World Health Organization grade 3 meningioma

World Health Organization grade 3 meningioma

Papillary meningioma

Rhabdoid meningioma

Anaplastic meningioma

Mast cells (MCs) were present in as many as 90 % of all high grade meningiomas mainly found in the perivascular areas of the tumor. A correlation between peritumoral edema and MCs was found.

Accumulation of MCs in meningiomas could contribute to the aggressiveness of tumors and to brain inflammation that may be involved in the pathogenesis of additional disorders 1).

From the available data, surgical resection followed by RT and salvage therapy can lead to extended survival 2).

For a systematic review, studies analyzing the effectiveness of adjuvant radiotherapy and stereotactic radiosurgery in grade 3 (gr. 3) meningioma were reviewed. Thirty studies met the inclusion criteria for qualitative synthesis, and 6 studies were assessed in quantitative analysis. In quantitative analysis, the weighted average of hazard ratios for adjuvant RT in univariate analyses of overall survival (OS) was 0.55 (CI: 0.41; 0.69). The median 5-year OS after adjuvant RT in gr. 3 meningiomas were 56.3%, and the median OS ranged from 24 to 80 months for patients treated with adjuvant RT versus 13 to 41.2 months in patients not treated. For stereotactic radiosurgery, the 3-year progression-free survival was 0% in one study and 57% in another. The 2-year OS ranged from 25 to 75% in 2 studies. The quality of evidence was rated as “very low” in 14 studies analyzed, and considerable allocation bias was detected. Treatment toxicity was reported in 47% of the studies. The severity, according to the CTCAE, ranged from grades I-V and 5.3 to 100% of patients experiencing complications. Adjuvant RT is usually considered the standard of care for WHO grade 3 meningiomas, although supporting evidence was of low quality. Better evidence from registries and prospective trials can improve the evidence base for adjuvant fractionated radiotherapy in malignant meningioma3).


Polyzoidis S, Koletsa T, Panagiotidou S, Ashkan K, Theoharides TC. Mast cells in meningiomas and brain inflammation. J Neuroinflammation. 2015 Sep 17;12(1):170. doi: 10.1186/s12974-015-0388-3. PubMed PMID: 26377554.

Rosenberg LA, Prayson RA, Lee J, Reddy C, Chao ST, Barnett GH, Vogelbaum MA, Suh JH. Long-term experience with World Health Organization grade III (malignant) meningiomas at a single institution. Int J Radiat Oncol Biol Phys. 2009 Jun 1;74(2):427-32. doi: 10.1016/j.ijrobp.2008.08.018. PMID: 19427553.

Bergner A, Maier AD, Mirian C, Mathiesen TI. Adjuvant radiotherapy and stereotactic radiosurgery in grade 3 meningiomas – a systematic review and meta-analysis. Neurosurg Rev. 2022 May 11. doi: 10.1007/s10143-022-01773-9. Epub ahead of print. PMID: 35543810.

5-aminolevulinic acid fluorescence guided resection of low-grade glioma

5-aminolevulinic acid fluorescence guided resection of low-grade glioma

Radiologically suspected low-grade gliomas (LGG) represent a special challenge for the neurosurgeon during surgery due to their histopathological heterogeneity and indefinite tumor margin. Therefore, new techniques are required to overcome these current surgical drawbacks. Intraoperative visualization of brain tumors with the assistance of 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence is one of the major advancements in the neurosurgical field in the last decades. Initially, this technique was exclusively applied for fluorescence-guided surgery of high-grade glioma (HGG). In the last years, the use of 5-ALA was also extended to other indications such as radiologically suspected LGG. Kiesel et al. discussed the current role of 5-ALA for intraoperative visualization of focal malignant transformation within suspected LGG. Furthermore, they discussed the current limitations of the 5-ALA technology in pure LGG which usually cannot be visualized by visible fluorescence. Finally, they introduced new approaches based on fluorescence technology for improved detection of pure LGG tissue such as spectroscopic PpIX quantification fluorescence lifetime imaging of PpIX and confocal microscopy to optimize surgery 1).

A growing body of evidence has revealed the potential utility of 5-aminolevulinic acid (5-ALA) as a surgical adjunct in selected lower-grade gliomas. However, a reliable means of identifying which lower-grade gliomas will fluoresce has not been established.

Widhalm found that 5-ALA induced PpIX fluorescence is capable as a novel intra-operative marker to detect anaplastic foci within initially suspected low-grade gliomas independent of brainshift 2).

A systematic review of PubMedGoogle Scholar, and Cochrane was performed from the date of inception to February 1, 2019. Studies that correlated 5-aminolevulinic acid fluorescence with low-grade glioma in the setting of operative resection were selected. Studies with biopsy only were excluded. Positive fluorescence rates were calculated. The quality index of the selected papers was provided. No patient information was used, so Institutional Review Board approval and patient consent were not required.

A total of 12 articles met the selection criteria with 244 histologically confirmed low-grade glioma patients who underwent microsurgical resection. All patients received 20 mg/kg body weight of 5-aminolevulinic acid. Only 60 patients (n = 60/244; 24.5%) demonstrated visual intraoperative 5-aminolevulinic acid fluorescence. The extent of resection was reported in 4 studies; however, the data combined low- and high-grade tumors. Only 2 studies reported on tumor location. Only 3 studies reported on clinical outcomes. The Zeiss OPMI Pentero microscope was most commonly used across all studies. The average quality index was 14.58 (range: 10-17), which correlated with an overall good quality.

There is an overall low correlation between 5-aminolevulinic acid fluorescence and low-grade glioma. Advances in visualization technology and using standardized fluorescence quantification methods may further improve the visualization and reliability of 5-aminolevulinic acid fluorescence in low-grade glioma resection 3).

Müther et al. investigated a cohort of patients with WHO Grade 2 glioma and WHO Grade 3 gliomas who received 5-ALA before resection at a single institution. Using a logistic regression-based model, they evaluated 14 clinical and molecular variables considered plausible determinants of fluorescence. They then distilled the most predictive features to develop a model for predicting both fluorescence and tumor grade. They also explored the relationship between intraoperative fluorescence and diagnostic molecular markers.

One hundred seventy-nine subjects were eligible for inclusion. Our logistic regression classifier accurately predicted intraoperative fluorescence in our cohort with 91.9% accuracy and revealed enhancement as the singular variable in determining intraoperative fluorescence. There was a direct relationship between enhancement on MRI and the likelihood of observed fluorescence. Observed fluorescence correlated with MIB-1 index but not with isocitrate dehydrogenase (IDH) status, 1p19q codeletion, or methylguanine DNA methyltransferase promoter methylation.

They demonstrated a strong correlation between enhancement on preoperative MRI and the likelihood of visible fluorescence during surgery in patients with intermediate-grade glioma. The analysis provides a robust method for predicting 5-ALA-induced fluorescence in patients with grade II and grade III gliomas 4).

Valdés et al. describe their initial experience with 5-aminolevulinic acid (ALA)-induced PpIX fluorescence in twelve patients with presumed LGGs after receiving 20 mg/kg of ALA approximately 3 hours prior to surgery under an institutional review board-approved protocol.

Intraoperative assessments of the resulting PpIX emissions using both qualitative, visible fluorescence and quantitative measurements of PpIX concentration were obtained from tissue locations that were subsequently biopsied and evaluated histopathologically. Mixed models for random effects and receiver operating characteristic curve analysis for diagnostic performance were performed on the fluorescence data relative to the gold-standard histopathology.

Five of the 12 LGGs (1 ganglioglioma, 1 oligoastrocytoma, 1 pleomorphic xanthoastrocytoma, 1 oligodendroglioma, and 1 ependymoma) demonstrated at least 1 instance of visible fluorescence during surgery. Visible fluorescence evaluated on a specimen-by-specimen basis yielded a diagnostic accuracy of 38.0% (cutoff threshold: visible fluorescence score ≥ 1, area under the curve = 0.514). Quantitative fluorescence yielded a diagnostic accuracy of 67% (for a cutoff threshold of the concentration of PpIX [CPpIX] > 0.0056 μg/ml, area under the curve = 0.66). The authors found that 45% (9/20) of nonvisibly fluorescent tumor specimens, which would have otherwise gone undetected, accumulated diagnostically significant levels of CPpIX that were detected quantitatively.

The authors’ initial experience with ALA-induced PpIX fluorescence in LGGs concurs with other literature reports that the resulting visual fluorescence has poor diagnostic accuracy. However, the authors also found that diagnostically significant levels of CPpIX do accumulate in LGGs, and the resulting fluorescence emissions are very often below the detection threshold of current visual fluorescence imaging methods. Indeed, at least in the authors’ initial experience reported here, if quantitative detection methods are deployed, the diagnostic performance of ALA-induced PpIX fluorescence in LGGs approaches the accuracy associated with visual fluorescence in HGGs 5).


Kiesel B, Freund J, Reichert D, Wadiura L, Erkkilae MT, Woehrer A, Hervey-Jumper S, Berger MS, Widhalm G. 5-ALA in Suspected Low-Grade Gliomas: Current RoleLimitations, and New Approaches. Front Oncol. 2021 Jul 30;11:699301. doi: 10.3389/fonc.2021.699301. PMID: 34395266; PMCID: PMC8362830.

Widhalm G. Intra-operative visualization of brain tumors with 5-aminolevulinic acid-induced fluorescence. Clin Neuropathol. 2014 Jul-Aug;33(4):260-78. PubMed PMID: 24986206.

Almekkawi AK, El Ahmadieh TY, Wu EM, Abunimer AM, Abi-Aad KR, Aoun SG, Plitt AR, El Tecle NE, Patel T, Stummer W, Bendok BR. The Use of 5-Aminolevulinic Acid in Low-Grade Glioma Resection: A Systematic Review. Oper Neurosurg (Hagerstown). 2020 Jul 1;19(1):1-8. doi: 10.1093/ons/opz336. Erratum in: Oper Neurosurg (Hagerstown). 2020 Jul 1;19(1):107. PMID: 31828346.

Müther M, Jaber M, Johnson TD, Orringer DA, Stummer W. A Data-Driven Approach to Predicting 5-Aminolevulinic Acid-Induced Fluorescence and World Health Organization Grade in Newly Diagnosed Diffuse Gliomas. Neurosurgery. 2022 Mar 16. doi: 10.1227/NEU.0000000000001914. Epub ahead of print. PMID: 35285461.

Valdés PA, Jacobs V, Harris BT, Wilson BC, Leblond F, Paulsen KD, Roberts DW. Quantitative fluorescence using 5-aminolevulinic acid-induced protoporphyrin IX biomarker as a surgical adjunct in low-grade glioma surgery. J Neurosurg. 2015 Jul 3:1-10. [Epub ahead of print] PubMed PMID: 26140489.

World health organization grade 2 meningioma

World health organization grade 2 meningioma

Chordoid meningioma

Clear Cell meningioma

Atypical meningioma

Extent of resection independently predicts progression-free and overall survivals in patients with World health organization grade 2 meningioma. In an era of increasing support for adjuvant treatment modalities in the management of meningiomas. Data support maximal safe resection as the primary goal in treatment of these patients 1).

In a large retrospective cohort, Rebchuk et al. from the UBC Hospital, found no survival or local recurrence benefit to adjuvant radiotherapy in treatment of grade 2 meningiomas. Sensitivity analysis limited to initial GTR and STR also failed to demonstrate any OS or LR benefit with adjuvant radiotherapy. There is limited utility to upfront adjuvant radiotherapy following initial surgical resection in the treatment of grade 2 meningiomas 2).

see Atypical meningioma treatment.

189 patients with mean age 57.4±14.6 years, 64.0% female and median follow-up was 64 (IRQ: 20-96) months. At initial treatment, 21 patients received adjuvant radiotherapy and 168 received surgery alone. There was no significant difference for OS (HR=1.3 [95% CI 0.4-4.5], p=0.92) overall or when limited to gross total resection (GTR) (p=0.38) or subtotal resection (STR) (p=0.85). There was no significant difference in local recurrence (LR) overall (p=0.75) or when restricted to GTR (p=0.77) or STR (p=0.20). No patient had radiotherapy stopped or altered because of side-effects, however 71.4% reported tolerable side-effects during the treatment period and 14.3% reported side-effects persisting longer than 12 months post-treatment.

In a large retrospective cohort, Rebchuk et al. found no survival or local recurrence benefit to adjuvant radiotherapy in treatment of grade 2 meningiomas. Sensitivity analysis limited to initial GTR and STR also failed to demonstrate any OS or LR benefit with adjuvant radiotherapy. There is limited utility to upfront adjuvant radiotherapy following initial surgical resection in the treatment of grade 2 meningiomas 3).

Increasing evidence suggests that genomic and molecular markers need to be integrated into the grading of meningiomaTelomerase reverse transcriptase promoter (TERTp) mutation is receiving attention due to its clinical relevance in the treatment of meningiomas. The predictive ability of conventional and diffusion MRI parameters for determining the TERTp mutation status in World health organization grade 2 meningiomas has yet been identified.

In this study, 63 patients with surgically confirmed grade II meningiomas (56 TERTp wildtypes, 7 TERTp mutants) were included. Conventional imaging features were qualitatively assessed. The maximum diameter, the volume of the tumors, and histogram parameters from the apparent diffusion coefficient (ADC) were assessed. Independent clinical and imaging risk factors for TERTp mutation were investigated using multivariable logistic regression. The discriminative value of the prediction models with and without imaging features was evaluated.

In the univariable regression, older age (odds ratio [OR] = 1.13, P = 0.005), larger maximum diameter (OR = 1.09, P = 0.023), larger volume (OR = 1.04, P = 0.014), lower mean ADC (OR = 0.02, P = 0.025), and lower ADC 10th percentile (OR = 0.01, P = 0.014) were predictors of TERTp mutation. In multivariable regression, age (OR = 1.13, P = 0.009) and ADC 10th percentile (OR = 0.01, P = 0.038) were independent predictors of variables for predicting the TERTp mutation status. The performance of the prediction model increased upon inclusion of imaging parameters (area under the curves of 0.86 and 0.91, respectively, without and with imaging parameters).

Older age and lower ADC 10th percentile may be useful parameters to predict TERTp mutation in grade II meningiomas 4).

A retrospective database review between 1995 and 2019. Kaplan-Meier analysis was used to compare overall and progression-free survivals between patients who underwent gross total resection (GTR) and those who underwent subtotal resection (STR). Multivariable Cox proportional-hazards analysis was used to identify independent predictors of tumor recurrence and mortality.

Results: Of 214 patients who underwent surgical resection for WHO grade II meningiomas (median follow-up 53.4 months), 158 had GTR and 56 had STR. In Kaplan-Meier analysis, patients who underwent GTR had significantly longer progression-free (p = 0.002) and overall (p = 0.006) survivals than those who underwent STR. In multivariable Cox proportional-hazards analysis, GTR independently predicted prolonged progression-free (HR 0.57, p = 0.038) and overall (HR 0.44, p = 0.017) survivals when controlling for age, tumor location, and adjuvant radiation.

Conclusions: Extent of resection independently predicts progression-free and overall survivals in patients with WHO grade II meningiomas. In an era of increasing support for adjuvant treatment modalities in the management of meningiomas, our data support maximal safe resection as the primary goal in treatment of these patients 5).

Poulen et al. retrospectively analyzed patients in the database with WHO grade II meningioma, operated on between 2007 and 2010 in the university hospitals of Montpellier and Bordeaux, France. Clinical and radiological data, treatments and survival were analyzed.

Eighty-eight patients were included. Five-year overall survival was 89.7%. Nineteen patients received radiotherapy during follow-up, without a significant impact on survival (p=0.27).

In WHO grade II meningioma, it is currently difficult to establish clear recommendations for radiotherapy. The present study is in accordance with the literature that early postoperative radiotherapy is not mandatory in grade II meningioma with macroscopically total resection 6).

Between January 2000 and August 2015, 178 cases of World Health Organisation (WHO) Grade II meningioma were operated.

This population underwent a total of 224 surgical resections and 36 patients received a radiotherapy. Median follow-up was 3.6 years, interquartile ranges (IQR)[1.5 – 6.2].

28 patients (16.1%) were re operated for a relapse of their grade II meningioma. The median time between the first and the second surgery was 4.2 years, IQR[1.4-5.3]. Surgical recurrence-free survival at 1, 2, 5 and 10 years were respectively: 96.9%, 95 %CI[94.2, 99.6]; 91.7%, 95 %CI[87.3, 96.3], 85%, 95 %CI[78.6, 92] and, 70.8%, 95 %CI[60.1,83.5].At the end of the study, 93 patients (57.8%) had no residual tumour on the last scan. Age at diagnosis (HR=0.17, 95 %CI[0.05,0.56], p-value<0.001), extent of resection (HR=0.22, 95 %CI[0.08,0.64], p-value=0.01), and Ki-67 index (HR=0.18, 95 %CI[0.06,0.56], p-value<0.001) were independent factors associated with the surgical recurrence-free survival.

Younger patients with a lower proliferation rate and gross total resection are less likely to undergo a reintervention for WHO grade II meningioma recurrence. Observation rather than systematic adjuvant radiotherapy may be preferred. If possible, a redo surgery may be considered in case of relapse or tumor residual progression, as radiotherapy may not decrease the surgical recurrence-free survival after complete or incomplete resection 7).

1) , 5) 

Soni P, Davison MA, Shao J, Momin A, Lopez D, Angelov L, Barnett GH, Lee JH, Mohammadi AM, Kshettry VR, Recinos PF. Extent of resection and survival outcomes in World Health Organization grade II meningiomas. J Neurooncol. 2020 Nov 17. doi: 10.1007/s11060-020-03632-3. Epub ahead of print. PMID: 33205354.
2) , 3) 

Rebchuk AD, Alam A, Hounjet CD, Chaharyn BM, Gooderham PA, Yip S, Ma RM, Nichol A, Makarenko S. Survival and Recurrence Outcomes Following Adjuvant Radiotherapy for Grade 2 Intracranial Meningiomas: a 13-year experience in a tertiary-care center. World Neurosurg. 2022 Feb 28:S1878-8750(22)00235-2. doi: 10.1016/j.wneu.2022.02.088. Epub ahead of print. PMID: 35240308.

Shin I, Park YW, Ahn SS, Kang SG, Chang JH, Kim SH, Lee SK. Clinical and Diffusion Parameters may Noninvasively Predict TERT Promoter Mutation Status in Grade II Meningiomas. J Neuroradiol. 2021 Mar 11:S0150-9861(21)00056-0. doi: 10.1016/j.neurad.2021.02.007. Epub ahead of print. PMID: 33716047.

Poulen G, Vignes JR, Corre ML, Loiseau H, Bauchet L. WHO Grade II Meningioma: epidemiology, survival and interest of post-operative radiotherapy in a multicenter cohort of 88 patients. Neurochirurgie. 2020 Mar 4. pii: S0028-3770(20)30034-5. doi: 10.1016/j.neuchi.2019.12.008. [Epub ahead of print] PubMed PMID: 32145249.

Champeaux C, Dunn L. World Health Organization grade II meningioma. A 10-year retrospective study for recurrence and prognostic factor assessment. World Neurosurg. 2016 Feb 2. pii: S1878-8750(16)00143-1. doi: 10.1016/j.wneu.2016.01.055. [Epub ahead of print] PubMed PMID: 26850975.
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