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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 6  |  Page : 1482-1487

Estrogen and progesterone receptor in meningiomas: An immunohistochemical analysis


1 Department of Pathology, Christian Medical College and Hospital, Vellore, Tamil Nadu, India
2 Department of Pathology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
3 Department of Neurosurgery, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India

Date of Submission29-Sep-2016
Date of Decision28-Jun-2017
Date of Acceptance24-Feb-2018
Date of Web Publication24-Oct-2018

Correspondence Address:
Amit Kumar Chowhan
Department of Pathology, Sri Venkateswara Institute of Medical Sciences, Tirupati - 517 507, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1075_16

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 > Abstract 


Background: Meningiomas are common slow-growing primary intracranial neoplasms attached to the dura mater and are composed of neoplastic meningothelial cells. Increased incidence of meningiomas in women with an increased tumor growth during pregnancy and a possible association with breast cancer suggested that female sex hormones have been involved in the growth of meningiomas. Antihormonal-targeted therapy would be beneficial in such patients.
Aim: The aim of this study is to correlate the expression of estrogen receptor (ER) and progesterone receptor (PR) in meningiomas with gender, location, histological subtypes, and grade.
Materials and Methods: This is a 3½-year prospective and retrospective study of intracranial and intraspinal meningiomas. Clinical details of all the patients were noted from the computerized hospital information system. Immunohistochemistry for ER and PR was performed. Statistical analysis was performed using Chi-square test.
Results: During the study period, there were 80 Grade I, 18 Grade II, and 2 Grade III meningiomas categorized as per the World Health Organization 2007 classification. The female-to-male ratio was 1.9:1 and the mean age was 47.8 years. ER was expressed in 2% of meningiomas. PR was expressed in 67.5% of Grade I and 66.6% of Grade II and none of Grade III meningiomas. Brain-invasive meningiomas showed 54.5% PR immunopositivity and negative for ER.
Conclusion: ER and PR were expressed in 2% and 66% of meningiomas, respectively. Statistically significant relationship was not found between the positivity of PR in females and males of Grade I and Grade II/III meningiomas, intracranial and spinal tumors, Grade I and Grade II/III cases, and various histological subtypes of meningiomas.

Keywords: Hormone, meningioma, receptor, targeted therapy, tumor


How to cite this article:
Telugu RB, Chowhan AK, Rukmangadha N, Patnayak R, Phaneendra BV, Mowliswara Prasad BC, Reddy MK. Estrogen and progesterone receptor in meningiomas: An immunohistochemical analysis. J Can Res Ther 2020;16:1482-7

How to cite this URL:
Telugu RB, Chowhan AK, Rukmangadha N, Patnayak R, Phaneendra BV, Mowliswara Prasad BC, Reddy MK. Estrogen and progesterone receptor in meningiomas: An immunohistochemical analysis. J Can Res Ther [serial online] 2020 [cited 2021 Dec 4];16:1482-7. Available from: https://www.cancerjournal.net/text.asp?2020/16/6/1482/243464




 > Introduction Top


Meningiomas are common slow-growing primary nonglial intracranial neoplasms attached to the dura mater and are composed of neoplastic meningothelial cells. These tumors occur mainly in the fifth and sixth decades of life with female predilection (female-to-male ratio of 2:1) and account for 36.4% of all primary intracranial tumors.[1],[2] The World Health Organization (WHO) 2007 classification of tumors of the central nervous system graded meningiomas into three grades – benign (Grade I), atypical (Grade II), and anaplastic or malignant (Grade III).[2]

Literature search revealed that increased incidence of meningiomas in women with an increased tumor growth during pregnancy and a possible association with breast cancer suggested that female sex hormones have been involved in the growth of meningiomas.[3],[4]

Steroid hormone nuclear receptor family acts as transcription factors by regulating gene expression and mediates the biological action of the steroids. Reported literature described the presence of approximately 0%–33% estrogen receptors (ERs) and 48%–88% progesterone receptors (PRs) in meningiomas.[4],[5] Moreover, in vivo and in vitro studies revealed that meningioma growth can be controlled by antiprogesterone (mifepristone) drugs.[4]

Surgical excision is the standard treatment of meningioma.

However, cases with tumor recurrence, inoperable tumors resistant to radiation, and unaccessibility lead to incomplete surgical removal of the tumor, and in malignant cases, if the receptors being present in the tumor, additional treatment procedure with antihormonal targeted therapy would be beneficial in such patients.[6] In the present study, we aimed to correlate the positivity of ER and PR expression between gender, location, various histologic subtypes, and grade of meningiomas.


 > Materials and Methods Top


This is a 3½-year prospective (March 2010–October 2011) and retrospective (May 2008–February 2010) study of primary intracranial and intraspinal meningiomas diagnosed in the department of pathology. The study was approved by the institutional ethics committee (no. 132). The clinical data of the patients were noted from the computerized hospital information system. Sections of 4–5 μ thickness were prepared from the tumor tissue samples fixed in 10% neutral-buffered formalin and paraffin-embedded tissue blocks and stained with routine hematoxylin and eosin stain. Meningioma grading and histological subtyping were done according to the WHO 2007 classification [Table 1] and [Table 2].[2] Immunohistochemical staining was performed in 100 cases for ER and PR receptors by polymer-horseradish peroxidase (HRP) method.
Table 1: Meningioma grades and histological subtypes according to the 2007 World Health Organization classification

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Table 2: World Health Organization 2007 criteria for grading of meningioma

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Inclusion criteria

All the prospective (March 2010–October 2011) and retrospective (May 2008–February 2010) cases of meningiomas diagnosed in our department were included in the study.

Exclusion criteria

  1. Meningiomas with scanty tissue where immunostain could not be performed
  2. Cases in which paraffin blocks could not be retrieved (cases referred from other hospitals where only slides were available) were excluded from the study.


Immunohistochemistry procedure

Sections of 3 μ thin, formalin-fixed, paraffin-embedded tissue mounted on? 3-aminopropyltriethoxysilane-precoated slides were prepared. The slides were incubated overnight at 37°C. For antigen retrieval, heat-induced method using pressure cooker (3 whistles) in Tris ethylenediaminetetraacetic acid pH 9.0 was applied. Endogenous peroxidase activity was blocked by 3% hydrogen peroxide (H2O2). Sections were washed in Tris buffer (pH 7.6) and incubated with anti-ER (rabbit monoclonal primary antibody, clone SP1, Ventana, prediluted) and anti-PR primary antibody (rabbit monoclonal primary antibody, clone 1E2, Ventana, prediluted) for 30 min at room temperature. The slides were treated by poly-HRP reagent and diaminobenzidine chromogen with intervening washes in Tris buffer (pH 7.6). Then, counterstaining with Harris's hematoxylin, dehydration and mounting with dibutyl phthalate xylene were performed. Section of ER- and PR-positive invasive ductal carcinoma of the breast was used as positive control and negative control by excluding the primary antibody. It was considered to be positive if the tumor cells showed nuclear staining for ER and PR antibody.

The nuclear staining intensity was scored as follows: 0 – no staining, 1 – mild staining, 2 – moderate staining, and 3 – strong staining. The percentage of positive cells was scored as follows: 0: 0%, 1: ≤25%, 2: >25%–≤50%, 3: >50%–≤75%, and 4: >75%. The final score was calculated by adding the points obtained from both proportion and intensity scoring systems, ranging 0–7.[7]

Statistical analysis

The statistical analysis performed in this study was Chi-square test to assess the association of gender, location, grade, and histological subtype of meningioma with PR. P <0.05 was considered to be statistically significant. Grade II and Grade III meningiomas were combined for statistical analysis since there were only two cases of Grade III meningioma in the study sample. Statistical analysis was not done for ER since there were only two cases positive for ER.


 > Results Top


During the study period, there were a total of 100 (43 prospective and 57 retrospective) cases of meningiomas, of which 89 were intracranial and 11 were intraspinal. Among the 100 patients, 66 were female and 34 were male with female-to-male ratio of 1.9:1 and the mean age was 47.8 years (range: 5–85 years). There were 80% Grade I, 18% Grade II, and 2% Grade III meningiomas. Cerebral convexity was the most common intracranial location followed by thoracic segment of the intraspinal region. Among the 16 histological subtypes of meningioma described in the WHO 2007 classification of tumors of the central nervous system, the present study includes 10 histological subtypes. [Table 3] shows histological subtypes with grade in the study group. Although not mentioned under Grade II in the WHO 2007 classification, 27.3% of meningothelial, 14.3% each of psammomatous and angiomatous, 5.9% of fibroblastic, and 6.2% of transitional meningioma subtypes were found to be of Grade II rather than Grade I because of atypical histological features. Most common subtype was psammomatous meningioma (28%) followed by meningothelial (22%), fibroblastic (17%), and transitional (16%) meningiomas.
Table 3: Histological subtypes with grades in the study group

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Immunohistochemistry

Among the 100 cases of meningiomas, ER immunoreactivity was demonstrated in scattered occasional cell nuclei in 2 cases (2%), especially of Grade I meningothelial subtype [Figure 1] with total staining scores of 2 and 3. These two cases were also positive for PRs. There was equal distribution between female and male in the ER-positive group (female/male ratio – 1:1).
Figure 1: Photomicrograph showing scattered occasional cell nuclei staining (score, 2 + 1 = 3) of estrogen receptor (broad arrow) in meningothelial meningioma (IHC, ×200)

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Sixty-six (66%) of the 100 cases of meningiomas contained cell nuclei that showed a positive reaction for the PR, ranging from a focal few cells (≤25%) to diffuse (>75%) staining of the tumor cell population [Table 4]. Immunoreactivity for PR was found strong and distinct nuclear positivity in only tumor cell nuclei but not in cytoplasm, connective tissue, or blood vessels. PR positivity was noted mild, moderate, and strong nuclear staining [Figure 2]. Nearly 67.5% of benign and 66.6% of atypical tumors were PR positive. Malignant meningiomas were negative for PR.
Table 4: Frequency distribution of variables by progesterone receptor status in meningiomas

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Figure 2: Photomicrograph showing (a) mild (score, 1 + 2 = 3), (b) moderate (score, 2 + 4 = 6), and (c) strong nuclear positivity (score, 3 + 4 = 7) in tumor cell nuclei of progesterone receptors in meningioma (IHC, ×200)

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Highest PR immunopositivity were noted in meningothelial (81.8%) and transitional (81.3%) subtypes followed by clear cell (66.7%), fibroblastic (64.7%), psammomatous (60.7%), atypical (50%), angiomatous (42.9%), and metaplastic (33.3%) meningiomas. Anaplastic and papillary meningiomas were negative for PR.

Positivity of PR in females and males was 66.7% and 64.7%, respectively, which is not statistically significant at 5% level of significance including those of Grade I and Grade II/III meningiomas. PR immunopositivity in none of the histological subtypes was statistically significant at 5% level of significance with Chi-square test. In the anaplastic and papillary meningioma subtypes, PR was negative. Statistically significant relationship was not found between the positivity of PR in intracranial (66.2%) and intraspinal (66.3%) meningiomas. The positivity of PR within the Grade I (67.5%) was higher than that in the Grade II/III (60%) meningiomas, this difference did not reach statistical significance with Chi-square test [Table 5]. Brain invasion was noted in 11 cases of meningioma with PR positivity in 6 (54.5%) cases. All the cases were primary tumors and recurrence was not noted in the study group.
Table 5: Relationship between gender, location, grade, subtype and progesterone receptor expression

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 > Discussion Top


Many studies described the presence of PR in meningioma ranging from 48% to 88%; however, the presence of ER in meningioma is still a point of debate with ER immunopositivity ranging from 0% to 33% in these tumors.[4],[5] Molecular analysis by polymerase chain reaction (PCR) and reverse transcriptase PCR has described the presence of messenger RNA coding for ERs in 68%–100% of tumors, whereas ligand-binding assay has described ERs in 11.1%–36% of meningiomas.[5] In the present study, PRs were noted in 66% of meningiomas and ERs were noted staining occasional cell nuclei in 2% of cases, especially of Grade I meningothelial subtype, which were also positive for PRs.

It is well known that meningiomas show predilection for women than men, with a female-to-male ratio of 2:1.[1],[2] In our study, the female-to-male ratio was 1.9:1 in PR-positive group. ER-positive group showed equal gender distribution (female/male ratio – 1:1). There was no statistically significant difference between men and women in the distribution of Grade I and Grade II/III tumors.

In the recent WHO 2016 classification of tumors of the central nervous system, brain invasion has been added as independent criteria for diagnosing Grade II atypical meningioma, in addition to mitosis and other criteria;[8] however, the present study follows the WHO 2007 criteria.

Marciscano et al.[9] studied 77 benign meningiomas with atypia and 71 without atypia. Meningioma with atypical histological features was statistically associated with progression/recurrence independent of the MIB-1 labeling index. In our study also, we found few cases of benign histological subtype with atypical features and therefore were placed under Grade II.

In a study by Taghipour et al.,[10] 68.6% of meningiomas were positive for PRs and all the cases were negative for ERs. Another study by Konstantinidou et al.[11] described the presence of 75.5% and 35.4% of PR and ER in the meningiomas mostly in Grade I than Grade II tumors. PR and ER were expressed high in Grade I meningothelial meningiomas, and atypical meningiomas had very low ER expression. In the present study, ER and PR expression was higher in Grade I meningiomas than in Grade II/III meningiomas. Benign meningothelial subtype contained highest PR and ER. ER was not expressed in Grade II/III meningiomas.

Pravdenkova et al.[5] stated that PR-positive meningiomas had a statistically significant lower proliferative index and less aggressive histopathological findings and chromosomal abnormalities. The receptor-negative and ER-positive group had a significantly higher percentage of recurrent tumors and a low percentage of de novo cases compared with the PR-positive group. In another study,[12] Grade I meningiomas had a significantly higher PRs than Grade II/III tumors. There was no statistically significant correlation at 5% level of significance between PR-positive cases and recurrent tumors in the WHO Grade I totally removed meningiomas. However, a combination of PR status and proliferation indices was shown to predict the biological nature of meningiomas reliably. In our study, PR-positive meningiomas were noted high in Grade I than Grade II/III tumors and did not reach statistically significant difference at 5% level of significance. A study by Tao et al.[13] reported 53 recurrent meningiomas during the follow-up period of 3–5 years after surgery with a recurrence rate of 32.7%. The immunohistochemical positive or strong positive nuclear expression of androgen receptor, ER, PR, and Ki-67 was 38.8%, 60.5%, 58.6%, and 26.5%, respectively. There was a significant correlation between tumor size (>5 cm), irregular tumor shape, pathological grade, Ki-67 index, and tumor recurrence. The current study includes only primary tumors, and no recurrent cases were noted to correlate the ER and PR immunoreactivity with tumor behavior.

Kumar et al.[14] reported that, among convexity meningiomas, isolated 1p36 deletion was seen in 20%, 28.6%, and 30.8% Grade I, Grade II, and Grade III tumors and isolated 14q deletion in one Grade III convexity tumor. 1p/14q co-deletion was observed in none of Grade I, 28.5% Grade II, and 30% Grade III convexity meningiomas. PR immunoreactivity was more frequent in Grade I (86.7%) than Grade III (30.7%) tumors, suggesting that PR is inversely correlated with grade of tumor. 1p/14q co-deletion is characteristically seen in Grade II/III meningiomas, while identification of 1p/14q co-deletion in Grade I tumors suggests that these meningiomas are biologically more aggressive. In our study, chromosomal analysis was not performed; however, PR is strongly expressed in Grade I tumors and none of Grade III meningiomas.

Ji et al.[15] described a multicenter, randomized prospective, placebo-controlled double-blind Phase III trial among 164 patients. Among the group assigned to mifepristone, 30% completed 2 years of mifepristone without any disease progression, side effects, or other reasons for discontinuation. About 33% in the placebo group completed 2-year trial. Statistical significant difference was not found between the two groups in terms of failure-free or overall survival. A study by Grunberg et al.[16] stated that long-term administration of mifepristone is possible and clinically well tolerated with few side effects; however, endometrial hyperplasia and endometrial carcinoma were noted in 14.28% of cases.

Kerschbaumer et al.[17] reported a case of sphenoid wing meningioma in a 32-year-old female who presented with severe headache and vision disturbances at the end of her second pregnancy. Magnetic resonance imaging (MRI) revealed a left-sided sphenoid wing mass suspected to be a meningioma. The patient's symptoms were improved after delivery, and postpartum MRI revealed significant shrinkage of the tumor, possibly due to hormone withdrawal. Histopathological examination of microsurgical resection specimen showed microcystic meningioma (WHO Grade I) with over 90% PR expression and negative for ERs. In a study by Olson et al.,[18] cell culture assay demonstrated inhibition of meningioma growth by mifepristone in all three tumors, ranging from 18% to 36%.

Complete surgical excision is the standard treatment for all symptomatic meningiomas, followed by radiotherapy in malignant tumors. However, cases such as tumor recurrence, complications, and unaccessibility lead to incomplete surgical removal of the tumor, and in malignant cases, if the receptors being present in the tumor, additional treatment procedure with antihormonal-targeted therapy would be beneficial in such patients. Hydroxyurea, mifepristone, tamoxifen, interferon-alpha alone, or in combination with calcium channel blockers and newer molecular inhibitors could be successful in the treatment of recurrent unresectable meningiomas.[19]

Limitations

  1. There were no recurrent tumors in our study group to evaluate the prognostic significance of ER and PR in recurrent meningiomas
  2. Follow-up data were available in only a limited number of cases. This is required to ascertain true prognostic relevance of ER and PR expression
  3. The presence of low number of ER precluded to confirm the exact biological nature of meningiomas
  4. 100 cases were selected for the study, due to financial constraints.



 > Conclusion Top


PR was expressed in 66% of meningiomas, including 67.5% of Grade I and 60% of Grade II/III meningiomas; however, ER was expressed in only 2% cases. Slightly higher PR immunopositivity was seen in females compared to males, and ER showed equal gender distribution. Statistically significant relationship was not found between the positivity of PR in gender, location, tumor grade, and various histological subtypes. Highest PR immunopositivity was noted in meningothelial subtype. Almost 54.5% brain-invasive meningiomas showed PR expression. The role of ER or PR alone may not predict the prognosis but if combined with proliferative indices may be a useful prognostic tool for benign meningiomas. Expression of PRs and the availability of antihormonal-targeted therapy in addition to radiotherapy would be beneficial in patients with recurrence and unaccessibility leading to incomplete removal of the tumor. It is also suggested to conduct larger studies to evaluate the possibilities of the progesterone treatment effect on the tumor in order to evaluate the prognosis of these patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C, et al. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the united states in 2008-2012. Neuro Oncol 2015;17 Suppl 4:iv1-iv62.  Back to cited text no. 1
    
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Perry A, Louis DN, Scheithauer BW, Budka H, Deimling VA. Meningiomas. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. World Health Organization Classification of the Central Nervous System. Lyon: IARC; 2007. p. 164-72.  Back to cited text no. 2
    
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Korhonen K, Salminen T, Raitanen J, Auvinen A, Isola J, Haapasalo H, et al. Female predominance in meningiomas cannot be explained by differences in progesterone, estrogen, or androgen receptor expression. J Neurooncol 2006;80:1-7.  Back to cited text no. 3
    
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Guevara P, Escobar-Arriaga E, Saavedra-Perez D, Martinez-Rumayor A, Flores-Estrada D, Rembao D, et al. Angiogenesis and expression of estrogen and progesterone receptors as predictive factors for recurrence of meningioma. J Neurooncol 2010;98:379-84.  Back to cited text no. 4
    
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Pravdenkova S, Al-Mefty O, Sawyer J, Husain M. Progesterone and estrogen receptors: Opposing prognostic indicators in meningiomas. J Neurosurg 2006;105:163-73.  Back to cited text no. 5
    
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Gruber T, Dare AO, Balos LL, Lele S, Fenstermaker RA. Multiple meningiomas arising during long-term therapy with the progesterone agonist megestrol acetate. Case report. J Neurosurg 2004;100:328-31.  Back to cited text no. 6
    
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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 2011;25:707-13.  Back to cited text no. 7
    
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Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathol 2016;131:803-20.  Back to cited text no. 8
    
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Marciscano AE, Stemmer-Rachamimov AO, Niemierko A, Larvie M, Curry WT, Barker FG 2nd, et al. Benign meningiomas (WHO grade I) with atypical histological features: Correlation of histopathological features with clinical outcomes. J Neurosurg 2016;124:106-14.  Back to cited text no. 9
    
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Taghipour M, Rakei SM, Monabati A, Nahavandi-Nejad M. The role of estrogen and progesterone receptors in grading of the malignancy of meningioma. Iran Red Crescent Med J 2007;9:17-21.  Back to cited text no. 10
    
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Konstantinidou AE, Korkolopoulou P, Mahera H, Kotsiakis X, Hranioti S, Eftychiadis C, et al. Hormone receptors in non-malignant meningiomas correlate with apoptosis, cell proliferation and recurrence-free survival. Histopathology 2003;43:280-90.  Back to cited text no. 11
    
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Roser F, Nakamura M, Bellinzona M, Rosahl SK, Ostertag H, Samii M, et al. The prognostic value of progesterone receptor status in meningiomas. J Clin Pathol 2004;57:1033-7.  Back to cited text no. 12
    
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Tao Y, Liang G, Li Z, Wang Y, Wu A, Wang H, et al. Clinical features and immunohistochemical expression levels of androgen, estrogen, progesterone and ki-67 receptors in relationship with gross-total resected meningiomas relapse. Br J Neurosurg 2012;26:700-4.  Back to cited text no. 13
    
14.
Kumar S, Kakkar A, Suri V, Kumar A, Bhagat U, Sharma MC, et al. Evaluation of 1p and 14q status, MIB-1 labeling index and progesterone receptor immunoexpression in meningiomas: Adjuncts to histopathological grading and predictors of aggressive behavior. Neurol India 2014;62:376-82.  Back to cited text no. 14
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15.
Ji Y, Rankin C, Grunberg S, Sherrod AE, Ahmadi J, Townsend JJ, et al. Double-blind phase III randomized trial of the antiprogestin agent mifepristone in the treatment of unresectable meningioma: SWOG S9005. J Clin Oncol 2015;33:4093-8.  Back to cited text no. 15
    
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Grunberg SM, Weiss MH, Russell CA, Spitz IM, Ahmadi J, Sadun A, et al. Long-term administration of mifepristone (RU486): Clinical tolerance during extended treatment of meningioma. Cancer Invest 2006;24:727-33.  Back to cited text no. 16
    
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Kerschbaumer J, Freyschlag CF, Stockhammer G, Taucher S, Maier H, Thomé C, et al. Hormone-dependent shrinkage of a sphenoid wing meningioma after pregnancy: Case report. J Neurosurg 2016;124:137-40.  Back to cited text no. 17
    
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Olson JJ, Beck DW, Schlechte J, Loh PM. Hormonal manipulation of meningiomas in vitro. J Neurosurg 1986;65:99-107.  Back to cited text no. 18
    
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Sioka C, Kyritsis AP. Chemotherapy, hormonal therapy, and immunotherapy for recurrent meningiomas. J Neurooncol 2009;92:1-6.  Back to cited text no. 19
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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