Correlation Between Digital and Manual Determinations of Ki-67/MIB-1 Proliferative Indices in Human Meningiomas.

Objective. Proliferative activity in tumor tissues is assessed as the percentage of Ki-67/MIB-1-positive cells, or the proliferative index (PI). The PI is routinely assessed manually. However, the subjectivity of manual assessments might result in poor reproducibility. We hypothesized that digital assessments might reduce the error. Method. In our study, we assessed Ki-67/MIB-1 PIs, both manually and digitally, with tissue microarrays constructed from 141 human meningioma samples. Spearman-rank correlation and κ statistics were applied for correlation and agreement analyses, respectively. Mann-Whitney U tests were used to compare MIB-1 PIs between groups. Prognostic ability was assessed with Kaplan-Meier and Cox regression analyses. Results. We found a significant, high correlation (Spearman ρ = 0.832, P < .01) and moderate agreement (κ coefficient = 0.617, observed agreement = 80.9%) between the 2 methods. Both methods found significantly different Ki-67/MIB-1 PIs for different World Health Organization grades (P < .05). Neither method showed significant prognostic value. Conclusion. Digital determinations of Ki-67/MIB-1 PIs in human meningiomas are feasible for the daily routine.

Prognostic value of ErbB2/HER2 in human meningiomas.

INTRODUCTION: Among clinical challenges regarding human meningiomas is their propensity to recur even in cases with benign histology. Reliable biomarkers that can identify these cases are therefore highly desired. ErbB2/HER2 status is important in the medical management of patients with various human malignancies, whereas its clinical relevance in human meningiomas is ambiguous. For this reason, we wanted to investigate the expression of intra- and extracellular domains of ErbB2/HER2 as well as the level of activated receptor in these tumors. Further, we wanted to elucidate any clinicopathological associations to antibody expression and if gene amplification was present. METHODS: In total, 186 human meningiomas of all malignancy grades were included in the study, 163 of these were in tissue microarrays (TMA). Antibody expression was assessed by means of immunohistochemistry (IHC) and gene amplification by fluorescence in situ hybridization (FISH). RESULTS: All cases were immunoreactive with antibodies targeting the intracellular domain, whereas about 48% and 11% were positive with antibodies against the extracellular domain and against the activated receptor, respectively. Normal meninges were not immunoreactive. There were no relations to malignancy grade, and only the activated receptor was significantly correlated with increased risk for recurrence or death (time to recurrence: HR 1.568, CI (1.153 to 2.132), p = 0.004). No gene amplification was found. CONCLUSION: ErbB2/HER2 is generally upregulated in human meningiomas, but in an activated state only in a few cases. Only the activated receptor is associated with poorer prognosis, a link that needs further investigations.

The anti-apoptotic protein survivin can improve the prognostication of meningioma patients.

BACKGROUND: The 2016 WHO histopathological grading includes a substantial within-variation in recurrence risk, and is thus insufficient to predict prognosis after initial surgery of patients suffering from meningiomas. The aim of this study was to compare the prognostic value of the histopathological grading and the conventional biomarker MIB-1 with expression of the anti-apoptotic protein survivin to see if this biomarker could complement recurrence prediction. METHODS: Using immunohistochemistry, the expression of MIB-1 and survivin were determined as labeling indices (LIs) in tissue micro arrays from 160 human meningiomas. The accuracy of prognostication was assessed with receiver operator characteristics analyses and standard survival analyses. RESULTS: The expression of survivin was significantly associated with both histopathological grade (P = 0.022) and recurrence status (P = 0.035). A survivin LI of 1% was identified as the optimal cutoff value to predict recurrence (P = 0.003), and was proven as more reliable than the histopathological grading (P = 0.497) and MIB-1 expression (P = 0.091). This result was further strengthened in multivariate analyses where survivin expression was revealed as an independent predictor of recurrence-free survival, while the histopathological grading and MIB-1 expression did not reach significance (P ≥ 0.156). CONCLUSIONS: These findings suggest that incorporation of survivin in the clinical practice might be useful as complement for the histopathological grading and should further be evaluated in independent prospective studies.

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

BACKGROUND: The 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. METHODS: The 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. RESULTS: Expression 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). CONCLUSIONS: The 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.

Significance of the Extent of Resection in Modern Neurosurgical Practice of World Health Organization Grade I Meningiomas.

OBJECTIVE: Since the prognostic importance of radical resection was introduced in 1957, the neurosurgery practice has undergone several technologic advancements. The aim of this study was to evaluate whether the prognostic value of the extent of resection is still relevant in modern neurosurgical practice. METHODS: Over a 10-year period, all patients with histologic-confirmed World Health Organization grade I meningiomas and who underwent meningioma surgery were retrospectively analyzed. Survival analyses were performed using Kaplan-Meier analysis and univariate and multivariate Cox proportional-hazards regression analyses. RESULTS: There were 113 patients included in this study. A better Simpson grade was associated with recurrence-free survival (RFS) 5, 10, and 15 years after surgery (P < 0.001). Comparing Simpson grade I with Simpson grades III and IV, 13.1 and 36.6 times higher hazard ratios were revealed with respect to RFS, respectively. A 7.5 times higher hazard ratio was revealed when comparing Simpson grades II and IV. Additional survival analyses were performed within specific locations and groups with low and high mitotic indices, demonstrating that the extent of resection can add additional information about RFS. CONCLUSIONS: Simpson grade remains a highly significant predictor of RFS in meningioma-resected patients in modern neurosurgical practice. Extent of resection should therefore be emphasized when predicting prognosis and considering postoperative treatment and frequency of radiologic follow-up after surgery.

MCM7 expression is a promising predictor of recurrence in patients surgically resected for meningiomas.

Patients with high risk of recurrence after meningioma resection might benefit from adjuvant radiation therapy and closer clinical follow-up. While the World Health Organization (WHO) classification and the MIB-1 biomarker are applied in the clinical practice to identify these patients, the reliability of these methods is questionable. To improve the prediction of tumor recurrence, this study evaluated and compared the prognostic usefulness of the biomarker MCM7 with the conventional mitotic index and the MIB-1 biomarker. One hundred sixty patients were retrospectively analyzed. The expression of MIB-1 and MCM7 was determined as proliferative indices (PI-percentage of positive immunoreactive cells among 1000 tumor cells) in tissue microarrays. MCM7 PI revealed significantly higher indices in recurrent meningiomas compared with non-recurrent meningiomas (p = 0.020), while mitotic index and MIB-1 PI did not reach statistical significance (p ≥ 0.547). The optimal cutoff values for recurrence prediction were 3% for MIB-1 PI and 8% for MCM7 PI. MCM7 PI was significantly associated with recurrence-free survival in COX multivariate survival analyses (p = 0.005), while no association was found with mitotic index or MIB-1 (p ≥ 0.153). MCM7 PI allowed for the most accurate prediction of recurrence, obtaining the highest sensitivity and the greatest area under the ROC curve. These results proved that MCM7 PI is a better method for identifying patients with risk of recurrence compared with the traditional methods used in the current clinical practice. MCM7 may thus improve diagnostics, prediction of prognosis and treatment decision making in patients suffering from meningiomas.

Phosphohistone-H3 Proliferation Index Is Superior to Mitotic Index and MIB-1 Expression as a Predictor of Recurrence in Human Meningiomas.

OBJECTIVES: This study investigated the prognostic value of the phosphohistone-H3 (PHH3) proliferation index (PI) in human meningiomas and compared the reliability with the conventional mitotic index and MIB-1 biomarker. METHODS: Proliferative activity was determined in 160 patients by standardized immunohistochemistry on tissue microarrays and related to recurrence. RESULTS: All three proliferation assessment methods were significantly associated with World Health Organization grade. The optimal cutoff values for recurrence prediction were 3% for the MIB-1 PI and 0.5% for the PHH3 PI. Increased PHH3 PI was significantly associated with recurrence-free survival in univariate Cox proportional hazards regression analysis (P = .011) and remained an independent predictor in multivariate analysis (P = .005). Mitotic index and MIB-1 PI did not reach statistical significance. CONCLUSIONS: PHH3 immunostaining allowed for the easiest, fastest, and most objective assessment of proliferation and proved to be the most accurate and reliable method for predicting recurrence in patients resected for meningiomas.