- Email: [email protected]
The Value of Intraoperative Magnetic Resonance Imaging in Endoscopic and Microsurgical Transsphenoidal Pituitary Adenoma Resection
Accepted Manuscript The value of intraoperative MRI in endoscopic and microsurgical transsphenoidal pituitary adenoma resection Andrej Paľa, MD, Andreas Knoll, MD, Christine Brand, MD, Gwendolin Etzrodt-Walter, MD, Jan Coburger, MD, Christian Rainer Wirtz, MD, PhD, Michal Hlaváč, MD PII:
S1878-8750(17)30306-6
DOI:
10.1016/j.wneu.2017.02.132
Reference:
WNEU 5363
To appear in:
World Neurosurgery
Received Date: 17 December 2016 Revised Date:
27 February 2017
Accepted Date: 28 February 2017
Please cite this article as: Paľa A, Knoll A, Brand C, Etzrodt-Walter G, Coburger J, Wirtz CR, Hlaváč M, The value of intraoperative MRI in endoscopic and microsurgical transsphenoidal pituitary adenoma resection, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.02.132. 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.
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Andrej Paľa1, MD, Andreas Knoll1, MD, Christine Brand1, MD, Gwendolin Etzrodt-Walter2, MD, Jan Coburger1, MD, Christian Rainer Wirtz1, MD, PhD, Michal Hlaváč1, MD
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1 University of Ulm, Department of Neurosurgery, Ludwig-Heilmeyerstr. 2, 89312 Günzburg, Deutschland
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2 Endokrinologiezentrum Ulm, Bahnhofplatz 7, 89073 Ulm, Germany
MUDr. Andrej Pala, MD University of Ulm Department of Neurosurgery Ludwig Heilmeyerstr. 2 89312 Günzburg Germany Tel: +4982219628866 Fax: +4982219622509 Email: [email protected]
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Keywords: endoscopic transsphenoidal surgery, intraoperative MRI, pituitary adenoma, tumor volume, microsurgical technique
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ACCEPTED MANUSCRIPT The value of intraoperative MRI in endoscopic and microsurgical transsphenoidal pituitary adenoma resection
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Abstract
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Introduction
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The routine use of iMRI helps to achieve gross total resection in transsphenoidal pituitary surgery. We have compared the added value of iMRI for extent of resection in endoscopic versus microsurgical transsphenoidal adenomectomy.
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Methods
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A total of 96 patients with pituitary adenoma were included. 28 consecutive patients underwent endoscopic transsphenoidal tumor resection. For comparison, we used a historic cohort of 68 consecutive patients treated microsurgically. We evaluated the additional resection after conducting iMRI using intraoperative and late postoperative volumetric tumor analysis 3 months after surgery. Demographic data, clinical symptoms, complications as well as pituitary function were evaluated.
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Results
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We found significantly less additional resections after conducting iMRI in the endoscopic group (p=0.042). The difference was even more profound in Knosp 0-2 adenomas (p=0.029). There was no significant difference in Knosp 3-4 adenomas (p=0.520). The endoscopic approach was associated with smaller intraoperative tumor volume (p=0.023). No significant difference was found between both techniques in postoperative tumor volume (p=0.228). Satisfactory results of pituitary function were significantly more often associated with an endoscopic approach in the multiple regression analysis (P=0.007, OR 17.614, CI 2.164-143.396).
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Conclusion
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With endoscopic approach, significantly more tumor volume reduction was achieved before conducting iMRI decreasing the need for further resection. This was even more pronounced in adenomas graded Knosp 0-2. In the case of extensive and invasive adenomas with infiltration of cavernous sinus and suprasellar or parasellar extension additional tumor resection and increase in the extent of resection was achieved with iMRI in both groups. Endoscopic approach seems to result in better endocrine outcomes, especially in Knosp 0-2 pituitary adenomas.
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Introduction:
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Selective microsurgical transsphenoidal adenomectomy was the main operative technique for decades. The endoscopic technique has become a common alternative after its introduction and further development in transnasal transsphenoidal skull base surgery.1,2 Improved visualization of the sella and less trauma to the nasal mucosa are potential benefits of this approach.2 Furthermore, endoscopic approach seems to be superior for invasive pituitary tumors.3
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Our previously published data show that the routine use of an intraoperative MRI increases the EoR and decreases the residual volume of pituitary adenomas.4 Sylvester et al has demonstrated the longer PFS in patients with gross total resection of pituitary adenomas.5 Furthermore, complementarity and benefit of a combined approach with iMRI and endoscopy has been demonstrated.5
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In our study, we have evaluated the influence of surgical technique and additional use of iMRI on EoR and residual tumor volume in intraoperative and postoperative MRI in transnasal transsphenoidal pituitary surgery. Additionally, we have evaluated pituitary function, postoperative tumor volume and surgical complications.
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Methods:
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Patients and follow-up assessment:
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Patients operated on pituitary adenoma between 2009 and 2016 were assessed retrospectively. Endoscopic transsphenoidal approach has been performed at our department since 2015 by two neurosurgeons without previous experience with the endoscopic technique. Since then elective patients with pituitary adenoma were treated with this approach. A historic cohort of 68 consecutive patients treated microsurgically was used for evaluation. The transsphenoidal microsurgical adenomectomy was performed by 3 neurosurgeons experienced with the microsurgical approach. Follow-up assessment including clinical and endocrine status as well as MRI imaging was performed at 3 months after surgery. Preoperative MRI images included coronar T2-weigted turbo spin echo as well as coronar, axial and sagittal T1 sequences with and without gadolinium enhancement. Knosp classification was used to stratify the invasive growth pattern of adenomas in cavernous sinus. Endocrine function was evaluated in cooperation with endocrinologists in multidisciplinary approach before and after surgery. Preservation, worsening or improving of pituitary function were reexamined in 4-6 weeks and in 3-6 months after surgery. Additionally to standard monitoring of pituitary hormone levels, hypoglycemic test was mostly used for determination of cortisol and GH dynamics under stress conditions. For statistical analysis, we defined improvement or stable postoperative pituitary function compared to preoperative examination as satisfactory result. The worsening of pituitary function was considered unsatisfactory result. Remission in patients with acromegaly was defined as a normal IGF-1 level and either suppressed GH less than 0,4 ng/ml during an oral glucose tolerance test or GH level less than 1.0 ng/ml in random examination. Remission in Cushing patients was defined either if cortisol substitution was necessary or if morning cortisol level was in normal range.
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OR Setup and MRI:
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An intraoperative 1.5 T MRI Espree scanner is available (Espree, Siemens AG, Erlangen, Germany) at our department as a one-room solution since October 2008. The analysis of intraoperative residual tumor was performed on thin slice (2mm) high resolution coronar T2 and contrast enhanced T1 images using Brainlab iPlan 3.0 (BrainLab AG, Feldkirchen, Germany). Postoperative MRI was performed 3 months after surgery. Pre- and postoperative MRI images were performed either with the intraoperative scanner or with 1.5 T MRI Symphony system (Siemens AG, Erlangen, Germany).
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MRI volumetric assessment:
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Tumor volume was measured after image fusion using iPlan 3.0. Tumor borders were segmented manually on coronar or sagittal T2 and T1 images with gadolinium enhancement. Intraoperative MRI image data as well as MRI data 3 months after surgery were used for the analysis.
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Surgical procedure:
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Binasal transsphenoidal approach has been performed in all endoscopic cases. We started using this technique in 2015. Rigid 0°, 30° and 45° endoscopes with 4 hands technique and Brainlab iPlan navigation system were used intraoperatively. In the case of invasive adenomas with skull base infiltration extended endoscopic approaches in cooperation with ENT surgeons were employed. Skull base reconstruction was performed with fibrin coated sponge in the case of small or no intraoperative CSF fistula. Large defects were sealed using multilayer technique with abdominal subcutaneous fat graft and fibrin coated sponge or a Hadad flap.6 The microsurgical procedure was performed with unilateral transnasal paraseptal and submucosal approach. 1,7
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Surgical complications:
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Postoperative meningitis was defined when antibiotic treatment was initiated because of typical clinical signs of meningeal inflammation even if no pathogen was isolated. CSF fistula was considered as a complication if a lumbar drain or revision surgery was necessary. We distinguished between intraoperative and postoperative CSF leaks. Furthermore, intra- and postoperative bleeding, thromboembolic complications and new transient or permanent neurological deficits were included.
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Data analysis:
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The data of 96 patients were evaluated retrospectively. Statistical analysis was performed using SPSS 21.0 (Lead Technologies, INC, Charlotte, USA). Mann-Whitney-U and Fisher exact tests were used for the analysis. Furthermore, univariate and multiple regression models for GTR after iMRI and after surgery as well as for endocrine outcome were built. Influencing variables were preoperative tumor volume, surgical technique, Knosp grade, age, gender and recurrent surgery. The study was conducted according to the international Declaration of Helsinki. The approval of the local ethic committee has been obtained (Nr.137/16).
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Results:
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Patient characteristics:
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A total number of 96 patients treated with pituitary adenoma were assessed. A mean age of 54 (range 7 - 78) years was noted. Males were mostly treated (74%, N=71). The demographic data are summarized in table 1.
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Tumor characteristics and surgical procedure:
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The most common histological subtype was non-functioning adenoma (N=65, 67.7%) followed by GH- (N=16, 16.7%) and ACTH-secreting adenoma (N=10, 10.4%, table 1). 49 (51%) patients were graded according to Knosp classification as 0-2 (microsurgical N=34, endoscopic N=15) and 47 (49%) as Grade 3-4 (microsurgical N=34, endoscopic N=13, table 1). As far as the surgical procedure is concerned, 68 (70.8%) patients were treated via microsurgical and 28 (29.2%) via endoscopic approach. Recurrent tumor was treated in 25 cases (26%).
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Volumetric and statistical analysis:
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The mean preoperative tumor volume was 7.848 cm3 (range 0.058 – 49.698 cm3). Intraoperative MRI was available for all patients. No subsequent resection was performed in 52 (54.2%) cases (microsurgical N=32/68 (47.1%), endoscopic N=20/28 (71.4%), table 2). The difference is statistically significant with Fisher exact test (p=0.042, table 2). In the subsequent stratification according to Knosp grade, 49 (51.0%) patients were grade 0-2 and 47 (49.0%) patients were grade 3-4.8 In the group of patients with Knosp 0-2, significantly more additional resections were found following iMRI with microsurgical technique (47.1%, N=16) than with endoscopic technique (13.3%, N=2, p=0.029). On the contrary, in Knosp 3-4 adenomas there was no significant difference concerning additional resection following iMRI with microsurgical (58.8%, N=20) or with endoscopic technique (46.2%, N=6, p=0.520). The mean intraoperative tumor volume was 1.752 cm3 (range 0.000 – 26.037 cm3). The postoperative MRI was available for 93 (96.9%) patients (microsurgical N=67, endoscopic N=26). The mean postoperative tumor volume was 0.810 cm3 (range 0.000 – 23.008 cm3. The volumetric results according to surgical technique are summarized in table 2. The use of endoscopic approach is significantly associated with smaller intraoperative tumor volume (p=0.023, Mann-Whitney-U test, figure 1.). There was no significant difference with regard to postoperative tumor volume between both techniques (p=0.228, MannWhitney-U test, table 2). According to iMRI, GTR was achieved in 46 (47.9%) cases (microsurgical N=29 (42.6% of all microsurgical procedures), endoscopic N=17 (60.7% of all endoscopic procedures), p=0.121 with Fisher exact test). After additional resection following iMRI, GTR was achieved in 58 (60.4%) cases (microsurgical N=38 (55.9%), endoscopic N=20 (71.4%), p=0.176).
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In the subgroup analysis, iMRI confirmed GTR in Knosp grade 0-2 in 33 (67.3%) and in Knosp grade 3-4 in 13 (27.7%) patients and could be significantly increased to 41 (83,7%, p=0.001 with Fisher exact test) and 17 (36,2%, p<0.001 with Fisher exact test) respectively with iMRI. GTR data stratified according to surgical technique and Knosp grade are summarized in table 3. This shows the largest increase in GTR rate in microsurgical resection of Knosp grade 0-2 of 20,6% and endoscopic resection of Knosp grade 3-4 tumors 15,4%.
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Univariate and multiple models based on the iMRI data showed significant influence of preoperative tumor volume and recurrent surgery on GTR (p=0.012, OR 1.174, CI 1.036-1.330 and p=0.034, OR 0.282, CI 0.087-0.911 respectively). Additionally, in univariate simple regression model Knosp grading showed significant influence on GTR as well (p<0.001, OR 5.394, CI 2.25912.935). No significant association was found for surgical technique, age and gender. Similar univariate and multiple regression models were built for GTR according to postoperative MRI. In these models, initial tumor volume, Knosp grading and recurrent surgery were strongly associated with GTR (p=0.024, OR 1.155, CI 1.019-1.310, p=0.005, OR 5.672, CI 1.690-19.036 and p=0.001, OR 0.110, CI 0.28-0.49 respectively)
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In our population 33/95 (34.7%) patients (microsurgical N=21, endoscopic N=12) presented initially with normal pituitary function. 2 patients were not evaluated systematically before surgery and were excluded from this analysis. 4 patients were lost to endocrine follow up. Anterior hypopituitarism was found in 35 (36.1%, microsurgical N=24, endoscopic N=11) cases and partial pituitary insufficiency in 27 (28.4%, microsurgical N=23, endoscopic N=4) patients. 7/96 (7.3%) patients developed new permanent diabetes insipidus after surgery and all of them were treated with microsurgical approach. No permanent diabetes insipidus was noted in endoscopic group. The difference was not statistically significant (p=0.102, Fisher exact test). Having analyzed 92 cases, 65 (70.7%) patients (microsurgical N=40/66, 60.6%, endoscopic N=25/26, 96.2%, table 2) achieved a satisfactory endocrine result, whereas in 27 (29.3%) patients (microsurgical N= 26/66, 39.4%, endoscopic N=1/26, 0.04%) pituitary function worsened after the surgery. Satisfactory results of pituitary function were significantly associated with an endoscopic approach (p=0.001, Fisher exact test). Having performed the subgroup analysis according to Knosp classification, there was a
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significant advantage of endoscopic approach in patients with Knosp 0-2 (p=0.004), whereas the difference in patients with Knosp 3-4 was not statistically significant (p=0.135). Univariate and multiple logistic regression models showed significant advantage of endoscopic technique for satisfactory results of pituitary function (p=0.007, OR 17.614, CI 2.164-143.396). No significant association was found for initial tumor volume, age, gender, Knosp grading and tumor recurrence. 23 patients were diagnosed with hormone active pituitary adenoma (Cushing, N=8, acromegaly, N= 15). Remission after surgical treatment was achieved in 5/8 (62.5%) patients in endoscopic cohort and in 9/15 (60%) cases of microsurgical treatment. The difference was not statistically significant (p=0.100 in Fisher exact test). Two patients had silent ACTH- and one patient silent STHproducing adenoma. These patients were not evaluated in this cohort.
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Complications:
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In both cohorts, surgical complications were documented in 25 (26.0%) cases (microsurgical N=17 (25% of all microsurgical procedures), endoscopic N=8 (28.6% of all endoscopic procedures). 11 patients developed CSF fistula. One patient was readmitted due to pneumocephalus. 4 patients had meningitis after surgery. Bleeding was documented in 4 cases on postoperative CT without a need for revision and 1 patient had a profound intraoperative bleeding. One patient sustained pulmonary embolism. 2 patients developed transient and 1 patient permanent neurological deficit (ophtalmoplegia). There was no significant difference between both cohorts in Fisher exact test (p=0.799). CSF fistula was documented in 11 (11.5%) patients (microsurgical N=8 (11.8% of all microsurgical cases), endoscopic N=3 (10.7% of all endoscopic cases)) without significant difference between both cohorts (p=1.000). Surgical revision for repair of CSF fistula and one case of pneumocephalus was necessary in 8 (8.3%) cases (microsurgical N=4 (5.9% of all microsurgical procedures), endoscopic N=4 (14.3% of all endoscopic procedures)). There was no significant association between revision surgery and surgical technique (p=0.226).
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45 (46.9%) patients suffered from visual disturbances before the surgery. New visual impairment was not documented in both cohorts. Visual improvement was noted in 30 cases (66.7%) and we found no significant difference between both surgical techniques (microsurgical N=24/38, endoscopic 6/7, p=0.395). Meningitis was observed in 4 (4.2%) cases (microsurgical N=2, endoscopic N=2). There was no significant difference in occurrence of meningitis between both surgical techniques (p=0.578). Mortality was 1% (N=1). The probable cause of death was the pulmonary embolism two weeks after the surgery, however no autopsy was performed.
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Discussion:
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The main aim of our study was to analyze the influence of surgical technique on the EoR prior to intraoperative MRI and to evaluate the extent of additional resection after iMRI. According to our results, iMRI reveals significantly more often resectable tumor remnants after microsurgical than after endoscopic approach. This effect is even more pronounced in case of less invasive pituitary adenomas (Knosp 0-2). Moreover, the tumor remnant volume in iMRI images is significantly higher with microsurgical technique. Only in two cases a tumor remnant was identified on iMRI, when endoscopic approach was used. One case was a giant nonfunctioning adenoma classified as Knosp 2 (figure 2). A small tumor remnant was identified in iMRI between the wall of cavernous sinus and a diaphragm fold and removed thereafter (figure 3). The second case was an ACTH producing adenoma classified as Knosp 2 with clival infiltration, a significant retrosellar extension and herniation of the suprasellar cistern. The iMRI showed retrosellar remnant which could not be completely resected. The patient exhibited a persistence of Cushing disease of lower intensity postoperatively.
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In the case of invasive pituitary adenomas (Knosp 3-4) the additional resection after iMRI was regularly performed regardless of the technique employed and resulted in significantly higher number of GTR rates (table 3). Tough our data showed higher percentage of GTR in invasive
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adenomas treated endoscopically, the difference between surgical techniques was not statistically significant. Due to low sample size, it is not possible to draw any firm conclusion from this finding. Nevertheless, based on our experience, endoscopic transsphenoidal resection enables better visualization of the sella and adjacent structures, thereby allowing for more extensive tumor resection. The additional use of iMRI might be beneficial if unclear anatomy or bleeding from cavernous sinus complicates resection of these tumors. iMRI scan might under these circumstances result in the increase of EoR through the possibility of anatomical reorientation and navigation update. McLaughlin et al demonstrated that in large pituitary adenomas (diameter > 2 cm) endoscopic visualization of resection cavity after microsurgical resection lead to additional resection in 54% cases.9 Based on our data, we postulate that the additional use of iMRI in large pituitary adenomas (Knosp 3-4) might increase EoR more in combination with the endoscopic than with the microsurgical technique. Sylvester et al has shown more favorable resection rates using iMRI assisted endoscopic surgery than iMRI assisted microsurgical technique in both univariate (OR=1.83, CI 95% 1.17-2.87, p < 0.01) and multivariate analysis (OR 2.05, CI 95%1.21-3.46, p < 0.01).5 Our results are congruent with their findings and confirm the complementary role of iMRI and endoscopy. Interestingly, the comparison between endoscopic and microsurgical procedure without iMRI has shown trend to more profound EoR in the endoscopic cohort but results were statistically not significant in the study performed by Sylvester et al.5 In our study, the volume of tumor remnant was significantly smaller after endoscopic resection. Similarly, as the study performed by Sylvester et al, our data underline the important role of iMRI for higher EoR which is similarly relevant for longer PFS.5 Dallapiazza et al reported significantly higher EoR in adenomas with Knosp 0-2 compared to Knosp 3-4 (89% vs 28%, p<0.05).10 Our data confirm this finding and suggest that the added value of iMRI increases with the complexity of the treated tumor. While the iMRI can only marginally increase the already high resection rate in endoscopically treated Knosp 0-2 tumors, there is scope for significantly more extensive resection in complex Knosp 3-4 adenomas.
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Pituitary adenomas are benign tumors. However, the recurrence rate is still high. In the literature the reported recurrence rates are up to 20% in long-term follow-up.10,11 The recurrent tumors are prone to more aggressive growth with infiltration of the parasellar region.11 Furthermore, the loss of anatomical landmarks due to scarring make the surgical resections of recurrent adenomas more challenging.11 The additional treatment options, such as stereotactic radiosurgery can improve tumor control. However, the progress of neurological symptoms, such as visual disturbances or the risk of hypopituitarism might be difficult to avoid. Therefore, the value of complete tumor removal during the first surgical procedure is very high. Especially the combination of iMRI and endoscopy may help to achieve this goal. Furthermore, stereotactic radiosurgery might be more efficient and have less side effects in the case of smaller tumor remnants, which can be delivered by the combination of endoscopic approach and iMRI.12
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The longer surgical time needed for endoscopic approach and iMRI might provoke more surgical complications. As shown in our previous work, the routine use of iMRI in combination with microsurgical approach does not generate higher infection rates.4 Considering an endoscopic approach, the higher risk for cerebrospinal fluid has been reported by some authors. Sylvester et al demonstrated CSF leak in 17.5% of cases and their occurrence was slightly higher in the endoscopic group. In our results, the rate for CSF leak is lower than in the study from Sylvester et al.5 There was neither significant difference between CSF fistula nor between postoperative meningitis or revision surgeries in both cohorts. Given adequate reconstruction of the skull base, endoscopic surgery is not associated with increased risk of postoperative CSF-leak compared to microsurgical approach. Similarly, no significant difference was reported in the occurrence of CSF-leak comparing both techniques in the study performed by Sylvester et al.5 Magro et al evaluated 300 patients with non-functioning adenomas treated with endoscopic approach and found postoperative CSF leak rate of 2.7% .13 Postoperative meningitis was reported in 3.3% of cases in this study and was significantly associated with intraoperative and postoperative CSF leak (p<0.001).13 Our cohort
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shows a higher rate of CSF-fistula, but we found no higher occurrence of postoperative meningitis. The endoscopic group represents our initial experience with this technique, so that the inevitable learning curve of endoscopic approach might account for some part of the difference. Sella reconstruction in the historical cohort treated microsurgically was almost exclusively performed with fibrin coated sponge. After introduction of the endoscopic technique, autologous fat graft, Haddad flap or a combination were used in large adenomas. These different closure techniques might have influenced the rate of CSF leaks in our study. According to our data endoscopic approach exhibits a low risk profile and is comparable to microsurgical technique in regard to surgical complications.
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Mortini et al evaluated a large cohort of 788 microsurgically treated pituitary adenomas and described the visual normalization in 40.5% and improvement in 51.2% of patients in with large pituitary adenomas.14 Dehdashti et al published results of 200 pituitary adenomas operated via endoscopic approach and has shown visual normalization in 50% and improvement in 39% cases.15 In our study we distinguished only between visual improvement or no improvement after surgery. Our visual improvement rate (66.7%) is not as high as in both studies which might be attributed to smaller cohort of patients with visual dysfunction in our study group. The safety of both techniques is confirmed by the fact that there was no visual worsening in our study. Nevertheless, postoperative visual improvement achieved no significant difference between both techniques and both seem appropriate for optic nerve decompression.
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Preservation or improvement of pituitary function is an important goal of treatment strategy in pituitary adenomas. It has been suggested that the better visualization of pituitary gland using endoscopic transsphenoidal approach might decrease accidental intraoperative manipulation and the risk of pituitary gland injury and consequent iatrogenic hypopituitarism.16 Consistent with these findings, our data have shown significantly higher rate of satisfactory result with endoscopic transsphenoidal approach compared to microsurgical transsphenoidal approach in regard to pituitary function. In our population 29.3% of patients developed new hypopituitarism of some extent after surgery. This result correlates with published data.2,17,18 Interestingly, only one patient treated with endoscopic approach achieved an unsatisfactory result. These findings implicate possible advantage of this surgical technique in regard to pituitary function. In the study published by Margo et al anterior pituitary function generally worsened in 13.7% and new diabetes insipidus occurred in 11.6% among 300 evaluated patients treated endoscopically.13 Our endoscopic cohort has shown better preservation or improvement of pituitary function, however our population is much smaller and not as representative as in the study from Magro et al.13 Laws Jr. et al has evaluated the cohort of 80 patients with pituitary macroadenomas treated with endoscopic transnasal transsphenoidal approach and has shown the worsening of pituitary function in 6.3% of patients.13,16 This data is comparable with our results concerning the endoscopic approach although our evaluation is not limited to macroadenomas. In our study, pituitary function was an outcome criterion and worsening not regarded a complication but unfavorable outcome. We think that the improved visualization of the pituitary gland is one potential benefit of endoscopy that might reduce intraoperative injury of the gland and thus lead to better endocrine outcomes. Our cohort of patients with functioning adenomas was small, therefore we were not able to detect any difference in remission rates.
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Our study encompasses several biases. The comfortable availability of intraoperative visualization and reorientation using iMRI might lead to a bias by provoking the initiation of imaging by the surgeon even before he would finish the surgery, relying solely on optical visualization, thereby artificially reducing the extent of resection and GTR prior to iMRI. This bias might be more pronounced in the microsurgical approach, where optical visualization is more restricted. The smaller cohort of endoscopically treated patients might have influenced our results. Both cohorts were not treated simultaneously, so we have to assume some bias due to general improvements in care. The evaluation of pituitary function after 6 months is short. Longer follow-up might reveal additional improvement of hypopituitarism. Additionally, we combine functioning and non-
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functioning adenomas with categorical stratification as satisfactory and not satisfactory. Interpretation of a more detailed analysis would have been impossible due to small groups and retrospective character of this study. A prospective randomized study might provide us with a higher degree of evidence in determining the role of iMRI in microsurgical and endoscopic pituitary surgery.
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Intraoperative MRI seems to level the playing field between endoscopic and microsurgical resection of pituitary adenomas by identifying hidden tumor remnants. These can be identified and ultimately targeted by the surgeon leading to similar rates of GTR and EoR using either technique. The microsurgical approach with limited visualization of the surgical site benefits disproportionately. The relative benefit of iMRI appears to be smaller with endoscopic approach and tumors graded Knosp 0-2. Using iMRI, excellent results can be achieved employing either technique in Knosp 0-2 adenomas. Both techniques feature similar complication profiles. In our opinion patients with large invasive adenomas seem to benefit most from the combination of endoscopic technique and iMRI. Endoscopic approach seems to result in better endocrine outcomes.
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Sylvester PT, Evans JA, Zipfel GJ, et al. Combined high-field intraoperative magnetic resonance imaging and endoscopy increase extent of resection and progression-free survival for pituitary adenomas. Pituitary. 2015;18(1):72-85. doi:10.1007/s11102-014-0560-2.
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Knosp E, Steiner E, Kitz K, Matula C. Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery. 1993;33(4):610–7–discussion617–8.
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McLaughlin N, Eisenberg AA, Cohan P, Chaloner CB, Kelly DF. Value of endoscopy for maximizing tumor removal in endonasal transsphenoidal pituitary adenoma surgery. Journal of Neurosurgery. 2013;118(3):613-620. doi:10.3171/2012.11.JNS112020.
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Dallapiazza RF, Grober Y, Starke RM, Laws ER Jr, Jane JA Jr. Long-term Results of Endonasal Endoscopic Transsphenoidal Resection of Nonfunctioning Pituitary Macroadenomas. Neurosurgery. 2015;76(1):42-53. doi:10.1227/NEU.0000000000000563.
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11.
Przybylowski CJ, Dallapiazza RF, Williams BJ, et al. Primary versus revision transsphenoidal resection for nonfunctioning pituitary macroadenomas: matched cohort study. Journal of Neurosurgery. May 2016:1-8. doi:10.3171/2016.3.JNS152735.
410 411 412 413
12.
Pomeraniec IJ, Dallapiazza R, Xu Z, Jane J, Jane J Jr, Sheehan JP. 115 Early vs Late Gamma Knife Radiosurgery Following Transsphenoidal Resection for Nonfunctioning Pituitary Macroadenomas. Neurosurgery. 2015;62(August):202. doi:10.1227/01.neu.0000467077.55355.a9.
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13.
Magro E, Graillon T, Lassave J, et al. Complications Related to the Endoscopic Endonasal Transsphenoidal Approach for Nonfunctioning Pituitary Macroadenomas in 300 Consecutive Patients. World Neurosurgery. 2016;89(C):442-453. doi:10.1016/j.wneu.2016.02.059.
417 418 419
14.
Mortini P, Losa M, Barzaghi R, Boari N, Giovanelli M. Results of Transsphenoidal Surgery in a Large Series of Patients with Pituitary Adenoma. Neurosurgery. 2005;56(6):1222-1233. doi:10.1227/01.NEU.0000159647.64275.9D.
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15.
Dehdashti AR, Ganna A, Karabatsou K, Gentili F. Pure endoscopic endonasal approach for pituitary adenomas: Early surgical results in 200 patients and comparison with previous microsurgical series. 2008;62(5):1006-1015.
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16.
Laws ER Jr, Laws ER, Hsu L, et al. A Benchmark for Preservation of Normal Pituitary Function After Endoscopic Transsphenoidal Surgery for Pituitary Macroadenomas. World Neurosurgery. 2016;91:371-375. doi:10.1016/j.wneu.2016.04.059.
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17.
Frank G, Pasquini E, Farneti G, et al. The endoscopic versus the traditional approach in pituitary surgery. Neuroendocrinology. 2006;83(3-4):240-248. doi:10.1159/000095534.
428 429 430
18.
Yamamoto N, Grober Y, Magro E, et al. Complications Related to the Endoscopic Endonasal Transsphenoidal Approach for Nonfunctioning Pituitary Macroadenomas in 300 Consecutive Patients. 2016;89:442-453. doi:10.1016/j.wneu.2016.02.059.
431 Figure legend
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Figure 1: Intraoperative tumor volume prior to intraoperative MRI (cm3). Figure 2: Large intra- and suprasellar pituitary adenoma on T2 weighted coronal MRI image. Figure 3: Small tumor remnant on enhanced T1 weighted coronal MRI images (Arrow).
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ACCEPTED MANUSCRIPT Table 1. Patients and tumor characteristics. Total
Microsurgery
Endoscopy
96
68
28
54
56
55
7 - 78
22 - 74
7 - 78
74% (71)
76% (52)
7.848
8.206
Knosp 0-2
51% (49)
50% (34)
Knosp 3-4
49% (47)
50% (34)
non-functioning
67.7% (65)
69% (47)
GH
16.7% (16)
16% (11)
18% (5)
ACTH
10.4% (10)
9% (6)
18% (5)
Prolactinoma
2.1% (2)
3% (2)
0
GnRH
2.1% (2)
3% (2)
0
1% (1)
0
3% (1)
n
median min - max
male ratio Mean tumor Volume
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68% (19) 6.976
54% (15) 46% (13)
61% (17)
ACCEPTED MANUSCRIPT Table 2. Volumetric and endocrinological results. endoscopic
Mean preoperative volume (cm3)
8.206 (0.127 – 49.698)
6.976 (0.058 – 39.125)
0.158
Mean intraoperative volume (cm3)
2.137 (0.000 – 26.037)
0.873 (0.000 – 17.751)
0.023
Mean postoperative volume (cm3)
0.994 (0.000 – 23.008)
0.329 (0.000 – 17.751)
0.228
No resection after iMRI
47.1% (n=32/68)
71.4% (n=20/28)
0.042
Satisfactory endocrine Outcome
60.6% (n=40/66)
96.2% (n=25/26)
0.001
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Table 3. Gross total resection (GTR) inACCEPTED intraoperativeMANUSCRIPT and postoperative MRI stratified according to surgical technique and Knosp grade and iMRI influence on GTR.
GTR according to iMRT
GTR according to post-OP MRI
Endoscopy
p
Knosp 0-2
58.8% (20)
86.7% (13)
0.097
Knosp 3-4
26.5% (9)
30.8% (4)
1.000
Microsurgery
Endoscopy
p
Microsurgery
Endoscopy
79.4% (27)
93.3% (14)
0.406
0.012
0.122
32.4% (11)
46.2% (6)
0.5
0.002
0.021
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20,000
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Endoscopic approach results in significantly less tumor volume before iMRI scanning Higher EoR may be achieved in invasive pituitary adenomas with para- or suprasellar extension through combination of endoscopy and iMRI Endoscopic approach seems to result in better endocrine outcome especially in Knosp 0-2 pituitary adenomas
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ACCEPTED MANUSCRIPT Abbreviations and Acronyms
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CSF: Cerebrospinal fluid, EoR: Extent of resection, GH: Growth hormone, GTR: Gross total resection, iMRI: Intraoperative magnetic resonance image, PFS: Progression free survival
S1878-8750(17)30306-6
DOI:
10.1016/j.wneu.2017.02.132
Reference:
WNEU 5363
To appear in:
World Neurosurgery
Received Date: 17 December 2016 Revised Date:
27 February 2017
Accepted Date: 28 February 2017
Please cite this article as: Paľa A, Knoll A, Brand C, Etzrodt-Walter G, Coburger J, Wirtz CR, Hlaváč M, The value of intraoperative MRI in endoscopic and microsurgical transsphenoidal pituitary adenoma resection, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.02.132. 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.
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Andrej Paľa1, MD, Andreas Knoll1, MD, Christine Brand1, MD, Gwendolin Etzrodt-Walter2, MD, Jan Coburger1, MD, Christian Rainer Wirtz1, MD, PhD, Michal Hlaváč1, MD
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1 University of Ulm, Department of Neurosurgery, Ludwig-Heilmeyerstr. 2, 89312 Günzburg, Deutschland
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2 Endokrinologiezentrum Ulm, Bahnhofplatz 7, 89073 Ulm, Germany
MUDr. Andrej Pala, MD University of Ulm Department of Neurosurgery Ludwig Heilmeyerstr. 2 89312 Günzburg Germany Tel: +4982219628866 Fax: +4982219622509 Email: [email protected]
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Keywords: endoscopic transsphenoidal surgery, intraoperative MRI, pituitary adenoma, tumor volume, microsurgical technique
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Corresponding author:
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ACCEPTED MANUSCRIPT The value of intraoperative MRI in endoscopic and microsurgical transsphenoidal pituitary adenoma resection
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Abstract
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Introduction
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The routine use of iMRI helps to achieve gross total resection in transsphenoidal pituitary surgery. We have compared the added value of iMRI for extent of resection in endoscopic versus microsurgical transsphenoidal adenomectomy.
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Methods
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A total of 96 patients with pituitary adenoma were included. 28 consecutive patients underwent endoscopic transsphenoidal tumor resection. For comparison, we used a historic cohort of 68 consecutive patients treated microsurgically. We evaluated the additional resection after conducting iMRI using intraoperative and late postoperative volumetric tumor analysis 3 months after surgery. Demographic data, clinical symptoms, complications as well as pituitary function were evaluated.
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Results
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We found significantly less additional resections after conducting iMRI in the endoscopic group (p=0.042). The difference was even more profound in Knosp 0-2 adenomas (p=0.029). There was no significant difference in Knosp 3-4 adenomas (p=0.520). The endoscopic approach was associated with smaller intraoperative tumor volume (p=0.023). No significant difference was found between both techniques in postoperative tumor volume (p=0.228). Satisfactory results of pituitary function were significantly more often associated with an endoscopic approach in the multiple regression analysis (P=0.007, OR 17.614, CI 2.164-143.396).
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Conclusion
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With endoscopic approach, significantly more tumor volume reduction was achieved before conducting iMRI decreasing the need for further resection. This was even more pronounced in adenomas graded Knosp 0-2. In the case of extensive and invasive adenomas with infiltration of cavernous sinus and suprasellar or parasellar extension additional tumor resection and increase in the extent of resection was achieved with iMRI in both groups. Endoscopic approach seems to result in better endocrine outcomes, especially in Knosp 0-2 pituitary adenomas.
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Introduction:
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Selective microsurgical transsphenoidal adenomectomy was the main operative technique for decades. The endoscopic technique has become a common alternative after its introduction and further development in transnasal transsphenoidal skull base surgery.1,2 Improved visualization of the sella and less trauma to the nasal mucosa are potential benefits of this approach.2 Furthermore, endoscopic approach seems to be superior for invasive pituitary tumors.3
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Our previously published data show that the routine use of an intraoperative MRI increases the EoR and decreases the residual volume of pituitary adenomas.4 Sylvester et al has demonstrated the longer PFS in patients with gross total resection of pituitary adenomas.5 Furthermore, complementarity and benefit of a combined approach with iMRI and endoscopy has been demonstrated.5
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In our study, we have evaluated the influence of surgical technique and additional use of iMRI on EoR and residual tumor volume in intraoperative and postoperative MRI in transnasal transsphenoidal pituitary surgery. Additionally, we have evaluated pituitary function, postoperative tumor volume and surgical complications.
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Methods:
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Patients and follow-up assessment:
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Patients operated on pituitary adenoma between 2009 and 2016 were assessed retrospectively. Endoscopic transsphenoidal approach has been performed at our department since 2015 by two neurosurgeons without previous experience with the endoscopic technique. Since then elective patients with pituitary adenoma were treated with this approach. A historic cohort of 68 consecutive patients treated microsurgically was used for evaluation. The transsphenoidal microsurgical adenomectomy was performed by 3 neurosurgeons experienced with the microsurgical approach. Follow-up assessment including clinical and endocrine status as well as MRI imaging was performed at 3 months after surgery. Preoperative MRI images included coronar T2-weigted turbo spin echo as well as coronar, axial and sagittal T1 sequences with and without gadolinium enhancement. Knosp classification was used to stratify the invasive growth pattern of adenomas in cavernous sinus. Endocrine function was evaluated in cooperation with endocrinologists in multidisciplinary approach before and after surgery. Preservation, worsening or improving of pituitary function were reexamined in 4-6 weeks and in 3-6 months after surgery. Additionally to standard monitoring of pituitary hormone levels, hypoglycemic test was mostly used for determination of cortisol and GH dynamics under stress conditions. For statistical analysis, we defined improvement or stable postoperative pituitary function compared to preoperative examination as satisfactory result. The worsening of pituitary function was considered unsatisfactory result. Remission in patients with acromegaly was defined as a normal IGF-1 level and either suppressed GH less than 0,4 ng/ml during an oral glucose tolerance test or GH level less than 1.0 ng/ml in random examination. Remission in Cushing patients was defined either if cortisol substitution was necessary or if morning cortisol level was in normal range.
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OR Setup and MRI:
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An intraoperative 1.5 T MRI Espree scanner is available (Espree, Siemens AG, Erlangen, Germany) at our department as a one-room solution since October 2008. The analysis of intraoperative residual tumor was performed on thin slice (2mm) high resolution coronar T2 and contrast enhanced T1 images using Brainlab iPlan 3.0 (BrainLab AG, Feldkirchen, Germany). Postoperative MRI was performed 3 months after surgery. Pre- and postoperative MRI images were performed either with the intraoperative scanner or with 1.5 T MRI Symphony system (Siemens AG, Erlangen, Germany).
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MRI volumetric assessment:
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Tumor volume was measured after image fusion using iPlan 3.0. Tumor borders were segmented manually on coronar or sagittal T2 and T1 images with gadolinium enhancement. Intraoperative MRI image data as well as MRI data 3 months after surgery were used for the analysis.
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Surgical procedure:
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Binasal transsphenoidal approach has been performed in all endoscopic cases. We started using this technique in 2015. Rigid 0°, 30° and 45° endoscopes with 4 hands technique and Brainlab iPlan navigation system were used intraoperatively. In the case of invasive adenomas with skull base infiltration extended endoscopic approaches in cooperation with ENT surgeons were employed. Skull base reconstruction was performed with fibrin coated sponge in the case of small or no intraoperative CSF fistula. Large defects were sealed using multilayer technique with abdominal subcutaneous fat graft and fibrin coated sponge or a Hadad flap.6 The microsurgical procedure was performed with unilateral transnasal paraseptal and submucosal approach. 1,7
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Surgical complications:
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Postoperative meningitis was defined when antibiotic treatment was initiated because of typical clinical signs of meningeal inflammation even if no pathogen was isolated. CSF fistula was considered as a complication if a lumbar drain or revision surgery was necessary. We distinguished between intraoperative and postoperative CSF leaks. Furthermore, intra- and postoperative bleeding, thromboembolic complications and new transient or permanent neurological deficits were included.
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Data analysis:
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The data of 96 patients were evaluated retrospectively. Statistical analysis was performed using SPSS 21.0 (Lead Technologies, INC, Charlotte, USA). Mann-Whitney-U and Fisher exact tests were used for the analysis. Furthermore, univariate and multiple regression models for GTR after iMRI and after surgery as well as for endocrine outcome were built. Influencing variables were preoperative tumor volume, surgical technique, Knosp grade, age, gender and recurrent surgery. The study was conducted according to the international Declaration of Helsinki. The approval of the local ethic committee has been obtained (Nr.137/16).
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Results:
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Patient characteristics:
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A total number of 96 patients treated with pituitary adenoma were assessed. A mean age of 54 (range 7 - 78) years was noted. Males were mostly treated (74%, N=71). The demographic data are summarized in table 1.
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Tumor characteristics and surgical procedure:
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The most common histological subtype was non-functioning adenoma (N=65, 67.7%) followed by GH- (N=16, 16.7%) and ACTH-secreting adenoma (N=10, 10.4%, table 1). 49 (51%) patients were graded according to Knosp classification as 0-2 (microsurgical N=34, endoscopic N=15) and 47 (49%) as Grade 3-4 (microsurgical N=34, endoscopic N=13, table 1). As far as the surgical procedure is concerned, 68 (70.8%) patients were treated via microsurgical and 28 (29.2%) via endoscopic approach. Recurrent tumor was treated in 25 cases (26%).
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Volumetric and statistical analysis:
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The mean preoperative tumor volume was 7.848 cm3 (range 0.058 – 49.698 cm3). Intraoperative MRI was available for all patients. No subsequent resection was performed in 52 (54.2%) cases (microsurgical N=32/68 (47.1%), endoscopic N=20/28 (71.4%), table 2). The difference is statistically significant with Fisher exact test (p=0.042, table 2). In the subsequent stratification according to Knosp grade, 49 (51.0%) patients were grade 0-2 and 47 (49.0%) patients were grade 3-4.8 In the group of patients with Knosp 0-2, significantly more additional resections were found following iMRI with microsurgical technique (47.1%, N=16) than with endoscopic technique (13.3%, N=2, p=0.029). On the contrary, in Knosp 3-4 adenomas there was no significant difference concerning additional resection following iMRI with microsurgical (58.8%, N=20) or with endoscopic technique (46.2%, N=6, p=0.520). The mean intraoperative tumor volume was 1.752 cm3 (range 0.000 – 26.037 cm3). The postoperative MRI was available for 93 (96.9%) patients (microsurgical N=67, endoscopic N=26). The mean postoperative tumor volume was 0.810 cm3 (range 0.000 – 23.008 cm3. The volumetric results according to surgical technique are summarized in table 2. The use of endoscopic approach is significantly associated with smaller intraoperative tumor volume (p=0.023, Mann-Whitney-U test, figure 1.). There was no significant difference with regard to postoperative tumor volume between both techniques (p=0.228, MannWhitney-U test, table 2). According to iMRI, GTR was achieved in 46 (47.9%) cases (microsurgical N=29 (42.6% of all microsurgical procedures), endoscopic N=17 (60.7% of all endoscopic procedures), p=0.121 with Fisher exact test). After additional resection following iMRI, GTR was achieved in 58 (60.4%) cases (microsurgical N=38 (55.9%), endoscopic N=20 (71.4%), p=0.176).
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In the subgroup analysis, iMRI confirmed GTR in Knosp grade 0-2 in 33 (67.3%) and in Knosp grade 3-4 in 13 (27.7%) patients and could be significantly increased to 41 (83,7%, p=0.001 with Fisher exact test) and 17 (36,2%, p<0.001 with Fisher exact test) respectively with iMRI. GTR data stratified according to surgical technique and Knosp grade are summarized in table 3. This shows the largest increase in GTR rate in microsurgical resection of Knosp grade 0-2 of 20,6% and endoscopic resection of Knosp grade 3-4 tumors 15,4%.
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Univariate and multiple models based on the iMRI data showed significant influence of preoperative tumor volume and recurrent surgery on GTR (p=0.012, OR 1.174, CI 1.036-1.330 and p=0.034, OR 0.282, CI 0.087-0.911 respectively). Additionally, in univariate simple regression model Knosp grading showed significant influence on GTR as well (p<0.001, OR 5.394, CI 2.25912.935). No significant association was found for surgical technique, age and gender. Similar univariate and multiple regression models were built for GTR according to postoperative MRI. In these models, initial tumor volume, Knosp grading and recurrent surgery were strongly associated with GTR (p=0.024, OR 1.155, CI 1.019-1.310, p=0.005, OR 5.672, CI 1.690-19.036 and p=0.001, OR 0.110, CI 0.28-0.49 respectively)
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In our population 33/95 (34.7%) patients (microsurgical N=21, endoscopic N=12) presented initially with normal pituitary function. 2 patients were not evaluated systematically before surgery and were excluded from this analysis. 4 patients were lost to endocrine follow up. Anterior hypopituitarism was found in 35 (36.1%, microsurgical N=24, endoscopic N=11) cases and partial pituitary insufficiency in 27 (28.4%, microsurgical N=23, endoscopic N=4) patients. 7/96 (7.3%) patients developed new permanent diabetes insipidus after surgery and all of them were treated with microsurgical approach. No permanent diabetes insipidus was noted in endoscopic group. The difference was not statistically significant (p=0.102, Fisher exact test). Having analyzed 92 cases, 65 (70.7%) patients (microsurgical N=40/66, 60.6%, endoscopic N=25/26, 96.2%, table 2) achieved a satisfactory endocrine result, whereas in 27 (29.3%) patients (microsurgical N= 26/66, 39.4%, endoscopic N=1/26, 0.04%) pituitary function worsened after the surgery. Satisfactory results of pituitary function were significantly associated with an endoscopic approach (p=0.001, Fisher exact test). Having performed the subgroup analysis according to Knosp classification, there was a
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significant advantage of endoscopic approach in patients with Knosp 0-2 (p=0.004), whereas the difference in patients with Knosp 3-4 was not statistically significant (p=0.135). Univariate and multiple logistic regression models showed significant advantage of endoscopic technique for satisfactory results of pituitary function (p=0.007, OR 17.614, CI 2.164-143.396). No significant association was found for initial tumor volume, age, gender, Knosp grading and tumor recurrence. 23 patients were diagnosed with hormone active pituitary adenoma (Cushing, N=8, acromegaly, N= 15). Remission after surgical treatment was achieved in 5/8 (62.5%) patients in endoscopic cohort and in 9/15 (60%) cases of microsurgical treatment. The difference was not statistically significant (p=0.100 in Fisher exact test). Two patients had silent ACTH- and one patient silent STHproducing adenoma. These patients were not evaluated in this cohort.
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Complications:
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In both cohorts, surgical complications were documented in 25 (26.0%) cases (microsurgical N=17 (25% of all microsurgical procedures), endoscopic N=8 (28.6% of all endoscopic procedures). 11 patients developed CSF fistula. One patient was readmitted due to pneumocephalus. 4 patients had meningitis after surgery. Bleeding was documented in 4 cases on postoperative CT without a need for revision and 1 patient had a profound intraoperative bleeding. One patient sustained pulmonary embolism. 2 patients developed transient and 1 patient permanent neurological deficit (ophtalmoplegia). There was no significant difference between both cohorts in Fisher exact test (p=0.799). CSF fistula was documented in 11 (11.5%) patients (microsurgical N=8 (11.8% of all microsurgical cases), endoscopic N=3 (10.7% of all endoscopic cases)) without significant difference between both cohorts (p=1.000). Surgical revision for repair of CSF fistula and one case of pneumocephalus was necessary in 8 (8.3%) cases (microsurgical N=4 (5.9% of all microsurgical procedures), endoscopic N=4 (14.3% of all endoscopic procedures)). There was no significant association between revision surgery and surgical technique (p=0.226).
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45 (46.9%) patients suffered from visual disturbances before the surgery. New visual impairment was not documented in both cohorts. Visual improvement was noted in 30 cases (66.7%) and we found no significant difference between both surgical techniques (microsurgical N=24/38, endoscopic 6/7, p=0.395). Meningitis was observed in 4 (4.2%) cases (microsurgical N=2, endoscopic N=2). There was no significant difference in occurrence of meningitis between both surgical techniques (p=0.578). Mortality was 1% (N=1). The probable cause of death was the pulmonary embolism two weeks after the surgery, however no autopsy was performed.
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The main aim of our study was to analyze the influence of surgical technique on the EoR prior to intraoperative MRI and to evaluate the extent of additional resection after iMRI. According to our results, iMRI reveals significantly more often resectable tumor remnants after microsurgical than after endoscopic approach. This effect is even more pronounced in case of less invasive pituitary adenomas (Knosp 0-2). Moreover, the tumor remnant volume in iMRI images is significantly higher with microsurgical technique. Only in two cases a tumor remnant was identified on iMRI, when endoscopic approach was used. One case was a giant nonfunctioning adenoma classified as Knosp 2 (figure 2). A small tumor remnant was identified in iMRI between the wall of cavernous sinus and a diaphragm fold and removed thereafter (figure 3). The second case was an ACTH producing adenoma classified as Knosp 2 with clival infiltration, a significant retrosellar extension and herniation of the suprasellar cistern. The iMRI showed retrosellar remnant which could not be completely resected. The patient exhibited a persistence of Cushing disease of lower intensity postoperatively.
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In the case of invasive pituitary adenomas (Knosp 3-4) the additional resection after iMRI was regularly performed regardless of the technique employed and resulted in significantly higher number of GTR rates (table 3). Tough our data showed higher percentage of GTR in invasive
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adenomas treated endoscopically, the difference between surgical techniques was not statistically significant. Due to low sample size, it is not possible to draw any firm conclusion from this finding. Nevertheless, based on our experience, endoscopic transsphenoidal resection enables better visualization of the sella and adjacent structures, thereby allowing for more extensive tumor resection. The additional use of iMRI might be beneficial if unclear anatomy or bleeding from cavernous sinus complicates resection of these tumors. iMRI scan might under these circumstances result in the increase of EoR through the possibility of anatomical reorientation and navigation update. McLaughlin et al demonstrated that in large pituitary adenomas (diameter > 2 cm) endoscopic visualization of resection cavity after microsurgical resection lead to additional resection in 54% cases.9 Based on our data, we postulate that the additional use of iMRI in large pituitary adenomas (Knosp 3-4) might increase EoR more in combination with the endoscopic than with the microsurgical technique. Sylvester et al has shown more favorable resection rates using iMRI assisted endoscopic surgery than iMRI assisted microsurgical technique in both univariate (OR=1.83, CI 95% 1.17-2.87, p < 0.01) and multivariate analysis (OR 2.05, CI 95%1.21-3.46, p < 0.01).5 Our results are congruent with their findings and confirm the complementary role of iMRI and endoscopy. Interestingly, the comparison between endoscopic and microsurgical procedure without iMRI has shown trend to more profound EoR in the endoscopic cohort but results were statistically not significant in the study performed by Sylvester et al.5 In our study, the volume of tumor remnant was significantly smaller after endoscopic resection. Similarly, as the study performed by Sylvester et al, our data underline the important role of iMRI for higher EoR which is similarly relevant for longer PFS.5 Dallapiazza et al reported significantly higher EoR in adenomas with Knosp 0-2 compared to Knosp 3-4 (89% vs 28%, p<0.05).10 Our data confirm this finding and suggest that the added value of iMRI increases with the complexity of the treated tumor. While the iMRI can only marginally increase the already high resection rate in endoscopically treated Knosp 0-2 tumors, there is scope for significantly more extensive resection in complex Knosp 3-4 adenomas.
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Pituitary adenomas are benign tumors. However, the recurrence rate is still high. In the literature the reported recurrence rates are up to 20% in long-term follow-up.10,11 The recurrent tumors are prone to more aggressive growth with infiltration of the parasellar region.11 Furthermore, the loss of anatomical landmarks due to scarring make the surgical resections of recurrent adenomas more challenging.11 The additional treatment options, such as stereotactic radiosurgery can improve tumor control. However, the progress of neurological symptoms, such as visual disturbances or the risk of hypopituitarism might be difficult to avoid. Therefore, the value of complete tumor removal during the first surgical procedure is very high. Especially the combination of iMRI and endoscopy may help to achieve this goal. Furthermore, stereotactic radiosurgery might be more efficient and have less side effects in the case of smaller tumor remnants, which can be delivered by the combination of endoscopic approach and iMRI.12
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The longer surgical time needed for endoscopic approach and iMRI might provoke more surgical complications. As shown in our previous work, the routine use of iMRI in combination with microsurgical approach does not generate higher infection rates.4 Considering an endoscopic approach, the higher risk for cerebrospinal fluid has been reported by some authors. Sylvester et al demonstrated CSF leak in 17.5% of cases and their occurrence was slightly higher in the endoscopic group. In our results, the rate for CSF leak is lower than in the study from Sylvester et al.5 There was neither significant difference between CSF fistula nor between postoperative meningitis or revision surgeries in both cohorts. Given adequate reconstruction of the skull base, endoscopic surgery is not associated with increased risk of postoperative CSF-leak compared to microsurgical approach. Similarly, no significant difference was reported in the occurrence of CSF-leak comparing both techniques in the study performed by Sylvester et al.5 Magro et al evaluated 300 patients with non-functioning adenomas treated with endoscopic approach and found postoperative CSF leak rate of 2.7% .13 Postoperative meningitis was reported in 3.3% of cases in this study and was significantly associated with intraoperative and postoperative CSF leak (p<0.001).13 Our cohort
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shows a higher rate of CSF-fistula, but we found no higher occurrence of postoperative meningitis. The endoscopic group represents our initial experience with this technique, so that the inevitable learning curve of endoscopic approach might account for some part of the difference. Sella reconstruction in the historical cohort treated microsurgically was almost exclusively performed with fibrin coated sponge. After introduction of the endoscopic technique, autologous fat graft, Haddad flap or a combination were used in large adenomas. These different closure techniques might have influenced the rate of CSF leaks in our study. According to our data endoscopic approach exhibits a low risk profile and is comparable to microsurgical technique in regard to surgical complications.
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Mortini et al evaluated a large cohort of 788 microsurgically treated pituitary adenomas and described the visual normalization in 40.5% and improvement in 51.2% of patients in with large pituitary adenomas.14 Dehdashti et al published results of 200 pituitary adenomas operated via endoscopic approach and has shown visual normalization in 50% and improvement in 39% cases.15 In our study we distinguished only between visual improvement or no improvement after surgery. Our visual improvement rate (66.7%) is not as high as in both studies which might be attributed to smaller cohort of patients with visual dysfunction in our study group. The safety of both techniques is confirmed by the fact that there was no visual worsening in our study. Nevertheless, postoperative visual improvement achieved no significant difference between both techniques and both seem appropriate for optic nerve decompression.
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Preservation or improvement of pituitary function is an important goal of treatment strategy in pituitary adenomas. It has been suggested that the better visualization of pituitary gland using endoscopic transsphenoidal approach might decrease accidental intraoperative manipulation and the risk of pituitary gland injury and consequent iatrogenic hypopituitarism.16 Consistent with these findings, our data have shown significantly higher rate of satisfactory result with endoscopic transsphenoidal approach compared to microsurgical transsphenoidal approach in regard to pituitary function. In our population 29.3% of patients developed new hypopituitarism of some extent after surgery. This result correlates with published data.2,17,18 Interestingly, only one patient treated with endoscopic approach achieved an unsatisfactory result. These findings implicate possible advantage of this surgical technique in regard to pituitary function. In the study published by Margo et al anterior pituitary function generally worsened in 13.7% and new diabetes insipidus occurred in 11.6% among 300 evaluated patients treated endoscopically.13 Our endoscopic cohort has shown better preservation or improvement of pituitary function, however our population is much smaller and not as representative as in the study from Magro et al.13 Laws Jr. et al has evaluated the cohort of 80 patients with pituitary macroadenomas treated with endoscopic transnasal transsphenoidal approach and has shown the worsening of pituitary function in 6.3% of patients.13,16 This data is comparable with our results concerning the endoscopic approach although our evaluation is not limited to macroadenomas. In our study, pituitary function was an outcome criterion and worsening not regarded a complication but unfavorable outcome. We think that the improved visualization of the pituitary gland is one potential benefit of endoscopy that might reduce intraoperative injury of the gland and thus lead to better endocrine outcomes. Our cohort of patients with functioning adenomas was small, therefore we were not able to detect any difference in remission rates.
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Our study encompasses several biases. The comfortable availability of intraoperative visualization and reorientation using iMRI might lead to a bias by provoking the initiation of imaging by the surgeon even before he would finish the surgery, relying solely on optical visualization, thereby artificially reducing the extent of resection and GTR prior to iMRI. This bias might be more pronounced in the microsurgical approach, where optical visualization is more restricted. The smaller cohort of endoscopically treated patients might have influenced our results. Both cohorts were not treated simultaneously, so we have to assume some bias due to general improvements in care. The evaluation of pituitary function after 6 months is short. Longer follow-up might reveal additional improvement of hypopituitarism. Additionally, we combine functioning and non-
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functioning adenomas with categorical stratification as satisfactory and not satisfactory. Interpretation of a more detailed analysis would have been impossible due to small groups and retrospective character of this study. A prospective randomized study might provide us with a higher degree of evidence in determining the role of iMRI in microsurgical and endoscopic pituitary surgery.
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Conclusion:
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Intraoperative MRI seems to level the playing field between endoscopic and microsurgical resection of pituitary adenomas by identifying hidden tumor remnants. These can be identified and ultimately targeted by the surgeon leading to similar rates of GTR and EoR using either technique. The microsurgical approach with limited visualization of the surgical site benefits disproportionately. The relative benefit of iMRI appears to be smaller with endoscopic approach and tumors graded Knosp 0-2. Using iMRI, excellent results can be achieved employing either technique in Knosp 0-2 adenomas. Both techniques feature similar complication profiles. In our opinion patients with large invasive adenomas seem to benefit most from the combination of endoscopic technique and iMRI. Endoscopic approach seems to result in better endocrine outcomes.
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References:
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1.
Jho HD, Alfieri A. Endoscopic endonasal pituitary surgery: evolution of surgical technique and equipment in 150 operations. Minim Invasive Neurosurg. 2001;44(1):1-12. doi:10.1055/s-2001-13590.
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2.
Schaberg MR, Anand VK, Schwartz TH, Cobb W. Microscopic versus endoscopic transnasal pituitary surgery. Current Opinion in Otolaryngology & Head and Neck Surgery. 2010;18(1):8-14. doi:10.1097/MOO.0b013e328334db5b.
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3.
Singh H, Essayed WI, Cohen-Gadol A, Zada G, Schwartz TH. Resection of pituitary tumors: endoscopic versus microscopic. J Neurooncol. 2016;130(2):309-317. doi:10.1007/s11060016-2124-y.
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4.
Coburger J, König R, Seitz K, Bäzner U, Wirtz CR, Hlavac M. Determining the utility of intraoperative magnetic resonance imaging for transsphenoidal surgery: a retrospective study. Journal of Neurosurgery. 2014;120(2):346-356. doi:10.3171/2013.9.JNS122207.
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5.
Sylvester PT, Evans JA, Zipfel GJ, et al. Combined high-field intraoperative magnetic resonance imaging and endoscopy increase extent of resection and progression-free survival for pituitary adenomas. Pituitary. 2015;18(1):72-85. doi:10.1007/s11102-014-0560-2.
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6.
Hadad G, Bassagasteguy L, Carrau RL, et al. A Novel Reconstructive Technique After Endoscopic Expanded Endonasal Approaches: Vascular Pedicle Nasoseptal Flap. The Laryngoscope. 2006;116(10):1882-1886. doi:10.1097/01.mlg.0000234933.37779.e4.
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7.
Jho HD, Carrau RL. Endoscopic endonasal transsphenoidal surgery: experience with 50 patients. Journal of Neurosurgery. 1997;87(1):44-51. doi:10.3171/jns.1997.87.1.0044.
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8.
Knosp E, Steiner E, Kitz K, Matula C. Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery. 1993;33(4):610–7–discussion617–8.
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9.
McLaughlin N, Eisenberg AA, Cohan P, Chaloner CB, Kelly DF. Value of endoscopy for maximizing tumor removal in endonasal transsphenoidal pituitary adenoma surgery. Journal of Neurosurgery. 2013;118(3):613-620. doi:10.3171/2012.11.JNS112020.
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10.
Dallapiazza RF, Grober Y, Starke RM, Laws ER Jr, Jane JA Jr. Long-term Results of Endonasal Endoscopic Transsphenoidal Resection of Nonfunctioning Pituitary Macroadenomas. Neurosurgery. 2015;76(1):42-53. doi:10.1227/NEU.0000000000000563.
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11.
Przybylowski CJ, Dallapiazza RF, Williams BJ, et al. Primary versus revision transsphenoidal resection for nonfunctioning pituitary macroadenomas: matched cohort study. Journal of Neurosurgery. May 2016:1-8. doi:10.3171/2016.3.JNS152735.
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12.
Pomeraniec IJ, Dallapiazza R, Xu Z, Jane J, Jane J Jr, Sheehan JP. 115 Early vs Late Gamma Knife Radiosurgery Following Transsphenoidal Resection for Nonfunctioning Pituitary Macroadenomas. Neurosurgery. 2015;62(August):202. doi:10.1227/01.neu.0000467077.55355.a9.
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13.
Magro E, Graillon T, Lassave J, et al. Complications Related to the Endoscopic Endonasal Transsphenoidal Approach for Nonfunctioning Pituitary Macroadenomas in 300 Consecutive Patients. World Neurosurgery. 2016;89(C):442-453. doi:10.1016/j.wneu.2016.02.059.
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14.
Mortini P, Losa M, Barzaghi R, Boari N, Giovanelli M. Results of Transsphenoidal Surgery in a Large Series of Patients with Pituitary Adenoma. Neurosurgery. 2005;56(6):1222-1233. doi:10.1227/01.NEU.0000159647.64275.9D.
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15.
Dehdashti AR, Ganna A, Karabatsou K, Gentili F. Pure endoscopic endonasal approach for pituitary adenomas: Early surgical results in 200 patients and comparison with previous microsurgical series. 2008;62(5):1006-1015.
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16.
Laws ER Jr, Laws ER, Hsu L, et al. A Benchmark for Preservation of Normal Pituitary Function After Endoscopic Transsphenoidal Surgery for Pituitary Macroadenomas. World Neurosurgery. 2016;91:371-375. doi:10.1016/j.wneu.2016.04.059.
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17.
Frank G, Pasquini E, Farneti G, et al. The endoscopic versus the traditional approach in pituitary surgery. Neuroendocrinology. 2006;83(3-4):240-248. doi:10.1159/000095534.
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18.
Yamamoto N, Grober Y, Magro E, et al. Complications Related to the Endoscopic Endonasal Transsphenoidal Approach for Nonfunctioning Pituitary Macroadenomas in 300 Consecutive Patients. 2016;89:442-453. doi:10.1016/j.wneu.2016.02.059.
431 Figure legend
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Figure 1: Intraoperative tumor volume prior to intraoperative MRI (cm3). Figure 2: Large intra- and suprasellar pituitary adenoma on T2 weighted coronal MRI image. Figure 3: Small tumor remnant on enhanced T1 weighted coronal MRI images (Arrow).
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ACCEPTED MANUSCRIPT Table 1. Patients and tumor characteristics. Total
Microsurgery
Endoscopy
96
68
28
54
56
55
7 - 78
22 - 74
7 - 78
74% (71)
76% (52)
7.848
8.206
Knosp 0-2
51% (49)
50% (34)
Knosp 3-4
49% (47)
50% (34)
non-functioning
67.7% (65)
69% (47)
GH
16.7% (16)
16% (11)
18% (5)
ACTH
10.4% (10)
9% (6)
18% (5)
Prolactinoma
2.1% (2)
3% (2)
0
GnRH
2.1% (2)
3% (2)
0
1% (1)
0
3% (1)
n
median min - max
male ratio Mean tumor Volume
M AN U
Adenoma subtype
SC
Sex
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Age
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68% (19) 6.976
54% (15) 46% (13)
61% (17)
ACCEPTED MANUSCRIPT Table 2. Volumetric and endocrinological results. endoscopic
Mean preoperative volume (cm3)
8.206 (0.127 – 49.698)
6.976 (0.058 – 39.125)
0.158
Mean intraoperative volume (cm3)
2.137 (0.000 – 26.037)
0.873 (0.000 – 17.751)
0.023
Mean postoperative volume (cm3)
0.994 (0.000 – 23.008)
0.329 (0.000 – 17.751)
0.228
No resection after iMRI
47.1% (n=32/68)
71.4% (n=20/28)
0.042
Satisfactory endocrine Outcome
60.6% (n=40/66)
96.2% (n=25/26)
0.001
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p
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microsurgical
SC
Operation technique
Table 3. Gross total resection (GTR) inACCEPTED intraoperativeMANUSCRIPT and postoperative MRI stratified according to surgical technique and Knosp grade and iMRI influence on GTR.
GTR according to iMRT
GTR according to post-OP MRI
Endoscopy
p
Knosp 0-2
58.8% (20)
86.7% (13)
0.097
Knosp 3-4
26.5% (9)
30.8% (4)
1.000
Microsurgery
Endoscopy
p
Microsurgery
Endoscopy
79.4% (27)
93.3% (14)
0.406
0.012
0.122
32.4% (11)
46.2% (6)
0.5
0.002
0.021
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Microsurgery
iMRI influence on GTR
30,000
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20,000
RI PT
15,000
SC
10,000
,000 Microsurgical
M AN U
5,000
Endoscopic
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Surgical technique
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Intraoperative tumor volume
25,000
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ACCEPTED MANUSCRIPT Research highlights
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Endoscopic approach results in significantly less tumor volume before iMRI scanning Higher EoR may be achieved in invasive pituitary adenomas with para- or suprasellar extension through combination of endoscopy and iMRI Endoscopic approach seems to result in better endocrine outcome especially in Knosp 0-2 pituitary adenomas
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ACCEPTED MANUSCRIPT Abbreviations and Acronyms
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CSF: Cerebrospinal fluid, EoR: Extent of resection, GH: Growth hormone, GTR: Gross total resection, iMRI: Intraoperative magnetic resonance image, PFS: Progression free survival