Clinical Factors Related to Histopathologic Grade in Meningioma

Kevin.


Introduction
Meningioma is the most common primary tumor in the Central Nervous System (CNS) around 25,5% of all CNS neoplasms. 1,2 Meningioma originates from arachnoid, especially from the outer layers of arachnoid and arachnoid villi, which are also referred to as arachnoid cap cells and the distribution is spread throughout the CNS. 3 Based on histopathological characteristics, the World Health Organization (WHO) divides meningioma into three grades, namely, grade I, II, and III. Among these three grades, grade I meningioma has the most frequent occurrences, while grade II and III only occur in 21-27,8% of all meningioma cases. 1 Despite their lower prevalence rates, grade II and III meningioma are considered high-grade meningioma. This high-grade meningioma has a higher mitosis rate so that it develops more progressively, has a higher risk of recurrence, and a lower survival rate. Histologically grade III meningiomas are malignant with atypical nuclei. 3 A variety of modalities can be used to support the diagnosis of meningioma, including computed tomography (CT scan) imaging and magnetic resonance imaging (MRI). 4 The standard management of meningioma is operative resection. However, patients with small lesions can be managed with Gamma Knife Surgery (GKS) and no longer candidates for operative surgery. Radiologically findings, such as an invasion of the brain, bone and peritumoral edema around the brain area are also related to high-grade meningioma, and if managed with GKS, subsequent management will be complicated. 5,6 Therefore, the ability to differentiate the grade of meningioma before treatment can contribute to a significant clinical benefit in assisting surgeons to develop an operative plan so that it runs as well as possible. Providing information about the tumor's grade can be useful intra-operatively because the surgeon has to decide considering the risks and benefits of more aggressive resection of the tissue around the tumor. 6,7 The aim of this study is to examine the relationship between clinical factors and grades of meningioma because of its essential role in the clinical course and management of the disease.

Material And Methods
Samples are obtained from patient medical records with a diagnosis of meningioma at Siloam Hospital Lippo Village, which includes demographic data such as gender and age, clinical factors such as tumor location, tumor size, edema, necrosis, and also tumor pathology based on WHO grade between 2014 to 2018. Tumor location, size, edema, and necrosis were assessed through radiologic findings. For patients who did not undergo a histopathological examination of tumor tissue and incomplete clinical information are excluded. Statistical analysis was performed using SPSS 22.
As an illustration, we confirmed the radiological features with microscopic images in patients with grade II and III meningioma. (Figure 1 and 2).

Bivariate analysis -Relationship between Location and Grade of Meningioma
Most people who are diagnosed with highgrade meningioma were located in the parasagittal/falx/convection region, and low-grade meningioma was located in the cranial base region. This analysis was tested using Fisher-exact test and yielded a p-value <0.001.
- -Relationship of Gender with Grade Meningioma A total of 23 (43.4%) men suffer from highgrade meningioma, and 21 (23.6%) women suffer from high-grade meningioma. The relationship between the two variables was carried out using chi-square test with p=0.014, which means there is a significant relationship between the two variables.

Multivariate analysis
All six variables, tumor location, size, edema, necrosis, age, and gender were tested in multivariate analysis of tumor grade with linier regression. The analysis result is shown in Table 1.

Discussion
Grade I (low-grade) meningioma has a relatively good prognosis. In contrast, grade II and III (high-grade) meningioma have a worse prognosis and often require adjuvant therapy. 7 The ability to predict the tumor's grade will help the clinician provide a more accurate direction for the management, without waiting for a histological diagnosis, which sometimes requires a longer time. 6,7 Lots of research that focuses on molecular characteristics using genomic and proteomic technology. However, these approaches require invasive procedures to take tissue samples, and usually, only a small portion of the sample can be analyzed and cannot reflect the composition and heterogeneity of the tumor. 1 Conversely, imaging tests that do not have invasive properties have great potential in assisting tumor stratification and guiding management because imaging examinations provide a more comprehensive picture of the whole tumor and help monitor the ongoing therapeutic response, development, and recurrence process. 6,7

Relationship between Location and Grade of Meningioma
This study found a significant relationship between location and grade of meningioma (p <0.05). These results are similar to previous studies which state that anatomic location is a risk factor for atypical and malignant meningioma, where there is a more significant increase in risk at non-base of skull tumor (27% vs. 12%; p <0.001). 8 Previous studies have suggested that meningioma in non-skull locations have a more aggressive nature. Previous studies using genomic analysis have shown that meningioma located in the area around the cerebral hemisphere and cerebellum often have higher grades and have more frequent NF2 gene mutations and / or lose chromosome 22 with concurrent genomic instability. 9 A study by Hashimoto et al. showed that meningioma on the skull base had a significantly higher percentage of chromosome loss of 1p (20.31%) compared to meningioma in the non-skull base. These results suggest that genetics play an essential role where tumors in the skull base region tend to be at a minimum of genetic defects and have less aggressive biological properties. 10

Relationship of Size with Grade of Meningioma
In this study, as many as 46.6% meningioma with size ≥3.2 cm were high grade, while 14.5% meningioma with size <3.2 cm experienced high grade, with significant differences. A study by Palaniandy et al. also showed similar results and found that high-grade meningioma had a mean tumor volume three times greater than low-grade meningioma. This result was also statistically significant (p=0.001). 3,5

Relationship of Edema with Grade Meningioma
This study compares the percentage of meningioma accompanied by edema and without edema with high-grade tumors that are twice different. Hale et al. examined the relationship between degrees of edema divided into 4 degrees with meningioma grade. 17 The study results showed a significant correlation between edema and meningioma grade with a value of p = 0.022.
Atypical and malignant meningiomas are reported to infiltrate more frequently around the tissue. 3 This also underlies the occurrence of edema around the tumor, while grade I meningioma are less likely to develop edema. There are various etiologies proposed for the mechanism of edema, namely compressive ischemia due to disruption of the blood-brain barrier, vascular shunting due to parasitism of the micro vial vessels, mechanical venous obstruction, increased elevated hydrostatic pressure in the tumor, and the phenomenon of secretory excretory tumor cells. 18,19

Relationship of Necrosis with Grade Meningioma
The incidence of necrosis in this study was significantly different where 45.4% of tumors with necrosis were high-grade meningioma, while those without necrosis were only 54.6%. A study by Backer et al. reported that necrosis was found in 23% of cases of meningioma spread in 11.9% grade I meningioma, 45.8% grade II meningioma, and 100% grade III meningioma. 20 Necrosis comes from nutritional insufficiency and hypoxia due to high metabolic demands, which suggest that this condition is associated with more aggressive development. Necrosis can be found in small and large tumor foci. Hypoxic tumor cells involving necrotic tissue can show areas that have experienced differentiation and transformation of malignant cells. 21

Relationship between age and grade of meningioma
In this study, a significant relationship was found between age and the incidence of high-grade meningioma, where the age group ≥65 years had a higher percentage of high-grade meningioma (50%) compared to the age group <65 years (35.9%). However, the results of other studies are still controversial. Some studies state a relationship between age and grade of meningioma, where age ≥65 years shows a significantly higher percentage suffering from high-grade meningioma. 22 However, other studies report conflicting results. 5 The relationship between age and grade of meningioma is still not known. Zhou et al. found that the pediatric group had a higher risk of developing meningioma with a higher grade. The reason that can explain this relationship may be due to embryogenic abnormalities, such as genetic mutations.
But in this study, there were no samples with pediatric age. 1

Relationship of Gender with Grade of Meningioma
In this study, men tend to experience higher meningioma grade (p <0.05). Liang et al. conducted a study of 1,239 cases and reported that men had a higher risk of developing high-grade meningioma, whereas, in that study, the ratio of men to women with high-grade meningioma was 21.7% compared to 12.9% p <0.001. 23 The reason between the male gender and the occurrence of high-grade meningioma are still not clear. Various studies have suggested that hormone levels, hormone receptors, and chromosomal abnormalities can affect the tendency of high tumor grade. 23,24 Other studies have also shown an inverse relationship between levels of progesterone receptor expression and tumor histology grading. 24

Conclusion
In this study, we concluded that clinical factors such as, tumor location, size, edema, necrosis, age and gender have a significant relationship to histopathological meningioma grade. Predicting clinical factors can be useful for surgeons to plan treatment strategies.

Conflicts of Interest
The authors affirm no conflict of interest in this study.

Funding Sources
This study does not need any funding.