Biomarkers for differentiating grade II meningiomas from grade I: a systematic review

Abstract

IntroductionThere are a number of prognostic markers (methylation, CDKN2A/B) described to be useful for the stratification of meningiomas. However, there are currently no clinically validated biomarkers for the preoperative prediction of meningioma grade, which is determined by the histological analysis of tissue obtained from surgery.Accurate preoperative biomarkers would inform the pre-surgical assessment of these tumours, their grade and prognosis and refine the decision-making process for treatment. This review is focused on the more controversial grade II tumours, where debate still surrounds the need for adjuvant therapy, repeat surgery and frequency of follow up. MethodsWe evaluated current literature for potential grade II meningioma clinical biomarkers, focusing on radiological, biochemical (blood assays) and immunohistochemical markers for diagnosis and prognosis, and how they can be used to differentiate them from grade I meningiomas using the post-2016 WHO classification. To do this, we conducted a PUBMED, SCOPUS, OVID SP, SciELO, and INFORMA search using the keywords; 'biomarker', 'diagnosis', 'atypical', 'meningioma', 'prognosis', 'grade I', 'grade 1', 'grade II' and 'grade 2'. ResultsWe identified 1779 papers, 20 of which were eligible for systematic review according to the defined inclusion and exclusion criteria. From the review, we identified radiological characteristics (irregular tumour shape, tumour growth rate faster than 3cm 3 /year, high peri-tumoural blood flow), blood markers (low serum TIMP1/2, high serum HER2, high plasma Fibulin-2) and histological markers (low H3K27me3, low SMARCE1, low AKAP12, high ARIDB4) that may aid in differentiating grade II from grade I meningiomas ConclusionBeing able to predict meningioma grade at presentation using the radiological and blood markers described may influence management as the likely grade II tumours will be followed up or treated more aggressively, while the histological markers may prognosticate progression or post-treatment recurrence. This to an extent offers a more personalised treatment approach for patients.

Receptor Tyrosine Kinases as Candidate Prognostic Biomarkers in Meningioma

“…Validating clinically useful prognostic markers remains a major challenge in neuro-oncology. The availability of accurate preoperative biomarkers in MGM patients would improve the pre-surgical assessment of these tumors, their grade and clinical prognosis, and help direct treatment decisions [43]. Advances in the identification of biomarkers in liquid biopsies using samples of cerebrospinal fluid and blood should enable the development of less invasive diagnostic and prognostic methods that will also allow the monitoring of treatment efficacy during disease [83].…”

“…Many radiological, plasmatic, histological, and molecular prognostic markers have been put forward to help to stratify MGMs. However, to date there are no clinically validated biomarkers to help inform determination of tumor grade and clinical prognosis [20,43]. Investigation of gene expression features of progressing, recurrent, or grade III MGM tumors revealed that notably aggressive tumor subsets share a substantial group of differentially expressed genes, in addition to identifying genes separating non-recurring from recurrent and malignant grade I or grade II tumors.…”

“…GFAP expression correlated with the stem cell markers CD133, stage specific embryo antigen 4 (SSEA4), and vimentin in cell populations enriched in grade II/III tumors[52].Measurement of protein serum markers has revealed significant increases in amphiregulin (AREG), EGF, HB-EGF and caspase3 in patients with MGM of different grades, helping to establish an MGM protein signature in the blood[53].Epigenetic changes have been put forward as prognostic markers in MGM[2].Enhancer of Zeste homolog-2 (EZH2) and trimethyl histone-3 (H3K27me3), which mediate histone modifications related to chromatin state, have been examined. Low histological levels of H3K27me3 were found by a systematic review as a marker that may aid the differentiation between grade I and grade II tumors[43]. Immunohistochemical analysis of 149 cases of MGM tumors grade I (n = 102) or grade II (n = 47) has indicated that positivity for EZH2 and negativity for H3K27me3 are associated with higher tumor cell proliferation and significantly more common in grade II MGM compared to grade I tumors.…”

“…Also using a proteomic strategy, one group has put forward retinoblastoma associated protein-1 (RB1) as a critical marker to identify grade I MGM tumors with high risk for recurrence[48].Other studies quantifying protein content via multiple techniques have aided in the identification of possible protein MGM biomarkers. Semiquantitative analysis of nuclear expression of karyopherin a2 and chromosome region maintenance protein 1, members of the karyopherin protein family that comprises nucleocytoplasmic shuttling receptors importins and exportins, revealed that expression of these proteins correlated significantly with MGM histological grade and predicted tumor recurrence[49].Expression changes in securin (PTTG1), which prevents sister chromatid separation, and leptin receptor (LEPR) were associated with MGM malignancy[43]. The somatostatin receptor 2A (SST2A) has been proposed as a good immunostain target due to its high sensitivity[50].…”

Receptor Tyrosine Kinases as Candidate Prognostic Biomarkers and Therapeutic Targets in Meningioma

“…Many radiological, plasmatic, histological, and molecular prognostic markers have been put forward to help to stratify MGMs. However, to date there are no clinically validated biomarkers to help inform the determination of tumor grade and clinical prognosis [ 21 , 44 ]. Investigation of gene expression features of progressing, recurrent, or grade III MGM tumors revealed that notably aggressive tumor subsets share a substantial group of differentially expressed genes, in addition to identifying genes separating non-recurring from recurrent and malignant grade I or grade II tumors.…”