Proliferation rate of intracranial meningiomas as defined by the monoclonal antibody MIB-1: correlation with peritumoural oedema and other clinicoradiological and histological characteristics

Paraffin-embedded surgical specimens from 55 meningiomas were immunostained after microwave processing using the streptavidin/peroxidase method and the monoclonal antibody (moAb) MIB-1 to the Ki-67 antigen. The authors assessed proliferative labelling index (LI) from a series of surgically removed meningiomas using immunohistochemical methods and MIB-1, and they correlated this index with clinical, radiological, and histological factors. No relationship was found between LI, sex, age, resection and histological grades, or volume. Symptoms, location, and peritumoural oedema did have a significant relationship to the MIB-1 LI. The symptomatic patients, i.e. those with tumours at the base of the skull and with GR3 peritumoural oedema (grade 3), had a greater chance of higher MIB-1 LI. It was proven that the increase of one unit in peritumoural oedema classification gave an increased risk of 3.312 and an LI greater than 3%. The authors also discuss the different methods of evaluating LIs in meningiomas, based on the available literature.     

Peritumoural brain oedema in intracranial meningiomas: Influence of tumour size, location and histology

Summary Peritumoural brain oedema was examined retrospectively in 175 patients with 179 intracranial meningiomas. The influence of tumour size, location and histology were investigated.Tumour volume and localization, and the presence of peritumoural brain oedema (PTBOe) were determined by computed tomography (CT). The oedema-tumour volume ratio was defined as Oedema Index (Oel). All patients underwent microsurgical removal of the tumour. Surgically resected meningiomas were classified histopathologically based on criteria of the new World Health Organization (WHO) classification. A close relationship was found between the tumour size and the incidence of peritumoural oedema: with increasing size of the tumour the incidence of oedema also rises, the oedema index, however decreases. Frontobasal and temporobasal meningiomas showed a significant increase in the oedema incidence and the mean oedema index. If major parts of the surface of meningiomas were adjacent to subarachnoid cisterns only a slight tendency for the development of oedema was observed. WHO-III-meningiomas showed a significantly higher oedema incidence (61.1% vs. 94.4%; p<0.004) and mean oedema index (Oel=2.7 vs. 3.7; p<0.0009) than WHO-I-meningiomas. Brain tissue was affected in 59 cases. 19 meningiomas with infiltration into adjacent brain parenchyma revealed a statistically significant increase in oedema incidence (94.7% vs. 51.7%; p<0.0003) and mean oedema index (Oel=3.9 vs. Oel=2.2; p<0.0001) when compared to tumours without any brain tissue involvement in the histopathological specimens. Tumours with large volume, fronto-temporo-basal location and anaplastic histology were not only associated with the highest incidence of oedema formation but also presented with an overproportionate infiltrative growth. Thus, a disruption of the arachnoid or a true brain infiltration may be an essential factor for the development of a PTBOe.     

Angiogenesis and Brain Oedema in Intracranial Meningiomas: Influence of Vascular Endothelial Growth Factor

Summary The correlation between angiographic neovascularization, peritumoural brain oedema (PTBOe) and the expression of vascular endothelial growth factor (VEGF) , was analysed in 30 patients with intracranial meningiomas. Pre-operative angiograms were examined for the existence of either an exclusively dural tumour blush or an additionally pial tumour supply from cerebral arteries. Furthermore the presence of macroscopic tumour-neovascularization and dysplastic changes of tumour-draining cerebral veins was evaluated. VEGF expression was investigated on histological tissue samples, using immunohistochemical techniques. VEGF immunohistochemistry and neuroradiological evaluations were performed in double blind fashion. Tumour volume and the amount of oedema were calculated by computerized tomography (CT) or magnetic resonance imaging (MRI). The oedema-tumour volume ratio was defined as oedema index (OeI). Compared to VEGF-negative meningiomas, tumours with striking VEGF staining revealed a significant higher mean oedema index (OeI=4,2 vs. OeI=1,5; p<0.018), and a higher oedema incidence (91,7% vs. 44,4%; p<0.046). Equally, meningiomas with additionally tumour supply from cerebral arteries were associated with a significant higher mean OeI (OeI=4.1 vs. OeI=1.2; p<0.01) and oedema incidence (94,7% vs. 20,0%; p<0,0023) than meningiomas with exclusively tumour supply from dural arteries. All meningiomas with striking VEGF-expression were associated with vascular tumour supply from cerebral arteries, but VEGF-negative tumours only in 50% (p<0.029). These data suggest a link between VEGF-expression, arterial tumour supply and peritumoural brain oedema. The development of tumour supply from cerebral arteries may be important for formation of meningioma-related oedema. Therefore, VEGF may represent a potent mediator in the evolution of this type of vascularization in meningiomas.     

Cerebral oedema associated with WHO-I,WHO-II,and WHO-III-meningiomas: Correlation of clinical,computed tomographic,operative and histological findings

Summary Meningiomas were studied in 60 patients retrospectively. Clinical, operative and histological findings were correlated with the occurrence and extension of peritumoural oedema as measured by computerized tomography. A relationship was found between both oedema and seizures and between oedema and tumour location. No relationship between tumour size, arachnoid breaching, WHO-grade or tumour vascularity and oedema was detected. In four patients with severe pre-operative oedema, cerebral signs and symptoms persisted despite uncomplicated tumour removal.The present study shows that peritumoural oedema is not only epileptogenic but that it can also cause irreversible cerebral damage as well. Since this study purports to demonstrate that meningiomas with intact leptomeninges can show severe peritumoural oedema, the blood barrier breakdown theory cannot be considered as the only aetiological factor.     

Cystic meningioma

Summary Meningiomas are usually solid tumours. Cystic changes in meningiomas are rare. These cysts may occur extratumoural, peritumoural or intratumoural. Diagnostic difficulties arise in cases of cystic meningiomas. Nine cases of cystic meningiomas were operated on in the past 6 years at the department of neurosurgery, University of Alexandra. The mean age of patients was 46.2 years. Male to female ratio was 1/2. Less oedema was observed in extratumoural cysts, and more oedema in intratumoural cysts. The fluid contained was dark brown or dirty yellow in intratumoural cysts (type C), xanthochromic in peritumoural cysts surrounded by tumour tissue (Type B), or clear fluid in extratumoural cysts (Type A). Based on these two observations it is proposed that the cyst fluid and peritumoural oedema may represent variable degrees of degeneration or secretion by tumour cells. Pre-operatively diagnostic criteria are presented.     

Significance of MIB-1 staining indices in meningiomas: comparison of two counting methods

The authors evaluated the predictability of MIB-1 immunohistochemistry for growth and recurrences of meningiomas using two different counting methods: 1) in the area of the highest MIB-1 labeling (HL method) and (2) in randomly selected fields (RS method). The MIB-1 staining indices (SIs) determined by the HL method were approximately twice as high as those by the RS method, and the correlation coefficient between them was high (R = 0.86) in 139 meningiomas when transformed logarithmically. The differences in SIs in histologic grades were significant with either method. Tumor doubling time (Td) was calculated in 22 meningiomas from serial radiologic examinations. The RS method yielded a slightly higher correlation coefficient between log Td and log SI than the HL method. When the authors examined the predictability of recurrence in 112 totally removed meningiomas, the RS method distinguished the recurrent group more definitively. Several benign meningiomas with low SIs by the RS method exhibited focal accumulation of MIB-1-positive cells. Although they were assigned high MIB-1 values by the HL method, these meningiomas did not recur, and therefore obscured the prognostic importance of the MIB-1 value with the HL method. Focal accumulation of MIB-1-positive cells in meningiomas is not likely to correlate with their biologic aggressiveness.     

Radiosurgery for Atypical and Anaplastic Meningiomas: Histopathological Predictors of Local Tumor Control

Objectives: We investigated the radiosurgical outcomes of patients with nonbenign meningiomas retrospectively and sought to identify prognostic factors for local tumor control after radiosurgery with an emphasis on histopathology. Methods: Between 1998 and 2010, 35 patients with 49 atypical or anaplastic meningiomas were treated with radiosurgery. The mean tumor volume and marginal irradiation dose were 3.5 cm(3) (range 0.3-25.3) and 16 Gy (range 12-21), respectively. Results: The actuarial local tumor control rates for patients with atypical meningiomas at 1, 2 and 3 years after radiosurgery were 78, 53 and 36%, respectively, whereas those for anaplastic meningiomas were 35% at 1 year and 10% at 2 years. Multivariate analysis revealed that the mitotic count (≤8 per 10 high-power fields; HPF) and the MIB-1 proliferation marker labeling index (LI; ≤8%) were significant favorable prognostic factors for the radiosurgical outcomes of patients with nonbenign meningiomas (p = 0.014 and p = 0.012, respectively). Conclusions: Radiosurgery could be a treatment option for patients with atypical meningiomas, but more aggressive treatments are needed for those with anaplastic meningiomas. Histopathological factors such as mitotic count and MIB-1 LI are significant prognostic factors for the radiosurgical outcomes of patients with nonbenign meningiomas and should be considered before radiosurgery.     

A study on peritumoural brain oedema around meningiomas by CT and MRI scanning

Summary There is a great variability in the amount of peritumoural brain oedema accompanying meningiomas. In a previous study it was found that the degree of brain oedema in the white matter around meningiomas correlated with disruption of the layers (especially the cerebral cortex), which separate the tumour from the white matter, as well as with the size and histological subtype of the tumour.In the present study comprising 9 meningiomas, the volume of oedema was calculated by integration of the cross-sectional oedematous areas on serial MRI slices. The volume of oedema was zero in 3 cases and ranged from 11 to 176.4 ml in the other 6 cases. The MRI-scans also showed disruption of the cortex in all cases, ranging from slight to severe. T₁ and T₂ measurements were made at the level of maximum extension, using a mixed sequence at a field strength of 1.5 T. From the T₂ values tissue water content in % was calculated using the equations: WC=39.36/(R₂ + 37.2) for cortex, and WC=29.63/(R₂ + 27.8) for white matter. These had been obtained by correlating water content with relaxation rates, measured in vitro on human brain autopsy specimens which were subjected to hydration with distilled water or dehydration by hyperosmolar solutions. Mean water content amounted to 82.53% for normal cortex, 74.72% for normal white matter, and 84.59% for oedematous white matter around the tumour.On the assumption that the spread of contrast agent marks the advancement of the front of oedema produced by the tumour, CT-studies were made before, and at 1 1/2, 3 and 6h after contrast infusion. The increase in diameter of the contrast-stained area on the CT-scan allows calculation of the excess of oedema production per unit tumour volume. Of 6 tumours with oedema (mean peritumoural water content of 91% and mean volume of oedema of 69.2 ml) the production excess at the steady-state was 0.18–1.08 ml/h/cm³ tumour volume, whereas 3 tumours without associated oedema had a production excess of 0.03–0.12 ml/h/cm³. Moreover, penetration of the cortex seems to constitute a separate factor determinig the spread of oedema.     

Microcystic meningiomas: radiological characteristics of 16 cases

Summary Background. As a rare subtype of meningioma, only a few reports deal with radiological characteristics of microcystic meningiomas and the problem remains controversial. The authors have analyzed the radiological findings of a series of microcystic meningiomas with a special focus on magnetic resonance images (MRI) and conventional angiography.Method. Sixteen patients of histologically proven microcystic meningiomas were included. Analysis of preoperative MRI including signal intensity characteristics, enhancement patterns and peritumoural edema were performed and correlated with angiographic and histological findings. Peritumoural edema was graded using edema index (EI) which was defined as the ratio of V_E/V_T.Findings. The tumours were uniformly visualized as a high-signal mass lesion in T2-weighted images and as a low-signal mass lesion in T1-weighted images regardless of tumour vascularity shown by angiography. T2-weighted images revealed that peritumoural brain edema was severe in 11, moderate in 1, mild in 2 and negligible in 2 patients and this was closely related to the co-existence of irregular tumour marginal enhancement. However, other features failed to distinguish these lesions from other subtypes of meningioma.Conclusions. The cases presented demonstrate that characteristic MRI findings suggestive of microcystic meningiomas are; (1) low signal intensity mass in T1- and high signal intensity mass in T2-weighted images; (2) high incidence of peritumoural edema.     

Potential doubling time and tumour doubling time in meningiomas and neurinomas

Summary Cell kinetic study plays an important role in treatment planning of brain tumour patients. MIB-1 antibody has recently become available, which detects Ki-67 antigen even in the formalin-fixed paraffin-embedded specimens. We performed MIB-1 immunostaining in 50 meningiomas and 50 neurinomas, and estimated the cell cycle time (tc) and potential doubling time (Tpot) from MIB-1 staining index (MIB-1 SI) and mitotic index (MI). MIB-1 SI logarithmically correlated with MI in both meningiomas and neurinomas. The tc and the Tpot were expressed as a function of the mitosis time (tm), while the tm is known to be around one hour and not exceeding two hours. When the tm was assumed to be one hour, the average tcs of meningiomas and neurinomas were 6.53±3.56 days and 7.67±3.27 days, respectively. The Tpots were447 × (MIB-1 SI)^–1.29 × tm in meningiomas, and490 × (MIB-1 SI) ^–0.98 × tm in neurinomas.The tumour doubling times (Tds) were calculated from serial imaging studies in 22 neurinomas and 15 meningiomas. The Tds were formulated as794 × (MIB-1 SI) ^–0.83 in meningiomas and1380 × (MIB-1 SI) ^–0.97 in neurinomas. Most of the Tds correlated well with the Tpots in meningiomas and neurinomas, and exceeded values of the Tpot when the tm is assumed to be one hour, although a few tumours showed unexpectedly longer Tds. The Tpot and the tc estimated from MIB-1 SI and MI are clinically useful parameters for predicting the growth potential of meningiomas and neurinomas where no other simple methods are available.     

Role of ischaemia in the genesis of oedema surrounding meningiomas assessed using magnetic resonance imaging and spectroscopy

Oedema surrounding meningiomas is well known, but its pathogenesis remains obscure. Perfusion and metabolism in this peritumoural parenchyma were studied preoperatively in eight patients using magnetic resonance imaging, dynamic perfusion scanning and proton spectroscopy. Relative cerebral blood volumes (CBV) and metabolite ratios were calculated for the tumour and peritumoural brain. All meningiomas showed gadolinium enhancement, high choline (Ch), low creatine (Cr) and low N-acetyl aspartate (NAA) [Ch: (Ch + Cr) 0.67, SD 0.13, NAA: (Ch + Cr) 0.18, SD 0.15]. Lactate was present in four tumours [lactate: (Ch + Cr) 0.32, SD 0.27]. Extremely low gadolinium passage and low CBV were seen in the 2 cm peritumoural region, with elevated lactate [lactate: (Ch + Cr) 0.26, SD 0.18]. Four centimetres from tumour margin the CBV was still reduced (65, SD 20% with less lactate [lactate: (Ch + Cr) 0.12, SD 0.01]. Relative CBV is reduced around meningiomas and is associated with lactate, suggesting that oligaemia and altered metabolism may be part of the pathology in peritumoural oedema. Such changes may be important in determining functional recovery after surgery.     

Noninvasive evaluation of the malignant potential of intracranial meningiomas performed using proton magnetic resonance spectroscopy

OBJECT: Controversy exists about correlations between histological tumor grade and magnetic resonance (MR) spectroscopy data. The authors studied single-voxel proton MR spectroscopy as a noninvasive way to evaluate grade of malignancy in intracranial meningiomas. METHODS: The authors compared the results of MR spectroscopy with those derived by the MIB-1 staining index (SI) in 29 meningiomas. Proton MR spectroscopy was performed using stimulated echo acquisition and volume-localized solvent-attenuated proton nuclear MR sequences before surgery or other therapy. Twenty-four tumors were histologically benign (13 meningothelial, three fibrous, four transitional, three angiomatous, and one chordoid); four were atypical (Grade II), and one was papillary (Grade III). The mean MIB-1 SI in the benign group was significantly lower than those in the other groups (p = 0.0041). The mean choline-containing compound (Cho)/ creatine and phosphocreatine (Cr) ratios in the benign and nonbenign groups were 2.56+/-1.26 and 7.85+/-3.23, respectively (p = 0.0002). A significant linear correlation was observed between the Cho/Cr ratio and the MIB-1 SI (r0.05 = 0.74, p<0.001). Necrosis was present histologically in four of the five meningiomas classified either as atypical or papillary. Magnetic resonance spectroscopy revealed a methylene signal in these meningiomas that was not detected in benign meningiomas. Of the five meningiomas in which only a lactate signal was observed, two were benign and the MIB-1 SI in these two benign meningiomas was higher than the mean value for the benign group. Alanine, detected in 12 of 30 meningiomas, did not correlate with either tumor grade or Cho/Cr ratio. CONCLUSIONS: Proton MR spectroscopy is a useful diagnostic method for determining the proliferative or malignant potential of meningiomas according to the Cho/Cr ratio. A lactate and/or methylene signal suggests a high-grade tumor.     

Proliferative activity and branching morphogenesis in the human prostate: a closer look at pre- and postnatal prostate growth

BACKGROUND: To gain further insight into the molecular cell biologic features of prostate development, we investigated the proliferative activity of prostate epithelial and stromal cells and their topographic relationship with neuroendocrine (NE) cell distribution and regional heterogeneity. METHODS: Consecutive sections from 43 prostates taken during autopsy representing fetuses (12-38 weeks of gestation), infants, prepubertal males and adults were double stained for chromogranin A and MIB-1. MIB-1 labeling index (LI) was calculated in the budding tips, forming acini, major collecting ducts, adjacent and non-adjacent stromal compartments. Furthermore, the topographic relationship between proliferating cells and NE cells was evaluated. RESULTS: In the first half of gestation, cell proliferation as revealed by MIB-1 LI was significantly higher in epithelial structures and stroma than in older fetuses and other age groups. MIB-1 LI was higher in budding tips than in other epithelial regions. MIB-1 LI in stroma adjacent to budding tips was not higher than that adjacent to other epithelial branching segments. Co-expression of chromogranin A and MIB-1 staining was not observed. MIB-1 LI was lower in cells in the direct vicinity of chromogranin A positive NE cells than at a distance from NE cells. CONCLUSIONS: Prostate development in the first half of gestation is explosive. Thereafter, the prostate basically is a slow-growing organ. Budding tips are the major growth foci during early prostate development, while stromal growth is evenly distributed throughout the prostate, probably indicating that stromal-epithelial interactions do not manifest in enhanced proliferation at their interface. NE cells may have an inhibitory effect on proliferation of exocrine epithelial cells and are probably only associated with differentiation of prostate exocrine cells in the prostate.     

Value of MIB-1 labelling index (LI) in gliomas and its correlation with other prognostic factors. A clinicopathologic study

BACKGROUND: In recent years, the monoclonal antibody MIB-1 has become the main factor to measure the proliferative potential of glial tumors. This antibody is equivalent to Ki-67, which is used in frozen sections, and reacts with a nuclear protein that is expressed through the cell cycle. We have investigated the value of MIB-1 Labelling Index (LI) as an independent prognostic factor in gliomas and its relationship with clinical and pathological parameters. METHODS: MIB-1 LI was determined in 139 gliomas by using the Streptavidin-Biotin Complex (SBC) immunohistochemical method. MIB-1 LI immunoreactivity was measured with an automatic cell counting system. Survival was studied by using the Kaplan-Meier bivariant analysis and Cox multivariant regression. RESULTS: In bivariant analysis MIB-1 LI increased with age, histological grade and a supratentorial lateral location. Only size and tumor grade were significant in Cox regression. CONCLUSIONS: Perhaps this proliferation marker is influenced by many factors which reduce its value as an isolated prognostic parameter.     

Meningiomas: clinical implications of a high proliferative potential determined by bromodeoxyuridine labeling.

The clinical behavior of meningiomas with a high proliferative potential was analyzed to determine if the bromodeoxyuridine (BUdR) labeling index (LI) could be used to predict recurrence and the time to reoperation. Each patient received an intraoperative infusion of BUdR to label cells in DNA synthesis; the percentage of S-phase cells, or BUdR LI, of each tumor was determined immunohistochemically. Of 178 meningiomas studied, 53 had BUdR LIs greater than or equal to 1%. Of these 53 tumors, 21 were diagnosed histopathologically as malignant meningioma. Twenty-two percent of nonmalignant tumors and 81% of malignant tumors were recurrent or recurred after the BUdR study; repeat studies were performed in four patients. The mean BUdR LI of recurrent tumors was significantly higher than that of the nonrecurrent tumors [3.9 +/- 2.6 versus 1.9 +/- 1.0% (SD), P less than 0.005]. The recurrence rate was 100% for tumors with LIs greater than or equal to 5%, 55.6% for those with LIs of 3 to 5%, and 30.6% for those with LIs of 1 to 3%; the percentages of malignant meningiomas in these groups were 88%, 78%, and 19%, respectively. Logarithmic regression analysis showed that the time to reoperation (in months) can be predicted from the BUdR LI as: 70.0 x LI (%)-1.2 (R = 0.76). This formula can be used to estimate the doubling time of individual tumors and to predict the period of greatest risk of recurrence of meningiomas with a high proliferative potential.     

MIB-1 staining index of pediatric meningiomas

OBJECTIVE: For adult meningiomas, the staining index (SI) for the anti-Ki-67 monoclonal antibody MIB-1 is well correlated with histological atypia and tumor recurrence. MIB-1 SIs for meningiomas in the pediatric population have not been previously reported. Meningiomas tend to be more histologically aggressive and to recur more frequently in children, compared with adults. The objectives of this study were to determine whether MIB-1 SIs are correlated with pathological atypia and recurrence among pediatric meningiomas and to compare the MIB-1 SIs of pediatric meningiomas with those of adult meningiomas. METHODS: MIB-1 SIs were assessed on paraffin-embedded sections of 14 pediatric meningiomas (patient age, 2-17 yr), 5 of which contained atypical or malignant features. For comparison with benign pediatric meningiomas, MIB-1 SIs were also assessed on paraffin-embedded sections of 14 adult meningiomas (patient age, 38-90 yr), none of which displayed atypical or malignant features or recurred within a 5-month median follow-up period. RESULTS: MIB-1 SIs of pediatric meningiomas ranged from 1.2 to 31.6% (median, 9.1%). Significant differences were observed between the MIB-1 SIs for tumors with atypical or malignant features (median, 12.3%; range, 7.0-31.6%) and those for tumors without atypia (median, 7.0%; range, 1.2-12.6%; P = 0.045). There were six recurrences after gross total resection, during a 36.5-month median follow-up period. All five of the tumors with pathological atypia recurred; one tumor without atypia recurred. Significant differences were observed between MIB-1 SIs for nonrecurrent tumors (median, 6.6%; range, 1.2-12.2%) and those for recurrent tumors (median, 12.5%; range, 7.0-31.6%; P = 0.012). The median MIB-1 SI for adult control specimens was 8.8% (range, 1.2-19.3%), which did not differ significantly from that for pediatric meningiomas without atypia (P = 0.68). CONCLUSION: For this cohort of pediatric meningiomas, pathological atypia and the tendency to recur were correlated with elevated MIB-1 SIs. The median MIB-1 SI for pediatric meningiomas without histological atypia did not differ significantly from that for adult meningiomas without atypia, suggesting that the more aggressive clinical features of meningiomas in children may be attributable to factors other than the rate of cellular proliferation.     

Analysis of Ki-67 antigen expression, DNA proliferative fraction, and survival in resected cancer of the pancreas

BACKGROUND: Prognostic markers for pancreas cancer, such as CEA, CA19-9, ploidy analysis, and S-phase determination using flow cytometry, have not been consistently predictive. We chose to evaluate nuclear proliferation, as measured by the MIB-1 monoclonal antibody and digital image analysis, as a prognostic marker in pancreatic carcinoma, and compare the findings with DNA ploidy and S-phase analysis. MIB-1 identifies the Ki67 antigen present in nuclei of cells in all phases of the cell cycle except G0. METHODS: We retrospectively reviewed 33 patients with pancreatic adenocarcinoma resected for cure between 1989 and 1994 with available fixed tissue. Sectioned tissue was stained with MIB-1, and the number of positively stained nuclei determined and expressed as a MIB-1 labeling index (LI) by quantitative image analysis. Disaggregated nuclei were analyzed by flow cytometry using standard techniques. RESULTS: MIB-1 LI for pancreas cancers was heterogeneous within and between cancers. The MIB-1 LI for the cancers was 28 +/- 15 (median 29). There was no correlation between survival and MIB-1 expression (R(2) = 0.03). Likewise, there was no correlation between MIB-1 LI and percentage of cells in S-phase, G(2)/M, or total proliferating cells (S+G(2)/M; R(2) = 0.01), nor was there a difference between MIB-1 LI and ploidy (P = 0.88). CONCLUSIONS: We conclude that in our patient population, nuclear proliferation in pancreatic cancer, as determined by expression of Ki67 nuclear antigen, does not appear to correlate with survival and is not a useful prognostic marker. Despite intuitive thoughts to the contrary, there is no correlation between cell cycle analysis as determined by flow cytometry and Ki67 expression in pancreas cancer. Current methods of assessing prognosis after curative resection of cancer of the pancreas, including lymph node and margin status, tumor size, and possibly DNA ploidy as determined by flow cytometry, are not augmented by the assessment of nuclear proliferation by image analysis using the MIB-1 monoclonal antibody.     

P53 Overexpression and Proliferative Potential in Malignant Meningiomas

Summary  Meningiomas are generally benign, but some meningiomas show malignancy with invasion and high recurrence rates. We investigated whether alterations in p53 protein may contribute to malignant progression in meningiomas. Immunostaining for p53 protein was performed on paraffin and frozen sections from 61 patients with different grades of meningiomas using monoclonal antibodies (mAbs) DO-1 and pAb240. Immunoblot analysis was performed to quantitate the amount of p53 protein. Mutations in p53 genes were assessed by single-strand conformational polymorphism (SSCP) analysis. MIB-1 immunostaining was used to detect proliferative potentials of meningiomas. We found an overexpression of p53 protein in all of five cases of anaplastic meningiomas by immunohistochemistry using DO-1 mAb. No p53 positive cells were recognized in atypical meningiomas, and several cells were weakly stained in only two of 52 benign meningiomas.  p53 staining index and immunoblot analysis indicated increasing amounts of p53 protein associated with subsequent recurrences of anaplastic meningiomas. The MIB-1 staining index was positively correlated with tumour grade and p53 protein overexpression. Immunostaining of frozen sections using the mutant-specific mAb pAb240, as well as mutation gene analysis by SSCP, indicate that the overexpressed p53 protein is not a mutant- but wild-type p53 protein. Four atypical meningiomas did not recur after surgical removal and radiation, while 4 anaplastic meningiomas with overexpressed p53 protein recurred repeatedly at short intervals even after radiation. Our results suggest that accumulation of p53 protein associated with highly proliferative potentials is a common and characteristic feature that may indicate malignant biological behaviour in meningiomas.     

Clinical and radiological features related to the growth potential of meningioma

Clinical and radiological features that help predict the growth potential of meningioma would be beneficial. The purpose of this study is to clarify the characteristics related to proliferating potential using the MIB-1 staining index. We analyzed the relationship of MIB-1 staining indices to characteristics of 342 consecutive patients with meningioma surgically removed between 1995 and 2004 by logistic regression analysis. One hundred and forty-nine of the patients with meningioma were ≥60 in age; 89 male; 48 recurrent; 203 symptomatic; 157 at the skull base; 124 over 20 cm³; 24 multiple; 136 with edema; 117 with calcification. The MIB-1 staining index in 56 of 296 grade I meningiomas in WHO classification was ≥ 3.0; in 27 of 28 grade II; and in 17 of 18 grade III, respectively. Logistic regression analysis demonstrated that male (odds ratio [OR], 2.374, p=0.003), recurrence (OR, 7.574, p=0.0001), skull base (OR, 0.540, p=0.035), calcification (OR, 0.498, p=0.019) were independent risk factors for a high MIB-1 staining index (≥3.0); age, symptomatic, volume, multiple, edema were not. Male, recurrence, non-skull base, absence of calcification are independent risk factors for a high proliferative potential. These should be taken into consideration when managing meningiomas.     

Early malignant transformation of a petroclival meningothelial meningioma

Although some authors have reported the malignant transformation of meningiomas, there has been no previous report describing that a meningothelial meningioma transformed into an atypical meningioma within 1 year. This report documents a 57-year-old woman who presented with right hearing disturbance. Magnetic resonance imaging revealed a right petroclival meningioma. The tumor was subtotally removed and was diagnosed to be a meningothelial meningioma. Seven months after surgery, a recurrence of the tumor was confirmed. The diagnosis of this recurrent tumor was an atypical meningioma. The MIB-1 index and the percent of p53 protein-positive cells in the primary tumor were 4.6% and 35.4%, respectively, whereas those of the recurrent tumor were 34.7% and 33.1%, respectively. A chromosomal DNA copy number loss was observed on 1p, 6q, 10, 14q, and −22q detected in both the primary and the recurrent tumors. These results suggest that the present case had a potentially malignant tumor in the early stage, although it had the histological features of benign meningiomas. An evaluation of the MIB-1 index, as well as the expression of p53 and chromosomal aberrations, may be useful for predicting the malignant transformation of meningiomas.