Clinico-Histomorphological and Mib-1 Analysis of Recurrent Meningiomas: A Retrospective Study

Abstract

Introduction

Meningiomas are the most common primary brain tumors in adults, comprising 37.6% of central nervous system neoplasms. Though gross total resection is the treatment of choice, meningiomas recur even after complete resection. Additionally, meningiomas with a high Ki67/MIB-1 labeling index (LI) have a higher recurrence rate.

Aim

This article analyzes the clinico-histomorphological features of recurrent meningiomas and compares the expression of MIB-1 LI of primary and recurrent tumors.

Materials and Methods

This was a retrospective observational study of 50 recurrent meningiomas diagnosed between 2019 and 2023. Tumors were analyzed for site, radiological/histopathological features, and expression of MIB-1 LI in both primary and recurrent tumors.

Results

Thirty-four percent of the recurrent cases were between 41 and 50 years of age, 58% of the recurrent cases were males. Recurrence was most commonly seen in the frontal region (26%; n = 13) and 52% cases recurred between 1 and 10 years after primary resection. Of the primary tumors, 30 cases (60%) were grade 1, 16 cases (32%) were grade 2, and 4 cases (8%) were grade 3. Mean MIB-1 of primary meningiomas was 4.25% overall and 1.8% for grade 1. Progression in grade was noted in 15 cases with 5 cases showing brain invasion on recurrence while 17/30 grade 1, 14/16 grade 2, and 4/4 grade 3 tumors recurred with no change in grade. Overall mean MIB-1 LI of recurrent tumors was 5.4%.

Conclusion

Although MIB-1 LI is not an independent criterion for tumor grading, it can be used as an additional tool to identify at-risk patients and recommend close follow-up.

 

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Keywords

histomorphology - MIB-1 LI - Ki67 - meningioma - recurrence

Introduction

Meningiomas are the most common primary brain tumors in adults comprising 37.6% of central nervous system (CNS) neoplasms.[1] [2] Gross total microsurgical resection is the treatment of choice and histopathological examination is done for confirmation and grading of the tumors.[3] Grade 1 and 2 make up 97 to 99% of the tumors and grade 3 comprise 1 to 3% of the cases with a high rate of mortality and metastases.[4] [5] It has been observed that although a complete plane of resection can be achieved in many cases, meningiomas still have a propensity to recur and can have an unpredictable behavior, that is, the tumors may remain of the grade same as before or may show features of a higher grade on recurrence. Additionally, Menger et al has observed that meningiomas with subtotal resections have a higher rate of recurrence with a high MIB-1 labeling index (LI).[6] As the current World Health Organization (WHO) grading system includes only mitotic counts as cutoff with no fixed cutoff for MIB-1 LI, it is proposed that correlation of MIB-1 LI of primary and recurrent tumors can be a useful predictor of recurrence of tumor as it is a relatively objective alternative to manually counting mitoses on hematoxylin and eosin (H&E)-stained slides.[3] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39]

 

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Objectives

This article compares and analyzes the clinico-histomorphological features and MIB-1 LI of the primary and recurrent meningiomas.

 

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Materials and Methods

Fifty cases of recurrent meningiomas were diagnosed from January 2019 to December 2023 and were included in the study. Recurrent tumors along with the primary tumor were analyzed for site, radiological features, completeness of resection based on postoperative imaging, histopathological features like unequivocal glial invasion or mitotic counts, increased cellularity, sheeting, small cells with high N:C ratio, prominent nucleoli, and necrosis along with histological variants. Furthermore, expression of MIB-1 LI was expressed as a percentage in the recurrent meningiomas and was compared with that of the primary tumors. Tumors were classified and graded according to the WHO 2021 classification of CNS. The paraffin-embedded representative sections were studied by two qualified observers. The interpretation of the LI was done in the highest area of proliferation and was expressed as a percentage.

 

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Statistical Analysis

Statistical analysis of data was expressed in descriptive statistics mentioning the frequency, proportions, and percentages. The correlations were performed in SPSS software version v29 and for statistical significance, a p-value of less than 0.05 was considered. Spearman's rank correlation (Pearson's and Spearman's rho) was used for correlation between numerical and categorical variables. The Institutional Ethics Committee clearance was obtained.

 

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Results

Out of 50 recurrent meningiomas, 34% cases (n = 17) were in the age group of 41 to 50 years. Majority of the recurrences were seen between the 4th and 6th decade (54%; n = 27). Fifty-eight percent were males and 42% were females with a male:female ratio of 1.4:1. Frontal/frontoparietal region (26%; n = 13) was the most common site where meningiomas recurred followed by sphenoid wing (18%; n = 9). Headache was the most common symptom followed by diminution of vision. Frontal meningiomas presented with seizures as a common symptom. However, in one case of frontal meningioma, seizures developed as a symptom on recurrence and the tumor had brain invasion on histopathological examination.

Sixteen percent (n = 8) cases recurred within 6 months and 20% (n = 10) cases within a year. Fifty-two percent (n = 26) cases recurred between 1 and 10 years and 12% (n = 6) cases recurred after 10 years. Seventy percent (n = 35) cases remained of the same grade as the primary irrespective of the interval of recurrence. Progression was noted in 30% cases (n = 15). Seven out of 15 (50%) cases which became a higher grade on recurrence (with brain invasion) were located in the anterior skull base and frontal region followed by sphenoid wing. Of the 30 (60%) grade 1 meningiomas, 12 (36.7%) recurred as grade 2 (11 atypical meningiomas; 1 clear cell meningioma) and 1 (3.3%) recurred as a grade 3 meningioma (papillary meningioma). Seventeen cases remained grade 1 on recurrence.

Of the 16 (32%) grade 2 meningiomas, 2 (12.5%) recurred as grade 3 meningiomas (rhabdoid meningioma 1; anaplastic meningioma 1). Two cases which were diagnosed primarily as chordoid meningioma recurred as chordoid meningiomas and one case recurred as clear cell meningioma. All the grade 3 (8%) tumors recurred as grade 3 meningiomas with histology similar to primary tumors ([Table 1]).

Table 1 Comparison of histological variants and grade of recurrent meningiomas

Histological variant of the primary tumor	Grade of primary tumor	Histological variant of the recurrent tumor	Grade of secondary tumor	No. of cases
Meningothelial meningioma	Grade 1	Meningothelial meningioma	Grade 1	5
		Atypical meningioma	Grade 2	6
		Clear cell meningioma	Grade 2	1
		High grade invasive meningioma favoring papillary variant (multiple)	Grade 3	1
Psammomatous meningioma	Grade 1	Psammomatous meningioma	Grade 1	3
Fibroblastic meningioma	Grade 1	Atypical meningioma	Grade 2	1
Transitional meningioma	Grade 1	Transitional meningioma	Grade 1	7
		Atypical meningioma	Grade 2	2
Angiomatous meningioma	Grade 1	Angiomatous meningioma	Grade 1	1
		Atypical meningioma	Grade 2	1
Metaplastic meningioma	Grade 1	Atypical meningioma	Grade 2	1
		Multiple meningiomas; 1 being transitional meningioma	Grade 1	1
Atypical meningioma	Grade 2	Atypical meningioma	Grade 2	11
		Rhabdoid meningioma	Grade 3	1
		Anaplastic meningioma	Grade 3	1
Chordoid meningioma	Grade 2	Atypical meningioma	Grade 2	2
Clear cell meningioma	Grade 2	Clear cell meningioma	Grade 2	1
Anaplastic meningioma	Grade 3	Anaplastic meningioma	Grade 3	1
Papillary meningioma	Grade 3	Papillary meningioma	Grade 3	2
Rhabdoid meningioma	Grade 3	Rhabdoid meningioma	Grade 3	1
Total	–	–	–	50

Hypercellularity was noted in 8 (16%) cases, sheeting was noted in 12 (24%) cases, small cell change was noted in 1 (2%) case, necrosis was noted in 15 (30%) cases, and prominent nucleoli was noted in 12 (24%) cases. Only 2 cases had more than ⅗ of the above histological features making it an atypical meningioma (grade 2). These tumors recurred as atypical meningiomas within a year with bone and soft tissue extensions. Brain invasion was seen in 7 (14%) primary tumors, which included 5 atypical meningiomas, 1 rhabdoid, and 1 chordoid meningioma. Four cases recurred within a year. In 41 cases, mitosis was less than 4/10 high-power field (HPF). Out of these, 11 cases (26.8%) were grade 2/grade 3 meningiomas on the basis of brain invasion/histological features and they recurred with similar features. Most of the cases in this category recurred between 5 and 10 years (n = 13). Eight primary tumors had mitosis between 4 and 19/10 HPF, of which 6 tumors were atypical meningiomas, 1 was an anaplastic meningioma, and 1 was a papillary meningioma. The average interval of recurrence spanned from < 6 months to 5 to 10 years. It was observed that those tumors which recurred as grade 2 or grade 3 meningiomas had a significant increase in the lymphoplasmacytic infiltration as compared with their primary cases. The Spearman's rho correlation showed that more the abnormal histological features in a tumor, shorter was the interval of recurrence. However, the results were not statistically significant ([Table 2]).

Table 2 Tabulation of histological features of the primary tumor and the interval of recurrence

Histological features	No. of cases	Recurrence rate
		< 6 mo	6 mo–1 y	1–5 y	5–10 y	10–20 y
Hypercellularity	8	–	4	1	3	–
Sheeting	12	1	3	5	1	2
Small cell change	1	1	–	–	–	–
Necrosis	15	1	3	5	6	1
Prominent nucleoli	12	1	5	3	3	–
Mitosis < 4/10 HPF	41	6	8	9	13	5
Mitosis 4–19/10 HPF	8	2	2	2	2	–
Mitosis > 20/10 HPF	1	–	–	–	1	–
Brain invasion	7	1	4	2	–	–
Specific histology	Clear cell	–	–	1	–	–
	Chordoid	–	1	–	1	–
	Papillary	1	–	–	1	–
	Rhabdoid	–	–	1	–	–
	Anaplastic	1	–	–	–	–

Abbreviation: HPF, high-power field.

A Spearman's rank correlation (Spearman's rho) comparing MIB-LIs of primary meningiomas and the time interval of recurrence was performed. The correlation was inversely proportional with an R value of –0.20722 indicating that higher the MIB-1 LI, shorter is the interval of recurrence. However, a significance could not be established indicating that recurrence did not only depend on MIB-LI. Other factors like incomplete resection, residual tumor, and grade of tumor played equally important roles. Furthermore, it also indicated that a low MIB-1 LI did not preclude a possibility of recurrence if the other factors exist.

A Spearman's rank correlation (Pearson's) comparing the MIB-1 LIs of the primary and the recurrent meningiomas was performed. A positive correlation was established (r = 0.5765). The p-value was 0.000012 and the result was statistically significant at p < 0.05, indicating that recurrent tumors present with proportionately high MIB-1 LIs when compared with that of the primary counterparts and that high MIB-LI may be considered as an indicator of recurrence ([Table 3], [Fig. 1]).

Table 3 Comparison of MIB-1 in recurrent meningiomas with recurrence interval

MIB-1 LI of primary tumor	No. of cases	%	MIB-1 LI of recurrent tumor	No. of cases	Recurrence interval					R Value; p-Value
					< 6 mo	6 mo–1 y	1–5 y	5–10 y	10–20 y
≤ 1%	27	54%	≤ 1%	12	1	2	4	1	4	Correlation of primary and recurrent MIB-LIs p = 0.000012 (< 0.05) Significant
			1–5%	13	2	2	3	4	2
			6–10%	1				1
			11–15%	1				1
1–5%	13	26%	≤ 1%	1				1
			1–5%	8	3	1	2	2
			6–10%	1		1
			11–15%	3	1	1	1
6–10%	5	10%	≤ 1%	1			1
			1–5%	2		1	1
			6–10%	1				1
			11–15%	1		1
11–15%	2	4%	≤ 1%	–
			1–5%	1				1
			> 20%	1			1
16–20%	2	4%	≤ 1–5%	–
			6–10%	1				1
			11–15%	1		1
> 20%	1	2%	1–20%	–
			> 20%	1	1
Total	50	100		50

Abbreviation: LI, labeling index.

Fig. 1 (A) Photomicrograph showing a meningothelial meningioma, grade 1 (hematoxylin and eosin [H&E], 100Xz). (B) Photomicrograph showing a MIB-1 labeling index (LI) of 10–12% in the grade 1 tumor (immunohistochemistry [IHC], 400×). (C) Photomicrograph showing recurrence of the meningioma as a grade 1 tumor (H&E, 100×); no histology of a higher grade. (D) MIB-1 LI: 4–5% in the recurrent meningioma (IHC, 400×).

Fifty-four percent tumors had a MIB LI of 1% in the primary tumor of which 5 tumors recurred as a higher grade with a similar MIB-1 LI. All such cases had brain invasion.

A Spearman's rank correlation (Spearman's rho) was performed between the grade of recurrent meningioma and MIB-1 LI of the tumor and a positive correlation was observed with R = 0.36409, p (two-tailed) = 0.00934. The p-value was significant at p < 0.05, indicating that higher grade of tumors expressed higher MIB-1 LIs ([Table 4]). The grade-wise comparison of mean MIB-1 LIs of primary and recurrent meningiomas were proportional and MIB-1 was higher in grade 2 and grade 3 meningiomas. The overall MIB-1 of primary meningiomas was 4.25% and that of recurrent was 5.4% ([Table 5], [Fig. 2]).

Table 4 Comparison of MIB-1 in recurrent meningiomas and grade

MIB-1 LI of primary tumor	No. of cases	%	MIB-1 LI of recurrent tumor	No. of cases	Grade						p-Value
					Grade 1 to 1	Grade 1 to 2	Grade 1 to 3	Grade 2 to 2	Grade 2 to 3	Grade 3 to 3
≤ 1%	27	54%	≤ 1%	12	6	5		1			R = 0.36409; p (two-tailed) = 0.00934. (< 0.05) Significant
			1–5%	13	7	3		3
			6–10%	1			1
			11–15%	1		1
1–5%	13	26%	≤ 1%	1	1
			1–5%	8	2	2		3		1
			6–10%	1		1
			11–15%	3				2	1
6–10%	5	10%	≤ 1%	1				1
			1–5%	2				1		1
			6–10%	1						1
			11–15%	1				1
11–15%	2	4%	≤ 1%	–
			1–5%	1	1
			> 20%	1					1
16–20%	2	4%	≤ 1–5%	–
			6–10%	1				1
			11–15%	1				1
> 20%	1	2%	1–20%	–
			> 20%	1						1
Total	50	100		50

Abbreviation: LI, labeling index.

Table 5 The comparison of mean MIB-LI of the primary and recurrent meningiomas according to the grade

Grade	Primary meningioma (mean MIB-1 LI%)	Recurrent meningioma (mean MIB-1 LI)
Grade 1	1.76%	1.92%
Grade 2	6.41%	5.42%
Grade 3	14.37%	14.43%
Mean MIB-1 (overall)	4.25%	5.4%

Abbreviation: LI, labeling index.

Fig. 2 (A) Coronal magnetic resonance imaging (MRI) slices show contrast enhancing tumor in the base of the skull (red arrow). (B) Photomicrograph of the resected tumor shows a meningothelial meningioma (hematoxylin and eosin [H&E]. 100×). (C) MIB-labeling index (LI) of the resected tumor is 1–2% (immunohistochemistry [IHC], MIB-1). (D) Coronal MRI slices show a recurrent contrast enhancing tumor in the base skull (red arrow). (E) Photomicrograph of the recurrent meningioma shows brain-invasive atypical meningioma (H&E, 40×, red arrow). (F) MIB- LI of the resected recurrent tumor is 4–5% approximately (IHC, MIB-1).

Ninety-two percent (n = 46) underwent resection only whereas 8% cases (n = 8%) underwent resection plus radiation. All the patients who underwent radiation were brain invasive meningiomas. On follow-up, 44% cases are asymptomatic, 30% cases are living with deficits, and 26% cases have succumbed to the disease.

 

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Discussion

Meningiomas are dural-based, extra-axial tumors common in the 6th decade of life with a female preponderance.[6] [10] Our study had 54% cases in the age group of 40 to 60 years with an age range of 16 to 86 years. Our findings concurred with Menger et al, Haddad et al, and Nilkanthe et al.[6] [9] [10] Fifty-eight percent cases were males. This was in contradiction with the fact that meningiomas are more common in females (approx. M:F = 1:2).[27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] However, Gaillard et al observed that that atypical meningiomas and anaplastic meningiomas were more common in males.[39] The current study had 40% (n = 20) primary grade 2/grade 3 meningiomas (males: 12/20). Hence, it was inferred that the proportion of higher grade meningiomas may have contributed to the higher number of male patients.

Of the 50 tumors, recurrence was seen mostly in the frontal/frontoparietal convexity (26%; n = 13) followed by tumors of the sphenoid wing (18%; n = 9). Our findings concurred with de Carvalho et al and Haddad et al.[10] [24] de Carvalho et al had 51% tumors in the parasagittal region and convexities whereas Haddad et al had 41.8% tumors in the same region.[10] [27]

Recurrent meningiomas presented with similar clinical features as the primary tumors among which pressure symptoms (headache, diminution of vision, and weakness of limbs) were more common. It was also observed that the recurrent cases showing brain invasion presented with seizures and altered sensorium. Spinal cord tumors presented with pain and paraparesis. Our findings concurred with those of Prat-Acin et al who had 66.1% cases with pressure symptoms.[11]

Fifty-two percent of the tumors recurred between 1 and 10 years of primary resection. The recurrence interval ranged from 1 to 211 months with an average interval of 51.2 months. Our findings concurred with Haddad et al.[10] In their study, the mean months to recurrence was 33.2 ± 23.7, and median months to recurrence ranged from 6 to 105 months. Forty-four percent (n = 22) meningiomas recurred with a size greater than the primary tumor of which 11 tumors recurred as a higher grade due to brain invasion/mitotic activity or specific histological features. All the tumors showed intense homogenous to heterogeneous enhancement. Hortobágyi et al mentioned that tumors with vasogenic edema have a strong correlation with recurrence as edema represents the invading front of the tumor.[38] Our study had 4 cases of recurrent/residual atypical meningiomas with vasogenic edema.

Thirty-six percent (n = 18) cases in our study recurred within a year. Of them, 6 cases remained grade 1 on recurrence, 5 of which were located at sites difficult/sensitive to access (spinal cord/planum sphenoidal/petroclival region). Six cases remained grade 2 and all were atypical meningiomas. Fifty-two percent (n = 26) cases recurred between 1 and 10 years of which 8 cases remained grade 1 on recurrence and were at sites difficult to access. Fourteen cases were grade 2 and 4 cases were grade 3 meningiomas on recurrence. Twelve percent (n = 6) cases recurred after 10 years, of which 4 cases remained grade 1 and 2 cases were grade 2 meningiomas on recurrence. It was observed that majority of the cases which remained grade 1 irrespective of the interval of recurrence were at sites difficult to access. Fifty percent (n = 25) cases were reported as grade 2 on recurrence of which 14 (28%) cases were primary grade 2 tumors (prone to recurrence) and 19 (38%) cases had brain invasion. Fourteen percent (n = 7) cases were grade 3 on recurrence including a meningothelial meningioma of the frontal region, which recurred after 5 years as multiple tumors at the same site with papillary architecture and brain invasion ([Table 1]). Our findings were in line with Perry and Brat and Abry et al who mentioned that residual tumors were the most common cause of recurrence in sites which were difficult to access irrespective of grade and size of tumor.[31] [40] Furthermore, Perry and Brat emphasized that grade 2 meningiomas are prone to recurrence even after complete resection.[40]

Sixty percent (n = 30) tumors were primary grade 1 tumors, 32% (n = 16) were primary grade 2 tumors, and 8% (n = 4) were primary grade 3 tumors. Among grade 1 tumors, 36% (n = 18) remained grade 1 on recurrence, 22% (n = 11) recurred as grade 2, and 2% (n = 1) recurred as grade 3 tumors. Among grade 2 tumors, 28% remained grade 2 on recurrence and 4% recurred as grade 3. The histological features, location, size, and proliferative activity were correlated. Thirteen of 18 tumors which remained grade 1 on recurrence had sizes more than 2 cm and majority were located at sites difficult to access like olfactory groove/cerebellopontine angle/petroclival/sphenoid or spine. It was inferred that the size and location of these may have been instrumental factors for recurrence due to incomplete resection. The tumors which became grade 2 or grade 3 had brain invasion or increased mitosis or at least three of the following features of hypercellularity, sheeting, necrosis, small cell change, prominent nucleoli, or specific histology like clear cell meningioma or papillary meningioma. Our inferences concurred with the documented literature and the comparison has been documented in [Table 6].

Table 6 Comparison of histological features of current study with the existing literature on recurrent meningiomas

Literature	Hypercellularity	Sheeting	Necrosis	Prominent nucleoli	Small change	Brain invasion	Mitosis/10 HPF
							< 3	3–5	> 5
Haddad et al[10]	11.5%	11.5%	15.4%	19.2%	–	–	–	–	–
Ho et al[26]	34.9%	27.7%	38.5%	71%	8.4%	13.3%	55.4%	19.3%	25.3%
Barrett et al[28]	80%	69%	42%	82%	–	31%	–	–	44%
Chen et al[30]	49%	59%	17%	29%	–	24%	–	17%	–
Marciscano et al[49]	57%	44%	10%	44%	4%	–	–	–	–
Current study	16%	24%	30%	24%	2%	14%	82%	2%	16%

Abbreviation: HPF, high-power field.

Additionally, our study had special histological variants like clear cell, chordoid, papillary, rhabdoid, and anaplastic meningiomas, which recurred with brain invasion. The histological features of the primary tumor were correlated with the MIB-1 LI of the primary tumor. The findings were statistically significant at p = 0.00242.

Although MIB-1 LI is not a criterion for grading meningiomas, it is considered an additional and important parameter for predicting recurrence. Hence, mentioning MIB-LI is a recommended practice in reporting meningiomas in addition to other histological features.[8] However, as there are differences in reporting MIB-1 LI with inter- and intralaboratory variability, a standardized cutoff has not been established.

A comparison of MIB-1 LIs of meningiomas in majority of the studies showed that an index of > 4% (approximately) was a significant risk factor for recurrence. Our study had a mean MIB LI of 4.25% in the primary tumor and 5.4% in the recurrent tumor. [Table 7] shows the comparison of MIB-1 LIs of different studies on recurrent meningiomas.

Table 7 Comparison of MIB-1 LIs (primary with recurrence) with the current study

Literature	Mean MIB-1 LI for primary tumors*	Mean MIB-1 LI for recurrent tumors	Recurrence rate
Menger et al[6]	9.8%	22.2%	–
Lampmann et al[8]	4.9 ± 2.3%	–	6.2%
Haddad et al[10]	3.3% (4.27 ± 3.70)	–	18.5%
Prat-Acin et al[11]	> 3%	–	66.6%
Nagahama et al[13]	> 5%	–	–
Behling et al[14]	2.62%	5.36%	–
de Carvalho et al[24]	2.61%	–	85.4%
Ho et al[26]	8.4%	–	71% (for grade2; 5-year rate)
Nguyen et al[27]	2.5%	–	–
Barrett et al[28]	15%	–	30.3%
Lee et al[35]	9.75%	–	–
Marciscano et al[49]	4.3%		–
Current study	4.25%	5.4%	16.5%

Abbreviation: LI, labeling index.

The table shows that a mean MIB-1 of approximately > 4% in the primary tumors predisposes even a grade 1 meningioma to recurrence. Our study concurred with the literature. It was also observed that recurrent meningiomas presented with higher MIB-1 LIs than the primary tumors and the results were statistically significant. Behling et al mentioned in their study that recurrent meningiomas had a mean MIB-1 LI expression of 2.62% in the primary tumors and 5.36% in the recurrent tumors and it was statistically significant (p < 0.0001).[14] The current study had similar observations with a statistical significance of p = 0.000012, indicating that the mean MIB-LIs of the recurrent meningiomas are higher than the primary tumors. Furthermore, MIB-1 expression was higher in grade 2/grade3 meningiomas.[41] [42] Lampmann et al, Behling et al, and Marciscano et al showed statistically significant results for the same in their studies (p < 0.05). The current study concurred and concluded that higher grade meningiomas expressed higher MIB-1 LIs with a statistical significance of p = 0.00934. Comparison of the mean MIB-1 LIs of recurrent meningiomas of other studies with the current study has been discussed in [Table 8]. The studies mentioned have compared the mean MIB-1 LIs of recurrent meningiomas with that of the nonrecurrent meningiomas. Our findings concurred with the literature analysis of MIB-1 LI of recurrent meningiomas and were higher than those of nonrecurrent meningiomas ([Table 8]).

Table 8 Comparison of MIB-LI of recurrent meningiomas and nonrecurrent meningiomas with the current study

Literature	Mean MIB-1 LI (recurrent meningiomas)	Mean MIB-1 LI (nonrecurrent meningiomas)
Vankalakunti et al[43]	4.21%	2.66%
Abramovich and Prayson[44]	5.4%	1.5%
Okada et al[45]	7.4%	1.6%
Yang et al[46]	3.15%	0.39%
Kalala et al[47]	10.45	2.4%
Current study	5.4%	–

Abbreviation: LI, labeling index.

Although individual assessments of MIB-1 expression has been done for primary tumors with recurrence and recurrent tumors, there is limited data on the comparison of MIB-1 LI of the primary tumor with that of its recurrence.[31] [43] [44] [45] [46] [47] The current study was on the follow-up and comparison of the MIB-1 LI of the primary tumor with that of its recurrence with a focus on the primary mean MIB-1 expression, which can help in predicting recurrences and guiding management. This is one of the very few studies done on recurrent meningiomas in the Indian subcontinent. The mean MIB-1 LI of the primary tumors in the current study was 4.25%. The recurrent tumors had a higher mean MIB-1 LI. However, in the tumors where MIB-1 LI was not high in the primary or the recurrent, the tumors either had a large size (at least > 2 cm) or were at a location difficult to access or developed brain invasion on recurrence. Kim et al did study on the prognostic significance of using the mitosis marker anti-phosphohistone H3 in meningiomas to circumvent the subjectivity of counting mitotic index on H&E-stained slides.[48] They concluded that it can be an independent predictor of recurrence. However, as the observations had interlaboratory variability, there were no standard cutoffs as was the case with MIB-LI.

Hence, it was strongly indicated from the existing literature and the current study that MIB-LI could be used in addition to the existing histological criteria to predict recurrence irrespective of the grade of the tumor. According to our findings, tumors located in the anterior base of the skull or spine and/or atypical histological features and/or with MIB-1 LI more than > 4% should be followed up diligently. In the current study, a standard follow-up protocol was practiced. The patient was called at an interval of 3 months, 6 months, and 1 year postoperatively, followed by annually for 3 years then once in every 3 years. The average recurrence interval in our study was 51.2 months/4.3 years.

Forty-four percent cases (15 cases remained grade 1, 4 cases remained grade 2, and 1 case remained grade 3 on recurrence) are on follow-up and are doing well. One case received radiation and was reported as grade 3 on recurrence but is doing well on follow-up.

Thirty percent (n = 15) cases have presented with recurring symptoms on follow-up. In two cases, radiation had been advised after the primary but the patient was lost to follow-up and presented directly with recurring symptoms (brain-invasive atypical meningioma and papillary meningioma).

One case of rhabdoid meningioma (both primary and recurrent) received radiation therapy (RT) after the first resection and is doing well on follow-up whereas three cases (two brain-invasive meningiomas and one papillary meningioma) developed recurring symptoms even after receiving RT and resection of the recurrent tumor.

Twenty-six percent (n = 13) cases died after the recurrent tumor of which 2 cases died of postoperative complications (1 being a grade 1 meningioma). Of the 13 cases, 9 cases were grade 2 meningiomas and 3 cases were grade 3 meningiomas on recurrence. According to Lampmann et al, Behling et al, and Perry and Brat, grade 3 tumors had a high mortality rate.[8] [14] [40]

Kent et al performed a study on the long-term outcomes of grade 2/grade3 meningiomas with or without radiation and concluded that adjuvant radiation prolongs the progression-free survival of atypical/anaplastic meningiomas. They also observed that a high Ki67 worsens the prognosis and hence warrants a systematic monitoring.[34]

 

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Limitations

1. The sample size had to be limited to 50 cases as there were cases in which primary resections had not been performed in our institution and the data of the previous resections were unavailable. The retrospective nature of data collection caused biases like missing information in some cases and also observer bias while interpreting MIB LI as there is interobserver variability.

2. Molecular studies could not be done due to limited resources, hence grade 3 meningiomas were diagnosed only on the basis of mitotic index and/or anaplastic features.

3. There is nonhomogeneity of the included cases in regards with, location within the cranium, size, grading in H&E staining, surgical techniques, surgeons' impact, and experience.

4. According to the primary histopathological diagnosis and grade, the follow-up period of the patients differed. A patient with grade 1 tumor had a different follow-up interval as compared with a patient diagnosed as a primary grade 2 and grade 3 meningioma.

 

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Conclusion

In this retrospective and observational study of 50 recurrent meningiomas, vasogenic edema, parafalcine/skull base location, and incomplete resection were major contributors in recurrence, irrespective of the grade and proliferative index of the tumor. However, even in cases with complete resection, recurrences were quite common and they primarily depended upon the histological features and proliferative indices. Features like brain invasion, high mitotic index (> 4/10 HPF), hypercellularity, loss of architecture, small cell change, necrosis, and prominent nucleoli had significant role in grading the tumors and also indicated the prognosis. Although MIB-1 proliferative index/LI has not been incorporated in the grading system, it was concluded that it is an important ancillary tool in predicting recurrences. It was observed that even in grade 1 tumors (devoid of atypical histological features) and in tumors having complete resection, a high MIB-1 LI (> 4%) had a higher rate of recurrence and warranted a regular follow-up. Also, tumors with such MIB-1 LIs (> 4%) recurred at shorter intervals. The recurrent tumors had a higher MIB-1 expression than the primary meningiomas and MIB-1 expression also increased with higher grades of meningiomas. Therefore, although MIB-LI is not an independent criterion for grading the tumors, it can be used as an additional tool in reporting meningiomas to help in diligent monitoring and follow-up of at-risk patients.

 

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Conflict of Interest

None declared.

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Publication History

Article published online:
08 September 2025