Pituitary Adenomas Associated with Intracranial Aneurysms – The Clinical Characteristics, Therapeutic Strategies, and Possible Effects of Vascular Remodeling Factors

Objective: Pituitary adenoma coexists with intracranial aneurysms in 2.3% to 3.6%, and intracranial aneurysms is thought to be incidental. On the other hand higher age and cavernous sinus invasion are reported to increase the coexistence rate, so these two diseases may be related. Ten males and 14 females with coexistence of pituitary adenomas and intracranial aneurysms were retrospectively investigated among 923 patients (2.6%). Patients were subdivided into two groups with/without direct attachment of cerebral aneurysms to the pituitary adenomas. The clinical characteristics, therapeutic strategies, and possible effects of vascular remodeling factors were investigated. Results: Twelve patients had functioning pituitary adenomas, and cavernous sinus invasion was identied in 7 of 24 patients. Five of these 7 patients were treated with priority for the cerebral aneurysms until 2007, whereas 14 of 17 patients without involvement of the aneurysm tip in the tumor were treated with priority for pituitary adenomas in the later period. Among vascular remodeling factors strong expression of vascular endothelial growth factor (VEGF) was signicantly associated with coexistence of pituitary adenoma and cerebral aneurysm (p < 0.05). So VEGF-induced arterial wall remodeling may be part of the mechanism of association between pituitary adenomas and cerebral aneurysms, suggesting possible causative mechanism.


Introduction
Pituitary adenoma associated with intracranial aneurysms requires complex and individual case discussions to establish the therapeutic strategies, and pituitary adenoma is reported to coexist with intracranial aneurysms in the anterior circulation of the circle of Willis in 2.3-3.6% of cases [1][2][3][4], but in the posterior circulation in much lower percentages [5][6]. Such rates of coexistence may be higher in acromegaly patients [6][7][8]. Therefore, the coexistence of pituitary adenomas and intracranial aneurysms is incidental. On the other hand, the coexistence rate is higher with age and cavernous sinus invasion, so the coexistence of these two diseases may be related [4,[9][10]. Some statistical risk evaluations have examined coexistence, but no clinical or basic examinations have investigated the possible mechanism of association.
The present study investigated the clinical characteristics, therapeutic strategies and possible involvement of vascular remodeling factors within pituitary adenomas with tumor-related aneurysm formation.

Materials And Methods
This study retrospectively identi ed 10 males and 14 females aged from 37 to 75 years (mean 56.8 years) with pituitary adenomas coexisting with intracranial aneurysms among the 923 patients (2.6%) initially treated by surgery with histological con rmation at the Department of Neurosurgery, Kohnan Hospital between April 2005 and October 2018. No patients had previously undergone treatment for the aneurysms and all aneurysms were un-ruptured. All patients were investigated preoperatively and just after the operation with coronal and sagittal T1-weighted, with and without contrast medium, and T2weighted magnetic resonance (MR) imaging, and MR angiography with the time of ight method (1.5 T system, Magnetom, Siemens, Erlangen, Germany and Signa Horizon, General Electric Medical Systems, Milwaukee, WI; 3.0 T system, Signa Excite HD 3T, General Electric Medical Systems). Therapeutic strategies were established through discussions between neurosurgeons and endovascular neurosurgeons specialized in cerebrovascular diseases to decide the therapeutic priority and method of treatment of the cerebral aneurysms for each individual case.
The surgical specimens were immediately xed for histological and immunohistochemical examinations with 10% buffered formalin, embedded in para n, and serial sections were cut to 3 µm thickness.
Hematoxylin and eosin, and periodic acid-Schiff staining were performed in all cases. The avidin-biotin-

Results
Twelve patients with functioning pituitary adenomas suffered from hormonal excess symptoms, and the remaining 12 patients had non-functioning pituitary adenomas. Four patients with functioning adenomas had acromegaly with GH excess, and these patients accounted for 3.7% of 108 acromegaly patients treated within the same period. Most tumors were macroadenomas with average maximum diameters of 22.4 mm, and only 3 tumors were microadenomas with maximum diameter of less than 10 mm. Cavernous sinus invasion was identi ed in 7 patients and was not found in the remaining 17 patients.
Direct attachment between the tumor and cerebral aneurysm was identi ed in 15 patients and not in the remaining 9 patients. All aneurysms were located in the anterior circulation of the circle of Willis except for 1 case of VA-PICA aneurysm (Table 1). Five of 7 patients with cavernous sinus invasion were treated with priority for the cerebral aneurysms until 2007. In contrast, 3 of 17 patients with the aneurysm tip involved in the tumor were treated with priority for the cerebral aneurysms, and 5 of 17 patients were treated with priority for the pituitary adenomas in the later period. The other 9 patients were treated only for pituitary adenomas with simple observation of the cerebral aneurysms. Patients with pituitary adenomas without direct attachment to cerebral aneurysms and with direct attachment to the aneurysm neck were treated with priority for the pituitary adenomas, and all patients were discharged without complications. Consequently, the emphasis of treatment priority had shifted from cerebral aneurysms to pituitary adenomas ( Table 2).  with direct attachment and without direct attachment, and the data were compared with a control group containing 21 patients without cerebral aneurysms. Expression of MMP-9 and CD68 was stronger in the control group and weakest in the patients with direct attachment to cerebral aneurysms. No theoretical explanation can be proposed based on the coexistence of pituitary adenomas and cerebral aneurysms. In contrast, VEGF was only faintly expressed in the control group and patients without direct attachment, but stronger expression was identi ed in the patients with direct attachment (Table 3) (Fig. 1). Strong expression of VEGF was signi cantly associated with the coexistence of pituitary adenoma and cerebral aneurysm (p < 0.05).

Discussion
Meta-analyses have shown that aneurysm has high risk of coexistence with autosomal familial polycystic kidney, familial history with cerebral aneurysm, and subarachnoidal hemorrhage, whereas lower risk is found for pituitary adenomas than overall brain tumors, and in the normal population without speci c risk factors [11]. However the present study found stronger expression of vascular remodeling factor VEGF in patients with direct attachment of pituitary adenomas and cerebral aneurysms. Aneurysm formation is thought to be a result of complex interactions between biochemical and mechanical forces, and various vascular remodeling factors have been considered as causative of cerebral aneurysms and used in experimental aneurysm formation [12][13][14][15][16][17]. The present study may indicate possible VEGF-induced remodeling of the arterial walls. Therefore, preoperative screening examination for cerebral aneurysm using MR or computed tomography angiography should be performed in all the patients with attachment between pituitary adenomas and major cerebral arteries.
All the patients enrolled in this investigation had autocrine hormonal secretion and/or compression syndrome to neuronal structures by the tumors, whereas all the aneurysms were un-ruptured without compression syndrome. Clari cation of the natural history of un-ruptured cerebral aneurysms [18] has changed the priority of treatment to pituitary adenomas as symptomatic lesions rather than asymptomatic un-ruptured aneurysms. Moreover, surgery is performed without discontinuation of antithrombotic therapy even in patients receiving anti-thrombotic agent in our institute [19], treatment strategy is not biased by the possibility of newly-introduced anti-platelets after intra-aneurysmal embolization. However, institutional and/or personal strategy is likely to be chosen for the patients receiving anti-thrombotic therapy, so individual case study discussion is still recommended.

Conclusions
Intracranial aneurysms were found to coexist in 2.6% of cases of surgically treated pituitary adenomas. Stronger expression of VEGF was shown in patients with pituitary adenomas with direct attachment to the aneurysms. VEGF-induced arterial wall remodeling may be part of the mechanism of cerebral aneurysm formation in case with coexisted pituitary adenomas.

Limitations
Finally there are some limitations in this study. This investigation analyzed a single institutional cohort containing a rather small number of patients, so prospective registration and accumulation of experience at multiple centers are essential to clarify the possible involvement of pituitary adenoma in tumor-related aneurysm formation.
Abbreviations MR: magnetic imaging; GH: growth hormone; ACTH: adrenocorticotropic hormone; PRL: prolactin; LH: luteinizing hormone; FSH: follicle stimulating hormone; MMP-9: matrix metalloproteinase 9; VEGF: vascular endothelial growth factor Declarations Ethics approval and consent to participate This is a retrospective and observational study, and no need to ethics approval and consent to participate are required. The therapeutic protocol was approved by the internal ethics committee of Kohnan Hospital 2019.