J.Sales-Llopis

Neurosurgery Service, Alicante University General Hospital, Alicante, Spain.

• Brain Invasion and Trends in Molecular Research on Meningioma
• Pediatric meningioma with rhabdoid features developed at the site of skull fracture: illustrative case
• Radiation therapy for atypical and anaplastic meningiomas: an overview of current results and controversial issues
• Impact of Adjuvant Radiotherapy on Recurrence of Surgically Treated Atypical Meningiomas and Retrospective Analysis of Prognostic Factors
• Clinical and pathological impact of an optimal assessment of brain invasion for grade 2 meningioma diagnosis: lessons from a series of 291 cases
• Risk Stratification to Define the Role of Radiotherapy for Benign and Atypical Meningioma: A Recursive Partitioning Analysis
• Molecular neuropathology of brain-invasive meningiomas
• The impact of brain invasion criteria on the incidence and distribution of WHO grade 1, 2, and 3 meningiomas

The World Health Organization Classification of Tumors of the Central Nervous System 2016 edition added brain invasion (BI) as a criterion for atypical meningioma.

Perry believes that the original definition of brain invasion, which requires a breach of the pial barrier, is still the best method. The two scenarios that are most often mistaken for (or do not show sufficient evidence of) microscopic brain invasion are: 1) an irregular interface with the adjacent brain that nevertheless shows an intervening layer of leptomeninges/collagen and 2) perivascular spread along Virchow-Robin spaces ¹⁾.

An accurate assessment of brain invasion is mandatory as brain invasion is a strong predictor of meningioma progression ²⁾. Including brain invasion as a standalone diagnostic criterion for Grade 2, meningiomas had minimal impact on the incidence of specific meningioma-grade tumors. There is strong agreement between the 2007 and 2016 WHO criteria, likely due to the cosegregation of grade elevating features ³⁾

Go et al. introduced the mechanisms of brain invasion in atypical meningioma and review the genetic factors involved along with epigenetic regulation. First, it is important to understand the three major steps for brain invasion of meningeal cells:

1) degradation of extracellular matrix by proteases, 2) promotion of tumor cell migration to resident cells by adhesion molecules, and 3) neovascularization and supporting cells by growth factors. Second, the genomic landscape of meningiomas should be analyzed by major categories, such as germline mutations in NF2 and somatic mutations in non-NF2 genes (TRAF7, KLF4, AKT1, SMO, and POLR2A). Finally, epigenetic alterations in meningiomas are being studied, with a focus on DNA methylation, histone modification, and RNA interference. Increasing knowledge of the molecular landscape of meningiomas has allowed the identification of prognostic and predictive markers that can guide therapeutic decision-making processes and the timing of follow-up ⁴⁾.

The volume of peritumoral edema was significantly higher in the brain-invasive meningioma group compared to the non-brain-invasive group. The presence of a complete cleft was a rare finding that was only found in non-brain-invasive meningiomas. The presence of enlarged pial feeding arteries was a rare finding that was only found in brain-invasive meningiomas ⁵⁾.

For Xiao et al. the combined model (radiomics classifier with BTI4mm ROI + PEV) had greater diagnostic performance than other models ⁶⁾

Von Spreckelsen et al. summarize preclinical models studying targeted therapies with potential inhibitory effects ⁷⁾

Studies have raised doubts about the prognostic significance of BI in otherwise benign meningiomas.

Invasion of brain tissue by meningiomas has been identified as one key factor for meningioma recurrence. The identification of meningioma tumor tissue surrounded by brain tissue in neurosurgical samples has been touted as a criterion for atypical meningioma (CNS WHO grade 2) but is only rarely seen in the absence of other high-grade features, with brain-invasive otherwise benign (BIOB) meningiomas remaining controversial ⁸⁾

Behling et al. were able to show the prognostic impact of CNS invasion in a large comprehensive retrospective meningioma cohort including other established prognostic factors. They discuss the growing experiences that have been gained on this matter, with a focus on the currently nonuniform histopathological assessment, imaging characteristics, and intraoperative sampling as well as the overall outlook on the future role of this potential prognostic factor ⁹⁾.

Garcia-Segura et al. published that the combination of necrosis and brain invasion is a strong predictor of tumor recurrence and radio-resistance in meningioma, regardless of EOR or adjuvant RT. The findings question the sensibility of brain invasion as an absolute criterion for World health organization grade 2 meningioma status ¹⁰⁾.

Nakasu systematically reviewed studies published after 2000 and performed a PRISMA-compliant meta-analysis of the hazard ratios (HRs) for progression-free survival (PFS) between brain-invasive and noninvasive meningiomas. In five studies that included both benign and higher-grade meningiomas, brain invasion was a significant risk factor for recurrence (HR = 2.45, p = 0.0004). However, in 3 studies comparing “brain-invasive meningioma with otherwise benign histology (BIOB)” with grade I meningioma, brain invasion was not a significant predictor of PFS (HR = 1.49, p = 0.23). Among GIIM per the WHO 2000 criteria, brain invasion was a significant predictor of shorter PFS than noninvasive GIIM (HR = 3.40, p = 0.001) but not per the WHO 2016 criteria (HR 1.13, p = 0.54), as the latter includes BIOB. Meta-regression analysis of seven studies of grade II meningioma showed that more frequent BIOB was associated with lower HRs (p < 0.0001). Hence, there is no rationale for brain invasion as a standalone criterion for grade II meningioma, although almost all studies were retrospective and exhibited highly heterogeneous HRs due to differences in brain-tumor interface data availability ¹¹⁾

Banan et al. investigated the reproducibility of such a prognostic effect.

They identified two cohorts one consisting of 483 patients with meningioma WHO grade I (M°I) or atypical meningioma WHO grade II (M°II) from Hannover Medical School and the other including atypical meningiomas defined according to the classical WHO criteria (M°IIb) from University Hospital Heidelberg. Follow-up data with a median observation time of 38.2 months were available from 308 cases. These included 243 M°I and 65 M°II patients with the latter group consisting of 25 patients with otherwise benign meningiomas with BI (M°IIa) and 40 with M°IIb.

A significant difference in the progression-free interval (PFI) was found between patients with M°I and M°II, M°I and M°IIa, and those with M°I and M°IIb of both cohorts and each separately. However, PFI of M°IIa and M°IIb patients showed no significant difference. In the multivariate regression analysis adjusted for M°I/M°IIa versus M°IIb, sex, age, extent of resection, and tumor location, BI exhibited the strongest risk of relapse (Hazard ratio: 4.95) serving as an independent predictor of PFI (p = 0.002).

The results clearly support the definition of BI as a single criterion of atypia in WHO classification of 2016 ¹²⁾.

Several studies are providing increasing insights into reliable markers to improve the diagnostic and prognostic assessment of meningioma patients. The evidence of brain invasion (BI) signs and its associated variables has been focused on, and currently, scientific research is investing in the study of key aspects, different methods, and approaches to recognize and evaluate BI. This paradigm shift may have significant repercussions for the diagnostic, prognostic, and therapeutic approach to higher-grade meningioma, as long as the evidence of BI may influence patients’ prognosis and inclusion in clinical trials and indirectly impact adjuvant therapy. We intended to review the current knowledge about the impact of BI in meningioma in the most updated literature and explore the most recent implications on both clinical practice and trials and future directions. According to the PRISMA guidelines, systematic research in the most updated platform was performed in order to provide a complete overview of characteristics, preoperative applications, and potential implications of BI in meningiomas. Nineteen articles were included in the present paper and analyzed according to specific research areas. The detection of brain invasion could represent a crucial factor in meningioma patients’ management, and research is flourishing and promising ¹³⁾

In 2017 Brokinkel et al. reviewed the current knowledge about brain invasion with emphasis on its implications on current and future clinical practice. We found various definitions of brain invasion and approaches for evaluation in surgically obtained specimens described over the past decades. This heterogeneity is reflected by a weak correlation with prognosis and remains controversial. Similarly, associated clinical factors are largely unknown. Preoperative, imaging-guided detection of brain invasion is unspecific, and intraoperative assessment using standard and new high-magnification microscopic techniques remains imprecise. Despite the increasing knowledge about molecular alterations of the tumor/ brain surface, pharmacotherapeutic options targeting brain invasive meningiomas are lacking. Finally, they summarize the impact of brain invasion on histopathological grading in the WHO classifications of brain tumors since 1979. In conclusion, standardized neurosurgical sampling and neuropathological analyses could improve the diagnostic reliability and reproducibility of future studies. Further research is needed to improve pre-and intraoperative visualization of brain invasion and to develop adjuvant, targeted therapies ¹⁴⁾.