A systematic review and individual participant data meta-analysis of gonadal steroid hormone receptors in meningioma
Authors: Miyagishima Danielle F. , Sundaresan Vinaik , Gutierrez Ana Gabriella , Barak Tanyeri , Yeung Jacky , Moliterno Jennifer , McGuone Declan , Claus Elizabeth B. , Günel Murat 
Published: May 2023

OBJECTIVE
The relationship between patient and meningioma characteristics and hormone receptors (HRs) of progesterone, estrogen, and androgen remains poorly defined despite literature suggesting that meningiomas are sensitive to gonadal steroid hormones. Therefore, the authors sought to collect and compare data on this topic by performing a systematic review and meta-analysis of reported studies of HR status in meningiomas.

METHODS
A MEDLINE PubMed literature review conducted for articles published between January 1, 1951, and December 31, 2020, resulted in 634 unduplicated articles concerning meningiomas and HRs. There were 114 articles that met the criteria of detailed detection protocols for progesterone receptor (PR), estrogen receptor (ER), and/or androgen receptor (AR) using immunohistochemistry (IHC) or ligand-binding (LB) assays and simultaneous reporting of HR status with at least one variable among age, sex, histology, location, grade, or recurrence. Between-study heterogeneity and risk of bias were evaluated using graphical and statistical methods. The authors performed a multilevel meta-analysis using random-effects modeling on aggregated data (n = 4447) and individual participant data (n = 1363) with subgroup results summarized as pooled effects. A mixed-effects meta-regression using individual participant data was performed to analyze independently associated variables.

RESULTS
The 114 selected articles included data for 5810 patients with 6092 tumors analyzed to determine the expression of three HRs in human meningiomas: PRs, ARs, and ERs. The proportions of HR+ meningiomas were estimated to be 0.76 (95% CI 0.72–0.80) for PR+ and 0.50 (95% CI 0.33–0.66) for AR+ meningiomas. ER+ meningioma detection varied depending on the measurement method used and was 0.06 (95% CI 0.03–0.10) with IHC and 0.11 (95% CI 0.06–0.20) with LB assays. There were associations between age and PR and ER expression that varied between male and female patients. PR+ and AR+ were more common in female patients (OR 1.84, 95% CI 1.47–2.29 for PR and OR 4.16, 95% CI 1.62–10.68 for AR). Additionally, PR+ meningiomas were enriched in skull base locations (OR 1.89, 95% CI 1.03–3.48) and meningothelial histology (OR 1.86, 95% CI 1.23–2.81). A meta-regression showed that PR+ was independently associated with age (OR 1.11 95% CI 1.09–1.13; p < 0.0001) and WHO grade I tumors (OR 8.09, 95% CI 3.55–18.44; p < 0.0001). ER+ was negatively associated with meningothelial histology (OR 0.94, 95% CI 0.86–0.98; p = 0.044) and positively associated with convexity location (OR 1.12, 95% CI 1.05–1.18; p = 0.0003).

CONCLUSIONS
The association between HRs and meningioma features has been investigated but unexplained for decades. In this study the authors demonstrated that HR status has a strong association with known meningioma features, including WHO grade, age, female sex, histology, and anatomical location. Identifying these independent associations allows for a better understanding of meningioma heterogeneity and provides a foundation for revisiting targeted hormonal therapy in meningioma on the basis of proper patient stratification according to HR status.