Accepted Manuscript Flow-related aneurysm within glioblastoma: A case report and review of literature Chibawanye I. Ene, MD PhD, John D. Nerva, MD, Lynn McGrath, MD, Margaret E. Flanagan, MBChB, Marc C. Chamberlain, MD, Daniel L. Silbergeld, MD PII:
S1878-8750(16)00156-X
DOI:
10.1016/j.wneu.2016.01.068
Reference:
WNEU 3672
To appear in:
World Neurosurgery
Received Date: 18 November 2015 Revised Date:
12 January 2016
Accepted Date: 13 January 2016
Please cite this article as: Ene CI, Nerva JD, McGrath L, Flanagan ME, Chamberlain MC, Silbergeld DL, Flow-related aneurysm within glioblastoma: A case report and review of literature, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.01.068. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Flow-related aneurysm within glioblastoma: A case report and review of literature
Chibawanye I. Ene MD PhD1*, John D. Nerva MD1, Lynn McGrath MD1, Margaret E.
1
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Flanagan MBChB2, Marc C. Chamberlain MD3, Daniel L. Silbergeld MD1
Department of Neurological Surgery, University of Washington, Seattle WA Department of Pathology, University of Washington, Seattle WA
3
Department of Neurology, University of Washington, Seattle WA
*Corresponding Author: Chibawanye I. Ene University of Washington
1959 NE Pacific Street Campus Box 356470
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Seattle. WA 98195
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Department of Neurological Surgery
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2
Phone: (206) 543-3570
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E-mail: [email protected]
Reprint requests can be made to the corresponding author
Keywords: Angiography, aneurysm, embolization, glioblastoma, glioma, Abbreviations: Anterior cerebral artery (ACA), Glioblastoma multiforme (GBM), subarachnoid hemorrhage (SAH), Temozolomide (TMZ)
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Abstract Background Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults with
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a median survival of 13 months despite surgery and chemo-radiation. GBMs are often hypervascular tumors due to abnormal over-secretion of growth factors such as vascular endothelial growth factor (VEGF). These angiogenic factors are hypothesized to promote
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increased blood flow and possibly secondary changes to arterial walls thus facilitating the formation of flow related aneurysms.
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Case Description
A 59-year old female presented with headaches, confusion, nausea and emesis. CT and MRI scans revealed a hypervascular lesion, likely high-grade glioma, in the right frontal lobe, with a dilated vessel within the tumor. Cerebral angiography demonstrated a flow-
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related aneurysm on the right frontopolar artery supplying the tumor. The aneurysm was embolized with coils and she later underwent craniotomy for near total resection of the lesion without complication. Final pathology returned glioblastoma multiforme (GBM)
Conclusions
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with dilated vessels noted.
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Hypervascular lesions, such as GBMs, may be associated with flow-related aneurysms on feeding arteries, but aneurysms within the gross tumor are quite unusual. While rare, this finding needs to be recognized on pre-operative imaging prior to tumor resection to prevent potentially catastrophic intra-operative complications.
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Highlights GBMs are highly vascular lesions
•
GBMs are associated with flow related aneurysm
•
Pre-operative embolization, if safely performed, prevents intra-operative
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•
catastrophe
SC
Introduction
Glioblastoma multiforme (GBM) is the most common primary brain tumor in
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adults with a median survival of 13 months despite surgery and chemo-radiation(12). The extent of resection has been shown to correlate with overall survival, therefore, maximum surgical resection while minimizing the risk of postoperative neurological deficits is typically the goal of surgery(16). GBMs are often hypervascular tumors due to
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abnormal over-secretion of growth factors such as vascular endothelial growth factor (VEGF)(2, 19). These angiogenic factors are hypothesized to promote increased blood flow and possibly secondary changes to arterial walls thus facilitating the formation of
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flow related aneurysms(1). Although rare, these aneurysms need to be recognized in preoperative scans to prevent catastrophic complications such as intra-operative rupture (7,
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20).
Here, we describe a case of a patient presenting with an intra-tumoral flow-related
aneurysm.
Case Report History and Examination
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The patient was a 59 year-old right-handed female with a history of stage IIB breast cancer status-post lumpectomy and radiation therapy who presented with headaches, nausea, emesis and confusion. Upon examination, the patient had no pronator
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drift, weakness or sensory deficits.
Initial Imaging
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An MRI brain was obtained on admission (Fig. 1A). T2-weighted MRI demonstrated a hypervascular lesion with a dilated vessel within the tumor (Fig. 1B;
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arrow). For a more detailed evaluation of this anomalous tumor vasculature, a cerebral angiogram was obtained, which demonstrated arterial supply from the medial and lateral lenticulostriate arteries and the A2 segment of the ACA. The dilated vessel seen on the MRI corresponded to a flow-related aneurysm of the right frontopolar artery, located
Treatment
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within the tumor blush (Fig. 2A-B).
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She underwent coil-embolization of the flow-related aneurysm. A right internal carotid artery run demonstrated tumor blush corresponding to the intra-axial lesion seen
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on prior MRI. Feeder branches were noted from the lenticulostriate arteries from M1 and A1 segments as well as branches from the A2 segment of the anterior cerebral artery. The aneurysm was visualized within the tumor blush and fed by a branch of the frontopolar artery (Fig 2A-B). There was also evidence of early venous filling near the aneurysm suggesting AV shunting (Fig. 2A). Embolization was performed using coils with a small area of active extravasation noted from the area of the proximal coils.
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Heparin was revered with protamine and a repeat angiography showed no further extravasation and no filling of the aneurysm (Fig. 2C-D). The following day, we performed an MRI guided stereotactic biopsy of the lesion, which returned as a
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glioblastoma multiforme (GBM). Ten days later, she underwent a craniotomy for near total resection (NTR) of the tumor using MRI-guided navigation. Following a right frontal craniotomy, dura was opened in a stellate fashion. Ultrasound and MRI guided
SC
navigation were used to delineate the borders of the tumor. A circular corticectomy was performed over the tumor. The resection began along the superior frontal gyrus using a
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sub-pial technique with an ultrasonic aspirator and bipolar cautery. As expected, the tumor was vascular with arterial supply from both the anterior cranial fossa dura as well as perforators from the anterior cerebral arteries. The tumor was then debulked in a subpial fashion using a combination of the ultrasonic aspirator and bipolar cautery until the
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arterial aneurysm that had been previously coiled was encountered and removed. Further tumor resection in the sub-pial plane was performed until a small remnant of tumor encasing the anterior perforating arteries was encountered. At this point, we had achieved
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Pathology
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a near total resection with an estimated blood loss of 350ml.
The initial biopsy contained portions of a diffusely infiltrative astrocytic neoplasm
(Fig. 3A) in a fibrillary background composed of cells with indistinct cytoplasmic borders and irregular, variably enlarged hyperchromatic nuclei with course chromatin. The neoplastic cells showed variable but strong immunoreactivity for glial fibrillary acidic protein. Scattered gemistocytic forms were noted and microvascular proliferation
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was focally identified (Fig. 3B). Although geographic necrosis was seen, it was not used to upgrade the neoplasm as the tumor underwent pre-operative embolization. No pseudopallisading necrosis was seen.
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Mitotic activity was increased up to four mitotic figures per ten high power fields (Fig. 3C). The Ki-67 proliferative index via visual quantification was 3%. The neoplastic cells were negative for isocitrate dehydrogenase 1 (R132H) and demonstrated increased
SC
p53 expression by immunohistochemistry (not shown). Methylation of the MGMT (0(6)methylguanine-DNA methyltransferase) gene was detected using methylation specific
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PCR technologies. Ultimately, this specimen warranted a designation of glioblastoma, WHO grade IV, based on the presence of microvascular proliferation. No definitive aneurysm was seen were in the specimen designated “aneurysm” but a large dilated blood vessel and several other smaller blood vessels were present (Fig.
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3D). A Verhoeff-Van Gieson elastin (Fig. 3F-E) stain was performed on multiple levels on the aneurysm specimen but showed no disruption of the elastin layer.
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Post-operative course and Follow-up
Post-operatively, she was continued on Dexamethasone and phenytoin. A post-
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operative head CT showed no acute hemorrhage following resection. A post-operative MRI brain showed evidence of areas of nodular enhancement in the inferior-medial margin of the resection cavity, consistent with residual tumor. Clinically, she had no deficits and she was discharged home on post-operative day 3. Following discharge, she underwent involved field radiotherapy to a total dose of 60Gy given in 30 fractions in conjunction with daily Temozolomide (TMZ) at 75mg/m2
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daily (140 mg daily for 42 days). She was continued on post-radiation TMZ. Upon follow-up visitation 6 months post-operation, apart from a mildly ataxic gait, she remained in good condition with a KPS 70 (pre-op KPS 80). Surveillance imaging
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showed no disease progression.
Discussion
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Tumor-associated aneurysms have been linked to pituitary adenomas, gliomas, lipomas, and metastatic tumors(3, 6, 13, 14, 18, 23). A recent literature review on GBMs
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and aneurysms showed 19 case reports in existence for patients with both entities (Table 1. Adapted from Ali et al (1). 43% of aneurysms were unrelated to the tumor, 16% of the aneurysms were pseudoaneurysms or dissecting aneurysms, and 8% were flow-related aneurysms. 80% of patients presented with symptoms relating to the tumor while 8%
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presented with subarachnoid hemorrhage. Most tumors were located in the frontal lobe (39.1%) and temporal lobe (26%).
The precise pathophysiology of flow-related aneurysms in GBM is not well
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understood, but arterio-venous (AV) shunting, as seen in our case, is thought to contribute to disease progression. Yoshikawa et. al.(23) demonstrated that AV shunting
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was visualized in 72% of patients with peri-sylvian GBMs. Angiograms of these tumors show a characteristic capillary blush with early venous drainage suggestive of AV shunting. Intra-operatively, the presence of arterialized veins within GBMs also supports the theory that AV shunting may contribute to the development of flow related aneurysms within GBMs(11). To assess for intra-tumoral AV shunting within tumors, Mariani et. al.(11) utilized cerebral and pulmonary scintigraphy following intra-
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arterial/intra-tumoral injection of radiolabeled macro-aggregated albumin (MAA) in 7 patients with malignant gliomas (6 with GBM). They found that most micro-particles injected into the tumor via the arterial route bypassed the tumor and reached the lungs.
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The measured AV shunting was greater when the injection was performed in an artery exclusively perfusing the tumor. These results validate the existence of AV shunting within gliomas.
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Another theory postulated to contribute to aneurysm formation within tumors is the gradual development of friable neoplastic vasculature resulting in spontaneous
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subarachnoid hemorrhage (SAH)(10). Hashguchi et. al.(4) reported a patient with recurrent glioblastoma found to have gradual enlargement of a feeding arterial vessel that led to the development of an intra-tumoral aneurysm and aneurysmal hemorrhage. In one report, SAH was attributed to the GBM(9). Here, a cerebral angiogram was negative for a
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source of SAH and an MRI showed the lesion in left uncus. The authors argued that for angiogram-negative SAH, an MRI should be performed to exclude other etiologies such as tumors.
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In terms of management, several studies demonstrated good outcomes in cases where intracranial aneurysms and brain tumors were simultaneously treated(5, 8, 17, 21,
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22). In one case, where the aneurysm was discovered within a pituitary adenoma, complete endovascular obliteration of the aneurysm with coils was performed prior to the trans-sphenoidal resection of the tumor(15). In our case, the aneurysm was located on a major arterial branch of the anterior circulation that could be accessed safely for embolization. Therefore, embolization of the aneurysm was performed to minimize control intra-operative blood loss and allow for safer resection.
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In conclusion, flow related aneurysms associated with hypervascular lesions such as GBMs represent a challenge to tumor surgeons. They are a potential source of intraoperative complication if not recognized on routine pre-operative imaging and managed
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appropriately(20). In our case, given the location of the aneurysm, endovascular coiling was successfully performed prior to near total resection of the tumor with no intraoperative complications.
5 6 7
8
9
10
11
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Ali R, Pabaney A, Robin A, Marin H, Rosenblum M. Glioblastoma and intracranial aneurysms: Case report and review of literature. Surgical neurology international 2015;6:66. Charalambous C, Hofman FM, Chen TC. Functional and phenotypic differences between glioblastoma multiforme-derived and normal human brain endothelial cells. Journal of neurosurgery 2005;102(4):699-705. Fischer BR, Palkovic S, Holling M, Niederstadt T, Jeibmann A, Wassmann H. Coexistence of cerebral aneurysm and meningioma--pure accident? Clin Neurol Neurosurg 2009;111(8):647-54. Hashiguchi A, Morioka M, Ichimura H, Mimata C, Kuratsu J. Glioblastoma with an intratumoral feeding-artery aneurysm. Clin Neurol Neurosurg 2007;109(3):302-4. Heiskanen O, Poranen A. Surgery of incidental intracranial aneurysms. Surgical neurology 1987;28(6):432-6. Helmer FA. Oncotic aneurysm. Case report. Journal of neurosurgery 1976;45(1):98-100. Imamura J, Okuzono T, Okuzono Y. Fatal epistaxis caused by rupture of an intratumoral aneurysm enclosed by a large prolactinoma--case report. Neurologia medico-chirurgica 1998;38(10):654-6. Javalkar V, Guthikonda B, Vannemreddy P, Nanda A. Association of meningioma and intracranial aneurysm: report of five cases and review of literature. Neurology India 2009;57(6):772-6. Joki T, Ohashi S, Mori R, Sakai H, Fujigasaki J, Matsushima S, Abe T. [Intracranial malignant glioma presenting as subarachnoid hemorrhage]. No Shinkei Geka 2013;41(1):37-43. Liwnicz BH, Wu SZ, Tew JM, Jr. The relationship between the capillary structure and hemorrhage in gliomas. Journal of neurosurgery 1987;66(4):536-41. Mariani L, Schroth G, Wielepp JP, Haldemann A, Seiler RW. Intratumoral arteriovenous shunting in malignant gliomas. Neurosurgery 2001;48(2):3537; discussion 7-8.
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References
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18
19
20
21 22
23
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Mirimanoff RO, Gorlia T, Mason W, Van den Bent MJ, Kortmann RD, Fisher B, Reni M, Brandes AA, Curschmann J, Villa S, Cairncross G, Allgeier A, Lacombe D, Stupp R. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981NCIC CE3 phase III randomized trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2006;24(16):2563-9. Nguyen HS, Doan N, Gelsomino M, Shabani S, Mueller W, Zaidat OO. Coincidence of an anterior cerebral artery aneurysm and a glioblastoma: case report and review of literature. Int Med Case Rep J 2015;8:295-9. Oh MC, Kim EH, Kim SH. Coexistence of intracranial aneurysm in 800 patients with surgically confirmed pituitary adenoma. Journal of neurosurgery 2012;116(5):942-7. Sade B, Mohr G, Tampieri D, Rizzo A. Intrasellar aneurysm and a growth hormone-secreting pituitary macroadenoma. Case report. Journal of neurosurgery 2004;100(3):557-9. Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection threshold for newly diagnosed glioblastomas. Journal of neurosurgery 2011;115(1):3-8. Shigemori M, Tokunaga T, Miyagi J, Eguchi G, Kuramoto S, Irie K, Morimatsu M. Multiple brain tumors of different cell types with an unruptured cerebral aneurysm--case report. Neurologia medico-chirurgica 1991;31(2):96-9. Sommet J, Schiff M, Evrard P, Blanc R, Elmaleh-Berges M. Pericallosal lipoma and middle cerebral artery aneurysm: a coincidence? Pediatr Radiol 2010;40(8):1417-20. Sonoda Y, Kanamori M, Deen DF, Cheng SY, Berger MS, Pieper RO. Overexpression of vascular endothelial growth factor isoforms drives oxygenation and growth but not progression to glioblastoma multiforme in a human model of gliomagenesis. Cancer Res 2003;63(8):1962-8. Suzuki H, Muramatsu M, Murao K, Kawaguchi K, Shimizu T. Pituitary apoplexy caused by ruptured internal carotid artery aneurysm. Stroke 2001;32(2):567-9. Tancioni F, Egitto MG, Tartara F. Aneurysm occurring within a meningioma: case report. Br J Neurosurg 1998;12(6):588-91. Yasargil MG, Gasser JC, Hodosh RM, Rankin TV. Carotid-ophthalmic aneurysms: direct microsurgical approach. Surgical neurology 1977;8(3):155-65. Yoshikawa A, Nakada M, Kita D, Watanabe T, Kinoshita M, Miyashita K, Furuta T, Hamada JI, Uchiyama N, Hayashi Y. Visualization of angiographical arteriovenous shunting in perisylvian glioblastomas. Acta Neurochir (Wien) 2013;155(4):715-9.
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Legends
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Figure 1. A. MRI brain with contrast showing the lesion. B. Showing T2-weighted MRI and a dilated vessel within the tumor (white arrow). Figure 2. A-B. Digital subtracted angiography of the right internal carotid artery showing
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early venous drainage (AP view, white arrow) from the flow related aneurysm (lateral view, black arrow). C-D. Following embolization, the aneurysm is completely obliterated (AP (C) and Lateral views (D)).
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Figure 3. A-D. H&E showing tumor cell infiltration (A, 40x), micro-vascular proliferation (B, 40x, asterisk), mitotic activity (C, 100x) and dilated vessels (D, 40x). F-
(F 100x, E 400x, double asterisk).
Tables
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E. Verhoeff-Van Gieson elastin stain showing large and dilated vessels within the tumor
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Table 1. Literature review on previous 19 case reports on Glioblastoma multiforme and aneurysms(1). GBM Glioblastoma multiforme, SAH Subarachnoid hemorrhage, HA Headache, ICA Internal carotid artery, MCA Middle cerebral artery, AComm Anterior
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communicating artery ACA anterior cerebral artery, PComm Posterior communicating artery, PCA Posterior cerebral artery, HTN hypertension, STR Subtotal resection, GTR
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Gross total resection, M male, F Female.
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44, F
Intratumoral hemorrhage Left frontal
GBM
Cohen et al 2005
35, F
Right frontal
GBM
Cheng et al 2004
67, F
Left supraclinoid ICA
57, M
Left parietal Right frontotemporal Right temporooccipital
GBM
Aoki et al 1999
Cognitive changes Neurodeficit due to tumor Neurodeficit due to tumor Hemiparesis and hemianopsia
Left lenticulostraite Left pericallosal pseudoaneurysm
GBM
Right proximal MCA
Tumor resection with clip sacrifice of MCA Fair
GBM
Right Pcomm
Tumor resection, aneurysm not treated
Poor (Dead)
Right temporal
GBM
Right ICA
Fair
Left temporal
GBM
Left M2 MCA
Aneurysm clipped, tumor partially resected Tumor resected, aneurysm trapped and resected
Left frontal Left frontal Left temporal Left temporooccipital
GBM GBM GBM
Left MCA trifurcation Acomm Acomm
Tumor resected and aneurysm clipped Tumor resected and aneurysm clipped STR then clip
Good Poor (Dead) Good
GBM
Acomm
Pathology Aneurysm Location GBM Angio negative SAH GBM Right distal ACA
Treatment Biopsy STR then clip Observation
Outcome Unknown Good Poor (Vegetative)
GTR then coiling
Poor (Dead)
Clipping then tumor resection
Good
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Plannger et al 1987 69, M Dechiara et al 1986 52,F Andrews et al 1985 53, F
Tumor location Left uncus Right frontal
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Age/Sex Symptoms 31,M SAH 57, M HA, SAH
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Author and year Joki et al 2013 Yoon et al 2011 Hashiguchi et al 2007
Obrador et al 1972 54, M
Tumor symptoms
Evans et al 1972 55, M Kraus et al 1972 Krayenbuehl et al 1965 50 Taylor et al 1961 33, M
SAH Tumor symptoms
Right Parietal
GBM GBM
Right PCA MCA
STR then clip Good Tumor resection, spontaneous thrombosis of aneurysm Poor (Dead) Tumor resected and aneurysm clipped Good
Tumor symptoms Tumor symptoms
GBM GBM
Left ACA Right ACA
Tumor resection only Aneurysm clipped
Poor (Dead) Poor (Dead)
Heppner et al 1953 50, M Beller et al 1951 32, ?
Tumor symptoms Tumor symptoms Tumor symptoms Tumor symptoms Tumor symptoms
Left frontal Right frontal Right frontotemporal Right temporal Right frontal Left temporal Left Parietal
GBM GBM GBM GBM GBM
Right MCA Right ICA Right ICA Left ICA Left ICA
Aneurysm clipped Aneurysm clipped Tumor resected and aneurysm not treated
Poor (Dead) Unknown Unknown Poor (Dead) Good
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Paoletti et al 1983 59, M Golkalp et al 1980 50, M Honda et al 1980 59, F
SAH SAH, intratumoral hemorrhage Confusion, Intracranial HTN Visual disturbance Hemiparesis
Unknown
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S1878-8750(16)00156-X
DOI:
10.1016/j.wneu.2016.01.068
Reference:
WNEU 3672
To appear in:
World Neurosurgery
Received Date: 18 November 2015 Revised Date:
12 January 2016
Accepted Date: 13 January 2016
Please cite this article as: Ene CI, Nerva JD, McGrath L, Flanagan ME, Chamberlain MC, Silbergeld DL, Flow-related aneurysm within glioblastoma: A case report and review of literature, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.01.068. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Flow-related aneurysm within glioblastoma: A case report and review of literature
Chibawanye I. Ene MD PhD1*, John D. Nerva MD1, Lynn McGrath MD1, Margaret E.
1
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Flanagan MBChB2, Marc C. Chamberlain MD3, Daniel L. Silbergeld MD1
Department of Neurological Surgery, University of Washington, Seattle WA Department of Pathology, University of Washington, Seattle WA
3
Department of Neurology, University of Washington, Seattle WA
*Corresponding Author: Chibawanye I. Ene University of Washington
1959 NE Pacific Street Campus Box 356470
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Seattle. WA 98195
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Department of Neurological Surgery
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2
Phone: (206) 543-3570
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E-mail: [email protected]
Reprint requests can be made to the corresponding author
Keywords: Angiography, aneurysm, embolization, glioblastoma, glioma, Abbreviations: Anterior cerebral artery (ACA), Glioblastoma multiforme (GBM), subarachnoid hemorrhage (SAH), Temozolomide (TMZ)
ACCEPTED MANUSCRIPT
Abstract Background Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults with
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a median survival of 13 months despite surgery and chemo-radiation. GBMs are often hypervascular tumors due to abnormal over-secretion of growth factors such as vascular endothelial growth factor (VEGF). These angiogenic factors are hypothesized to promote
SC
increased blood flow and possibly secondary changes to arterial walls thus facilitating the formation of flow related aneurysms.
M AN U
Case Description
A 59-year old female presented with headaches, confusion, nausea and emesis. CT and MRI scans revealed a hypervascular lesion, likely high-grade glioma, in the right frontal lobe, with a dilated vessel within the tumor. Cerebral angiography demonstrated a flow-
TE D
related aneurysm on the right frontopolar artery supplying the tumor. The aneurysm was embolized with coils and she later underwent craniotomy for near total resection of the lesion without complication. Final pathology returned glioblastoma multiforme (GBM)
Conclusions
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with dilated vessels noted.
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Hypervascular lesions, such as GBMs, may be associated with flow-related aneurysms on feeding arteries, but aneurysms within the gross tumor are quite unusual. While rare, this finding needs to be recognized on pre-operative imaging prior to tumor resection to prevent potentially catastrophic intra-operative complications.
ACCEPTED MANUSCRIPT
Highlights GBMs are highly vascular lesions
•
GBMs are associated with flow related aneurysm
•
Pre-operative embolization, if safely performed, prevents intra-operative
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•
catastrophe
SC
Introduction
Glioblastoma multiforme (GBM) is the most common primary brain tumor in
M AN U
adults with a median survival of 13 months despite surgery and chemo-radiation(12). The extent of resection has been shown to correlate with overall survival, therefore, maximum surgical resection while minimizing the risk of postoperative neurological deficits is typically the goal of surgery(16). GBMs are often hypervascular tumors due to
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abnormal over-secretion of growth factors such as vascular endothelial growth factor (VEGF)(2, 19). These angiogenic factors are hypothesized to promote increased blood flow and possibly secondary changes to arterial walls thus facilitating the formation of
EP
flow related aneurysms(1). Although rare, these aneurysms need to be recognized in preoperative scans to prevent catastrophic complications such as intra-operative rupture (7,
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20).
Here, we describe a case of a patient presenting with an intra-tumoral flow-related
aneurysm.
Case Report History and Examination
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The patient was a 59 year-old right-handed female with a history of stage IIB breast cancer status-post lumpectomy and radiation therapy who presented with headaches, nausea, emesis and confusion. Upon examination, the patient had no pronator
RI PT
drift, weakness or sensory deficits.
Initial Imaging
SC
An MRI brain was obtained on admission (Fig. 1A). T2-weighted MRI demonstrated a hypervascular lesion with a dilated vessel within the tumor (Fig. 1B;
M AN U
arrow). For a more detailed evaluation of this anomalous tumor vasculature, a cerebral angiogram was obtained, which demonstrated arterial supply from the medial and lateral lenticulostriate arteries and the A2 segment of the ACA. The dilated vessel seen on the MRI corresponded to a flow-related aneurysm of the right frontopolar artery, located
Treatment
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within the tumor blush (Fig. 2A-B).
EP
She underwent coil-embolization of the flow-related aneurysm. A right internal carotid artery run demonstrated tumor blush corresponding to the intra-axial lesion seen
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on prior MRI. Feeder branches were noted from the lenticulostriate arteries from M1 and A1 segments as well as branches from the A2 segment of the anterior cerebral artery. The aneurysm was visualized within the tumor blush and fed by a branch of the frontopolar artery (Fig 2A-B). There was also evidence of early venous filling near the aneurysm suggesting AV shunting (Fig. 2A). Embolization was performed using coils with a small area of active extravasation noted from the area of the proximal coils.
ACCEPTED MANUSCRIPT
Heparin was revered with protamine and a repeat angiography showed no further extravasation and no filling of the aneurysm (Fig. 2C-D). The following day, we performed an MRI guided stereotactic biopsy of the lesion, which returned as a
RI PT
glioblastoma multiforme (GBM). Ten days later, she underwent a craniotomy for near total resection (NTR) of the tumor using MRI-guided navigation. Following a right frontal craniotomy, dura was opened in a stellate fashion. Ultrasound and MRI guided
SC
navigation were used to delineate the borders of the tumor. A circular corticectomy was performed over the tumor. The resection began along the superior frontal gyrus using a
M AN U
sub-pial technique with an ultrasonic aspirator and bipolar cautery. As expected, the tumor was vascular with arterial supply from both the anterior cranial fossa dura as well as perforators from the anterior cerebral arteries. The tumor was then debulked in a subpial fashion using a combination of the ultrasonic aspirator and bipolar cautery until the
TE D
arterial aneurysm that had been previously coiled was encountered and removed. Further tumor resection in the sub-pial plane was performed until a small remnant of tumor encasing the anterior perforating arteries was encountered. At this point, we had achieved
AC C
Pathology
EP
a near total resection with an estimated blood loss of 350ml.
The initial biopsy contained portions of a diffusely infiltrative astrocytic neoplasm
(Fig. 3A) in a fibrillary background composed of cells with indistinct cytoplasmic borders and irregular, variably enlarged hyperchromatic nuclei with course chromatin. The neoplastic cells showed variable but strong immunoreactivity for glial fibrillary acidic protein. Scattered gemistocytic forms were noted and microvascular proliferation
ACCEPTED MANUSCRIPT
was focally identified (Fig. 3B). Although geographic necrosis was seen, it was not used to upgrade the neoplasm as the tumor underwent pre-operative embolization. No pseudopallisading necrosis was seen.
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Mitotic activity was increased up to four mitotic figures per ten high power fields (Fig. 3C). The Ki-67 proliferative index via visual quantification was 3%. The neoplastic cells were negative for isocitrate dehydrogenase 1 (R132H) and demonstrated increased
SC
p53 expression by immunohistochemistry (not shown). Methylation of the MGMT (0(6)methylguanine-DNA methyltransferase) gene was detected using methylation specific
M AN U
PCR technologies. Ultimately, this specimen warranted a designation of glioblastoma, WHO grade IV, based on the presence of microvascular proliferation. No definitive aneurysm was seen were in the specimen designated “aneurysm” but a large dilated blood vessel and several other smaller blood vessels were present (Fig.
TE D
3D). A Verhoeff-Van Gieson elastin (Fig. 3F-E) stain was performed on multiple levels on the aneurysm specimen but showed no disruption of the elastin layer.
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Post-operative course and Follow-up
Post-operatively, she was continued on Dexamethasone and phenytoin. A post-
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operative head CT showed no acute hemorrhage following resection. A post-operative MRI brain showed evidence of areas of nodular enhancement in the inferior-medial margin of the resection cavity, consistent with residual tumor. Clinically, she had no deficits and she was discharged home on post-operative day 3. Following discharge, she underwent involved field radiotherapy to a total dose of 60Gy given in 30 fractions in conjunction with daily Temozolomide (TMZ) at 75mg/m2
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daily (140 mg daily for 42 days). She was continued on post-radiation TMZ. Upon follow-up visitation 6 months post-operation, apart from a mildly ataxic gait, she remained in good condition with a KPS 70 (pre-op KPS 80). Surveillance imaging
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showed no disease progression.
Discussion
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Tumor-associated aneurysms have been linked to pituitary adenomas, gliomas, lipomas, and metastatic tumors(3, 6, 13, 14, 18, 23). A recent literature review on GBMs
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and aneurysms showed 19 case reports in existence for patients with both entities (Table 1. Adapted from Ali et al (1). 43% of aneurysms were unrelated to the tumor, 16% of the aneurysms were pseudoaneurysms or dissecting aneurysms, and 8% were flow-related aneurysms. 80% of patients presented with symptoms relating to the tumor while 8%
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presented with subarachnoid hemorrhage. Most tumors were located in the frontal lobe (39.1%) and temporal lobe (26%).
The precise pathophysiology of flow-related aneurysms in GBM is not well
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understood, but arterio-venous (AV) shunting, as seen in our case, is thought to contribute to disease progression. Yoshikawa et. al.(23) demonstrated that AV shunting
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was visualized in 72% of patients with peri-sylvian GBMs. Angiograms of these tumors show a characteristic capillary blush with early venous drainage suggestive of AV shunting. Intra-operatively, the presence of arterialized veins within GBMs also supports the theory that AV shunting may contribute to the development of flow related aneurysms within GBMs(11). To assess for intra-tumoral AV shunting within tumors, Mariani et. al.(11) utilized cerebral and pulmonary scintigraphy following intra-
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arterial/intra-tumoral injection of radiolabeled macro-aggregated albumin (MAA) in 7 patients with malignant gliomas (6 with GBM). They found that most micro-particles injected into the tumor via the arterial route bypassed the tumor and reached the lungs.
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The measured AV shunting was greater when the injection was performed in an artery exclusively perfusing the tumor. These results validate the existence of AV shunting within gliomas.
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Another theory postulated to contribute to aneurysm formation within tumors is the gradual development of friable neoplastic vasculature resulting in spontaneous
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subarachnoid hemorrhage (SAH)(10). Hashguchi et. al.(4) reported a patient with recurrent glioblastoma found to have gradual enlargement of a feeding arterial vessel that led to the development of an intra-tumoral aneurysm and aneurysmal hemorrhage. In one report, SAH was attributed to the GBM(9). Here, a cerebral angiogram was negative for a
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source of SAH and an MRI showed the lesion in left uncus. The authors argued that for angiogram-negative SAH, an MRI should be performed to exclude other etiologies such as tumors.
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In terms of management, several studies demonstrated good outcomes in cases where intracranial aneurysms and brain tumors were simultaneously treated(5, 8, 17, 21,
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22). In one case, where the aneurysm was discovered within a pituitary adenoma, complete endovascular obliteration of the aneurysm with coils was performed prior to the trans-sphenoidal resection of the tumor(15). In our case, the aneurysm was located on a major arterial branch of the anterior circulation that could be accessed safely for embolization. Therefore, embolization of the aneurysm was performed to minimize control intra-operative blood loss and allow for safer resection.
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In conclusion, flow related aneurysms associated with hypervascular lesions such as GBMs represent a challenge to tumor surgeons. They are a potential source of intraoperative complication if not recognized on routine pre-operative imaging and managed
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appropriately(20). In our case, given the location of the aneurysm, endovascular coiling was successfully performed prior to near total resection of the tumor with no intraoperative complications.
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Ali R, Pabaney A, Robin A, Marin H, Rosenblum M. Glioblastoma and intracranial aneurysms: Case report and review of literature. Surgical neurology international 2015;6:66. Charalambous C, Hofman FM, Chen TC. Functional and phenotypic differences between glioblastoma multiforme-derived and normal human brain endothelial cells. Journal of neurosurgery 2005;102(4):699-705. Fischer BR, Palkovic S, Holling M, Niederstadt T, Jeibmann A, Wassmann H. Coexistence of cerebral aneurysm and meningioma--pure accident? Clin Neurol Neurosurg 2009;111(8):647-54. Hashiguchi A, Morioka M, Ichimura H, Mimata C, Kuratsu J. Glioblastoma with an intratumoral feeding-artery aneurysm. Clin Neurol Neurosurg 2007;109(3):302-4. Heiskanen O, Poranen A. Surgery of incidental intracranial aneurysms. Surgical neurology 1987;28(6):432-6. Helmer FA. Oncotic aneurysm. Case report. Journal of neurosurgery 1976;45(1):98-100. Imamura J, Okuzono T, Okuzono Y. Fatal epistaxis caused by rupture of an intratumoral aneurysm enclosed by a large prolactinoma--case report. Neurologia medico-chirurgica 1998;38(10):654-6. Javalkar V, Guthikonda B, Vannemreddy P, Nanda A. Association of meningioma and intracranial aneurysm: report of five cases and review of literature. Neurology India 2009;57(6):772-6. Joki T, Ohashi S, Mori R, Sakai H, Fujigasaki J, Matsushima S, Abe T. [Intracranial malignant glioma presenting as subarachnoid hemorrhage]. No Shinkei Geka 2013;41(1):37-43. Liwnicz BH, Wu SZ, Tew JM, Jr. The relationship between the capillary structure and hemorrhage in gliomas. Journal of neurosurgery 1987;66(4):536-41. Mariani L, Schroth G, Wielepp JP, Haldemann A, Seiler RW. Intratumoral arteriovenous shunting in malignant gliomas. Neurosurgery 2001;48(2):3537; discussion 7-8.
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References
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Mirimanoff RO, Gorlia T, Mason W, Van den Bent MJ, Kortmann RD, Fisher B, Reni M, Brandes AA, Curschmann J, Villa S, Cairncross G, Allgeier A, Lacombe D, Stupp R. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981NCIC CE3 phase III randomized trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2006;24(16):2563-9. Nguyen HS, Doan N, Gelsomino M, Shabani S, Mueller W, Zaidat OO. Coincidence of an anterior cerebral artery aneurysm and a glioblastoma: case report and review of literature. Int Med Case Rep J 2015;8:295-9. Oh MC, Kim EH, Kim SH. Coexistence of intracranial aneurysm in 800 patients with surgically confirmed pituitary adenoma. Journal of neurosurgery 2012;116(5):942-7. Sade B, Mohr G, Tampieri D, Rizzo A. Intrasellar aneurysm and a growth hormone-secreting pituitary macroadenoma. Case report. Journal of neurosurgery 2004;100(3):557-9. Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection threshold for newly diagnosed glioblastomas. Journal of neurosurgery 2011;115(1):3-8. Shigemori M, Tokunaga T, Miyagi J, Eguchi G, Kuramoto S, Irie K, Morimatsu M. Multiple brain tumors of different cell types with an unruptured cerebral aneurysm--case report. Neurologia medico-chirurgica 1991;31(2):96-9. Sommet J, Schiff M, Evrard P, Blanc R, Elmaleh-Berges M. Pericallosal lipoma and middle cerebral artery aneurysm: a coincidence? Pediatr Radiol 2010;40(8):1417-20. Sonoda Y, Kanamori M, Deen DF, Cheng SY, Berger MS, Pieper RO. Overexpression of vascular endothelial growth factor isoforms drives oxygenation and growth but not progression to glioblastoma multiforme in a human model of gliomagenesis. Cancer Res 2003;63(8):1962-8. Suzuki H, Muramatsu M, Murao K, Kawaguchi K, Shimizu T. Pituitary apoplexy caused by ruptured internal carotid artery aneurysm. Stroke 2001;32(2):567-9. Tancioni F, Egitto MG, Tartara F. Aneurysm occurring within a meningioma: case report. Br J Neurosurg 1998;12(6):588-91. Yasargil MG, Gasser JC, Hodosh RM, Rankin TV. Carotid-ophthalmic aneurysms: direct microsurgical approach. Surgical neurology 1977;8(3):155-65. Yoshikawa A, Nakada M, Kita D, Watanabe T, Kinoshita M, Miyashita K, Furuta T, Hamada JI, Uchiyama N, Hayashi Y. Visualization of angiographical arteriovenous shunting in perisylvian glioblastomas. Acta Neurochir (Wien) 2013;155(4):715-9.
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Legends
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Figure 1. A. MRI brain with contrast showing the lesion. B. Showing T2-weighted MRI and a dilated vessel within the tumor (white arrow). Figure 2. A-B. Digital subtracted angiography of the right internal carotid artery showing
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early venous drainage (AP view, white arrow) from the flow related aneurysm (lateral view, black arrow). C-D. Following embolization, the aneurysm is completely obliterated (AP (C) and Lateral views (D)).
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Figure 3. A-D. H&E showing tumor cell infiltration (A, 40x), micro-vascular proliferation (B, 40x, asterisk), mitotic activity (C, 100x) and dilated vessels (D, 40x). F-
(F 100x, E 400x, double asterisk).
Tables
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E. Verhoeff-Van Gieson elastin stain showing large and dilated vessels within the tumor
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Table 1. Literature review on previous 19 case reports on Glioblastoma multiforme and aneurysms(1). GBM Glioblastoma multiforme, SAH Subarachnoid hemorrhage, HA Headache, ICA Internal carotid artery, MCA Middle cerebral artery, AComm Anterior
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communicating artery ACA anterior cerebral artery, PComm Posterior communicating artery, PCA Posterior cerebral artery, HTN hypertension, STR Subtotal resection, GTR
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Gross total resection, M male, F Female.
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44, F
Intratumoral hemorrhage Left frontal
GBM
Cohen et al 2005
35, F
Right frontal
GBM
Cheng et al 2004
67, F
Left supraclinoid ICA
57, M
Left parietal Right frontotemporal Right temporooccipital
GBM
Aoki et al 1999
Cognitive changes Neurodeficit due to tumor Neurodeficit due to tumor Hemiparesis and hemianopsia
Left lenticulostraite Left pericallosal pseudoaneurysm
GBM
Right proximal MCA
Tumor resection with clip sacrifice of MCA Fair
GBM
Right Pcomm
Tumor resection, aneurysm not treated
Poor (Dead)
Right temporal
GBM
Right ICA
Fair
Left temporal
GBM
Left M2 MCA
Aneurysm clipped, tumor partially resected Tumor resected, aneurysm trapped and resected
Left frontal Left frontal Left temporal Left temporooccipital
GBM GBM GBM
Left MCA trifurcation Acomm Acomm
Tumor resected and aneurysm clipped Tumor resected and aneurysm clipped STR then clip
Good Poor (Dead) Good
GBM
Acomm
Pathology Aneurysm Location GBM Angio negative SAH GBM Right distal ACA
Treatment Biopsy STR then clip Observation
Outcome Unknown Good Poor (Vegetative)
GTR then coiling
Poor (Dead)
Clipping then tumor resection
Good
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Plannger et al 1987 69, M Dechiara et al 1986 52,F Andrews et al 1985 53, F
Tumor location Left uncus Right frontal
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Age/Sex Symptoms 31,M SAH 57, M HA, SAH
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Author and year Joki et al 2013 Yoon et al 2011 Hashiguchi et al 2007
Obrador et al 1972 54, M
Tumor symptoms
Evans et al 1972 55, M Kraus et al 1972 Krayenbuehl et al 1965 50 Taylor et al 1961 33, M
SAH Tumor symptoms
Right Parietal
GBM GBM
Right PCA MCA
STR then clip Good Tumor resection, spontaneous thrombosis of aneurysm Poor (Dead) Tumor resected and aneurysm clipped Good
Tumor symptoms Tumor symptoms
GBM GBM
Left ACA Right ACA
Tumor resection only Aneurysm clipped
Poor (Dead) Poor (Dead)
Heppner et al 1953 50, M Beller et al 1951 32, ?
Tumor symptoms Tumor symptoms Tumor symptoms Tumor symptoms Tumor symptoms
Left frontal Right frontal Right frontotemporal Right temporal Right frontal Left temporal Left Parietal
GBM GBM GBM GBM GBM
Right MCA Right ICA Right ICA Left ICA Left ICA
Aneurysm clipped Aneurysm clipped Tumor resected and aneurysm not treated
Poor (Dead) Unknown Unknown Poor (Dead) Good
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Paoletti et al 1983 59, M Golkalp et al 1980 50, M Honda et al 1980 59, F
SAH SAH, intratumoral hemorrhage Confusion, Intracranial HTN Visual disturbance Hemiparesis
Unknown
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