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Table of Contents    
Year : 2017  |  Volume : 65  |  Issue : 6  |  Page : 1239-1240

Proliferation in meningiomas: Introducing objectivity in assessment

1 Department of Pathology, Institute of Human Behaviour and Allied Sciences, New Delhi, India
2 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication10-Nov-2017

Correspondence Address:
Dr. Sujata Chaturvedi
Department of Pathology, Institute of Human Behaviour and Allied Sciences, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.217989

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How to cite this article:
Chaturvedi S, Suri V. Proliferation in meningiomas: Introducing objectivity in assessment. Neurol India 2017;65:1239-40

How to cite this URL:
Chaturvedi S, Suri V. Proliferation in meningiomas: Introducing objectivity in assessment. Neurol India [serial online] 2017 [cited 2018 Dec 12];65:1239-40. Available from:

Meningiomas comprise more than 1/3rd of all primary central nervous system tumours and are generally considered benign. The histopathological criteria for grading a meningioma into grades I, II or III, though easy to apply, are often found wanting in predicting its biologic behaviour. Substantial within-grade variation of recurrence-risk is observed, as some patients, despite being diagnosed with grade I meningiomas, experience recurrence. Prediction of recurrence in meningiomas and, for malignant variants, prediction of survival, remain major issues. In routine practice, the World Health Organisation (WHO) grade and extent of resection are the strongest predictors of recurrence but imperfections exist relating to the prediction of recurrence risk and survival. Proliferation markers, which are objective assessment tools, are being increasingly used to circumvent this problem.[1]

According to the WHO Classification of Tumours of the Central Nervous System, 2016, the label of 'atypical meningioma' relies not as much on the nuclear atypia but a combination of increased mitotic activity, findings of brain invasion on histology, or at least three of the following features: increased cellularity, small cells with a high nuclear-to-cytoplasmic ratio, prominent nucleoli, as well as with sheeting and foci of spontaneous necrosis. In most laboratories, the cut off value for an increased mitotic activity in atypical meningiomas has been defined as ≥4 mitoses/10 hpf. An anaplastic (malignant) meningioma exhibits overtly malignant cytology and/or markedly elevated mitotic activity of ≥20 mitoses/10 hpf. Similarly, meningiomas with the Ki67 labeling index of >4% have an increased risk of recurrence similar to that of atypical meningiomas, whereas those with an index of >20% are associated with death rates analogous with that of anaplastic meningiomas. The article 'Objective assessment of proliferative indices by immunohistochemistry and automated counting method' by Chavali P, et al., published in this issue adds great value to the assessment of the two most important markers of proliferation, that is, mitotic count and Ki67 labeling index. The authors rightly state that both the methods, that is, the assessment of mitotic activity and proliferative index with Ki67, though reliable correlates of recurrence risk in meningiomas, are subject to considerable inter-observer variability. The article makes a valuable contribution in assessing grade wise: (a) the correlation of mitotic count on hematoxylin and eosin stained sections with the immunohistochemical method using antibody against phosphohistone H3 (PHH3) for counting mitotic figures; (b) the correlation of manually evaluated Ki 67 labeling index (LI) with the automated counting method using a freely available online software, Immunoratio (IR); and, (c) the correlation of Ki67, both manual and IR, with the grade of the tumor as well as the manual mitotic count and the PHH3 stained mitotic count. The authors conclude that the modified methods of using PHH3 immunostaining to assess mitotic activity, and the utilization of IR software to assess Ki67 LI, correlated well with the existing methods and can be applied to routine use.[2]

Correlation of the meningioma grade with Ki67 values has been published in this journal before [3] and the diagnostic validity of Ki67 LI in grading of meningiomas has been elucidated.[4] These studies agreed that Ki67 as a marker of proliferation can be used in conjunction with histological features to help in making a recommendation regarding the potentially aggressive behaviour of meningiomas. Satoshi N et al., added another dimension by comparing the two counting methods utilized for the assessment of Ki67/MIB-1 LI. The predictability of MIB-1 immunohistochemistry for assessing growth and recurrence in meningiomas using the two different counting methods: (1) in the area of the highest MIB-1 labeling (HL); and, (2) in randomly selected fields (RS), was evaluated by them. The RS method distinguished the recurrent group more definitively. Several benign meningiomas demonstrating low staining indices 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. This finding, therefore, obscured the prognostic importance of combining the MIB-1 value with the HL method.[5] The study by Chavali P et al., goes a step further and compares the manual and automated counting method for assessing Ki67 LI. The fact that the software used is available as a freely downloadable software should make this automated process more amenable to use.

Mitotic index (MI), which is defined as the sum of mitotic figures (MFs) per 10 consecutive high power fields in the area of highest mitotic activity, has been shown to be one of the most reliable prognostic factors in meningiomas. However, the reliability and reproducibility of the MI are limited due to several factors. These factors include a selection bias related to the selection of the high power fields (HPFs) with the highest mitotic activity and, also, the heterogeneity of mitotic activity in various parts of the tumour. Further factors are the variations in the sample size of the tumour biopsy and the resected samples, as well as the cellularity of the tumor, both of which influence the number of evaluable cells. Distinguishing MFs in hematoxylin and eosin stained sections from similar chromatin changes, that is, apoptotic nuclei, crush artefact, karyorrhectic debris or pyknosis, is a subjective task. Mitosis-specific staining or labelling techniques have been suggested as promising tools to correctly identify MFs. An antibody for the phosphorylated form of the amino terminus of histone 3, anti-phosphohistone H3 (PHH3), has been used to lend specificity to the counting of MFs. The rationale behind using PHH3 is that correlation exists between the phosphorylation of H3 and the mitotic chromosomal condensation during the early prophase. Kim YJ et al., in their retrospective study of 265 meningiomas, concluded that the PHH3 staining method possessed greater sensitivity in the detection of MFs and facilitated MF counting.[6] Statistically significant correlation between the mitotic count in each grade with the PHH3 values has also been demonstrated by Chavali et al.[2]

If the MI and Ki67 LI are in consonance, the decision making becomes easier. It is the discrepant MI and Ki67 LI which pose a dilemma. Studies recording a close follow-up of patients harbouring a meningioma, who showed discrepant MI and Ki67 values, may provide the answers.

  References Top

Olar A, Wani KM, Sulman EP, Mansouri A, Zadeh G, Wilson CD, DeMonte F, Fuller NF, Aldape KD. Mitotic index is an independent predictor of recurrence free survival in meningioma. Brain Pathol 2015;25:266-75.  Back to cited text no. 1
Chavali P, Uppin MS, Uppin SG, Challa S. Meningiomas: Objective assessment of proliferative indices by immunohistochemistry and automated counting method. Neurol India 2017;65:1345-9.  Back to cited text no. 2
[PUBMED]  [Full text]  
Babu S, Uppin SV, Uppin MS, Panigrahi MK, Saradhi V, Bhattacharjee V, Sahu BP, Purohit AK, Challa S. Meningiomas: Correlation of Ki67 with histological grade. Neurol India 2011;59: 204-7.  Back to cited text no. 3
[PUBMED]  [Full text]  
Devaprasath A, Chacko G. Diagnostic validity of the Ki-67 labeling index using the MIB-1 monoclonal antibody in the grading of meningiomas. Neurol India 2003;51:336-40.  Back to cited text no. 4
[PUBMED]  [Full text]  
Nakasu S, Li DH, Okabe H, Nakajima M, Matsuda M. Significance of MIB-1 staining indices in meningiomas: Comparison of two counting methods. Am J Surg Pathol 2001;25:472-8.  Back to cited text no. 5
Kim YJ, Ketter R, Steudel WI, Feiden W. Prognostic significance of the mitotic index using the mitotic marker anti phosphohistone H3 in meningiomas. Am J Clin Pathol 2007;128:118-25.  Back to cited text no. 6


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