Purely Endoscopic Transsphenoidal Surgery versus Traditional Microsurgery for Resection of Pituitary Adenomas: Systematic Review

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1 ARTICLE Purely Endoscopic Transsphenoidal Surgery versus Traditional Microsurgery for Resection of Pituitary Adenomas: Systematic Review Julie Strychowsky, BHSc, MD, Smriti Nayan, MD, Kesava Reddy, MD, FRCSC, Forough Farrokhyar, MPh, PhD, and Doron Sommer, MD, FRCSC ABSTRACT Objective: To determine, in a systematic review, whether purely endoscopic transsphenoidal resection of pituitary adenomas offers improved outcomes and decreased complications compared to the traditional microscopic approach. Design: Systematic review. Setting: The literature was searched using Medline, EMBASE, and the Cochrane Library (inception to October 2009) by two independent review authors. Methods: Studies were included if they compared the two surgical approaches for the management of pituitary adenomas and at least one main outcome measure. Main Outcome Measures: Gross tumour resection (GTR), recurrence, visual field improvement, hormone resolution, mean blood loss, mean operative time, mean hospital length of stay, cerebrospinal fluid (CSF) leak, hormone deterioration, vision deterioration, nasal complications, meningitis, and death. Results: Ten studies met the inclusion criteria (one prospective and nine retrospective) and involved 687 patients. The purely endoscopic approach was associated with less mean blood loss, shorter hospital stays and operative times, and fewer nasal complications. There was also a trend toward better GTR and decreased incidence of postoperative diabetes insipidus. However, a higher incidence of postoperative CSF leak was also noted with the endoscopic approach. Other outcomes and complication rates appeared to be similar between the two groups. Conclusions: Purely endoscopic transsphenoidal resection of pituitary adenomas seems to be safe and efficacious when compared to the traditional microscopic approach and may offer some benefit. SOMMAIRE Objectif: L étude avait pour objectif de déterminer, dans le cadre d un examen méthodique, si l exérèse d adénomes de l hypophyse par la chirurgie transsphénoïdale exclusivement endoscopique améliorait les résultats et permettait de diminuer les complications par rapport à la chirurgie microscopique classique. Type d étude: Il s agit d un examen méthodique. Lieu: La recherche documentaire a été réalisée dans les bases de données Medline et EMBASE ainsi que dans la Bibliothèque Cochrane (du début jusqu à octobre 2009) par deux auteurs-examinateurs indépendants. Méthodes: Les études étaient retenues si elles établissaient une comparaison entre les deux techniques chirurgicales pour le traitement d adénomes de l hypophyse et si elles faisaient état d au moins un des principaux critères d évaluation. Principaux critères d évaluation: Les principaux critères étaient l exérèse de tumeurs macroscopiques (ETM), les récidives, l amélioration du champ visuel, la résolution hormonale, les pertes moyennes de sang, la durée opératoire moyenne, la durée moyenne du séjour à l hôpital, les fuites de liquide céphalorachidien (LCR), le déséquilibre hormonal, l affaiblissement de la vue, les complications nasales, la méningite et la mort. Résultats: Dix études (1 prospective et 9 rétrospectives) respectaient les critères de sélection et totalisaient 687 patients. La chirurgie exclusivement endoscopique a été associée à une diminution des pertes moyennes de sang, du séjour à l hôpital, de la Julie Strychowsky, Smriti Nayan, and Doron Sommer: Division of Otolaryngology-Head and Neck Surgery; Kesava Reddy: Division of Neurosurgery; and Forough Farrokhyar: Department of Surgery, McMaster University, Hamilton, ON. Address reprint requests to: Julie Strychowsky, BHSc, MD, Otolaryngology- Head and Neck Surgery, McMaster University, 1200 Main St W, Hamilton, ON L8N 3Z5; juliestrychowsky@medportae.ca. DOI / # 2011 The Canadian Society of Otolaryngology-Head & Neck Surgery Journal of Otolaryngology-Head & Neck Surgery, Vol 40, No 2 (April), 2011: pp

2 176 Journal of Otolaryngology-Head & Neck Surgery, Volume 40, Number 2, 2011 durée opératoire et des complications nasales. Une tendance à une meilleure ETM et à une réduction de l incidence du diabète insipide postopératoire a également été relevée. Par contre, une fréquence accrue de fuites postopératoires de LCR a été observée dans le contexte de la chirurgie endoscopique. Enfin, les taux d autres résultats et d autres complications étaient du même ordre de grandeur dans les deux groupes. Conclusions: L exérèse d adénomes de l hypophyse par la chirurgie transsphénoïdale exclusivement endoscopique semble sûre et efficace comparativement à la chirurgie microscopique classique, et peut même offrir certains avantages. Key words: endoscopic surgery, microsurgery, pituitary adenoma S urgical approaches to anterior skull base tumours have evolved considerably. The first successful pituitary resection was achieved by Horsely via the transcranial approach in In 1906, Schloffer used the lateral rhinotomy transsphenoidal approach, 2 and 4 years later, Hirsch used a modified endonasal approach using the Killian submucosal resection of the septum and preserving intact intranasal mucosal flaps. 3 Halstead initiated the use of an incision in the gingivolabial sulcus in 1910, 4 and Cushing combined Hirsch s and Halstead s approaches and devised the sublabial transseptal approach, eliminating external incisions in Hardy and Wigser popularized the sublabial transsphenoidal approach with the introduction of operating microscopics and intraoperative fluoroscopy in the 1950s, 6,7 and the sublabial transseptal approach became the gold standard. The endoscopic approach to paranasal sinus surgery has a history of more than 30 years in clinical practice. 8 The collaborative efforts of otolaryngologists and neurosurgeons in the early 1990s extended this technology to pathologies of the skull base, creating the new subspecialty of endoscopic skull base surgery. 8 Jankowski was the pioneer of this approach, 9 and this technique underwent further refinement and popularization by Cappabianca and colleagues, 10 Carrau and colleagues, 11 Jho, 12 and others. Two surgical techniques in current use are the traditional microsurgical and purely endoscopic transsphenoidal approach. Microscopy offers a three-dimensional view and requires the use of a nasal speculum, which may traumatize nasal tissue. In contrast, endoscopy provides a wider panoramic view with the use of a variety of wide-angled endoscopes and allows for visualization around corners that may be out of view of a standard microscope. There is the additional benefit of flexibility of the surgical trajectory and hence greater rates of resection. Although a classic three-dimensional view is not afforded with this technique, the surgeon can appreciate some three-dimensionalism by the visualization, movement of the camera, and tactile sensation. However, the purely endoscopic approach requires the collaborative approach of otolaryngologists and neurosurgeons, additional training, and expensive equipment. Many single-arm studies have reported on outcomes following either the traditional microsurgical or purely endoscopic approach, and some studies have compared both approaches. However, we have not identified any publications that have summarized the evidence of studies that directly compare the two surgical interventions. The purpose of this systematic review is to compare purely endoscopic transsphenoidal resection to the traditional microsurgical approach to pituitary adenomas by comparing outcome measures (gross tumour resection [GTR], tumour recurrence, visual field improvement, hormone resolution of secreting adenomas, blood loss, operative time, hospital length of stay) and complication rates (cerebrospinal fluid [CSF] leak, visual field deterioration, diabetes insipidus, anterior pituitary dysfunction, nasal complications, meningitis, death). We hypothesize that endoscopic transsphenoidal resection will correlate with better outcomes and fewer complications versus the traditional approach to managing pituitary adenomas. Methods This systematic review was performed in accordance with a protocol that prescribed eligibility criteria, search strategy, outcomes, and statistical analyses. Primarily, our aim was to perform a pooled analysis of the outcomes if appropriate. Literature Search Strategy The literature was searched using OVID Medline (1966 through October 2009), EMBASE (1980 to October 2009), and the Cochrane Library (Cochrane Database of Systematic Reviews, 2009, Issue 1). We used similar strategies to search all databases. Relevant articles and abstracts were selected and reviewed, and the reference lists from these sources and recent review articles were searched for additional publications. We searched for systematic

3 Strychowsky et al, Endoscopic Transsphenoidal Surgery versus Traditional Microsurgery for Resection of Pituitary Adenomas 177 reviews or meta-analyses to review the references to ensure that we captured all relevant articles. The literature search of the electronic databases combined disease-specific terms (pituitary and macroadenoma or microadenoma or sellar or suprasellar or parasellar) with outcome-specific terms (outcome or tumour mass or endocrine or recurrence or visual improvement) or complication-specific terms (complication or mortality or morbidity or CSF leak or meningitis) for the following study designs and publication types: retrospective studies, randomized controlled trials (RCTs), systematic reviews, and meta-analyses. The literature search was not limited for study design or publication date to ensure that all relevant published articles were captured. Study Selection Criteria Articles were included in the systematic review of the evidence if they were fully published reports or abstracts of observational studies, RCTs, systematic reviews, or metaanalyses comparing outcomes and complications following endoscopic transsphenoidal resection for pituitary adenomas versus the traditional microscopic approach. Trials were to report at least one of the above outcomes or complications. Systematic reviews or meta-analyses explicitly based on retrospective data or RCTs were also eligible for inclusion in the systematic review of the evidence. Articles were excluded if they were published in a language other than English or reported on heterogeneous patient populations (e.g., included patients with craniopharyngiomas, meningiomas, or other). Data Extraction Relevant data were extracted from fully published reports by two independent review authors using prescribed tables. Any disagreement was resolved with discussion and consensus. Results Ten studies that fulfilled the inclusion criteria were identified (Figure 1) There was one RCT 15 and nine retrospective observational studies Some were comparative groups and others were case series. Thirty studies were excluded based on inclusion criteria. 12,25 53 Trial Characteristics All published studies were conducted in single centres between 1995 and 2008 and included 687 patients in total (Table 1) Study designs included one small prospective RCT with 20 patients 15 and 9 retrospective studies with a combined total of 667 patients (purely endoscopic surgery, 314 patients; traditional microsurgery, 373 patients) Traditional microsurgical approaches also varied between studies. The included studies did not show statistically significant differences in baseline characteristics of mean age and sex between groups; however, three studies did show a significantly shorter follow-up period among patients in the purely endoscopic treatment arms (p,.05), 17,19,23 and a similar trend was evident in three other studies. 16,20,21 Quality Assessment Two independent review authors performed quality assessment based on the following two scales: the Detsky quality scale for randomized studies and the Methodological Index for Non-randomized Studies (MINORS) scale for nonrandomized studies. The Detsky scale is a validated scale, and the maximum global score is 20 for positive trials and 21 for negative trials. 13 The MINORS scale is also a validated scale, and the global ideal score is 16 for noncomparative studies and 24 for comparative studies. 14 The reliability score was measured by a statistician using the intraclass correlation coefficient with a two-way mixed effects model using SPSS version 17 (SPSS Inc, Chicago, IL). Any disagreement between the reviewers was resolved with consensus. Figure 1. Identification of relevant studies. RCT 5 randomized controlled trial.

4 178 Journal of Otolaryngology-Head & Neck Surgery, Volume 40, Number 2, 2011 Table 1. Trial Characteristics Study Country Study Dates Surgical Intervention No. of Patients Mean Age 6 SD (range) (yr) Patient Characteristics (%) M Sex F Mean Followup 6 SD (range) (mo) Prior Surgery NR Endoscopic * 9 (35) { 11(55) { 6.95 NR Prospective (randomized) Jain et al, India Microscopic Retrospective D Haens et al, Belgium Endoscopic (10 70) 19 (32) 41 (68) 18 (1 76) NR Microscopic (10 68) 16 (27) 44 (73) 61 (1 144) Graham et al, USA Endoscopic 71 NR 37 (52) 34 (48) 18.8 (4 192) NR Microscopic (57) 53 (43) 49.3 (4 578) Duz et al, Turkey Endoscopic (61) { 36 (38) { { NR Microscopic 25 (19 81) { Higgins et al, USA Endoscopic (58) 8 (42) (11) Microscopic (48) 15 (52) (17) O Malley et al, (subgroup) Neal et al, USA Endoscopic (18 73) 15 (60) 10 (40) 4.9 (1 25) NR Microscopic (23 78) 16 (64) 9 (36) 8.9 (1 43) Microscopic (33) 10 (67) 50 USA Endoscopic (53) 6 (42) 7 NR Casler et al, USA Endoscopic (29 60) 6 (40) 9 (60) NR NR Microscopic (26-79) 10 (67) 5 (33) White et al, USA Endoscopic (48) 26 (52) (22) Microscopic (66) 17 (34) 58 3 (6) Cho et al, China Endoscopic (22 60) 0 22 (100) 42 (6 60) { NR Microscopic (18 56) 1 (5) 21 (95) NR 5 not reported. *Mean for both groups (range 18 58). { Not stratified by surgical intervention. Bold face indicates statistical significance (p,.05) Quality Analysis Quality analysis performed by two independent review authors according to the Detsky 13 and MINORS 14 criteria revealed a good level of agreement as illustrated by the interclass correlation coefficient of 93% (95% CI 71 98). The Detsky score was 12 by both reviewers for the randomized study included in this review. 15 The mean and standard deviation of MINORS scale for each of the reviewers were as follows: J.S., (minimum 5 14, maximum 5 19), and S.N., (minimum 5 13, maximum 5 21). Tumour Characteristics Reporting of tumour characteristics was nonuniform across studies and varied considerably where reported (Table 2). When stratified by surgical intervention, the percentage of patients with macroadenomas varied from 50 to 90% in the purely endoscopic study arms and from 45 to 93% in the microscopic arms ,20,21,24 Functional adenomas comprised 10 to 100% of patients treated with the purely endoscopic approach 15 21,24 and 17 to 100% of those treated with the traditional microscopic approach ,24 Three studies included patients with functional adenomas only, 16,19,24 and Higgins and colleagues only included patients with prolactinomas. 19 Postoperative Outcomes Reporting of postoperative outcomes varied between studies (Table 3). Studies demonstrating the outcome of interest are summarized below. Six publications reported GTR 15,18 22 ; however, no statistically significant difference was reported between groups among the included studies. However, three studies

5 Strychowsky et al, Endoscopic Transsphenoidal Surgery versus Traditional Microsurgery for Resection of Pituitary Adenomas 179 Table 2. Tumour Characteristics Study Surgical Intervention No. of Patients Volume (cm 3 ) Macroadenoma (%) Microadenoma (%) Nonfunctional Adenoma (%) Functional Adenoma ACTH (%) GH (%) PRL (%) TSH (%) All (%) Prospective (randomized) (90) 1 (10) 9 (45)* 3* (15) 5* (25) 3* (15) 0* 11 (55)* Jain et al, Endoscopic Microscopic (80) 2 (20) Retrospective D Haens et al, Microscopic (45) 33 (55) 0 13 (22) 11 (18) 36 (60) 0 60 (100) Endoscopic 60 NR 31 (52) 29 (48) 0 16 (21) 13 (22) 29 (48) 2 (3) 60 (100) Graham et al, Microscopic (93) 4 (3) 101 (83) 21 (17) Endoscopic 71 NR 54 (77) 3 (4) 60 (89) NR NR NR NR 7 (10) Duz et al, Endoscopic 28 NR 58 (62)* 18 (19)* 12 (43) (11) (29) 2 (7) 0 13 (46) Microscopic 25 9 (36) 3 (12) 6 (24) 3 (12) 2 (8) 16 (64) Higgins et al, Endoscopic 19 NR NR NR 12 (63) NR NR NR NR 3 (16) Microscopic (55) 11 (40) O Malley et al, (subgroup) Endoscopic 25 NR 22 (88) 3 (12) 1 (4) 2 (8) 1 (4) 3 (12) 1 (4) 10 (40) Microscopic (92) 2 (8) 1 (4) 1 (4) 1 (4) (48) Neal et al, Endoscopic 14 NR 9 (64) 4 (19) 6 (43) NR NR NR NR 8 (57) Microscopic 15 7 (46) 7 (46) 5 (33) 10 (66) Casler et al, Microscopic 15 Endoscopic 15 NR NR NR NR NR NR NR NR NR White et al, Microscopic 50 Endoscopic 50 NR NR NR NR NR NR NR NR NR Cho and Liau, Microscopic (45) 12 (55) (100) 0 22 (100) Endoscopic 22 NR 11 (50) 11 (50) (100) 0 22 (100) ACTH 5 adenocorticotropic hormone; GH 5 growth hormone; NR 5 not reported; PRL 5 prolactin; TSH 5 thyroid-stimulating hormone. *Not stratified by surgical intervention.

6 180 Journal of Otolaryngology-Head & Neck Surgery, Volume 40, Number 2, 2011 Table 3. Postoperative Outcomes No. of Cases (%) Mean 6 SD (range) Study Surgical Intervention No. of Patients GTR Recurrence Visual Field Improvement Hormone Resolution of Secreting Adenomas ACTH GH PRL TSH All Blood Loss (ml) Operative Time (min) Hospital LOS (d) Prospective (randomized) Jain et al, Endoscopic 10 5 (50) NR 5/5 (100) NR NR NR NR 4/6 (67) ( ) Retrospective D Haens, Microscopic 10 5 (50) 5/5 (100) 4/7 (57) (50 250) (50 100) (55 120) et al Microscopic 60 0/1 (0) 6/13 (46) 3/11 (27) 21/36 (58) NA 30 (50) Endoscopic 60 NR NR 4/4 (100) 9/16 (56) 8/13 (62) 20/29 (69) 1/2 (50) 38 (63) NR NR NR Graham Endoscopic 71 NR 8 (18) 30/65 (46) NR NR NR NR NR NR 266 ( ) 4.1 (1 22) et al, Microscopic (28) 64/122 (52) 208 (13 553) 6.0 (2 55) Duz et al, Endoscopic (54) NR NR NR NR NR NR NR NR NR NR Microscopic 25 8 (32) Higgins et al, Microscopic (83) Endoscopic (89) NR NR NR NR NR NR NR O Malley Endoscopic 25 14/21 (66) NR NR NR NR NR NR NR NR 176 (91 247) 3.9 (3 9) et al, Microscopic 25 17/22 (77) 265 ( ) 4.8 (3 9) Neal et al, Endoscopic (79) 0 NR NR NR NR NR NR NR NR Microscopic (67) 1 (7) 8.3 Casler et al, Endoscopic (67) NR NR NR NR NR NR NR 125 (25 280) 255 ( ) 4.4 (2 7) Microscopic (80) 243 ( ) 246 ( ) 5.7 (3 8) (subgroup) White et al, Microscopic Endoscopic 50 NR NR NR NR NR NR NR NR NS NR 3.7 Cho and Liau, Endoscopic 22 NR NR 5/8* (63) NA NA 15 (68) NA 15 (68) NR 102 (60 180) 3.2 (2 5) Microscopic 22 6/10 (60) 17 (77) 17 (77) 162 (90 240) 5.3 (4 8) NR ACTH 5 adrenocorticotropic hormone; GH 5 growth hormone; GTR 5 gross total resection; LOS 5 length of stay; NA 5 not applicable; NR 5 not reported; NS 5 not significant; PRL 5 prolactin; TSH 5 thyroid-stimulating hormone. *Patients with macroadenoma. Boldface indicates statistical significance (p,.05).

7 Strychowsky et al, Endoscopic Transsphenoidal Surgery versus Traditional Microsurgery for Resection of Pituitary Adenomas 181 demonstrated a trend for higher GTR in the purely endoscopic group (54% vs 32%, 18 89% vs 83%, 19 and 79% vs 67% 21 ). Two small studies in fact showed a trend for better resection in the microsurgical group (66% vs 77% 20 and 67% vs 80% 22 ). GTR measurement was based on postoperative imaging, either computed tomography or magnetic resonance imaging, in the three studies that reported this methodology. 15,19,20 Two studies reported tumour recurrence and showed a trend for lower recurrence in the purely endoscopic group (18% vs 28% 17 and 0% vs 7% 21 ); however, this was not statistically significant. There was no statistically significant difference in visual field improvement between surgical interventions in the four studies reporting this outcome ,24 Three publications reported the incidence of hormone resolution for secreting adenomas. 15,16,24 There was no statistically significant difference illustrated in two studies, 15,24 and the remaining study by D Haens and colleagues only showed a trend favouring the purely endoscopic approach 63% versus 50%; however, a statistically significant difference was detected for grade II tumours (noninvasive macroadenomas) only (78% vs 43%, p 5.043). 16 Significantly less mean blood loss was reported in the purely endoscopic group in comparison with the traditional microscopic approach in two studies ( vs ml, p, ; 101 vs 182 ml, p, ), and a third study by Casler and colleagues was not sufficiently powered to detect a statistical difference between groups. 22 The mean operative time was reported in seven studies and shown to be significantly shorter in the purely endoscopic group in three studies (117 vs 152 minutes 17 ; 176 vs 265 minutes 20 ; 102 vs 162 minutes 24 ; p,.05). Similar trends were shown in two additional studies. 15,22 In contrast, Graham and colleagues found significantly longer operative times in the purely endoscopic group (266 vs 208 minutes, p,.05). 17 All seven publications that reported the mean hospital length of stay showed statistically significant shorter stays among patients treated with the purely endoscopic approach (purely endoscopic [range days] versus microscopic [range days] groups, p,.05 for all individual studies). 17,19 24 Postoperative Complications The reporting of postoperative complications varied between studies (Table 4). The incidence of postoperative CSF leak was reported in nine studies. Minor intraoperative leaks that were successfully repaired during the initial surgery were not considered a complication. Graham and colleagues showed significantly more cases in the purely endoscopic group (11% vs 3%, p 5.035). 17 Of the patients treated with purely endoscopic surgery, three patients underwent early and successful repairs, three stopped spontaneously within 48 hours with bed rest and laxatives, and one required a lumbar drain for 5 days. The three patients in the microsurgical group were treated successfully with surgery. There was a trend for a higher incidence of postoperative CSF leak in three studies 16,18,20 and no difference between surgical interventions in the remaining four studies reporting the outcome. 15,19,21,23 There was no statistically significant difference for postoperative surgical repair ,20,22,23 Reporting of the timing of lumbar drain use was nonuniform. Higgins and colleagues reported a significantly lower use of lumbar drains in patients undergoing purely endoscopic surgery (0 vs 21%, p,.001); however, only one patient in each arm had a postoperative CSF leak. 19 The remaining studies did not illustrate a statistically significant difference between surgical techniques in lumbar drain use ,20,21,23 Cases of transient and permanent diabetes insipidus were reported in nine studies, 15 17,19 24 and only one study found significantly fewer cases of both transient (15% vs 23%) and permanent (0% vs 8%) for patients undergoing the purely endoscopic approach (p 5.017). 17 No statistically significant difference was noted in the remaining studies. 15,16,19 24 Nasal complications were reported in eight studies. Significantly fewer events of nasal septal perforation, epistaxis, and other (anosmia, nasal anesthesia, deviated septum, synechiae) were reported among patients in the purely endoscopic group in the study by White and colleagues (4 vs 38%). 23 There was a trend for a similar relationship in five studies, 15,16,19,22,24 and no reported events in one study. 18 Of note, Graham and colleagues used the mean Sino-Nasal Outcome Test-22 (SNOT-22) and showed a lower score for patients in the endoscopy group (20.4) versus the microscopic group (23.2) (p 5.41); however, patients in the endoscopy group had significantly lower rhinology-specific mean scores (6.5 vs 9.2, p 5.03). 17 No statistically significant difference was detected between surgical interventions for incidence of postoperative anterior pituitary dysfunction in eight studies, 15 17,19,20 22,24 meningitis in five studies, 17,20 23 or death in six studies. 16,17,20 23

8 182 Journal of Otolaryngology-Head & Neck Surgery, Volume 40, Number 2, 2011 Table 4. Postoperative Complications No. of Cases (%) Study Surgical Intervention No. of Patients Incidence CSF Leak Surgical Repair DI Visual Lumbar Field Drain Deterioration Transient Permanent Anterior Pituitary Dysfunction Sinus Infections Nasal Septum Perforation Epistaxis Other Nasal Complications Meningitis Death Prospective (randomized) Jain et al, Endoscopic 10 1 (10) 0 NR 0 1 (10) 0 4 (40) NR NR Microscopic 10 1 (10) (20) 0 4 (40) 2 (20) 0 0 2* (20) Retrospective D Haenset al, Microscopic 60 1 (2) (2) 0 0 Endoscopic 60 6 (10) 3 (5) 3 (5) NR NR 0 1 (2) NR NR 0 NR 1 (2) 0 Graham et al, Microscopic (3) 3 (3) 0 1 (1) 28 (23) 10 (8) 25/85 (29) 4 (3) 1 { (1) Endoscopic 71 7 (11) 3 (4) 1 (1) 0 10 (15) 0 14/51 (27) NR NR 1 (1) NR { NR 0 Duz et al, Microscopic 25 5 (20) 2 (8) 5 (20) 0 Endoscopic 28 8 (29) 8 (29) 0 NR NR NR NR NR 0 NR NR NR NR Higgins et al, Microscopic 29 1 (3) 6 (21) 7 (24) 17 (59) 4 (14) Endoscopic 19 1 (5) N 0 NR 5 (26) 8 (42) NR 1 (5) NR NR NR NR O Malley et al, Microscopic 25 1 (4) 1 (4) 1 (4) 1 (4) 2 (8) 2 (8) 1 (4) Endoscopic 25 3 (12) 1 (4) 0 1 (4) 1 (4) 0 0 NR NR NR NR Neal et al, Microscopic (40) 5 (33) 1 (7) Endoscopic 14 1 (7) NR 1 (7) NR 1 (7) 1 (7) NR NR NR NR Casler et al, (subgroup) Endoscopic NR NR 3 (20) 0 0 NR 0 0 NR 0 Microscopic (13) (20) 1 (7) 1 1 (7) White et al, Endoscopic 50 6 (12) 0 6 (12) 0 9 (18) 2 (4) NR NR 0 1 (2) 1 (2) Microscopic 50 7 (14) 2 (4) 7 (14) 2 (4) 9 (18) 2 (4) 1 (2) 8 (16) 11 " (22) 0 0 Cho and Liau, Microscopic 22 1 (5) 1 (5) 2 (9) 1 (5) 1 (5) 0 0 Endoscopic 22 NR NR NR NR NR (5) 0 0 NR 1 (5) 0 CSF 5 cerebrospinal fluid; DI 5 diabetes insipidus; NR 5 not reported. *Synechiae (one patient), saddle nose (one patient). { Sinonasal symptoms evaluated with the SNOT-22 questionnaire. { Hypothalamic infarction. 1 Myocardial infarction. Anosmia (one patient). " Nasal anesthesia (two patients), deviated septum (five patients), synechiae (three patients), anosmia (one patient). Boldface indicates statistical significance (p,.05).

9 Strychowsky et al, Endoscopic Transsphenoidal Surgery versus Traditional Microsurgery for Resection of Pituitary Adenomas 183 Discussion To our knowledge, this is the first systematic review comparing the purely endoscopic approach to microscopic resection of pituitary adenomas. The methodologic quality of the studies was independently evaluated by two of the authors. Most studies were of low or medium quality and of retrospective design. This literature is limited by small sample sizes, short follow-up periods (purely endoscopic approach), and primarily nonrandomized studies. Metaor pooled analysis of the data was not possible owing to the heterogeneous nature of surgical interventions, patient population, variability of outcome definitions, different follow-up times, and nonuniform reporting of data, thereby affecting the potentially robust conclusions. Many single-arm studies have reported on outcomes and complication rates following the purely endoscopic approach, 12,34 43 and surgical practice in recent years has favoured the purely endoscopic surgical intervention. Tabaee and colleagues published a systematic review and metaanalysis of the impact of purely endoscopic surgery on shortterm outcomes; however, they did not compare outcomes to those of the traditional microscopic approach. 54 Their pooled analysis included nine studies involving 821 patients and reported GTR of 78% (95% CI 67 89, p,.0001), hormone resolution of 81% (95% CI 71 91, p 5.01), CSF leak of 2% (95% CI 0 4, p ), and incidence of permanent diabetes insipidus of 1% (95% CI 0 2, p 5.026). Our institution s experience with the purely endoscopic versus the traditional microsurgical approach was published as a retrospective review in However, this review included a heterogeneous patient population; only 70% of patients had a diagnosis of pituitary adenoma. Therefore, it was excluded from this present review of the literature. GTR was found to be statistically significantly better in the purely endoscopic approach (50 vs 15%, p,.05). To date, this is the only study to illustrate this difference. The implication of this finding is difficult to interpret in the absence of long-term follow-up data to elucidate recurrence rates. The authors also reported significant improvement in pituitary function (p,.05) and a lower incidence of epistaxis (3 vs 60%, p,.05) among patients treated with purely endoscopic surgery. Although this study does include a heterogeneous population, the significant findings are noted in the context of this review. In examining the evidence of the 10 included studies, the purely endoscopic approach appears to be both safe and efficacious when compared to the microscopic approach. The endoscopic approach yields significantly fewer nasal complications, less mean blood loss, less mean operative time, and less mean hospital length of stay, as well as a trend toward a benefit in greater GTR, higher incidence of hormone resolution of secreting adenomas, and lower incidence of diabetes insipidus. However, there appears to be a higher incidence of postoperative CSF leak among patients treated with the purely endoscopic approach. This may be a result of the wider surgical field afforded with the endoscope, which allows for greater GTR at the expense of a CSF leak. The utility of GTR can be questioned given that pituitary adenomas are benign and generally slow growing. The mean age of patients in the included studies ranged from 31 to 54. The average life expectancy in North American is approximately 80 years; therefore, it remains possible that even a slow-growing lesion may become sufficiently large and symptomatic given this potential growth period. An important outcome is tumour recurrence; given the significantly shorter follow-up periods for patients treated with the purely endoscopic approach, it is difficult to elucidate any statistically significant conclusion. There may be a higher rate of intraoperative identification of small leaks owing to improved visualization with the purely endoscopic approach; however, there was no significant difference in the need for delayed surgical repair of the leak. The incidence of intraoperative CSF leak was not reported in this review as it was not deemed to be a complication if repaired successfully intraoperatively. However, the issue of postoperative CSF leak is important to consider, including the necessity for further surgery or lumbar drain. One study reported significantly more cases of postoperative CSF leak among patients undergoing purely endoscopic surgery, 17 and four studies showed a similar trend. 16,18 20 There was no significant difference between groups for surgical repair. The timing of lumbar drain use (during the primary surgery versus postoperative period) was nonuniformly or simply not reported in the studies. Thus, it is difficult to interpret its use in the context of postoperative complication management. The study that reported a statistically significant lower use of lumbar drains in patients treated with the purely endoscopic approach only reported one case of postoperative CSF leak in each surgical treatment arm. 19 This result may reflect a changing trend in clinical practice that favours surgical repair to the use of a lumbar drain in the postoperative period or less frequent use during the primary surgery owing to improved surgical techniques of intraoperative leak repair. It can be postulated that as surgeons become more experienced and revise surgical techniques that the incidence of postoperative CSF leak

10 184 Journal of Otolaryngology-Head & Neck Surgery, Volume 40, Number 2, 2011 may decrease. Duz and colleagues examined the incidence of postoperative CSF leak between early and late time periods among patients undergoing the purely endoscopic approach, 60 versus 6%, respectively. 18 The investigators attributed this decrease in incidence to their revised technique in the later time period of repositioning of the middle turbinate as a pedicled flap to intensify the reconstruction, along with the use of fat tissue underneath and fibrin glue (Tisseel) overlay. To date, there is no systematic review of the evidence that compares the efficacy of intraoperative CSF leak repair techniques. It appears that such a summary of the literature is warranted. Conclusions The purely endoscopic transsphenoidal resection of pituitary adenomas seems to be safe and efficacious when compared to the traditional microscopic approach and may offer some benefit. Standardized procedures with better defined outcomes and larger sample sizes are needed to perform a pooled analysis to investigate these and other outcomes. Ideally, a large, prospective, randomized study may be considered; however, one must also consider disease heterogeneity and the ethical issues associated with randomization given the evidence that supports improved outcomes with the purely endoscopic approach in the literature. Collaboration between otolaryngologists, neurosurgeons, and other health care professionals is paramount, as is the use of adequate instrumentation and training. Future directions may focus on the refinement of the purely endoscopic approach to further minimize complication rates, evaluation of long-term outcomes, and development of training, instrumentation, and resources to strive for optimal patient care. Acknowledgement Financial disclosure of authors and reviewers: None reported. References 1. Horsley V. Disease of the pituitary gland. Br Med J 1906;1:323, doi: /bmj Schloffer H. Zur Frage der Operationen an der Hypophyse. Beitr Klin Chir 1906;50: Hirsch O. Endonasal method of removal of hypophyseal tumors with a report of two successful cases. JAMA 1910;55: Halstead A. Remarks on the operative treatment of tumors of the hypophysis. With the report of two cases operated on by an oronasal method. Trans Am Surg Assoc 1910;28: Cushing H. The pituitary body and its disorders. Philadelphia: JB Lippincott; Hardy J. Transsphenoidal removal of pituitary adenomas. Union Med Can 1962;91: Hardy J, Wigser SM. Transsphenoidal surgery of pituitary fossa tumors with televised radiofluoroscopic control. J Neurosurg 1965; 23:612 9, doi: /jns Prevedello DM, Doglietto F, Jane JA, et al. History of endoscopic skull base surgery: its evolution and current reality. J Neurosurg 2007;107:206 13, doi: /jns-07/07/ Jankowski R, Auque J, Simon C, et al. Endoscopic pituitary tumour surgery. Laryngoscope 1992;102: , doi: / Cappabianca P, Cavallo LM, de Devitiis E. Endoscopic endonasal transsphenoidal surgery. Neurosurgery 2004;55:933 40, doi: /01.NEU D. 11. Carrau RL, Kassam AB, Snyderman CH. Pituitary surgery. Otolaryngol Clin North Am 2001;34: , doi: /s (05) Jho HD. Endosocpic transsphenoidal surgery. J Neurooncol 2001; 54:187 95, doi: /a: Detsky AS, Naylor CD, O Rourke K, et al. Incorporating variations in the quality of individual randomized trials into meta-analysis. J Clin Epidemiol 1992;45:225 65, doi: / (92) Slim K, Nini E, Forestier D, et al. Methodological index for nonrandomized studies (MINORS): development and validation of a new instrument. Aust N Z J Surg 2003;73:712 6, doi: / j x. 15. Jain AK, Gupta AK, Pathak A, et al. Excision of pituitary adenomas: randomized comparison of surgical modalities. Br J Neurosurg 2007;21:328 31, doi: / D Haens J, Van Rompaey K, Stadnik T, et al. Fully endoscopic transsphenoidal surgery for functioning pituitary adenomas: a retrospective comparison with traditional transsphoidal microsurgery in the same institution. Surg Neurol 2009;72:336 40, doi: /j.surneu Graham SM, Iseli TA, Karnell LH, et al. Endoscopic approach for pituitary surgery improves rhinological outcomes. Ann Otol Rhinol Laryngol 2009;118: Duz B, Harman F, Secer HI, et al. Transsphenoidal approaches to the pituitary: a progression in experience in a single centre. Acta Neurochir (Wien) 2008;150:1133 9, doi: /s y. 19. Higgins TS, Courtemanche C, Karakla D, et al. Analysis of transnasal endoscopic versus transseptal microscopic approach for excision of pituitary tumors. Am J Rhinol 2008;22:649 52, doi: /ajr O Malley BW, Grady MS, Gabel BC, et al. Comparison of endoscopic and microscopic removal of pituitary adenomas: single-surgeon experience and the learning curve. Neurosurg Focus 2008;25(6): Neal JG, Patel SJ, Kulbersh JS, et al. Comparison of techniques for transsphenoidal pituitary surgery. Am J Rhinol 2007;21:203 6, doi: /ajr Casler JD, Doolittle AM, Mair EA. Endoscopic surgery of the anterior skull base. Laryngoscope 2005;115:16 24, doi: / 01.mlg

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