Meningiomas are one of the most common tumors of the central nervous system in adults (Onak Kandemir et al., 2010). Although the majority of these tumors are histologically benign, meningiomas have shown significant rates of recurrence, morbidity, and mortality in studies with a long-term follow-up (Özer et al., 2009). The clinical progress of meningiomas is difficult to predict, and risk stratification on the basis of histomorphology alone remains problematic. (Abdelzaher et al., 2010).
Over the recent years, interest in this clinically diverse group of tumors has intensified, bringing new questions and challenges to the fore, leading researchers to investigate combinations of predictive and prognostic factors, aiming to facilitate the identification of patients with meningioma who should be followed more closely for evidence of recurrent tumor or may be treated more aggressively at the time of diagnosis.
In the present study, we detected the immunohistochemical expression of PR, Ki-67, and the potential molecular marker for targeted therapy Her-2 in WHO grades I–III meningiomas. In addition, we related the expression profiles of these factors to clinicopathological parameters such as tumor grade and histological subtype and finally investigated the prognostic value of the studied factors on meningioma patients’ disease-free survival.
Seventy-nine percent of the patients included in the study were women, a finding consistent with that reported in the literature that meningiomas are more commonly diagnosed in women, occurring at a ratio of 2.09:1 (Cancer Agency Information System, 2006).
Our results were in accordance with the common agreement that most meningiomas are benign as classical-grade I meningiomas constituted the majority of the tumors accounting for 82% of the studied cases, whereas only 18% of cases fell in the atypical/anaplastic group (grades II–III), a frequency within the same range reported by Mawrin and Perry (2010), who reported high-grade meningiomas (atypical and anaplastic) to comprise roughly 20% of all cases. However, Louis et al. (2007) report the agreed-upon frequency of atypical/anaplastic meningioma to be much lesser, stating that atypical meningiomas are believed to comprise about 4.7 to 7.2%, whereas anaplastic meningiomas comprise 1.0 to 2.8% of all meningioma diagnoses. Although the percentage of atypical/ anaplastic cases in this study was markedly less than benign cases, yet it exceeds the values reported by Louis et al. (2007). The possibility that this higher frequency is due to a more aggressive nature of meningiomas in Egyptian patients should be investigated. Such a biological difference between tumors in Egyptian patients compared with worldwide counterparts is not unprecedented; in fact, breast cancer was found to be more aggressive in nature among Egyptian patients (Zaghloul et al., 2001).
As regards the tumor histological subtype, the most common subtype in the current study among both classical and atypical/anaplastic tumors was meningothelial (45.2 and 57.1%, respectively), followed by transitional representing 35.5% of the classical and 14.3% of the atypical/anaplastic group and then fibroblastic, with a frequency of 7.9% of the classical group. These findings fall within the values specified by the WHO classification of tumors of the central nervous system. Our study has also included a case of papillary meningioma. Papillary meningioma is a rare variant that is classified as WHO grade III (Louis et al., 2007; Mawrin and Perry, 2010).
No significant statistical relationship was found between the tumor histological subtype and tumor grade or any of the other studied factors, a finding that is in agreement with Campbell et al. (2009), who highlighted that although there is a range of meningioma subtypes, on the basis of their histologic appearances, the clinical behavior and outcomes correlate with the WHO grade, rather than the histologic subtype.
The Her-2/neu (c-erb-B2) gene is localized to chromosome 17q and encodes a transmembrane tyrosine kinase receptor protein, which is a member of the epidermal growth factor receptor HER family. This family of receptors is involved in cell–cell and cell–stromal communication primarily through the process of signal transduction. The major pathways involved in signal transduction ultimately affect cell proliferation, survival, motility, and adhesion (Craven et al., 2003).
In the present study, HER-2 positivity was detected in 13 (34.2%) of the 38 meningioma specimens studied, which is within the wide range of 2.5 to 67.3% reported for Her-2/neu overexpression in meningiomas in the literature (Potti et al., 2004a, 2004b; Loussouarn et al., 2006; Durand et al., 2008; Abdelzaher et al., 2010; Onak Kandemir et al., 2010; Wang et al., 2010).
Her-2/neu was detected in meningioma specimens in the literature using immunohistochemistry, fluorescence in-situ hybridization (FISH) (Özer et al., 2009), or both (Loussouarn et al., 2006; Wang et al., 2010). In the current study, immunohistochemistry was used for the detection of Her2/neu because of its advantages over FISH as it is, according to Potti et al. (2004b), a relatively inexpensive analytic method that can be performed on permanent sections and most importantly because interpretation is not influenced by nontumor material present in the specimen. Experience has also shown that if definitive immunostaining (immunohistochemistry score ≥2+) is observed in paraffin sections, absolute concordance occurs with FISH (Jimenez et al., 2000).
The variation in the studied samples’ microscopic histologic subtypes, methods of detection, and staining interpretation could explain the wide variation in expression frequencies in different studies. For instance, among the studies using immunohistochemical detection like ours, Torp et al. (1993) and Loussouarn et al. (2006) performed the Her-2/neu immunostaining using the same monoclonal antibody CB11 on frozen sections, yet with different tumoral subtypes resulting in detection rates of 63 and 28.5%, respectively. Onak Kandemir et al. (2010), working on formalin fixed paraffin-embedded samples as we did in this study and using the same CB11 monoclonal antibody, reported a Her-2/neu expression rate of 22.6%.in their study.
Our finding of more frequent Her-2/neu overexpression in meningothelial meningioma (43% of the classic and 50% of the atypical/anaplastic meningothelial meningiomas) is in accordance with that of Loussouarn et al. (2006) and Onak Kandemir et al. (2010), who reported more frequent Her-2/neu overexpression in meningiomas displaying epithelial differentiation, such as meningothelial and secretory histological subtypes. Durand et al. (2008), however, have not found such an increased frequency of detection.
Staining interpretation also differs from one study to another in the literature, with some studies devising a semiquantitative grading system on the basis of a 4-point scale and yet different from that reported for breast cancer (Torp et al., 1993; Loussouarn et al., 2006) and other studies using the same scoring system as that used for breast cancer (Potti et al., 2004b). In the current study, we used the same method used by Loussouarn et al., (2006) as, in agreement with their findings as well as those of Torp et al. (1993) and Onak Kandemir et al. (2010), Her-2/neu expression was not detected in normal brain or arachnoid tissue.
In terms of the relation of Her-2/neu expression to grades of meningioma, we observed a clinically significant difference between Her-2/neu expression within the grade II/III atypical/anaplastic group (57.1%) as compared with the grade I classical meningiomas (29%); However, the difference did not reach statistical significance (Fisher exact test). Our findings fall between those of Wang et al. (2010), who found that a higher meningioma grade was correlated with a higher rate of Her-2/neu expression, and those of Loussouarn et al. (2006), who reported absence of a clinically or a statistically significant relationship between Her-2/neu expression and meningioma grade.
In the current study, PR-positive meningiomas constituted 47.4% of the cases (18 out of the 38 studied cases), a frequency that lies within the range reported in the literature of 42.8–88% (Blankenstein et al., 2000; Loussouarn et al., 2006; Pravdenkova et al., 2006; Onak Kandemir et al., 2010). The more frequent PR positivity in grade I meningiomas, 54.8% as opposed to 14.3% in grade II/III meningiomas, reported in our study is in accordance with the results of the previous studies.
The present study has found no statistically significant relation between Her-2/neu and PR expression. This is in accordance with the results of Loussouarn et al. (2006). In contrast, Her-2/neu and PR expressions were positively correlated in the studies of Onak Kandemir et al. (2010) and Abdelzaher et al. (2010). In the latter study, which was conducted as a retrospective immunohistochemical study including 60 Egyptian patients, Her-2/neu expression showed a significant inverse correlation with PR. However, the study sample was selected only from benign intracranial meningiomas and no atypical/anaplastic cases were included. To our knowledge, no other studies have explored the relation between Her-2/neu and PR expression, a fact stated by Onak Kandemir et al. (2010) and investigated by the authors of the current study, who have only found in addition to the studies by Loussouarn et al. (2006) and Onak Kandemir et al. (2010) that of Abdelzaher et al. (2010) mentioned above. Further studies are required to obtain additional information on the relation between Her-2/neu and PR expression in patients with meningiomas of different grades.
MIB-1 is an anti-ki-67 monoclonal antibody that is useful for the analysis of proliferative potentials. The MIB-1 immunohistochemical staining index correlates with the histologic grade of meningiomas (Campbell et al., 2009), a finding that is in complete agreement with the results of the present study, where the MIB-1 proliferation index ranged from 0.5 to 18.6, with a statistically significant difference between grade I (range PI of 0.5–2.2 and mean of 1.197) and grades II/III meningiomas (range PI of 4.6–18.6, mean of 10.15) (analysis of variance test). These figures are also in accordance with those reported in the literature by Matsuno et al. (2005) and Loussouarn et al. (2006), and are both logical and predicted as mitotic activity according to the WHO grading of meningioma is a main criterion in the diagnosis of atypical/anaplastic meningiomas.
Despite the fact that the role of Her-2/neu in cell proliferation and growth is well established in the literature (Akiyama et al., 1986; Craven et al., 2003), controversy exists in terms of the relation between Her-2/neu overexpression and proliferative activity of meningiomas, with some studies describing no relationship between Her-2/neu and Ki-67 expression such as those of Potti et al. (2004b), Loussouarn et al. (2006), Durand et al. (2008), and Onak Kandemir et al. (2010). Other studies including ours (mean MIB-index of 4.77 in Her-2/neu-positive cases as compared with 1.8 in Her-2/neu-negative cases) and those of Abdelzaher et al. (2010) and Wang et al. (2010) have found a statistically significant relationship between Her-2/neu and Ki-67 expression.
The current study revealed a statistically significant higher mean MIB-1 proliferation index in the PR-negative (1.8%) than in the PR-positive group (4.77%). This finding is in agreement with that of Abdelzaher et al. (2010), and can be attributed to the fact that PR-positive tumors tend to be grade I tumors and hence have a low PI and vice versa for PR-negative tumors. In fact, it has been proposed that meningioma grading can also be supplemented with the use of immunohistochemical markers, namely the proliferation marker Ki-67 (MIB-1) and the PR. MIB-1 helps to assess the proliferation potential of a meningioma, whereas PR expression is roughly inversely correlated to tumor grade (Mawrin and Perry, 2010). Our findings, however, contradict those of Loussouarn et al. (2006) and Onak Kandemir et al. (2010), who failed to find such an association. This disagreement could be related to the fact that although the only adjunct marker commonly used in the evaluation of meningioma is the proliferation marker ki-67, there is still variability in the results obtained in different laboratories as reported by Commins et al. (2007). The reasons for this include differences in staining techniques, counting methods, and interpretation of results (Willis et al., 2005).
Although meningiomas generally grow slowly, some recur even after radical resection (Moradi et al., 2008). Meningiomas have shown significant rates of recurrence, morbidity, and mortality in studies with a long-term follow-up (Louis et al., 2007). Clinical progress is difficult to predict (Özer et al., 2009). Recurrences can be attributed not only to incomplete removal but also to histologic and biologic aggressiveness (Moradi et al., 2008).
In the current study, patients were followed up for occurrence of recurrence or disease related deaths. The mean follow-up period was 49 months, with a median of 36 months. Eleven meningiomas (29%) recurred. A statistically significant relationship was found between disease-free survival and tumor grade on univariate analysis by the log-rank test (P=0.01). This result is in accordance with those reported in the literature that atypical and anaplastic/malignant histologies have a greater risk of local recurrence than benign meningiomas (Campbell et al., 2009; Mawrin and Perry, 2010). The rate of recurrence in our study, which was 57% in the atypical/anaplastic group as compared with 23% in the classical meningiomas, is in complete agreement with the recurrence rates reported by Louis et al. (2007) of 50–94%, for anaplastic meningiomas, 29–52% for atypical meningiomas, and 7–25% for benign meningiomas. As for the tumor histological subtype, our results are in agreement with those of other authors indicating that clinically, there is no distinction in the behavior or the prognostic significance of the numerous histological variants of benign meningioma (De Monte, 1995).
In our study, PR-negative tumors constituted 63.6% of all recurrences; yet, the percentage of recurring PR-positive tumors was 22.2 versus 35% in the PR-negative group. These findings might be of clinical significance but have shown no statistical significance on univariate analysis (P>0.05). Many investigators researching the predictive and prognostic value of the expression of the hormone receptors in meningiomas reported PR negativity as a statistically significant predictor of recurrence (Pravdenkova et al., 2006; Maiuri et al., 2007; Abdelzaher et al., 2010). Abdelzaher et al. (2010); the results, however, were based on a retrospective study and patients were not followed up for recurrence, and the duration of follow-up and values of censored data were not considered. In contrast, Campbell et al. (2009) – on account of the limited success of hormonal therapies in the treatment of meningiomas – have questioned whether the link between meningiomas and hormones is only a confounder effect, concluding that further research is required to determine the influence of the hormonal microenvironment on meningioma pathogenesis, a conclusion that we totally agree upon in view of the debate about the role of hormonal receptors in the literature.
Two variables in the current study were found to be significant predictors for recurrence on univariate analysis and retained their relation to recurrence on multivariate analysis: the MIB-1 proliferation index and Her-2/neu overexpression. In the current study, the mean MIB-1 index in recurrent tumors was 5.309 compared with 1.844 in the nonrecurring group. Our results were in accordance with a bulk of literature reporting that meningiomas with MIB-1 staining index of at least 3% have a significantly higher risk of recurrence; this index has been found to be predictive of recurrence independent of the Simpson surgical resection grade (Abdelzaher et al., 2010). Furthermore, Matsuno et al. (2005) also demonstrated that multiply recurrent tumors have the highest MIB-1 staining when compared with meningiomas at first recurrence and nonrecurring primary meningiomas.
Mawrin and Perry (2010)’s argument of the prognostic value of MIB 1 being related to the fairly good correlation between histological grading and MIB-1 labeling led to their recommendation that the MIB-1 labeling of a given tumor must be interpreted cautiously and in the context of other clinicopathological features. In the current study, the MIB1 LI means within the classical meningioma group were 1.09 and 1.55 for the nonrecurring and the recurring groups, respectively. The same significant difference held true for the atypical/anaplastic group, in which the means were 7.867 and 11.875 for the nonrecurring and the recurring groups, respectively, confirming the value of the prognostic role of MIB 1 for tumors of the same grade.
In the current study, Her-2/neu expression was significantly related to disease-free survival on multivariate analysis. Also, the mean disease-free survival time for HER-2/neu-positive cases was shorter than those patients whose tumors were HER-2/neu negative (37 months vs. 55 months). Five of the11 HER-2/neu-positive tumors that recurred were grade I tumors, a finding similar to that of Loussouarn et al. (2006), who found the rate of recurrence to be higher in HER2-positive meningiomas (50%) than in HER2-negative meningiomas (20%), reporting two of the HER2-positive recurrent meningiomas to be grade I tumors and strongly suggesting that HER2 may be an independent prognostic factor to predict the recurrence of meningiomas.
Other studies that have investigated the relation between Her-2/neu and survival of patients with meningioma include those of Potti et al. (2004b), Abdelzaher et al. (2010), and Wang et al. (2010). Potti et al. (2004b); in their large study, including 237 patients with meningioma, no association was found between Her-2/neu overexpression, which was detected in only 2.5% of the studied tumors, and outcome/behavior of meningiomas and hence they concluded that HER-2/neu does not play a role in the prognosis and management of meningiomas. The low detection rate reported in this study in addition to the methodology used, where the staining score interpretation method applied was that used for breast tissue, might explain the contrast in results. In accordance with our results, Abdelzaher et al. (2010)’s results have shown, on univariate analysis, that recurrence was significantly associated with HER2 expression; however, the relation was not retained on multivariate analysis. Wang et al. (2010)’s results, in contrast, agree with our findings, as they reported high levels of HER2 and Ki-67 expression to correlate with an increase in tumor grades and tumor recurrence, and concluded that a combination of a biomarker study including HER2/neu, Ki-67, and TK1 may be useful in predicting the biological behavior of meningiomas.
To our knowledge, this is the first study to investigate the disease-free survival of Egyptian patients with meningioma on the basis of follow-up after the primary surgical intervention. The study concludes that Her-2/neu expression and the MIB-1 proliferation index can be independent prognostic factors for meningioma patients’ disease-free survival. We suggest that those patients with tumors showing HER2 positivity and high MIB-1 LI should be followed more closely for evidence of tumor recurrence. Studies conducted in larger patient groups may provide reliable information for assessing the roles of these parameters in the pathogenesis and progression of meningiomas as well as in formulating alternative individualized treatment choices.
Conflicts of interest
There are no conflicts of interest.
Abdelzaher E, El-Gendi SM, Yehya A, Gowil AG. Recurrence of benign meningiomas: predictive value of proliferative index, BCL2, p53, hormonal receptors and HER2 expression. Br J Neurosurg. 2010 [Epub ahead of print]
Abry E, Thomassen IT, Salvesen TO, Torp SH. The significance of Ki-67/MIB-1 labeling index in human meningiomas: a literature study. Pathol Res Pract. 2010;206:810–815
Akiyama T, Sudo C, Ogawara H, Toyoshima K, Yamamoto T. The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity. Science. 1986;232:1644–1646
Blankenstein MA, Verheijen FM, Jacobs JM, Donker TH, van Duijnhoven MW, Thijssen JH. Occurrence, regulation and significance of progesterone receptors in human meningioma. Steroids. 2000;65:795–800
Campbell BA, Jhamb A, Maguire JA, Toyota B, Ma R. Meningiomas in 2009. Controversies and future challenges. Am J Clin Oncol. 2009;32:73–85
Oncology reporting system application. 2006 Vancouver, BC Cancer Agency Information System
Commins DL, Atkinson RD, Burnett ME. Review of meningioma histopathology. Neurosurg Focus. 2007;23:E3
Craven RJ, Lightfoot H, Cance WG. A decade of tyrosine kinases: from gene discovery to therapeutics. Surg Oncol. 2003;12:39–49
Custer BS, Koepsell TD, Mueller BA. The association between breast carcinoma and meningioma in women. Cancer. 2002;94:1626–1635
De Monte F. Current management of meningiomas. Oncology (Huntingt). 1995;9:83–91 , 96; discussion 96, 99–101
Durand A, Champier J, Jouvet A, Labrousse F, Honnorat J, Guyotat J, et al. Expression of c-Myc, neurofibromatosis Type 2, somatostatin receptor 2 and erb-B2 in human meningiomas: relation to grades or histotypes. Clini Neuropathol. 2008;27:334–345
Jimenez RE, Wallis T, Tabasczka P, Visscher DW. Determination of Her-2/Neu status in breast carcinoma: comparative analysis of immunohistochemistry and fluorescent in situ hybridization. Mod Pathol. 2000;13:37–45
Lee E, Grutsch J, Persky V, Glick R, Mendes J, Davis F. Association of meningioma with reproductive factors. Int J Cancer. 2006;119:1152–1157
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK WHO classification of tumours of the central nervous system. 2007 Lyon IARC
Loussouarn D, Brunon J, Avet Loiseau H, Campone M, Mosnier JF. Prognostic value of HER2 expression in meningiomas: an immunohistochemical and fluorescence in situ hybridization study. Hum Pathol. 2006;37:415–421
Maiuri F, De Caro MB, Esposito F, Cappabianca P, Strazzullo V, Pettinato G, et al. Recurrences of meningiomas: predictive value of pathological features and hormonal and growth factors. J Neurooncol. 2007;82:63–68
Matsuno A, Nakaguchi H, Nagashima T, Fujimaki T, Osamura RY. Histopathological analyses of proliferative potentials of intracranial meningiomas using bromodeoxyuridine and MIB-1 immunohistochemistry. Acta Histochem. 2005;38:9–15
Mawrin C, Perry A. Pathological classification and molecular genetics of meningiomas. J Neurooncol. 2010;99:379–391
Moradi A, Semnani V, Djam H, Tajodini A, Zali AR, Ghaemi K, et al. Pathodiagnostic parameters for meningioma grading. J Clin Neurosci. 2008;15:1370–1375
Onak Kandemir N, Ege Gül A, Doğan Gün B, Karadayi N, Yurdakan G, Özdamar SO. Her-2/neu, estrogen and progesterone receptor expression in WHO grade I meningiomas. Trakya Univ Tip Fak Derg. 2010;27:292–296
Özer Ö, Şahin FI, Aydemir F, Özen Ö, Yilmaz Z, Altinörs N. HER-2/neu gene amplification in paraffin-embedded tissue sections of meningioma patients. Turk Neurosurg. 2009;19:135–138
Potti A, Forseen SE, Koka VK, Pervez H, Koch M, Fraiman G, et al. Determination of HER-2/neu overexpression and clinical predictors of survival in a cohort of 347 patients with primary malignant brain tumors. Cancer Invest. 2004a;22:537–544
Potti A, Panwalkar A, Langness E, Sholes K, Tendulkar K, Chittajalu S, et al. Role of HER-2/neu overexpression and clinical features at presentation as predictive factors in meningiomas. Am J Clin Oncol. 2004b;27:452–456
Pravdenkova S, Al Mefty O, Sawyer J, Husain M. Progesterone and estrogen receptors: opposing prognostic indicators in meningiomas. J Neurosurg. 2006;105:163–173
Simpson D. The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry. 1957;20:22–39
Torp SH, Helseth E, Unsgaard G, Dalen A. C-erbB-2/HER-2 protein in human intracranial tumours. Eur J Cancer. 1993;29A:1604–1606
Wang CL, Mei JH, Wang SS, Xu S, Xu LL, Xiong YF. Expression of HER2/neu in meningiomas: an immunohistochemistry and fluorescence in situ hybridization study. Chin J Pathol. 2010;39:156–160
Willis J, Smith C, Ironside JW, Erridge S, Whittle IR, Everington D. The accuracy of meningioma grading: a 10-year retrospective audit. Neuropathol Appl Neurobiol. 2005;31:141–149
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Zaghloul AS, Ghoneim WA, Abd-El-Moneim T, Kaddah NT, El-Bolkainy N, Khafagy MM. Patterns of axillary lymph node metastasis from breast cancer in Egyptian patients. J Egypt Natl Cancer Inst. 2001;13:1–8