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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 25  |  Issue : 1  |  Page : 17-20

Progesterone receptor expression and Ki-67 labelling index of meningiomas in the Lagos university teaching hospital


1 Department of Anatomic and Molecular Pathology, Lagos University Teaching Hospital, Idi-Araba, Lagos, Nigeria
2 Department of Surgery, Neurosurgery Unit, Lagos University Teaching Hospital, Idi-Araba, Lagos, Nigeria

Date of Web Publication17-Apr-2018

Correspondence Address:
Dr. Nzechukwu Zimudo Ikeri
Department of Anatomic and Molecular Pathology, Lagos University Teaching Hospital, Idi-Araba, Lagos, PMB 12003
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/npmj.npmj_16_18

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  Abstract 

Background: Meningioma in Nigeria has been poorly studied. Its location within the intracranial cavity is associated with significant morbidity and mortality. Even when completely excised, it has a tendency to recur and this is associated with repeat operations and shortened survival. The World Health Organization (WHO) grade, progesterone receptor (PR) expression and Ki-67 index are predictive for recurrence and are, therefore, useful for individualised management. The aim of this study was therefore to determine the PR expression and Ki-67 index of meningiomas received in our institution. Materials and Methods: A retrospective review of the forms, slides and results of meningiomas received at the Department of Anatomic and Molecular Pathology, Lagos University Teaching Hospital, from January 2005 to December 2014, was undertaken. Immunohistochemistry for PR and Ki-67 was performed and correlated with other histologic parameters. Results: Meningioma was the most common primary CNS tumour seen. The male-to-female ratio was 1:3.8; with a peak in the 4th decade. Most cases were WHO Grade I tumours (86.1%) and transitional histologic subtype (31.8%). PR immunoreactive score and Ki-67 index varied widely within WHO Grade I tumours and overlapped considerably with Grade II tumours. PR expression reduced and Ki-67 index increased with increasing WHO grade (P = 0.000). A moderate inverse correlation was found between Ki-67 index and PR score (R = −0.7371). Conclusion: The peak age of meningioma in our patients is five decades earlier than in western populations. Although PR expression reduces and Ki-67 index increases with increasing grade, there is nevertheless a considerable overlap. Management therefore must be individualised.

Keywords: Immunohistochemistry, Lagos University Teaching Hospital, meningioma


How to cite this article:
Ikeri NZ, Anunobi CC, Bankole OB. Progesterone receptor expression and Ki-67 labelling index of meningiomas in the Lagos university teaching hospital. Niger Postgrad Med J 2018;25:17-20

How to cite this URL:
Ikeri NZ, Anunobi CC, Bankole OB. Progesterone receptor expression and Ki-67 labelling index of meningiomas in the Lagos university teaching hospital. Niger Postgrad Med J [serial online] 2018 [cited 2018 Dec 10];25:17-20. Available from: http://www.npmj.org/text.asp?2018/25/1/17/230191


  Introduction Top


Meningiomas are among the most common primary intracranial tumours.[1] Although most are benign, their intracranial location and tendency for recurrence often lead to serious and potentially lethal consequences.[2] Without surgery, meningiomas have a mortality rate of 61%.[3] Sixty-seven per cent of adult long-term survivors of meningiomas post-operation show at least one neurological deficit, and 27% of them are unable to perform their usual daily activities.[4] In children and adolescents with better neurological recovery, 44.5% of survivors show meningioma-associated morbidity which include visual deficits, cranial deficits and seizure disorder among others.[5] In Nigeria, meningiomas have been poorly studied with only a few reports available about long-term morbidity and mortality.[6] One report from Eastern Nigeria showed a surgical mortality of 3.9%, of which 29.4% of the patients followed up at 3 years had recurrences.[7] In another study done in patients with visual impairment, only 2.9% of cases recovered useful vision. Late presentation in Nigerians has been associated with a large mean tumour size and correlated with poor visual outcome.[8]

Even after complete resection, recurrence is common and has been estimated to occur in 10%–32% of cases.[9] Recurrence is associated with numerous repeat operations and shortened survival.[10] Various histopathological parameters have been shown to be of prognostic and predictive significance in the management of meningiomas. These include increasing World Health Organization (WHO) grade, negative progesterone receptor (PR) expression and increasing Ki-67 labelling index. Evaluation of these parameters is useful for determining the frequency of follow-up and aggressiveness of treatment of meningiomas at the time of diagnosis.[11] The aim of this study was therefore to determine the PR expression and Ki-67 labelling index of meningiomas received in our institution and to correlate with other histological parameters of prognostic significance.


  Materials and Methods Top


Ethical approval for this study was obtained from the Health and Research Ethics Committee of the Lagos University Teaching Hospital (LUTH) (HREC no: AGM/DSCT/HREC/APP/2138, date 29/09/14). The study was a 10-year retrospective hospital-based study conducted to assess the expression of Ki-67 labelling index in meningiomas diagnosed at the Department of Anatomic and Molecular Pathology, LUTH, from January 2005 to December 2014. The materials that provided data for this study included histology request forms, patients' case notes, duplicate copies of histopathological reports, tissue blocks and corresponding archival slides. Cases with missing or damaged blocks were excluded from the study.

Archival routine haematoxylin and eosin (H and E)-stained slides of all the cases confirmed as meningioma within the study period were retrieved, reviewed and classified according to the WHO 2016 criteria.[12] Fresh sections from the paraffin-embedded tissue blocks were taken in situ ations where the original slides were not found or were damaged. Immunohistochemistry for PR and Ki-67 was performed. PR was scored semiquantitatively using the immunoreactive score (IRS).[13] The intensity of staining was scored as 0 for no staining, 1 for weak staining, 2 for moderate and 3 for strong staining. The percentage of positive tumour cells was scored as follows: 0 indicating absence of positive nuclei, 1 for positive nuclei < 10% in the entire section, 2 for 10%–50% positive nuclei, 3 for 51%–80% positive nuclei and 4 for > 80% positive nuclei. The IRS for each tumour was derived by multiplying the score for staining intensity by the score for the proportion of tumour cells staining positive. Tumours with an IRS of > 2 were considered PR positive.

The Ki-67 index was calculated by determining the proportion of cells showing nuclear positivity among 1000 counted cells and multiplying this value by 100.[14] These results as well as other relevant demographic data such as age, sex, hospital numbers, laboratory numbers and location of the tumour which were extracted from the departmental records and patient's folders were analysed using the Statistical Package for the Social Sciences for Windows version 22.0 (IBM, Armonk, NY, USA). The Student's t and ANOVA tests were used for comparison of the means of continuous variables, and the Chi-square test was used for comparison of discontinuous variables, with P < 0.05 considered as significant. Statistical analysis for any correlation between PR, Ki-67 and WHO grade was also done. The results obtained were presented in tables, figures, relative frequencies and group percentages.


  Results Top


Seventy-two (72) meningiomas met the inclusion criteria for this study. Fifteen of these occurred in males, while 57 occurred in females giving a male-to-female ratio of 1:3.8. The ages ranged from 8 months to 80 years with a mean age of 46 years and a median age of 45.5 years. The peak age of occurrence was in the 30s. Paediatric meningiomas accounted for only 2.8% of all cases. Transitional, fibroblastic and syncytial meningiomas were the most common histologic subtypes seen, constituting 31.8%, 25.0% and 16.7%, respectively. [Figure 1] shows the distribution of the various histologic subtypes of meningioma. The vast majority of cases (86.1%) were WHO Grade I tumours as shown in [Figure 2].
Figure 1: Distribution of histologic subtypes of meningioma

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Figure 2: Distribution of cases of meningioma by World Health Organization grade

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[Table 1] shows the PR expression, PR scores and Ki-67 index of the various WHO groups. No statistical significance was seen between the various WHO groups for PR expression (P = 0.192). There was a statistically significant decrease in the immunoreactive PR score with increasing WHO grade (P = 0.000), as well as a statistically significant increase in the Ki-67 proliferation index with increasing WHO grade (P = 0.001). [Table 2] shows the mean PR IRS and Ki-67 proliferation index of the various histologic subtypes of Grade I meningiomas. No statistically significant difference was seen among these groups regarding both parameters. A moderate inverse correlation was seen between PR scores and Ki-67 labelling index with a Pearson correlation coefficient of − 0.7371.
Table 1: Progesterone receptor expression, progesterone receptor score and Ki-67 index for the different World Health Organization grades

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Table 2: Progesterone receptor and Ki-67 results for the different histologic subtypes of World Health Organization Grade I tumours

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  Discussion Top


All over the world, meningiomas are seen more commonly in females than in males as was the case in this study (male-to-female ratio of 1:3.8).[7],[8],[15],[16],[17] They also occurred much earlier in our study population than in western societies (five decades earlier).[17] Since the majority of meningiomas express PR receptors, the higher progesterone levels in females have been queried as a possible reason for the higher incidence of meningiomas in females than males.[18] Indeed, meningiomas have been known to enlarge during pregnancy and in the luteal phase of the menstrual cycle.[19],[20],[21] However, Roser et al. found slightly higher PR expressions in Grade I and II meningiomas in males than females.[13] In this study, there was no significant difference in the IRS of meningiomas across the sexes (P = 0.075). This brings into question the role played by progesterone in the aetiology of meningioma.

Grade I meningiomas, especially the syncytial, fibroblastic and transitional subtypes, are the most common histologic variants seen in most studies. In our study, these three histologic subtypes accounted for 74.5% of all meningiomas, which is similar to 83.4% published in Ibadan, 71.3% published in Kenya and 74.9% in Turkey.[8],[21],[22] Transitional subtype of meningioma was the most common variant seen in this study (31.8%). In some other reports, syncytial or fibroblastic meningiomas were the most common.[14],[21] This is probably due to the lack of strict criteria employed in categorising meningiomas into these subtypes. It is well known that categorising Grade I tumours into the various histologic subtypes is of no clinical significance.[12] This is further corroborated by the findings of this study, as no correlation was seen between these histologic subtypes and PR expression (P = 0.129) or Ki-67 labelling index (P = 0.994), which are histologic predictive and prognostic factors.

Non-neoplastic meningothelial cells express PR. This expression is lost as the histologic grade of the tumour increases.[13],[22] This loss can therefore be taken to mean a loss of differentiation in higher grade tumours. The association of reduced PR expression with poor prognosis further buttresses this fact. However, one study was unable to demonstrate the prognostic importance of PR expression in meningiomas.[23] In this study, there was no significant statistical difference in PR expression between Grade I and II meningiomas when PR was reported as positive or negative (P = 0.192). However, when PR expression was reported as a quantitative value (i.e., the IRS), Grade I tumours showed higher PR scores than Grade II tumours and Grade II tumours showed higher scores than Grade III tumours. These differences in PR scores between the WHO grades were statistically significant (P = 0.000). These findings suggest that assigning an immunoreactive PR score will be more clinically useful for prognostication than designating PR expression of tumours qualitatively as either positive or negative. Indeed, in the study conducted by Hernández Faraco et al., where PR expression was reported quantitatively as a labelling index, an index < 40% was recommended as a reasonable cut-off that predicted for recurrence of meningiomas with 82.61% sensitivity and a positive predictive value of 65.52%.[24]

This study showed an increase in Ki-67 labelling index of meningiomas with increasing WHO grade (P = 0.000), which is consistent with reports from other studies.[22],[25],[26] This highlights the prognostic importance of Ki-67 labelling index between the various WHO categories. Ki-67 retains its prognostic importance even within the same WHO category, as tumours with higher Ki-67 index recur more frequently than those with lower Ki-67 index within the same WHO grade.[11] This is not surprising as there is considerable overlap in Ki-67 expression between WHO Grade I and II tumours.[22] This overlap was demonstrated in our study, where the mean Ki-67 indices for Grade I and II tumours were 2.46 + 1.59 and 7.24 + 3.59, respectively. It is, therefore, expected that Grade I tumours that have proliferation indices comparable to those of Grade II tumours will behave more aggressively than tumours with lower proliferation index. Grade I tumours with Ki-67 index > 4% have been shown to be particularly associated with recurrence and poor survival.[21]

An inverse relationship between PR and Ki-67 expression of meningiomas was demonstrated in this study (Pearson correlation coefficient − 0.7371). This is consistent with the finding of Roser et al. in their study of 588 meningiomas.[13] This implies that as tumours become of higher grade, they lose differentiation-associated markers such as PR and also exhibit greater proliferative activity which is quantified by the Ki-67 labelling index. PR and Ki-67 can, therefore, be taken together to give a true picture of the degree of differentiation of meningiomas. These markers are useful for defining the biologic behaviour of the tumour as there is some overlap in these parameters between Grade I and II meningiomas. It is no surprise that they correlate well with the WHO grade, which was also demonstrated in this study.[11],[13] Since these parameters vary even in WHO Grade I tumours, routine evaluation of Ki-67 status and quantitation of PR expression will, therefore, identify patients who are at greater risk of recurrence and require closer follow-up.


  Conclusion Top


This study shows an inverse correlation between WHO grade and PR expression and a direct correlation between increasing WHO grade and Ki-67 labelling index though there is significant overlap between the different WHO grades. We therefore recommend that PR IRS and Ki-67 labelling index be performed routinely on cases of meningioma submitted for histopathologic assessment as it can identify a subset of patients with increased risk of recurrence who will benefit from a more individualised treatment and follow-up.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

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