Hemangiopericytoma: Radical Resection Remains the Cornerstone of Therapy ⇑ Rohan Ramakrishna, Robert Rostomily, Laligam Sekhar, Jason Rockhill, Manuel Ferreira

Journal of Clinical Neuroscience 21 (2014) 612–615

Contents lists available at ScienceDirect

Journal of Clinical Neuroscience

journal homepage: www.elsevier.com/locate/jocn

Clinical Study Hemangiopericytoma: Radical resection remains the cornerstone of therapy ⇑ Rohan Ramakrishna, Robert Rostomily, Laligam Sekhar, Jason Rockhill, Manuel Ferreira

Department of Neurological Surgery, University of Washington, Seattle, WA, USA article info abstract

Article history: Hemangiopericytomas (HPC) are mesenchymal tumors with a propensity towards chronicity and metas- Received 13 August 2013 tasis. This study aimed to reflect a single institution experience with both World Health Organization Accepted 19 August 2013 (WHO) grade II and III HPC. Pathology records from the years 1990–2013 at the University of Washington were searched to identify tumors unequivocally classified as HPC. Electronic chart review was then uti- lized to collect pertinent patient data. Of the WHO grade II HPC, there were four men and two women Keywords: (average age 52 years) while the grade III HPC group had eight men and two women (average age Brain tumor 51 years). Sixty-six percent of WHO grade II tumors were located in the middle or posterior fossa as com- Hemangiopericytoma pared to none of the grade III tumors. Survival analysis revealed a significant survival benefit for patients Solitary fibrous tumor who underwent complete resection (223 months) versus those with subtotal resection (138 months, p < 0.05). Factors such as age, sex, the use of up-front radiation, and whether the patient had a recurrence did not show statistical significance related to overall survival or progression free survival. Radiation in the form of external beam radiotherapy given at the time of the first recurrence did trend towards improved progression free survival (56 months) compared to those patients who were not radiated (22 months, p = 0.09) All patients with radical resection went on to never have a recurrence. Our results indicate that HPC are tumors with limited response to radiation and best treated with aggressive resection. Future studies will determine whether molecular-based therapies may provide added adjuvant benefit. Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction patients with gross total resection, the decision to radiate is criti- cally important given that many patients are relatively young at Hemangiopericytomas (HPC) are rare tumors, thought to com- the time of diagnosis. The purpose of this study was to evaluate prise 2–3% of all primary meningeal tumors and 1% of all intracra- the efficacy of gross total resection with radiation in a single insti- nial tumors [1–5]. Histologically, HPC is believed to arise from tution series of 16 patients with a mean follow-up of 91 months. Zimmerman pericytes, which are contractile spindle cells sur- rounding capillaries in any part of the human body [1,2,6]. These tumors were previously thought to be angioblastic variants of 2. Methods meningioma; however in 1993 the World Health Organization (WHO) recognized these tumors as distinct clinicopathological The study involved 16 patients with primary HPC of the central entities on the basis of their histologic characteristics and their nervous system who were treated at the University of Washington tendency to recur and metastasize extraneurally [1,7–13]. Aca- between 1990 and 2013. Patients were identified from histopathol- demic progress on these entities has been halting, mainly because ogical records. Medical records were analyzed retrospectively to of their rarity and potential chronicity [1–12,14–40]. collect demographic, treatment, and outcome data. Recent literature has advocated gross total resection with or The extent of tumor resection was established from operative without postoperative external beam radiotherapy (EBRT) on the notes and imaging review. Extent of tumor resection was defined basis of one large series [1] and another meta-analysis [2]. As long using a modified Simpson grade with grade 1 delineating radical term survival is quite possible with these tumors, particularly in tumor resection with dural margins and bony drilling while grade 2 conferred subtotal resection status. Pathology reports were re- viewed to confirm diagnosis and determine if the tumor was low ⇑ Corresponding author. Tel.: +1 206 543 0492. or high grade on the basis of WHO criteria. With regards to E-mail address: [email protected] (M. Ferreira). radiation, modality (such as EBRT or Gamma Knife [Elekta AB,

Stockholm, Sweden]) was recorded along with treatment dose. No Table 1 patients received chemotherapy. Factors affecting mortality in patients with hemangiopericytoma Mortality p value 2.1. Follow-up data HPC grade Low 0% 0.15 High 40% ± 16% Recurrence was defined as local tumor growth as identified on Surgical excision Grade 1 10% ± 9% 0.04 serial imaging. Local recurrences were treated with revision sur- Grade 2 50% ± 22% gery followed by radiation when radical excision was not possible. Up-front radiation None 22% ± 14% 0.39 Adjuvant radiation was performed if significant tumor bulk re- EBRT 29% ± 18% mained after the first operation. The modified Rankin scale (mRS) Multiple radiation Yes 16% ± 15% 0.29 was used to assess quality of life at last follow-up. No 30% ± 15% Age < 40 years Yes 25% ± 24% 0.50 2.2. Statistical analysis No 25% ± 13% Recurrence Yes 14% ± 13% 0.20 Clinical data related to survival analysis was analyzed using the No 33% ± 16% Statistical Package for the Social Sciences (SPSS, Chicago, IL, USA) BBRT = external beam radiotherapy, HPC = hemangiopericytoma. using the Kaplan–Meier method [41]. Univariate comparison of Data are presented as mean ± standard error of the mean. parameters was performed using log-rank analysis. Multivariate analyses were not performed given the small sample size of the Table 2 study population thus precluding meaningful results. Factors affecting hemangiopericytoma tumor recurrence Progression p value 3. Results HPC grade Low 16% ± 17% 0.10 High 50% ± 16% Sixteen patients underwent microsurgical resection for HPC be- Surgical excision Grade 1 30% ± 15% 0.22 tween 1990 and 2013. The minimum number of operations was Grade 2 50% ± 22% one and maximum nine. There were three women (25%) and 13 Up-front radiation Yes 29% ± 0.18% 0.71 men (75%) with a mean age at diagnosis of 51 years (range 24– No 44% ± 17% 74 years). The mean follow-up was 91 months (range 0.16– Age < 40 years Yes 75% ± 25% 0.04 246 months). No patient was lost to follow-up. The mortality rate No 25% ± 13% was 25%. The 5 year survivor rate was 70%. Only one patient devel- HPC = hemangiopericytoma. oped extraneural metastases. The mRS score at last follow-up indi- Data are presented as mean ± standard error of the mean. cated a score of 0 (indicating independent symptom free life) for nine patients, a score of 6 (indicating death) for four patients, and a score of 3 (indicating mild disability but independent) for one patient. Twenty-seven percent of patients received up-front radiation mostly with EBRT (only one patient received up-front stereotactic radiosurgery).

3.1. Recurrence rate

Six patients (37.5%) developed local recurrence at an average of 59 months (range 9–117 months). Four patients suffered from a minimum of four recurrences and a maximum of nine. The average follow-up for those with recurrences was 164 months. Only one patient with recurrences died.

3.2. Factors affecting prognosis and recurrence

Univariate statistics were used to evaluate demographic and treatment data including extent of resection, up-front radiation, the use of multiple radiation treatments, age less than 40, sex, and the presence of recurrence with regards to mortality and tumor recurrence (Table 1, 2). Mortality was observed to be increased in tumors exhibiting high grade (40%) features compared Fig. 1. Kaplan–Meier survival curve showing radical resection imparts significantly to lower grade tumors, but not significantly so (0%, p = 0.15). Addi- increased survival (median 6708 days) compared to subtotal resection (median tionally, radical resection imparted a significant survival benefit 4147 days, p = 0.04). Notably, there were six high grade tumors in the total resection group thus suggesting extent of resection affects overall survival with a mortality of 10% in completely resected tumors and 50% independent of tumor grade. Cum = cumulative. in subtotally resected tumors (p = 0.04, Fig. 1). Age, sex, and the use of radiation either up-front or repeated as salvage therapy 4. Discussion did not impart a survival benefit (Fig. 2, 3). With regards to progression, none of the studied factors seemed HPC are rare and potentially aggressive lesions. Recent case ser- to significantly affect whether or not a tumor recurred. Notably, of ies and meta-analyses have revived the debate regarding the role of the three tumors that recurred in the subtotally resected group, all radiation in the treatment of these lesions [1,2]. We present a series three were completely removed at the time of recurrence with no of 16 patients with central nervous system HPC treated at a single further recurrence following the second operation. center. The most notable findings included the lack of effect of 614 R. Ramakrishna et al. / Journal of Clinical Neuroscience 21 (2014) 612–615

Extent of resection has increasingly been shown to correlate with improved long term and recurrence free survival. In clinical series ranging in samples sizes from 17 to 40, overall survival ran- ged from 59 to 232 months (mean of 57 months in current study among those who died) [1,3,4,25–27,37,38,40]. In these same studies, one-third to one-half of patients underwent EBRT and 50–75% of patients underwent gross total resection (43% and 63%, respec- tively, in the current series). Moreover a recent meta-analysis demonstrated a 10 year survival rate of 69% in those patients undergoing gross total resection compared to 44% in those who underwent subtotal resection [2]. Our study further validates the claim that these lesions should be treated by physicians who can safely achieve radical resection; this is of special import given the propensity of these lesions to involve difficult-to-access loca- tions in the skull base and/or along venous sinuses. With regards to radiation, our study does not support the use of radiation as an adjunct to gross total resection. Certainly, a recent meta-analysis of over 250 patients demonstrated that gross total resection is significantly better than subtotal resection, even when subtotal resection is paired with adjuvant radiation therapy [2]. Moreover, the addition of adjuvant radiotherapy to gross total Fig. 2. Kaplan–Meier survival curve showing up-front radiation does not signifi- resection did not improve overall survival. On the other hand, cantly affect time to recurrence. Cum = cumulative, ttprogress = time to the radiation literature regarding fractionated radiotherapy has progression. sometimes shown benefit in preventing tumor progression [3–5,11,15,36] but meta-analyses indicate very little gain from radiation and perhaps even harm in doses over 50 Gy [2].In addition, studies from the stereotactic radiosurgery literature report local control rates of approximately 50% (rates range from 50–80% in the literature [7,20,21,23–25,30]) in residual or recurrent tumors though the 5 year progression free survival was only 28.7% (improved in lower grade patients and those who received a higher marginal dose >14 Gy) [33,34]. In our series, we also examined whether EBRT given at the time of first recurrence improved progression free survival which did reveal a trend towards improvement in the radiated group (Fig. 2). Therefore, the use of radiation with regards to these lesions should be carefully examined with respect to each individual patient. The low frequency of HPC makes its study particularly challenging. Given the small size of even the largest case series, conclusions that can be drawn regarding prognostication and factors affecting treatment outcome are limited. Increasingly, however, it has be- come most apparent that radical resection offers the best chance of long term tumor control, regardless of tumor grade. Given that the a priori diagnosis of HPC is often not possible, central nervous system lesions that may be HPC should be resected as radically as possible, including dural margins, bony resection, and even resection of venous sinus disease if feasible. Fig. 3. Kaplan–Meier survival curve showing external beam radiotherapy given at Because of the rarity of HPC and potential long term chronicity time of first recurrence displays a trend towards improving progression free survival (p = 0.09). Cum = cumulative, ttprog2 = time to progression after first with radical treatment, no single institution is likely to have a large recurrence. enough series to answer all the relevant questions about the behavior and treatment response of HPC. Future studies should radiation on overall survival or time to progression. Greater extent therefore be directed at studying the basic biology of these tumors, of resection in the first operation imparted significantly increased in an effort to determine molecular characteristics and potential survival regardless of tumor grade. Notably, in those tumors that avenues of drug therapy for sensitive tumors. For example, given did recur, those with complete resection went on to never have a the well-known vascularity of these tumors, it is possible that recurrence at latest follow-up. Additionally, patients with multiple anti-angiogenic agents such as bevacizumab may be useful (this recurrent tumors fared best with repeat surgery (up to nine times in has been attempted in combination with temozolomide in a small our series) rather than adjuvant and salvage radiotherapy. Finally, series of patients with metastatic HPC with marginal results [35]). outcome data revealed nearly all patients living independent lives Certainly salvage chemotherapeutic approaches, where published, apart from the minority that died (70% 5 year survival with mode have shown only marginal efficacy thus requiring more robust mRS of 0). As such, aggressive surgical resection appears to be the clinical and basic research to find better salvage treatment options definitive treatment to effect long term survival. Furthermore, [29]. Recent reports identifying the NAB2-STAT6 fusion protein in repeat surgical resection can relegate the disease to a chronic both central nervous system HPC and solitary fibrous tumor (of illness. Finally, it appears that radiation offers limited benefit to pa- which HPC is thought to be a closely related variant), identifiable tients who suffer with HPC either at presentation or at time of by STAT6 immunostaining are encouraging directions in this line recurrence(s). of work [42,43]. R. Ramakrishna et al. / Journal of Clinical Neuroscience 21 (2014) 612–615 615

5. Study limitations [15] Pitkethly DT, Hardman JM, Kempe LG, et al. Angioblastic meningiomas; clinicopathologic study of 81 cases. J Neurosurg 1970;32:539–44. [16] Goellner JR, Laws Jr ER, Soule EH. Hemangiopericytoma of the meninges. Mayo Obvious concerns arise when performing retrospective analyses Clinic experience. Am J Clin Pathol 1978;70:375–80. of small clinical populations, particularly when analyses require [17] Kabus D, Sidhu GS, Wieczorek RL, et al. Metastatic meningioma. separation of the entire cohort into smaller groups for the purposes Hemangiopericytoma or angioblastic meningioma? Am J Surg Pathol 1993;17:1144–50. of univariate analyses. As such, our study has purposefully [18] Chiechi MV, Smirniotopoulos JG, Mena H. Intracranial hemangiopericytomas: restricted the number of study variables to analyze and avoided MR and CT features. AJNR Am J Neuroradiol 1996;17:1365–71. multivariate analysis altogether. As such, the small sample size re- [19] Brunori A, Delitala A, Oddi G, et al. Recent experience in the management of meningeal hemangiopericytomas. Tumori 1997;83:856–61. stricts the ability to make concrete inferences. Nevertheless, given [20] Galanis E, Buckner JC, Scheithauer BW, et al. Management of recurrent the rarity of this tumor, and the significance of including radiation meningeal hemangiopericytoma. Cancer 1998;82:1915–20. within the treatment armamentarium, this study corroborates [21] Payne BR, Prasad D, Steiner M, et al. Gamma surgery for hemangiopericytomas. Acta Neurochir (Wien) 2000;142:527–36 [discussion other studies suggesting the lack of benefit with regards to 536–7]. radiation. [22] Alen JF, Lobato RD, Gomez PA, et al. Intracranial hemangiopericytoma: study of 12 cases. Acta Neurochir (Wien) 2001;143:575–86. [23] Sheehan J, Kondziolka D, Flickinger J, et al. Radiosurgery for treatment of 6. Conclusions recurrent intracranial hemangiopericytomas. Neurosurgery 2002;51:905–10 [discussion 910–1]. HPC continues to reflect a challenging clinicopathological entity [24] Chang SD, Sakamoto GT. The role of radiosurgery for hemangiopericytomas. Neurosurg Focus 2003;14:e14. whose optimal treatment remains to be defined. Certainly, gross [25] Ecker RD, Marsh WR, Pollock BE, et al. Hemangiopericytoma in the central total resection provides the most robust predictor of long term out- nervous system: treatment, pathological features, and long-term follow up in come but given the frequent challenge of achieving this surgical 38 patients. J Neurosurg 2003;98:1182–7. [26] Kim JH, Jung HW, Kim YS, et al. Meningeal hemangiopericytomas: long-term goal, other treatment modalities need to be refined. Recent studies outcome and biological behavior. Surg Neurol 2003;59:47–53 [discussion 44– that molecularly relate central nervous system HPC with solitary 53]. fibrous tumor may open new doors of treatment from solitary fi- [27] Soyuer S, Chang EL, Selek U, et al. Intracranial meningeal hemangiopericytoma: the role of radiotherapy: report of 29 cases and brous tumor oncology experience. It is these types of studies review of the literature. Cancer 2004;100:1491–7. exploring the molecular nature of these tumors that will ultimately [28] Fountas KN, Kapsalaki E, Kassam M, et al. Management of intracranial lead to durable non-surgically based adjuvant treatments. meningeal hemangiopericytomas: outcome and experience. Neurosurg Rev 2006;29:145–53. [29] Chamberlain MC, Glantz MJ. Sequential salvage chemotherapy for recurrent Conflicts of interest/disclosure intracranial hemangiopericytoma. Neurosurgery 2008;63:720–6 [author reply 726–7]. [30] Kano H, Niranjan A, Kondziolka D, et al. Adjuvant stereotactic radiosurgery The authors declare that they have no financial or other con- after resection of intracranial hemangiopericytomas. Int J Radiat Oncol Biol flicts of interest in relation to this research and its publication. Phys 2008;72:1333–9. [31] Bonde VR, Goel A. Two patients with intracavernous haemangiopericytoma. J Clin Neurosci 2009;16:330–3. References [32] Park WH, Jang IS, Kim CJ, et al. Gamma knife radiosurgery after stereotactic aspiration for large cystic brain metastases. J Korean Neurosurg Soc [1] Schiariti M, Goetz P, El-Maghraby H, et al. Hemangiopericytoma: long-term 2009;46:360–4. outcome revisited. Clinical article. J Neurosurg 2011;114:747–55. [33] Kim JW, Kim DG, Chung HT, et al. Gamma Knife stereotactic radiosurgery for [2] Rutkowski MJ, Sughrue ME, Kane AJ, et al. Predictors of mortality following intracranial hemangiopericytomas. J Neurooncol 2010;99:115–22. treatment of intracranial hemangiopericytoma. J Neurosurg 2010;113:333–9. [34] Olson C, Yen CP, Schlesinger D, et al. Radiosurgery for intracranial [3] Dufour H, Metellus P, Fuentes S, et al. Meningeal hemangiopericytoma: a hemangiopericytomas: outcomes after initial and repeat Gamma Knife retrospective study of 21 patients with special review of postoperative surgery. J Neurosurg 2010;112:133–9. external radiotherapy. Neurosurgery 2001;48:756–62 [discussion 762–3]. [35] Park MS, Patel SR, Ludwig JA, et al. Activity of temozolomide and bevacizumab [4] Guthrie BL, Ebersold MJ, Scheithauer BW, et al. Meningeal in the treatment of locally advanced, recurrent, and metastatic hemangiopericytoma: histopathological features, treatment, and long-term hemangiopericytoma and malignant solitary fibrous tumor. Cancer follow-up of 44 cases. Neurosurgery 1989;25:514–22. 2011;117:4939–47. [5] Jaaskelainen J, Servo A, Haltia M, et al. Intracranial hemangiopericytoma: [36] Rutkowski MJ, Bloch O, Jian BJ, et al. Management of recurrent intracranial radiology, surgery, radiotherapy, and outcome in 21 patients. Surg Neurol hemangiopericytoma. J Clin Neurosci 2011;18:1500–4. 1985;23:227–36. [37] Zweckberger K, Jung CS, Mueller W, et al. Hemangiopericytomas grade II are [6] Stout AP, Murray MR. Hemangiopericytoma: a vascular tumor featuring not benign tumors. Acta Neurochir (Wien) 2011;153:385–94. Zimmermann’s pericytes. Ann Surg 1942;116:26–33. [38] Demicco EG, Park MS, Araujo DM, et al. Solitary fibrous tumor: a [7] Coffey RJ, Cascino TL, Shaw EG. Radiosurgical treatment of recurrent clinicopathological study of 110 cases and proposed risk assessment model. hemangiopericytomas of the meninges: preliminary results. J Neurosurg Mod Pathol 2012;25:1298–306. 1993;78:903–8. [39] Kumar N, Kumar R, Kapoor R, et al. Intracranial meningeal [8] Dardick I, Hammar SP, Scheithauer BW. Ultrastructural spectrum of hemangiopericytoma: 10 years experience of a tertiary care Institute. Acta hemangiopericytoma: a comparative study of fetal, adult, and neoplastic Neurochir (Wien) 2012;154:1647–51. pericytes. Ultrastruct Pathol 1989;13:111–54. [40] Rutkowski MJ, Jian BJ, Bloch O, et al. Intracranial hemangiopericytoma: clinical [9] Henn W, Wullich B, Thonnes M, et al. Recurrent t(12;19)(q13;q13.3) in experience and treatment considerations in a modern series of 40 adult intracranial and extracranial hemangiopericytoma. Cancer Genet Cytogenet patients. Cancer 2012;118:1628–36. 1993;71:151–4. [41] Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J [10] Joseph JT, Lisle DK, Jacoby LB, et al. NF2 gene analysis distinguishes Am Stat Assoc 1958;53:457–81. hemangiopericytoma from meningioma. Am J Pathol 1995;147:1450–5. [42] Schweizer L, Koelsche C, Sahm F, et al. Meningeal hemangiopericytoma and [11] Mena H, Ribas JL, Pezeshkpour GH, et al. Hemangiopericytoma of the central solitary fibrous tumors carry the NAB2-STAT6 fusion and can be diagnosed by nervous system: a review of 94 cases. Hum Pathol 1991;22:84–91. nuclear expression of STAT6 protein. Acta Neuropathol 2013;125:651–8. [12] Ramsey HJ. Fine structure of hemangiopericytoma and hemangio- [43] Chmielecki J, Crago AM, Rosenberg M, et al. Whole-exome sequencing endothelioma. Cancer 1966;19:2005–18. identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nat [13] Bailey P, Cushing H, Eisenhardt L. Angioblastic meningioma. Arch Pathol Lab Genet 2013;45:131–2. Med 1928;6:953–90. [14] Begg CF, Garret R. Hemangiopericytoma occurring in the meninges: case report. Cancer 1954;7:602–6.