Increased CD44 expression in primary meningioma: its clinical significance and association with peritumoral brain edema

Ryosuke Sawaya Departments of Neurosurgery and

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Shigeru Yamaguchi Departments of Neurosurgery and

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Yukitomo Ishi Departments of Neurosurgery and

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Michinari Okamoto Departments of Neurosurgery and

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Sumire Echizenya Departments of Neurosurgery and

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Hiroaki Motegi Departments of Neurosurgery and

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Noriyuki Fujima Diagnostic Imaging, Faculty of Medicine, Hokkaido University, Sapporo, Japan

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Miki Fujimura Departments of Neurosurgery and

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OBJECTIVE

CD44 is a major cell surface receptor involved in cell adhesion and migration. The overexpression of CD44 is a poor prognostic factor in many neoplasms, including meningiomas. The aim of this study was to investigate the association between CD44 gene expression and clinical signatures of primary meningiomas.

METHODS

CD44 gene expression was quantitatively evaluated by snap freezing tumor tissues obtained from 106 patients with primary meningioma. The relationships between CD44 expression and clinical signatures of meningiomas, including histological malignancy, tumor volume, and peritumoral brain edema (PTBE), were analyzed. PTBE was assessed using the Steinhoff classification (SC) system (from SC 0 to SC III).

RESULTS

CD44 gene expression in WHO grade 2 and 3 meningiomas was significantly higher than that in grade 1 meningiomas. In addition, CD44 expression increased with the severity of PTBE. Particularly, among the grade 1 meningiomas or small-sized tumors (maximum tumor diameter < 43 mm), CD44 expression in tumors with severe PTBE (SC II or III) was significantly higher than that in tumors without or with mild PTBE (SC 0 or I). Multivariate logistic regression analysis also revealed that overexpression of CD44 was an independent significant factor of severe PTBE development in primary meningiomas.

CONCLUSIONS

In addition to tumor cell aggressiveness, CD44 expression promotes the development of PTBE in meningioma. Since PTBE is a strong factor of tumor-related epilepsy or cognitive dysfunction in patients with meningioma, CD44 is thus a potential therapeutic target in meningioma with PTBE.

ABBREVIATIONS

IHC = immunohistochemical; MMP = matrix metalloproteinase; OS = overall survival; PBTE = peritumoral brain edema; PCR = polymerase chain reaction; PFS = progression-free survival; SC = Steinhoff classification.

OBJECTIVE

CD44 is a major cell surface receptor involved in cell adhesion and migration. The overexpression of CD44 is a poor prognostic factor in many neoplasms, including meningiomas. The aim of this study was to investigate the association between CD44 gene expression and clinical signatures of primary meningiomas.

METHODS

CD44 gene expression was quantitatively evaluated by snap freezing tumor tissues obtained from 106 patients with primary meningioma. The relationships between CD44 expression and clinical signatures of meningiomas, including histological malignancy, tumor volume, and peritumoral brain edema (PTBE), were analyzed. PTBE was assessed using the Steinhoff classification (SC) system (from SC 0 to SC III).

RESULTS

CD44 gene expression in WHO grade 2 and 3 meningiomas was significantly higher than that in grade 1 meningiomas. In addition, CD44 expression increased with the severity of PTBE. Particularly, among the grade 1 meningiomas or small-sized tumors (maximum tumor diameter < 43 mm), CD44 expression in tumors with severe PTBE (SC II or III) was significantly higher than that in tumors without or with mild PTBE (SC 0 or I). Multivariate logistic regression analysis also revealed that overexpression of CD44 was an independent significant factor of severe PTBE development in primary meningiomas.

CONCLUSIONS

In addition to tumor cell aggressiveness, CD44 expression promotes the development of PTBE in meningioma. Since PTBE is a strong factor of tumor-related epilepsy or cognitive dysfunction in patients with meningioma, CD44 is thus a potential therapeutic target in meningioma with PTBE.

In Brief

Researchers investigated the association between CD44 expression and clinical factors of meningiomas. Extent of CD44 gene expression was positively correlated with the severity of peritumoral brain edema (PTBE) in meningiomas. Multivariate analysis revealed that overexpression of CD44 was an independent factor of severe PTBE development in meningiomas. Since PTBE is associated with epilepsy or cognitive dysfunction in patients with meningioma, CD44 would be a potential therapeutic target for reducing these symptoms.

Meningiomas are the most common primary brain tumors, accounting for approximately 30% of cases. Using the WHO criteria, meningiomas are classified into three grades according to histological malignancy.1 While the majority of meningiomas are curable by complete resection, a subset of meningiomas have cumbersome clinical characteristics despite benign histology, such as persistent repeated recurrence after complete resection, intractable epilepsy, or symptoms associated with massive perifocal edema.25

Although the histological grade and proliferative index, Ki-67 labeling index, and phosphohistone-H3 are considered reliable predictors of the prognosis of meningioma,68 recent studies have identified several important molecular factors associated with prognosis, such as the presence of telomerase reverse transcriptase (TERT) promotor mutations,9 homozygous deletion of cyclin-dependent kinase inhibitor 2A (CDKN2A),10 overexpression of forkhead box M1 (FOXM1),11 and cluster of differentiation 44 (CD44).12,13

CD44 is a cell surface receptor for hyaluronan and many other extracellular matrix components. It is expressed on almost all human cells and is involved in cell adhesion, cell migration, angiogenesis, proliferation, and inflammation.13 CD44 also plays a crucial role in several inflammatory diseases, such as inflammatory bowel disease, arthritis, and cutaneous inflammation.1416

Only a few studies have investigated CD44 expression in meningioma,12,13 mainly focusing only on the association between CD44 expression and proliferative ability or prognosis. However, since CD44 expression regulates not only cell proliferation but also tumor cell adhesion and angiogenesis, CD44 expression might influence various clinical factors in meningiomas. In this study, we investigated the correlation between CD44 expression and clinical factors in various types of primary meningiomas using frozen surgical specimens. Through this investigation, we found that high CD44 expression is strongly correlated with peritumoral brain edema (PTBE), regardless of histological malignancy or tumor size.

Methods

Patient Population

We retrospectively evaluated 106 consecutive meningioma specimens obtained between 2003 and 2022 by the Department of Neurosurgery of Hokkaido University Hospital. All 106 cases were first-time surgeries; recurrent tumors were not included. Total RNA was extracted by snap freezing the tumor tissues. Clinical characteristics, including age, sex, tumor location, histopathological malignancy, histological subtype, and prognosis, were obtained from medical records. Tumor location was categorized as supratentorial or infratentorial, as described previously.17 All manipulations performed in the present study were in accordance with the 1964 Declaration of Helsinki and its later amendments. The study was approved by the local ethics committee at Hokkaido University Hospital. As this study was retrospective, the requirement for informed consent was waived by the same ethics committee.

Analysis of CD44 Expression

Commercially available human meningeal total RNA (catalog no. 1405, ScienCell Research Laboratories) was procured as a control reference. Total RNA was extracted from the snap-frozen tissues stored at −80°C using TRIzol reagent and the QuickGene-AutoS RNA tissue Kit (Kurabo Industries Ltd.). Complementary DNA was synthesized using the PrimeScript TM II 1st Strand cDNA Synthesis Kit (Takara Bio Inc.) with total RNA. The following primers were used for polymerase chain reaction (PCR): CD44 forward (5′-GATGGAGAAAGCTCTGAGCATC-3′) and CD44 reverse (5′-TTGCTGCACAGATGGAGTTG-3′); β-actin forward (5′-GTGAAGGTGACAGCAGTCGGTT-3′) and β-actin reverse (5′-GAAGTGGGGTGGCTTTTAGGAT-3′). Reverse transcription quantitative real-time PCR analysis was performed using FastStart Essential DNA Green Master with LightCycler 96 (Roche Diagnostics). Specificity of the PCR product was confirmed using melting curve analysis. All PCR experiments were performed in triplicate and expressed the means of three values. The relative target gene mRNA expression levels compared with β-actin were measured by quantitative PCR using the 2−ΔΔCT method.18

Immunohistochemical Staining of CD44 and IL-6

Tumor sections were deparaffinized, blocked, and processed for antigen retrieval using heat-induced sodium citrate buffer (pH 9.0 for CD44, pH 6.0 for IL-6). Sections were then incubated with mouse monoclonal anti-CD44 antibody diluted 1:1000 (catalog no. 60224-1-Ig, Proteintech) or rabbit polyclonal anti–IL-6 antibody diluted 1:1000 (catalog no. 21865-1-AP, Proteintech) overnight at 4°C. The secondary antibody used was peroxidase-conjugated goat polyclonal anti–rabbit/mouse IgG antibody (catalog no. 424151, Nichirei Biosciences). Diaminobenzidine was used for color precipitation, and counterstaining with hematoxylin was then conducted for contrast enhancement. Immunohistochemical (IHC) staining was assessed in accordance with previous reports.13,19

Evaluation of PTBE

Preoperative MR images of all 106 cases were analyzed retrospectively. Tumor size (maximum tumor diameter) was evaluated on postcontrast T1-weighted images, and PTBE was evaluated on FLAIR images by an experienced radiologist (N.F.) blinded to the patients’ clinical data. PTBE was graded using the Steinhoff classification (SC): 0, no signs of edema; I, PTBE limited to 2 cm; II, PTBE limited to half of the hemisphere; and III, more than half of the hemisphere.20,46 Representative cases are shown in Fig. 1.

FIG. 1.
FIG. 1.

MR images of representative cases. PTBE was evaluated on FLAIR images using SC as follows: SC 0, no signs of edema (A); SC I, PTBE limited to 2 cm (B); SC II, PTBE limited to half of the hemisphere (C); and SC III, PTBE encompassing more than half of the hemisphere (D).

PTBE was also evaluated quantitatively using the edema index as described by Park et al.19 The maximum diameter of the tumor (a) and the diameter perpendicular to the maximum diameter (b) were measured on postcontrast T1-weighted axial images, and the diameter in the coronal direction (c) was evaluated on coronal or sagittal images. Tumor volume (Vt) was calculated using the following sphere volume formula: V = 4π/3 × abc. The total volume of tumor and PTBE (VT) was measured on T2-weighted images using the same method. The edema volume around the tumor (Ve) was calculated as follows: Ve = VT − Vt. The ratio of Ve to Vt was defined as the edema index.

Statistical Analysis

Statistical analysis was performed using R software version 4.0.4 (The R Project for Statistical Computing). CD44 mRNA expression levels were compared using the Mann-Whitney U-test between two groups and the Kruskal-Wallis test among three or more groups. Survival analyses were performed using the Kaplan-Meier method, and between-group differences were compared using the log-rank test. Estimated overall survival (OS) and progression-free survival (PFS) were presented as Kaplan-Meier curves. OS and PFS were calculated from the time of primary surgery. The CD44 mRNA expression was classified into two groups, high and low expression, using the median value. To analyze the relationships of clinical factors and CD44 expression with PTBE, multivariate logistic regression analysis was performed to calculate the odds ratio with 95% confidence intervals. The variables included were age, sex, histological malignancy, tumor location, tumor maximum diameter, and CD44 expression level. A p value < 0.05 was defined as statistically significant.

Results

Patient Characteristics

Characteristics of the 106 patients are shown in Table 1. The median age at diagnosis was 60 years (range 20–84 years). Eighty-five tumors were diagnosed as WHO grade 1 and 21 as grade 2 or 3. The median maximum tumor diameter was 43 mm. PTBE was observed in 69 tumors, 27 of which were SC I, 30 were SC II, and 12 were SC III. Thirty-seven tumors had no PTBE (SC 0).

TABLE 1.

Patient characteristics

ParameterValue
All106
Sex
 Male35 (33.0)
 Female71 (67.0)
Median age, yrs (range)60 (20–84)
WHO grade
 185 (80.2)
 220 (18.9)
 31 (0.9)
Tumor location
 Supratentorial83 (78.3)
 Infratentorial23 (21.7)
SC of PTBE
 037 (34.9)
 I27 (25.5)
 II30 (28.3)
 III12 (11.3)
Median max diameter, mm (range)43 (14–93)

Values are presented as the number of patients (%) unless stated otherwise.

Relationship Between CD44 Expression and Clinicopathological Characteristics

CD44 expression in WHO grade 2 or 3 meningiomas was significantly higher than that in grade 1 meningiomas (p = 0.0044) (Fig. 2A), consistent with previous reports.13 CD44 expression in tumor from female patients was also significantly higher than that in male patients (p = 0.026) (Fig. 2B). Most notably, CD44 expression increased with the severity of PTBE. Compared with meningiomas with no PTBE (SC 0), CD44 expression levels were significantly higher in meningiomas with severe edema (i.e., SC II and SC III; p = 0.0037 and p = 0.021, respectively) (Fig. 2C). Conversely, no significant differences were found in CD44 expression based on age, tumor size, tumor location, and prognosis (OS and PFS) (Fig. 2D–F, Fig. S1).

FIG. 2.
FIG. 2.

Relationship between CD44 mRNA expression levels and clinicopathological characteristics in our cohorts regarding WHO grade of the meningioma (A); sex (B); PTBE graded using the SC (C); age (D); tumor size (E); and tumor location (F). *p < 0.05; **p < 0.01.

Correlation Between PTBE and CD44 Gene Expression in Various Types of Meningioma

We further analyzed the correlation between CD44 expression and PTBE. In the comparison of the volume of PTBE and CD44 expression, the expression level of CD44 was significantly correlated with the edema index (r = 0.413, p = 0.000011) (Fig. 3A). Among the malignant meningiomas (grades 2 and 3, n = 21), no significant difference was found in CD44 expression according to PTBE classification. However, among benign meningiomas, CD44 expression in meningiomas with SC II and SC III PTBE was significantly higher than that in meningiomas with SC 0 PTBE (n = 85; p = 0.040 and p = 0.022, respectively) (Fig. 3B). Since tumor size is potentially associated with PTBE,21 we also analyzed the correlation between CD44 expression and PTBE according to tumor size. Since the median maximum tumor diameter was 43 mm, tumors with a maximum diameter ≥ 43 mm were categorized as large tumors, while those with a diameter < 43 mm were categorized as small tumors. In large tumors (n = 53), no significant difference was found in CD44 expression according to PTBE classification. However, in small tumors (n = 53), CD44 expression in meningiomas with SC II or III PTBE was significantly higher than that of meningiomas with SC 0 PTBE (p = 0.0034) (Fig. 3C).

FIG. 3.
FIG. 3.

Relationship between CD44 expression and PTBE. A: Correlation between edema index and CD44 mRNA expression in this cohort (n = 106). B: Relationship between CD44 mRNA expression and PTBE graded using the SC for histopathological malignancy (left: WHO grade 1, right: WHO grade 2 or 3). C: Relationship between CD44 mRNA expression and PTBE grade (left: tumor size < 43 mm; right: ≥ 43 mm). *p < 0.05; **p < 0.01. Figure is available in color online only.

The histological subtype was determined in 57 of 85 cases of WHO grade 1 meningioma. Because angiomatous, microcystic, and secretory meningiomas are more likely to be accompanied by PTBE,4 we analyzed the association of histological subtypes and CD44 expression. CD44 expression was significantly higher in cases with these three histological components than in those without these components (p = 0.018) (Fig. S2).

The histological subtype was determined in 57 of 85 cases of WHO grade 1 meningioma. Because angiomatous, microcystic, and secretory meningiomas are more likely to be accompanied by PTBE,4 we analyzed the association of histological subtypes and CD44 expression. CD44 expression was significantly higher in cases with these three histological components than in those without these components (p = 0.018) (Fig. S2).

IHC Staining of CD44 and IL-6

Since CD44 is associated with inflammation,2224 we speculated that PTBE was associated with inflammation. To evaluate the correlation between CD44 expression and inflammation, we performed IHC staining for CD44 and IL-6, a representative inflammatory marker that has been associated with PTBE in meningioma,19 in 4 samples with high PTBE (SC II or III) and in 6 samples with low PTBE (SC 0 or I). Positive IHC staining for CD44 was observed in the high-PTBE group along with a trend toward positive IHC staining for IL-6 (Fig. 4A). In contrast, negative IHC staining for CD44 or IL-6 was observed in the low-PTBE group (Fig. 4B). IHC appearances of all 10 cases are shown in Fig. S3. CD44 expression was observed in the cytoplasm of tumor cells.

FIG. 4.
FIG. 4.

Relationship between PTBE, CD44 mRNA expression, and IHC staining for CD44 and IL-6. A: Tumors with high PTBE (SC III) and high CD44 mRNA expression showed positive IHC staining for CD44 and IL-6 on IHC (left). FLAIR images and IHC-stained micrographs for CD44 and IL-6 (right; original magnification ×40). B: Tumors with low PTBE (SC 0) and low CD44 mRNA expression showed negative IHC staining for CD44 and IL-6 (left). FLAIR and IHC-stained micrographs for CD44 and IL-6 8 (right; original magnification ×40). Figure is available in color online only.

Clinical Factors Potentially Correlated With PTBE

We evaluated whether other clinical factors influenced CD44 expression on PTBE in primary meningiomas. Table 2 shows the results of the univariate and multivariate logistic regression analyses. The odds ratio of the development of severe PTBE (SC II or III) was calculated. In addition to patient age (OR 1.05, p = 0.0056) and tumor size (OR 1.04, p = 0.026), CD44 expression was an independent risk factor for severe PTBE after adjusting for other clinical factors (OR 1.63, p = 0.0050).

TABLE 2.

Factors potentially correlated with PTBE in patients with primary meningiomas

Univariate AnalysisMultivariate Analysis
OR95% CIp ValueOR95% CIp Value
Age1.041.01–1.070.00661.051.01–1.080.0056
Sex 
 Female1 
 Male2.070.91–4.730.083 
WHO grade 
 11 
 2 or 34.071.48–11.20.00661.550.47–5.140.48
Tumor location 
 Infratentorial1 
 Supratentorial5.911.63–21.40.00672.610.63–10.80.18
Tumor size1.031.01–1.060.0191.041.00–1.070.026
CD44 expression1.521.11–2.080.00921.631.16–2.300.0050

Boldface type indicates statistical significance. Multivariate analysis was performed using candidate factors that were p < 0.05 on univariate analysis.

Discussion

CD44 is a multifunctional cell surface adhesion receptor for the extracellular matrix mucopolysaccharide hyaluronic acid that is regarded as a cancer stem cell marker.25,26 Many lines of evidence indicate that the interaction between CD44 and hyaluronic acid mediated tumor invasiveness and migration in various cancers.2729 In addition, CD44 has other ligands, including osteopontin and matrix metalloproteinases (MMPs). The interaction between osteopontin and CD44 may promote lymphatic metastasis in tumors.30

So far, only a few studies have investigated the association between CD44 expression and prognosis in meningiomas. Mostafa and Khairy13 reported that CD44 is highly expressed in grade 2 or 3 meningiomas and is correlated with higher Ki-67 proliferation indices. They concluded that CD44 is a marker of aggressiveness in meningioma. Kamamoto et al.12 found that high CD44 expression demonstrated a tendency toward shorter PFS in patients with WHO grade 2 or 3 meningiomas. Similarly, in the present study, we also validated that CD44 expression in WHO grade 2 or 3 meningiomas was significantly higher than that in grade 1 meningiomas. Furthermore, the expression of osteopontin, which is one of the binding partners of CD44, is also a strong predictor for meningioma recurrence in WHO grade 1 benign meningiomas.31 These studies indicate that the overexpression of CD44 and, probably, the interaction of CD44 and ligand partners promote tumor proliferative activity in meningiomas.

In addition to tumor aggressiveness, our study found a positive correlation between the extent of CD44 expression and PTBE in meningiomas. Meningiomas, even benign ones, are often associated with PTBE. In previous reports, PTBE has been found in 38%–67% of meningioma cases.4,32 PTBE has been associated with clinical symptoms, morbidity, and mortality due to increasing brain shift and intracranial pressure.33,34 The mechanisms of PTBE development in meningiomas are not straightforward, and various factors may be involved. Brain ischemia or impaired venous return due to tumor compression is a relatively logical cause of peritumoral edema.21,35 However, even patients with small meningiomas that do not cause compression of the brain or cerebral venous sinus can unexpectedly develop severe PTBE.36 Nevertheless, the pathogenesis of PTBE in meningiomas remains unclear, and various theories have been reported. Previous studies have shown that the development of PTBE is associated with vascular endothelial growth factor (VEGF) A,37 aquaporin 4,38 and MMP-9.37

In the present study, CD44 expression in meningiomas with severe PTBE was higher than that in meningiomas without severe PTBE, even in grade 1 histology or small tumors, indicating that CD44 expression could be a molecular factor that promotes the development of PTBE in meningioma. One possible mechanism is the inflammatory reaction caused by CD44 expression. Several studies have confirmed that the interaction between CD44 and hyaluronic acid in cellular processes is involved in the inflammatory response in tissues.2224 Hägg et al. reported that increased CD44 expression was correlated with increased secretion of IL-6, an inflammatory marker, in patients with atherosclerosis.39 Park et al. also found a significant correlation between IL-6 expression and PTBE severity in meningiomas, concluding that IL-6 expression may contribute to the development of brain edema associated with meningiomas.19 In the present study, we also observed trends of a positive correlation between CD44 expression and IL-6 expression according to PTBE status by immunostaining. Together with these previous findings, our results support that PTBE of meningioma might be caused by CD44-induced inflammation.

Another possible mechanism of PTBE development is the interaction between CD44 and MMP-9. MMP-9 is a proteolytic enzyme involved in the degradation of the extracellular matrix that is also correlated with PTBE.37,40 Iwado et al.41 reported that MMP-9 expression in meningioma is associated with VEGF expression and pial blood flow and induces PTBE due to the disruption of the arachnoid membrane. MMP-9 is another ligand of CD44, and CD44-associated cell surface MMP-9 mediates tumor cell invasion and metastasis.30,42 These facts suggest that the activation of MMP-9 induced by its binding to CD44 promotes PTBE in meningioma.

However, in large tumors, no difference was found between CD44 expression levels and severity of PTBE. The development of PTBE is associated with various mechanisms, and parenchymal ischemia or venous insufficiency due to tumoral compression of parenchyma or veins is a possible contributing factor.35 Large tumors are likely to compress brain parenchyma, involve veins, and be associated with PTBE.43 Therefore, the relevance of CD44 expression in the development of PTBE would be attenuated in large meningiomas.

PTBE is one of the strong clinical factors of pre- and postoperative epilepsy in meningioma.43,44 Intractable epilepsy negatively affects quality of life or impairs cognitive function in patients with meningioma.3 In addition, van Nieuwenhuizen et al.45 recently found a significant association between volume of preoperative PTBE and poorer postoperative cognitive function, concluding that the development of PTBE might be a risk of long-term cognitive impairment in patients with meningioma. The overexpression of CD44 is a potential therapeutic target for PTBE in meningioma since further elucidation of the mechanism of PTBE in meningioma may help manage meningioma-related complications.

The current study has several limitations. The main limitation is its observational design, which makes determining the exact mechanisms involved impossible. Second, the generalizability of the results is low because this is a single-center study. Furthermore, since our cohort included only surgical cases, we were unable to analyze patients with mild PTBE who did not undergo surgery. A validation study with an independent dataset including a much larger number of cases and sufficient analysis of clinical variables would be required to confirm the correlation between CD44 expression and PTBE in meningiomas. Moreover, further functional in vivo studies, including animal and gene knockdown experiments, are warranted to confirm that CD44 is the causative agent of PTBE in meningiomas.

Conclusions

CD44 expression is associated with PTBE development in meningioma, especially in small tumors. Although molecular mechanisms have to be investigated in further studies, CD44 is a potential therapeutic target for PTBE in meningioma.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Yamaguchi. Acquisition of data: Sawaya, Motegi. Analysis and interpretation of data: Yamaguchi, Sawaya, Fujima. Drafting the article: Yamaguchi, Sawaya. Critically revising the article: Ishi, Fujima, Fujimura. Reviewed submitted version of manuscript: Ishi, Okamoto, Fujima. Approved the final version of the manuscript on behalf of all authors: Yamaguchi. Statistical analysis: Sawaya. Administrative/technical/material support: Ishi, Echizenya, Fujima. Study supervision: Fujimura.

Supplemental Information

Online-Only Content

Supplemental material is available with the online version of the article.

Preprint Server

An earlier version of this article can be found on a preprint server.

Preprint server name: Research Square.

Preprint DOI: 10.21203/rs.3.rs-2718997/v1.

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    Yan Y, Zuo X, Wei D. Concise review: emerging role of CD44 in cancer stem cells: a promising biomarker and therapeutic target. Stem Cells Transl Med. 2015;4(9):10331043.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Xu H, Niu M, Yuan X, Wu K, Liu A. CD44 as a tumor biomarker and therapeutic target. Exp Hematol Oncol. 2020;9(1):36.

  • 27

    Wang CY, Huang CS, Yang YP, et al. The subpopulation of CD44-positive cells promoted tumorigenicity and metastatic ability in lung adenocarcinoma. J Chin Med Assoc. 2019;82(3):196201.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Liu X, Taftaf R, Kawaguchi M, et al. Homophilic CD44 interactions mediate tumor cell aggregation and polyclonal metastasis in patient-derived breast cancer models. Cancer Discov. 2019;9(1):96113.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Rooprai HK, Liyanage K, King A, Davies D, Martin K, Pilkington GJ. CD44 expression in human meningiomas: an immunocytochemical, immunohistochemical and flow cytometric analysis. Int J Oncol. 1999;14(5):855860.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Yu Q, Stamenkovic I. Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev. 1999;13(1):3548.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Tseng KY, Chung MH, Sytwu HK, et al. Osteopontin expression is a valuable marker for prediction of short-term recurrence in WHO grade I benign meningiomas. J Neurooncol. 2010;100(2):217223.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Lee KJ, Joo WI, Rha HK, et al. Peritumoral brain edema in meningiomas: correlations between magnetic resonance imaging, angiography, and pathology. Surg Neurol. 2008;69(4):350355.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Alaywan M, Sindou M. Prognostic factors in the surgery for intracranial meningioma. Role of the tumoral size and arterial vascularization originating from the pia mater. Study of 150 cases. Article in French. Neurochirurgie. 1993;39(6):337347.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Marmarou A, Takagi H, Shulman K. Biomechanics of brain edema and effects on local cerebral blood flow. Adv Neurol. 1980;28:345358.

  • 35

    Lobato RD, Alday R, Gómez PA, et al. Brain oedema in patients with intracranial meningioma. Correlation between clinical, radiological, and histological factors and the presence and intensity of oedema. Acta Neurochir (Wien). 1996;138(5):485494.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Azar M, Fattahi A, Tabibkhooei A, Taheri M. A small meningioma with extensive peritumoral brain edema: a case report. Iran J Med Sci. 2019;44(3):265269.

  • 37

    Reszec J, Hermanowicz A, Rutkowski R, Turek G, Mariak Z, Chyczewski L. Expression of MMP-9 and VEGF in meningiomas and their correlation with peritumoral brain edema. BioMed Res Int. 2015;2015:646853.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Gawlitza M, Fiedler E, Schob S, Hoffmann KT, Surov A. Peritumoral brain edema in meningiomas depends on aquaporin-4 expression and not on tumor grade, tumor volume, cell count, or Ki-67 labeling index. Mol Imaging Biol. 2017;19(2):298304.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Hägg D, Sjöberg S, Hultén LM, et al. Augmented levels of CD44 in macrophages from atherosclerotic subjects: a possible IL-6-CD44 feedback loop? Atherosclerosis. 2007;190(2):291297.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Jung S, Moon KS, Kim ST, et al. Increased expression of intracystic matrix metalloproteinases in brain tumors: relationship to the pathogenesis of brain tumor-associated cysts and peritumoral edema. J Clin Neurosci. 2007;14(12):11921198.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Iwado E, Ichikawa T, Kosaka H, et al. Role of VEGF and matrix metalloproteinase-9 in peritumoral brain edema associated with supratentorial benign meningiomas. Neuropathology. 2012;32(6):638646.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Peng ST, Su CH, Kuo CC, Shaw CF, Wang HS. CD44 crosslinking-mediated matrix metalloproteinase-9 relocation in breast tumor cells leads to enhanced metastasis. Int J Oncol. 2007;31(5):11191126.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Simis A, Pires de Aguiar PH, Leite CC, Santana PA Jr, Rosemberg S, Teixeira MJ. Peritumoral brain edema in benign meningiomas: correlation with clinical, radiologic, and surgical factors and possible role on recurrence. Surg Neurol. 2008;70(5):471477.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Englot DJ, Magill ST, Han SJ, Chang EF, Berger MS, McDermott MW. Seizures in supratentorial meningioma: a systematic review and meta-analysis. J Neurosurg. 2016;124(6):15521561.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    van Nieuwenhuizen D, Slot KM, Klein M, et al. The association between preoperative edema and postoperative cognitive functioning and health-related quality of life in WHO grade I meningioma patients. Acta Neurochir (Wien). 2019;161(3):579588.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Kazner E, Lanksch W, Steinhoff H, Wilske J. Computerized axial tomography of the skull—diagnostic possibilities and clinical results (author’s transl). Article in German. Fortschr Neurol Psychiatr Grenzgeb. 1975;43(10):487574.

    • PubMed
    • Search Google Scholar
    • Export Citation

Supplementary Materials

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  • FIG. 1.

    MR images of representative cases. PTBE was evaluated on FLAIR images using SC as follows: SC 0, no signs of edema (A); SC I, PTBE limited to 2 cm (B); SC II, PTBE limited to half of the hemisphere (C); and SC III, PTBE encompassing more than half of the hemisphere (D).

  • FIG. 2.

    Relationship between CD44 mRNA expression levels and clinicopathological characteristics in our cohorts regarding WHO grade of the meningioma (A); sex (B); PTBE graded using the SC (C); age (D); tumor size (E); and tumor location (F). *p < 0.05; **p < 0.01.

  • FIG. 3.

    Relationship between CD44 expression and PTBE. A: Correlation between edema index and CD44 mRNA expression in this cohort (n = 106). B: Relationship between CD44 mRNA expression and PTBE graded using the SC for histopathological malignancy (left: WHO grade 1, right: WHO grade 2 or 3). C: Relationship between CD44 mRNA expression and PTBE grade (left: tumor size < 43 mm; right: ≥ 43 mm). *p < 0.05; **p < 0.01. Figure is available in color online only.

  • FIG. 4.

    Relationship between PTBE, CD44 mRNA expression, and IHC staining for CD44 and IL-6. A: Tumors with high PTBE (SC III) and high CD44 mRNA expression showed positive IHC staining for CD44 and IL-6 on IHC (left). FLAIR images and IHC-stained micrographs for CD44 and IL-6 (right; original magnification ×40). B: Tumors with low PTBE (SC 0) and low CD44 mRNA expression showed negative IHC staining for CD44 and IL-6 (left). FLAIR and IHC-stained micrographs for CD44 and IL-6 8 (right; original magnification ×40). Figure is available in color online only.

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    Yan Y, Zuo X, Wei D. Concise review: emerging role of CD44 in cancer stem cells: a promising biomarker and therapeutic target. Stem Cells Transl Med. 2015;4(9):10331043.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Xu H, Niu M, Yuan X, Wu K, Liu A. CD44 as a tumor biomarker and therapeutic target. Exp Hematol Oncol. 2020;9(1):36.

  • 27

    Wang CY, Huang CS, Yang YP, et al. The subpopulation of CD44-positive cells promoted tumorigenicity and metastatic ability in lung adenocarcinoma. J Chin Med Assoc. 2019;82(3):196201.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Liu X, Taftaf R, Kawaguchi M, et al. Homophilic CD44 interactions mediate tumor cell aggregation and polyclonal metastasis in patient-derived breast cancer models. Cancer Discov. 2019;9(1):96113.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Rooprai HK, Liyanage K, King A, Davies D, Martin K, Pilkington GJ. CD44 expression in human meningiomas: an immunocytochemical, immunohistochemical and flow cytometric analysis. Int J Oncol. 1999;14(5):855860.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Yu Q, Stamenkovic I. Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev. 1999;13(1):3548.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Tseng KY, Chung MH, Sytwu HK, et al. Osteopontin expression is a valuable marker for prediction of short-term recurrence in WHO grade I benign meningiomas. J Neurooncol. 2010;100(2):217223.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Lee KJ, Joo WI, Rha HK, et al. Peritumoral brain edema in meningiomas: correlations between magnetic resonance imaging, angiography, and pathology. Surg Neurol. 2008;69(4):350355.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Alaywan M, Sindou M. Prognostic factors in the surgery for intracranial meningioma. Role of the tumoral size and arterial vascularization originating from the pia mater. Study of 150 cases. Article in French. Neurochirurgie. 1993;39(6):337347.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Marmarou A, Takagi H, Shulman K. Biomechanics of brain edema and effects on local cerebral blood flow. Adv Neurol. 1980;28:345358.

  • 35

    Lobato RD, Alday R, Gómez PA, et al. Brain oedema in patients with intracranial meningioma. Correlation between clinical, radiological, and histological factors and the presence and intensity of oedema. Acta Neurochir (Wien). 1996;138(5):485494.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Azar M, Fattahi A, Tabibkhooei A, Taheri M. A small meningioma with extensive peritumoral brain edema: a case report. Iran J Med Sci. 2019;44(3):265269.

  • 37

    Reszec J, Hermanowicz A, Rutkowski R, Turek G, Mariak Z, Chyczewski L. Expression of MMP-9 and VEGF in meningiomas and their correlation with peritumoral brain edema. BioMed Res Int. 2015;2015:646853.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Gawlitza M, Fiedler E, Schob S, Hoffmann KT, Surov A. Peritumoral brain edema in meningiomas depends on aquaporin-4 expression and not on tumor grade, tumor volume, cell count, or Ki-67 labeling index. Mol Imaging Biol. 2017;19(2):298304.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Hägg D, Sjöberg S, Hultén LM, et al. Augmented levels of CD44 in macrophages from atherosclerotic subjects: a possible IL-6-CD44 feedback loop? Atherosclerosis. 2007;190(2):291297.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Jung S, Moon KS, Kim ST, et al. Increased expression of intracystic matrix metalloproteinases in brain tumors: relationship to the pathogenesis of brain tumor-associated cysts and peritumoral edema. J Clin Neurosci. 2007;14(12):11921198.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Iwado E, Ichikawa T, Kosaka H, et al. Role of VEGF and matrix metalloproteinase-9 in peritumoral brain edema associated with supratentorial benign meningiomas. Neuropathology. 2012;32(6):638646.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Peng ST, Su CH, Kuo CC, Shaw CF, Wang HS. CD44 crosslinking-mediated matrix metalloproteinase-9 relocation in breast tumor cells leads to enhanced metastasis. Int J Oncol. 2007;31(5):11191126.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Simis A, Pires de Aguiar PH, Leite CC, Santana PA Jr, Rosemberg S, Teixeira MJ. Peritumoral brain edema in benign meningiomas: correlation with clinical, radiologic, and surgical factors and possible role on recurrence. Surg Neurol. 2008;70(5):471477.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Englot DJ, Magill ST, Han SJ, Chang EF, Berger MS, McDermott MW. Seizures in supratentorial meningioma: a systematic review and meta-analysis. J Neurosurg. 2016;124(6):15521561.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    van Nieuwenhuizen D, Slot KM, Klein M, et al. The association between preoperative edema and postoperative cognitive functioning and health-related quality of life in WHO grade I meningioma patients. Acta Neurochir (Wien). 2019;161(3):579588.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Kazner E, Lanksch W, Steinhoff H, Wilske J. Computerized axial tomography of the skull—diagnostic possibilities and clinical results (author’s transl). Article in German. Fortschr Neurol Psychiatr Grenzgeb. 1975;43(10):487574.

    • PubMed
    • Search Google Scholar
    • Export Citation

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