Brain invasion in atypical meningioma [Neurosurgery Wiki]

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====== Brain invasion in atypical meningioma ======

//[[J.Sales-Llopis]]//

//Neurosurgery Department, [[General University Hospital Alicante]], [[Spain]]//

===== Latest Pubmed Related Articles =====

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===== Controversy =====

The [[controversy]] surrounding [[brain invasion]] in [[atypical meningioma]]s relates to whether the presence of tumor cells within the [[brain tissue]] adjacent to the [[tumor]] should be considered a separate [[criterion]] for [[meningioma classification]] or prognosis. Brain invasion refers to the infiltration of tumor cells into the brain parenchyma (the functional tissue of the brain) beyond the tumor's original location.

Some researchers and clinicians argue that brain invasion should be considered a separate feature when diagnosing and grading meningiomas. They believe that the presence of tumor cells within the brain tissue is indicative of a more aggressive tumor behavior and a higher likelihood of recurrence. This viewpoint suggests that tumors with brain invasion should potentially be classified as a higher grade (such as upgrading an atypical meningioma to a more malignant category).

On the other hand, there is another perspective that argues against considering brain invasion as a separate criterion. This viewpoint points out that the definition and assessment of brain invasion can be subjective and inconsistent. It may also be challenging to distinguish between true invasion and the tumor's compression or displacement of brain tissue without actual infiltration. Additionally, there might be cases where apparent brain invasion is due to artifacts in tissue processing or imaging techniques.

The debate around brain invasion in atypical meningiomas revolves around the challenges in accurate diagnosis and grading. Pathologists and clinicians need clear and standardized criteria to assess tumor behavior and make treatment decisions. The controversy highlights the need for ongoing research to better understand the biological behavior of these tumors, develop more precise diagnostic techniques, and determine the clinical significance of brain invasion in predicting outcomes.



===== Definition =====

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 [[pia]]l 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 [[leptomeninge]]s/[[collagen]] and 2) perivascular spread along [[Virchow-Robin spaces]]
((Perry, A. (2021). The definition and role of brain invasion in meningioma grading: Still controversial after all these years. Free Neuropathology, 2, 8. https://doi.org/10.17879/freeneuropathology-2021-3276)).




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An accurate assessment of brain invasion is mandatory as brain invasion is a strong predictor of [[meningioma progression]]
((Picart T, Dumot C, Guyotat J, Pavlov V, Streichenberger N, Vasiljevic A, Fenouil T, Durand A, Jouanneau E, Ducray F, Jacquesson T, Berhouma M, Meyronet D. Clinical and pathological impact of an optimal assessment of brain invasion for grade 2 meningioma diagnosis: lessons from a series of 291 cases. Neurosurg Rev. 2022 Aug;45(4):2797-2809. doi: 10.1007/s10143-022-01792-6. Epub 2022 Apr 29. PMID: 35488071.)).
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
((Rebchuk AD, Chaharyn BM, Alam A, Hounjet CD, Gooderham PA, Yip S, Makarenko S. The impact of brain invasion criteria on the incidence and distribution of WHO grade 1, 2, and 3 meningiomas. Neuro Oncol. 2022 Sep 1;24(9):1524-1532. doi: 10.1093/neuonc/noac032. PMID: 35139206; PMCID: PMC9435498.))




===== Mechanisms =====
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 molecule]]s, and 3) [[neovascularization]] and supporting cells by [[growth factor]]s. 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 [[meningioma]]s 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
((Go KO, Kim YZ. Brain Invasion and Trends in Molecular Research on Meningioma. Brain Tumor Res Treat. 2023 Jan;11(1):47-58. doi: 10.14791/btrt.2022.0044. PMID: 36762808; PMCID: PMC9911709.)).

===== Diagnosis =====
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
((Ong T, Bharatha A, Alsufayan R, Das S, Lin AW. MRI predictors for brain invasion in meningiomas. Neuroradiol J. 2020 Sep 14:1971400920953417. doi: 10.1177/1971400920953417. Epub ahead of print. PMID: 32924772.)).
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For Xiao et al. the combined model (radiomics classifier with BTI4mm ROI + PEV) had greater diagnostic performance than other models
((Xiao D, Zhao Z, Liu J, Wang X, Fu P, Le Grange JM, Wang J, Guo X, Zhao H, Shi J, Yan P, Jiang X. Diagnosis of Invasive Meningioma Based on Brain-Tumor Interface Radiomics Features on Brain MR Images: A Multicenter Study. Front Oncol. 2021 Aug 20;11:708040. doi: 10.3389/fonc.2021.708040. PMID: 34504789; PMCID: PMC8422846.))

===== Treatment =====
Von Spreckelsen et al. summarize preclinical models studying targeted therapies with potential inhibitory effects
((von Spreckelsen N, Kesseler C, Brokinkel B, Goldbrunner R, Perry A, Mawrin C. Molecular neuropathology of brain-invasive meningiomas. Brain Pathol. 2022 Mar;32(2):e13048. doi: 10.1111/bpa.13048. PMID: 35213084; PMCID: PMC8877755.))

===== Outcome =====
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
((von Spreckelsen N, Kesseler C, Brokinkel B, Goldbrunner R, Perry A, Mawrin C. Molecular neuropathology of brain-invasive meningiomas. Brain Pathol. 2022 Mar;32(2):e13048. doi: 10.1111/bpa.13048. PMID: 35213084; PMCID: PMC8877755.))

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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
((Behling F, Hempel JM, Schittenhelm J. Brain Invasion in Meningioma-A Prognostic Potential Worth Exploring. Cancers (Basel). 2021 Jun 29;13(13):3259. doi: 10.3390/cancers13133259. PMID: 34209798; PMCID: PMC8267840.)).
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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
((Garcia-Segura ME, Erickson AW, Jairath R, Munoz DG, Das S. Necrosis and Brain Invasion Predict Radio-Resistance and Tumor Recurrence in Atypical Meningioma: A Retrospective Cohort Study. Neurosurgery. 2020 Dec 15;88(1):E42-E48. doi: 10.1093/neuros/nyaa348. PMID: 32818240.)).
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Nakasu systematically reviewed studies published after 2000 and performed a [[PRISMA]]-compliant [[meta-analysis]] of the [[hazard ratio]]s (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
((Nakasu S, Nakasu Y. Prognostic significance of brain invasion in meningiomas: systematic review and meta-analysis. Brain Tumor Pathol. 2021 Jan 6. doi: 10.1007/s10014-020-00390-y. Epub ahead of print. PMID: 33403457.))
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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
((Banan R, Abbetmeier-Basse M, Hong B, Dumitru CA, Sahm F, Nakamura M, Krauss JK, Hartmann C. The prognostic significance of clinicopathological features in meningiomas: microscopic brain invasion can predict patient outcome in otherwise benign meningiomas. Neuropathol Appl Neurobiol. 2021 Jan 28. doi: 10.1111/nan.12700. Epub ahead of print. PMID: 33508895.)).


===== Systematic reviews =====

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
((Brunasso L, Bonosi L, Costanzo R, Buscemi F, Giammalva GR, Ferini G, Valenti V, Viola A, Umana GE, Gerardi RM, Sturiale CL, Albanese A, Iacopino DG, Maugeri R. Updated Systematic Review on the Role of Brain Invasion in Intracranial Meningiomas: What, When, Why? Cancers (Basel). 2022 Aug 27;14(17):4163. doi: 10.3390/cancers14174163. PMID: 36077700; PMCID: PMC9454707.))

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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
((Brokinkel B, Hess K, Mawrin C. Brain invasion in meningiomas-clinical considerations and impact of neuropathological evaluation: a systematic review. Neuro Oncol. 2017 Oct 1;19(10):1298-1307. doi: 10.1093/neuonc/nox071. PMID: 28419308; PMCID: PMC5596167.)).

===== Case Report from the HGUA =====

 **Abstract**  

We present the case of a 75-year-old male with multiple comorbidities who developed an acute neurological episode characterized by [[transient]] [[hemiparesis]] secondary to a right frontal meningioma with suspected cortical infiltration. Surgical resection confirmed the diagnosis. This case highlights the challenges of managing intracranial pathology in elderly patients with significant comorbidities, requiring a multidisciplinary approach.
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#### **Introduction**  

Meningiomas are common primary intracranial tumors, typically benign. However, atypical or malignant subtypes may exhibit cortical invasion, complicating surgical management. This report describes a case of right frontal meningioma with suspected cortical infiltration and its multidisciplinary management.
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#### **Case Presentation**

**Relevant medical history:**

- [[Lung adenocarcinoma]] treated with lobectomy 

- [[Non-muscle invasive bladder carcinoma]].  

- [[Calcium pyrophosphate deposition disease]] (treated with colchicine). 
 
- Bilateral intermittent claudication.  

- Chronic kidney disease (glomerular filtration rate: 18.62 mL/min).  

- Incidentally diagnosed left parasagittal calcified meningioma

**Chief complaint:** Sudden onset of involuntary movements in the left arm followed by transient hemiparesis, resolving after five hours. First episode of this nature.  

**Neurological examination:**  

- Alert, without aphasia or dysarthria.  

- Left brachio-crural hemiparesis (4/5 strength).  

- Preserved tactile sensitivity.  

**Imaging findings:**  

- **Brain MRI** Right frontal extra-axial lesion (3.6 x 1.8 x 2.8 cm), suggesting cortical infiltration and associated vasogenic edema.  

{{:pasted:20241226-124046.png}}

- **CT-TAP:** Post-lobectomy changes without signs of recurrence.  
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#### **Surgical Intervention**  

**Procedure:** Right parietal craniotomy and resection of the right frontal meningioma.  

- Tumor resected en bloc; adherence to dura mater and cortex observed.  

- Poor cleavage plane and venous cortical involvement required vessel coagulation and section.  

**Intraoperative complications:** Hemodynamic instability necessitating intubated transfer to the ICU postoperatively.  
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#### **Postoperative Course**  

- **Initial status:** Agitation and disorientation attributed to urinary tract infection (Morganella morganii and Klebsiella pneumoniae) and acute-on-chronic kidney disease exacerbation.  

- **Radiological findings:** Small intraparenchymal hemorrhagic focus within residual vasogenic edema.  

- **Neurological status:** Persistent left hemiparesis (proximal 3/5, distal 2/5 strength).  

**Management:** Multidisciplinary adjustments by nephrology and ICU teams, with initiation of physical rehabilitation.  

**Discharge:** Patient clinically stable for transfer to the referring hospital for ongoing care and rehabilitation.
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#### **Discussion** 
 
This case underscores the challenges of managing atypical meningiomas with cortical invasion in elderly patients with complex comorbidities. Acute presentation, vasogenic edema, and postoperative complications necessitate a multidisciplinary approach to optimize outcomes.  

**Clinical relevance:**  

- Cortical invasion is a predictor of surgical complexity and potential recurrence in meningiomas.  

- Chronic kidney disease limits diagnostic and therapeutic options, including contrast-enhanced neuroimaging.  
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#### **Conclusion**  
This report highlights the importance of individualized and multidisciplinary management in atypical meningioma cases. Clinical and radiological findings should guide surgical decision-making to achieve maximal tumor resection while minimizing complications.




===== References =====