Treatment strategy of intracranial hemangiopericytoma : Clinical efficacy of Surgical grading system Department of Neurosurgery The Catholic University of Korea Jae Hyun Park, Young Il Kim, Sin Soo Jeun

Intracranial Hemangiopericytoma (HPC) Introduction Intracranial Hemangiopericytoma (HPC) Rare mesenchymal tumor (1st decribed in 1942) 2.5% of all meningeal tumors <1% of all primary CNS tumors Extent of surgical resection & Postoperative radiotherapy ▶ Overall survival ▲ & Recurrence free survival ▲ Complete resection ? Grossly total resection ? In most reported cases, HPC is attached to the venous sinuses or major vessels ▶Actually impossible to completely remove the tumor Hemangiopericytoma is a rare mesenchymal tumor which was first described in 1942. It accounts for 2.5% of all meningeal tumors and less than 1% of all primary CNS tumors. Recent studies insist that the extent of surgical resection and postoperative radiotherapy correlate with improved overall survival and recurrence-free survival. But the definitions of complete resection or grossly total resection in previous studies are equivocal. In most reported cases, since HPC is attached to the venous sinuses or major vessels, so it is actually impossible to literally completely remove the tumor. Assuming that these ambiguous classifications on the extent of resection might have had a measurement bias, we reviewed our cases of HPCs focusing on the clinical efficacy of surgical resection graded by Simpson grading system (which is largely used in meningioma removal). The disease features, treatment strategies, and clinical courses of relevant cases from our experience were also analyzed.

Retrospective analysis Material & Method Retrospective analysis Duration : Jan,1995 ~ Dec, 2014 (20-year period) Total case : 17 cases Clinical presentation Radiological appearance Results of treatment Follow-up outcomes We retrospectively reviewed the patients with HPC treated in our institute from January 1995 to December 2014 (the 20-year period). The total number of patients was 17. The medical records of the 17 patients were reviewed and analyzed. Clinical presentations, radiologic finding, pathology, the extent of resection, radiation, follow-up outcomes. Operative records, including notes and video, were reviewed to determine gross tumor extension to adjacent vessels and completeness of resection.

Simpson grading system Complete resection or Grossly total resection Material & Method Simpson grading system Grade Degree of removal I Macroscopically complete removal with excision of dural attachment and abnormal bone (including sinus resection when involved) II Macroscopically complete with endothermy coagulation of dural attachment III Macroscopically complete without resection or coagulation of dural attachment or of its extradural extensions IV Partial removal leaving tumor in situ V Simple decompression (±Biopsy) Complete resection or Grossly total resection Assuming that these ambiguous classifications on the extent of resection might have had a measurement bias, we reviewed our cases of HPCs focusing on the clinical efficacy of surgical resection graded by Simpson grading system (which is largely used in meningioma removal). The disease features, treatment strategies, and clinical courses of relevant cases from our experience were also an The extent of resection was divided into three categories (gross total resection, partial resection, biopsy); it was also divided into five categories by Simpson grading system. alyzed.

Patient Characteristics Results Patient Characteristics Case No. Sex Age Tumor location Adjacent vessels Tumor size (mm) Extent of resection Simpson grade Mitosis (/10HPF) Ki-67 (%) Pathology (WHO grade) Radiotherapy (cGy) KPS score (PreOp/Final) Overall survival (month) Recurrence Metastasis 1 M 29 Sphenoid wing YES 50 PR 4 N/A II 6000 20/0 13 3 None 2 41 Parasagittal 40 GTR 17 5580 20/20 197 104 20 30 III 51 22 12 9 54 11 85 10 2700 (CK) 20/30 5 58 Convexity NO 60 3.6 60/60 138 52 Tentorial Biopsy 90/90 171 90/100 36 27 25 1500 (CK) 63 33 24 26 73 15 5400 80/80 21 6 59 5949 80/90 53 7 72 56 40/40 61 40/0 8 5940 Falx 80/30 19 35 55 38 32 F 42 45 5500 90/80 CPA 5000 118 14 37 70/80 16 48 23 28 80/100

Patient Characteristics Results Patient Characteristics Age : 26 ~ 73 (mean : 48) M : F = 14 : 3 Initial symptom : Headache (m/c : 67%) Tumor location : Parasagittal (8, 47.1%), Tentorial (3, 17.6%), Falx (2, 11.8%), Convexity (2, 11.8%), Sphenoid wing (1, 5.9%), CPA (1, 5.9%) Operation : 26 (including reOp for recurrences) No operative mortality The mean age at the time of the initial diagnosis was 48 years, with the range from 26 to 73 years. The patient group included 14 (82.4%) males and 3 (17.6%) females. The most common presenting symptom was headache, followed by vomiting, visual field defects, and seizures. The preferential area of tumor origin was parasagittal (8 patients, 47.1%), which is adjoined to superior sagittal sinus. Distributions of the remaining tumor locations were as follows: tentorial (3 patients, 17.6%), falx (2 patients, 11.8%), convexity (2 patients, 11.8%), cerebellopontine angle (1 patient, 5.9%), and sphenoid wing (1 patient, 5.9%). A total number of 26 operations were performed for the resection of either primary or recurrent intracranial HPCs.

Adjoin adjacent vessels Results Adjoin adjacent vessels No adjacent vessels To evaluate the correlation between location and the extent of resection, these locations were grouped into 2 categories (Table 2): those that adjoin adjacent vessels such as superior sagittal sinus, transverse sinus (Figure 1), or sigmoid sinus, and those that have no adjacent major vessels (Figure 2). The results of Fisher’s exact test suggest, that the extent of resection was statistically significantly associated neither with the location of tumor, nor with the existence of adjacent vessels (p=0.35 and 0.60, respectively). Extent of resection & Location of tumor (p=0.35) Extent of resection & Existence of adjacent vessels (p=0.60)

Histopathological results All specimens obtained in each surgery including recurrence were reviewed WHO grade II : 11 (42.3%) WHO grade III : 15 (57.7%) Progression (WHO GII ▶ GIII) : 2 patients (11.8%) Ki-67 proliferative index : 1~40% (Mean : 14%) ▶ WHO GII : 4.8% / WHO GIII 21.2% The clinical outcomes were evaluated according to the Karnofsky performance scale (KPS). The mean KPS at final outcome was 65 (initial mean KPS was 65.8). The mean follow-up period was 55 months, with the range from 10 to 197 months.

Treatment modalities Both at convexity Results Treatment modalities Surgery & Adjuvant radiotherapy No perioperative mortalities / No unexpected events during surgery GTR ▶11 (64.7%) : Simpson G1 - 2 (11.8%) / G2 – 7 (41.2%) / G3 – 2 (11.8%) PR (Simpson G4) ▶ 4 (23.5%) Biopsy (Simpson G5) ▶ 2 (11.8%) PostOp RTx : 16 (94.1%) (Dose : 5000~6000cGy, mean 5757cGy) CK radiosurgery : 2 patients for recurred HPC (1500cGy, 2700cGy) Both at convexity Treatment modalities consisted of surgery and adjuvant radiotherapy. All patients were initially treated with surgery and there were no perioperative mortalities and no unexpected events during the operations. At the initial operation, a grossly total resection (GTR) was accomplished in 11 patients (64.7%), a partial resection (PR) in 4 patients (23.5%), and an endoscopic biopsy in 2 patients (11.8%). In Simpson grading system (Table 1), GTR was divided into 3 grades, grades 1 to 3. PR was the same as Simpson grade 4 and biopsy was same as Simpson grade 5. Dividing GTR group into Simpson grading system, grade 1 was done in 2 patients (11.8%), grade 2 in 7 patients (41.2%), and grade 3 in 2 patients (11.8%). In most cases, because of the location of tumor adjoined to the venous sinus, surgical resection was possible only by Simpson grade 2 or 3. Venous sinus was preserved in all patients. The location of tumor in 2 patients who underwent surgical resection by Simpson grade 1 was both at convexity. Postoperative radiotherapy (RT) was delivered in 16 patients (94.1%), regardless of the extent of resection. One patient (Case Number 9 in Table 2) rejected active treatment after initial surgery. The mean total dose of radiotherapy was 5757cGy, with the range from 5000 to 6000cGy. 2 patients (11.8%) underwent stereotactic radiosurgery using cyberknife for the treatment of recurred HPC (total dose of 1500cGy and 2700cGy each).

Karnofsky performance scale (KPS) Results Clinical outcomes Karnofsky performance scale (KPS) Final mean KPS : 65 / Initial mean KPS : 65.8 Follow up : 10~197 months (mean : 55) Distant metastases : None The clinical outcomes were evaluated according to the Karnofsky performance scale (KPS). The mean KPS at final outcome was 65 (initial mean KPS was 65.8). The mean follow-up period was 55 months, with the range from 10 to 197 months. 2 of the 17 patients died during the follow-up period. Clinical follow-up and additional image studies, such as PET-CT scans, did not suggest distant metastases.

Results Local recurrence : 5 (29.4%) Median RFS : 51 months Overall survival (Month) Survival Probability Local recurrence : 5 (29.4%) Median RFS : 51 months Recurrence-free survival (Month) Survival Probability The mean overall survival (OS) was 13 months with median OS not reached. 5 patients (29.4%) developed local recurrence and the median recurrence-free survival (RFS) was 51 month. Median OS : not reached Mean OS : 13 months

Extent of resection Results GTR PR Biopsy Recurrence-free survival (Month) Survival Probability Biopsy PR GTR The mean time for local recurrence of patient who underwent GTR was 68.3 months, PR was 37.1 months, and biopsy was 3.5 months, which was statistically significant (p=0.003 by log-rank test) P=0.003

Simpson grade Results Grade 1 Grade 3 Grade 2 Grade 4 Grade 5 Recurrence-free survival (Month) Survival Probability Grade 5 Grade 2 Grade 1 Grade 3 Grade 4 Additionally, Simpson grading system for surgical resection of intracranial HPC was significantly associated with higher RFS (p=0.011 by log-rank test) P=0.011

Radiotherapy Results Adjuvant radiotherapy Survival Probability None Recurrence-free survival (Month) Survival Probability None Adjuvant radiotherapy Regarding adjuvant RT, the mean time for local recurrence was 80.5 months in patients who received RT against 19.5 months in those who did not Although the mean time values for local recurrence were 66.2 months and 38.1 months in the patients with WHO grade II HPC and WHO grade III HPC, respectively, the pathological diagnosis for WHO grades II and III was not statistically significantly associated with the time for local recurrence (p=0.49 by log-rank test). P=0.0003

WHO grade II WHO grade III Results Pathology WHO grade II : 66.2month WHO grade III : 38.1month Mean time value for local recurrence Although the mean time values for local recurrence were 66.2 months and 38.1 months in the patients with WHO grade II HPC and WHO grade III HPC, respectively, the pathological diagnosis for WHO grades II and III was not statistically significantly associated with the time for local recurrence (p=0.49 by log-rank test). However, possibly due to the small number of the investigated cases, this difference did not reach statistical significance. P=0.49

Adjuvant radiation ? Extent of resection ? Simpson grading system ? Discussion Extent of resection ? Simpson grading system ? Statistically significant correlation between each grade & RFS ▶ Seems to be safer to remove the tumor as much as possible Adjuvant radiation ? Completely removed tumor ? Grade II HPC ? As suggested by Bassiouni et al., the classification introduced by Simpson in 1957 to describe the resection rate in meningiomas can also be usefully applied in intracranial HPCs, since, in most cases, these tumors are dura-based. We divided GTR into 3 Simpson grades, grades 1 to 3. The results of the statistical analysis of the correlation between the extent of resection and recurrence suggest statistical significance like other several studies. Conventional classification of dividing into GTR, PR and biopsy showed that each class of resection is significantly associated with RFS; Simpson grading system showed statistically significant correlations between each grade and RFS as well. To prevent local recurrence, it seems to be safer to remove the tumor as much as possible, even when the remaining tumor is adjoined to the adjacent structures, such as the dural sinus. In many series, intracranial HPCs have been shown to recur even after complete GTR. Thus, several authors have recommended adjuvant RT for a better outcome. Similarly to other series, our experience shows that the patients who received adjuvant RT tend to have longer RFS . We performed adjuvant RT regardless of the extent of resection and pathologic grade in most of the patients. 16 out of 17 patients (94.1%) received adjuvant RT to the mean dose of 5757cGy; no significant radiation-related complications were observed. Regardless of the extent of resection and pathologic grade

Complete tumor resection Conclusion Complete tumor resection Adjuvant RTx Long term follow up Attempt to reach Simpson grade 1 removal Surgical resection of intracranial HPC, in an attempt to reach Simpson grade 1 removal of the tumor, is necessary in the initial surgery. This attempt to reach Simpson grade 1 removal should be performed within the safe limit. Additionally, adjuvant RT should be done to prevent recurrence, even in the patients who have tumor completely resected and who have been diagnosed as WHO grade II HPC.