Clinical Neurology and Neurosurgery 119 (2014) 75–79
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Results and risk factors for recurrence following endoscopic endonasal transsphenoidal surgery for pituitary adenoma Imithri Bodhinayake a,1 , Malte Ottenhausen a,1 , Michael A. Mooney a , Kartik Kesavabhotla a , Paul Christos b , Justin T. Schwarz a , John A. Boockvar a,∗ a b
Weill Cornell Brain Tumor Center, Department of Neurosurgery, Weill Medical College of Cornell University, New York, USA Division of Biostatistics and Epidemiology, Department of Public Health, Weill Medical College of Cornell University, New York, USA
a r t i c l e
i n f o
Article history: Received 28 August 2013 Received in revised form 13 December 2013 Accepted 19 January 2014 Available online 27 January 2014 Keywords: Endoscopic Pituitary Recurrence Risk factors Transsphenoidal
a b s t r a c t Background: Endoscopic endonasal (EE) transsphenoidal surgery is an important surgical approach to the treatment of sellar pathology, particularly for pituitary adenomas. Risk factors for the radiographic recurrence of pituitary adenomas resected using a purely endoscopic approach have not been established. This study investigates outcomes and identifies risk factors for recurrence following EE transsphenoidal surgery for pituitary adenoma. Methods: We performed a retrospective review of 64 patients with pituitary adenomas undergoing EE surgery by a single, right-handed surgeon preferentially operating through the right nares. Post-operative MRI studies were utilized to monitor for residual disease or disease recurrence. Results: Residual tumor was found in 31.2% of patients. Over a median follow-up period of 23.1 months (range 4–62.5), 4 (20%) of these patients showed recurrence. Two patients with inconclusive postoperative imaging had subsequent imaging consistent with recurrence, making the total recurrence in our series 9.4%. While no statistically significant effects of gender, age or history of previous treatment were seen, amenorrhea on presentation and maximum tumor diameter >10 mm were significant risk factors for radiographic recurrence (p = 0.044 and 0.005, respectively). No predominant side of residual tissue was identified in these tumors operated through the right nares. Conclusions: Only 20% of patients with residual tumor developed recurrent disease over a median follow up of 23.1 months. This recurrence rate may be an important consideration in cases where gross total resection is not feasible. Preferentially operating from the right does not seem to influence the location of residual tumor. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Transsphenoidal surgery is the preferred approach for a wide range of pathology involving the sella turcica, including the surgical treatment of pituitary adenomas. Since its introduction by Schloffer in 1906, transsphenoidal surgery has advanced significantly from the use of a headlight for visualization to the endoscopic techniques that are becoming common practice today [1]. These endoscopic techniques allow for excellent visualization of regional anatomy and extensive tumor resection.
∗ Corresponding author at: Weill Medical College of Cornell University, 525 East 68th Street, Box 99, New York, 10065, USA. Tel.: +1 212 746 2820; fax: +1 212 746 8226. E-mail addresses: [email protected] (I. Bodhinayake), [email protected] (J.A. Boockvar). 1 These authors contributed equally to the work. 0303-8467/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2014.01.020
Numerous studies have documented the success of the endoscopic endonasal (EE) approach to date [2–7]. Several direct comparisons to microscopic or transcranial approaches have demonstrated comparable, or superior, results with the EE approach [8–14]. However, the EE approach to the resection of pituitary adenomas does have its limitations, which include post-operative nasal complaints as well as risk for post-operative CSF leak [15]. Additionally, limitations inherent to surgical disease of the pituitary gland remain in the EE approach: these include subtotal resection, the recurrence of tumors postoperatively, and the risk for serious intra-operative complications [13]. Given the relatively recent implementation of EE transsphenoidal surgery for pituitary tumors, risk factors for residual or recurrent disease following this procedure have not been defined [16]. Additionally, tumor re-growth rates in patients with residual disease have not been well examined. To our knowledge, this is the first study directly examining risk factors for recurrence following
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a purely EE approach to pituitary pathology. We examined a series of 64 patients undergoing surgery by a single surgeon at our institution between 2006 and 2011. We report our results, including residual rates and recurrence rates, in an effort to define outcomes and identify risk factors for recurrence with this rapidly evolving neurosurgical approach to pituitary pathology. 2. Materials and methods 2.1. Patient demographics This study was conducted in accordance with institutional policies. We reviewed a retrospectively collected database of patients with pathology-confirmed pituitary adenoma who underwent EE surgery at our institution by a single surgeon between April 2006 and June 2011. However, those with less than 4 months of followup time or those undergoing a biopsy procedure were excluded. Presenting symptoms, operative details, pathological diagnoses, post-operative outcomes, and post-operative complaints were all recorded. Data were collected by chart review. 2.1.1. Radiographic evaluation Preoperative and postoperative MRI was performed on all patients. An MRI was done on post-operative day (POD) 1, approximately POD 90, and at varying intervals thereafter based on patient characteristics. All MRI reports were reviewed for the presence of post-operative residual and/or evidence of tumor growth. Residual disease was defined as characteristic tissue identified on POD 1 or POD 90 MRI, as reported by the radiologist at the time of the study. Recurrence was defined as interval tumor growth on MRI between tumor resection and the last follow-up imaging study. Radiographic recurrence was reported by the radiologist at the time of the study. 2.2. Surgical technique The right nares was preferentially entered by this right-handed surgeon. After application of topical cocaine to the nasal mucosa, the mucosa of the middle turbinates was infiltrated with a mixture of 1% lidocaine and epinephrine (1:100,000). The sphenoid ostia were identified bilaterally and enlarged by removal of bone. A tissue shaver was used to resect the posterior third of the nasal septum. Using a highspeed drill and curettes, the anterior wall of the sella was opened. We attempted to resect microadenomas en bloc, whereas macroadenomas were decompressed internally first by removing the inferior portion of the tumor, followed by resection of the lateral portions. The dura mater was opened medial to the internal carotid artery in cases of cavernous sinus (CS) invasion. Brainlab neuronavigation was used for all cases. Skull base defects were closed in a multilayered fashion, as described previously [17]. 2.3. Statistical evaluation Fisher Exact Test was performed to determine significant risk factors for recurrence. Significance was defined as p < 0.05. Kaplan–Meier survival analysis was performed on patients with recurrence. Statistical analyses were performed using MedCalc for Windows, version 12.2.1 (MedCalc Software, Mariakerke, Belgium). 3. Results Our cohort of patients consisted of 64 individuals who underwent a purely EE transsphenoidal resection of pituitary adenomas by a single surgeon at our institution between April 2006 and June 2011 (Table 1). The median age of patients in this study was 46 years, and female patients made up 62.5% of the cohort. The mean
Table 1 Patient characteristics. Number of patients Age (years) Mean ± SD Median (range) Sex Male Female Follow-up time (months) Mean Median (range) Presenting symptoms Headaches Visual deficits Amenorrhea Incidental Galactorrhea Decreased libido Diplopia Acromegaly Apoplexy Seizure Prior surgery Yes No Maximum diameter (mm) Mean Median (range) Maximum diameter > 10 mm Yes No
64 46.7 ± 16.7 46 (12–81) 24 (37.5%) 40 (62.5%) 24.3 23.1 (4.0–62.5) 28 (43.8%) 25 (39.1%) 10 (15.6%) 11 (17.2%) 13 (20.3%) 5 (7.8%) 6 (9.4%) 3 (4.7%) 1 (1.6%) 1 (1.6%) 4 (6.3 %) 60 (93.8%) 18.9 19 (8–40) 50 (78.1%) 9 (14.1%)
Table 2 Surgical outcomes. Outcome
# patients (%)
Post-operative CSF leak Diabetes insipidus Panhypopituitarism Wound infection New visual field deficits Improvement in presenting visual deficits Residual Yes - Within CS - Outside CS No residual (GTR) Surgical revision Adjuvant stereotactic radiosurgery Recurrence
4 (4.1%) 2 (3.1%) 3 (4.7%) 1 (1.6%) 0 23/25 (92%) 20 (31.3%) 9 (14.1%) 11 (17.2%) 44 (68.7%) 7 (10.9%) 7 (10.9%) 6 (9.4%)
follow-up time was 24.3 months in this study (median 23.1, range 4.0–62.5). Headache and visual deficits were the most common complaints on initial patient evaluation, occurring in 43.8% and 39.1% of patients, respectively. Visual deficits included decreased visual acuity and decreased peripheral vision. The majority of lesions had a maximum diameter greater than 10 mm (78.1%). Surgical outcomes and complications are reported (Table 2). Residual disease was reported by the radiologist evaluating the post-operative and 3-month follow-up MRI. Gross total resection (GTR) was achieved in 68.7% of patients. Residual tumor, classified as intracavernous or extracavernous based on MRI findings, was intracavernous in 14.1% of cases. However, only 4 of these patients (20%) showed evidence of radiologic recurrence during the follow-up period. Two additional patients who had post-operative imaging that was inconclusive for residual disease versus normal pituitary gland had recurrence, making a total of 6 patients (9.4%) with recurrence in our series. Three out of these 6 patients subsequently required surgical revision with repeat EE surgery and three patients received stereotactic radiosurgery. The decision for stereotactic radiosurgery on these three patients was based on patient
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Table 4 Risk factors for radiographic recurrence in patients with residual tumor. Variable
Fig. 1. Kaplan–Meier survival analysis demonstrating the probability of radiographic recurrence-free survival over the follow-up period in this study.
preference and the location of the residual tumor. Kaplan–Meier analysis of recurrence free survival during the follow-up period is shown (Fig. 1). When risk factors for recurrence were analyzed in this patient cohort (Table 3), age and gender were not associated with an increased risk of recurrence. Presentation with amenorrhea and maximum tumor diameter greater than 10 mm significantly increased the risk for recurrence (p = 0.044 and 0.005, respectively). Notably, the presence of post-operative residual and residual outside the CS was nearly significantly associated with increased risk of recurrence in these patients (p = 0.071 and 0.058, respectively). Risk factors for recurrence were further analyzed in the subset of patients with residual tumor in an attempt to identify factors that place these patients at increased risk for recurrence (Table 4). When these 20 patients were analyzed, presentation with amenorrhea was found to be an independent risk factor for recurrence in these patients (p = 0.032). Age, gender, other presenting symptoms, and reported tumor characteristics were not found to be risk factors for recurrence in these patients.
Table 3 Risk factors for radiographic recurrence. Variable Gender Male Female Age 50 Presenting symptoms Headache Visual field deficits Diplopia Amenorrhea Galactorrhea Acromegaly Apoplexy Seizure Incidental Prior surgery Prior therapy Tumor characteristics Max diameter > 10 mm Prolactin staining Post-operative residual Residual within cavernous sinus Residual outside cavernous sinus *
# with recurrenceN (%)
p-Value
3 (12.5%) 3 (7.5%)
0.402
2 (20%) 1 (3.7%)
0.234 0.188
1 (3.6%) 3 (12%) 1 (16.7%) 3 (30%) 3 (23.1) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (25%) 0 (0%)
0.167 0.435 0.460 0.044* 0.092 0.741 0.906 0.908 0.306 0.332 0.668
4 (8%) 1 (8.4%) 4 (20%) 1 (11.1%) 3 (23.1%)
0.005* 0.687 0.071 0.613 0.058
Denotes the statistically significant values.
Gender Male Female 12 Age 50 Presenting symptoms Headache Visual field deficits Diplopia Amenorrhea Galactorrhea Acromegaly Incidental Prior surgery Tumor characteristics Max diameter > 10 mm Prolactin staining *
# with recurrenceN (%)
p-Value
2 (25%) 2 (16.7%)
0.618
2 (40%) 0 (0%)
0.249 0.148
1 (14.3%) 2 (22.2%) 1 (50%) 2 (100%) 2 (66.7%) 0 (0%) 0 (0%) 1 (50%)
0.561 0.625 0.368 0.032* 0.080 0.800 0.272 0.368
2 (13.3%) 1 (33.3%)
0.249 0.530
Denotes the statistically significant values.
Table 5 Location of residual tumor. Number of patients with residual tumor
Side of residual
8 (40%) 5 (25%) 5 (25%) 2 (10%)
Midline Left Right Unclear (outside imaging)
Review of post-operative MRI reports revealed that residual tumor was located on both the left and the right side (Table 5). No preferential tumor burden on the side ipsilateral to the right nares was discovered. 4. Discussion While the EE approach to pituitary pathology is becoming increasingly utilized, long-term outcomes and clinical predictors of prognosis remain largely undefined with this technique. In this study, we present a group of patients with pituitary adenoma who underwent EE surgery with a single surgeon at our institution, and we begin to define the risk factors for recurrence in this population of patients. The mean follow-up time of 2 years allows for analysis of tumor re-growth and recurrence rates in this patient population, outcomes which are important considerations in the evolving EE pituitary surgery. 4.1. Gross total resection (GTR) rates Gross total resection rates in our study are comparable to results reported by other groups using the EE approach for various subtypes of pituitary tumors [6,13,14,16,18,19]. Two studies of non-functional pituitary adenomas (NFPAs), which are defined as endocrinologically inactive tumors, reported a GTR rate of 74–76.9% using the EE approach [6,14]. In a recent study of pituitary macroadenomas, the overall GTR rate was 76.1% using the EE approach [18]. Tabaee et al. reported a GTR in 89% of patients with pituitary adenomas, and found tumor size to be the only significant predictor of the extent of tumor removal, with smaller tumors being more likely to be completely removed [16]. Hofstetter et al. expanded upon this finding and found that volumetric analysis revealing a tumor volume greater than 10 cm3 for pituitary adenomas was a powerful predictor of resectability [18]. Although we did not perform volumetric analysis, the majority (78.1%) of tumors in our study had a maximum diameter greater than 10 mm, which
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likely contributed to the slightly lower GTR percentage (68.7%) in this study. 4.2. Recurrence rates Literature for recurrence rates following purely EE pituitary surgery is lacking. In our study, imaging results were utilized to define tumor recurrence, so both functional (hormone secretion) and non-functional (no functional hormone secretion) pituitary adenomas (NFPAs) were studied. With this approach, we found that 6 out of 64 patients (9.4%) who underwent EE surgery experienced radiographic recurrence within the study’s follow-up period. Two cases recurred within the first year of follow-up, 1 case recurred in the second year, 2 cases recurred in the third year, and 1 case recurred in the fourth year of follow-up (Fig. 1). As endocrinological data were not collected in our study, these rates of recurrence can be best compared to other studies using radiographic outcomes. Most studies using radiographic outcomes of recurrence have focused on NFPAs. While recurrence of NFPAs following non-EE transsphenoidal surgery is well defined [20–25], data examining radiographic recurrence of NFPAs following EE surgery are sparse. In one recent study utilizing the EE technique, Kabil et al. reported that radiographic NFPA recurrence was 7% over a mean follow-up of 38.2 months [26]. This percentage is similar to the recurrence rate observed for all tumors in our study over a shorter follow-up period (7.1% over mean follow-up of 24 months). However, Kabil et al. did not report the incidence of recurrence per year in this study, which limits the comparison to recurrence in our study. One other recent study by Dehdashti et al. assessed long-term outcomes of NFPAs following EE surgery and reported a GTR of 88% for NFPAs and reported zero cases of recurrence at a mean follow-up of 22 months. We hypothesize that our recurrence rate is higher than Dehdashti et al.’s rate due to the lower GTR percentage in our series (68.7% versus 88%), as well as our low threshold for defining radiographic recurrence. Several cases of recurrence in our study involved only 1–2 mm increases in size of the tumor on follow-up imaging studies. The low threshold for defining radiographic recurrence and the close imaging follow-up of patients in our study are important considerations when interpreting our study’s recurrence rates. Recurrence rates for functional pituitary adenomas are often reported separately in the literature, as biochemical assays allow for improved sensitivity when monitoring these tumors. A recent report by Hofstetter et al. examined rates of recurrence in functional pituitary adenomas following endocrinological cure when using the EE approach and found that 100% of those with endocrinological cure remained disease free at a mean of 22.8 months follow-up, regardless of the tumor’s functional subtype (prolactin secreting vs. ACTH secreting vs. GH secreting) [7]. Other studies utilizing the EE approach for functional adenomas reported similar results [13,14]. As our study did not analyze the hormonal characteristics of tumors, comparison to these studies regarding endocrinological cure is limited. Additionally, longer-term followup is warranted in all of these studies, since late recurrence after presumed cure is well established for functional adenomas [27,28]. 4.3. Risk factors for recurrence In one of the most comprehensive analyses of risk factors for recurrence to date, Roelfsema et al. reported a meta-analysis of clinical predictors of recurrence in both microscopic and EE pituitary surgeries over the past 3 decades [29]. They reported that the majority of recurrences occurred between 1 and 5 years after surgery and that patients with a prolactinoma had a higher recurrence incidence than patients with acromegaly or Cushing’s disease. Recurrence rates of prolactinoma were not significantly
different than those of NFPA in this analysis. Age, gender, tumor size, and tumor invasion were generally unrelated to recurrence, but some studies included in this analysis did show an increased risk for recurrence with increased tumor size. This increased risk of recurrence with increased tumor size is consistent with our results showing a significant risk of recurrence in tumors with a maximum diameter greater than 10 mm. The Roelfsema et al. study did not examine the impact of post-operative residual as a risk factor for recurrence, however, subtotal resection has been strongly linked to increased tumor recurrence in non-EE transsphenoidal studies in the past [20–24]. Notably, 95% of the studies included in the Roelfsema et al. analysis utilized a microscopic approach to the sella, as there are few reports of recurrence using the EE approach to date. To our knowledge, the study presented here is the first to specifically address risk factors for recurrence following a purely EE approach to pituitary pathology. In our study, while there were 20 patients with post-operative residual tumor, only 4 of them showed radiographic recurrence. We feel that these findings may be an important consideration when a surgeon is faced with pursuing aggressive resection for fear of recurrence from residual tumor. Furthermore, the anatomical location of residual tumor within or outside the cavernous sinus was not associated with increased risk of recurrence. The preferential operation through the right nares did not lead to preferential residual tumor burden on the ipsilateral side. When the subset of patients with post-operative residual tumor is analyzed separately, presentation with amenorrhea was an independent risk factor for recurrence. This suggests that patients presenting with a hormonally active tumor (likely a gonadotrophic tumor or prolactinoma) who undergo a subtotal resection were at significantly increased risk for tumor re-growth/recurrence. While endocrinological data is not available to confirm this finding in our study, these results are consistent with the analysis by Roelfsema et al. which reported that prolactinomas are more likely to recur following transsphenoidal surgery [29]. Our results suggest that this association holds true for EE pituitary surgery today. 4.4. Limitations While this study outlines our results with a purely EE approach to the resection of pituitary adenomas and raises important considerations for recurrence in patients undergoing this procedure, it is not without limitations. First, the retrospective design of this study is a limiting factor: clinical presentations, surgical outcomes, and post-operative complications were all based on chart review, which restricts the analysis to the information provided in charts. Second, tumor recurrence was only established radiographically, without accompanying endocrinological data. Third, while a mean follow-up time of 24.3 months captured several recurrences, longer follow-up is necessary to fully assess the risk for recurrence in this population of patients. 4.5. Conclusions This report outlines the patient characteristics, surgical results, and complications of 64 endoscopic endonasal surgeries performed for pituitary adenomas by a single surgeon at our institution. It specifically addresses risk factors for radiographic recurrence following the EE approach. Over a mean follow-up time of 24.3 months, 6 individuals were deemed to have disease recurrence on follow-up imaging studies. Risk factor analysis revealed that maximal tumor diameter greater than 10 mm was significantly associated with recurrence. Gender, patient age and presenting symptoms (apart from amenorrhea) were not significantly associated with recurrence within this time period. While patients with residual tumor identified on post-operative MRI were at
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increased risk for developing recurrence, they represented only 20% of patients with evidence of post-operative residual tumor. The independent risk factor of amenorrhea suggest that this subset of patients may benefit from more stringent follow-up imaging or more aggressive use of adjuvant therapy or re-resection. Future studies are necessary to define long-term outcomes and prognosis for patients undergoing EE surgery. Acknowledgements We would like to acknowledge the following medical students for their assistance in data collection: Joon-Hyung Kim, Evan Bander, Ana Pacheco-Navarro, Stacy Y. Chu, Matthew W. Rosenbaum, and Nicolas A. Yannuzzi. Financial disclosures: Paul Christos, Dr. P.H., was partially supported by the following grant: Clinical Translational Science Center (CTSC) (UL1-RR024996). Conflict of interests: The authors declare that they have no conflicts of interest. References [1] Prevedello DM, Doglietto F, Jane JA, Jagannathan J, Han J, Laws ER. History of endoscopic skull base surgery: its evolution and current reality. J Neurosurg 2007;107:206–13. [2] Heilman CB, Shucart WA, Rebeiz EE. Endoscopic sphenoidotomy approach to the sella. Neurosurgery 1997;41:602–7. [3] Jho HD, Carrau RL. Endoscopic endonasal transsphenoidal surgery: experience with 50 patients. J Neurosurg 1997;87:44–51. [4] Jho HD, Carrau RL, Ko Y, Daly MA. Endoscopic pituitary surgery: an early experience. Surg Neurol 1997;47:213–22 [discussion 222-213]. [5] Rodziewicz GS, Kelley RT, Kellman RM, Smith MV. Transnasal endoscopic surgery of the pituitary gland: technical note. Neurosurgery 1996;39:189–92 [discussion 192-183]. [6] Messerer M, De Battista JC, Raverot G, Kassis S, Dubourg J, Lapras V, et al. Evidence of improved surgical outcome following endoscopy for nonfunctioning pituitary adenoma removal. Neurosurg Focus 2011;30:E11. [7] Hofstetter CP, Shin BJ, Mubita L, Huang C, Anand VK, Boockvar JA, et al. Endoscopic endonasal transsphenoidal surgery for functional pituitary adenomas. Neurosurg Focus 2011;30:E10. [8] O’Malley BW, Grady MS, Gabel BC, Cohen MA, Heuer GG, Pisapia J, et al. Comparison of endoscopic and microscopic removal of pituitary adenomas: single-surgeon experience and the learning curve. Neurosurg Focus 2008;25:E10. [9] Cho DY, Liau WR. Comparison of endonasal endoscopic surgery and sublabial microsurgery for prolactinomas. Surg Neurol 2002;58:371–5 [discussion 375376]. [10] Jain AK, Gupta AK, Pathak A, Bhansali A, Bapuraj JR. Excision of pituitary adenomas: randomized comparison of surgical modalities. Br J Neurosurg 2007;21:328–31.
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[11] Komotar RJ, Starke RM, Raper DM, Anand VK, Schwartz TH. Endoscopic endonasal compared with microscopic transsphenoidal and open transcranial resection of giant pituitary adenomas. Pituitary 2012;15:150–9. [12] Couldwell WT. Transsphenoidal and transcranial surgery for pituitary adenomas. J Neurooncol 2004;69:237–56. [13] 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. Neurosurgery 2008;62:1006–15 [discussion 1015-1007]. [14] Frank G, Pasquini E, Farneti G, Mazzatenta D, Sciarretta V, Grasso V, et al. The endoscopic versus the traditional approach in pituitary surgery. Neuroendocrinology 2006;83:240–8. [15] Gondim JA, Schops M, de Almeida JP, de Albuquerque LA, Gomes E, Ferraz T, et al. Endoscopic endonasal transsphenoidal surgery: surgical results of 228 pituitary adenomas treated in a pituitary center. Pituitary 2010;13:68–77. [16] Tabaee A, Anand VK, Barrón Y, Hiltzik DH, Brown SM, Kacker A, et al. Predictors of short-term outcomes following endoscopic pituitary surgery. Clin Neurol Neurosurg 2009;111:119–22. [17] Leng LZ, Brown S, Anand VK, Schwartz TH. “Gasket-seal” watertight closure in minimal-access endoscopic cranial base surgery. Neurosurgery 2008;62:342–3 [discussion ONSE343]. [18] Hofstetter CP, Nanaszko MJ, Mubita LL, Tsiouris J, Anand VK, Schwartz TH. Volumetric classification of pituitary macroadenomas predicts outcome and morbidity following endoscopic endonasal transsphenoidal surgery. Pituitary 2012;15:450–63. [19] Jho HD. Endoscopic transsphenoidal surgery. J Neurooncol 2001;54:187–95. [20] Brochier S, Galland F, Kujas M, Parker F, Gaillard S, Raftopoulos C, et al. Factors predicting relapse of nonfunctioning pituitary macroadenomas after neurosurgery: a study of 142 patients. Eur J Endocrinol 2010;163:193–200. [21] Chang EF, Zada G, Kim S, Lamborn KR, Quinones-Hinojosa A, Tyrrell JB, et al. Long-term recurrence and mortality after surgery and adjuvant radiotherapy for nonfunctional pituitary adenomas. J Neurosurg 2008;108:736–45. [22] Ferrante E, Ferraroni M, Castrignanò T, Menicatti L, Anagni M, Reimondo G, et al. Non-functioning pituitary adenoma database: a useful resource to improve the clinical management of pituitary tumors. Eur J Endocrinol 2006;155: 823–9. [23] Greenman Y, Ouaknine G, Veshchev I, Reider-Groswasser II, Segev Y, Stern N. Postoperative surveillance of clinically nonfunctioning pituitary macroadenomas: markers of tumour quiescence and regrowth. Clin Endocrinol (Oxf) 2003;58:763–9. [24] Losa M, Mortini P, Barzaghi R, Ribotto P, Terreni MR, Marzoli SB, et al. Early results of surgery in patients with nonfunctioning pituitary adenoma and analysis of the risk of tumor recurrence. J Neurosurg 2008;108:525–32. [25] O’Sullivan EP, Woods C, Glynn N, Behan LA, Crowley R, O’Kelly P, et al. The natural history of surgically treated but radiotherapy-naïve nonfunctioning pituitary adenomas. Clin Endocrinol (Oxf) 2009;71:709–14. [26] Kabil MS, Eby JB, Shahinian HK. Fully endoscopic endonasal vs. transseptal transsphenoidal pituitary surgery. Minim Invasive Neurosurg 2005;48: 348–54. [27] Amar AP, Couldwell WT, Chen JC, Weiss MH. Predictive value of serum prolactin levels measured immediately after transsphenoidal surgery. J Neurosurg 2002;97:307–14. [28] Hammer GD, Tyrrell JB, Lamborn KR, Applebury CB, Hannegan ET, Bell S, et al. Transsphenoidal microsurgery for Cushing’s disease: initial outcome and longterm results. J Clin Endocrinol Metab 2004;89:6348–57. [29] Roelfsema F, Biermasz NR, Pereira AM. Clinical factors involved in the recurrence of pituitary adenomas after surgical remission: a structured review and meta-analysis. Pituitary 2012;15:71–83.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Results and risk factors for recurrence following endoscopic endonasal transsphenoidal surgery for pituitary adenoma Imithri Bodhinayake a,1 , Malte Ottenhausen a,1 , Michael A. Mooney a , Kartik Kesavabhotla a , Paul Christos b , Justin T. Schwarz a , John A. Boockvar a,∗ a b
Weill Cornell Brain Tumor Center, Department of Neurosurgery, Weill Medical College of Cornell University, New York, USA Division of Biostatistics and Epidemiology, Department of Public Health, Weill Medical College of Cornell University, New York, USA
a r t i c l e
i n f o
Article history: Received 28 August 2013 Received in revised form 13 December 2013 Accepted 19 January 2014 Available online 27 January 2014 Keywords: Endoscopic Pituitary Recurrence Risk factors Transsphenoidal
a b s t r a c t Background: Endoscopic endonasal (EE) transsphenoidal surgery is an important surgical approach to the treatment of sellar pathology, particularly for pituitary adenomas. Risk factors for the radiographic recurrence of pituitary adenomas resected using a purely endoscopic approach have not been established. This study investigates outcomes and identifies risk factors for recurrence following EE transsphenoidal surgery for pituitary adenoma. Methods: We performed a retrospective review of 64 patients with pituitary adenomas undergoing EE surgery by a single, right-handed surgeon preferentially operating through the right nares. Post-operative MRI studies were utilized to monitor for residual disease or disease recurrence. Results: Residual tumor was found in 31.2% of patients. Over a median follow-up period of 23.1 months (range 4–62.5), 4 (20%) of these patients showed recurrence. Two patients with inconclusive postoperative imaging had subsequent imaging consistent with recurrence, making the total recurrence in our series 9.4%. While no statistically significant effects of gender, age or history of previous treatment were seen, amenorrhea on presentation and maximum tumor diameter >10 mm were significant risk factors for radiographic recurrence (p = 0.044 and 0.005, respectively). No predominant side of residual tissue was identified in these tumors operated through the right nares. Conclusions: Only 20% of patients with residual tumor developed recurrent disease over a median follow up of 23.1 months. This recurrence rate may be an important consideration in cases where gross total resection is not feasible. Preferentially operating from the right does not seem to influence the location of residual tumor. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Transsphenoidal surgery is the preferred approach for a wide range of pathology involving the sella turcica, including the surgical treatment of pituitary adenomas. Since its introduction by Schloffer in 1906, transsphenoidal surgery has advanced significantly from the use of a headlight for visualization to the endoscopic techniques that are becoming common practice today [1]. These endoscopic techniques allow for excellent visualization of regional anatomy and extensive tumor resection.
∗ Corresponding author at: Weill Medical College of Cornell University, 525 East 68th Street, Box 99, New York, 10065, USA. Tel.: +1 212 746 2820; fax: +1 212 746 8226. E-mail addresses: [email protected] (I. Bodhinayake), [email protected] (J.A. Boockvar). 1 These authors contributed equally to the work. 0303-8467/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2014.01.020
Numerous studies have documented the success of the endoscopic endonasal (EE) approach to date [2–7]. Several direct comparisons to microscopic or transcranial approaches have demonstrated comparable, or superior, results with the EE approach [8–14]. However, the EE approach to the resection of pituitary adenomas does have its limitations, which include post-operative nasal complaints as well as risk for post-operative CSF leak [15]. Additionally, limitations inherent to surgical disease of the pituitary gland remain in the EE approach: these include subtotal resection, the recurrence of tumors postoperatively, and the risk for serious intra-operative complications [13]. Given the relatively recent implementation of EE transsphenoidal surgery for pituitary tumors, risk factors for residual or recurrent disease following this procedure have not been defined [16]. Additionally, tumor re-growth rates in patients with residual disease have not been well examined. To our knowledge, this is the first study directly examining risk factors for recurrence following
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a purely EE approach to pituitary pathology. We examined a series of 64 patients undergoing surgery by a single surgeon at our institution between 2006 and 2011. We report our results, including residual rates and recurrence rates, in an effort to define outcomes and identify risk factors for recurrence with this rapidly evolving neurosurgical approach to pituitary pathology. 2. Materials and methods 2.1. Patient demographics This study was conducted in accordance with institutional policies. We reviewed a retrospectively collected database of patients with pathology-confirmed pituitary adenoma who underwent EE surgery at our institution by a single surgeon between April 2006 and June 2011. However, those with less than 4 months of followup time or those undergoing a biopsy procedure were excluded. Presenting symptoms, operative details, pathological diagnoses, post-operative outcomes, and post-operative complaints were all recorded. Data were collected by chart review. 2.1.1. Radiographic evaluation Preoperative and postoperative MRI was performed on all patients. An MRI was done on post-operative day (POD) 1, approximately POD 90, and at varying intervals thereafter based on patient characteristics. All MRI reports were reviewed for the presence of post-operative residual and/or evidence of tumor growth. Residual disease was defined as characteristic tissue identified on POD 1 or POD 90 MRI, as reported by the radiologist at the time of the study. Recurrence was defined as interval tumor growth on MRI between tumor resection and the last follow-up imaging study. Radiographic recurrence was reported by the radiologist at the time of the study. 2.2. Surgical technique The right nares was preferentially entered by this right-handed surgeon. After application of topical cocaine to the nasal mucosa, the mucosa of the middle turbinates was infiltrated with a mixture of 1% lidocaine and epinephrine (1:100,000). The sphenoid ostia were identified bilaterally and enlarged by removal of bone. A tissue shaver was used to resect the posterior third of the nasal septum. Using a highspeed drill and curettes, the anterior wall of the sella was opened. We attempted to resect microadenomas en bloc, whereas macroadenomas were decompressed internally first by removing the inferior portion of the tumor, followed by resection of the lateral portions. The dura mater was opened medial to the internal carotid artery in cases of cavernous sinus (CS) invasion. Brainlab neuronavigation was used for all cases. Skull base defects were closed in a multilayered fashion, as described previously [17]. 2.3. Statistical evaluation Fisher Exact Test was performed to determine significant risk factors for recurrence. Significance was defined as p < 0.05. Kaplan–Meier survival analysis was performed on patients with recurrence. Statistical analyses were performed using MedCalc for Windows, version 12.2.1 (MedCalc Software, Mariakerke, Belgium). 3. Results Our cohort of patients consisted of 64 individuals who underwent a purely EE transsphenoidal resection of pituitary adenomas by a single surgeon at our institution between April 2006 and June 2011 (Table 1). The median age of patients in this study was 46 years, and female patients made up 62.5% of the cohort. The mean
Table 1 Patient characteristics. Number of patients Age (years) Mean ± SD Median (range) Sex Male Female Follow-up time (months) Mean Median (range) Presenting symptoms Headaches Visual deficits Amenorrhea Incidental Galactorrhea Decreased libido Diplopia Acromegaly Apoplexy Seizure Prior surgery Yes No Maximum diameter (mm) Mean Median (range) Maximum diameter > 10 mm Yes No
64 46.7 ± 16.7 46 (12–81) 24 (37.5%) 40 (62.5%) 24.3 23.1 (4.0–62.5) 28 (43.8%) 25 (39.1%) 10 (15.6%) 11 (17.2%) 13 (20.3%) 5 (7.8%) 6 (9.4%) 3 (4.7%) 1 (1.6%) 1 (1.6%) 4 (6.3 %) 60 (93.8%) 18.9 19 (8–40) 50 (78.1%) 9 (14.1%)
Table 2 Surgical outcomes. Outcome
# patients (%)
Post-operative CSF leak Diabetes insipidus Panhypopituitarism Wound infection New visual field deficits Improvement in presenting visual deficits Residual Yes - Within CS - Outside CS No residual (GTR) Surgical revision Adjuvant stereotactic radiosurgery Recurrence
4 (4.1%) 2 (3.1%) 3 (4.7%) 1 (1.6%) 0 23/25 (92%) 20 (31.3%) 9 (14.1%) 11 (17.2%) 44 (68.7%) 7 (10.9%) 7 (10.9%) 6 (9.4%)
follow-up time was 24.3 months in this study (median 23.1, range 4.0–62.5). Headache and visual deficits were the most common complaints on initial patient evaluation, occurring in 43.8% and 39.1% of patients, respectively. Visual deficits included decreased visual acuity and decreased peripheral vision. The majority of lesions had a maximum diameter greater than 10 mm (78.1%). Surgical outcomes and complications are reported (Table 2). Residual disease was reported by the radiologist evaluating the post-operative and 3-month follow-up MRI. Gross total resection (GTR) was achieved in 68.7% of patients. Residual tumor, classified as intracavernous or extracavernous based on MRI findings, was intracavernous in 14.1% of cases. However, only 4 of these patients (20%) showed evidence of radiologic recurrence during the follow-up period. Two additional patients who had post-operative imaging that was inconclusive for residual disease versus normal pituitary gland had recurrence, making a total of 6 patients (9.4%) with recurrence in our series. Three out of these 6 patients subsequently required surgical revision with repeat EE surgery and three patients received stereotactic radiosurgery. The decision for stereotactic radiosurgery on these three patients was based on patient
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Table 4 Risk factors for radiographic recurrence in patients with residual tumor. Variable
Fig. 1. Kaplan–Meier survival analysis demonstrating the probability of radiographic recurrence-free survival over the follow-up period in this study.
preference and the location of the residual tumor. Kaplan–Meier analysis of recurrence free survival during the follow-up period is shown (Fig. 1). When risk factors for recurrence were analyzed in this patient cohort (Table 3), age and gender were not associated with an increased risk of recurrence. Presentation with amenorrhea and maximum tumor diameter greater than 10 mm significantly increased the risk for recurrence (p = 0.044 and 0.005, respectively). Notably, the presence of post-operative residual and residual outside the CS was nearly significantly associated with increased risk of recurrence in these patients (p = 0.071 and 0.058, respectively). Risk factors for recurrence were further analyzed in the subset of patients with residual tumor in an attempt to identify factors that place these patients at increased risk for recurrence (Table 4). When these 20 patients were analyzed, presentation with amenorrhea was found to be an independent risk factor for recurrence in these patients (p = 0.032). Age, gender, other presenting symptoms, and reported tumor characteristics were not found to be risk factors for recurrence in these patients.
Table 3 Risk factors for radiographic recurrence. Variable Gender Male Female Age 50 Presenting symptoms Headache Visual field deficits Diplopia Amenorrhea Galactorrhea Acromegaly Apoplexy Seizure Incidental Prior surgery Prior therapy Tumor characteristics Max diameter > 10 mm Prolactin staining Post-operative residual Residual within cavernous sinus Residual outside cavernous sinus *
# with recurrenceN (%)
p-Value
3 (12.5%) 3 (7.5%)
0.402
2 (20%) 1 (3.7%)
0.234 0.188
1 (3.6%) 3 (12%) 1 (16.7%) 3 (30%) 3 (23.1) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (25%) 0 (0%)
0.167 0.435 0.460 0.044* 0.092 0.741 0.906 0.908 0.306 0.332 0.668
4 (8%) 1 (8.4%) 4 (20%) 1 (11.1%) 3 (23.1%)
0.005* 0.687 0.071 0.613 0.058
Denotes the statistically significant values.
Gender Male Female 12 Age 50 Presenting symptoms Headache Visual field deficits Diplopia Amenorrhea Galactorrhea Acromegaly Incidental Prior surgery Tumor characteristics Max diameter > 10 mm Prolactin staining *
# with recurrenceN (%)
p-Value
2 (25%) 2 (16.7%)
0.618
2 (40%) 0 (0%)
0.249 0.148
1 (14.3%) 2 (22.2%) 1 (50%) 2 (100%) 2 (66.7%) 0 (0%) 0 (0%) 1 (50%)
0.561 0.625 0.368 0.032* 0.080 0.800 0.272 0.368
2 (13.3%) 1 (33.3%)
0.249 0.530
Denotes the statistically significant values.
Table 5 Location of residual tumor. Number of patients with residual tumor
Side of residual
8 (40%) 5 (25%) 5 (25%) 2 (10%)
Midline Left Right Unclear (outside imaging)
Review of post-operative MRI reports revealed that residual tumor was located on both the left and the right side (Table 5). No preferential tumor burden on the side ipsilateral to the right nares was discovered. 4. Discussion While the EE approach to pituitary pathology is becoming increasingly utilized, long-term outcomes and clinical predictors of prognosis remain largely undefined with this technique. In this study, we present a group of patients with pituitary adenoma who underwent EE surgery with a single surgeon at our institution, and we begin to define the risk factors for recurrence in this population of patients. The mean follow-up time of 2 years allows for analysis of tumor re-growth and recurrence rates in this patient population, outcomes which are important considerations in the evolving EE pituitary surgery. 4.1. Gross total resection (GTR) rates Gross total resection rates in our study are comparable to results reported by other groups using the EE approach for various subtypes of pituitary tumors [6,13,14,16,18,19]. Two studies of non-functional pituitary adenomas (NFPAs), which are defined as endocrinologically inactive tumors, reported a GTR rate of 74–76.9% using the EE approach [6,14]. In a recent study of pituitary macroadenomas, the overall GTR rate was 76.1% using the EE approach [18]. Tabaee et al. reported a GTR in 89% of patients with pituitary adenomas, and found tumor size to be the only significant predictor of the extent of tumor removal, with smaller tumors being more likely to be completely removed [16]. Hofstetter et al. expanded upon this finding and found that volumetric analysis revealing a tumor volume greater than 10 cm3 for pituitary adenomas was a powerful predictor of resectability [18]. Although we did not perform volumetric analysis, the majority (78.1%) of tumors in our study had a maximum diameter greater than 10 mm, which
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likely contributed to the slightly lower GTR percentage (68.7%) in this study. 4.2. Recurrence rates Literature for recurrence rates following purely EE pituitary surgery is lacking. In our study, imaging results were utilized to define tumor recurrence, so both functional (hormone secretion) and non-functional (no functional hormone secretion) pituitary adenomas (NFPAs) were studied. With this approach, we found that 6 out of 64 patients (9.4%) who underwent EE surgery experienced radiographic recurrence within the study’s follow-up period. Two cases recurred within the first year of follow-up, 1 case recurred in the second year, 2 cases recurred in the third year, and 1 case recurred in the fourth year of follow-up (Fig. 1). As endocrinological data were not collected in our study, these rates of recurrence can be best compared to other studies using radiographic outcomes. Most studies using radiographic outcomes of recurrence have focused on NFPAs. While recurrence of NFPAs following non-EE transsphenoidal surgery is well defined [20–25], data examining radiographic recurrence of NFPAs following EE surgery are sparse. In one recent study utilizing the EE technique, Kabil et al. reported that radiographic NFPA recurrence was 7% over a mean follow-up of 38.2 months [26]. This percentage is similar to the recurrence rate observed for all tumors in our study over a shorter follow-up period (7.1% over mean follow-up of 24 months). However, Kabil et al. did not report the incidence of recurrence per year in this study, which limits the comparison to recurrence in our study. One other recent study by Dehdashti et al. assessed long-term outcomes of NFPAs following EE surgery and reported a GTR of 88% for NFPAs and reported zero cases of recurrence at a mean follow-up of 22 months. We hypothesize that our recurrence rate is higher than Dehdashti et al.’s rate due to the lower GTR percentage in our series (68.7% versus 88%), as well as our low threshold for defining radiographic recurrence. Several cases of recurrence in our study involved only 1–2 mm increases in size of the tumor on follow-up imaging studies. The low threshold for defining radiographic recurrence and the close imaging follow-up of patients in our study are important considerations when interpreting our study’s recurrence rates. Recurrence rates for functional pituitary adenomas are often reported separately in the literature, as biochemical assays allow for improved sensitivity when monitoring these tumors. A recent report by Hofstetter et al. examined rates of recurrence in functional pituitary adenomas following endocrinological cure when using the EE approach and found that 100% of those with endocrinological cure remained disease free at a mean of 22.8 months follow-up, regardless of the tumor’s functional subtype (prolactin secreting vs. ACTH secreting vs. GH secreting) [7]. Other studies utilizing the EE approach for functional adenomas reported similar results [13,14]. As our study did not analyze the hormonal characteristics of tumors, comparison to these studies regarding endocrinological cure is limited. Additionally, longer-term followup is warranted in all of these studies, since late recurrence after presumed cure is well established for functional adenomas [27,28]. 4.3. Risk factors for recurrence In one of the most comprehensive analyses of risk factors for recurrence to date, Roelfsema et al. reported a meta-analysis of clinical predictors of recurrence in both microscopic and EE pituitary surgeries over the past 3 decades [29]. They reported that the majority of recurrences occurred between 1 and 5 years after surgery and that patients with a prolactinoma had a higher recurrence incidence than patients with acromegaly or Cushing’s disease. Recurrence rates of prolactinoma were not significantly
different than those of NFPA in this analysis. Age, gender, tumor size, and tumor invasion were generally unrelated to recurrence, but some studies included in this analysis did show an increased risk for recurrence with increased tumor size. This increased risk of recurrence with increased tumor size is consistent with our results showing a significant risk of recurrence in tumors with a maximum diameter greater than 10 mm. The Roelfsema et al. study did not examine the impact of post-operative residual as a risk factor for recurrence, however, subtotal resection has been strongly linked to increased tumor recurrence in non-EE transsphenoidal studies in the past [20–24]. Notably, 95% of the studies included in the Roelfsema et al. analysis utilized a microscopic approach to the sella, as there are few reports of recurrence using the EE approach to date. To our knowledge, the study presented here is the first to specifically address risk factors for recurrence following a purely EE approach to pituitary pathology. In our study, while there were 20 patients with post-operative residual tumor, only 4 of them showed radiographic recurrence. We feel that these findings may be an important consideration when a surgeon is faced with pursuing aggressive resection for fear of recurrence from residual tumor. Furthermore, the anatomical location of residual tumor within or outside the cavernous sinus was not associated with increased risk of recurrence. The preferential operation through the right nares did not lead to preferential residual tumor burden on the ipsilateral side. When the subset of patients with post-operative residual tumor is analyzed separately, presentation with amenorrhea was an independent risk factor for recurrence. This suggests that patients presenting with a hormonally active tumor (likely a gonadotrophic tumor or prolactinoma) who undergo a subtotal resection were at significantly increased risk for tumor re-growth/recurrence. While endocrinological data is not available to confirm this finding in our study, these results are consistent with the analysis by Roelfsema et al. which reported that prolactinomas are more likely to recur following transsphenoidal surgery [29]. Our results suggest that this association holds true for EE pituitary surgery today. 4.4. Limitations While this study outlines our results with a purely EE approach to the resection of pituitary adenomas and raises important considerations for recurrence in patients undergoing this procedure, it is not without limitations. First, the retrospective design of this study is a limiting factor: clinical presentations, surgical outcomes, and post-operative complications were all based on chart review, which restricts the analysis to the information provided in charts. Second, tumor recurrence was only established radiographically, without accompanying endocrinological data. Third, while a mean follow-up time of 24.3 months captured several recurrences, longer follow-up is necessary to fully assess the risk for recurrence in this population of patients. 4.5. Conclusions This report outlines the patient characteristics, surgical results, and complications of 64 endoscopic endonasal surgeries performed for pituitary adenomas by a single surgeon at our institution. It specifically addresses risk factors for radiographic recurrence following the EE approach. Over a mean follow-up time of 24.3 months, 6 individuals were deemed to have disease recurrence on follow-up imaging studies. Risk factor analysis revealed that maximal tumor diameter greater than 10 mm was significantly associated with recurrence. Gender, patient age and presenting symptoms (apart from amenorrhea) were not significantly associated with recurrence within this time period. While patients with residual tumor identified on post-operative MRI were at
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increased risk for developing recurrence, they represented only 20% of patients with evidence of post-operative residual tumor. The independent risk factor of amenorrhea suggest that this subset of patients may benefit from more stringent follow-up imaging or more aggressive use of adjuvant therapy or re-resection. Future studies are necessary to define long-term outcomes and prognosis for patients undergoing EE surgery. Acknowledgements We would like to acknowledge the following medical students for their assistance in data collection: Joon-Hyung Kim, Evan Bander, Ana Pacheco-Navarro, Stacy Y. Chu, Matthew W. Rosenbaum, and Nicolas A. Yannuzzi. Financial disclosures: Paul Christos, Dr. P.H., was partially supported by the following grant: Clinical Translational Science Center (CTSC) (UL1-RR024996). Conflict of interests: The authors declare that they have no conflicts of interest. References [1] Prevedello DM, Doglietto F, Jane JA, Jagannathan J, Han J, Laws ER. History of endoscopic skull base surgery: its evolution and current reality. J Neurosurg 2007;107:206–13. [2] Heilman CB, Shucart WA, Rebeiz EE. Endoscopic sphenoidotomy approach to the sella. Neurosurgery 1997;41:602–7. [3] Jho HD, Carrau RL. Endoscopic endonasal transsphenoidal surgery: experience with 50 patients. J Neurosurg 1997;87:44–51. [4] Jho HD, Carrau RL, Ko Y, Daly MA. Endoscopic pituitary surgery: an early experience. Surg Neurol 1997;47:213–22 [discussion 222-213]. [5] Rodziewicz GS, Kelley RT, Kellman RM, Smith MV. Transnasal endoscopic surgery of the pituitary gland: technical note. Neurosurgery 1996;39:189–92 [discussion 192-183]. [6] Messerer M, De Battista JC, Raverot G, Kassis S, Dubourg J, Lapras V, et al. Evidence of improved surgical outcome following endoscopy for nonfunctioning pituitary adenoma removal. Neurosurg Focus 2011;30:E11. [7] Hofstetter CP, Shin BJ, Mubita L, Huang C, Anand VK, Boockvar JA, et al. Endoscopic endonasal transsphenoidal surgery for functional pituitary adenomas. Neurosurg Focus 2011;30:E10. [8] O’Malley BW, Grady MS, Gabel BC, Cohen MA, Heuer GG, Pisapia J, et al. Comparison of endoscopic and microscopic removal of pituitary adenomas: single-surgeon experience and the learning curve. Neurosurg Focus 2008;25:E10. [9] Cho DY, Liau WR. Comparison of endonasal endoscopic surgery and sublabial microsurgery for prolactinomas. Surg Neurol 2002;58:371–5 [discussion 375376]. [10] Jain AK, Gupta AK, Pathak A, Bhansali A, Bapuraj JR. Excision of pituitary adenomas: randomized comparison of surgical modalities. Br J Neurosurg 2007;21:328–31.
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