Why do hemangiopericytomas have such high recurrence rates?

KEYWORDS:

• Hemangiopericytoma
• recurrence
• surgical resection
• radiation therapy
• stereotactic radiosurgery
• angiogenesis
• Eph receptor family

Hemangiopericytomas are rare intracranial tumors that are thought to arise from pericytes, support cells found in the wall of meningeal capillaries [1]. They are part of a spectrum of mesenchymal tumors that also include solitary fibrous tumors, which can arise in virtually any part of the body. They tend to occur in middle-aged patients with a slight male predominance [2]. Histologically, they can be classified as low-grade (grade 2) and high-grade (grade 3) tumors. However, even lower grade tumors often behave aggressively, with high rates or local recurrence even after seemingly gross-total surgical resection. They can also present with metastatic extracranial dissemination, with reported rates up to 64% at 15 years after diagnosis [2]. They usually grow as extra-axial tumors and present with focal neurological symptoms related to adjacent brain compression or increased intracranial pressure. On diagnostic imaging, they are often indistinguishable from meningiomas, which are much more frequent. However, the presence of extensive edema, important vascularization, and irregular or lobulated borders should arise suspicion of the diagnosis of hemangiopericytoma [3].

In view of the aggressive behavior of this tumor, the optimal management of hemangiopericytomas remains maximal surgical resection. Local tumor control and patient survival are clearly improved when gross-total resection is performed compared to subtotal resection. A recent systematic review reported a mean survival of 158 months when complete resection was performed and 111 months in cases of subtotal resection [4]. The use of radiation therapy after resection seems to be associated with reduced tumor recurrence and improved survival [5]. In their study, Ghia et al. found that patients undergoing adjuvant radiation therapy after subtotal resection had overall survival comparable to patient undergoing gross-total resection alone [5]. Rutkowski et al. found that the use of any form of adjuvant radiation after surgery, whatever fractionation scheme used, improved the time to recurrence significantly (from 3.9 to 6.6 years), independent of the extent of tumor resection [6]. They even reported a trend toward improvement of time to recurrence in patients undergoing subtotal resection and radiation compared to complete resection. Lee et al. also reported a benefit in patients receiving postoperative radiation, independent of resection, with increases in local control time of 14 months and overall survival of 13 months compared to patients who did not have radiation [7]. Tumor grade also obviously has a major prognostic role. Grade 2 tumors have been found to be associated with longer recurrence-free interval and improved survival [8]. For recurrent tumors, repeat surgery can be of value when safely feasible [9]. Stereotactic radiosurgery also represents a safe and effective alternative for small to moderate volume recurrent tumors or when there is a contraindication to open surgery [10,11]. Due to the scarcity of the literature on this subject, the role of standard cytotoxic chemotherapy remains unclear in the management of intracranial hemangiopericytomas. One study reported the use of sequential multiple drug regimen in 15 patients with recurrent hemangiopericytomas who had prior surgery and radiation [12]. The first line consisted in cyclophosphamide, doxorubicine, and vincristine (CAV). Alpha-interferon and then ifosfamide, cisplatin, and etoposide (ICE) were used in case of subsequent recurrence. A few temporary responses and stabilizations were observed with CAV and interferon, and the overall survival was 14 months after treatment initiation.

Despite all these therapeutic options, hemangiopericytomas still frequently recur. What are the reasons behind this phenomenon, especially when compared to the more benign behavior of meningiomas? Since the risk of recurrence is strongly correlated with the extent of tumor resection, it is worth noting that the complete resection of a hemangiopericytoma can be a significant neurosurgical challenge. These tumors are usually hypervascular, prone to extensive bleeding, and tend to have indistinct margins with the surrounding brain. In addition, they are often in close proximity to major venous sinuses and prone to bony invasion. For all those reasons, it is often impossible to do a complete resection. However, limited tumor resection is certainly not the only reason for the increased risk of recurrence. In a recent series, 57% of patients who had gross-total resection eventually had tumor recurrence [6]. In comparison, complete resection of meningiomas is associated with a risk of recurrence of only 5% [13]. Obviously, there must be intrinsic factors related to tumor biology that are implicated in this difference. Unfortunately, because of the rarity of this tumor, literature focusing on biology and pathophysiology of hemangiopericytomas remains limited.

A recently published article, however, might explain one of the key features leading their increased risk of recurrence and metastasis [14]. In view of the hypervascular nature of hemangiopericytomas, the investigators have performed pathologic studies of multiple known angiogenic pathways on resected tumor specimens. They were able to demonstrate upregulation of several key signaling pathway markers, including VEGF-VEGFR2, EphrinB2-EphB4, and DLL4-Notch. Interestingly, these findings were not different between grade 2 and grade 3 tumors. Since angiogenesis is one of the key features leading to tumor invasion and metastasis, these pathways can be used as potential therapeutic targets. Bevacizumab, a monoclonal antibody against VEGFR that is commonly used for the treatment of colorectal cancer and recurrent glioblastoma, has been reported to have activity against recurrent meningeal and systemic hemangiopericytomas when given in combination with temozolomide [15]. Besides its role in angiogenesis, the Eph receptor family has been known to independently affect tumor cell proliferation, invasiveness, and metastasis. The demonstration of upregulation of this pathway thus makes it another interesting potential target against hemangiopericytoma. Tyrosine kinase inhibitors targeting either EphA2 or EphB4 are actively being developed and tested in clinical trials against different solid tumors [16]. In the preliminary experience reported so far, the toxicity profile seems favorable. Other avenues used against the Eph pathway include liposomes delivering siRNA, Eph extracellular domains fused to albumin, humanized antibodies targeting Eph receptors, and peptide vaccines [16]. Even though published results are still limited, these approaches certainly represent a promising future strategy to treat recurrent hemangiopericytomas.

In conclusion, neurosurgeons should remain suspicious of the possibility of a hemangiopericytoma whenever they encounter a meningeal-based tumor with unusual features on imaging, including hypervascularity. Performing gross-total resection significantly improves recurrence-free survival for affected patients. Adjuvant radiation therapy and radiosurgery can be of value in cases of incomplete resection. Targeted therapy against specific angiogenic pathways seems to represent the most promising research area for future studies against recurrent and metastatic hemangiopericytomas.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

This paper was not funded.