Intracranial Meningeal Hemangiopericytomas: An Analysis of Factors Affecting Outcome in 39 Cases Managed with Multimodality Treatment
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.271251
Source of Support: None, Conflict of Interest: None
Keywords: Adjuvant radiotherapy, extent of excision, intracranial, meningeal hemangiopericytomas, overall survival, recurrence-free survival, tumor gradeKey Message: Greater extent of excision, low grade of tumor and adjuvant radiotherapy positively impact overall as well as recurrence free survival in MHPCs; however, only tumor grade is associated with statistically significant OS benefits, while both tumor grade and adjuvant radiotherapy prolong RFS in a statistically significant manner.
Hemangiopericytomas are rare mesenchymal tumors arising from the Zimmerman's pericytes around the blood vessels., They can occur anywhere in the body but have a predilection for the head and neck. The intracranial meningeal hemangiopericytomas (MHPCs) have a close resemblance to meningiomas with respect to radiological appearance and clinical manifestations; however, MHPCs are locally aggressive with a very high local recurrence rate and their natural history is punctuated by development of systemic metastasis.,, The results of various genetic, immuno-histochemical, and ultrastructural studies have conclusively proven the MHPCs to be distinct from meningiomas.,,, The World Health Organization recognized the MHPCs as a separate entity of meningeal tumors in 1993 and graded them into grade II and grade III or anaplastic MHPCs. As MHPCs are rare tumors, very few studies are available in the literature that have addressed the management and outcome of MHPCs.,,,,,,,,,,,,, In this study, we retrospectively analyzed our results with respect to the management of patients with MHPCs operated at our institute with the aim to understand the impact of various factors (patient age, microsurgical resection, histopathological grade, and adjuvant therapy) on patient outcome.
We retrospectively reviewed the patients who underwent microsurgical resection for intracranial hemangiopericytomas at our institute from 2009 to 2015. In all patients, immunohistochemical analysis was performed for making a diagnosis of hemangiopericytomas. A total of 60 patients were operated from 2009 to 2015 of which complete clinical and radiological follow-up was available for 39 patients and these patients were included in the study. The patients operated during this period included patients undergoing surgery for the first time as well as those who had been previously operated at our institute and underwent repeat surgery for recurrence during the study period. In these cases, the clinical course starting from first surgery was taken into consideration for the analysis.
The in-patient and out-patient records and operation notes were analyzed to gather the data. The following parameters including demographic characteristics of patients, clinical presentation, radiological characteristics of tumors, intraoperative details including total blood loss, grade of tumor on histopathological examination, extent of resection on follow-up imaging, details of adjuvant therapy received, duration of recurrence-free period and overall survival (OS) were taken into consideration while analyzing the results. All the patients included in the study had at least 3 years postsurgical follow-up. Follow-up was out-patient department (OPD)-based and the first postoperative magnetic resonance imaging (MRI) was done usually at 3 months and thereafter at 6 month/1 year intervals depending on patient follow-up visits in OPD. In patients who did not develop recurrence and were alive at last follow-up, their last follow-up period was taken into consideration for calculating the recurrence-free period and OS.
Definition of extent of resection
The extent of resection was defined based on the first postoperative contrast-enhanced MRI usually done at 3 months after surgery. Patients with no contrast-enhancing lesion on first postoperative scan were considered to have undergone gross total excision (GTE). Presence of a contrast-enhancing residual mass qualified as subtotal excision (STE).
Definition of OS and recurrence-free survival (RFS)
OS was defined as the time interval between surgery and death, or the duration till last follow-up was available, if the patient was living. RFS was defined as the time interval between surgery and either the appearance of new lesions or the increase in size of the residual tumor on follow-up imaging in patients who did not undergo GTE.
All patients were advised adjuvant radiotherapy (RT) after surgery irrespective of the extent of tumor resection. Follow-up MRI was done initially at 3 months after surgery and thereafter in 6 month intervals.
A Chi-square test was used to compare the categorical variables. The independent sample Student's t-test or Mann–Whitney U-test were used for continuous variables. The Kaplan–Meier method was used to perform univariate survival analysis to evaluate the prognostic significance of various factors and treatment modalities. The log-rank test was used to determine significance, with the P value considered significant at the 5% (P < 0.05) level.
Patient and tumor characteristics
A total of 39 patients with a histopathologically proven diagnosis of MHPC and with available follow-up were included in the study. There were 30 males and 9 females with M: F ratio of 3.3:1. However, the overall M: F ratio among the 60 patients operated during this period was 1.6:1 (M = 37; F = 23). The mean age of patients was 40.6 years with a range of 18–71 years. The most common presenting symptom was headache that was present in most cases. Other symptoms included hearing loss, visual diminution, and ataxia [Table 1]. The most common location of tumor in our study was parasagittal with others being temporal, occipital, cerebellopontine angle, and tentorial [Table 2].
Management strategy [Table 3]
All patients underwent microsurgical excision of the tumor. A total of 27 patients (69.2%) underwent GTE [Figure 1] and the rest 12 underwent STE (30.8%) [Figure 2]. Average blood loss was around 2650 mL. In two patients, surgery had to be stopped because of massive blood loss (>5000 mL) and these were staged. One of these patients underwent embolization followed by re-exploration and the other patient underwent second surgery after hemodynamic stabilization. There was one peri-operative death due to massive intraoperative blood loss.
All patients were advised adjuvant RT for any grade of tumor and for any extent of excision. A total of 25 patients received RT. The patients received either conventional RT or Gamma Knife therapy (GKT) (Model B Leksell Gamma Knife (Elekta, Inc.). The conventional RT was given with a mean dose of 50 Gy (range 45–54 Gy) in 1.8–2.0 Gy fractions.
The average OS was 77.2 months with a range of 36–192 months. GTE was achieved in 27 (69.2%) patients while 12 (30.8%) patients underwent STE. A total of 21 patients had a low-grade hemangiopericytoma and 18 had the anaplastic variant. A total of 20 patients (51.3%) developed recurrences. The average RFS period was 56 months (range: 12–180 months) and the overall recurrence-free rates at 1, 3, 5, and 10 years were 92.3, 79.4, 66.7, and 51.3% [Figure 3]a, respectively. Eight patients (20.5%) included in the study died during the study period. The OS rates at 1, 3, 5, and 10 years were 100, 89.7, 82, and 79.5%, respectively [Figure 3]b. Two patients (5.1%) developed systemic metastases during follow-up. In the GTE group, 16 patients (59.25%) had grade II tumors and 18 patients (66.67%) received adjuvant RT. In the STE group, five patients (41.67%) had grade II tumors and seven patients (58.33%) received adjuvant RT.
Among the 20 patients who developed recurrences, nine had not received adjuvant radiation therapy after first surgery, while the rest 11 had received adjuvant therapy (GKT-8; RT-3). Five of these patients died because of massive recurrences before receiving any further treatment. Thirteen patients underwent repeat surgery. One patient died due to massive blood loss during surgery. Seven of these patients had not received adjuvant therapy after first surgery and were this time given adjuvant therapy (RT-5; GKT-2). Two patients had received GKT previously and after second surgery, one was given repeat GKT and the other was given conventional RT. Two patients had received conventional RT previously and this time, one of them was given GKT and the other received repeat conventional RT (previous RT was given 8 years previously) after second surgery. One of the patients undergoing repeat surgery did not receive any adjuvant therapy. Two patients refused repeat surgery. They had not received adjuvant therapy after initial surgery and thus were given conventional RT. Two patients died 2 and 5 years, respectively, after second surgery. Of the 20 patients, 12 are still living and under follow-up.
Factors affecting the incidence of recurrence, RFS, and OS
A total of 20 patients developed recurrences and eight patients died during the course of the study. Patient age, extent of excision, histopathological grade of tumor, and adjuvant therapy were the factors that were considered in the analysis.
Age of patients
For the purpose of analysis, patients were divided into two age groups: age >40 years and age ≤40 years. No difference in RFS or OS was found in these two age groups [Figure 4]a and [Figure 4]b.
Extent of excision
Patients undergoing GTE were less likely to develop recurrences (12/27; 44.44%) as compared to those with STE (8/12; 66.67%). The mean RFS of patients undergoing GTE was 58.68 months, while it was 50.04 months for STE group; however, this difference was not statistically significant (P-value = 0.160). Similarly, there was no statistically significant difference in OS of GTE and STE group (P-value = 0.414) [Figure 4]c and [Figure 4]d.
Nine patients (42.8%) with grade II tumors and 11 patients (61.11%) with grade III developed recurrences. The mean RFS and OS of patients with grade II tumors were 65.76 and 89.16 months, while that of patients with grade III were 44.64 and 63.36 months, respectively. The difference in RFS (21.12 months) as well as OS (25.8 months) between the two groups was statistically significant (P-values = 0.049 and 0.013, respectively) [Figure 5]a and [Figure 5]b.
A total of 25 patients received adjuvant therapy (RT or GKT). Among 25 patients, 15 patients received conventional RT while 10 patients received GKT. In the adjuvant therapy group (n = 25), 11 recurrences (44%) were observed, while patients who did not receive any adjuvant therapy (n = 14) had nine recurrences (64.3%). The mean RFS and OS in the adjuvant therapy group and no adjuvant therapy group were 65.28 and 78.72 months and 39.48 and 74.52 months, respectively. Between these two groups, the difference in RFS was statistically significant (P-value = 0.016) but adjuvant therapy was not associated with statistically significant OS benefits (P-value = 0.758) [Figure 5]c and [Figure 5]d.
Summarizing the results of our study, the age of the patients did not have any effect on RFS/OS; extent of excision did prolong the RFS/OS but the difference was not statistically significant; low tumor grade was associated with statistically significant prolongation of RFS as well as OS, and adjuvant therapy leads to prolongation of both RFS and OS but statistical significance was achieved only for RFS.
Hemangiopericytomas are rare but aggressive mesenchymal tumors. The intracranial MHPCs constitute <1% of all primary intracranial tumors and 2–4% of tumors arise from meninges., The role of various factors in determining the prognosis in patients with MHPCs has not been clearly elucidated in the literature.
Unlike meningiomas, the MHPCs are usually considered to affect the males more commonly than females. A review of major recent studies on MHPCs revealed that in the majority of these studies, either males and females were equally affected or males outnumbered females,,,,,,,,,, though some studies reported them to be more frequent among females.,, In the present study also the males were more affected than females (M: F; 3.3:1).
In the present study, the average age of patients at presentation was 40.6 years. In the literature too, the most common age of presentation for MHPCs is in the fourth and fifth decade of life.,,,,,,,,, The MHPCs more commonly involve the supratentorial compartment as compared with the infratentorial compartment. In our study group, 69% patients had supratentorial location of tumors, which is similar to what was reported in the literatures.,,,,,,,,,
We were able to achieve GTE in 69% of patients. Various authors have reported a gross total resection (GTR) rate ranging from 38.4 to 88.9%,,,,,,,,,, and the most common factor considered as responsible for incomplete excision is close proximity to or involvement of venous sinuses. In our study also, the most common reason (in 75% cases of STE) for incomplete excision was involvement of sinuses.
The recurrence rate for MHPCs reported in the literature ranges from 29.1 to 71.7%.,,,,,,,,, In our study, the recurrence rate was 51.3%, which is similar to that reported by many authors.,,, Similarly, the average RFS for MHPCs reported by various authors in different studies ranges from 53 to 113 months.,,,,, In our study also, the RFS was 56.2 months.
Impact of extent of excision on tumor recurrence and OS [Table 4] and [Table 5]
There have been inconsistent observations made in different studies with respect to the impact of extent of excision on RFS and OS. Some studies have reported statistically significant differences in RFS,,,,, and OS,,, in patients undergoing complete excision, while others have reported that the extent of excision does not have a statistically significant impact on RFS,,, and OS.,,,, Although the impact of extent of resection might not have reached a statistical significance in all the studies, most of these studies suggest that GTE leads to longer RFS and/or OS.
In the study by Soyuer et al., the authors found the difference in the 5-year recurrence-free rates between GTR group (84%) and subtotal resection (STR) group (38%) to be statistically significant. However, they did not find the extent of excision to impact the OS. Schiariti et al. found a statistically significant difference in RFS between patients undergoing complete versus incomplete excision (117 versus 54 months). They also reported a longer OS in the complete excision group (235 months) than in the incomplete excision group (175 months), though this difference was not statistically significant. Chen et al. and Zhu et al. also found the extent of excision to be a statistically significant predictor of both RFS as well as OS. Rutkowski et al., on the contrary, did not find any difference in time to recurrence between the GTR and STR group; however, they found a statistically significant longer OS of patients undergoing GTR than those undergoing STE.
In our study also, patients undergoing GTE were found to have longer RFS and OS as compared with the STE group; however, the difference did not reach statistical significance.
Impact of tumor grade on tumor recurrence and OS [Table 4] and [Table 5]
Most of the authors studying the effect of tumor grade on outcome have reported longer RFS and/or OS among patients with low-grade tumors.,,, In some of these studies this difference in RFS, and OS,, was statistically significant, while in others the difference in RFS,, and OS, was not statistically significant. Zhang et al. in the largest series of MHPCs till date (n = 120), included only patients with WHO grade II tumors. In their series, the recurrence rate and mortality are lowest among the various major series reported in the recent literature. In addition, the RFS is longest in their series [Table 4]. Though it cannot be concluded that the better outcome in their series is the result of favorable tumor grade, it does point toward the role of lower tumor grade in better patient outcome. Another study by Damodaran et al. analyzed the outcome of the patients with respect to the histopathological grade. They found that a low tumor grade was associated with statistically significant longer OS, while the tumor grade did not affect the recurrences.
In the present study, the rate of recurrence was lower in patients with grade II tumors and the mean RFS was longer among patients with grade II tumors. This was statistically significant (P-value = 0.049). Similarly, the OS of patients with grade II tumors was longer (P-value = 0.013).
Impact of adjuvant therapy on tumor recurrence and OS [Table 4] and [Table 5]
A review of various studies in literature reveals different opinions of various authors with respect to the impact of adjuvant RT on RFS and OS.,,,,,,, There are studies that report no significant impact of RT on RFS,, and OS.,,,,, On the contrary, there are studies which concluded that RT confers longer RFS,,,, and longer OS.,
Rutkowsky et al. found the adjuvant RT to be associated with longer RFS but this finding did not reach statistical significance and they did not find any positive relation between RT and OS. Similarly, Ecker et al. also could not find any significant difference in time to recurrence or OS with adjuvant RT. Bassiouni et al. concluded that adjuvant RT conferred no additional advantage following GTE; however, they recommended adjuvant RT following STE. Ghia et al. reported the local RFS to be longer in patients receiving adjuvant RT as compared to those who did not receive RT (143 versus 72 months; P value = 0.008). However, they could not find any correlation between RT and OS. Zhu et al. found that the adjuvant radiation improved RFS in patients without p53 expression in tumor cells but failed to show any impact of radiation on OS.
In our study, the addition of adjuvant RT resulted in a decreased recurrence rate (44%), compared to those who did not receive adjuvant therapy (64.3%). Among the patients who developed recurrences, the RFS was significantly longer in adjuvant treatment group (difference: 25.8 months; P value = 0.016). The OS, however, was only slightly longer in adjuvant therapy group and the difference was also not statistically significant.
MHPCs are rare tumors of central nervous system. Though radiologically similar to meningiomas, their behavior is much more aggressive with a greater tendency for local recurrence as well as systemic metastases. The literature is divided on the effects of different variables including extent of excision, tumor grade, and adjuvant RT on RFS and OS. Our study suggests that extent of excision, low grade of tumor, and addition of adjuvant RT have a positive impact on both RFS as well as OS; however, low-grade histopathology and adjuvant RT were the only factors associated with statistically significant prolongation of RFS and only tumor grade was associated with statistically significant OS benefits.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]