, there is substantial within‐grade heterogeneity with respect to recurrence‐free survival (RFS). Most meningiomas are graded according to mitotic counts per unit area on hematoxylin and eosin sections, a method potentially confounded by tumor cellularity, as well as potential limitations of accurate mitotic figure detection on routine histology. To refine mitotic figure assessment, we evaluated 363 meningiomas with phospho‐histone H3 (Ser10) and determined the mitotic index (number of mitoses per 1000 tumor cells). The median mitotic indices among WHO grade I (n = 268), grade II (n = 84) and grade III (n = 11) tumors were 1, 4 and 12. Classification and regression tree analysis to categorize cut‐offs identified three subgroups defined by mitotic indices of 0–2, 3–4 and ≥5, which on univariate analysis were associated with RFS (P < 0.01). In multivariate analysis, mitotic index subgrouped in this manner was significantly associated with RFS (P < 0.01) after adjustment for Simpson grade, WHO grade and MIB‐1 index. Mitotic index was then examined within individual WHO grade, showing that for grade I and grade II meningiomas, mitotic index can add additional information to RFS risk. The results suggest that the use of a robust mitotic marker in meningioma could refine risk stratification.     

Atypical meningioma: morphometric analysis of nuclear pleomorphism

The revised edition of the WHO classification of brain tumours now includes the "atypical" meningioma (grade II) which should be placed between the common type (grade I) and anaplastic type (grade III) according to histomorphological features and prognosis. However, diagnostic criteria for atypical meningioma are vague and the significance of brain invasion in the determination of malignancy is controversial. Nuclear pleomorphism and mitoses are usually considered the most important parameters to distinguish atypical and malignant meningiomas. According to WHO classification we selected eight cases of meningioma diagnosed as atypical (3 cases) and malignant (5 cases). All the tumours were supratentorially located. Nine cases of benign meningiomas were also studied as a control group. Morphometrical analysis was carried out by S.A.M. (Shape Analytical Morphometry) system. S.A.M. logical architecture assumes that each irregular shape contains elements of two distinct logical domains: gross distortions that interest the contour and its local perturbations. These features were investigated separately by analytical procedures to acquire independent parameters both on the logical and the numerical level. The results, statistically evaluated, show that nuclear pleomorphism is not a satisfactory criterion, if used alone, to distinguish atypical from malignant meningioma (Discriminant Analysis: 19% of minimum error).     

Hypermethylation and Transcriptional Downregulation of the TIMP3 Gene is Associated with Allelic Loss on 22q12.3 and Malignancy in Meningiomas

The gene for the tissue inhibitor of metalloproteinase 3 (TIMP3) on 22q12.3 had been reported to be inactivated by promoter methylation in various types of cancers, with controversial findings in meningiomas. We performed direct sodium bisulfite sequencing in a series of 50 meningiomas, including 27 benign meningiomas [World Health Organization (WHO) grade I], 11 atypical meningiomas (WHO grade II) and 12 anaplastic meningiomas (WHO grade III), and found hypermethylation of TIMP3 in 67% of anaplastic meningiomas, but only 22% of atypical and 17% of benign meningiomas. Moreover, TIMP3 methylation scores were significantly inversely correlated with TIMP3 mRNA expression levels (P = 0.0123), and treatment of the meningioma cell line Ben‐Men‐1 with demethylating agents induced an increased TIMP3 mRNA expression. TIMP3 is located in the chromosomal band 22q12, the allelic loss of which occurs early in meningioma tumorigenesis and preferentially targets the NF2 tumor suppressor gene. In our tumor panel, all meningiomas with TIMP3 hypermethylation—except for a single case—exhibited allelic losses on 22q12.3. Thus, TIMP3 inactivation by methylation seems fairly exclusive to meningiomas with allelic losses on 22q12 but—in contrast to NF2 mutation—appears to be involved in meningioma progression as it is associated with a more aggressive, high‐grade meningioma phenotype.     

The histopathological spectrum of human meningiomas

Histopathological examination and grading of meningiomas gives valuable prognostic information, although the method is subject for interobserver variability. The aim of this study was to review a large series of human meningiomas in order to examine the frequency of benign (grade I), atypical (grade II), and anaplastic (grade III) forms depending on various WHO classification schemes. In addition, we wanted to describe the frequency of various histopathological features and their mutual correlations. Sections from 196 consecutively treated primary human meningioma patients were revised retrospectively. The established criteria to grade meningiomas, which are also known to be associated with tumorigenesis, were shown to correlate significantly. The number of grade II meningiomas increased when using the WHO 2007 classification (30%) compared with previous editions, mainly due to the definition of brain infiltrating meningiomas as atypical (grade II). bimodal frequency distribution among age groups of females was observed. Continuous revision of histopathological classification systems is required to improve the diagnostic accuracy.     

Expression of somatostatin receptors (SSTR1-SSTR5) in meningiomas and its clinicopathological significance

Meningiomas are benign brain tumors that are usually to recur. Studies have shown in vitro and in vivo that meningiomas, regardless of histology and classification, express somatostatin receptors (SSTRs). We investigated the immunohistochemical expression of five SSTR subtypes (SSTR1-SSTR5) in tumor tissue sections from 60 patients with diagnosis of meningioma who underwent surgical resection and relating it to patient age and sex, tumor histology, location, regrowth/recurrence and follow-up. Mean (SD) patients age was 53.18 (12.6) years and 44 were women (73.3%). According to the WHO histological grading criteria, 47 (78.3%) meningiomas were grade I, 11 (18.3%) were grade II, and 2 (3.3%) were grade III. All five SSTRs were expressed in our sample, at frequencies ranging from 61.6 to 100%, with a predominance of SSTR2. SSTR5 was more frequently expressed in tumors benign than in tumors malignant (P<0.013). Recurrence-free survival rate at 2 years was 75.2%. There were no significant differences in SSTR expression regarding age, sex, tumor location and regrowth/recurrence. SSTR expression was detected at a significant frequency in this series. SSTR5 showed higher expression in tumors benign supporting the use of these SSTRs in diagnostic of meningiomas and their influence in process of tumorigenesis in meningiomas recurrence.     

New developments in the pathology of skull base tumors

As an anatomical interface between various tissues, the skull base harbors an exceptionally broad variety of neoplasms, some of which pose a major challenge for surgical pathology. The characterization of distinct immunohistochemical expression profiles and the identification of molecular genetic alterations associated with different tumor entities have significantly advanced this field. The new World Health Organization (WHO) classification of tumors of the nervous system lists 15 histopathological variants of meningioma. Of clinical importance are those entities that carry an increased risk of recurrence and a poor prognosis, i.e., the atypical meningioma (WHO grade II), clear-cell meningioma (WHO grade II), chordoid meningioma (WHO grade II), rhabdoid meningioma (WHO grade III), papillary meningioma (WHO grade III), and anaplastic meningioma (WHO grade III). Diagnostic criteria for atypical and anaplastic meningioma variants have now been stringently defined. The differential diagnosis of meningiomas includes hemangiopericytoma, hemangioblastoma, solitary fibrous tumor, sarcomas, and chordoid neoplasms. Recent data highlight the importance of distinguishing chordoma and chondrosarcoma of the skull base since chondrosarcomas show a significantly better clinical outcome. Among the less common, aggressive tumor entities in this anatomical region, infiltrating pituitary adenoma/pituitary carcinoma, superficial malignant gliomas, rhabdomyosarcoma, olfactory neuroblastoma, various sarcomas, and malignant lymphoma must be considered. Profiles of molecular genetic alterations have been established for several of these neoplasms and may facilitate the differential diagnosis. This review summarizes recent developments in the histopathological characterization, classification, and molecular pathology of neoplasms arising at the skull base.     

Multiple meningioma with different grades of malignancy: case report with genetic analysis applying single-nucleotide polymorphism array and classical cytogenetics

Multiple meningiomas with synchronous tumor lesions represent only 1-9% of all meningiomas and usually show a uniform histology. The simultaneous occurrence of different grades of malignancy in these nodules is observed in only one third of multiple meningiomas. We report a case of a sporadic multiple meningioma presenting with different histopathological grades (WHO I and II). The tumor genome of both nodules was analyzed by GTG-banding, spectral karyotyping (SKY), locus-specific FISH, and single nucleotide polymorphism array (SNP-A) karyotyping. GTG-banding and SKY revealed 25 structural and 33 numerical aberrations with a slightly increased aberration frequency in the WHO grade II nodule. We could confirm terminal deletions on chromosomes 1p [ish del(1)(p36)(p58-,pter-) 16.5% WHO grade I and 20.9% WHO grade II], partial deletions on 22q, and/or monosomy 22 (monosomy 22 14% WHO grade I and 34% WHO grade II) as the most frequent aberrations in both meningioma nodules. In the meningioma WHO grade II, in addition, a de novo paracentric inversion within chromosomal band 1p36 was detectable. Furthermore, for meningiomas de novo, dicentric chromosomes 4 could be identified in both tumor nodules. We also detected previously published segmental uniparental disomy regions 1p31.1, 6q14.1, 10q21.1, and 14q23.3 in normal control DNA of the patient and in both tumor nodules. Taken together, we describe a very rare case of multiple meningioma with overlapping but also distinct genetic aberration patterns in two nodules of different WHO grades of malignancy.     

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.     

Molecular neuropathology of brain‐invasive meningiomas

Invasion of brain tissue by meningiomas has been identified as one key factor for meningioma recurrence. The identification of meningioma tumor tissue surrounded by brain tissue in neurosurgical samples has been touted as a criterion for atypical meningioma (CNS WHO grade 2), but is only rarely seen in the absence of other high‐grade features, with brain‐invasive otherwise benign (BIOB) meningiomas remaining controversial. While post‐surgery irradiation therapy might be initiated in brain‐invasive meningiomas to prevent recurrences, specific treatment approaches targeting key molecules involved in the invasive process are not established. Here we have compiled the current knowledge about mechanisms supporting brain tissue invasion by meningiomas and summarize preclinical models studying targeted therapies with potential inhibitory effects.     

High Incidence of Activating TERT Promoter Mutations in Meningiomas Undergoing Malignant Progression

Meningiomas are common central nervous system tumors. The World Health Organization (WHO) defines three grades, predictive of the risk of recurrence. These tumors can relapse frequently and sometimes undergo malignant transformation. Maintenance of telomere length is a key process in malignant progression, and mutations in TERT promoter have recently been identified in various types of cancer. We sequenced the TERT promoter in 85 meningiomas from 73 patients. We found a high incidence of TERT promoter mutations in patients with meningiomas undergoing malignant histological progression (28%, n = 5/18 patients). In this subset of patients with histological progression, TERT promoter mutations were found in both the lowest and the highest grade tumors, and in both NF2‐mutated and nonmutated samples. In contrast, one mutation was identified in 35 meningiomas without recurrence or progression, belonging to various histological grades. This sample was an aggressive meningioma in a patient who died shortly after surgery. Interestingly, tumors showing relapse without histological progression were not mutated for TERT promoter (n = 20). Finally, TERT promoter mutations were associated with a marked increase in TERT expression. Thus, TERT promoter mutations are pivotal genetic alterations involved in malignant progression of meningiomas and could be used as a biomarker to identify meningiomas at risk of malignant transformation.     

A conceptual shift in the grading of meningiomas

Grading schemes for meningiomas have traditionally designated tumors as "meningioma," "atypical meningioma," or "anaplastic (malignant) meningioma," depending upon the presence of histopathologic features thought to indicate aggressive behavior. In the past, most systems have considered brain invasion by tumor as the best evidence of malignancy. Perry et al. have recently investigated the significance brain invasion as a prognostic feature in meningiomas. The authors studied a series of 116 patients who had been diagnosed previously with "malignant meningioma" due to the presence of brain invasion, histologic anaplasia, or metastasis. On the basis of a multivariate analysis of histopathologic features and their relationship to tumor recurrence and patient survival, the authors concluded that brain invasion should be considered one of the diagnostic features of atypical meningioma. Accordingly, the diagnosis of malignant meningioma should be reserved for those tumors that are frankly anaplastic and/or contain (> = 20 mitoses per 10 high-power fields (HPF). Due in large part to the strength of evidence in this study, the World Health Organization (WHO) has adopted a grading scheme for meningiomas that incorporates many of the authors' proposals. New diagnostic criteria will result in improved reproducibility with fewer diagnoses of malignant meningioma (WHO grade III).     

Atypical,aplastic, and unusual meningiomas. Morphology and incidence in 300 consecutive cases

We morphologically studied 300 consecutive and primitive meningiomas surgically treated between march 1997 and april 2002 in order to evaluate the incidence of atypical, anaplastic, and morphologically unusual meningiomas. Two hundred and fifty-five meningiomas (85%) were WHO I, 33 (11%) were WHO II, 9 (3%) were WHO III; the remaining 3 meningiomas (1%) showed clear and diffuse oncocytic differentiation without cytologic or architectural atypia (oncocytic meningiomas). Forty-five of 255 WHO I meningiomas (18%) were infrequent histological subtypes: 18 (7%) psammomatous, 9 (4%) metaplastic, 9 (4%) secretory, 6 (2%) angiomatous, and 3 (1%) microcystic. Thirty of 33 WHO II meningiomas (91%) were atypical, 2 (6%) were clear cell meningiomas, and 1 (3%) was chordoid meningioma. Seven of 9 WHO III meningiomas (78%) were anaplastic and 2 (22%) were papillary. We evidenced the high morphological variability and the discrete occurrence of WHO I and WHO II meningiomas.     

Miniaturized Handheld Confocal Microscopy Identifies Focal Brain Invasion in a Mouse Model of Aggressive Meningioma

Invasion of the brain parenchyma by a meningioma classified by histological criteria as World Health Organization (WHO) grade I meningioma, implies that the tumor has greater likelihood of recurrence and a biological behavior similar to the more aggressive WHO grade II meningiomas. It is therefore important to detect microscopic foci of brain invasion during surgery in order to maximize the resection and/or adapt imaging follow‐up. In this study, we tested the sensitivity of two handheld confocal imaging devices to detect foci of brain invasion in two types of meningioma mouse models: in a genetically engineered mouse model and in a syngeneic xenograft model. Confocal imaging offered precise images of meningothelial and fibroblastic mouse meningiomas as well as malignant meningiomas, which corresponded exactly to the pathological findings. Imaging showed a sharp definition of the brain‐tumor interface and enabled identification of embedded nerves and vessels. Importantly, in both mouse models used in this study, extension of tumor along Virchow–Robin spaces into adjacent brain was detected by imaging. In conclusion, this novel technique, following validation in clinical trials, may open new possibilities for use in operating rooms to influence both decision making during the surgery and planning for additional treatments.     

Expression of extracellular matrix-degrading proteins in classic, atypical, and anaplastic meningiomas

Although the majority of meningiomas, commonly benign tumors (WHO I), are amenable to surgical resection, a percentage of up to 3% will recur as higher-grade meningiomas with potential brain invasion. Our study aims at the in situ identification of proteolytic, extracellular matrix-degrading enzymes in a broad spectrum of meningiomas. We examined 80 meningiomas (50 classic meningiomas WHO I, 19 meningiomas WHO II, including atypical, chordoid, and clear cell types, as well as 11 anaplastic meningiomas WHO III) for the immunohistochemical expression patterns of cathepsin D and metalloproteinases MMP-2 and MMP-9. Meningiomas of all types and grades revealed a distinct expression of MMP-9 and cathepsin D, while MMP-2 was found predominantly in WHO II and III meningiomas. There was a significant increase in positive tumor cells from WHO grade I to II and III for MMP-2 (p<0.001), but not for cathepsin D (p=0.099). MMP-9 displayed an increased number of positive tumor cells from WHO grade I to II, but a decrease in WHO III meningiomas (p<0.002). Routine screening for the expression of metalloproteinases and cathepsin D will not reveal any new diagnostically or prognostically relevant information. However, these factors may represent a potential target for pharmacological blocking as an anti-invasive therapy.     

Increased Co-Expression of Macrophage Migration Inhibitory Factor and Matrix Metalloproteinase 9 Is Associated with Tumor Recurrence of Meningioma

Background and Objective: We detected the expression of MIF and matrix metalloproteinase 9 (MMP9) in meningiomas to determine whether they are valuable recurrence predictor for meningioma.Methods: 67 cases of meningiomas, including 57 benign tumors (WHO grade I) and 10 non-benign tumors (WHO grade II and III), were collected, and expression of MIF and MMP9 in tissue microarray was evaluated immunohistochemically. The correlations between immunostainings and clinicopathological parameters, as well as the follow-up data of patients, were analyzed statistically.Results: Increased expressions of both MIF (58.2%, 39/67) and MMP9 (55.2%, 37/67) were significantly associated with microvessel density (MVD) of tumor, but only dual high-expression of MIF and MMP9 was in relation to tumor invasion (P=0.016) and tumor recurrence (P=0.001). Based on univariate analysis, histological grade, tumor invasion and co-expression of MIF and MMP9 were significant predictors for recurrence. However, only histological grade and co-expression of MIF and MMP9 in tumor were independent recurrence factors with a hazard ratio of 49.033 (P=0.002) and 37.766 (P=0.002) in multivariate analysis.Conclusions: Together with histological grade, increased co-expression of MIF and MMP9 in tumor might be a valuable predictor for recurrence, especially for benign meningiomas.     

Atypical and malignant meningiomas: importance of micronecrosis as a prognostic indicator

Twenty-eight patients with a diagnosis of either atypical or malignant meningioma, according to the World Health Organisation (WHO) classification, were followed up to relate histopathological features with times to recurrence and death. Five year disease-free survival was 41% with a median disease free survival of 27 months. Micronecrosis was the only histopathological feature associated with increased risk of recurrence (rate ratio, 3.73; 95% confidence interval 1.03–13.6). At 36 months, 32% of patients with micronecrosis were alive compared with 71% of patients without micronecrosis. Brain invasion was not associated with disease-free survival. After recurrence, median survival was 7 months and was not correlated with any histopathological feature. The prevalence of micronecrosis was estimated from random samples of benign, atypical and malignant meningiomas to be 8%, 42% and 71% respectively. The relevance of these findings and the current WHO classification is discussed.     

Role of p53 gene mutation in tumor aggressiveness of intracranial meningiomas.

The mutations that occur in the p53 tumor suppressor gene have been studied in various human malignant tumors. However, little is known about this gene in meningiomas. To investigate the relationship and frequency of p53 gene mutations, the p53 polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) and immunohistochemical study were performed on the 41 intracranial meningiomas (21 benign, 11 atypical, and 9 malignant). The higher the p53 protein expression rate, the poorer the histologic grade (9.5%, 72.7%, and 88.9% in benign, atypical and malignant meningioma, respectively) (p=0.000). The p53 protein expression rate was higher in recurrent meningioma (71.4%) than in nonrecurrent meningioma (10.5%) (p=0.002). PCR-SSCP method was performed in positive p53 protein immunoreactivity cases. p53 gene mutation rate was higher in the atypical (62.5%) and malignant (25%) meningiomas than in the benign meningioma (0%) (p=0.232). Also, the rate was higher in recurrent menigioma (20%) than in nonrecurrent meningioma (0%) (o=0.495). Among five to eight exons of the p53 gene, the mutation was observed on exon 7 more frequently. In conclusion, p53 immunoreactivity and p53 gene mutation are closely correlated with histologic grade and histologic atypia of intracranial meningiomas. p53 gene mutation would be considered as a useful marker to detect the progression of intracranial meningiomas.