Atypical meningiomas compared to other WHO Grade 2 meningiomas: Histological features and prognosis

Study design

This is a retrospective study of 74 who grade 2 meningioma diagnosed between January 2008 and December 2020 at King Saud University Medical City, Riyadh, Saudi Arabia. Data were collected from patients electronic and paper bases and final pathology reports. Patients with a confirmed pathological diagnosis of WHO grade 2 meningioma and underwent tumor resection in our center were included. Patients with no confirmed diagnosis, different meningioma grade, spinal meningioma and those with missing data/ follow-up were excluded. Borderline meningioma reports between grade 1 and grade 2 or between grade 2 and grade 3 were reviewed by a neuro- pathologist in our institute and the 2021 WHO classifications were applied to determine the final diagnosis.¹⁰

Data collection

Demographic data including age at diagnoses, gender and comorbidities were collected. The size and location of the tumor was determined from preoperative imaging, tumor size was defined by the largest diameter in centimeters, which is then subdivided to 2 groups, Tumors <5cm and ≥5 cm. The extent of resection was determined by the first postoperative imaging. Recurrence was determined by radiological evidence on follow- up imaging. Follow- up period was determined by their last documented out- patient clinic visit.

Postoperative assessment

The extent of resection was determined based on the first post operative MRI. Patients with evidence of subtotal resection on MRI received radiotherapy. Patients with gross total resection on MRI were observed with serial images. Patients with suspicion of recurrence on follow up MRI were discussed in our institutional tumor board and received radiotherapy after consensus.

Histopathology

All 74-pathology reports were reviewed to meet the 2021 WHO classification of tumors of the central nervous system as follows: fulfilling either 1 of 2 major criteria or 3 of 5 minor criteria. The major criteria are: 4 - 19 mitotic figures/10 high power fields and brain invasion. The minor criteria are: increased cellularity, small cells with high nuclear- cytoplasmic ratio, large and prominent nucleoli, patternless or sheet-like growth, foci of spontaneous or geographic necrosis.¹⁸ Ki-67 index (MIB-1) was also calculated.

Statistical analysis

Data entry and statistical analysis were performed using the Statistical Package for Social Sciences (SPSS) software version 26.0 (IBM Corporation, Armonk, NY, USA). Descriptive statistics (e.g. number, percentage, mean, range, standard deviation) and analytic statistics using Chi-square test, Fisher exact test and independent samples t-test were applied. P-values ≤0.05 were considered as statistically significant.

Ethical statement

The research was conducted ethically, with all study procedures being performed in accordance with the requirements of the World Medical Association’s declaration of Helsinki.

Histopathological features and type of WHO grade 2 meningioma

Increased nuclear- cytoplasmic ratio was found more in patients with atypical meningioma with p-value 0.008, as well as increased cellularity (p=0.044) compared to chordoid and clear cell meningiomas. No significant difference in the number of patients with atypia (4 patients), mitotic figures (7 patients), loss of architecture (31 patients), brain invasion (14 patients), bone invasion (3 patients), necrosis (20 patients) and increased Ki-67 (40 patients) between all three types of WHO grade 2 meningioma. (Table 3)

Characteristics associated with recurrence

A total of 12 patients (16.2%) of the 74 patients had evidence of radiological recurrence, with mean age of 51years (p=0.75). Nine patients (75%) were females, and 3 patients (25%) were males. Complete resection was achieved in 5 of the recurrence patients and partial resection was done in 7 of the recurrence patients (p=0.134). No significant association was found with histological subtype, size of the primary tumor or location of the tumor. (Table 4)

Pathological factors associated with recurrence

None of the pathological features examined in our study were significantly associated with recurrence rate in patients with WHO grade 2 meningioma. Ten patients (16.6%) diagnosed with atypical WHO grade 2 meningioma had evidence of recurrence compared to 2 patients (14.2%) with chordoid or clear cell meningioma (p=0.564). Recurrence rate in sheet- like growth (22.5%), increased cellularity (13.6%), high nuclear- cytoplasic ration (13.6%), necrosis (20%), increased mitotic figures (25%), brain invasion (14.2%) and increased Ki- 67 (18.2%) were not statistically significant (Table 5).

Patient related characteristics and recurrence

The recurrence rate for grade 2 meningiomas widely varies. It has been reported as low as 4.3%,¹⁴ and as high as 69%.¹⁵ In our study, 12 patients (16.2%) had evidence of radiological recurrence at mean follow-up period of 40.7 months.

Previous studies have shown that age, male gender, the size of surgical resection, and higher Ki-67 index have an impact on the prognosis of grade 2 meningioma patients.^5,16 Other studies have shown that WHO histopathological grade and the extent of surgical resection are considered to be the strongest prognostic factors of recurrence.¹⁷

The location distribution of grade 2 meningioma is comparable to grade 1 meningioma,¹⁸ with the most common location being in the convexity.^19,6 A study by Ruiz et al. demonstrated that convexity location is a protective prognostic factor against recurrence in grade 2 meningiomas.¹¹ In our study, most patients had skull base meningioma (46.6%), followed by convexity (31.5%) and midline meningioma (20.5%), with recurrence rate being 7% in skull base meningioma, 4.1% in convexity meningioma and 5.5% in midline meningiomas with no significant association with recurrence. Generally, larger size tumors are linked with higher recurrence rate.^19,16 However, few studies reported that smaller size grade 2 meningiomas are also associated with high recurrence rates.^21,6 In this study, the majority of the cases were less than 5 cm³ (71%). Of those, 6 cases had recurrence, with no significant association.

Maximum safe tumor resection and dural attachment remain the treatment goals for meningioma, with complete resection of the tumor being associated with lower recurrence rates in many studies.^22,23,16 Few studies have shown no difference in recurrence rate and extent of resection.²⁴ In our study, 58.3% of patients with recurrence had partially resected tumors, with no statistical difference found.

In our study, patients who underwent radiation therapy postoperatively were found to have significantly less recurrence rate compared to those who did not. (p=0.008) Adjuvant radiation therapy has been associated with decreased disease recurrence and progression in higher grades of meningioma in multiple studies.²⁵

Histopathologic features and recurrence

The pathologic subtype of meningiomas mainly determines the prognosis and recurrence rate. Higher atypical features are associated with higher recurrence rates.²⁶ In recent WHO classifications (2016 and beyond), brain invasion has been identified as a standalone criterion for atypical meningioma. Multiple studies have shown that brain invasion increases the risk of a recurrence even when the meningioma exhibits benign characteristics.^13,15 In our study, brain invasion was seen in 21.7% of all patients, with one patient experiencing recurrence (p=0.91).

Increased mitotic rate can be seen in up to 70% of grade 2 meningioma papers.^2,27 In our study, only 13.4% of meningiomas showed increased mitotic rate. Detecting mitotic figures can be difficult for a variety of reasons, including pyknotic cells and mitotic figure instability during fixation, which results in poor accuracy.² Studies have shown that increased mitotic activity is associated with recurrence of atypical meningiomas.^21,6 In our study, increased mitotic rate was not significantly associated with recurrence.

Increased cellularity, nuclear- cytoplasmic ratio and necrosis are minor atypical features of grade 2 meningioma. Few studies on the significance of each of those factors alone have shown no significant association with recurrence.²⁷ Other studies found that necrosis and sheet like pattern of cells can be associated with higher recurrence rates.²⁸ In our study, no significant association with recurrence was found between each minor criterion and recurrence.

This study is limited by its retrospective design and the collection of pathological features from previously reported pathology results. Inconsistent reporting by the neuro- pathologist might cause some features, especially minor features, to be missing in the final report. Patients labeled as WHO grade 1 meningioma with 1-2 features were not included in this study. Another limitation is the discrepancy in the number of patients in each subtype, however, the number of patients in each subgroup is consistent with the epidemiological distribution of WHO grade 2 meningiomas.⁴ Only operated patients were included in this study, with a small sample size for the considered pathology. Many patients were not included due to unavailable records or loss of follow-up. The average follow-up time of 40.7 months (median: 27 months) may be insufficient to detect recurrence in a not so aggressive pathology such as meningioma. Larger studies looking at each isolated criterion in meningiomas and its relation to recurrence are needed.