WHO Histopathological Grade Research Articles

Correlation between Magnetic Resonance Imaging (MRI) Grading with Histopathological Grading of Supratentorial Meningiomas

Background: Meningiomas, common intracranial tumors originating from meningeal cells, critically impact patient outcomes. Their histologic grade influences recurrence risk and treatment decisions, including radiation therapy. Identifying advanced-grade meningiomas via pre-operative MRI is vital for surgical planning, reducing complications, and guiding adjuvant therapies. Objective: To investigate the correlation between pre-operative MRI features and histopathological grade in supratentorial meningiomas. Methods: This cross-sectional study was conducted from July 2019 to December 2020 at the Department of Neurosurgery of Dhaka Medical College and Hospital. A total of 43 patients with supratentorial meningiomas underwent resection and were analyzed in terms of neuroimaging features of pre-operative MRI. The relationships between MRI features and WHO histopathological grade were analyzed and scored quantitatively. Results: The mean age of the study population was 37±11.86 (SD) years. Male female ratio was 1:2.7. Main clinical presentation was headache (90.7%). The most common location was convexity meningioma (37.2%). Out of all patients, high, grade and low-grade meningioma were diagnosed by MRI, 9 (20.93%) and 34 (79.09%), respectively; on the other hand, high, grade and low-grade meningiomas diagnosed by histopathology 7 (16.3%) and 36 (83.7%) respectively. A positive correlation was found between MRI grading and histopathological grading of supratentorial meningiomas and statistical significance (Spearman rho-0.547, p-value <0.001). A significant association was also observed between MRI grading and histopathological grading of supratentorial meningiomas (p-value 0.002). Unclear tumor brain interface, capsular enhancement, and irregular tumor margin in the MRI were identified factors in predicting advanced histopathological grade of meningiomas as p-values 0.002, 0.008, and 0.001, respectively. Conclusion: This scoring approach may be useful for neurosurgeons ...

Surgery of Intracranial Gliomas in Children.

Gliomas are the most common type of brain cancer in the pediatric patients, constituting about 50% of all childhood intracranial tumors. This is a highly heterogeneous group, varying from the benign WHO histopathological grades I and II to malignant WHO grades III and IV. The histology and location are significant prognostic factors, which influence the decision for surgical intervention, as well as the extent of possible tumor removal. In low-grade gliomas, surgery remains the initial option and should be directed at gross total resection in favorable locations, such as the cerebral hemispheres and the cerebellum. Management of high-grade gliomas (HGG), which are less common in children compared to adults, continue to pose a significant challenge. In non-brainstem HGG, the goal is safe maximal tumor removal, while it generally does not play any role in diffuse intrinsic pontine gliomas. Treatment must, thus, be individualized in the majority of cases of HGG. Surgery for gliomas in children continues to be aided by technological advancements facilitating tumor resection and improving patient safety and outcomes.

DNA topoisomerase IIα and mitosin expression predict meningioma recurrence better than histopathological grade and MIB-1 after initial surgery.

BackgroundThe 2016 WHO histopathological grade or conventional biomarker MIB-1 is insufficient for predicting meningioma recurrence after initial treatment and alternative strategies are required. In this study, we investigated whether DNA topoisomerase IIα and/or mitosin expression can predict tumor recurrence with greater accuracy than conventional methods.MethodsThe expression of MIB-1, topoisomerase IIα, and mitosin were determined as proliferation indices in tissue microarrays using immunohistochemistry. The accuracy of prognostication was assessed with receiver operating characteristic (ROC) analyses and standard survival analyses.ResultsExpression of topoisomerase IIα and mitosin was significantly higher in recurrent meningioma than in non-recurrent meningioma (P ≤ 0.031), but no difference in MIB-1 expression was observed (P = 0.854). ROC analysis found topoisomerase IIα and mitosin expression to be the most reliable predictors of recurrence compared to WHO histopathological grade and MIB-1 expression. This result was supported by the multivariate survival analysis, in which mitosin expression was a significant predictor of recurrence-free survival (P < 0.001) and no association was found with histopathological grade or MIB-1 expression (P ≥ 0.158).ConclusionsThe results suggest that topoisomerase IIα and mitosin improve prognostication of patients resected for meningioma. Tumors with higher topoisomerase IIα and/or mitosin expression have a higher risk of recurrence after initial treatment, and these patients may benefit from adjuvant treatment and closer radiological follow-up.

Usefulness of ¹¹C-methionine positron emission tomography for treatment-decision making in cases of non-enhancing glioma-like brain lesions.

The present study evaluated usefulness of the positron emission tomography with (11)C-methionine for prediction of the clinical course and treatment decision-making in adult patients with newly diagnosed non-enhancing brain lesions mimicking low-grade gliomas. Retrospective analysis was done in 163 cases. In overall, 131 tumors underwent surgical resection, which in 34 cases was done after initial period of observation. Among the latter 5 patients were operated on after significant clinical deterioration. In overall, 3 resected neoplasms corresponded to WHO histopathological grade I, 87 to grade II, 39 to grade III, and 2 to grade IV. In all 163 cases the tumor/normal brain uptake ratio (T/N ratio) of (11)C-methionine ranged from 0.68 to 8.02 (mean 2.21 ± 1.16, median 1.81). Mean T/N ratios of non-operated lesions, low-grade and high-grade tumors were 1.60 ± 0.85, 2.27 ± 1.22, and 2.54 ± 1.09, respectively (P < 0.0001), but overlap between 3 groups was prominent. In patients who had clinical deterioration during the period of observation T/N ratios of the lesion varied from 1.49 to 3.38 (mean 2.23 ± 0.70, median 2.15). Comparison of the deterioration-free survival of patients with T/N ratios of the lesion above and below 1.90 revealed statistically significant difference (P < 0.0001). In conclusion, "wait-and-scan" strategy with delay of surgical treatment does not seem reasonable option if T/N ratio of (11)C-methionine in the non-enhancing glioma-like brain lesion constitutes ≥1.90, since it may be associated with significant risk of tumor progression and clinical deterioration during follow-up.

Imaging and extent of surgical resection predict risk of meningioma recurrence better than WHO histopathological grade.

Risk stratification of meningiomas by histopathological grade alone does not reliably predict which patients will progress/recur after treatment. We sought to determine whether preoperative imaging and clinical characteristics could predict histopathological grade and/or improve prognostication of progression/recurrence (P/R). We retrospectively reviewed preoperative MR and CT imaging features of 144 patients divided into low-grade (2007 WHO grade I; n = 118) and high-grade (2007 WHO grades II/III; n = 26) groups that underwent surgery between 2002 and 2013 (median follow-up of 49 months). Multivariate analysis demonstrated that the risk factors most strongly associated with high-grade histopathology were male sex, low apparent diffusion coefficient (ADC), absent calcification, and high peritumoral edema. Remarkably, multivariate Cox proportional hazards analysis demonstrated that, in combination with extent of resection, ADC outperformed WHO histopathological grade for predicting which patients will suffer P/R after initial treatment. Stratification of patients into 3 risk groups based on non-Simpson grade I resection and low ADC as risk factors correlated with the likelihood of P/R (P < .001). The high-risk group (2 risk factors; n = 39) had a 45% cumulative incidence of P/R, whereas the low-risk group (0 risk factors; n = 31) had no P/R events at 5 years after treatment. Independent of histopathological grade, high-risk patients who received adjuvant radiotherapy had a lower 5-year crude rate of P/R than those without (17% vs 59%; P = .04). Patients with non-Simpson grade I resection and low ADC meningiomas are at significantly increased risk of P/R and may benefit from adjuvant radiotherapy and/or additional surgery.

Overexpression of Eg5 correlates with high grade astrocytic neoplasm.

To investigate the relationship between Eg5 and histopathological grade of astrocytoma, Eg5 expression was evaluated by immunohistochemical examination on 88 specimens including 25 cases of glioblastoma (WHO grade IV), 22 cases of anaplastic astrocytoma (WHO grade III), 20 cases of diffuse astrocytoma (WHO grade II), and 21 cases of pilocytic astrocytoma (WHO grade I). The histopathological characteristics and Eg5 expression level of each tumor were assessed and statistically analyzed. Astrocytic tumors exhibited significant correlation of expression of Eg5 with higher WHO histopathological grades (p < 0.001). Eg5 is expressed in 51-98% (mean 76.88%) of neoplastic cells in glioblastoma, 34-57% (mean 43.59%) of neoplastic cells in anaplastic astrocytoma, 6-36% (mean 18.60%) of neoplastic cells in diffuse astrocytoma, and 2-28% (mean 13.48%) of neoplastic cells in pilocytic astrocytoma. In conclusion, overexpression of Eg5 associates with high-grade astrocytic neoplasm, and it may represent an independent diagnostic and prognostic factor in grading astrocytic tumors and predicting prognosis of astrocytic tumor patients.

MiRNA Multiplayers in glioma. From bench to bedside.

Glioblastoma multiforme (GBM) is the most common type of malignant gliomas, characterized by genetic instability, intratumoral histopathological variability and unpredictable clinical behavior. Disappointing results in the treatment of gliomas with surgery, radiation and chemotherapy have fuelled a search for a new therapeutic targets and treatment modalities. A novel small non-coding RNA molecules, microRNAs (miRNAs), appear to represent one of the most attractive target molecules contributing to the pathogenesis of various types of tumors. They play crucial roles in tumorigenesis, angiogenesis, invasion and apoptosis. Some miRNAs are also associated with clinical outcome and chemo- and radiotherapy resistance. Moreover, miRNA have the potential to affect the responses to molecular-targeted therapies and they also might be associated with cancer stem cell properties, affecting tumor maintenance and progression. The expression profiles of miRNAs are also useful for subclassification of GBM, what underscores the heterogeneity of diseases that all share the same WHO histopathological grade. Importantly, molecular subtypes of GBM appear to correlate with clinical phenotypes, tumor characteristic and treatment outcomes. miRNAs are then biological markers with possible diagnostic and prognostic potential. They could also serve as one of the promising treatment targets in human glioblastoma.

CB-10 * INTRAOPERATIVE FLOW CYTOMETRY ANALYSIS OF GLIOMA TISSUE FOR RAPID DETERMINATION OF TUMOR PRESENCE AND ITS HISTOPATHOLOGICAL GRADE

OBJECTIVE: Intraoperative histopathological investigation plays an important role during surgery for gliomas. To facilitate the rapid characterization of resected tissue, an original technique of intraoperative flow cytometry (iFC) was established. The objective in this study was evaluation of this technique's efficacy for rapidly determining tumor presence in the surgical biopsy sample and WHO histopathological grade of the neoplasm. METHODS: In total, 328 separate biopsy specimens obtained during the resection of 81 intracranial gliomas were analyzed with iFC. The evaluated malignancy index (MI) was defined as the ratio of the number of cells with greater than normal DNA content to the total number of cells. The duration of iFC in all cases was approximately 10 minutes. Each sample was additionally investigated histopathologically on frozen and permanent formalin-fixed paraffin-embedded tissue sections. The latter process was used as a gold standard control for evaluation of the diagnostic efficacy of iFC analysis. RESULTS: The MI differed significantly between neoplastic and perilesional brain tissue (25.3% ± 22.0% vs 4.6% ± 2.6%, p < 0.01). Receiver operating characteristic curve analysis revealed a corresponding area under the curve value of 0.941. The optimal cutoff level of the MI for identification of tumor in the biopsy specimen was 6.8%, which provided 0.88 sensitivity, 0.88 specificity, 0.97 positive predictive value, 0.60 negative predictive value, and 0.88 diagnostic accuracy. Additionally, the MI showed a significant association with WHO histopathological grades of glioma (p < 0.01), but its values in Grade II, III, and IV tumors overlapped prominently and were on average 13.3% ± 11.0%, 35.0% ± 21.8%, and 46.6% ± 23.1%, respectively. CONCLUSIONS: Results of this study demonstrate that iFC with the determination of the MI may be feasible for rapidly determining glioma presence in a surgical biopsy sample.

Correlation between magnetic resonance imaging grading and pathological grading in meningioma.

This study investigated the specific preoperative MRI features of patients with intracranial meningiomas that correlate with pathological grade and provide appropriate preoperative planning. From 2006 to 2012, 120 patients (36 men and 84 women, age range 20-89 years) with newly diagnosed symptomatic intracranial meningiomas undergoing resection were retrospectively analyzed in terms of radiological features of preoperative MRI. There were 90 WHO Grade I and 30 WHO Grade II or III meningiomas. The relationships between MRI features and WHO histopathological grade were analyzed and scored quantitatively. According to the results of multivariate logistic regression analysis, age ≥ 75 years, indistinct tumorbrain interface, positive capsular enhancement, and heterogeneous tumor enhancement were identified factors in the prediction of advanced histopathological grade. The prediction model was quantified as a scoring scale: 2 × (age) + 5 × (tumor-brain interface) + 3 × (capsular enhancement) + 2 × (tumor enhancement). The calculated score correlated positively with the probability of high-grade meningioma. This scoring approach may be useful for clinicians in determining therapeutic strategy and in surgical planning for patients with intracranial meningiomas.

Intraoperative flow cytometry analysis of glioma tissue for rapid determination of tumor presence and its histopathological grade

Intraoperative histopathological investigation plays an important role during surgery for gliomas. To facilitate the rapid characterization of resected tissue, an original technique of intraoperative flow cytometry (iFC) was established. The objective in this study was evaluation of this technique's efficacy for rapidly determining tumor presence in the surgical biopsy sample and WHO histopathological grade of the neoplasm. In total, 328 separate biopsy specimens obtained during the resection of 81 intracranial gliomas were analyzed with iFC. The evaluated malignancy index (MI) was defined as the ratio of the number of cells with greater than normal DNA content to the total number of cells. The duration of iFC in all cases was approximately 10 minutes. Each sample was additionally investigated histopathologically on frozen and permanent formalin-fixed paraffin-embedded tissue sections. The latter process was used as a "gold standard" control for evaluation of the diagnostic efficacy of iFC analysis. The MI differed significantly between neoplastic and perilesional brain tissue (25.3% ± 22.0% vs 4.6% ± 2.6%, p < 0.01). Receiver operating characteristic curve analysis revealed a corresponding area under the curve value of 0.941. The optimal cutoff level of the MI for identification of tumor in the biopsy specimen was 6.8%, which provided 0.88 sensitivity, 0.88 specificity, 0.97 positive predictive value, 0.60 negative predictive value, and 0.88 diagnostic accuracy. Additionally, the MI showed a significant association with WHO histopathological grades of glioma (p < 0.01), but its values in Grade II, III, and IV tumors overlapped prominently and were on average 13.3% ± 11.0%, 35.0% ± 21.8%, and 46.6% ± 23.1%, respectively. Results of this study demonstrate that iFC with the determination of the MI may be feasible for rapidly determining glioma presence in a surgical biopsy sample.

Abstract 1210: Periostin expression in glioma correlates with genes related to mesenchymal transition and survival.

Abstract Background: Gliomas are the most common primary brain tumors and their prognosis is related to WHO histopathological grade. Glioblastoma (grade IV astrocytoma or GBM) is characterized by microscopic invasion into surrounding brain and universally poor prognosis despite treatment with surgery, radiation and chemotherapy . Recently, the matricellular protein periostin (POSTN) has been shown to be associated with increased parenchymal invasion (measured by edema on MRI) and poor prognosis in GBM. The specific aim of the present analysis was to determine the mechanistic impact of POSTN on glioma outcome. Methods: We used the gene expression of POSTN from 559 GBM patients (pts) included in the Cancer Genome Atlas (TCGA) to build a gene expression model of the expression of 12184 genes to predict POSTN expression using elastic net. This model was used to predict the POSTN expression in a testing set of 419 pts with gliomas included in Repository for Brain Neoplasia Data (REMBRANDT) (99 grade II, 71 grade III and 125 grade IV and 124 with no grade). Receiver-operating characteristic (ROC) and survival analysis were performed to measure the performance of the model, and gene-set enrichment analysis (GSEA) was used to reveal network topology perturbations. Results: The gene expression model discovered 721 genes highly correlated to POSTN expression that predict POSTN in the testing set with an area under the curve (AUC) of 0.96 on ROC curve. GSEA reveals genes involved in “mesenchymal transition,” transition of invasive ductal carcinoma (IDC) from ductal carcinoma in situ (DCIS) in breast cancer and stem cell signatures. Survival analysis of the TCGA GBM pts showed that the cohort with “high POSTN” had worse survival (median 12 months versus 15 months, log-rank p=0.0002). When applied to all pts in REMBRANDT, the model predicted classes also had significantly different survival (median 13.4 versus 38 months, log-rank p&amp;lt;0.0001). Interestingly, this classification of survival persists in the subset of pts with grade III (n=71, median survival 17.7 versus 42.4 months, p=0.0125) and grade II (n=99, median survival 17.9 versus 50.8, p=0.02) gliomas. Conclusions: We have developed a gene expression model related to POSTN, a gene linked to poor prognosis in GBM, to investigate the role correlated genes may play in the aggressive phenotype. Some of the genes found to be highly correlated to POSTN are related to mesenchymal transition, invasive behavior in breast cancer and stemness. We verify that high POSTN expression is a strong prognostic indicator for poor outcome in GBM, and reveal for the first time that pts with grade II and III glioma with a “high” POSTN signature have significantly worse survival. Given that low grade glioma pts often have less aggressive treatment at time of diagnosis, we propose studying the role of early chemoradiation in the subset of pts with poor POSTN signature to potentially improve their outcome. Citation Format: Andrew D. Trister, Andrei M. Mikheev, Jason K. Rockhill, Stephen H. Friend, Robert C. Rostomily. Periostin expression in glioma correlates with genes related to mesenchymal transition and survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1210. doi:10.1158/1538-7445.AM2013-1210

Neuroepithelial stem cell marker nestin regulates the migration, invasion and growth of human gliomas

Nestin, a class VI intermediate filament protein, was originally described as a neuronal stem cell marker during central nervous system development. Nestin is expressed in gliomas, and its expression levels are higher in gliomas with high WHO histopathological classification grades than in those with low grades. In the present study, we examined whether nestin regulates the biological activities of human glioma cells. Immunohistochemically, the nestin expression patterns in 10 human glioblastoma patients were examined. The expression levels of nestin in A172, a human high-grade glioma cell line, and KG-1-C, a human low-grade glioma cell line, were examined using real-time PCR, Western blot and immunofluorescence analyses. An expression vector carrying a short hairpin RNA targeting nestin was stably transfected into A172 (Sh) cells. The effects of decreased expression levels of nestin in Sh cells on cell growth, migration, invasion, adhesion to extracellular matrices and fibrillar actin expression on three-dimensional culture plates were examined. The nestin expression vector was transiently transfected into KG-1-C (Nes) cells, and the effects of the nestin overexpression on cell growth and migration were examined. Nestin was expressed in the cytoplasm of the glioblastoma cells in all cases examined. Sh cells showed marked decreases in the expression levels of nestin mRNA and protein, and the growth rate of Sh cells was lower than that of sham (Sc) cells. In contrast, the adhesion activity of Sh cells to types I and IV collagens, fibronectin and laminin was higher than that of Sc cells. Fibrillar actin was clearly detected at the periphery of colonies of Sh cells at the attachment sites on three-dimensional culture plates. The migration and invasion of Sh cells were markedly inhibited compared with those of Sc cells. In contrast, the levels of nestin expression markedly increased in the Nes cells, which were transiently transfected with the nestin expression vector. The growth rate and motility of Nes cells were higher than those of the mock cells. In conclusion, nestin plays important roles in cell growth, migration, invasion and adhesion to extra-cellular matrices in glioma cells. Nestin may serve as a novel candidate for molecular-targeted therapy for gliomas, including glioblastomas.

Risk Factors for Regrowth of Intracranial Meningiomas after Gamma Knife Radiosurgery: Importance of the Histopathological Grade and MIB-1 Index

The influence of histopathological grade and MIB-1 index of intracranial meningioma on the results of its radiosurgical management is not clear. The objective of the present retrospective study was to make an evaluation of these factors along with an analysis of other variables associated with progression-free survival after gamma knife radiosurgery (GKR). Thirty-four intracranial meningiomas with known detailed histopathological diagnosis were analyzed. Tumors of WHO histopathological grades I, II, and III were diagnosed in 24, 3, and 7 cases, respectively. The median MIB-1 index was 1.3% (range: 0-31.9%). In 14 cases the MIB-1 index was 3.0% and more. In 26 cases the treatment was done at the time of tumor recurrence. Median volume of the neoplasm at the time of GKR was 4.1 mL (range: 0.4-43.1 mL). Median marginal dose was 12 Gy (range: 8-19 Gy). Median length of follow-up constituted 63 months (range: 19-132 months). Actuarial progression-free survival at 1, 3, 5, and 10 years constituted 100, 94, 83, and 58%, respectively. Histopathological grade II or III (p<0.0001), MIB-1 index 3% and more (p=0.0004), and non-skull base location (p=0.0026) of the tumor showed negative associations with progression-free survival in multivariate analyses. Actuarial progression-free survival at 5 years after GKR for benign and non-benign meningiomas constituted 100 and 45%, respectively (p<0.0001). Radiosurgery is a highly effective management option for benign intracranial meningiomas, but growth control of non-benign ones is significantly worse. It requires close neuroradiological follow-up and necessitates the search for modified treatment strategies.

Analysis of prognostic factors of nasopharyngeal carcinoma: Impact of in situ hybridization for Epstein-Barr virus encoded small RNA 1

To evaluate the impact of clinical, histopathological, and molecular biological parameters on the prognosis of nasopharyngeal carcinoma (NPC). The clinical records of 48 patients with a diagnosis of NPC were retrospectively reviewed. In situ hybridization for Epstein-Barr virus encoded small RNA 1 (EBER-ISH) was applied for 30 paraffin-embedded specimens available. Prognostic factors of NPC were meticulously analyzed. The EBER-ISH signal was shown to be highly significant as a favorable prognostic factor (P = 0.007). Although EBV was more commonly associated with Type III NPC, EBER-ISH-positive Type I-II NPC had also significantly better survival rate than EBER-ISH-negative Type I-II NPC (P = 0.036). In addition to the WHO histopathological grade, the 1997 UICC staging, nodal status, and distant metastasis at presentation, the EBER-ISH signal was shown to be significant as a prognostic factor. This is the first report to describe the EBER-ISH as an independent prognostic factor of NPC regardless of histopathology. B-2b.